35 U.S.C. § 156 For: Inhibitors of Bruton's Tyrosine Kinase

Home , Epothilone, Osaterone, Rogletimide, Sparsomycin

UNITED STATES PATENT AND TRADEMARK OFFICE Commissioner for Patents United States Patent and Trademark Office P.O. Box 1450 Alexandria, VA 22313-1450 www uspto goy

Michael Hostetler Wilson Sonsini Goodrich & Rosati '!JEC T2 '2bW 12235 El Camino Real, Suite 200 San Diego, CA 92130

In re Patent Term Extension Application of U.S. Patent No. 8,008,309 Decision on Petition to Waive the Issue Date: August 30, 2011 EFS Legal Framework Prohibition Application No. : .12/499,005 on Filing Initial Application under PTE Filing Date: December 23, 2013 35 u.s.c. § 156 For: Inhibitors of Bruton's Tyrosine Kinase:

The above-identified application has been forwarded to the Office of Patent Legal Administration in the United States Patent and Trademark Office (the "Office") for consideration of a petition under 3 7 C.F .R. § 1.182 to waive the prohibition in the legal framework of the Office's Electronic Filing System (EFS), which prohibits filing of an initial application for patent term extension under 35 U.S.C. § 156 via EFS.

The petition is granted because the requirements of37 C.F.R. § 1.740 have now been met and the statutory requirements of35 U.S.C. § 156(d)(1)(A)-(E) were met upon filing.

Background and Analysis

On December 23, 2013, Petitioner filed an initial application for patent term extension ("PTE application") pursuant to the provisions of35 U.S.C. § 156(d)(1) via the Office EFS. Petitioner's EFS acknowledgement receipt indicates that a "PTE Interim Patent Extension Filed."

On January 20, 2014, Petitioner contacted USPTO seeking a status update on their application for patent term extension filed by the EFS. USPTO then informed Petitioner that the PTE application had been improperly filed usi.J::!g the EFS. The USPTO directed Petitioner to the Federal Register notice, 74 Fed. Reg. 55202, October 27, 2009, which provides information on the prohibition against filing initial applications for patent term extension via EFS. The Office directed Petitioner to file a petition to seek waiver of the prohibition and to comply with the additional filings requirements in 37 C.F.R. § 1.740(b).

On February 21, 2014, Petitioner filed the present petition seeking waiver of the EFS legal framework prohibition and an opportunity to comply with the filing requirements of 37 C.F.R. § 1.740(b).

The Office is treating the present petition under 3 7 C.F .R. § 1.182, which addresses all situations not specifically provided for in other regulations. Because Petitioner has now complied with 37 Page2 U.S. Patent No. 8,008,309

which complies C.P.R. 1.740(b) and had timely filed an application for patent term extension with the requirements in 35 U.S.C. § 156(d)(l)(A)-(E), the petition is granted.

Conclusion

The petition under 3 7 C.F .R. § 1.182 is granted. and Trademark The rules and statutory provisions governing the operations of the U.S. Patent The required Office require payment of a fee on filing each petition. See 37 C.P.R. § 1.17(f). petition fee was correctly set forth in the petition. Mary C. Till at Telephone inquiries with regard to this communication should be directed to (571) 272-7755. ~lftrldt)j Senior Legal Advisor Office of Patent Legal Administration Office of the Deputy Commissioner for Patent Examination Policy

(ibrutinib) cc: Office of Regulatory Policy RE: IMBRUVICA® Food and Drug Administration Docket No.: FDA-2014-E- 10903 New Hampshire Ave., Bldg. 51, Rm. 6222 Silver Spring, MD 20993-0002

Attention: Beverly Friedman

DEC 1 6 2014 Center for Drug Evaluation and Research PATENT

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

Patent No.: 8,008,309 Issued: August 30, 2011 Expiration Date: December 28, 2026

Inventors: Lee Honigberg, Erik Verner, and Zhengying Pan.

Title: INHIBITORS OF BRUTON'S TYROSINE KINASE RECEIVED DEC 2 3 2013 Mail Stop Patent Extension Commissioner for Patents PATENT EXTENSION P.O. Box 1450 OPLA Alexandria, VA 22303-1450

APPLICATION FOR EXTENSION OF PATENT TERM (37 C.F.R. §1.740)

Pursuant to 35 U.S.C. §156(d) and 37 C.P.R. §1.740, Pharrnacyclics, Inc., ("Applicant") as Assiguee and patent owner of the above-captioned patent, hereby petitions for extension of U.S. Patent No. 8,008,309 (the '309 Patent). In support of such Petition, Applicant provides the following information:

I. SIGNATURE REQUIREMENTS (37 C.F.R. §1.730)

A. IDENTIFICATION OF PERSON(S) SUBMITTING THE APPLICATION

I, Michael J. Hostetler, represent that I am a registered practitioner appointed by the patent owner of record.

B. RECORDAL OF ASSIGNMENT IN PTO

This application issued from U.S.S.N. 12/499,005, which is a divisional application of U.S.S.N. 12/356,498, now U.S. Patent No. 8,088,781; which is a divisional application of U.S.S.N. 11/617,645, now U.S. Patent No. 7,514,444; which claims priority to U.S. Provisional Application No. 60/828,590 filed October 06, 2006; and U.S. Provisional Application No. 60/826,720, filed September 22, 2006. An assigument of U.S.S.N. 12/356,498 was recorded as follows: Reel/Frame: 023408/0028 Recorded: Assignors: Lee Honigberg Execution: 10/21/2009 Erik Verner Execution: 10/2112009 Zhengying Pan Execution: 10/21/2009

C. PROOF OF AUTHORIZATION OF SIGNATORY TO ACT ON BEHALF OF THE PATENT OWNER

Attached as Exhibit 1 is a Power of Attorney establishing authorization of Michael J. Hostetler to act on behalf of the patent owner.

II. APPLICATION REQIDREMENTS (37 C.F.R. §1.740)

A. IDENTIFICATION OF APPROVED PRODUCT (§1.740{a)(1))

The United States Food and Drug Administration ("FDA") has approved New Drug Application ("NDA'') No. 205552 for IMBRUVICA'"' (ibrutinib). The active ingredient of IMBRUVICATM is ibrutinib. A copy of the approved labeling is attached hereto as Exhibit 2.

The chemical name for ibrutinib is 1-((R)-3-(4-amino-3-( 4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and the molecular formula is C 25H24N60 2•

Ibrutinib has the following structural formula:

Each capsule of IMBRUVICATM contains 140 mg of ibrutinib.

B. IDENTIFICATION OF THE FEDERAL STATUTE UNDER WHICH REGULATORY REVIEW OCCURRED (§1.740{a)(2))

2 Regulatory review for this product occurred under the Federal Food Drug & Cosmetic Act ("FDC Act") §505(b), 21 U.S.C. §355 (new drugs).

C. DATE OF APPROVAL (§1.740(a)(3))

The FDA approved No. 205552 for IMBRUVICA 1M for commercial marketing or use under §505 of the FDC Act on November 13, 2013.

D. IDENTIFICATION OF ACTIVE INGREDIENTS AND PREVIOUS APPROVAL INFORMATION (§1.740(a)(4))

IMBRUVICA1M (ibrutinib) is a human drug product, the sole active ingredient of which is ibrutinib. Ibrutinib has not been previously approved, alone or in combination, for commercial marketing or use under the Food, Drug & Cosmetic Act, the Public Health Service Act, or the Virus-Serum-Toxin Act.

E. TIMELY SUBMlSSION OF APPLICATION (60 DAYS) (§1.740(a)(5))

This application is being submitted within the sixty-day time period permitted for submission pursuant to 37 C.F.R. §1.720(f). The last date this application may be submitted is January 12,2014.

F. IDENTIFICATION OF PATENT (§1.740(a)(6), (7), (8)) Name of the Inventors: Lee Honigberg Erik Verner Zhengying Pan

Patent No. 8,008,309

Date of Issue: August 30, 2011

Date of Original Expiration: December 28, 2026

A copy of the patent, including the entire specification (with claims), and drawings, is attached as Exhibit 3.

A copy of the Terminal Disclaimer filed February 28, 2011, is attached hereto as Exhibit 4.

No Maintenance Fee Statement has issued in the '309 patent.

3 No reexamination certificate has issued in the '309 patent.

G. IDENTIFICATION OF CLAIMS READING ON THE APPROVED PRODUCT (§1.740(a)(9))

The '309 patent claims the active ingredient of the approved Product which is ibrutinib. The '309 patent includes 15 claims, of which claims 1-7, 10, and 14 claim the active ingredient ibrutinib. A claim chart that lists each applicable claim of the '309 Patent and demonstrates the manner in which each claim reads on the approved Product is attached as Exhibit 5.

4 H. RELEVANT DATES AND INFORMATION (§1.740(a)(10))

The patent claims a human drug product.

Effective date of the investigational new drug (IND) application was September 8, 2008 and the IND No. is 102,688.

The new drug application (NDA) was initially submitted on June 28, 2013.

The NDA No. is 205552.

The new drug application (NDA) was approved on November 13, 2013.

5 I. DESCRIPTION OF SIGNIFICANT ACTIVITIES OF APPLICANT DURING REGULATORY REVIEW (§1.740(a)(ll))

Attached as Exhibit 6 is a "Description of Significant Activities Of Applicant During Regulatory Review" that provides a description of the significant activities undertaken by the marketing applicant during the applicable regulatory review period with respect to the approved Product and the significant dates applicable to such activities.

6 J. STATEMENT THAT APPLICANT IS ELIGIBLE FOR EXTENSION (§1.740(a)(12))

Attached as Exhibit 7 is a "Statement That Applicant is Eligible For Extension And Length of Extension Claimed(§ 1.740(a)(12))"

K. ACKNOWLEDGEMENT OF DUTY OF DISCLOSURE (§1.740(a)(13))

I, Michael J. Hostetler, the person signing below, acknowledge the duty to disclose to the Director of the U.S. Patent and Trademark Office and to the Secretary of Health and Human Services any information which is material to the determination of entitlement to the extension which is being sought herein.

L. FEE (§1.740(a)(14))

The Application fee due is $1,120.00 (37 C.F.R. §1.740(a)(15) and §1.20G)).

Authorization is hereby made to charge the amount of $1,120.00 to Deposit Account No. 23- 2415.

Please also charge any additional fees required by this paper or credit any overpayment to Deposit Account No. 23-2415.

M. CORRESPONDENCE

Please direct all inquiries and correspondence relating to this application to:

Michael J. Hostetler Wilson Sonsini Goodrich & Rosati 12235 El Camino Real, Suite 200 San Diego CA, 92130 (858) 350-2306 (direct) (858) 350-2399 (facsimile) [email protected]

N. COPIES

Four additional copies of this application are attached, making a total of five copies being submitted.

7 Conclusion

In conclusion, on the basis of the information provided herein, Applicant respectfully asserts that U.S. Patent No. 8,008,309 is entitled to the requested 320 day extension of its term to November 13,2027.

Prompt action on this application is respectfully requested.

Date: December 23, 2013 /Michael Hostetler/

Signature of Practitioner Reg. No.: 47,664 Michael J. Hostetler, Esq. Tel. No.: 858-350-2306 Wilson Sonsini Goodrich & Rosati Customer No.: 116469 12235 El Camino Real, Suite 200 San Diego, CA 92130

8 Exhibit 1 Power of Attorney for 8.008.309

9 IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

In re Application: Inventor: Leo HONIG BERG Confirmation N'o.: 9452 Application No.; I 21499,005 Examiner: Not yet assigned Filed: J~ly 7, 2009 Group Art Unit: No! yet assigned Title: INHIBITORS OF BRlJT0~ 1 S TYROSINE KINAS~ Customor No. 0~1971

Flle No. 25922-750.403

POWER OF ATTORNEY TO PROSECUTE APPLICATIONS BEFORE THE USPTO and 3.73 STATEMENfT------, 181 I hereby appoint the practitionerS associa!ed with Customer Number:. I 021971

As attomey(s) "' agent(s) to ropresenttheundersigned before: the United States Patentand Trademark Office (USPTO).

(8J Please address all correspondence for the above-identified application 021971 to: STATEMENT UNDER37 CFR 3.73(b) Pharmacvr.lics Inc. a Deiaw:erc Comomtigr.. __-:-:-:--:-:--,--:------partnecship. university, govt:~rtm\cn! llgCil:cy, elc-.) (N3rnt 0~ A.l:$1gnee) ('Typ¢ ofA:s.!ligncc-, e.g., COIJ)Qrllflcnt, statt:li that His: the assignee of the eotire righl, Iitle and mte~est; in the pBicnl&pplictttiotl/palenl id~ntified above by virtue- of eith~r: in th~ United States A. t8l An a~ignmcnt from !he invcntor(s:) or the patent application/palant identified above. The assignment was recorded PAlcru and Trademark Otlice at Reel C ~ J .;c~l , Frarne t::C2 i!o , or for which a copy lht!reofis afla~hed.

OR shown below: B. 0 A chain of title (fom the invcnlor(s), oftllc p.alcnt applica!ionlpalent idclltified above, to the current assignee as 1. From: _ To: The document w~s recorded inlln! lJnitcd State.s Pat~t ;and Trademark Office~~ Reel_, Frame-' or j(}r which a copy lhrreofis attached. 2. From: To: The d~enl was recorded in the t.'ni1cd States Patent and 'Trademark Office a\ Re-el _, Fro~~ me__. orf(}r which a ct:Jpy Jkeuof is ~rtached.

Sig:1e.ture

Name/Title Date

3188979 !.DOC Rev. S/1612\>0? Exhibit 2 Aporoved Labeling for IMBRUVICA ™

10 .-~~-.,;~.~~,

(~DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993

NDA205552 ACCELERATED APPROVAL

Pharmacyclics, Inc. Attention: Christine Salido Executive Director, Regulatory Affairs 9995 East Arques Avenue Sunnyvale, CA 94085-4521

Dear Ms. Salido:

Please refer to your New Drug Application (NDA) dated June 28, 2013, received June 28, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutinib) Capsules, 140 mg.

We acknowledge receipt of your amendments dated May 6, 2013; May 13, 2013; June 6, 2013; June 20, 2013; July 12, 2013; July 25, 2013 (2); July 26, 2013 (3); July 30, 2013; August 1, 2013; August 2, 2013 (7); August 5, 2013(2); August 6, 2013; August 7, 2013; August 9, 2013; August 12, 2013; August 13, 2013 (3); August 14, 2013 (11); August 15, 2013; August 16, 2013; August 19, 2013; August 20, 2013; August 21, 2013; August 23, 2013; August 26, 2013; August 29, 2013; August 30, 2013; September 4, 2013; September 6, 2013; September 9, 2013 (3) September 11, 2013; September 12, 2013; September 17, 2013 (2); September 18, 2013; September 23, 2013; September 24, 2013; September 25, 2013; October 1, 2013; October 3, 2013(2); October 8, 2013; October 11, 2013; October 16, 2013(3); October 18, 2013; October 23, 2013; October 24, 2013; October 29, 2013(2); October 31,2013 (3); November 5, 2013; November 12, 2013; November 13, 2013(2).

This new drug application provides for the use of Imbruvica (ibrutinib) Capsules, 140 mg for the treatment of patients with Mantle Cell1ymphoma (MCL).

APPROVAL & LABELING

We have completed our review of this application, as amended. It is approved under the provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing ofthis drug product and related activities must adhere to the substance and procedures of the referenced accelerated approval regulations.

Reference ID: 3395788 NDA205552 Page2

We note that your November 12, 2013, submission includes final printed labeling (FPL) for your: package insert, patient package insert. We have not reviewed this FPL. You are responsible for assuring that the wording in this printed labeling is identical to that of the approved content of labeling in the structured product labeling (SPL) format.

CONTENT OF LABELING

As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(1)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system ( eLIST), as described at htt,p ://WVvw .fda. gov IF orindustrv/DataStandards/StructuredProductLabeling/default .htrn. Content oflabeling must be identical to the enclosed labeling (text for the package insert, text for the patient package insert). Information on submitting SPL files using eLIST may be found in the guidance for industry titled "SPL Standard for Content of Labeling Teclmical Qs and As" at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnfonnation/Guidances/U CM072392.pdf.

The SPL will be accessible via publicly available labeling repositories.

CARTON AND IMMEDIATE CONTAINER LABELS

We acknowledge your November 13, 2013, submission containing final printed carton and container labels.

ADVISORY COMMITTEE

Your application for Imbruvica (ibrutinib) Capsules, 140 mg was not referred to an FDA advisory committee because the application did not raise significant safety or efficacy issues in the intended population.

ACCELERATED APPROVAL REQUIREMENTS

Products approved under the accelerated approval regulations, 21 CFR 314.510, require further adequate and well-controlled studies/clinical trials to verify and describe clinical benefit. You are required to conduct such studies/clinical trials with due diligence. If postrnarketing studies/clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 314.530, withdraw this approval. We remind you of your postrnarketing requirements specified in your submission dated November 13, 2013. These requirements, along with required completion dates, are listed below.

Reference ID: 3395788 NDA205552 Page 3

PMR2060-l

Continue follow-up of patients (on treatment and in protocol defined post-treatment follow-up) and submit a final analysis report of trial PCYC-11 04-CA with a minimum follow-up of 24 months for each patient. If24 months follow-up is not possible for certain patients, provide justification for each patient. In addition, submit detailed assessment information regarding all sites of extranodal disease at baseline and follow-up, including assessments for response and progression. Summarize extranodal disease characteristics at baseline and at time of progression. Request further documentation as necessary from clinical trial sites in order to summarize the details of the extranodal disease progression.

Final Protocol Submission: Complete 01/2013 Trial Completion: 09/2014 Final Report Submission: 03/2015

PMR2060-2

Complete and submit the final results of the ongoing randomized, double-blind, placebo controlled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in combination with bendamustine and rituximab in patients with newly diagnosed mantle cell lymphoma. Enrollment of approximately 520 patients is expected. The primary endpoint is progression-free survival as assessed by investigators. Overall survival is a key secondary endpoint.

Final Protocol Submission: Completed 04/2013 Trial Completion: 12/2018 Final Report Submission: 03/2019

Submit final reports to this NDA as a supplemental application. For administrative purposes, all submissions relating to this postmarketing requirement must be clearly designated "Subpart H Postmarketing Requirement(s)."

REQUIRED PEDIATRIC ASSESSMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement.

Reference ID: 3395788 NDA205552 Page4

POSTMARKETING REQUIREMENTS UNDER 505fol

Section 505(o )(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute.

We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(l) of the FDCA will not be sufficient to identify an unexpected serious risk of inhibition of platelet function or assess a known serious risk of bleeding, including major hemorrhagic events.

Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.

Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following:

PMR2060-3

Determine the effect of a broad range of concentrations of ibrutinib on the potential to inhibit platelet function by conducting in vitro studies. Assessment methods should include evaluation of effects on platelet aggregation, including GPib-mediated aggregation. Evaluation should include samples from subjects with and without concomitant conditions associated with platelet dysfunction (e.g., severe renal dysfunction, use of a concomitant anticoagulant, and use of aspirin).

The timetable you submitted on November 13, 2013, states that you will conduct this study according to the following schedule:

Draft Protocol Submission: 06/2014 Final Protocol Submission: 12/2014 Study Completion: 06/2016 Final Report Submission: 12/2016

PMR2060-4

Conduct an assessment and an analysis of data from clinical trials and all post-marketing sources in order to characterize the risk of serious bleeding in patients treated with Imbruvica®, (ibrutinib) Capsules. The risks of special interest are major hemorrhagic events and their potential association with concomitant use of anti-platelet and/or anticoagulant drugs. Major hemorrhagic events are defined as any one of the following:

I. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardia!, or intramuscular with compartment syndrome,

Reference ID: 3395788 NDA205552 Page 5

II. Bleeding causing a fall in hemoglobin level of 20 giL or more, or leading to transfusion of two or more units of whole blood or red cells,

III. Bleeding resulting in a serious adverse drug experience [as per 21 CFR 314.80(a)]

This enhanced pharmacovigilance study will include:

1. Targeted and expedited surveillance with a guided collection form (as referenced in Pharmacyclics' Pharmacovigilance Plan dated August 23, 2013) to obtain additional salient clinical and diagnostic information related to major hemorrhagic events.

2. Submission of Post-marketing 15-day Alert Reports for all initial and follow-up reports of serious hemorrhagic adverse events from clinical trials and all post-marketing sources, including consumer reports, solicited reports, and foreign reports, utilizing the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) - Haemorrhages.

3. Submission of interval and cumulative analyses, as well as line listing for all major hemorrhagic events (utilizing the SMQ Haemorrhages) from clinical trials and all post marketing sources, including consumer reports, solicited reports, and foreign reports.

4. The interval and cumulative analyses should assess potential risk factors for cumulative major hemorrhagic events identified from both clinical trials and all postmarketing sources, and an overall assessment about these events in patients treated with Imbruvica® (ibrutinib) Capsules. In the overall assessment, discuss whether the data warrants further detailed assessment, labeling changes and/or other communication about these adverse events.

Continue the study for a period of four years from the date of final protocol submission as noted below. Prior to starting the study, submit for FDA review, a protocol describing how you will conduct the study and report results, according to the timeline below.

The timetable you submitted on November 13, 2013, states that you will conduct this study according to the following schedule:

Draft Protocol Submission: 03/2014 Final Protocol Submission: 06/2014 # 1 Interim Report Submission 12/2014 #2 Interim Report Submission 06/2015 #3 Interim Report Submission 12/2015 #4 Interim Report Submission 06/2016 #5 Interim Report Submission 12/2016 #6 Interim Report Submission 06/2017 #7 Interim Report Submission 12/2017 Study Completion: 06/2018 Final Report Submission: 11/2018

Reference ID: 3395788 NDA205552 Page 6

Finally, we have determined that only clinical trials (rather than a nonclinical or observational study) will be sufficient to identify unexpected serious risks of: • Altered ibrutinib exposures (plasma concentrations) and resultant serious adverse effects of treatment in patients with hepatic impairment, or with concomitant use of CYP3A inducers (e.g. rifampin); • Ibrutinib-induced Q-T prolongation and the potential for torsade de pointes.

Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following:

PMR2060-5

Evaluate the effect of hepatic impairment on ibrutinib pharmacokinetics. Submit the final report for trial PCI-32765CLL1 006 entitled, "An Open-Label, Multicenter, Pharmacokinetic Study of PCI-32765 in Subjects with Varying Degrees of Hepatic Impairment".

The timetable you submitted on November 13, 2013, states that you will conduct this trial according to the following schedule:

Final Protocol Submission: Completed 1112012 Trial Completion: 06/2014 Final Report Submission: 12/2014

PMR2060-6 Determine effect of a strong CYP3A Inducer on ibrutinib pharmacokinetics. Submit the final report for trial PCI-32765CLL1 010 entitled, "An Open-Label, Sequential Design Study to Assess the Effect ofRifampin on the Pharmacokinetics ofPCI-32765 in Healthy Subjects".

The timetable you submitted on November 13, 2013, states that you will conduct this trial according to the following schedule:

Final Protocol Submission: Completed 0112013 Trial Completion: Completed 0112013 Final Report Submission: 04/2014

PMR2060-7

Determine the effect ofibrutinib on the QT/QTc interval in healthy subjects on one or more therapeutic dose levels. Conduct and submit results of a thorough QT trial to evaluate the effects of ibrutinib on the QT /QTc interval.

The timetable you submitted on November 13, 2013, states that you will conduct this trial according to the following schedule:

Reference ID: 3395788 NDA205552 Page 7

Draft Protocol Submission: 03/2014 Final Protocol Submission: 06/2014 Trial Completion: 06/2015 Final Report Submission: 12/2015

Submit protocols for our review and concurrence prior to initiating and in time to reach agreement in advance of the final protocol submission date.

Submit the protocol to your IND 102688, with a cross-reference letter to this NDA. Submit all fmal report(s) to your NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: "Required Postmarketing Protocol Under SOS(o)", "Required Postmarketing Final Report Under SOS(o)", "Required Postmarketing Correspondence Under SOS(o)".

Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CPR 314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.

FDA will consider the submission of your annual report under section 506B and 21 CPR 314.81 (b )(2)( vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CPR 314.81(b)(2)(vii). We remind you thatto comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation ofFDCA section 505(o)(3)(E)(ii) and could result in enforcement action.

POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING REQUIREMENTS UNDER SECTION 506B

We remind you of your postmarketing commitment:

PMC 2060-8

Collect additional dissolution profile data (n=12 at release and n=12 on stability) using USP Apparatus Type 2 (Paddle) at 75 rpm in 3.0% w/v polysorbate 20 (Tween® 20) in 50 mM phosphate buffer pH 6.8 at 37.0°C from at least ten drug product release batches and from the drug product stability-registration/ primary batches through 12 months of storage at the long term condition. Use the overall dissolution data that were collected from the drug product's release and stability batches to set the final dissolution acceptance criteria.

Reference ID: 3395788 NDA205552 Page 8

Submit the final report with the complete dissolution information/data and a proposal for the dissolution acceptance under a supplement to the NDA within 15 months from action date.

Study Completion: 1112014 Final Report Submission: 02/2015

Submit clinical protocols to your IND I 02688 for this product. Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.8l(b)(2)(viii) you should include a status summary of each commitment in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. All submissions, including supplements, relating to these postmarketing commitments should be prominently labeled "Postmarketing Commitment Protocol," "Postmarketing Commitment Final Report," or "Postmarketing Commitment Correspondence."

PROMOTIONAL MATERIALS

Under 21 CFR 314.550, you are required to submit, during the application pre-approval review period, all promotional materials, including promotional labeling and advertisements, that you intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If you have not already met this requirement, you must immediately contact the Office of Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory project manager or the appropriate reviewer to discuss this issue.

As further required by 21 CFR 314.550, submit all promotional materials that you intend to use after the 120 days following marketing approval (i.e., your post-launch materials) at least 30 days before the intended time of initial dissemination of labeling or initial publication of the advertisement. We ask that each submission include a detailed cover letter together with three copies each of the promotional materials, annotated references, and approved package insert (PI)/Medication Guide/patient PI (as applicable).

Send each submission directly to:

OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotions (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266

Reference ID: 3395788 NDA205552 Page9

METHODS VALIDATION

We have not completed validation of the regulatory methods. However, we expect your continued cooperation to resolve any problems that may be identified.

REPORTING REQUIREMENTS

We remind you that you must comply with the reporting requirements for an approved NDA (21 CPR 314.80 and 314.81).

MEDWATCH- TO-MANUFACTURER PROGRAM

The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at http://www .taa.gov/Safety/MedWatch/HowToReport/ucmi 66910 .htm.

POST-APPROVAL FEEDBACK MEETING

New molecular entities and new biologics qualify for a post-approval feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application.

PDUFA V APPLICANT INTERVIEW

FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V ('the Program'). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review.

You will be contacted by ERG to schedule the interview following this action on your application; ERG will provide specifics about the interview process at that time. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments.

Reference ID: 3395788 NDA205552 Page 10

If you have any questions, call CAPT Diane Hanner, Regulatory Project Manager, at (301) 796-4058.

Sincerely,

{See appended electronic signature page)

Richard Pazdur, M.D. Director Office of Hematology and Oncology Products Center for Drug Evaluation and Research

ENCLOSURE(S): Content of Labeling Carton and Container Labeling

Reference ID: 3395788 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/

RICHARD PAZDUR 11/13/2013

Reference ID: 3395788 HIGHLIGHTS OF PRESCRIBING INFORMATION • Renal Toxicity: Monitor renal function and maintain hydration (5.4). These highlights do not include aU the information needed to use • Second Primary Malignancies: Other malignancies have occwred in IMBRUVICA safely and effectively. See full prescribing information for patients, including skin cancers, and other carcinomas (5.5). IMBRUVICA. • Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the IMBRUVICA™ (ibrutinib) capsules, for oral use potential risk to a fetus and to avoid pregnancy while taking the drug (5.6). Initial U.S. Approval: 2013 ------ADVERSE REACTIONS------ ------INDICATIONS AND USAGE------ The most common adverse reactions (~20%) in patients with MCL were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal IMBRlJVICA is a kinase inhibitor indicated for the treatment of patients with pain, peripheral edema, upper respiratory tract infection, nausea, bruising, mantle ceU lymphoma (MCL) who have received at lea.sl one prior therapy dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (!). (6). This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established (14.1 ). To report SUSPECTED ADVERSE REACfiONS, contact Pharmacyclics at lw877w877-3536 or FDA at 1-800wFDAw1088 or ------DOSAGE AND ADMINISTRATION------wWJv.fda.gov/medwatch 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2). ------DRUG INTERACfiONS.------ Capsule..'> should be taken orally with a glass of water. Do not open, break, or CYP3A Inhibitors: Avoid co-administration with strong and moderate CYP3A chew the capsules (2.1 ). inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA ------DOSAGE FORMS AND STRENGTHS------ dose (2.4, 7.1). Capsule: 140 mg{3) CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2). ------CONTRAINDICATIONS.------ ------USE IN SPECIF1C POPULATIONS------ None Hepatic Impairment: Avoid use ofiMBRUVICA in patients with baseline hepatic impairment (8. 7). ------WARNINGS AND PRECAUTIONS------• Hemorrhage: Monitor for bleeding (5.1). See 17 fo• PATIENT COUNSELING INFORMATION and FDA • Infections: Monitor patients for fever and infections and evaluate promptly approved patient labeling. (5.2). Revised: 11/2013 • Myelosuppression: Check complete blood counts monthly (5.3).

FULL PRESCRIBING INFORMATION' CONTENTS* I INDICATIONS AND USAGE 8 USE IN SPECIF"IC POPULATIONS 2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy 2.1 Dosing Guidelines 8.3 Nursing MotheJs 2.2 Dl)Sftge for Mantle Cell Lymphoma 8.4 Pediatric Use 2.3 Dose M1)difi.cati.ons tOr Adverse Reactions 8.5 C'reriatric Use 2.4 Dose Modifications for Use with CYP3A Inhibitors 8.6 Renallmpnirment 2.5 !v1isscd Dose 8. 7 Hepatic Impairment 3 DOSAGE FORl"IS AND STRENGTHS 8.8 Females and Males of Reproductive Potentia! 4 CONTRAINDICATIONS II DESCRIPTION 5 WARNINGSk'IDPRECAUTIONS 12 CLINICAL PHARMACOLOGY 5. J Hemorrhage 12.1 Mechanism of Action 5.2 Infections 12.2 Pharmacodynamics 5.3 Myelosuppression 12.3 Phnrmacokjuetics 5.4 Renal Toxicity 13 NONCLINICAL TOXICOLOGY 5.5 Second Primary Malignancies 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Embryo-Fetal Toxicity 14 CLINICAL STUDIES 6 ADVERSE REACI"IONS 14.1 Mantle Cell Lymphoma 7 DRUG INTERACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 7.1 CYP3A inhibitors 17 PATIENT COUNSELING INFORMATION 7.2 CYP3A Inducers * Sections or subsections omitted from the full prescribing information arc not listed.

Reference ID: 3395788 FULL PRESCRIBING INFORMATION l INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies ( 14.1 )} .

2 DOSAGE AND ADMINISTRATION 2.1 · Dosing Guidelines Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules. 2.2 Dosage for Mantle Cell Lymphoma The recommended dose ofiMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once daily. 2.3 Dose Modifications for Adverse Reactions Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue IMBRUVICA. Recommended dose modifications for these toxicities are described below:

MCL Dose Modification After Recovery Toxicity Occurrence Starting Dose = 560 mg

First Restart at 560 mg daily Second Restart at 420 mg daily Third Restart at 280 mg daily Fourth Discontinue IMBRUVICA

2.4 Dose Modifications for Use with CYP3A Inhibitors Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and

Reference ID: 3395788 antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer needed [see Drug Interactions (7.1)]. Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [see Drug Interactions (7.1)}. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs ofiMBRUVICA toxicity. 2.5 Missed Dose If a dose ofiMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.

3 DOSAGE FORMS AND STRENGTHS 140 mg capsules

4 CONTRAINDICATIONS None

5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14.1)}. 5.2 Infections Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6)}. Monitor patients for fever and infections and evaluate promptly.

Reference ID: 3395788 5.3 Myelosuppression Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly. 5.4 Renal Toxicity Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration. 5.5 Second Primary Malignancies Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers (4%), and other carcinomas (1 %). 5.6 Embryo-Fetal Toxicity Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL receiving the ibrutinib dose of 560 mg per day. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)}.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hemorrhage [see Warnings and Precautions (5.1)}

• Infections [see Warnings and Precautions (5.2)}

• Myelosuppression [see Warnings and Precautions (5.3)]

• Renal Toxicity [see Warnings and Precautions (5.4)}

• Second Primary Malignancies [see Warnings and Precautions (5.5)} Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of8.3 months.

Reference ID: 3395788 The most commonly occurring adverse reactions (?::: 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (?::: 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of?::: 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ::0:: 10% of Patients with Mantle Cell Lymphoma (N=l11)

System Organ Class Preferred Term All Grades(%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 51 5 Nausea 31 0 Constipation 25 0 Abdominal pain 24 5 Vomiting 23 0 Stomatitis 17 I Dyspepsia II 0 Infections and infestations Upper respiratory tract infection 34 0 Urinary tract infection 14 3 Pneumonia 14 7 Skin infections 14 5 Sinusitis 13 I General disorders and Fatigue 41 5 administrative site Peripheral edema 35 conditions 3 Pyrexia 18 I Asthenia 14 3 Skin and subcutaneous Bruising 30 0 tissue disorders Rash 25 3 Petechiae 11 0 Musculoskeletal and Musculoskeletal pain 37 I connective tissue disorders Muscle spasms 14 0 Arthralgia II 0 Respiratory, thoracic and Dyspnea 27 4 mediastinal disorders Cough 19 0 Epistaxis II 0 Metabolism and Decreased appetite 21 2 nutritional disorders Dehydration 12 4 Nervous system disorders Dizziness 14 0 Headache 13 0

5 Reference ID: 3395788 Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=lll)

Percent of Patients (N=lll) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 * Based on laboratory measurements and adverse reactions

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8% ). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

7 DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. 7.1 CYP3A Inhibitors In healthy volunteers, co-administration ofketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of840- 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng · hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration ofiMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs ofiMBRUVICA toxicity [see Dosage and Administration (2.4)]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors ofCYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

Reference ID: 3395788 7.2 CYP3A Inducers Administration ofiMBRUVICA with strong inducers ofCYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3)}.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)]. Risk Summary Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. IfiMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of I 0, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Ibrutinib at doses of 40 mg!kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. 8.3 Nursing Mothers It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness ofiMBRUVICA in pediatric patients has not been established. 8.5 Geriatric Use Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effecti:veness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

7 Reference ID: 3395788 8.6 Renal Impairment Less than I% of ibrutinib is excreted renally. lbrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Phannacology (12.3)]. 8. 7 Hepatic Impairment lbrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 2:3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Phannacology (I 2.3)]. 8.8 Females and Males of Reproductive Potential Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations (8.1)].

11 DESCRIPTION Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N602 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is I-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H pyrazolo[3,4-d]pyrimidin-1-yl]-I -piperidinyl]-2-propen-1-one and has the following structure: o--0

NH,

'-'IN

b-r0 IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain I 40 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium Iaury! sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink.

Reference ID: 3395788 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition ofBTK enzymatic activity. BTK is a signaling molecule of the B-ee!! antigen receptor (BCR) and cytokine receptor pathways. BTK' s role in signaling through the B-ee!! surface receptors results in activation of pathways necessary for B-ee! I trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-ee!! proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. 12.2 Pharmacodynamics In patients with recurrent B-celllymphoma > 90% occupancy ofthe BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of 2: 2.5 mg/kg/day (2: 175 mg/day for average weight of70 kg). 12.3 Pharmacokinetics Absorption

Ibrutinib is absorbed after oral administration with a median T max of 1 to 2 hours. lbrutinib exposure increases with doses up to 840 mg. The steady-state AUC observed in patients at 560 mg is (mean± standard deviation) 953 ± 705 ng·hlmL. Administration with food increases ibrutinib exposure approximately 2-fold compared with administration after overnight fasting. Distribution Reversible binding ofibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The apparent volume of distribution at steady state (V d,ss!F) is approximately 10000 L. Metabolism Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. Elimination Apparent clearance (CLIP) is approximately 1000 L/h. The half-life ofibrutinib is 4 to 6 hours. lbrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radio labeled C4C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of

Reference ID: 3395788 the radio labeled excretion product in feces and none in urine, with the remainder of the dose being metabolites. Age Age (3 7 to 84 years) does not alter ibrutinib systemic clearance. Gender Gender does not alter ibrutinib systemic clearance. Renal Impairment Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is< 10% of the dose. Creatinine clearance> 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. Hepatic Impairment lbrutinib is metabolized in the liver. No clinical trials have been completed in subjects with impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in healthy volunteer trials. Drug Interactions Coadministration ofibrutinib with CYPJA Inhibitors In a sequential design trial of 18 healthy volunteers, a single dose of 120 mg ofiMBRUVICA was administered alone on Day 1 and a single dose of 40 mg ofiMBRUVICA was administered on Day 7 in combination with 400 mg ofketoconazole (given daily on Days 4- 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that moderate CYP3A inhibitors (diltiazem and erythromycin) may increase the AUC ofibrutinib 6 to 9-fold in fasted condition. Coadministration ofIbrutinib with CYP JA Inducers Preliminary PK data from an ongoing dedicated drug interaction trial and simulations using PBPK indicate that rifampin (a strong CYP3A inducer) can decrease ibrutinib Cmox and AUC by more than 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer ( efavirenz) may decrease the AUC of ibrutinib up to 3-fold. Coadministration ofIbrutinib with CYP Substrates In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro.

Reference ID: 3395788 Coadministration ofIbrutinib with Substrates ofTransporters In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp ). Systemic ibrutinib is unlikely to be an inhibitor ofP-gp at clinical doses ([I]dKi < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with IMBRUVICA may increase their blood concentration.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with ibrutinib. Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs.

14 CLINICAL STUDIES 14.1 Mantle Cell Lymphoma The safety and efficacy ofiMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of Ill previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or I. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, I to 5 treatments), including II% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor~ 5 em, 49% had bone marrow involvement, and 54% had extranodal involvement at screening. IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 3.

Reference ID: 3395788 Table 3: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with Mantle Cell Lymphoma

Total (N=lll) ORR(%) 65.8 95% CI (%) (56.2, 74.5) CR(%) 17.1 PR(%) 48.6 Median DOR months 95% CI 17.5 (15.8, NR) CI = confidence interval; CR = complete response; PR = partial response; NR =not reached

An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of69%. The median time to response was 1.9 months. Lymphocytosis Upon initiation of IMBRUVICA, a temporary increase in lymphocyte counts (i.e., 2': 50% increase from baseline and above absolute lymphocyte count of5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks (median time 1.1 weeks) ofiMBRUVICA therapy and resolves by a median of8 weeks.

16 HOW SUPPLIED/STORAGE AND HANDLING The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available in white HDPE bottles with a child-resistant closure:

• 90 capsules per bottle: NDC 57962-140-09 • 120 capsules per bottle: NDC 57962-140-12 Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information)

• Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions (5.1)}.

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions (5.2)}.

12 Reference ID: 3395788 • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions (5.4)].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions (5.5)}.

• Embryo-fetal toxicity: Advise women ofthe potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.6)}. • Inform patients to take IMBRUVICA orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1)].

• Advise patients that in the event of a missed daily dose ofiMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5)}.

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions (6)}. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, P A USA 19044

Patent http://www.imbruvica.com IMBRUVICATM is a trademark owned by Pharmacyclics, Inc.

©Pharmacyclics, Inc. 2013 Issued: November 2013

Reference ID: 3395788 Patient Information IMBRUVICA (im-BRU-vih-kuh) (ibrutinib) capsules What is IMBRUVICA? IMBRUVICA is a prescription medicine used to treat people with mantle cell lymphoma (MCL) who have received at least one prior treatment. It is not known if IMBRUVICA is safe and effective in children. What should I tell my healthcare provider before taking IMBRUVICA? Before you take IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you: • have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure. • have bleeding problems • have liver problems • are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. You should not become pregnant while taking IMBRUVICA. • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take IMBRUVICA or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects. How should I take IMBRUVICA? • Take IMBRUVICA exactly as your healthcare provider tells you to take it. • Take IMBRUVICA 1 time a day. • Swallow IMBRUVICA capsules whole with a glass of water. Do not open, break, or chew IMBRUVICA capsules. • Take IMBRUVICA at about the same time each day. • If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take 2 doses of IMBRUVICA on the same day to make up for a missed dose. What should I avoid while taking IMBRUVICA? • You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) while you are taking IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood. What are the possible side effects of IMBRUVICA? IMBRUVICA may cause serious side effects, including: • Bleeding problems can happen during treatment with IMBRUVICA that can be serious. Tell your health care provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or that you can not control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feel dizzy or weak, confusion, change in your speech, or a headache that lasts a long time. • Infections can happen during treatment with IMBRUVICA. Infections can be serious and may lead to death. Tell your healthcare provider if you have fever, chills, or any other signs or symptoms of an infection while taking IMBRUVICA. • Decrease in blood cell counts. Your healthcare provider should do monthly blood tests to check your blood counts. • Kidney problems. Kidney failure and death have happened with IMBRUVICA treatment. Drink fluids during treatment with IMBRUVICA to help prevent too much fluid loss (dehydration). Your healthcare provider should do blood tests to check how well your kidneys are working. • Second primary cancers. New cancers have happened in people who have been treated with IMBRUVICA, including cancers of the skin or other organs.

Reference ID: 3395788 The most common side effects of IMBRUVICA include: low blood platelet count, diarrhea, low white blood cell count, low red blood cell count, fatigue, muscle and bone pain, swelling of legs and feet, upper respiratory tract infection, nausea, bruising, shortness of breath, constipation, rash, stomach (abdomen) pain, vomiting, and decreased appetite. Diarrhea is a common side effect in people who take IMBRUVICA. Tell your healthcare provider if you have diarrhea that does not go away. These are not all the possible side effects of IMBRUVICA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store IMBRUVICA? • Store IMBRUVICA at room temperature between 68°F to 77°F (20°C to 25°C). • Keep IMBRUVICA in the original container with the lid tightly closed. Keep IMBRUVICA and all medicines out of the reach of children. General information about the safe and effective use of IMBRUVICA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals. What are the ingredients in IMBRUVICA? Active ingredient: ibrutinib Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Distributed and Marketed by: Pharmacycltcs, Inc. Sunnyvale, CAUSA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 For more Information call 1-877-877-3536

This Patient Information has been approved by the u.s. Food and Drug Administration. Issued: 11/2013

Reference ID: 3395788 CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

2055520rigls000

LABELING HIGHLIGHTS OF PRESCRIBING INFORMATION • Renal Toxicity: Monitor renal function and maintain hydration (5.4). These highlights do not include all the information needed to use • Second Primary Malignancies: Other malignancies have occurred in IMBRUVICA safely and effectively. See fttU prescribing information for patients, including skin cancers, and other carcinomas (5.5). IMBRUVICA. • Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the IMBRUVICATM (ibrutinib) capsules, for oral use potential risk to a fetus and to avoid pregnancy while taking the drug (5.6). Initial U.S. Approval: 2013 ------ADVERSE REACTIONS------INDICATIONS AND USAGE------ The most common adverse reactions (~20%) in patients with MCL were thrombocytopenia, diarrhea, neutropenia, IMBRUVICA is a kinase inhibitor indicated for the treatment of patient<; with anemia, fatigue, musculoskeletal pain, mantle cell lymphoma (MCL) who have received at least one prior therapy periphern.l edema, upper respiratory tract infection, nausea, bruising, (I). dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (6). This indication is based on overall response rate. An improvement in survival or disease~related symptoms has not been e..ortablished ( 14.1 ). To report SUSPECfED ADVERSE REACTIONS, contact PharmacycUcs at 1-877-877-3536 or FDA at 1-800-FDA-1088 or ------DOSAGE AND ADMINISTRATION------WWJv.fda.gov/medwatch 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2). ------DRUG INTERACTIONS------ Capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules (2.1 ). CYP3A Inhibitors: Avoid co-administration with strong and modemte CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA ------DOSAGE FORMS AND STRENGTHS------ dose (2.4, 7.1). Capsule: 140 mg (3) CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2). ------·------CONTRAINDICATIONS------ ------USE L'l SPECIFIC POPULATIONS------ None Hepatic Impairment: Avoid use ofiMBRUVICA in patients with baseline hepatic impairment (8. 7). ------WARNINGS AND PRECAUTIONS----·-- • Hemorrhage: Monitor for bleeding (5.1). See 17 for PATIENT COUNSELING INFORMATION and FDA • Infections: Monitor patients for fever and infections and evaluate promptly approved patient labeling. (5.2). Revised: 11/2013 • Myelosuppression: Check complete blood counts monthly (5.3).

FULL PRESCRIBING INFORMATION: CONTENTS* I INDICATIONS AND USAGE 8 USE IN SPECIF"IC POPULATIONS 2 DOSAGE ANTJ ADMINISTRATION 8.1 Pregnancy 2.1 Dosing Guidelines 8.3 Nursing Mothe1s 2.2 Dosage for Mantle Celt Lymphoma &.4 Pediatric Use 2.3 Dose Modifications for Adverse Reactions 8.5 C'reriatric Use 2.4 Dose Modifications fmUse with CYP3A Inhibitors 8.6 RenHllmpairwent 2.5 tvlisscd Dose 8. 7 Hepatic Impairment 3 DOSAGE FORli

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Guidelines

Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules. 2.2 Dosage for Mantle Cell Lymphoma The recommended dose ofiMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once daily. 2.3 Dose Modifications for Adverse Reactions Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade I or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue IMBRUVICA. Recommended dose modifications for these toxicities are described below:

MCL Dose Modification After Recovery Toxicity Occurrence Starting Dose = 560 mg

First Restart at 560 mg daily Second Restart at 420 mg daily Third Restart at 280 mg daily Fourth Discontinue IMBRUVICA

2.4 Dose Modifications for Use with CYP3A Inhibitors

Avoid co-administration with strong or moderate CYP3A iohibitors and consider alternative agents with less CYP3A inhibition. Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and

2 Reference ID: 3395788 antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer needed [see Drug Interactions (7.1)]. Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [see Drug Interactions (7.1)]. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs ofiMBRUVICA toxicity. 2.5 Missed Dose If a dose ofiMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.

3 DOSAGE FORMS AND STRENGTHS 140 mg capsules

4 CONTRAINDICATIONS None

5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (1 4.1)]. 5.2 Infections Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6)}. Monitor patients for fever and infections and evaluate promptly.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hemorrhage [see Warnings and Precautions (5.1)}

• Infections [see Warnings and Precautions {5.2)}

• Myelosuppression [see Warnings and Precautions {5.3)}

• Renal Toxicity [see Warnings and Precautions (5.4)}

Reference ID: 3395788 The most commonly occurring adverse reactions (2: 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (2: 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Adverse reactions from the MCL trial (N=lll) using single agent IMBRUVICA 560 mg daily occurring at a rate of?: 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in~ 10% of Patients with Mantle Cell Lymphoma (N=111)

System Organ Class Preferred Term All Grades(%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 51 5 Nausea 31 0 Constipation 25 0 Abdominal pain 24 5 Vomiting 23 0 Stomatitis 17 I Dyspepsia II 0 Infections and infestations Upper respiratory tract infection 34 0 Urinary tract infection 14 3 Pneumonia 14 7 Skin infections 14 5 Sinusitis 13 I General disorders and Fatigue 41 5 administrative site Peripheral edema 35 3 conditions Pyrexia 18 I Asthenia 14 3 Skin and subcutaneous Bruising 30 0 tissue disorders Rash 25 3 Petechiae 11 0 Musculoskeletal and Musculoskeletal pain 37 I connective tissue disorders Muscle spasms 14 0 Arthralgia II 0 Respiratory, thoracic and Dyspnea 27 4 mediastinal disorders Cough 19 0 Epistaxis 11 0 Metabolism and Decreased appetite 21 2 nutritional disorders Dehydration 12 4 Nervous system disorders Dizziness 14 0 Headache 13 0

Reference ID: 3395788 Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=lll)

Percent of Patients (N=lll) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 "' Based on laboratory measurements and adverse reactions

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=lll ). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

7 DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. 7.1 CYP3A Inhibitors In healthy volunteers, co-administration ofketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of840- 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng · hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration ofiMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs ofiMBRUVICA toxicity [see Dosage and Administration (2.4)]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

Reference ID: 3395788 7.2 CYP3A Inducers Administration ofiMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3)}.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5. 6)]. Risk Summary Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. IfiMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10,40 and 80 mglkglday. Ibrutinib at a dose of80 mglkglday was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of80 mglkglday in animals is approximately 14 times the exposure (AUC) inpatients with MCL administered the dose of 560 mg daily. Ibrutinib at doses of 40 mglkglday or greater was associated with decreased fetal weights. The dose of 40 mglkglday in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. 8.3 Nursing Mothers It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account tbe importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness ofiMBRUVICA in pediatric patients has not been established. 8.5 Geriatric Use Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Reference ID: 3395788 8.6 Renal Impairment Less than I% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)}. 8.7 Hepatic Impairment Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ~ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Females and Males of Reproductive Potential Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations (8.1)}.

11 DESCRIPTION Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N602 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-!H pyrazolo[3,4-d]pyrimidin-l-yl]-1-piperidinyl]-2-propen-1-one and has the following structure: o--0

IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium Iaury! sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink.

Reference ID: 3395788 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

Ibrutinib is a small-molecule inhibitor ofBTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition ofBTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. 12.2 Pharmacodynamics

In patients with recurrent B-celllymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ~ 2.5 mg/kg/day (~ 175 mg/day for average weight of70 kg). 12.3 Pharmacokinetics Absorption

Ibrutinib is absorbed after oral administration with a median T max of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC observed in patients at 560 mg is (mean± standard deviation) 953 ± 705 ng·h/mL. Administration with food increases ibrutinib exposure approximately 2-fold compared with administration after overnight fasting. Distribution Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The apparent volume of distribution at steady state (Vd,s/F) is approximately 10000 L. Metabolism

Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. Elimination Apparent clearance (CL/F) is approximately 1000 L/h. The half-life of ibrutinib is 4 to 6 hours.

Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radio labeled [ 14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of

Reference ID: 3395788 the radio labeled excretion product in feces and none in urine, with the remainder of the dose being metabolites. Age Age (37 to 84 years) does not alter ibrutinib systemic clearance. Gender Gender does not alter ibrutinib systemic clearance. Renal Impairment Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < I 0% of the dose. Creatinine clearance> 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. Hepatic Impairment Ibrutinib is metabolized in the liver. No clinical trials have been completed in subjects with impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in healthy volunteer trials. Drug Interactions Coadministration ofIbrutinib with CYP 3A Inhibitors In a sequential design trial of 18 healthy volunteers, a single dose of 120 mg ofiMBRUVICA was administered alone on Day I and a single dose of 40 mg ofiMBRUVICA was administered on Day 7 in combination with 400 mg ofketoconazole (given daily on Days 4- 9). Ketoconazole increased ibrutinib dose-normalized Cmox and AUC 29-fold and 24-fold, respectively. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that moderate CYP3A inhibitors ( diltiazem and erythromycin) may increase the AUC of ibrutinib 6 to 9-fold in fasted condition. Coadministration ofibrutinib with CYP3A Inducers Preliminary PK data from an ongoing dedicated drug interaction trial and simulations using PBPK indicate that rifampin (a strong CYP3A inducer) can decrease ibrutinib Cmax and AUC by more than I 0-fold. Simulations using PBPK suggested that a moderate CYP3A inducer ( efavirenz) may decrease the AUC of ibrutinib up to 3-fold. Coadministration ofIbrutinib with CYP Substrates In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (1/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers ofCYP450 isoenzymes in vitro.

Reference ID: 3395788 Coadministration ofIbrutinib with Substrates a/Transporters In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp ). Systemic ibrutinib is unlikely to be an inhibitor ofP-gp at clinical doses ([1] 1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after·an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with IMBRUVICA may increase their blood concentration.

14 CLINICAL STUDIES 14.1 Mantle Cell Lymphoma The safety and efficacy ofiMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of Ill previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or I. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including II% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor~ 5 em, 49% had bone marrow involvement, and 54% had extranodal involvement at screening. IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 3.

Reference ID: 3395788 Table 3: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with Mantle Cell Lymphoma

Total (N=lll) ORR(%) 65.8 95% CI (%) (56.2, 74.5) CR(%) 17.1 PR(%) 48.6 Median DOR months 95% CI 17.5 (15.8, NR) CI = confidence interval; CR =complete response; PR =partial response; NR =not reached

An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%. The median time to response was 1.9 months. Lymphocytosis Upon initiation ofiMBRUVICA, a temporary increase in lymphocyte counts (i.e.,?: 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks (median time 1.1 weeks) ofiMBRUVICA therapy and resolves by a median of 8 weeks.

16 HOW SUPPLIED/STORAGE AND HANDLING The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available in white HDPE bottles with a child-resistant closure:

• 90 capsules per bottle: NDC 57962-140-09

• 120 capsules per bottle: NDC 57962-140-12 Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between l5°C and 30°C (59°F to 86°F). Retain in original package.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information)

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions (5.2)}.

Reference ID: 3395788 • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions (5.4)].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.6)}. • Inform patients to take IMBRUVICA orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1)}.

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions (6)}. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044

Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc.

©Pharmacyclics, Inc. 2013 Issued: November 2013

Reference ID: 3395788 Patient Information IMBRUVICA {im-BRU-vih-kuh) (ibrutinib) capsules What is IMBRUVICA? IMBRUVICA is a prescription medicine used to treat people with mantle cell lymphoma (MCL) who have received at least one prior treatment. It is not known if IMBRUVICA is safe and effective in children. What should I tell my healthcare provider before taking IMBRUVICA? Before you take IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you: • have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure. • have bleeding problems • have liver problems • are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. You should not become pregnant while taking IMBRUVICA. • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take IMBRUVICA or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects. How should I take IMBRUVICA? • Take IMBRUVICA exactly as your healthcare provider tells you to take it. • Take IMBRUVICA 1 time a day. • Swallow IMBRUVICA capsules whole with a glass of water. Do not open, break, or chew IMBRUVICA capsules. • Take IMBRUVICA at about the same time each day. • If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take 2 doses of IMBRUVICA on the same day to make up for a missed dose. What should I avoid while taking IMBRUVICA? • You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) while you are taking IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood. What are the possible side effects of IMBRUVICA? IMBRUVICA may cause serious side effects, including: • Bleeding problems can happen during treatment with IMBRUVICA that can be serious. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or that you can not control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feel dizzy or weak, confusion, change in your speech, or a headache that lasts a long time. • Infections can happen during treatment with IMBRUVICA. Infections can be serious and may lead to death. Tell your healthcare provider if you have fever, chills, or any other signs or symptoms of an infection while taking IMBRUVICA. • Decrease in blood cell counts. Your healthcare provider should do monthly blood tests to check your blood counts. • Kidney problems. Kidney failure and death have happened with IMBRUVICA treatment. Drink fluids during treatment with IMBRUVICA to help prevent too much fluid loss (dehydration). Your healthcare provider should do blood tests to check how well your kidneys are working. • Second primary cancers. New cancers have happened in people who have been treated with IMBRUVICA, including cancers of the skin or other organs.

Reference ID: 3395788 The most common side effects of IMBRUVICA include: low blood platelet count, diarrhea, low white blood cell count, low red blood cell count, fatigue, muscle and bone pain, swelling of legs and feet, upper respiratory tract infection, nausea, bruising, shortness of breath, constipation, rash, stomach (abdomen) pain, vomiting, and decreased appetite. Diarrhea is a common side effect in people who take IMBRUVICA. Tell your healthcare provider if you have diarrhea that does not go away. These are not all the possible side effects of IMBRUVICA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store IMBRUVICA? • Store IMBRUVICA at room temperature between 68°F to 77°F (20°C to 25°C). • Keep IMBRUVICA in the original container with the lid tightly closed. Keep IMBRUVICA and all medicines out of the reach of children. General information about the safe and effective use of IMBRUVICA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals. What are the ingredients in IMBRUVICA? Active ingredient: ibrutinib Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Distributed and Marketed by: Pharmacydics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 For more Information call 1-877-877-3536

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 11/2013

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RICHARD PAZDUR 11/13/2013

Reference ID: 3395788 Exhibit 3 Copy of U.S. Patent No. 8.008.309

11 11111111111111 111111111111111111111111111111111111111111111111111111 US008008309B2

(12) United States Patent (I o) Patent No.: US 8,008,309 B2 Honigberg et al. (45) Date of Patent: *Aug. 30, 2011

(54) INHlliiTORS OF BRUTON'S TYROSINE 2009/0181987 A1 7/2009 Honigberg et al. KINASE 2010/0022561 A1 112010 Honigberg et al. 2010/0041677 A1 2/2010 Honigberg et al. (75) Inventors: Lee Honigberg, San Francisco, CA FOREIGN PATENT DOCUMENTS (US); Erik Verner, San Mateo, CA WO W0-97·28161 8/1997 (US); Zhengying Pan, Alpharetta, GA WO W0-00-56737 A2 912000 (US) WO WO-O 1-19829 A2 3/2001 wo wo.o 1-19829 A3 3/2001 WO W0-01·25238 A2 4/2001 (73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA WO W0-01-41754 6/2001 (US) WO W0-01-44258 A1 6/2001 WO W0-02-38797 A2 512002 ( •) Notice: Subject to any disclaimer, the term ofthis WO W0-02-080926 10/2002 WO W0-03-000187 112003 patent is extended or adjusted under 35 WO W0-2004-096253 1112004 U.S.C. 154(b) by 83 days. WO W0-2004·100868 A2 11/2004 WO W0-2004·100868 A3 11/2004 This patent is subject to a terminal dis~ WO W0-2005-005429 1/2005 claimer. WO W0-2005-014599 212005 WO W0-2008-054827 A2 5/2008 (21) Appl. No.: 12/499,005 OTHER PUBLICATIONS EP06850039 Supplemental Search Report dated Feb. 9, 2010. (22) Filed: Jul. 7, 2009 Arnold, L.D. et a!., "Pyrrolo[2,3-d]pyrimidines Containing an Extended 5-Substituent as Potent and Selective Inhibitors oflck 1," (65) Prior Publication Data Bioorg. Med. Chern. Ltrs. 10:2167-2170 (2000). Browning, J.L., "B cells move to centre stage: novel opportunities for US 2010/0004270 AI Jan. 7, 2010 autoimmune disease treatment", Nature Reviews/Drug Discovery vol. 5, Jul. 2006, pp. 564-576. Related U.S. Application Data Burchat et al., "Pyrazolo[3,4-d]pyrimidines Containing an Extended 3-Substituent as Potent Inhibitors of Lck-a Selectivity Insight," (62) Division of application No. 12/356,498, filed on Jan. Bioorg. Med. Chern. Ltrs. 12:1687-1690 (2002). 20, 2009, which is a division of application No. Cohen, M.S. et al., ''Structural Bioinfonnatics-Based Design of 11/617,645, filed on Dec. 28, 2006, now Pat. No. Selective, Irreversible Kinase Inhibitors," Science, vol. 308, May 27, 2005, pp. 1318·1321. 7,514,444. Desiderio, S., "Role of Btk in B cell development and signaling," Curr. Op. in Inununlogy 1997, 9:534-540. Provisional application No. 60/826,720, filed on Sep. (60) Fnunan, D.A., "Xid-like Phenotypes: A B Cell Signalosome Takes 22, 2006, provisional application No. 60/828,590, Shape,"lnununity 13:1-3 (Jul. 2000). filed on Oct. 6, 2006. Gold, Michael R., "To make antibodies or not:signaling by the B-cell antigen receptor," Trends in Pharmacological Sciences, 23(7):316- (51) lnt.Cl. 324 (Jul. 2002). Horwood, Nicole J. et al., "Bruton's Tyrosin Kinase Is Required for A01N 43/90 (2006.01) Lipopolysaccharide-----induced Tumor Necrosis Factor aProduction," A61K 311519 (2006.01) J. Exp. Med. 197(12):1603-1611 (Jun. 2003). (52) U.S. C! ...... 514/262.1 Iwaki, Shoki et al., "Btk Plays a Crucial Role in the Amplification of (58) Field of Classification Search ...... None FceRI-mediated Mast Cell Activation by Kit," J. Bioi. Chern. See application file for complete search history. 280(48):40261-40270 (Dec. 2, 2005). Jefferies, Caroline A. ct al., "Bruton's Tyrosine Kinase Is a Toll/ Interleukin-1 Receptor Domain-binding Protein That Participates in (56) References Cited Nuclear Factor KBActivation byToll-like Receptor4," J. Bioi. Chern. 278:26258-26264 (2003). U.S. PATENT DOCUMENTS 6,326,469 B1 12/2001 Ullrich et al. (Continued) 6,506,769 B2 112003 Snow et at. 6,660,744 Bl 12/2003 Hirst et al. Primary Examiner- Jeffrey Murray 6,753,348 B2 6/2004 Uckun et al. (74) Attorney, Agent, or Finn - Wilson Sonsini Goodrich & 6,770,639 B2 8/2004 Snow et al. Rosati 6,921,763 B2 7/2005 Hirst et al. 7,514,444 B2"' 4/2009 Honigberg et al...... 514/263.22 (57) ABSTRACT 2002/0016460 A1 2/2002 Snow et al. Disclosed herein are compounds that form covalent bonds 2003/0040461 A1 2/2003 Mcatee 2003/0125235 A1 7/2003 Foxwell with Bruton's tyrosine kinase (Btk). Also described are irre 2004/0006083 A1 l/2004 Hirst et al. versible inhibitors ofBtk. Methods for the preparation of the 2005/0008640 A1 l/2005 Waegell et at. compounds are disclosed. Also disclosed are pharmaceutical 200510090499 A1 4/2005 Currie et al. compositions that include the compounds. Methods of using 2005/0101604 A1 5/2005 Currie et al. the Btk inhibitors are disclosed, alone or in combination with 2005/0196851 AI 9/2005 Uckun 2005/0209255 A1 9/2005 Jimenez et al. other therapeutic agents, for the treatment of autoimmune 2006/0079494 A1 4/2006 Santi et al. diseases or conditions, heteroimmune diseases or conditions, 2006/0167090 AI 7/2006 Uckun et al. cancer, including lymphoma, and inflammatory diseases or 2008/0076921 AI 3/2008 Honigberg et al. conditions. 2008/0108636 AI 512008 Honigberg et al. 200810139582 A1 612008 Honigberg et al. 15 Claims, 8 Drawing Sheets US 8,008,309 B2 Page2

OTHER PUBLICATIONS Uckun, Fatih M. et al., "The Anti-leukemic Bruton's Tyrosin Kinase Kawakami, Yuko et al., "Terreic acid, a quinone cpoxidc inhibitor of Inhibitor a-cyano-~·hydroxy-~·mehyl-N-(2,5~ Bruton's tyrosine kinase," PNAS USA 96:2227~2232 (1999). dibromophenyl)Propenamide (LFM-Al3)Prevents Fatal Kuppers, R., "Mechanisms of B-cell lymphoma pathogenesis,'' Thromboembolism," Leuk. Lymphoma44(9):1569-1577 (2003). Uckun, Fatih M. et al., "In Vivo Phannacokinetic Features, Toxicity Nature Reviews/Cancer, vol. 5, Apr. 2005, pp. 251-262. Profile, and Chemosensitizing Activity of a-Cyano-!3-hydroxy-!3- KUiosaki, Tomohiro, "Functional dissection path ofBCR signaling methyi-N~(2,5~ dibromophenyl)propenamide (LFM-Al3), a Novel ways," Curr. Op. Inun. 12:276-281 (2000). Antileukemic Agent Targeting Bruton's Tyrosine Kinase,'' Clin. Can~ Mahajan, S. et al., "Rational Design and Synthesis of a Novel Anti cer Res. 8:1224-1233 (2002). leukemic Agent Targeting Bruton's Tyrosine Kinase (BTK), LFM Uckun, F.M., ''Bruton's Tyrosin Kinase (BTK) as a Dual-Function Al3 [a-Cyano-f3-Methyl-N-(2,5-Dibromopbenyl)Propenamlde],'' J. Regulator of Apoptosis," Biochem. Pharmacology, vol. 56, pp. 683- of Bioi. Chern., vol. 274, No. 14, Apr. 2, 1999, pp. 9587-9599. 691, 1998. Mangla, Anita ct al., "Pleiotropic consequences of Bruton tyrosin Uckun, Fatih M. et al., "BTK as a Mediator of Radiation-lnduced kinase deficiency in myeloid lineages lead to poor inflammatory Apoptosis in DT-40 LymphomaB Cells,"Science vol. 273 No. 5278, responses," Blood 104(4):1191-1197 (2004). pp. 1096-1100 (1996). Niiro, Hiroaki and Clark, Edward A., "Regulation of B-Cell Fate by Vassilev, A.O. and Uckun, F.M., "Therapeutic Potential of Inhibiting Antigen-Receptor Signals," Nature Reviews 2:945-956 (2002). Bruton's Tyrosine Kinase, (BTK)," Current Pharmaceutical Design, Nisitani, S. et al., "In situ detection of activated Bruton's tyrosine 2004, 10, 1757-1766. kinase in the Ig signaling complex by phosphopeptide-specific Vassilev,Aiexei et al., "Bruton's Tyrosine Kinase as an Inhibitor of monoclonal antibodies," PNAS USA 96:2221-2226 (1999). the Fas/CD95 Death-inducing Signaling Complex," J. Bioi. Chern. Oligino, Thomas J. and Dalrymple, Stacie A., "Targeting B cells for 274(3i1646-1656 (1999). the treatment of rheumatoid arthritis," Arthirits Res Ther 5(Suppl. Yamamoto, Noriyuki eta!., "The Orally Available Spleen Tyrosine 4),87-Sll (2002). Kinase Inhibitor 2-[7-(3,4-Dimethoxyphenyl)-imidazo[l,2- Pan, z. et at., "Discovery of Selectable Irreversible Inhibitors for c]pyrimidin-5-ylamino]-nicotinamide Dihydrochloride (BAY61- Bruton's Tyrosine Kinase," ChemMedChem 2006, 1, 1-5. 3606) Blocks Antigcn-Induced.Ainvay Inflammation in Rodents," J. Quek, L.S. eta!., "A role for Bruton's tyrosine kinase (Btk) in platelet Phanna. and Exp. Therapeutics 306(3):1174~1181 (2003). activation by collagen,'' Curr. Bioi. 8(20):1137-1140 (1998). Luskova, P. and Draber, P., "Modulation of the Fee Receptor 1 Sig Sada, Kiyonao and Yamamura, Hirohei, ''Protein-Tyrosine Kinases naling by Tyrosin Kinase Inhibitors: Search for Therapeutic Targets and Adaptor Proteins in FceRI -Mediated Signaling in Mast Cells," of Inflammatory and Allergy Diseases," Curr. Pharmaceutical Design Curr. Mol. Med. 3(1),85-94 (2003). 10,1727-1737 (2004). Schaeffer, Edward M. and Schwartzberg, Pamela L., "Tee family PCT/US06/49626 Search Report dated Apr. 9, 2008. kinases in lymphocyte signaling and function," Curr. Op. Imm. Y1ppagunta et al., "Crystalline Solids," Advanced Drug Delivery 12,282-288 (2000). Reviews 48:3-26 (200 1). Science IP CAS Search, Sep. 5, 2006. Dorwa1d, F. A. Side Reactions in Organic Symhesis, Wiley: VCH, Science IP CAS Search, Mar. 16, 2006. Weinhcimp. IX of Preface, Wiley-VCHVerlagGmbH & Co. KGaA Merged Markush Service Search, Jun. 27, 2005. (2005). Shaffer, A.L. eta!., Lymphoid malignancies: the dark side ofB-cell EP 06850386.1 Search Report and Written Opinion dated Sep. 10, differentiation, Nature Reviews/Immunology, vol. 2, Dec. 2002, pp. 2010. 920-932. Uckun and Qazi, "Bruton's tyrosine kinase as a molecular target in Smaill, J.B. et a!., ''Tyrosine Kinase Inhibitors. 15. trcabnent of leukemias and lymphomas as well as inflammatory 4-(Phenylamino)quinazoline and disorders and autoimmunity,"Expcrt Opinion Thcr. Patents 20(11 ): 1- 4-(Phenylamino)prido[dJpyrimidine Acrylamides as Irresversible 14 (2010). lnhibitors of the ATP Binding Site of the Epidermal Growth Factor Dorwald et al., Side Reactions in Organic Synthesis, 2005, Wiley: Receptor," J. Mcd. Chern. 42(10):1803-1815 (1999). VCH, Weinheim p. IX of Preface. Smith, C.l. Edvard et al., "The Tee family of cytoplasmic tyrosine U.S. Appl. No. 12/499,002 Office Action mailed Mar. 3, 2011. kinases: manunalian Btk, Bmx, Itk, Tee, Txk andhomologs in other U.S. Appl. No. 12/499,008 Office Action mailed Mar. 9, 2011. species," BioEssays 23:436-446 (2001). EP10155834.4 Search Report dated May 19,2010. Smolen, Josef S. and Steiner, Gunter, "Therapeutic Strategies for Rhewnatoid Arthritis," Nature Reviews 2:473-488 (2003). * cited by examiner N =

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...... • ,'gJ I.L US 8,008,309 B2 1 2 INHIBITORS OF BRUTON'S TYROSINE tion ofBtk provides therapeutic benefit to a patient having the KINASE disease). Further described are phannaceutical formulations that include an irreversible inhibitor of Btk. RELATED APPLICATIONS Compounds described herein include those that have a 5 structure ofany ofFormula (A), Formula (B), Formula (C), or This application is a divisional patent application of U.S. Formula (D), and pharmaceutically acceptable salts, solvates, patent application Ser. No. 12/356,498, entitled "INHIBI~ esters, acids and prodrugs thereof, In certain embodiments, TORS OF BRUTON'S TYROSINE KINASE" filed Jan. 20, isomers and chemically protected forms of compounds hav 2009, which is a divisional patent application of U.S. patent ing a structure represented by any of Formula (A), Formula application Ser. No. 11/617,645, entitled "INHIBITORS OF 10 (B), Formula (C), or Formula (D), are also provided. BRUTON'S TYROSINE KINASE" filed Dec. 28, 2006, In one aspect, provided herein is a compound of Formula issued as U.S. Pat. No. 7,514,444 on Apr. 7, 2009, which (D). Formula (D) is as follows: claims benefit of U.S. Provisional Application No. 60/826, 720 entitled "INHIBITORS OF BRUTON'S TYROSINE KINASE" filed Sep. 22, 2006; and U.S. ProvisionaiApplica- 15 Fonnula(D) tion No. 60/828,590 entitled "INHIBITORS OF BRUTON'S TYROSINE KINASE" filed Oct. 6, 2006, all of which are herein incorporated by reference.

FIELD OF THE INVENTION 20

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such com pounds and compositions to inhibit the activity of tyrosine 25 kinases.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase {Btk), a member ofthe Tee family 30 of non-receptor tyrosine kinases, is a key signa1ing enzyme expressed in all hematopoietic cells types except T lympho cytes and natural killer cells. Btk plays an essential role in the wherein: B-cell signaling pathway linking cell surface B-cell receptor La is CH2, 0, NH or S; (BCR) stimulation to downstream intracellular responses. 35 Ar is a substituted or unsubstituted aryl, or a substituted or Btk is a key regulator of B-cell development, activation, unsubstituted heteroacyl; signa1ing, and survival (Kurosaki, Curr Op Imm, 2000, 276- Y is an optionally substituted group selected from among 281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282- alkyl, heteroalkyl, cycloalkyl, beterocycloalkyl, aryl, 288). In addition, Btk plays a role in a number of other and heteroaryl; hematopoetic cell signaling pathways, e.g., Toll like receptor 40 Z is C(=O), OC(=O), NHC(-0), C{-S), S(=O), {TLR) and cytok.ine receptor-mediated TNF -a production in OS(=D), NHS(=O), where xis I or 2; macrophages, lgE receptor (FcepsilonRI) signaling in Mast R7 and R8 are independently selected from among H, cells, inhibition of Fas/AP0-1 apoptotic signaling in B-lin unsubstituted C 1-C4 alkyl, substituted C 1-C4 alkyl, eage lymphoid cells, and collagen-stimulated platelet aggre unsubstituted C1-C4 heteroalkyl, substituted gation. See, e.g., C. A. Jeffries, et al., (2003), Journal of 45 C1-CJ!eteroalkyl, unsubstituted C3 -C6cycloalkyl, sub- Biological Chemistry 278:26258-26264; N. J. Horwood, et stituted C3 -C6cycloalkyl, unsubstituted al., (2003), The Journal ofExperimental Medicine 197:1603- C -C heterocycloalkyl, and substituted of Biological Chemistry 2 6 1611; Iwaki et al. (2005), Journal CrC heterocycloalkyl; or 280(48):40261-40270; Vassi!ev eta!. (1999), Journal ofBio 6 ~ and R taken together form a bond; logical Chemistry 27 4(3 ): 1646-1656, and Quek eta!. (1998), so 5 R isH, substituted or unsubstituted C -C alkyl, substi Curnmt Biology 8(20): 1137-1140. 6 1 4 tuted or unsubstituted C1-C4 heteroalkyl, substituted SUMMARY OF THE INVENTION C 1-C6alkoxyalky1, C1-C8alkylaminoalkyl, or unsubstituted C3 -C6cycloalkyl, substituted or unsub- Described herein are inhibitors ofBruton's tyrosine kinase 55 stituted acyl, substituted or unsubstituted (Btk). Also described herein are irreversible inhibitors ofBtk. C2 -C8heterocycloalky I, substituted or unsubstituted bet- Further described are irreversible inhibitors ofBtk that form eroaryl, C1-C4alkyl(aryl), C1-C4 alkyl(heteroaryl), a covalent bond with a cysteine residue on Btk. Further C 1-C4alkyi(C,-C8cycloalkyl), or C 1-C4alkyi(C, described herein are irreversible inhibitors of other tyrosine C8heterocycloalkyl); and k.inases, wherein the other tyrosine kinases share homology 60 pharmaceutically active metabolites, or pharmaceutically with Btk by having a cysteine residue (including a Cys 481 acceptable solvates, pharmaceutically acceptable salts, or residue) that can form a covalent bond with the irreversible pharmaceutically acceptable prodrugs thereof. inhibitor (such tyrosine kinases, are referred herein as "Btk For any and all of the embodiments, substituents can be tyrosine kinase cysteine homo logs"). Also described herein selected from among from a subset of the listed alternatives. are methods for synthesizing such irreversible inhibitors, 65 For example, in some embodiments, La is CH2 , 0, or NH. In methods for using such irreversible inhibitors in the treatment other embodiments, La is 0 or NH. In yet other embodiments, of diseases (including diseases wherein irreversible inhibi- LaisO. US 8,008,309 B2 3 4 In some embodiments, A:r is a substituted or unsubstituted piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4- aryl In yet other embodiments, Ar is a 6~membered aryl. In amino-3-( 4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin- some other embodiments, AI is phenyl. 1-yl)piperidin-I-yl)prop-2-en-l-one (Compound 9); N-((Is, In some embodiments, xis 2. In yet other embodiments, Z 4s)-4-( 4-amino-3-(4- phenoxyphenyl)-1 H-pyrazolo [3 ,4-d] is C(-0), OC( 0), NHC(=O), S( 0), OS(-O)x, or 5 pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); NHS(=O). In some other embodiments, Z is C(=O), NHC 1-((R)-3-(4-amino-3-(4-phenoxyphenyi)-IH-pyrazolo[3,4- (-0), or 8(=0)2 . d]pyrimidin-l-y l)pyrrolidin-1-y I)prop- 2-en-1-one (Com In some embodiments, R7 and R8 are independently pound II); 1-((S)-3-( 4-arnino-3-(4-phenoxyphenyi)-IH selected from among H, unsubstituted C1 -C4 alkyl, substi pyrazolo [3 ,4-d]pyrimidin-I -yl)pyrrolidin-I -yl )prop-2-en-1- tuted C1-C4 alky1, unsubstituted C1-CJ1eteroa1ky1, and sub- 10 one (Compound 12); 1-((R)-3-(4-arnino-3-(4- stituted C -C heteroalkyl; or R and R taken together form a 1 4 7 8 phenoxyphenyl)-I H -pyrazolo[3,4-d]pyrimidin-1-yl) bond. In yet other embodiments, each ofR and R isH; or R 7 8 7 piperidin-1-ylprop-2-en-1-one (Compound 13); 1-((S)-3-(4- and R8 taken together form a bond. In some embodiments, R is I-1, substituted orunsubstituted arnino-3-(4-phenoxypheny I)-I H -pyrazolo[3,4-d]pyrimidin- 6 1-yl)piperidin-1-yl)prop-2-en-l-one (Compound 14); and C -C a1kyl, substituted or unsubstituted C -C heteroalkyl, 15 1 4 1 4 (E)-1-(3 -( 4-amino-3-(4-phenoxyphenyl )-1 H-pyrazolo[3,4- C 1-C 6a1koxyalkyl, C 1-C2 alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstitutcd hcteroaryl, d]pyrimidin-I -yl)piperidin-I -yl)-4-(dimethylamino )but-2- en-1-one (Compound 15). C, -C4 alkyl(aryl), C, -C4 alkyl(beteroaryl), c, -C4 alkyi(C3- In a further aspect are provided pharmaceutical composi C8cycloalkyl), or C,-C4 alkyi(C2 -C 8heterocycloalkyl). In some other embodiments, R6 is H, substituted or unsubsti- 20 tions, which include a therapeutically effective amount of at tutcd C1-C4 alkyl, substituted or unsubstituted least one of any of the compounds herein, or a pharmaceuti C, -C4 heteroalkyl, c, -C 6 alkoxyalkyl, C,-C2alkyi-N(C,- cally acceptable salt, pharmaceutica11y active metabolite, C3alkyl)2 , C, -C4 alkyl(aryl), C,-C4alkyl(heteroaryl), pharmaceutically acceptable prodrug, or pharmaceutically c, -C4 alkyi(C3-C8cycloalkyl), or c, -C4 alkyi(C2 - acceptable solvate. In certain embodiments, compositions C8heterocycloalkyl). In yet other embodiments, R6 isH, sub- 25 provided herein further include a pharmaceutically accept stituted or unsubstituted C1-C4alkyl, ---CH2..--.--Q...... -(C 1- able diluent, excipient and/or binder. C3alkyl), -CH2-N(C,-C3alkyl), C,-C4 alkyl(phenyl), or Pharmaceutical compositions formulated for administra C1-C4alkyl(5- or 6-membered heteroaryl). In yet other tion by an appropriate route and means containing effective embodiments, R6 is H, substituted or unsubstituted concentrations of one or more of the compounds provided C,-C4 alkyl, -CH2-0-(C,-C3alkyl), -CH-(C,- Jo herein, or pharmaceutically effective derivatives thereof, that C,alkylamino), C,-C4 alkyl(phenyl), or C,-C4 alkyl(5- or deliver amounts effective for the treatment, prevention, or 6-membered heteroaryl). In some embodiments, 1% is H, amelioration of one or more symptoms of diseases, disorders substituted or unsubstituted C 1-C4 alkyl, ---CH2-0-(C1 - or conditions that are modulated or otherwise affected by C3alkyl), -CI-!2-N(C, -C3alkyl),, C, -C4 alkyl(phenyl), or tyrosine kinase activity, or in which tyrosine kinase activity is C1-C4alkyl(5- or 6-memberedhctcroaryl containing 1 or 2 N 35 implicated, are provided. The effective amounts and concen atoms), or C1-C4alkyl(5- or 6-membered heterocycloalkyl trations are effective for ameliorating any of the symptoms of containing 1 or 2 N atoms). any of the diseases, disorders or conditions disclosed herein. In some embodiments, Y is an optionally substituted group In certain embodiments, provided herein is a pharmaceu selected from among alkyl, heteroalkyl, cycloalkyl, and het tical composition containing: i) a physiologically acceptable erocycloalkyl. In other embodiments, Y is an optionally sub- 40 carrier, diluent, and/or excipient; and ii) one or more com stituted group selected from among C1-C6alkyl, pounds provided herein. C1-C 6heteroalkyl, 4-, 5-, 6-, or ?-membered cycloalkyl, and In one aspect, provided herein are methods for treating a 4-, 5-, 6-, or ?-membered heterocycloalkyl. In yet other patient by administering a compound provided herein. In embodiments, Y is an optionally substituted group selected some embodiments, provided herein is a method of inhibiting from among C1-C6alky1, C1-C6heteroalkyl, 5- or 6-mem- 45 the activity oftyrsoine kinase(s), such as Btk, or of treating a bered cycloalkyl, and 5- or 6-membered heterocycloalkyl disease, disorder, or condition, which would benefit from containing 1 or 2 N atoms. In some other embodiments, Y is inhibition of tyrosine kinase(s), such as Btk, in a patient, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered het which includes administering to the patient a therapeutically erocycloalkyl containing 1 or 2 N atoms. In some embodi effective amount of at least one of any of the compounds ments, Y is a 4-, 5-, 6-, or ?-membered cycloalkyl ring; orY so herein, orphannaceutically acceptable salt, pharmaceutically is a 4-, 5-, 6-, or ?-membered heterocycloalkyl ring. active metabolite, pharmaceutically acceptable prodrug, or Any combination of the groups described above for the pharmaceutically acceptable solvate. various variables is contemplated herein. It is understood that In another aspect, provided herein is the use ofa compound substituents and substitution patterns on the compounds pro disclosed herein for inhibiting Bruton's tyrosine kinase (Btk.) vided herein can be selected by one of ordinary skill in the art 55 activity or for the treatment of a disease, disorder, or condi to provide compounds that are chemically stable and that can tion, which would benefit from inhibition of Bruton's be synthesized by techniques known in the art, as well as tyrosine kinase (Btk) activity. those set forth herein. In some embodiments, compounds provided herein are In one aspect, provided herein is a compound selected from administered to a human. among: 1-(3-(4-amino-3-( 4-phenoxyphenyl)-lH-pyrazolo 60 In some embodiments, compounds provided herein are [3,4-d] pyrimidin -I-yl)pi peridin-1-y !)prop-2-en-1-one orally administered. (Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)- In other embodiments, compounds provided herein are 1H -pyrazolo[3,4-d]pyrimidin-l-y I)piperidin-1-y !)but-2-en- used for the formulation of a medicament for the inhibition of 1-one (Compound 5); 1-(3-(4-amino-3-(4-pheooxyphenyl)- tyrosine kinase activity. In some other embodiments, com- 1H-pyrazolo[3,4-d]pyrimidin- I -yl)piperidin-1-yl) 65 pounds provided herein are used for the formulation of a sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4- medicament for the inhibition of Bruton's tyrosine kinase phenoxypheny I)-I H-pyrazolo[3 ,4-d] pyrimidin -I-yl) (Btk) activity. US 8,008,309 B2 5 6 Articles of manufacture including packaging material, a In certain embodiments, the subject in need is suffering compound or composition or pharmaceutically acceptable from an inflammatory disease, e.g., asthma, appendicitis, ble derivative thereof provided herein, which is effective for pharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholan inhibiting the activity of tyrosine kinase(s), such as Btk, gitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoad within the packaging material, and a label that indicates that enitis, dermatitis, dermatomyositis, encephalitis, the compound or composition, or pharmaceutically accept endocarditis, endometritis, enteritis, enterocolitis, epi able salt, pharmaceutically active metabolite, pharmaceuti condylitis, epididymitis, fasciitis, fibrositis, gastritis, gastro cally acceptable pro drug, or pharmaceutically acceptable sol enteritis, hepatitis, hidradenitis suppurativa, laryngitis, mas titis, meningitis, myelitis myocarditis, myositis, nephritis, vate thereof, is used for inhibiting the activity of tyrosine 10 oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, kinase(s), such as Btk, are provided. pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, In another aspect are inhibited tyrosine kinases comprising pneumonitis, pneumonia, proctitis, prostatitis, pyelonephri a Bruton's tyrosine kinase, a Bruton's tyrosine kinase tis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, ten homolog, or a Btk tyrosine kinase cysteine homolog thereof donitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. covalently bound to an inhibitor having the structure: 15 In further embodiments, the subject in need is suffering from a cancer. In one embodiment, the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, fo11icular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leuke- 20 mia, lymphoplasmacytic lymphoma/WaldenstrOm macroglo bulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, 25 intravascular large B cell lymphoma, primary effusion lym phoma, burkitt lymphoma/leukemia, or lymnphomatoid granulomatosis. In some embodiments, where the subject is suffering from a cancer, an anti-cancer agent is administered to the subject in addition to one of the above-mentioned 30 compounds. In one embodiment, the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002. wherein """"indicates the point of attachment between the 35 In further embodiments, the subject in need is suffering inhibitor and the tyrosine kinase. In a further embodiment the from a thromboembolic disorder, e.g., myocardial infarct, inhibitor is covalently bound to a cysteine residue on the angina pectoris, reocclusionafter angioplasty, restenosis after tyrosine kinase. angioplasty, reocclusion after aortocoronary bypass, resteno In a further aspect, provided herein is a method for inhib sis after aortocoronary bypass, stroke, transitory ischemia, a iting Bruton's tyrosine kinase in a subject in need thereof by 40 peripheral arterial occlusive disorder, pulmonary embolism, administering to the subject thereof a composition containing or deep venous thrombosis. a therapeutically effective amount of at least one compound In a further aspect, provided herein is a method for treating having the structure of any of Formula (A), Formula (B), an autoimmune disease by administering to a subject in need Formula (C), or Formula (D). In some embodiments, the thereof a composition containing a therapeutically effective subject in need is suffering from an autoimmune disease, e.g., 45 amount of at least one compound having the structure of any ofFormula (A), Formula(B), Formula (C), or Formula (D).ln inflammatory bowel disease, arthritis, lupus, rheumatoid one embodiment, the autoimmune disease is arthritis. In arthritis, psoriatic arthritis, osteoarthritis, Still's disease, another embodiment, the autoimmune disease is lupus. In juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's some embodiments, the autoimmune disease is inflammatory thyroiditis, Ord's thyroiditis, Graves' disease SjOgren's syn- 50 bowel disease (including Crohn's disease and ulcerative coli drome, multiple sclerosis, Guillain-Barre syndrome, acute tis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, disseminated encephalomyelitis,Addison's disease, opsoclo Still's disease, juvenile arthritis, lupus, diabetes, myasthenia nus-myoclonus syndrome, ankylosing spondylitisis, gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' antiphospholipid antibody syndrome, aplastic anemia, disease SjOgren's syndrome, multiple sclerosis, Guillain autoimmune hepatitis, coeliac disease, Goodpasture's syn- ss Barre syndrome, acute disseminated encephalomyelitis, drome, idiopathic thrombocytopenic purpura, optic neuritis, Addison's disease, opsoclonus-myoclonus syndrome, anky- scleroderma, primary biliary cirrhosis, Reiter's syndrome, losing spondylitisis, antiphospholipid antibody syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune aplastic anemia, autoimmune hepatitis, coeliac disease, hemolytic anemia, Wegener's granulomatosis, psoriasis, Goodpasture's syndrome, idiopathic thrombocytopenic pur alopecia universalis, Behc;et's disease, chronic fatigue, dys- 60 pura, optic neuritis, scleroderma, primary biliary cirrhosis, autonomia, endometriosis, interstitial cystitis, neuromyoto Reiter's syndrome, Takayasu's arteritis, temporal arteritis, nia, scleroderma, or vulvodynia. warm autoimmune hemolytic anemia, Wegener's granuloma In other embodiments, the subject in need is suffering from tosis, psoriasis, alopecia universalis, Behc;et's disease, a heteroimmune condition or disease, e.g., graft versus host chronic fatigue, dysautonomia, endometriosis, interstitial disease, transplantation, transfusion, anaphylaxis, allergy, 6? cystitis, neuromyotonia, scleroderma, or vulvodynia. type I hypersensitivity, allergic conjunctivitis, allergic rhini- In a further aspect, provided herein is a method for treating tis, or atopic dermatitis. a heteroimmune condition or disease by administering to a us 8,008,309 82 7 8 subject in need thereof a composition containing a therapeu forms a covalent bound with the activated form of Bruton's tically effective amount of at least one compound having the tyrosine kinase. In further or alternative embodiments, the structure of any of Formula (A), Formula (B), Formula (C), or compound irreversibly inhibits the Bruton's tyrosine kinase Formula (D). In some embodiments, the heteroimmune con to which it is covalently bound. In a further or alternative dition or disease is graft versus host disease, transplantation, 5 embodiment, the compound forms a covalent bond with a transfusion, anaphylaxis, a11ergy, type I hypersensitivity, cysteine residue on Bruton's tyrosine kinase. allergic conjunctivitis, allergic rhinitis, or atopic dermatitis. In a further aspect, provided herein is a method for treating In a further aspect, provided herein is a method for treating a heteroimmune condition or disease by administering to a an inflammatory disease by administering to a subject in need subject in need thereof a composition containing a therapeu thereof a composition containing a therapeutically effective 10 tically effective amount of a compound that forms a covalent amount of at least one compound having the structure of any bond with Bruton's tyrosine kinase. In one embodiment, the ofFormula (A), Formula (B), Formula (C), or Formula (D). In some embodiments, the inflammatory disease is asthma, compound forms a covalent bound with the activated form of inflammatory bowel disease (including Crohn's disease and Bruton's tyrosine kinase. In further or alternative embodiments, the compound irreversibly inhibits the Bruton's ulcerative colitis), appendicitis, blepharitis, bronchiolitis, 15 bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, coli- tyrosine kinase to which it is covalently bound. In a further or tis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, der alternative embodiment, the compound forms a covalent matomyositis, encephalitis, endocarditis, endometritis, bond with a cysteine residue on Bruton's tyrosine kinase. enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, In a further aspect, provided herein is a method for treating fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis sup- 20 an inflammatory disease by administering to a subject in need purativa, laryngitis, mastitis, meningitis, myelitis myocardi- thereof a composition containing a therapeutically effective tis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, amount of a compound that forms a covalent bond with Bru- pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, ton's tyrosine kinase. In one embodiment, the compound pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, pros forms a covalent bound with the activated form of Bruton's tatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomati- 25 tyrosine kinase. In further or alternative embodiments, the tis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vascu compound irreversibly inhibits the Bruton's tyrosine kinase litis, or vulvitis. to which it is covalently bound. In a further or alternative In yet another aspect, provided herein is a method for embodiment, the compmmd forms a covalent bond with a treating a cancer by administering to a subject in need thereof cysteine residue on Bruton's tyrosine kinase. In yet another a composition containing a therapeutically effective amount 30 aspect, provided herein is a method for treating a cancer by of at least one compound having the structure of any of administering to a subject in need thereof a composition Formula (A), Formula (B), Formula (C), or Formula (D). In containing a therapeutically effective amount of a compound one embodiment the cancer is a B-cell proliferative disorder, that fOrms a covalent bond with Bruton's tyrosine kinase. In e.g., diffuse large B cell lymphoma, follicular lymphoma, one embodiment, the compound forms a covalent bound with chronic lymphocytic lymphoma, chronic lymphocytic leuke- 35 the activated form of Bruton's tyrosine kinase. In further or mia, B-cell prolymphocytic leukemia, lymphoplasmacytic alternative embodiments, the compound irreversibly inhibits lymphoma/Waldenstrom macroglobulinemia, splenic mar the Bruton's tyrosine kinase to which it is covalently bound. ginal zone lymphoma, plasma cell myeloma, plasmacytoma, In a further or alternative embodiment, the compound forms extranodal marginal zone B cell lymphoma, nodal marginal a covalent bond with a cysteine residue on Bruton's tyrosine zone B cell lymphoma, mantle cell lymphoma, mediastinal 40 kinase. In another aspect, provided herein is a method for (thymic) large B cell lymphoma, intravascular large B cell treating a thromboembolic disorder by administering to a lymphoma, primary effusion lymphoma, burkitt lymphoma/ subject in need thereof a composition containing a therapeu leukemia, or lymphomatoid granulomatosis. In some tically effective amount of a compound that forms a covalent embodiments, where the subject is suffering from a cancer, an bond with Bruton's tyrosine kinase. In one embodiment, the anti-cancer agent is administered to the subject in addition to 45 compound forms a covalent bound with the activated form of one of the above-mentioned compounds. In one embodiment, Bruton's tyrosine kinase. In further or alternative embodi- the anti-cancer agent is an inhibitor of mitogen-activated ments, the compound irreversibly inhibits the Bruton's protein kinase signaling, e.g., U0126,PD98059, PD1184352, tyrosine kinase to which it is covalently bound. In a further or PD0325901, ARRY-142886, SB239063, SP600125, BAY alternative embodiment, the compound forms a covalent 43-9006, wortmannin, or LY294002. so bond with a cysteine residue on Bruton's tyrosine kinase. In another aspect, provided herein is a method for treating In another aspect are methods for modulating, including a thromboembolic disorder by administering to a subject in irreversibly inhibiting the activity of Btk or other tyrosine need thereof a composition containing a therapeutically kinases, wherein the other tyrosine kinases share homology effective amount of at least one compound having the struc with Btk by having a cysteine residue (including a Cys 481 ture of any of Formula (A), Formula (B), Formula (C), or 55 residue) that can form a covalent bond with at least one Formula (D). In some embodiments, the thromboembolic irreversible inhibitor described herein, in a mammal compris- disorder is myocardial infarct, angina pectoris, reocclusion ing administering to the mammal at least once an effective after angioplasty, restenosis after angioplasty, reocclusion amount of at least one compound having the structure of any after aortocoronruy bypass, restenosis after aortocoronary ofFormula (A), Formula (B), Formula (C), or Formula (D). In bypass, stroke, transitory ischemia, a peripheral arterial 60 another aspect are methods for modulating, including irre occlusive disorder, pulmonary embolism, or deep venous versibly inhibiting, the activity ofBtk in a mammal compris- thrombosis. ing administering to the mammal at least once an effective In a further aspect, provided herein is a method for treating amount of at least one compound having the structure of any an autoimmune disease by administering to a subject in need ofFormula (A), Formula (B), Formula (C), or Formula (D). In thereof a composition containing a therapeutically effective 65 another aspect are methods for treating Btk-dependent or Btk amount of a compound that forms a covalent bond with Bru mediated conditions or diseases, comprising administering to ton's tyrosine kinase. In one embodiment, the compound the mammal at least once an effective amount of at least one US 8,008,309 B2 9 10 compound having the structure of any of Formula (A), For- mammal; (h) the effective amountofthe compound is admin- mula (B), Formula (C), or Formula (D). istered by ophthalmic administration; or (i) the effective In another aspect are methods for treating inflammation amount ofthe compound is administered rectally to the mam- comprising administering to the mammal at least once an mal. effective amount of at least one compound having the struc- In any of the aforementioned aspects are further embodi- ture of Formula (A), (B), (C), or (D). ments comprising single administrations of the effective A further aspect are methods for the treatment of cancer amount of the compound, including further embodiments in comprising administering to the mammal at least once an which (i) the compound is administered once; (ii) the com- effective amount of at least one compound having the struc~ pound is administered to the mammal multiple times over the ture ofFormula (A), (B), (C), or (D). The type of cancer may 10 span of one day; (iii) continually; or (iv) continuously. include, but is not limited to, pancreatic cancer and other solid In any of the aforementioned aspects are further embodi~ or hematological tumors. ments comprising multiple administrations of the effective In another aspect are methods for treating respiratory dis~ amount of the compound, including further embodiments in eases comprising administering to the mammal at least once which (i) the compound is administered in a single dose; (ii) an effective amount of at least one compound having the 15 the time between multiple administrations is every 6 hours; structureofFormula(A),(B),(C),or(D).Inafurtherembodi~ (iii) the compound is administered to the mammal every 8 ment of this aspect, the respiratory disease is asthma. In a hours. In further or alternative embodiments, the method further embodiment of this aspect, the respiratory disease comprises a drug holiday, wherein the administration of the includes, but is not limited to, adult respiratory distress syn~ compound is temporarily suspended or the dose of the com- drome and allergic (extrinsic) asthma, non-allergic (intrinsic) 20 pound being administered is temporarily reduced; at the end asthma, acute severe asthma, chronic asthma, clinical asthma, of the drug holiday, dosing of the compound is resumed. The nocturnal asthma, allergen~ induced asthma, aspirin~sensitive length of the drug holiday can vary from 2 days to 1 year. asthma, exercise~ induced asthma, isocapnic hyperventila~ In any of the aforementioned aspects involving the treat~ tion, child~onset asthma, adult~onset asthma, cough~variant ment of proliferative disorders, including cancer, are further asthma, occupational asthma, steroid-resistant asthma, sea~ 25 embodiments comprising administering at least one addi~ sana] asthma, tiona! agent selected from the group consisting of alemtu- In another aspect are methods for preventing rheumatoid zumab, arsenic trioxide, asparaginase (pegylated or non-), arthritis and osteoartluitis comprising administering to the bevacizumab, cetuximab, platinum~based compounds such mammal at least once an effective amount of at least one as cisplatin, cladribine, daunorubicin/doxorubicin/idarubi- compound having the structure of Formula (A), (B), (C), or 30 cin, irinotecan, ftudarabine, 5-ftuorouracil, gemtuzumab, (D). methotrexate, Paclitaxel™, taxol, temozolomide, thiogua- In another aspect are methods for treating inflammatory nine, or classes ofdrugs including hormones (an antiestrogen, responses of the skin comprising administering to the roam- an antiandrogen, or gonadotropin releasing hormone ana~ mal at least once an effective amount of at least one com- logues, interferons such as alpha interferon, nitrogen mus- pound having the structure of Formula (A), (B), (C), or (D). 35 tards such as busulfan or melphalan or mechlorethamine, Such inflammatory responses of the skin include, by way of retinoids such as tretinoin, topoisomerase inhibitors such as example, dermatitis, contact dermatitis, eczema, urticaria, irinotecan or topotecan, tyrosine kinase inhibitors such as rosacea, and scarring. In another aspect are methods for gefinitinib or imatinib, or agents to treat signs or symptoms reducing psoriatic lesions in the skin,joints, or other tissues or induced by such therapy including allopurinol, filgrastim, organs, comprising administering to the mammal an effective 40 granisetron/ondansetron/palonosetron, dronabinol. amount of a first compound having the structure of Formula In any ofthe aforementioned aspects involving the preven~ (A), (B), (C), or (D). tion or treatment of Btk~dependent or tyrosine kinase medi~ In another aspect is the use of a compound of Formula (A), ated diseases or conditions are further embodiments compris- (B), (C), or (D) in the manufacture of a medicament for ing identifying patients by screening for a tyrosine kinase treating an inflammatory disease or condition in an animal in 45 gene haplotype. In further or alternative embodiments the which the activity of Btk or other tyrosine kinases, wherein tyrosine kinase gene haplotype is a tyrosine kinase pathway the other tyrosine kinases share homology with Btk by having gene, while in still further or alternative embodiments, the a cysteine residue (including a Cys 481 residue) that can form tyrosine kinase gene haplotype is a Btk haplotype. a covalent bond with at least one irreversible inhibitor In a further or alternative embodiment, the compound of described herein, contributes to the pathology and/or symp- so formula (A), (B), (C) or (D) are irreversible inhibitors of toms of the disease or condition. In one embodiment ofthis Bruton's tyrosine kinase (Btk), while in still further or alter- aspect, the tyrosine kinase protein is Btk. In another or further native embodiments, such irreversible inhibitors are selective embodiment of this aspect, the inflammatory disease or con- for Btk. In even further or alternative embodiments, such ditions are respiratory, cardiovascular, or proliferative dis~ inhibitors have an IC50 below 10 microM in enzyme assay. In eases. 55 one embodiment, a Btk irreversible inhibitor has an IC50 of In any of the aforementioned aspects are further embodi~ less than 1 microM, and in another embodiment, less than ments in which administration is enteral, parenteral, or both, 0.25 microM. and wherein (a) the effective amount of the compound is In further or alternative embodiment, the compound of systemically administered to the mammal; (b) the effective formula ((A), (B), (C) or (D) are selective irreversible inhibi- amount of the compound is administered orally to the mam~ 60 tors for Btk over Lck. In further or alternative embodiment, mal; (c) the effective amount of the compound is intrave~ the compound of formula (A), (B), (C) or (D) are selective nously administered to the mammal; (d) the effective amount irreversible inhibitors for Btk over Lck. In further or alterna- ofthe compound administered by inhalation; (e) the effective tive embodiment, the compound of formula (A), (B), (C) or amount of the compound is administered by nasal adminis- (D) are selective irreversible inhibitors for Btk over ABL. In tration; or (f) the effective amount of the compound is admin- 65 further or alternative embodiment, the compound of formula istered by injection to the mammal; (g) the effective amount (A), (B), (C) or(D)are selective irreversible inhibitors for Btk of the compound is administered topically (dermal) to the over CMET. In further or alternative embodiment, the com- US 8,008,309 B2 11 12 poundofformula (A), (B), (C) or(D) are selective irreversible recombinant DNA, oligonucleotide synthesis, and tissue cul inJribitors for Btk over EGFR. In further or alternative ture and transformation (e.g., electroporation, lipofection). embodiment, the compound of formula (A), (B), (C) or (D) Reactions and purification techniques can be performed e.g., are selective irreversible inhibitors for Btk over Lyn. using kits of manufacturer's specifications or as commonly In further or alternative embodiments, the irreversible Btk 5 accomplished in the art or as described herein. The foregoing inhibitors are also inhibitors of EGFR. techniques and procedures can be generally performed of Other objects, features and advantages of the methods and conventional methods well known in the art and as described compositions described herein will become apparent from the in various general and more specific references that are cited following detailed description. It should be understood, how and discussed throughout the present specification. ever, that the detailed description and the specific examples, 10 It is to be understood that the methods and compositions while indicating specific embodiments, are given by way of described herein are not limited to the particular methodol iilustration only, since various changes and modifications within the spirit and scope of the present disclosure will ogy, protocols, cell lines, constructs, and reagents described become apparent to those skilled in the art from this detailed herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing description. The section headings used herein are for organi- 15 zational purposes only and are not to be construed as limiting particular embodiments only, and is not intended to limit the the subject matter described. All documents, or portions of scope of the methods and compositions described herein, documents, cited in the application including, but not limited which will be limited only by the appended claims. to, patents, patent applications, articles, books, manuals, and All publications and patents mentioned herein are incor treatises are hereby expressly incorporated by reference in 20 porated herein by reference in their entirety for the purpose of their entirety for any purpose. describing and disc1osing, for example, the constructs and Certain Terminology methodologies that are described in the publications, which Unless defined otherwise, all technical and scientific terms might be used in connection with the methods, compositions used herein have the same meaning as is commonly under and compounds described herein. The publications discussed stood by one of skill in the art to which the claimed subject 25 herein are provided solely for their disclosure prior to the matter belongs. In the event that there are a plurality of defi filing date of the present application. Nothing herein is to be nitions for terms herein, those in this section prevail. Where construed as an admission that the inventors described herein reference is made to a URL or other such identifier or address, are not entitled to antedate such disclosure by virtue of prior it is understood that such identifiers can change and particular invention or for any other reason. information on the internet can come and go, but equivalent 30 An "alkyl" group refers to an aliphatic hydrocarbon group. information can be found by searching the internet Reference The alkyl moiety may be a "saturated alkyl'' group, which thereto evidences the availability and public dissemination of means that it does not contain any alkene or alkyne moieties. such information. The alkyl moiety may also be an "unsaturated alkyl" moiety, It is to be understood that the foregoing general description which means that it contains at least one alkene or alkyne and the following detailed description are exemplary and 35 moiety. An "alkene" moiety refers to a group that has at least explanatory only and are not restrictive of any subject matter one carbon-carbon double bond, and an "alkyne" moiety claimed. In this application, the use of the singular includes refers to a group that has at least one carbon-carbon triple the plural unless specifically stated otherwise. It must be bond. The alkyl moiety, whether saturated or unsaturated, noted that, as used in the specification and the appended may be branched, straight chain, or cyclic. Depending on the claims, the singular forms "a," "an" and "the" include plural 40 structure, an alkyl group can be a monoradical or a diradical referents unless the context clearly dictates otheiWise. In this (i.e., an alkylene group). The alkyl group could also be a application, the use of "or" means "and/or'' unless stated "lower alkyl" having 1 to 6 carbon atoms.

otherwise. Furthermore, use of the term "including" as well As used herein, C 1-Cx includes C 1-C2, C 1 -C3 ••• C1-Cx. as other forms, such as "include", "includes," and "included," The "alkyl" moiety may have 1 to 10 carbon atoms (when- is not limiting. 45 ever it appears herein, a numerical range such as "1 to 10" The section headings used herein are for organizational refers to each integer in the given range; e.g., "1 to 10 carbon purposes only and are not to be construed as limiting the atoms" means that the alkyl group may have I carbon atom, 2 subject matter described. All documents, or portions of docu carbon atoms, 3 carbon atoms, etc., up to and including 10 ments, cited in the application including, but not limited to, carbon atoms, although the present definition also covers the patents, patent applications, articles, books, manuals, and so occurrence of the term "alkyl" where no numerical range is treatises are hereby expressly incorporated by reference in designated). The alkyl group of the compounds described their entirety for any purpose. herein may be designated as "C1-C4 alkyl" or similar desig Defmition of standard chemistry terms may be found in nations. By way of example only, "C1-C4 alley 1" indicates that reference works, including Carey and Sundberg ''ADvANcED there are one to four carbon atoms in the alkyl chain, i.e., the ORGANIC CHEMISTRY 47H Eo". Vols. A (2000) and B (2001), 55 alkyl chain is selected from among methyl, ethyl, propyl, Plenum Press, New York. Unless otherwise indicated, con iso-propyl, n-butyl, iso-butyl, sec-butyl, and !-butyl. Thus

ventional methods of mass spectroscopy, NMR, HPLC, pro C1-C4 alkyl includes C 1-C2 alkyl and C 1-C3 alkyl. Alkyl tein chemistry, biochemistry, recombinant DNA techniques groups can be substituted or unsubstituted. Typical alkyl and pharmacology, within the skill of the art are employed. groups include, but are in no way limited to, methyl, ethyl, Unless specific definitions are provided, the nomenclature 60 propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, employed in connection with, and the laboratory procedures hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, and techniques of, analytical chemistry, synthetic organic cyclopentyl, cyclohexyl, and the like. chemistry, and medicinal and pharmaceutical chemistry As used herein, the term "non-cyclic alkyl" refers to an described herein are those known in the art. Standard tech alkyl that is not cyclic (i.e., a straight or branched chain niques can be used for chemical syntheses, chemical analy 65 containiD.g at least one carbon atom). Non-cyclic alkyls can ses, phannaceutical preparation, formulation, and delivery, be fully saturated or can contain non-cyclic alkenes and/or and treatment ofpatients. Standard techniques can be used for alkynes. Non-cyclic alkyls can be optionally substituted. US 8,008,309 B2 13 14 The term "alkenyl" refers to a type of alkyl group in which The term "ester'' refers to a chemical moiety with formula the first two atoms ofthe alkyl group form a double bond that ----COOR, where R is selected from among alkyl, cycloalkyl, is not part of an aromatic group. That is, an alkenyl group aryl, heteroaryl (bonded through a ring carbon) and hetei'oali begins with the atoms --C(R)=C(R)-R, wherein frefers to cyc!ic (bonded through a ring carbon). Any hydroxy, or car the remaining portions ofthe alkenyl group, which may be the s boxyl side chain on the compounds described herein can be same or different. The alkenyl moiety may be branched, esterified. The procedures and specific groups to make such straight chain, or cyclic (in which case, it would also be esters are known to those of skill in the art and can readily be known as a "cycloalkenyl" group). Depending on the strucR found in reference sources such as Greene and Wuts, Protec ture, an alkenyl group can be a monoradical or a diradical (i.e., tive Groups in Organic Synthesis, 3rd Ed., John Wiley & an alkenylene group). Alkenyl groups can be optionally sub- 10 Sons, New York, N.Y., 1999, which is incorporated herein by stiluted. Non-limiting examples of an alkenyl group include reference in its entirety. --CH=CH2 , --C(CH3 )=CH2 , -CH=CHCH3 , --C(CH3 ) As used herein, the term "ring" refers to any covalently =CHCH3 . Alkenylene groups include, but are not limited to, closed structure. Rings include, for example, carbocycles --CH-CH-, --C(CH3)=CH-, --CH=CHCH2-, (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls --CH=CHCH2CH2-and-C{CH3 )=CHCH2-.Alkenyl l5 and non-aromatic heterocycles), aromatics (e.g. aryls and groups could have 2 to 10 carbons. The alkenyl group could heteroaryls), and non-aromatics (e.g., cycloalkyls and non also be a "lower alkenyl" having 2 to 6 carbon atoms. aromatic heterocycles). Rings can be optionally substituted. The term "alkynyl" refers to a type of alkyl group in which Rings can be monocyclic or polycyclic. the first two atoms of the alkyl group form a triple bond. That As used herein, the term "ring" systems refers to one, or is, an alkynyl group begins with the atoms ~-R, 20 more than one ring. wherein R refers to the remaining portions of the alkynyl The term "membered ring" can embrace any cyclic struc group, which may be the same or different. The "R" portion of ture. The term "membered" is meant to denote the number of the alkynyl moiety may be branched, straight chain, or cyclic. skeletal atoms that constitute the ring. Thus, for example, Depending on the structure, an alkynyl group can be a mono cyclohexyl, pyridine, pyran and thiopyran are 6-membered radical or a diradical (i.e., an alkynylene group). Alkynyl 25 rings and cyclopentyl, pyrrole, furan, and thiophene are groups can be optionally substituted. Non-1imiting examples 5-membered rings. of an alkynyl group include, but are not limited to, ----C==CH, The term "fused" refers to structures in which two or more

-CfoECCH3 , -CfoECCH,CH3 , -~-, and rings share one or more bonds. --C=:a~H2-. Alkynyl groups can have 2 to 10 carbons. The term "carbocyclic" or "carbocycle" refers to a ring The alkynyl group could also be a "lower alkynyl" having 2 to 30 wherein each of the atoms forming the ring is a carbon atom. 6 carbon atoms. Carbocycle includes aryl and cycloalkyl. The term thus dis An "alkoxy" group refers to a (alkyl)O- group, where tinguishes carbocycle from heterocycle ("heterocyclic") in alkyl is as defined herein. which the ring backbone contains at least one atom which is "Hydroxyalkyl" refers to an alkyl radical, as defined different from carbon (i.e a heteroatom). Heterocycle herein, substituted with at least one hydroxy group. Non- 35 includes heteroaryl and heterocycloalky1. Carbocycles and limiting examples of a hydroxyalkyl include, but are not heterocycles can be optionally substituted. limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypro- The term "aromatic" refers to a planar ring having a delo py I, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, calized rc-electron system containing 4n+2rc electrons, where 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihy n is an integer. Aromatic rings can be formed from five, six, droxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihy- 40 seven, eight, nine, or more than nine atoms. Aromatics can be droxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3- optionally substituted The term "aromatic" includes both car hydroxypropy I. bocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "het ''Alkoxyalkyl" refers to an alkyl radical, as defined herein, eroaryl" or "heteroaromatic") groups (e.g., pyridine). The substituted with an alkoxy group, as defined herein. term includes monocyclic or fused-ring polycyclic (i.e., rings An "alkenyloxy" group refers to a (alkenyl)O- group, 45 which share adjacent pairs of carbon atoms) groups. where alkenyl is as defined herein. As used herein, the term "aryl" refers to an aromatic ring The term "alkylamine" refers to the -N(alkyl})ly group, wherein each of the atoms forming the ring is a carbon atom. where x andy are selected from among x=l, y=l and x=2, Aryl rings can be formed by five, six, seven, eight, nine, or y=O. When x=2, the alkyl groups, taken together with theN more than nine carbon atoms. Aryl groups can be optionally atom to which they are attached, can optionally form a cyclic so substituted. Examples of aryl groups include, but are not ring system. limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, "Alkylaminoalkyl" refers to an alkyl radical, as defined fluorenyl, and indenyl. Depending on the structure, an aryl herein, substituted with an alkylamine, as defined herein. group can be a monoradical or a diradical (i.e., an arylene An "amide" is a chemical moiety with the formula ----C(O) group). NHR or-NHC(O)R, where R is selected from runong alkyl, 55 An "aryloxy" group refers to an (aryl)O- group, where cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) aryl is as defined herein. and heteroalicyclic bonded through a ring carbon). An amide "Arakyl" means an alkyl radical, as defmed herein, substi moiety may form a linkage between an amino acid or a tuted with an aryl group. Non-limiting aralkyl groups include, peptide molecule and a compound described herein, thereby benzyl, phenethyl, and the like. forming a prodrug. Any amine, or carboxyl side chain on the 60 ''Aralkenyl" means an alkenyl radical, as defined herein, compounds described herein can be amidified. The proce substituted with an aryl group, as defmed herein. dures and specific groups to make such ami des are known to The term "cycloalkyl" refers to a monocyclic or polycyclic those of skill in the art and can readily be found in reference radical that contains only carbon and hydrogen, and may be sources such as Greene and Wuts, Protective Groups in saturated, partially 1msaturated, or fully unsaturated. Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, 65 Cycloalkyl groups include groups having from 3 to 10 ring N.Y., 1999, which is incorporated herein by reference in its atoms. Illustrative examples ofcycloalkyl groups include the entirety. following moieties: US 8,008,309 B2 15 16 ranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidi nyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thieta nyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydro- J;. [J> tb. · 5 pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H -pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, .imidazolinyl .imidazolidinyl, 3-azabicyclo W[>D·O·O· [3.l.O]hexanyl, 3-azabicyclo[4.l.O]heptanyl, 3H-indolyl and 10 quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, fury], thienyl, isoxazolyl, thiazolyl, Q.Q.(X) oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, 15 indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, ben 0>·~·0·0· zofurazanyl, benzothiophenyl, benzothiazolyl, benzox azolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furo pyridinyl. The foregoing groups, as derived from the groups 20 listed above, may be C-attached or N-attached where such is O·tb·OO=>· possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl or CO· CO· imidazol-3-yl (bothN-attached) orpyrrol-2-yl, imidazol-4-yl 25 or im.idazol-5-yl (all C-attached). The heterocyclic groups and the like. Depending on the structure, a cycloalkyl group include benzo-fuscd ring systems and ring systems substi can be a monoradical or a diradical (e.g., an cycloalkylene tuted with one or two oxo (=0) moieties such as pyrrolidin- group). The cycloalkyl group could also be a "lower 2-one. Depending on the structure, a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group). cycloalkyl" having 3 to 8 carbon atoms. 30 The term "heteroaryl" or, alternatively, "heteroaromatic" "Cycloalkylalkyl" means an alkyl radical, as defined refers to an aryl group that includes one or more ring heteroa herein, substituted with a cycloalkyl group. Non-limiting toms selected from nitrogen, oxygen and sulfur. AnN-con cycloalkylalkyl groups include cyclopropylmethyl, cyclobu taining "heteroaromatic" or "heteroaryl" moiety refers to an tylmethyl, cyclopeotylmethyl, cyclohexylmethyl, and the aromatic group in which at least one of the skeletal atoms of like. 35 the ring is a nitrogen atom. Illustrative examples ofheteroaryl The term "heterocycle" refers to heteroaromatic and het groups include the following moieties: eroalicyclic groups containing one to four heteroatoms each selected from 0, S and N, wherein each heterocyclic group has from 4 to I 0 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent 0 or 40 S atoms. Herein, whenever the number of carbon atoms in a

heterocycle is indicated (e.g., C 1-C6 heterocycle), at least one other atom (the heteroatom) must be present in the ring.

Designations such as "C1-C6 heterocyc1e" refer only to the number ofcarbon atoms in the ring and do not refer to the total 45 number of atoms in the ring.lt is understood that the hetero cylic ring can have additional heteroatoms in the ring. Des ignations such as "4-6 membered heterocycle" refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is so a carbon atom, at least one atom is a heteroatom and the remaining two to fOur atoms are either carbon atoms or het eroatoms). In heterocycles that have two or more heteroat oms, those two or more heteroatoms can be the same or different from one another. Heterocycles can be optionally 55 substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. Non-aromatic heterocyc1ic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring 60 and the 1ike. Depending on the structure, a heteroaryl group systems. An example of a 4-membered heterocyclic group is can be a monoradical or a diradical (i.e., a heteroarylene azetidinyl (derived from azetidine). An example of a 5-mem group). bered heterocyc1ic group is thiazolyl. An example of a As used herein, the term "non-aromatic heterocycle", "het 6-membered heterocyclic group is pyridyl, and an example of erocycloalkyl" or "heteroalicyclic" refers to a non-aromatic a I 0-membered heterocyclic group is quinolinyl. Examples 65 ring wherein one or more atoms forming the ring is a heteroa ofnon-aromatic heterocyclic groups are pyrrolidinyl, tetrahy tom. A ''non-aromatic heterocycle" or ''heterocycloalkyl" drofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropy- group refers to a cycloalkyl group that includes at least one US 8,008,309 B2 17 18 heteroatom selected from nitrogen, oxygen and sulfur. The halogen atom. In certain embodiments in which two or more radicals may be fused with an aryl or heteroaryl. Heterocy hydrogen atoms are replaced with halogen atoms, the halogen cloalkyl rings can be formed by three, four, five, six, seven, atoms are all the same as one another. In other embodiments eight, nine, or more than nine atoms. Heterocycloalkyl rings in which two or more hydrogen atoms are replaced with can be optionally substituted. In certain embodiments, non- 5 halogen atoms, the halogen atoms are not all the same as one aromatic heterocycles contain one or more carbonyl or thio another. carbonyl groups such as, for example, oxo- and thio-contain The term "ftuoroa1kyl," as used herein, refers to alkyl group ing groups. Examples of heterocycloalkyls include, but are in which at least one hydrogen is replaced with a fluorine not limited to, lactams, Jactones, cyclic imides, cyclic thio atom. Examples of ftuoroalkyl groups include, but are not imides, cyc1ic carbamates, tetrahydrothiopyran, 4H-pyran, 10 limited to, -CF3 , -CH2CF3 , --CF2 CF3 , -CH2CH2 CF3 tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-di and the like. oxin, I ,4-dioxane, piperazine, 1,3-oxathianc, I ,4.-oxathiin, As used herein, the terms ''heteroalkyl" "heteroalkenyl" 1,4-oxathiane, tetrahyd.ro-1 ,4-thiazine, 2H-1 ,2-oxazine, and ''heteroalkynyl" include optionally substituted alkyl, alk maleimide, succinimide, barbituric acid, thiobarbituric acid, enyl and alkynyl radicals in which one or more skeletal chain dioxopiperazine, hydantoin, dihydrouracil, morpholine, tri- 15 atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, oxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tet phosphorus or combinations thereof. The heteroatom(s) may rahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidi be placed at any interior position of the heteroalkyl group or one, pyrazoline, pyrazolidine, imidazoline, imidazolidine, at the position at which the heteroalkyl group is attached to 1,3-dioxole, I ,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isox the remainder of the molecule. Examples include, but are not azo1ine, isoxazolidine, oxazoline, oxazolidine, oxazolidi- 20 limited to, --CH2-0~CH3 , ~CH 2~CH 2-0-CH3 , none, thiazoline, thiazolidine, and 1,3-oxathiolane. Illustra -CH,-NH-C!-1,, -CH,-CH,-NH-C!-1,, -CH,- tive examples ofheterocycloalkyl groups, also referred to as N(CH,}---C!-12, -C!-12-CH,-NH-CH,, -CH, non-aromatic heterocycles, include: CH2-N(CH2)-CH2, -CH,-S-CH,-C!-12, -C!-1, C!-12, -S(O)-C!-12, -CH2-CH2-S(0)2-C!-12, 25 -CH=C!-1-0-CH,, -Si(CH,),, -C!-12-CH-N OCH,, and -CH=CH-N(CH,)-C!-12. In addition, up to __l\F__l__ljl two heteroatoms may be consecutive, such as, by way of example, -C!-12-NH-OCH, and -C!-12-0-Si(CH,),. \_] 0· \_I \_I The term ''heteroatom" refers to an atom other than carbon uo. 30 or hydrogen. Heteroatoms are typically independently 0 selected from among oxygen, sulfur, nitrogen, silicon and A N N N 0 phosphorus, but are not limited to these atoms. In embodi ments in which two or more heteroatoms are present, the two \_1' C/' 0· C} 0· or more heteroatoms can all be the same as one another, or 35 some or all of the two or more heteroatoms can each be different from the others. The term "bond" or "single bond" refers to a chemical bond (__). [> 0· (1. 0· between two atoms, or two moieties when the atoms joined by N N-N N the bond are considered to be part of larger substructure. 40 An "isocyanate" group refers to a -NCO group. An "isothiocyanato" group refers to a -NCS group. 0 s 0 ~ ]_ The term "moiety" refers to a specific segment or ftulc ()() I'()N 0, tional group of a molecule. Chemical moieties are often rec li li li liu ognized chemical entities embedded in or appended to a 45 molecule. 0 A "sulfinyl" group refers to a-S( 0)-R. o II A "sulfonyl" group refers to a -S(~Oh-R. bOO, coN , A "thioalkoxy" or "alkylthio" group refers to a-S-alkyl group. 50 A "alkylthioalkyl" group refers to an alkyl group substi tuted with aS-alkyl group. As used herein, the term "0-carboxy" or "acyloxy" refers N1 ~O) to a group of formula -C(-0)0-. £(;·~0 "Carboxy" means a --C(O)OH radical. 55 As used herein, the term "acetyl" refers to a group of formula -C(--O)CH,. and the like. The term heteroalicyclic also includes alJ ring ''Acyl" refers to the group -C(O)R. forms of the carbohydrates, including but not limited to the As used herein, the term "tribalomethanesulfonyl" refers to monosaccharides, the disaccharides and the oligosaccha a group of formula X3CS(=0)2- where X is a halogen. rides. Depending on the structure, a heterocycloalkyl group 60 As used herein, the term "cyano" refers to a group of can be a monoradical or a diradical (i.e., a heterocycloalky formula --CN. lene group). "Cyanoalkyl" means an alkyl radical, as defined herein, The term "halo" or, alternatively, "halogen" or "halide" substituted with at least one cyano group. means ftuoro, chloro, bromo and iodo. As used herein, the term "N-sulfonamido" or "sulfony- The terms "haloalkyl," "baloalkenyl," ''haloalkynyl" and 65 !amino" refers to a group of formula RS(=OhNH-. "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy As used herein, the term "0-carbamyl" refers to a group of structures in which at least one hydrogen is replaced with a formula -OC(=O)NR,. US 8,008,309 B2 19 20 As used herein, the term .. N~carbamyl" refers to a group of a protein that is of the same type as that resulting from the formula ROC(-O)NH-. presence of a naturally occurring ligand for the protein, but of As used herein, the term "0-thiocarbamyl" refers to a a lower magnitude. group offormula -DC(=S)NR2. As used herein the term "antagonist" refers to a compound, As used herein, the term "N-thiocarbamyl" refers to a the presence ofwhich results ina decrease in the magnitude of group offormula ROC{-S)NH-. a biological activity of a protein. In certain embodiments, the As used herein, the term "C-amido" refers to a group of presence of an antagonist results in complete inhibition of a formula -C(=O)NR2. biological activity of a protein, such as, for example, Btk. In "Aminocarbonyl" refers to a --CONH2 radical. certain embodiments, an antagonist is an inhibitor. 10 As used herein, the term "N-amido" refers to a group of As used herein, "amelioration" of the symptoms of a par- formula RC(=O)NH-. ticular disease, disorder or condition by administration of a As used herein, the substituent "R" appearing by itself and particular compound or pharmaceutical composition refers to without a number designation refers to a substituent selected any lessening of severity, delay in onset, slowing of progres- from among from alkyl cycloalkyl, aryl, heteroaryl (bonded 15 sian, or shortening of duration, whether permanent or tem through a ring carbon) and non-aromatic heterocycle (bonded porary, lasting or transient that can be attributed to or associ through a ring carbon). ated with administration of the compound or composition. The term "optionally substituted" or "substituted" means "Bioavailability" refers to the percentage of the weight of that the referenced group may be substituted with one or more compounds disclosed herein, such as, compounds of any of additional group(s) individually and independently selected 20 Formula (A), Formula (B), Formula (C), or Formula (D), from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicycJic, dosed that is delivered into the general circulation of the hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, animal or human being studied. The total exposure arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, (AUCco-oo)) of a drug when administered intravenously is nitro, haloalkyl, fiuoroalkyl, amino, including mono- and di usually defined as 1000/o bioavailable (F %). "Oral bioavail- substituted amino groups, and the protected derivatives 25 ability" refers to the extent to which compounds disclosed thereof. By way of example an optional substituents may be herein, such as, compounds of any of Formula (A), Formula LCR, wherein each L, is independently selected from a bond, (B), Formula (C), or Formula (D), are absorbed into the -0--, -C(-0)-, -S-, -S(=O}--, -S(=0)2-, general circulation when the pharmaceutical composition is -NH-, -NHC(O}--, -C(O)NH-, S(-0)2NH-, taken orally as compared to intravenous injection. , 30 -NHS(=0)2 -DC(O)NH-, -NHC(O)O-, (substi- "Blood plasma concentration" refers to the concentration tuted or unsubstituted C -C alkyl), or -(substituted or unsub 1 6 ofcompounds disclosed herein, such as, compounds ofany of stituted CrC alkenyl); and each R is independently selected 6 5 Formula (A), Formula (B), Formula (C), or Formula (D), in from H, (substituted or unsubstituted C -C alkyl), (substi 1 4 the plasma component of blood of a subject. It is understood tuted or unsubstituted C3 -C6cycloalkyl), heteroaryl, or het eroalkyl. The protecting groups that may form the protective 35 that the plasma concentration of compounds of any of For derivatives of the above substitucnts are known to those of mula (A), Formula (B), Formula (C), or Formula (D), may skill in the art and may be found in references such as Greene vary significantly between subjects, due to variability with and Wuts, above. respect to metabolism and/or possible interactions with other The term ''Michael acceptor moiety" refers to a functional therapeutic agents. In accordance with one embodiment dis- group that can participate in a Michael reaction, wherein a 40 closed herein, the blood plasma concentration of the com new covalent bond is formed between a portion of the pounds of any of Formula (A), Formula (B), Formula (C), or Michael acceptor moiety and the donor moiety. The Michael Formula (D), may vary from subject to subject. Likewise, acceptor moiety is an electrophile and the "donor moiety" is values such as maximum plasma concentration (C,.,ax) or time a nucleophile. The "G" groups presented in any of Formula to reach maximum plasma concentration (Tmax), or total area (A), Formula (B), or Formula (C) are non-limiting examples 45 under the plasma concentration time curve (AUCco-"")) may of Michael acceptor moieties. vary from subject to subject. Due to this variability, the The term "nucleophile" or "nucleophilic" refers to an elec amount necessary to constitute "a therapeutically effective tron rich compound, or moiety thereof. An example of a amount" of a compound of any of Formula (A), Formula (B), nucleophile includes, but in no way is limited to, a cysteine Formula (C), or Formula (D), may vary from subject to sub- residue of a molecule, such as, for example Cys 481 ofBtkc. 50 ject. The term "electrophile", or "electrophilic" refers to an The term "Bruton's tyrosine kinase," as used herein, refers electron poor or electron deficient molecule, or moiety to Bruton's tyrosine kinase from Homo sapiens, as disclosed thereof. Examples of electrophiles include, but in no way are in, e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No. limited to, Micheal acceptor moieties. NP _000052). The term "acceptable" or "pharmaceutically acceptable", 55 The tenn "Bruton's tyrosine kinase homolog," as used with respect to a formulation, composition or ingredient, as herein, refers to orthologs of Bruton's tyrosine kinase, e.g., used herein, means having no persistent detrimental effect on the orthologs from mouse (GenBank Acession No. the general health of the subject being treated or does not AAB47246), dog (GenBankAcession No. XP _549139.), rat abrogate the biological activity or properties of the com (GenBank Acession No. NP _001007799), chicken (Gen- pound, and is relatively nontoxic. 60 Bank Acession No. NP_989564), or zebra fish (GenBank As used herein, the term "agonist" refers to a compound, Acession No. XP~698117), and fusion proteins of any of the the presence of which results in a biological activity of a foregoing that exhibit kinase activity towards one or more protein that is the same as the biological activity resulting substrates ofBruton's tyrosine kinase (e.g. a peptide substrate from the presence of a naturally occurring ligand for the having the amino acid sequence "AVLESEEELYSSARQ"). protein, such as, for example, Btk. 65 The terms "co-administration" or the like, as used herein, As used herein, the term "partial agonist" refers to a com arc meant to encompass administration of the selected thera pound the presence of which results in a biological activity of peutic agents to a single patient and are intended to include US 8,008,309 B2 21 22 treatment regimens in which the agents are administered by identical" if the sequential units are about 60% identical, the same or different route of administration or at the same or about 65% identical, about 70% identical, about 75% identi different time. cal, about 80% identical, about 85% identical, about 90% The terms "effective amount" or "therapeutically effective identical, or about 95% identical over a specified region. Such amount," as used herein, refer to a sufficient amount of an 5 percentages to describe the "percent identity" of two or more agent or a compound being administered which will relieve to sequences. The identity of a sequence can exist over a region some extent one or more of the symptoms of the disease or that is at least about 7 5-l 00 sequential units in length, over a condition being treated. The result can be reduction and/or region that is about 50 sequential units in length, or, where not alleviation of the signs, symptoms, or causes of a disease, or specified, across the entire sequence. This definition also any other desired alteration of a biological system. For 10 refers to the complement of a test sequence. By way of example, an "effective amount" for therapeutic uses is the example only, two or more polypeptide sequences are iden amount of the composition including a compound as dis tical when the amino acid residues are the same, while two or closed herein required to provide a clinically significant more polypeptide sequences are "substantially identical" if decrease in disease symptoms without undue adverse side the amino acid residues are about 600/o identical about 65% effects. An appropriate "effective amount" in any individual 15 identical, about 700/o identical, about 75% identical, about case may be determined using techniques, such as a dose 800/o identical, about 85% identical, about 90% identical, or escalation study. The term "therapeutically effective amount" about 95% identical over a specified region. The identity can includes, for example, a prophylactically effective amount. exist over a region that is at least about 75-100 amino acids in An "effective amount" of a compound disclosed herein is an length, over a region that is about 50 amino acids in length, or, amount effective to achieve a desired pharmacologic effect or 20 where not specified, across the entire sequence of a polypep therapeutic improvement without undue adverse side effects. tide sequence. In addition, by way of example only, two or It is understood that "an effect amount" or "a therapeutically more polynucleotide sequences are identical when the effective amounf' can vary from subject to subject, due to nucleic acid residues are the same, while two or more poly variation in metabolism of the compound of any of Formula nucleotide sequences are "substantially identical" if the (A), Formula (B), Formula (C), or Formula (D), age, weight, 25 nucleic acid residues are about 60% identical, about 65% general condition of the subject, the condition being treated, identical, about 70% identical, about 75% identical, about the severity of the condition being treated, and the judgment 800/o identical, about 85% identical, about 900/o identical, or of the prescribing physician. By way of example only, thera about 95% identical over a specified region. The identity can peutically effective amounts may be determined by routine exist over a region that is at least about 75-100 nucleic acids experimentation, including but not limited to a dose escala 30 in length, over a region that is about 50 nucleic acids in length, tion c1inical trial. or, where not specified, across the entire sequence of a poly The terms "enhance" or "enhancing" means to increase or nucleotide sequence. prolong either in potency or duration a desired effect. By way The terms "inhibits", "inhibiting", or "inhibitor'' of a of example, "enhancing" the effect of therapeutic agents kinase, as used herein, refer to inhibition of enzymatic phos refers to the ability to increase or prolong, either in potency or 35 photransferase activity. duration, the effect of therapeutic agents on during treatment The term ••irreversible inhibitor," as used herein, refers to a of a disease, disorder or condition. An "enhancing-effective compound that, upon contact with a target protein (e.g., a amount," as used herein, refers to an amount adequate to kinase) causes the formation of a new covalent bond with or enhance the effect of a therapeutic agent in the treatment of a within the protein, whereby one or more ofthe target protein's disease, disorder or condition. When used in a patient, 40 biological activities (e.g., phosphotransferase activity) is amounts effective for this use will depend on the severity and diminished or abolished notwithstanding the subsequent course of the disease, disorder or condition, previous therapy, presence or absence of the irreversible inhibitor. the patient's health status and response to the drugs, and the The term "irreversible Btk inhibitor," as used herein, refers judgment of the treating physician. to an inhibitor of Btk that can form a covalent bond with an The term "homologous cysteine," as used herein refers to a 45 amino acid residue of Btk. In one embodiment, the irrevers cysteine residue found with in a sequence position that is ible inhibitor of Btk can form a covalent bond with a Cys homologous to that of cysteine 481 of Bruton's tyrosine residue of Btk; in particular embodiments, the irreversible kinase, as defined herein. For example, cysteine 482 is the inhibitor can form a covalent bond with a Cys 481 residue (or homologous cysteine of the rat ortholog of Bruton's tyrosine a homolog thereof) ofBtk or a cysteine residue in the homolo kinase; cysteine 479 is the homologous cysteine of the so gous corresponding position of another tyrosine kinase, as chicken ortholog; and cysteine 481 is the homologous cys shown in FIG.l. teine in the zebra fish ortholog. In another example, the The term "isolated," as used herein, refers to separating and homologous cysteine of TXK, a Tee kinase family member removing a component of interest from components not of related to Bruton's tyrosine, is Cys 350. Other examples of interest. Isolated substances can be in either a dry or semi-dry kinases having homologous cysteines are shown in FIG. 1. ss state, or in solution, including but not limited to an aqueous See also the sequence alignments of tyrosine kinases (fK) solution. The isolated component can be in a homogeneous published on the world wide web at kinase.comlhuman/ki state or the isolated component can be a part of a pharmaceu nomelphylogeny.html. tical composition that comprises additional pharmaceutically The term "identical," as used herein, refers to two or more acceptable carriers and/or excipicnts. By way of example sequences or subsequences which are the same. In addition, 60 only, nucleic acids or proteins are "isolated" when such the term "substantially identical," as used herein, refers to two nucleic acids or proteins are free of at least some of the or more sequences which have a percentage of sequential cellular components with which it is associated in the natural units which arc the same when compared and aligned for state, or that the nucleic acid or protein has been concentrated maximum correspondence over a comparison window, or to a level greater than the concentration of its in vivo or in designated region as measured using comparison algorithms 65 vitro production. Also, by way of example, a gene is isolated or by manual alignment and visual inspection. By way of when separated from open reading frames which flank the example only, two or more sequences may be "substantially gene and encode a protein other than the gene of interest. us 8,008,309 82 23 24 A .. metabolite" of a compound disclosed herein is a deriva~ As used herein, the term "selective modulator" refers to a tive of that compound that is formed when the compound is compound that selectively modulates a target activity relative metabolized. The term "active metabolite" refers to a biologi to a non-target activity. In certain embodiments, specific cally active derivative of a compound that is formed when the modulator refers to modulating a target activity at least 10, 50, compound is metabolized. The term "metabolized," as used 100, 250, 500, 1000 times more than a non-target activity. herein, refers to the sum of the processes (including, but not The term "substantially purified," as used herein, refers to limited to, hydrolysis reactions and reactions catalyzed by a component of interest that may be substantially or essen enzymes, such as, oxidation reactions) by which a particular tially free of other components which normally accompany or substance is changed by an organism. Thus, enzymes may interact with the component of interest prior to purification. produce specific structural alterations to a compound. For 10 By way of example only, a component of interest may be example, cytochrome P450 catalyzes a variety of oxidative "substantially purified" when the preparation of the compo nent and reductive reactions while uri dine diphosphate glucuronyl of interest contains less than about 300/o, less than about 25%, less than about 20%, less than about 15%, less than transferases catalyze the transfer of an activated glucuronic about 10%, less than about 5%, less than about 4%, less than acid molecule to aromatic alcohols, aliphatic alcohols, car 15 about 3%, less than about 2%, or less than about 1% (by dJy boxylic acids, amines and free sulfhydryl groups. Further weight) of contaminating components. Thus, a "substantially information on metabolism may be obtained from The Phar purified" component of interest may have a purity level of macological Basis of Therapeutics, 9th Edition, McGraw about 70%, about 75%, about 80%, about 85%, about 90%, Hill (1996). Metabolites of the compounds disclosed herein about 95%, about 96%, about 97%, about 98%, about 99% or can be identified either by administration of compounds to a 20 greater. host and analysis of tissue samples from the host, or by The term "subject" as used herein, refers to an animal incubation of compounds with hepatic cells in vitro and which is the object of treatment, observation or experiment. analysis of the resulting compounds. Both methods are well By way of example only, a subject may be, but is not limited known in the art. In some embodiments, metabolites of a to, a mammal including, but not limited to, a human. compound are formed by oxidative processes and correspond 25 As used herein, the term "target activity" refers to a bio- to the corresponding hydroxy-containing compound. In some logical activity capable of being modulated by a selective embodiments, a compound is metabolized to pharmacologi modulator. Certain exemplary target activities include, but cally active metabolites. are not limited to, binding affinity, signal transduction, enzy The term "modulate," as used herein, means to interact matic activity, tumor growth, inflammation or inflammation- with a target either directly or inclirectly so as to alter the 30 related processes, and amelioration ofone or more symptoms activity of the target, including, by way of example only, to associated with a disease or condition. enhance the activity of the target, to inhibit the activity of the As used herein, the term ''target protein" refers to a mol target, to limit the activity of the target, or to extend the ecule or a portion of a protein capable of being bound by a activity of the target. selective binding compound. In certain embodiments, a target As used herein, the term "modulator" refers to a compound 35 protein is Btk. that alters an activity ofa molecule. For example, a modulator The terms ''treat," "treating" or "treatment", as used herein, can cause anincreaseordecrease in the magnitude of a certain include alleviating, abating or ameliorating a disease or con activity of a molecule compared to the magnitude of the dition symptoms, preventing additional symptoms, amelio activity in the absence of the modulator. In certain embodi rating or preventing the underlying metabolic causes of ments, a modulator is an inhibitor, which decreases the mag 40 symptoms, inhibiting the disease or condition, e.g., arresting nitude of one or more activities of a molecule. In certain the development of the disease or condition, relieving the embodiments, an inhibitor completely prevents one or more disease or condition, causing regression of the disease or activities of a molecule. In certain embodiments, a modulator condition, relieving a condition caused by the disease or is an activator, which increases the magnitude of at least one condition, or stopping the symptoms of the disease or cond.i- activity of a molecule. In certain embodiments the presence 45 tion. The terms ''treat," ''treating" or "treatment'', include, but of a modulator results in an activity that does not occur in the are not limited to, prophylactic and/or therapeutic treatments. absence of the modulator. As used herein, the IC50 refers to an amount, concentration The term "prophylactically effective amount," as used or dosage of a particular test compound that achieves a 50% herein, refers that amount of a composition applied to a inhibition ofa maximal response, such as inhibition ofBtk, in patient which will relieve to some extent one or more of the 50 an assay that measures such response. symptoms of a disease, condition or disorder being treated. In As used herein, EC50 refers to a dosage, concentration or such prophylactic applications, such amounts may depend on amount of a particular test compound that elicits a dose the patient's state of health, weight, and the like. It is consid dependent response at 50% of maximal expression of a par ered well within the skill of the art for one to determine such ticular response that is induced, provoked or potentiated by prophylactically effective amounts by routine experimenta 55 the particular test compound. tion, including, but not limited to, a dose escalation clinical trial. BRIEF DESCRIPTION OF THE FIGURES As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of FIG.l presents a sequence comparison ofBtk with other one or more target proteins. 60 tyrosine kinases. As used herein, the term "selectively binds" refers to the FIG. 2 presents illustrative cell data regarding inhibition of ability of a selective binding compound to bind to a target B cell receptor induced Phospholipase-Cy phosphorylation protein, such as, for example, Btk, with greater affinity than it by compound 4. In this example, there were 2E6 Ramos binds to a non-target protein. In certain embodiments, spe ceUs/well in serum free media; the ceiis were pretreated with cific binding refers to binding to a target with an affinity that 65 compound for 1.5 hr. The B cell receptor was stimulated with is at least 10, 50, 100, 250, 500, 1000 or more times greater anti-IgM for 3 min; the lOx lysis buffer containing DNAse than the affinity for a non-target. was added directly to cells. The sample buffer was added and US 8,008,309 B2 25 26 loaded directly on gel. The samples were analyzed with west not limited to, rheumatoid arthritis, psonattc arthritis, em blot-phosphorylated Btk and PLCyl and total Btk and osteoarthritis, Still's disease, juvenile arthritis, lupus, diabe PLCyl. The blot was imaged with ChemiDoc CCD and quan tes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thy titated with ImageQuant. The phosphorylated band was nor roiditis, Graves' disease SjOgren's syndrome, multiple scle-

malized to total band and the IC50 was calculated. 5 rosis, GUillain-Barre syndrome, acute disseminated FIG. 3 presents illustrative cell data showing that com encephalomyelitis, Addison's disease, opsoclonus-myocio pound 4 and compound 15 inhibit growth ofDHL-6 cells. In nus syndrome, ankylosing spondylitisis, antiphospholipid this example, there were 3E4 DHL-6 cells/wel1 in complete antibody syndrome, aplastic anemia, autoimmune hepatitis, media. The cells were treated for the indicated time with coeliac disease, Goodpasture's syndrome, idiopathic throm compound@ 0.1% DMSO final concentration. The cell num- to bocytopenic purpura, optic neuritis, sclerodenna, primary her was measured using Alamar Blue assay according to biliary cirrhosis, Reiter's syndrome, Tak:ayasu's arteritis, standard protocol. temporal arteritis, warm autoimmune hemolytic anemia, FIG. 4 presents illustrative mass spectra showing that com Wegener's granulomatosis, psoriasis, alopecia universalis, pound 4 covalently modifies Btk. In this example, Incubate 30 Beb;:ets disease, chronic fatigue, dysautonom.nia, uM compound 4 with 6-7 uM recombinant BTK (Y->D IS endometriosis, interstitial cystitis, neuromyotonia, scleroder mutant, kinase domain only) overnight at RT. Desalt protein mna, and vulvodynia. inhibitor complex by reversed-phase HPLC and analyze In some embodiments, the methods described herein can directly in mass spec to determine molecularweight. >99% of recombinant Btk protein is covalently modified by compound be used to treat heteroimmune conditions or diseases, which 4. 20 include, but are not limited to graft versus host disease, trans FIG. S presents illustrative inhibition of arthritis develop plantation, transfusion, anaphylaxis, allergies (e.g., allergies ment in a mouse model by compound 4. to plant poilens, latex, drugs, foods, insect poisons, anllnal FIG. 6 presents illustrative data demonstrating that the hair, animal dander, dust mites, or cockroach calyx), type I efficacy ofcompound4 is associated with reduction of Rheu hypersensitivity, allergic conjunctivitis, allergic rhinitis, and matoid Factor andAnti-citrullinated cyclic peptide antibodies 25 atopic dermatitis. in the CAIA model. In these examples, *pdexamethasone. enteritis, hepatitis, hidrndenitis suppurativa, laryngitis, mas- 35 titis, meningitis, myelitis myocarditis, myositis, nephritis, INCORPORATION BY REFERENCE oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, All publications and patent applications mentioned in this pneumonitis, pneumonia, proctitis, prostatitis, pyelonephri specification are herein incorporated by reference to the same tis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, ten- extent as if each individual publication or patent application 40 donitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. was specifically and individually indicated to be incorporated In yet other embodiments, the methods described herein by reference. can be used to treat a cancer, e.g., B-cell proliferative disor ders, which include, but are not limited to diffuse large B cell DETAILED DESCRIPTION OF THE INVENTION lymphoma, follicular lymphoma, chronic lymphocytic lym- 45 phoma, chronic lymphocytic leukemia, B-cell prolympho The methods described herein include administering to a cytic leukemia, lymphoplasmacytic lymphoma/Waldenstr6m subject in need a composition containing a therapeutically macroglobulinemia, splenic marginal zone lymphoma, effective amount of one or more irreversible Btk inhibitor plasma cell myeloma, plasmacytoma, extranodal marginal compounds described herein. Without being bound by theory, zone B cell lymphoma, nodal marginal zone B cell lym- the diverse roles played by Btk: signaling in various hemato 50 phoma, mantle cell lymphoma, mediastinal (thymic) large B poietic cell functions, e.g., B-cell receptor activation, sug cell lymphoma, intravascular large B cell lymphoma, primary gests that small molecule Btk inhibitors are useful for reduc effusion lymphoma, burkitt lymphoma/leukemia, and lym ing the risk of or treating a variety of diseases affected by or phomatoid granulomatosis. affecting many cell types ofthe hematopoetic lineage includ In further embodiments, the methods described herein can ing, e.g., autoimmune diseases, heteroimmune conditions or 55 be used to treat thromboembolic disorders, which include, but diseases, inflammatory diseases, cancer (e.g., B-cell prolif are not limited to myocardial infarct, angina pectoris (includ erative disorders), and thromboembolic disorders. Further, ing unstable angina), reocclusions or restenoses after angio the irreversible Btk inhibitor compounds described herein can plasty or aortocoronary bypass, stroke, transitory ischemia, be used to inhibit a small subset of other tyrosine kinases that peripheral arterial occlusive disorders, pulmonary embo- share homology with Btk by having a cysteine residue (in 60 lisms, and deep venous thromboses. cluding a Cys 481 residue) that can form a covalent bond with Symptoms, diagnostic tests, and prognostic tests for each the irreversible inhibitor. See, e.g., protein kinases in FIG.l. of the above-mentioned conditions are known in the art. See, Thus, a subset of tyrosine kinases other than Btk: are also e.g., Harrison's Principles ofInternal Medicine©," 16th ed., expected to be useful as therapeutic targets in a number of 2004, The McGraw-Hill Companies, Inc. Dey eta!. (2006), health conditions. 65 Cytojoumal 3(24 ), and the "Revised European American In some embodiments, the methods described herein can Lymphoma" (REAL) classification system (see, e.g., the be used to treat an autoimmune disease, which includes, but is website maintained by the National Cancer Institute). US 8,008,309 B2 27 28 A number of animal models of are useful for establishing a in an in vitro assay, e.g., an acellular biochemical assay or a range of therapeutically effective doses of irreversible Btk cellular functional assay. Such assays are useful to determine inhibitor compounds for treating any of the foregoing dis~ an in vitro IC50 for an irreversible Btk inhibitor compound. eases. For example, an acellular kinase assay can be used to For example, dosing of irreversible Btk inhibitor com 5 determine Btk activity after incubation of the kinase in the pounds for treating an autoimmune disease can be assessed in absence or presence of a range of concentrations of a candi a mouse model of rheumatoid arthritis. In this model, arthritis date irreversible Btk inhibitor compound. If the candidate is induced in Balb/c mice by administering anti-collagen compound is in fact an irreversible Btk inhibitor, Btk kinase antibodies and lipopolysaccharide. See Nandakumar et al. activity will not be recovered by repeat washing with inhibi- (2003), Am. J. Patho/163:1827-1837. to tor-free medium. See, e.g., S. B. Smaill, et al. (1999), J. Med. In another example, dosing of irreversible Btk inhibitors Chem. 42(10):1803-1815. Further, covalent complex forma for the treatment of B-cell proliferative disorders can be tion between Btk and a candidate irreversible Btk inhibitor is examined in, e.g., a human-to-mouse xenograft model in a useful indicator of irreversible inhibition ofBtk that can be which human B-celllymphoma cells (e.g. Ramos cells) are readily determined by a number of methods known in the art implanted into immunodefficient mice (e.g., "nude" mice) as 15 (e.g., mass spectrometry). For example, some irreversible described in, e.g., Pagel etal. (2005), Clin Cancer Res 11(13): Btk-inhibitorcompounds can form a covalent bond with Cys 48574866. 481 ofBtk (e.g., via a Michael reaction). Animal models for treatment of thromboembolic disorders Cel1ular functional assays for Btk inhibition include mea are also known. suring one or more cellular endpoints in response to stimu The therapeutic efficacy of the compound for one of the 20 lating a Btk-mediated pathway in a cell line (e.g., BCR acti foregoing diseases can be optimized during a course of treat vation in Ramos cells) in the absence or presence of a range of ment For example, a subject being treated can undergo a concentrations of a candidate irreversible Btk inhibitor com diagnostic evaluation to correlate the relief of disease symp pound. Useful endpoints for determining a response to BCR toms or pathologies to inhibition of in vivo. Btk activity activation indude, e.g., autophosphorylation of Btk, phos achieved by administering a given dose of an irreversible Btk 25 phorylation of a Btk target protein (e.g., PLC-y ), and cyto inhibitor. Cellular assays known in the art can be used to plasmic calcium flux. determine in vivo activity ofBtk in the presence or absence of High throughput assays for many acellular biochemical an irreversible Btk inhibitor. For example, since activated Btk assays (e.g., kinase assays) and cellular functional assays is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (e.g., calcium flux) are well known to those of ordinary skill (Y551), phospho-specific immunocytochemical staining of 30 in the art. In addition, high throughput screening systems are P-Y223 or P-Y551-positive cells can be used to detect or commercially available (see, e.g., Zymark Corp., Hopkinton, quantify activation of Bkt in a population of cells (e.g., by Mass.; Air Technical Industries, Mentor, Ohio; Beckman FACS analysis of stained vs unstained cells). See, e.g., Nisi Instruments, Inc. Fullerton, Calif.; Precision Systems, Inc., tani et a!. (1999), Proc. Nat/. A cad. Sci, USA 96:2221-2226. Natick, Mass., etc.). These systems typically automate entire Thus, the amount ofthe Btk inhibitor inhibitor compound that 35 procedures including all sample and reagent pipetting, liquid is administered to a subject can be increased or decreased as dispensing, timed incubations, and final readings of the needed so as to maintain a level of Btk inhibition optimal for microplate in detectors) appropriate for the assay. Automated treating the subject's disease state. systems thereby allow the identification and characterization Compounds of a large number of irreversible Btk compounds without In the following description of irreversible Btk compounds 40 undue effort. suitable for use in the methods described herein, definitions of Irreversible Btkb inhibitor compounds can used for the referred-to standard chemistry terms may be found in refer manufacture of a medicament for treating any of the forego ence works (ifnot otheiWise defined herein), including. Carey ing conditions (e.g., autoimmune diseases, inflammatory dis- and Sundberg ·~ctvanced Organic Chemistry 4th Ed". Vols. A eases, allergy disorders, B-cell proliferative disorders, or (2000) and B (2001), Plenum Press, New York. Unless oth- 45 thromboembolic disorders). eiWise indicated, conventional methods of mass spectros In some embodiments, the irreversible Btk inhibitor com copy, NMR, HPLC, protein chemistry, biochemistry, recom pound used for the methods described herein inhibits Btk or a binant DNA techniques and pharmacology, within the Btk homolog kinase activity with an in vitro IC50 of less than ordinary skill of the art are employed. In addition, nucleic 10 f!M. (e.g., less than I f!M, less than 0.5 ~M, less than 0.4 acid and amino acid sequences for Btk (e.g., human Btk) are 50 f.l,M, less than 0.3 )lM, less than 0.1, Jess than 0.08 ).LM, less known in the art as disclosed in, e.g., U.S. Pat. No. 6,326,469. than 0.06 )lM, less than 0.05 )lM, less than 0.04 )lM, less than Unless specific definitions are provided, the nomendature 0.03 ).IM, less than less than 0.02 ).IM, less than 0.01, less than employed in connection with, and the laboratory procedures 0.008 ~M, less than 0.006 ~M, less than 0.005 f!M less than and techniques of, analytical chemistry, synthetic organic 0.004 f!M, less than 0.003 f!M, less than less than 0.002 f!M, chemistry, and medicinal and pharmaceutical chemistry 55 less than 0.001, less than 0.00099 ~M, less than 0.00098 SK, described herein are those known in the art. Standard tech- less than 0.00097 f!M, less than 0.00096 ~M, less than niques can be used for chemical syntheses, chemical analy 0.00095 f!M, less than 0.00094 ~M, less than 0.00093 f!M, ses, pharmaceutical preparation, formulation, and delivery, less than 0.00092, or less than 0.00090 ~- and treatment of patients In one embodiment, the irreversible Btk inhibitor com- The Btk inhibitor compounds described herein are selec 60 pound selectively and irreversibly inhibits an activated form tive for Btk and kinases having a cysteine residue in an amino of its target tyrosine kinase (e.g., a phosphorylated form of the acid sequence position of the tyrosine kinase that is homolo tyrosine kinase). For example, activated Btk is transphospho gous to the amino acid sequence position of cysteine 481 in rylated at tyrosine 551. Thus, in these embodiments the irre Btk. See, e.g., kinases in FIG. 1. Inhibitor compounds versible Btk inhibitor inhibits the target kinase in cells only described herein include a Michael acceptor moiety. 65 once the target kinase is activated by the signaling events. Generally, an irreversible inhibitor compound ofBtk used Described herein are compounds of any of Formula (A), in the methods described herein is identified or characterized Formula (B), Formula (C), or Formula (D). Also described US 8,008,309 B2 29 30 herein are pharmaceutically acceptable salts, pharmaceuti or L3 , X and L4 taken together form a nitrogen contain cally acceptable solvates, pharmaceutically active metabo ing heterocyclic ring; lites, and pharmaceutically acceptable prodrugs of such com Gis pounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, 5 pharmaceutically acceptable solvate, pharmaceutically active metabolite or pbarmaceutica1ly acceptable prodrug of such compound, are provided. In some embodiments, when com pounds disclosed herein contain an oxidizable nitrogen atom, 10 the nitrogen atom can be converted to anN-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by any of Formula (A), Formula (B), Formula (C), or Formula (D), are also provided. 15 In one aspect are compounds of Formula (A), pharmaceu tically acceptable salts, phannaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof. Formula (A) is as follows: 20

Fonnula(A)

wherein A is independently selected from Nor CR5 ; R1 isH, L2-(substitutedorunsubstitutedalkyl), L2-(substi tuted or unsubstituted cycloalkyl), L2-(substituted or 35 wherein, unsubstituted alkenyl), L 2 -(substituted or lUlsubstituted R , ~ and R are independently selected from among H, cycloalkcnyl), L -(substituted or unsubstituted hetero 6 5 2 lower alkyl or substituted lower alkyl, lower het cycle), L -(substituted or unsubstituted heteroaryl), or 2 eroalkyl or substituted lower heteroalkyl, substituted L -(substituted or unsubstituted aryl), where L is a 2 2 or unsubstituted lower cycloalkyl, and substituted or bond, 0, S, -S( 0), -S( 0) , C(-0), -(substi- 40 2 unsubstituted lower beterocycloalkyl; tuted or unsubstituted C1-C6 alkyl), or -(substituted or unsubstituted C2-C6 alkenyl); R isH, halogen, -L -(substituted or unsubstituted C1-C3 ~ and R3 are independently selected from H, lower alkyl 5 6 and substituted lower alkyl; alkyl), -L6-(substituted or unsubstituted C2 -C4 alkenyl), 45 -L -(substituted or unsubstituted heteroaryl), or -L6 - ~is L3 -X-L4-G, wherein, 6 (substituted orunsubstitutedaryl), wherein~ is a bond, L3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substi 0, S, -8(=0), S( 0),, NH, C(O), -NHC(O)O, tuted or unsubstituted cycloalkyl, optionally substi -OC(O)N-H, -NHC(O), or -C(O)NH; alkenyl, optionally substituted tuted or unsubstituted 50 each~ is independently selected from among H, substi or unsubstituted alkynyl; tuted or unsubstituted lower alkyl, and substituted or X is optional, and when present is a bond, 0, -C(=O), unsubstituted lower cycloalkyl; , -NR,, -NHC(O), S, -S( 0), -S(=0)2 -NH, each R is independently H, substituted or unsubstituted C(O), -C(O)NR,, -·S(-0) 10 -C(O)NH, -NR9 2 lower alkyl, or substituted or unsubstituted lower NH, -NHS(==D),, -S(-O),NR,-, -NR,S ss cycloalkyl; or (==0) , -OC(O)NH-, -NHC(O)O-, -OC(O) 2 groups can together forma 5-, 6-, 7-, or 8-mem NR,-, -NR C(O)O-, -CI-1 NO-, two R10 9 bered heterocyclic ring; or -ON=CH-, -NR10C(O)NR10-, heteroaryl, aryl, -NR10C( NR11)NR11-, -NR10C Rg and R10 can together form a 5-, 6-, 7-, or 8-membered ( NR,)-, -C( NR,)NRw-, -OC 60 heterocyclic ring; or (-NR ..)-, or-C( NR .. )O-; each R is independently selected from H, -S(==OhR8, L is optional, and when present is a bond. substituted or 11 4 -S(=0) NH , -C(O)R , -CN, -NO, heteroaryl, unsubstituted alkyl, substituted or lUlsubstitutcd 2 2 8 or beteroalkyl; and cycloalkyl, substituted or unsubstituted alk:enyl, sub stituted or llilSUbstituted alkynyl, substituted or 65 phannaceutically active metabolites, pharmaceutically unsubstituted aryl, substituted or unsubstituted het acceptable solvates, pharmaceutically acceptable salts, or eroaryl, substituted or unsubstituted heterocycle; pharmaceutically acceptable prodrugs thereof. US 8,008,309 B2 31 32 In a further or alternative embodiment, the compound of In further or alternative embodiments, G is selected from Formula (A) has the fOllowing structure of Formula (B): among Fonnu!a (B) 5 ~.~, 0 0

10 R•

20 wherein: Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered In further or alternative embodiments, cycloalkyl ring; 25 each Ra is independently H, halogen, -CF3, -CN, -N02 , OH, NH2 , -L0 -(substituted or unsubstituted - alkyl), -L0 -(subslituted or unsubstituted alkenyl), -L0

(substituted orunsubstituted. heteroaryl), or -L0 -(substi tuted or unsubstituted aryl), wherein La is a bond, 0, S, 30 --8(=0), --S(-0),, NH, C(O), CH2 , -NHC(O)O, -NHC(O), or -C(O)NH; is selected from among Gis

50 wherein, ~. R and R are independently selected from among H, 7 8 55 lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsub stituted lower cycloalkyl, and substiruted or unsubsti tuted lower heterocycloalkyl; 60 R 12 isH or lower alkyl; or

Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; and pharmaceutically acceptable active metabolites, pharma ceutically acceptable solvates, pharmaceutically accept- 65 able salts, or pharmaceutically acceptable prodrugs thereof. US 8,008,309 B2 33 34 In further or alternative embodiment, the compound of tion, and in vivo metabolism. In addition, in vivo metabolism Formula (B) has the following structure of Formula (C): may include, by way of example only, controlling in vivo PK properties, off-target activities, potential toxicities associated with cypP450 interactions, drug-drug interactions, and the Formula (C) 5 like. Further, modifications to C; allow for the tailoring of the in vivo efficacy of the compound through the modulation of, by way of example, specific and non-specific protein binding to plasma proteins and lipids and tissue distribution in vivo. In a further embodiment are compounds having the struc IO tureofFormula (D):

Fomwla(D)

Y is alkyl or substituted alkyl, or a 4~, 5-, or 6-membered cycloalkyl ring; 25 R12 is H or lower alkyl; or Y and R 12 taken together fom1 a 4-, 5-, or 6-membered heterocyclic ring; Gis

30 wherein La is CH 2, 0, NH or S; Ar is an optionally substituted aromatic carbocycle or an aromatic heterocycle; Y is an optionally substituted alkyl, heteroalkyl, car 35 bocycle, heterocycle, or combination thereof; Z is C(O), OC(O), NHC(O), C(S), S(O), OS(O), NHS (0)..,, where xis 1 or 2; and R6, R7 , and R8 are independently selected from H, alkyl, heteroalkyl, carbocycle, heterocycle, or combinations 40 thereof. In a further or alternative embodiment, La is 0. In a further or alternative embodiment, Ar is phenyL In a further or alternative embodiment, Z is C(O). Ina further or alternative embodiment, each ofR1, R2 , and 45 R3 is H. In another embodiment, provided herein is a compound of wherein, Formula (D). Fonnula (D) is as follows.

R6 , R7 and R5 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl 50 Fomwla(D) or substituted lower heteroalkyl, substituted or unsub stituted lower cycloalkyl, and substituted or unsubsti tuted lower heterocycloalkyl; and pharmaceutically acceptable active metabolites, pharma ceutically acceptable solvates,pharmaceutically accept- ss able salts, or pharmaceutica1ly acceptable prodrugs thereof. In a further or alternative embodiment, the "G" group of any ofFonnula (A), Fonnula (B), or Formula (C) is any group that is used to tailor the physical and biological properties of 60 the molecule. Such tailoring/modifications are achieved using groups which modulate Michael acceptor chemical reactivity, acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. The physical and bio logical properties modulated by such modifications to G 65 include, by way of example only, enhancing chemical reac tivity of Michael acceptor group, solubility, in vivo absorp- US 8,008,309 B2 35 36 wherein: In some embodiments, Y is an optionally substituted group

La is CH2, 0, NH or S; selected from among alkyl, heteroalkyl, cycloalkyl, and het Ar is a substituted or unsubstituted aryl, or a substituted or erocycloalkyl. In other embodiments, Y is an optionally sub

unsubstituted heteroaryl; stituted group selected from among C1-C6alkyl, Y is an optionally substituted group selected from among s C 1-CJleteroalkyl, 4-, 5-, 6- or ?-membered cycloalkyl, and alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, 4-, 5-, 6- or ?-membered heterocycloalkyl. In yet other and heteroaryl; embodiments, Y is an optionally substituted group selected Z is C(=

For example, in some embodiments, La is CH2, 0, or NH. In other embodiments, La is 0 or NH. In yet other embodiments, LaisO. In some embodiments, Ar is a substituted or unsubstituted 35 aryl In yet other embodiments, Ar is a 6-membered aryl. In some other embodiments, Ar is phenyl. In some embodiments, xis 2. In yet other embodiments, Z is C( 0), OC(-0), NHC(=

C, -C4 alkyl(aryl), C, -C4 alkyl(heteroaryl), C, -C4 alkyl(C3 - C8cycloalkyl), or C,-C4 alkyl(C,-C8heterocycloalkyl). In some other embodiments, R6 is H, substituted or unsubstituted C 1-C4 alkyl, substituted or unsubstituted 55 c, -C4heteroalkyl, C, -C,alkoxyalkyl, C,-C,alkyl-N(C,- C,alkyl),, C, -C4 alky !(aryl), C, -C4alkyl(heteroaryl), C, -C4 alkyl(C,-C8cyc!oalkyl), or C, -C4 alkyl(C,- C8heterocycloalkyl). In yet other embodiments, R6 isH, sub stituted or unsubstituted C1-C4 alkyl, --CH2--0-(C1- 60 C3a!kyl), -CH,-N(C, -C,alkyl), C, -C4 alkyl(phenyl), or C1-C4 alkyl(5- or 6-membered heteroaryl). In some embodi ments, R6 is H, substituted or unsubstituted C 1-C4 alkyl, -CH,--0-(C, -C3 alkyl), -CH,-N(C, -C,alkyl),, C,-C4 alkyl(phenyl), or C,-C4 alkyl(5- or 6-membered het- 65 eroaryl containing 1 or 2 N atoms), or C 1-C4 alky1(5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms). US 8,008,309 B2 37 38 -continued o--0-continued o--0 5 ~ ~ NH, NH2

10 'N I 'N/ ~)-{\ 15 q-\ 0 o--0 20

mr, 25 'N /' 30 b.-{" NH, o--0 35 ~ 40

b.-( 50 o--0 55 ¥ ~

65 US 8,008,309 B2 39 40 -continued -continued

o--0 5 o--0 '\ '\ ¥ NH, NH, ----"'

10 '\ N """' '\ I I l#N N

15 q~l o~~"0 0 20

0--0 25 ¥ '\ o--0 30 '\ NH, ----"' ¥ NH, N """' 'N -- I 35 N """' l#N 'N I l#N N q~0 40 o~~"0

o--0 50 o--0 '\ ¥ '\ NH, -- 55 NH, N """' 'N N """' 'N l# I I N l#N 60

Q ;=· HN-S~ 6~./ 0ll""o 65 o I us 8,008,309 82 41 42 -continued -continued

o--0 5 o--0· 1 NH, NH, """ """ 10 N """ N """ ~N ~N I I l-9 N l-9N N N 0~,/ l5 b 0 20 0~

25 o--0· o--0 NH, """ ¥ 30 NH, """ ~N I N N """ ~N I 35 l-9 N N b 0~ 40 0~ 0 45 o--0 ¥ 50 """ o--0· NH, ..&" N """ ~N I NH, """ 55 l-9N N

N """ ~N I l-9 N N 60 b b,s~ 0~ #~ 0 0 65 N---.. / ' US 8,008,309 B2 43 44 -continued -continued

o--0 5 f ~

'NI 35

0 40 0~ 45

o--0· 50 ~

65 US 8,008,309 B2 45 46 -continued -continued o--0· o--0 "\

NH2 Nll, 10 N N '\ """' 'N """' I I l,., l,., N N N N ~ 15 ~ /r HN~if'' 0 20 0 o--0 25 0--0

"\ 30 NH, NH2

'N 'N 35 I I N N ~ ~. 40 HN~N/• -N~o/' o I 0

o--0 50 o--0 "\ "\ NH, 55 NH,

N """' N N I > l,., N 60 N ~ ~ /N~N/' HN~, o I 65 0 us 8,008,309 82 47 48 . ~continued In still another embodiment,. camp ounds provided herem are selected from among:

o--0 5 ¥ ~ o--0 10 ¥ ~

NH, ~

N """' 15 ~N I l ... N N

0 20 C)--r 0

25 o--0· "'d 30 o--0 ~ NH, ¥ NH, ~ ~N 35 I N """' N ~N I l ... N N ~ 40 HN.,s~ #"., 0 0 bN~· 0

o--0 50 o--0 ~ ~ NH, 55 NH, ~N I ~N I ~ 60 N /N'-s~ N-s #"., o~. 0 0 65 1!'\, 0 us 8,008,309 82 49 50 -continued ~continued

o--0 5 o--0 ~ ~ NH2 NH2 ~ 10 '\N N ""' '\N I N I luN bN--(' 15 0 bY' 0 20

o--0· 25 o--0 NH2 30 ~

NH, N ""' '\N lu I N 35 N ""' '\N I luN 0 40 bY' 0~ 0

o--0· 50 ~ o--0 NH, 55 NH, ~ '\N I N '\N I 60 N

q--r 65 bN--r· 0 0 US 8,008,309 B2 51 52 ~continued The compounds of any of Formula (A), or Formula (B), or Formula (C), or Formula (D) can irreversibly inhibit Btk and may be used to treat patients suffering from Bruton's tyrosine o-0 kinase-dependent or Bruton's tyrosfue kinase mediated con- s ditions or diseases, including, but not limited to, cancer, '\ autoimmune and other inflammatory diseases. Preparation of Compounds NH, Compounds of any of Formula (A), (B), (C) or (D) may be synthesized using standard synthetic techniques known to 10 those of skill in the art or using methods known in the art in N"""' 'N combination with methods described herein. In additions, I solvents, temperatures and other reaction conditions preM lu N N sented herein may vary according to those of skill in the art. '' As a further guide the following synthetic methods may also 15 be utilized . ..ct The reactions can be employed in a linear sequence to ON--r· provide the compotmds described herein or they may be used 0 to synthesize fragments which are subsequently joined by the methods described herein and/or known in the art. 2° Formation of Covalent Linkages by Reaction of an Electro o-0 phile with a Nucleophile The compounds described herein can be modified using '\ various electrophiles or nucleophiles to form new functional groups or substituents. Table 1 entitled "Examples of CovaM ~ 25 NH, lent Linkages and Precursors Thereof' lists selected examples of covalent linkages and precursor functional groups which yield and can be used as guidance toward the N"""' 'N variety of electrophiles andnucleophiles combinations availM I able. Precursor functional groups are shown as electrophilic l# N 30 N groups and nucleophilic groups.

TABLE I l)--r-( Examples of Covalent Linkages a.nd Precursors Thereof 35 0 Covalent Linkage Product Electrophile Nuc!eophile

Carboxamidcs Activated esters amines/anilines In one aspect, provided herein is a compound selected from Carboxamides acyl s.zldes amincs/a.nilines among: 1-(3-( 4-amino-3-(4- phenoxypheny 1)-1 H-pyrazolo Carboxamides acyl halides amines/anilines acyl halides alcohols/phenols [3,4-d]pyrimidin-1-y1)piperidin-1-yl)prop-2-en-1-one 40 ::~ acyl nitriles alcohols/phenols (Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)- Carboxarnides acyl nitriles amincs/a.nilincs 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but -2-en- !min" Aldehydes amincs/a.nilincs 1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)- Hydrazones aldehydes or ketones Hydrazincs Oximes aldehydes or ketones Hydroxylwn.ines 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-y1) Alkyl arnines alkyl halides amincs/a.nilines sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4- 45 Esters alkyl hs.lidcs carboxylic acids phenoxypheny!)-1 H-pyrazolo[3 ,4 -d]pyrimidin -1-yl) Thioethers alkyl hs.lides Thiols Ethers alkyl hs.lides alcohols/phenols piperidin-1-yl)prop-2-yn-1-one (Compound 8); !-(4-( 4- Thioethers alkyl sulfonates Thiols amino-3 -( 4-phenoxypheny 1)-1 H -pyrazolo[3 ,4-d] pyrimidin- ""= alkyl sulfonates carboxylic acids 1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s, Ethers alkyl sulfonates alcohols/phenols 50 Esters Anhydrides a.lcoholslpheno!s 4s)-4-( 4-amino-3-( 4-phenoxypheny 1)-1 H -pyrazo lo [3,4-d] Carboxarnidt:S Anhydrides amines/anilines pyridin-1-yl)cyclohexyl)acrylamide (Compound 10); I -((R)- Thiopheno!s aryl hs.lides Thiols 3 -( 4-amino-3 -( 4-phenoxyphenyl )-1 H -pyrazolo [3 ,4-d] Aryl arnines aryl halides Amines Thioethers Azindines Thiols pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound Boronate esters Boronates Glycols 11 ); 1-((S)-3-(4-amino-3-( 4-phenoxyphenyl)-1 H-pyrazolo 55 Carboxarnides carboxylic acids amincs/llllilincs [3, 4-d]pyrimidin-I-y l)pyrrolidin-1-y !)prop-2-en-1-one carboxylic acids Alcohols hydrazines"""' Hydrazidcs carboxylic acids (Compound 12); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)- N·acylurcas or Anhydrides carbodiimides carboxylic acids 1H -pyrazolo [3, 4-d]pyrimidin-1-yI )piperidin -1- y !)prop-2- diazoalka.nes carboxylic ucids en-1-one (Compound 13); 1-((S)-3-(4-amino-3-(4-phenox Thioethers"""' Epoxides Thiols hs.loacctrunidcs Thiols ypheny I)-I H -pyrazolo[3 ,4-d]pyrimidin-1-y I)piperidin-1- yI) 60 =~:::zines halotriazines amincs/a.nilines prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3- Triazinyl ethers ha.lotriazincs s.lcobolslphenols ( 4-phenoxyphenyl )-1 H -pyrazolo[3 ,4-d]pyrimidin -I-y I) Ami dines imido esters amincs/a.nilines piperidin-1-yl)-4-(dimethylamino )but-2-en-1-one Ureas Isocya.natcs amines/a.nilines (Compotmd 15). Urethanes lsocyanatcs a.lcoholslphenols Thioureas isothiocya.nates arnines/anilines Throughout the specification, groups and substituents 65 Thioethers Maleimides Thiols thereof can be chosen by one skilled in the field to provide Phosphite esters phosphommidites Alcohols stable moieties and compounds. US 8,008,309 B2 53 54 TABLE !-continued Typically blocking/protecting groups may be selected from: Examples of Covalent Linkages and Precwsors Thereof

Covalent Linkage Product Elcctrophile Nucleophile

Silyl ethers . silyl halides Alcohols Alkyl amines sulfonate esters amines/anilines Thioethers sulfonate esters Thiols Esters sulfo!UI.te esters carboxylic acids Ethers sulfonate esters Alcohols 10 Sulfonamides sulfonyl halides amines/anilines Sulfonate esters sulfonyl halides phenols/alcohols Alkyl thiol a,(hmsa.turatcd ester thiols Alkyl ethers a,jl-unsatumtcd ester alcohols Alkyl amines a,~-unsatumted ester amines 15 Alkyl thiol Vmyl sulfone thiols Alkyl ethers Vmyi5Ulfone alcohols alloc Alkyl amines Vmyl sulfone amines H3C\ lH3 Vmyl sulfide Propargyl amide thiol _..,..si'-. (H3C)JC 20 TBDMS Use of Protecting Groups In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the 25 Teoc Bo' reactions. Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In one embodiment, each protective group be removable by a 30 different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid 35 labile and may be used to protect carboxy and hydroxy reac tive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile 40 groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such Fmoc as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. Other protecting groups, plus a detailed description of 45 Carboxylic acid and hydroxy reactive moieties may also be techniques applicable to the creation ofprotecting groups and blocked with hydrolytically removable protective groups their removal are described in Greene and Wuts, Protective such as the benzyl group, while amine groups capable of Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, hydrogen bonding with acids may be blocked with base labile New York, N.Y., 1999, and Kocienski, Protective Groups, groups such as Fmoc. Carboxylic acid reactive moieties may 50 Theme Verlag, New York, N.Y., 1994, which are incorporated be protected by conversion to simple ester compmmds as herein by reference in their entirety. exemplified herein, or they may be blocked with oxidatively Synthesis of Compounds removable protective groups such as 2,4-dimethoxybenzyl, In certain embodiments, provided herein are methods of while co-existing amino groups may be blocked with fluoride making and methods of using tyrosine kinase inhibitor com- labile silyl carbamates. 55 pounds described herein. In certain embodiments, com pounds described herein can be synthesized using the follow Allyl blocking groups are useful in then presence of acid ing synthetic schemes. Compounds may be synthesized using groups since the former are stable and and base-protecting methodologies analogous to those described below by the use can be subsequently removed by metal or pi-acid catalysts. of appropriate alternative starting materials. For example, an allyl-blocked carboxylic acid can be depro- 60 Described herein are compounds that inhibit the activity of 0 tected with a Pd -catalyzed reaction in the presence of acid tyrosine lOnase(s ), such as Btk, and processes for their prepa labile t-butyl carbamate or base-labile acetate amine protect ration. Also described herein are pharmaceutically acceptable ing groups. Yet another form of protecting group is a resin to salts, pharmaceutically acceptable solvates, pharmaceuti which a compound or intermediate may be attached. As long cally active metabolites and pharmaceutica11y acceptable as the residue is attached to the resin, that functional group is 65 prodrugs of such compounds. Pharmaceutical compositions blocked and cannot react. Once released from the resin, the that include at least one such compound or a pharmaceuti functional group is available to react. cally acceptable salt, pharmaceutically acceptable solvate, us 8,008,309 82 55 56 pharmaceutically active metabolite or pharmaceutically -continued acceptable prodrug of such compound, are provided. The starting material used for the synthesis of the com pounds described herein may be synthesized or can be 5 obtained .from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Tor + rance, Calif), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds having different substituents can be synthesized using tech- 10 niques and materials known to those of skill in the art, such as 2 described, for example, in March, ADVANCED ORGANIC CHEMIS lRY 4"' Ed., (Wiley 1992); Carey and Sundherg, ADvANcED 1 ORGANIC CHEMISTRY 4 h Ed., Vols. A and B (Plenum 2000, Diisopropyl a.zodicarboxylate 2001 ); Green and Wuts, PROTECTIVE GROUPS INORGANIC SYNTIIE- IS resin bound PPb3, 24 hr srs 3m Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (Joha Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 20 1991); and Larock's Comprehensive Organic Transforma tions (VCH Publishers Inc., 1989). (all of which are incorpo rated by reference in their entirety). Other methods for the l.) 4.0M HCI/dioXJllle, synthesis of compounds described herein may be found in 25 ~N 2m International Patent Publication No. WO 01/01982901, I 2.) Acryloyl chloride, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 CH2CI2, TEA (2000) 2167-2170; Burchet et al. Bioorganic & Medicinal RT., 2 hr Chemistry Letters 12 (2002) 1687-1690. General methods for the preparation of compound as disclosed herein may be 30 derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and con 0--<"~'-0 ditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods 35 may be utilized. The products of the reactions may be isolated and purified, if desired, using conventional techniques, inc1uding, but not limited to, filtration, distillation, crystallization, chromatog raphy and the like. Such materials may be characterized using 40 NH, conventional means, including physical constants and spec tral data. Compounds described herein may be prepared using the ~N I synthetic methods described herein as a single isomer or a 45 N mixture of isomers. A non-limiting example of a synthetic approach towards the preparation ofcompounds of any of Formula (A), (B), (C) or (D) is shown in Scheme I. b~--r 50 0 4

NH, Halogenation of commercially available 1H-pyrazolo[3,4- 55 d]pyrimid.in-4-amine provides an entry into the synthesis of N-iodosuccinamide compounds of Formula (A), (B), (C) and/or (D). In one DMF,beat ~~N embodiment, 1H-pyrazolo[3,4-d]pyrimidin-4-amine is ~NJ__~~ treated with N-iodosuccinamide to give 3-iodo-1H-pyrazolo [3,4-d]pyrimidin-4-amine. Metal catalyzed cross coupling 60 reactions are then carried out on 3-iodo-1H-pyrazolo[3,4-d] pyrimid.in-4-amine. In one embodiment, palladium mediated cross-coupling of a suitably substituted phenyl boronic acid under basic conditions constructs intermediate 2. Intermedi cat. Pd(dppf)CI2 CH2CI2 ate 2 is coupled with N-Boc-3-hyd.roxypiperidine (as non- aq. K2COYdioxnnc 65 limiting example) via Mitsunobu reaction to give the Boc microwave, 180° C., 10 min (tert-butyloxycarbonyl) protected intermediate 3. After deprotection with acid, coupling with, but not limited to, an US 8,008,309 B2 57 58 acid chloride, such as, but not limited to, acryloyl chloride, In some embodiments, compounds described herein are completes the synthesis to give compound 4. prepared as prodrugs. A "prodrug" refers to an agent that is Using the synthetic methods described herein, as well as converted into the parent drug in vivo. Prodrugs are often those known in the art, tyrosine kinase inhibitors as disclosed useful because, in some situations, they may be easier to herein are obtained in good yields and purity. The compounds administer than the parent drug. They may, for instance, be prepared by the methods disclosed herein are purified by bioavailable by oral administration whereas the parent is not. conventional means known in the art, such as, for example, The prodrug may also have improved solubility in pharma filtration, recrystallization, chromatography, disti1lation, and ceutical compositions over the parent drug. An example, combinations thereof. without limitation, of a prodrug would be a compound Any combination of the groups described above for the 10 described herein, which is administered as an ester (the "pro drug") to facilitate transmittal across a cell membrane where various variables is contemplated herein. It is understood that water solubility is detrimental to mobility but which then is substituents and substitution patterns on the compounds pro metabo1ically hydrolyzed to the carboxylic acid, the active vided herein can be selected by one of ordinary skill in the art entity, once inside the cell where water-solubility is benefi to provide compounds that are chemically stable and that can 15 ciaL A further example of a prodrug might be a short peptide be synthesized by techniques known in the art, as well as (polyaminoacid) bonded to an acid group where the peptide is those set forth herein. metabolized to reveal the active moiety. In certain embodi Further Forms of Compounds ments, upon in vivo administration, a prodrug is chemically Compounds disclosed herein have a structure of any of converted to the biologica1ly, pharmaceutically or therapeu Formula (A), Formula (B), Formula (C), or Formula (D). It is 20 tically active form of the compound. In certain embodiments, understood that when reference is made to compounds a prodrug is enzymatically metabolized by one or more steps described herein, it is meant to include compounds of any of or processes to the biologically, pharmaceutically or thera Formula (A), Formula (B), Formula (C), or Formula (D), as peutically active form of the compound. To produce a pro well as to all of the specific compounds that fall within the drug, a pharmaceutically active compound is modified such scope of these generic formulae, unless otherwise indicated. 25 that the active compound will be regenerated upon in vivo The compounds described herein may possess one or more administration. The prodrug can be designed to alter the stereocenters and each center may exist in the R or S configuM metabolic stability or the transport characteristics ofa drug, to ration. The compounds presented herein include all diasteM mask side effects or toxicity, to improve the flavor of a drug or reomeric, enantiomeric, and epimeric forms as well· as the to alter other characteristics or properties of a drug. By virtue appropriate mixtures thereof. Stereoisomers may be 30 of knowledge of pharmacodynamic processes and drug obtained, if desired, by methods known in the art as, for metabolism in vivo, those of skill in this art, once a pharma example, the separation of stereoisomers by chiral chromatoM ceutically active compound is known, can design pro drugs of graphic columns. the compound. (see, for example, Nogrady (1985)Medicinal Diasteromeric mixtures can be separated into their indiM Chemistry A Biochemical Approach, Oxford University vidual diastereomers on the basis of their physical chemical 35 Press, New York, pages 388-392; Silverman (1992), The differences by methods known, for example, by chromatog Organic Chemistry of Drug Design and Drug Action, Aca raphy and/or fractional crystallization. In one embodiment, demic Press, Inc., San Diego, pages 352-401, Saulnier et al., enantiomers can be separated by chiral chromatographic calM (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, umns. In other embodiments, enantiomers can be separated p. 1985). by converting the enantiomeric mixture into a diastereomeric 40 Prodrug forms of the herein described compounds, mixture by reaction with an appropriate optically active com wherein the prodrug is metabolized in vivo to produce a pound (e.g., alcohol), separating the diastereomers and con derivative as set forth herein are included within the scope of verting (e.g., hydrolyzing) the individual diastereomers to the the claims. In some cases, some of the herein described com corresponding pure enantiomers. All such isomers, including pounds may be a prodrug for another derivative or active diastereomers, enantiomers, and mixtures thereof are consid- 45 compound. ered as part of the compositions described herein. Prodrugs are often useful because, in some situations, they The methods and formulations described herein include may be easier to administer than the parent drug. They may, the use ofN-oxides, crystalline forms (also known as poly for instance, be bioavailable by oral administration whereas morphs), or pharmaceutically acceptable salts of compounds the parent is not. The prodrug may also have improved solu described herein, as weii as active metabolites of these comM so bility in pharmaceutical compositions over the parent drug. pounds having the same type of activity. In some situations, Prodrugs may be designed as reversible drug derivatives, for compounds may exist as tautomers. All tautomers are use as modifiers to enhance drug transport to site-specific included within the scope of the compounds presented herein. tissues. In some embodiments, the design of a prodrug In addition, the compounds described herein can exist in increases the effective water solubility. See, e.g., Fedorak et unsolvated as well as solvated forms with pharmaceutically 55 a!., Am. J. Physio/., 269:G210-218 (1995); McLoed eta!., acceptable solvents such as water, ethanol, and the like. The Gastroentero/, 106:405-413 (1994 ); Hochhaus et ai.,Biomed. solvated forms of the compounds presented herein are also Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. considered to be disclosed herein. J. Phannaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Phar Compounds of any of Formula (A), Formula (B), Formula maceutics, 47, 103 (1988); Sinkula et al., J. Phann. &i., (C), or Formula (D) in unoxidizedformcan be prepared from 60 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs os N-oxides of compounds of any of Formula (A), Formula (B), Novel Delivery Systems, Vol. 14 of the AC.S. Symposium Formula (C), or Formula (D) by treating with a reducing Series; and Edward B. Roche, Bioreversible Carriers in Drug agent, such as, but not limited to, sulfur, sulfur dioxide, triph Design, American Pharmaceutical Association and Perga enyl phosphine, lithium borohydride, sodium borohydride, mon Press, 1987, all incorporated herein in their entirety. phosphorus trichloride, tribrornide, or the like in a suitable 65 Sites on the aromatic ring portion of compounds of any of inert organic solvent, such as, but not limited to, acetonitrile, Formula (A), Formula (B), Formula (C), or Formula (D) can ethanol, aqueous dioxane, or the like at 0 to 80° C. be susceptible to various metabolic reactions, therefore incor- us 8,008,309 82 59 60 poration of appropriate substituents on the aromatic ring It should be understood that a reference to a pharmaceuti structures, such as, by way of example only, halogens can cally acceptable salt includes the solvent addition forms or reduce, minimize or eliminate this metabolic pathway. crystal forms thereof, particularly solvates or polymorphs. Compounds described herein include isotopically-labeled Solvates contain either stoichiometric or non-stoichiometric compounds, which are identical to those recited in the various amounts of a solvent, and may be formed during the process formulas and structures presented herein, but for the fact that of crystallization with pharmaceutically acceptable solvents one or more atoms are replaced by an atom having an atomic such as water, ethanol, and the like. Hydrates are formed mass or mass number different from the atomic mass or mass when the solvent is water, or alcoholates are formed when the number usually found in nature. Examples of isotopes that solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or fOrmed during the processes can be incorporated into the present compounds include iso- 10 described herein. In addition, the compounds provided herein topes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2H JH 'JC '4C 'sN 'so t7o 3ss 'sF can exist in unsolvated as well as solvated forms. ln general, 36 the solvated forms are considered equivalent to the unsol Cl, re~pectively. Certain is~topi~ally:Iabel~d c~mp~und~ vated fonns for the purposes of the compounds and methods described herein, for example those into which radioactive 3 14 15 provided herein. isotopes such as H and C are incorporated, are useful in It should be understood that a reference to a salt includes drug and/or substrate tissue distribution assays. Further, sub the solvent adclition forms or crystal forms thereof, particu 2 stitution with isotopes such as deuterium, i.e., H, can afford larly solvates or polymorphs. Solvates contain either sto certain therapeutic advantages resulting from greater meta ichiometric or non-stoichiometric amounts of a solvent, and bolic stability, for example increased in vivo half-life or 20 are often formed during the process of crystallization with reduced dosage requirements. pharmaceutically acceptable solvents such as water, ethanol, In additional or further embodiments, the compounds and the like. Hydrates are formed when the solvent is water, or described herein are metabolized upon administration to an alcoholates are formed when the solvent is alcohol. Polymer organism in need to produce a metabolite that is then used to phs include the different crystal packing arrangements of the produce a desired effect, including a desired therapeutic 25 same elemental composition of a compound. Polymorphs effect. usua1ly have different X-ray diffraction patterns, infrared Compounds described herein may be formed as, and/or spectra, melting points, density, hardness, crystal shape, opti used as, pharmaceutically acceptable salts. The type of phar cal and electrical properties, stability, and solubility. Various maceutical acceptable salts, include, but are not limited to: (1) factors such as the recrystallization solvent, rate of crystalli acid addition salts, formed) by reacting the free base form of 30 zation, and storage temperature may cause a single crystal the compound with a pharmaceutically acceptable: inorganic form to dominate. acid such as hydrochloric acid, hydrobromic acid, sulfuric Compounds described herein may be in various forms, acid, nitric acid, phosphoric acid, metaphosphoric acid, and including but not limited to, amorphous forms, milled forms the like; or with an organic acid such as acetic acid, propionic and nano-particulate forms. In addition, compounds acid, hexanoic acid, cyclopentanepropionic acid, glycolic 35 described herein include crystalline forms, also known as acid, pyruvic acid, lactic acid, malonic acid, succinic acid, polymorphs. Polymorphs include the different crystal pack malic acid, maleic acid, fumaric acid, trifluoroacetic acid, ing arrangements of the same elemental composition of a tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) compound. Polymorphs usually have different X-ray diffrac benzoic acid, cinnamic acid, mandelic acid, methanesulfonic tion patterns, infrared spectra, melting points, density, hard acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hy- 40 ness, crystal shape, optical and electrical properties, stability, droxyethanesulfonic acid, benzenesulfonic acid, toluene and solubility. Various factors such as the recrystallization sulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo solvent, rate of crystallization, and storage temperature may [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4' cause a single crystal form to dominate. methylenebis-(3-hyd.roxy-2-ene-1-carboxylie acid), The screening and characterization of the pharmaceuti 3-phenylpropionic acid, trimethylacetic acid, tertiary buty- 45 ca1ly acceptable salts, polymorphs and/or solvates may be }acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, accomplished using a variety of techniques including, but not hydroxynaphthoic acid, salicylic acid, stearic acid, muconic limited to, thermal analysis, x-ray diffraction, spectroscopy, acid, and the like; (2) salts formed when an acidic proton vapor sorption, and microscopy. 1bermal analysis methods present in the parent compound either is replaced by a metal address thermo chemical degradation or thermo physical pro ion, e.g., an alkali metal ion(e.g.lithium, sodium, potassium), so cesses including, but not limited to, polymorphic transitions, an alkaline earth ion (e.g. magnesium, or calcium), or an and such methods are used to analyze the relationships aluminum ion; or coordinates with an organic base. Accept between polymorphic forms, determine weight loss, to find able organic bases include ethanolamine, diethanolamine, the glass lransition temperature, or for excipient compatibil triethanolamine, tromethamine, N-methylglucamine, and the ity studies. Such methods include, but are not limited to, like. Acceptable inorganic bases include aluminum hydrox- 55 Differential scanning calorimetry (DSC), Modulated Differ ide, calcium hydroxide, potassium hydroxide, sodium car ential Scanning Calorimetry (MDCS), Thermogravimetric bonate, sodium hydroxide, and the like. analysis (TGA), and Thermogravi-metric and Infrared analy The corresponding counterions of the pharmaceutically sis (TGIIR). X-ray cliffraction methods include, but are not acceptable salts may be analyzed and identified using various limited to, single crystal and powder diffractometers and methods including, but not limited to, ion exchange chroma- 60 synchrotron sources. The various spectroscopic techniques tography, ion chromatography, capillary electrophoresis, used include, but are not limited to, Raman, FTIR, UV1S, and inductively coupled plasma, atomic absorption spectroscopy, NMR (liquid and solid state). The various microscopy tech mass spectrometry, or any combination thereof. niques include, but are not limited to, polarized light micros The salts are recovered by using at least one of the follow copy, Scanning Electron Microscopy (SEM) with Energy ing techniques: filtration, precipitation with a non-solvent 65 Dispersive X-Ray Analysis (EDX), Environmental Scanning followed by filtration, evaporation of the solvent, or, in the Electron Microscopy with EDX (in gas or water vapor atmo case of aqueous solutions, lyophilization. sphere), IR microscopy, and Raman microscopy. us 8,008,309 82 61 62 Throughout the specification, groups and substituents and a co-agent, are administered to a patient as separate thereof can be chosen by one skilled in the field to provide entities either simultaneously, concurrently or sequentially stable moieties and compounds. with no specific intervening time limits, wherein such admin- Pharmaceutical Composition/Formulation istration provides effective levels ofthetwo compounds in the Pharmaceutical compositions may be formulated in a con~ s body of the patient. The latter also applies to cocktail therapy, ventional manner using one or more physiologically acceptR e.g. the ad.m.inistration of three or more active ingredients. able carriers including excipients and auxiliaries which facili The pharmaceutical formulations described herein can be tate processing of the active compounds into preparations administered to a subject by multiple administration routes, which can be used pharmaceutically. Proper formulation is including but not limited to, oral, parenteral (e.g., intrave dependent upon the route of administration chosen. Any of 10 nous, subcutaneous, intramuscular), intranasal, buccal, topi the well-known teclmiques, carriers, and excipients may be cal, rectal, or transdennal administration routes. The pharma- used as suitable and as understood in the art. A summary of ceutical formulations described herein include, but are not pharmaceutical compositions described herein may be found, limited to, aqueous liquid dispersions, self-emulsifying dis for example, in Remington: The Science and Practice of persions, solid solutions, liposomal dispersions, aerosols, Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing 15 solid dosage forms, powders, immediate release formula Company, 1995); Hoover, John E., Remington's Phannaceu~ tions, controlled release formulations, fast melt formulations, tical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liber tablets, capsules, pills, delayed release formulations, man, H. A and Lachman, L., Eds., Phannaceutical Dosage extended release formulations, pulsatile release formulations, Fonns, Marcel Decker, New York, N.Y., 1980; andPhamw multiparticulate formulations, and mixed immediate and con ceutical Dosage Fon11s and Drug Delivery Systems, Seventh 20 trolled release formulations. Ed. (Lippincott Williams & Wilkins 1999), herein incorpo Pharmaceutical compositions including a compound rated by reference in their entirety. described herein may be manufactured in a conventional A pharmaceutical composition, as used herein, refers to a manner, such as, by way of example only, by means of con- mixture of a compound described herein, such as, for ventional mixing, dissolving, granulating, dragee-making, example, compounds of any of Formula (A), Formula (B), 25 levigating, emulsifying, encapsulating, entrapping or com Formula (C), or Formula (D), with other chemical compo pression processes. nents, such as carriers, stabilizers, diluents, dispersing agents, The pharmaceutical compositions will include at least one suspending agents, thickening agents, and/orexcipients. The compound described herein, such as, for example, a com pharmaceutical composition facilitates administration of the pound of any of Formula (A), Formula (B), Formula (C), or compound to an organism. In practicing the methods of treat~ 30 Formula (D), as an active ingredient in free-acid or free-base ment or use provided herein, therapeutically effective form, or in a pharmaceutically acceptable salt form. In addi- amounts of compounds described herein are administered in tion, the methods and pharmaceutical compositions a pharmaceutical composition to a mammal having a disease, described herein include the use of N-oxides, crystalline disorder, or condition to be treated. Preferably, the mammal is forms (also known as polymorphs), as well as active metabo a human. A therapeutically effective amount can vary widely 35 lites of these compounds having the same type of activity. In depending on the severity of the disease, the age and relative some situations, compounds may exist as tautomers. All tau~ health of the subject, the potency of the compound used and tamers are included within the scope of the compounds pre other factors. The compounds can be used singly or in com sented herein. Additionally, the compounds described herein bination with one or more therapeutic agents as components can exist in unsolvated as well as solvated forms with phar- of mixtures. 40 maceutically acceptable solvents such as water, ethanol, and In certain embodiments, compositions may also include the like. The solvated forms of the compounds presented one or more pH adjusting agents or buffering agents, includ herein are also considered to be disclosed herein. ing acids such as acetic, boric, citric, lactic, phosphoric and "Antifoaming agents" reduce foaming during processing hydrochloric acids; bases such as sodium hydroxide, sodium which can result in coagulation of aqueous dispersions, phosphate, sodium borate, sodium citrate, sodium acetate, 45 bubbles in the finished film, or generally impair processing. sodium lactate and tris-hydroxymethylaminomethane; and Exemplary anti-foaming agents include silicon emulsions or buffers such as citrate/dextrose, sodium bicarbonate and sorbitan sesquoleate. ammonium chloride. Such acids, bases and buffers are ''Antioxidants" include, for example, butylated hydroxy included in an amount required to maintain pH of the com toluene (BHT), sodium ascorbate, ascorbic acid, sodium met- position in an acceptable range. 50 abisulfite and tocopherol. In certain embodiments, antioxi In other embodiments, compositions may also include one dants enhance chemical stability where required. or more sa1ts in an amount required to bring osmolality of the In certain embodiments, compositions provided herein composition into an acceptable range. Such salts include may also include one or more preservatives to inhibit micro those having sodium, potassium or ammonium cations and bial activity. Suitable preservatives include mercury-contain chloride, citrate, ascorbate, borate, phosphate, bicarbonate, 55 ing substances such as merfen and thiomersal; stabilized sulfate, thiosulfate or bisulfite anions; suitable salts include chlorine dioxide; and quaternary ammonium compounds sodium chloride, potassium chloride, sodium thiosulfate, such as benzalkonium chloride, celyltrimethylammonium sodium bisulfite and ammonium sulfate. bromide and cetylpyridinium chloride. The term ''pharmaceutical combination" as used herein, Formulations described herein may benefit from antioxi means a product that results from the mixing or combining of 60 dants, metal chelating agents, thiol containing compounds more than one active ingredient and includes both fixed and and other general stabilizing agents. Examples of such stabi non-fixed combinations of the active ingredients. The term lizing agents, include, but are not limited to: (a) about 0.5% to "fixed combination" means that the active ingredients, e.g. a about 2% w/v glycerol, (b) about 0.1% to about 1% w/v compound described herein and a co-agent, are both admin methionine, (c) about 0.1% to about 2% w/v monothioglyc istered to a patient simultaneously in the form of a single 65 erol, (d) about 1 mMtoabout 10mMEDTA, (e)about0.01% entity or dosage. The term "non-fixed combination" means to about2% w/v ascorbic acid, (f) 0.003% to about0.02%w/v that the active ingredients, e.g. a compound described herein polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate US 8,008,309 B2 63 64 20, (h) arginine, (i) heparin, 6) dextran sulfate, (k) cyclodex poloxamers (e.g., Pluronics F68®, FSS®, andFlO®S, which trins, (1) pentosan polysulfate and other heparinoids, (m) are block copolymers of ethylene oxide and propylene divalent cations such as magnesium and zinc; or (n) combi~ oxide); and poloxamines (e.g., Tetronic 90S®, also known as nations thereof. Poloxamine 90S®, which is a tetrafonctional block copoly- "Binders" impart cohesive qualities and include, e.g., alg 5 mer derived from sequential addition of propylene oxide and inic acid and salts thereof; cellulose derivatives such as car ethylene oxide to ethylenediamine (BASF Corporation, Par boxymethylcellulose, methylcellulose (e.g., Methocel®), sippany, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrroli hydroxypropylmethylcellulose, hydroxyethylcellulose, done K17, polyvinylpyrrolidone K25, or polyvinylpyrroli~ hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., done K30, polyvinylpyrrolidone/vinyl acetate copolymer Ethocel®), and microcrystalline cellulose (e.g., Avice!®); 10 (S-630), polyethylene glycol, e.g., the polyethylene glycol microcrystalline dextrose; amylose; magnesium aluminum can have a molecular weight of about 300 to about 6000, or silicate; polysaccharide acids; bentonites; gelatin; polyvi about 3350 to about 4000, or about 7000 to about 5400, nylpyrrolidone/vinyl acetate copolymer; crosspovidonc; sodium carboxymethylcellulose, methylcel1ulose, polysor povidone; starch; pregelatinized starch; tragacanth, dextrin, a bate-SO, sodium alginate, gums, such as, e.g., gum tragacanth sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, 15 and gum acacia, guar gum, xanthans, including xantban gum, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and sugars, cellulosics, such as, e.g., sodium carboxymethylcel lactose; a natural or synthetic gum such as acacia, tragacanth, lulose, methylcellulose, sodium carboxymethylcellulose, ghatti gum mucilage of isapol husks, polyvinylpyrrolidone polysorbate-SO, sodium alginate, polyethoxylated sorbitan (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® monolaurate, polyethoxylated sorbitan monolaurate, povi- XL-I 0), larch arabogalactan, Veegum®, polyethylene glycol, 20 done, carbomers, polyvinyl alcohol (PVA), alginates, chi to waxes, sodium alginate, and the like. sans and combinations thereof. Plasticizcers such as cellulose A "carrier'' or "carrier materials" include any commonly or triethyl cellulose can also be used as dispersing agents. used excipients in pharmaceutics and should be selected on Dispersing agents particularly useful in liposomal disper the basis of compatibility with compounds disclosed herein, sions and self-emulsifYing dispersions are dimyristoyl phos- such as, compounds of any of Formula (A), Formula (B), 25 phatidyl choline, natura] phosphatidyl choline from eggs, Formula (C), or Formula (D), and the release profile proper natural phosphatidyl glycerol from eggs, cholesterol and iso ties of the desired dosage form Exemplary carrier materials propyl myristate. include, e.g., binders, suspending agents, disintegration Combinations of one or more erosion facilitator with one or agents, fi1ling agents, surfactants, solubilizers, stabilizers, more diffusion facilitator can also be used in the present lubricants, wetting agents, diluents, and the like. "Pharma 30 compositions. ceutically compatible carrier materials" may include, but are The term "diluent" refers to chemical compounds that are not limited to, acacia, gelatin, colloidal silicon dioxide, cal used to dilute the compound of interest prior to delivery. cium glycerophosphate, calcium lactate, maltodextrin, glyc Diluents can also be used to stabilize compounds because erine, magnesiumsi1icate, polyvinylpyrrollidone (PVP), cho they can provide a more stable environment Salts dissolved in lesterol, cholesterol esters, sodium caseinate, soy lecithin, 35 buffered solutions (which also can provide pH control or taurocholic acid, phosphotidylcholine, sodium chloride, tri maintenance) are utilized as diluents in the art, including, but calcium phosphate, dipotassium phosphate, cellulose and not limited to a phosphate buffered saline solution. In certain ceilulose conjugates, sugars sodium stearoyllactylate, carra embodiments, diluents increase bulk of the composition to geenan, monoglyceride, diglyceride, pregelatinized starch, facilitate compression or create sufficient bulk for homog- and the like. See, e.g., Remington: The Science and Practice 40 enous blend for capsule filling. Such compounds include e.g., ofPharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing lactose, starch, mannitol, sorbitol, dextrose, microcrystalline Company, 1995); Hoover, John E., Remington's Phannaceu cellulose such as Avice!®; dibasic calcium phosphate, dical tical Sciences, Mack Publishing Co., Easton, Pa. 1975; Libet cium phosphate dihydrate; tricalcium phosphate, calcium man, H. A. and Laclunan, L., Eds., Pharmaceutical Dosage phosphate; anhydrous lactose, spray-dried lactose; pregelati- Fonns, Marcel Decker, New York, N.Y., 19SO; and Phamw 45 nized starch, compressible sugar, such as Di-Pac® (Amstar); ceutica/ Dosage Forms and Drug Delivery Systems, Seventh mannitol, hydroxypropylmethylcellulose, hydroxypropylm Ed. (Lippincott Willians & Willins 1999). etbylcellulose acetate stearate, sucrose-based diluents, con "Dispersing agents," and/or "viscosity modulating agents" fectioner's sugar; monobasic calcium sulfate monohydrate, include materials that control the diffusion and homogeneity calcium sulfate dihydrate; calcium lactate trihydrate, dex- of a drug through liquid media or a granulation method or 50 trates; hydrolyzed cereal solids, amylose; powdered cellu blend method. In some embodiments, these agents a1so facili lose, calcium carbonate; glycine, kaolin; mannitol, sodium tate the effectiveness of a coating or eroding matrix. Exem chloride; inositol, bentonite, and the like. plary diffusion facilitators/dispersing agents include, e.g., The term "disintegrate" includes both the dissolution and hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, dispersion of the dosage form when contacted with gas- polyvinylpyrrolidone (PVP; commercially known as Plas 55 trointestinal fluid. "Disintegration agents or disintegrants" done®), and the carbohydrate~based dispersing agents such facilitate the breakup or disintegration of a substance. as, for example, hydroxypropyl celluloses (e.g., HPC, Examples of disintegration agents include a starch, e.g., a H-PC-SL, and HPC-L), hydroxypropyl methylcelluloses natural starch such as com starch or potato starch, a pregela (e.g., HPMC KJOO, RPMC K4M, HPMC K15M, and HPMC tinized starch such as National1551 or Amijel®, or sodium KlOOM), carboxymethylcellulose sodium, methylcellulose, 60 starch glycolate such as Promogel® or Explotab®, a cellu hydroxyethylcellulose, hydroxypropylcellulose, hydrox lose such as a wood product, methylcrystalline cellulose, e.g., ypropylmethylcellulose phthalate, hydroxypropylmethylcel Avice!®, Avice!® PHI OJ, Avice!® PH 102, Avice!® PHJ05, lulose acetate stearate (HPMCAS), noncrystalline cellulose, Elceme® PIOO, Emcocel®, Vivace!®, Ming Tia®, and magnesium aluminum silicate, triethanolamine, polyvinyl Solka-Floc®, methylcellulose, croscarmellose, or a cross- alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer 65 linked cellulose, such as cross-linked sodium carboxymeth (8630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellu ethylene oxide and formaldehyde (also known as tyloxapol), lose, or cross-linked croscarmellose, a cross-linked starch us 8,008,309 82 65 66 such as sodium starch glycolate, a cross-linked polymer such waxes, Stearowet®, boric acid, sodium benzoate, sodium as crosspovidone, a cross-linked polyvinylpyrrolidone, algi acetate, sodium chloride, leucine, a polyethylene glycol (e.g., nate such as alginic acid or a salt of alginic acid such as PEG4000) or a methoxypolyethylene glycol such as Carbo sodium alginate, a clay such as Veegum® HV (magnesium wax™, sodium oleate, sodium benzoate, glyceryl behenate, aluminum silicate), a gum such as agar, guar, locust bean, polyethylene glycol, magnesium or sodium lauryl sulfate, Karaya, pectin, or tragacanth, sodium starch glycolate, ben colloidal silica such as Syloid™, Cab-0-Sil®, a starch such tonite, a natural sponge, a surfactant, a resin such as a cation as com starch, silicone oil, a surfactant, and the like. exchange resin, citrus pulp, sodium lauryl sulfate, sodium A "measurable serum concentration" or "measurable lauryl sulfate in combination starch, and the like. plasma concentration" describes the blood serum or blood "Drug absorption" or "absorption" typically refers to the 10 plasma concentration, typically measured in mg, ~. or ng of process of movement of drug from site of administration of a therapeutic agent per ml, dl, or 1 of blood serum, absorbed drug across a barrier into a blood vessel or the site of action, into the bloodstream after administration. As used herein, e.g., a drug moving from the gastrointestinal tract into the measurable plasma concentrations are typically measured in portal vein or lymphatic system. nglml or ~glml. An "enteric coating" is a substance that remains substan- 15 "Pharmacodynamics" refers to the factors which deter tially intact in the stomach but dissolves and releases the drug mine the biologic response observed relative to the concen in the sma11 intestine or colon. Generally, the enteric coating tration of drug at a site of action. comprises a polymeric material that prevents release in the "Pharmacokinetics" refers to the factors which determine low pH environment of the stomach but that ionizes at a the attainment and maintenance of the appropriate concentra- higher pH, typica1ly a pH of 6 to 7, and thus dissolves suffi 20 tion of drug at a site of action. ciently in the small intestine or colon to release the active "Plasticizers" are compounds used to soften the microen agent therein. capsulation material or film coatings to make them less "Erosion facilitators" include materials that control the brittle. Suitable plasticizers include, e.g., polyethylene gly erosion of a particular material in gastrointestinal fluid. Ero cols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG sion facilitators are generally known to those of ordinary skill 25 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, in the art. Exemplary erosion facilitators include, e.g., hydro triethyl cellulose and triacetin. In some embodiments, plasti philic polymers, electrolytes, proteins, peptides, and amino cizers can also function as dispersing agents or wetting acids. agents. "Filling agents" include compounds such as lactose, cal "Solubilizers" include compounds such as triacetin, trieth- cium carbonate, calcium phosphate, dibasic calcium phos 30 ylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, phate, calcium sulfate, microcrystalline cellulose, cellulose sodium doccusate, vitamin E TPGS, dimethylacetamide, powder, dextrose, dextrntes, dextran, starches, pregelatinized N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvi starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium nylpyrrolidone, hydroxypropylmethyl cellulose, hydrox chloride, polyethylene glycol, and the like. ypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, "Flavoring agents" and/or "sweeteners" useful in the for 35 cholesterol, bile salts, polyethylene glycol200-600, glycofu mulations described herein, include, e.g., acacia syrup, rol, transcutol, propylene glycol, and dimethyl isosorbide and acesulfame K, alitame, anise, apple, aspartame, banana, the like. Bavarian cream berry, black currant, butterscotch, calcium "Stabilizers" include compounds such as any antiox.idation citrate, camphor, caramel, cherry, cherry cream chocolate, agents, buffers, acids, preservatives and the like. cinnamon, bubble gum, citrus, citrus punch, citrus cream, 40 "Steady state," as used herein, is when the amount of drug cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, administered is equal to the amount of drug eliminated within cylamate, dextrose, eucalyptus, eugenol, fructose, fruit one dosing interval resulting in a plateau or constant plasma punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, drug exposure. grape, grapefruit, honey, isomalt,lemon, lime, lemon cream, "Suspending agents" include compounds such as polyvi- monoamm.onium glyrrhizinate (MagnaSweet®), maltol, 45 nylpyrrolidone, e.g., polyvinylpyrrolidone K112, polyvi mannitol, maple, marshmallow, menthol, mint cream, mixed nylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvi berry, neohesperidine DC, neotame, orange, pear, peach, pep nylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate permint, peppermint cream, Prosweet® Powder, raspberry, copolymer (8630), polyethylene glycol, e.g., the polyethyl root beer, rum, saccharin, safrole, sorbitol, spearmint, spear ene glycol can have a molecular weight of about 300 to about mint cream, strawberry, strawberry cream, stevia, sucralose, 50 6000, or about 3350 to about 4000, or about 7000 to about sucrose, sodium saccharin, saccharin, aspartame, acesulfame 5400, sodium carboxymethylcellulose, methylcellulose, potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss hydroxypropylmetllylcellulose, hydroxymethylcellulose cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, acetate stearate, polysorbate-SO, hydroxyethylcellulose, walnut, watermelon, wild cherry, wintergreen, xylitol, or any sodium alginate, gums, such as, e.g., gum tragacanth and gum combination of these flavoring ingredients, e.g., anise-men 55 acacia, guar gum, xanthans, including xanthan gun, sugars, thol, cherry-anise, ciimamon-orange, cherty-cinnamon, cellulosics, such as, e.g., sodium carboxymethylcellulose, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, methylcellulose, sodium carboxymethylcellulose, hydrox menthol-eucalyptus, orange-cream, vanilla-mint, and mix ypropylmethylcellulosc, hydroxyethylcellulose, polysor tures thereof. bate-SO, sodium alginate, polyethoxylated sorbitan monolau- "Lubricants" and "glidants" are compounds that prevent, 60 rate, polyethoxylated sorbitan monolaurate, povidone and the reduce or inhibit adhesion or friction of materials. Exemplary like. lubricants include, e.g., stearic acid, calcium hydroxide, talc, "Surfactants" include compounds such as sodium lawyl sodium stearyllumerate, a hydrocarbon such as mineral oil, sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E or hydrogenated vegetable oil such as hydrogenated soybean TPGS, sorbitan monooleate, polyoxyethylene sorbitan oil (Sterotex®), higher fatty acids and their alkali-metal and 65 monooleate, polysorbates, polaxomers, bile salts, glyceryl alkaline earth metal salts, such as aluminum, calcium, mag monostearate, copolymers of ethylene oxide and propylene nesium, zinc, stearic acid, sodium stearates, glycerol, talc, oxide, e.g., Pluronic® (BASF), and the like. Some other US 8,008,309 B2 67 68 surfactants includepolyoxyethylene fatty acid glycerides and sealed capsules made of gelatin and a plasticizer, such as vegetable oils, e.g., polyoxyethylene (60) hydrogenated cas glycerol or sorbitol. The push-fit capsules can contain the tor oil; and polyoxyethylene alkylethers and alkylphenyl active ingredients in admixture with filler such as lactose, ethers, e.g. octoxynol 10, octoxynol 40. In some embodi binders such as starches, and/or lubricants such as talc or ments, surfactants may be included to enhance physical sta- s magnesium stearate and, optionally, stabilizers. In soft cap bility or for other purposes. sules, the active compounds may be dissolved or suspended in "Viscosity enhancing agents" include, e.g., methyl cellu suitable liquids, such as fatty oils, liquid paraffin, or liquid lose, xanthan gum, carboxymethyl cellulose, hydroxypropyl polyethylene glycols. In addition, stabilizers may be added. cellulose, hydroxypropyhnethyl cellulose, hydroxypropylm All formulations for oral administration should be in dosages ethyl cellulose acetate stearate, hydroxypropylmethyl cellu- 10 suitable for such administration. lose phthalate, carbomer, polyvinyl alcohol alginates, acacia, In some embodiments, the solid dosage forms disclosed chitosans and combinations thereof herein may be in the form of a tablet, (including a suspension "Wetting agents" include compounds such as oleic acid, tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid glyceryl monostearate, sorbitan monooleate, sorbitan mono disintegration tablet, an effervescent tablet, or a caplet), a pill, laurate, triethanolamine oleate, polyoxyethylene sorbitan 15 a powder (including a sterile packaged powder, a dispensable monooleate, polyoxyethylene sorbitan monolaurate, sodium powder, or an effervescent powder) a capsule (including both docusate, sodium oleate, sodium Iaury! sulfate, sodium doc soft or hard capsules, e.g., capsules made from animal-de cusate, triacetin, Tween 80, vitamin E TPGS, ammonium rived gelatin or plant-derived HPMC, or "sprinkle capsules"), salts and the like. solid dispersion, solid solution, bioerodible dosage form, Dosage Forms 20 controlled release formulations, pulsatile release dosage The compositions described herein can be formulated for forms, multiparticulate dosage fonns, pellets, granules, or an administration to a subject via any conventional means aerosol In other embodiments, the pharmaceutical formula including, but not limited to, oral, parenteral (e.g., intrave tion is in the form of a powder. In still other embodiments, the nous, subcutaneous, or intramuscular), buccal, intranasal, pharmaceutical formulation is in the form of a tablet, includ- rectal or transdermal administration routes. As used herein, 25 ing but not limited to, a fast-melt tablet. Additionally, phar the term "subject" is used to mean an animal, preferably a maceutical formulations described herein may be adminis mammal, including a human or non-human. The terms tered as a single capsule or in multiple capsule dosage form. patient and subject may be used interchangeably. In some embodiments, the pharmaceutical formulation is Moreover, the pharmaceutical compositions described administered in two, or three, or fOur, capsules or tablets. herein, which include a compound of any of Formula (A), 30 In some embodiments, solid dosage forms, e.g., tablets, Formula (B), Formula (C), or Formula (D) can be formulated effervescent tablets, and capsules, are prepared by mixing into any suitable dosage form, including but not limited to, particles of a compound of any of Formula (A), Formula (B), aqueous oral dispersions, liquids, gels, syrups, elixirs, slur Formula (C), or Formula (D), with one or more pharmaceu ries, suspensions and the like, for oral ingestion by a patient to tical excipients to form a bulk blend composition. When be treated, solid oral dosage forms, aerosols, controlled 35 referring to these bulk blend compositions as homogeneous, release formulations, fast melt formulations, effervescent for it is meant that the particles of the compound of any of mulations, lyophilized formulations, tablets, powders, pills, Formula (A), Formula (B), Formula (C), or Formula (D), are dragees, capsules, delayed release formulations, extended dispersed evenly throughout the composition so that the com release formulations, pulsatile release formulations, multi position may be readily subdivided into equally effective unit particulate formulations, and mixed immediate release and 40 dosage forms, such as tablets, pills, and capsules. The indi controlled release formulations. vidual unit dosages may also include film coatings, which Pharmaceutical preparations for oral use can be obtained disintegrate upon oral ingestion or upon contact with diluent. by mixing one or more so1id excipient with one or more ofthe These formulations can be manufactured by conventional compounds described herein, optionally grinding the result pharmacological techniques. ing mixture, and processing the mixture of granules, after 45 Conventional pharmacological techniques include, e.g., adding suitable auxiliaries, if desired, to obtain tablets or one or a combination of methods: (1) dry mixing, (2) direct dragee cores. Suitable excipients include, for example, fillers compression, (3) milling, (4) dry or non-aqueous granulation, such as sugars, including lactose, sucrose, mannitol, or sor (5) wet granulation, or (6) fusion. See, e.g., Lachman et al, bitol; cellulose preparations such as, for example, maize The Theory and Practice of Industrial Pharmacy (1986). starch, wheat starch, rice starch, potato starch, gelatin, gum so Other methods include, e.g., spray drying, pan coating, melt tragacanth, methylcellulose, microcrystalline cellulose, granulation, granulation, fluidized bed spray drying or coat hydroxypropylmethylcellulose, sodium carboxymethylcel ing (e.g., wurster coating), tangential coating, top spraying, lulose; or others such as: polyvinylpyrrolidone (PVP or povi tableting, extruding and the like. done) or calcium phosphate. If desired, disintegrating agents The pharmaceutical solid dosage forms described h~rein may be added, such as the cross-linked croscarmellose ss can include a compound described herein and one or more sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt pharmaceutically acceptable additives such as a compatible thereof such as sodium alginate. carrier, binder, filling agent, suspending agent flavoring Dragee cores are provided with suitable coatings. For this agent, sweetening agent, disintegrating agent, dispersing purpose, concentrated sugar solutions may be used, which agent, surfactant, lubricant, colorant diluent solubilizer, may optionally contain gum arabic, talc, polyvinylpyrroli 60 moistening agent, plasticizer, stabilizer, penetration done, carbopol gel, polyethylene glycol, and/or titanium enhancer, wetting agent anti-foaming agent antioxidant, pre dioxide, lacquer solutions, and suitable organic solvents or servative, or one or more combination thereof. In still other solvent mixtures. Dyestuffs or pigments may be added to the aspects, using standard coating procedures, such as those tablets or dragee coatings for identification or to characterize described in Remington's Phannaceutical Sciences, 20th different combinations of active compound doses. 65 Edition (2000), a film coating is provided around the formu Pharmaceutical preparations which can be used orally lation of the compound of any of Formula (A), Formula (B), include push-fit capsules made of gelatin, as well as soft, Formula (C), or Formula (D). In one embodiment, some or all us 8,008,309 82 69 70 of the particles of the compound of any of Formula (A), LF and HS), hydroxyethylcellulose, hydroxypropylce11ulose Formula (B), Formula (C), or Formula (D), are coated. In (e.g., Klucel®, ethylcellulose (e.g., Ethocel®), and microc another embodiment, some or all of the particles of the com rystalline cellulose (e.g., Avice!®), microcrystalline dex pound of any of Formula (A), Formula (B), Formula (C), or trose, amylose, magnesium aluminum silicate, polysaccha Formula (D), are microencapsulated. In still another embodi ride acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl ment, the particles of the compound of any of formula (A), acetate copolymer, crospovidone, povidone, starch, pregela Formula (B), Formula (C), or Formula (D), are not microen tinized starch, tragacanth, dextrin, a sugar, such as sucrose capsulated and are uncoated. (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbi Suitable carriers for use in the solid dosage forms tol, xylitol (e.g., Xylitab®), lactose, a narural or synthetic described herein include, but are not limited to, acacia, gela 10 gum such as acacia, tragacanth, ghatti gum, mucilage of isa tin, colloidal silicon dioxide, calcium glycerophosphate, cal pol husks, starch, polyvinylpyrrolidone (e.g., Povidone®CL, cium lactate, maltodextrin, glycerine, magnesium silicate, Kollidon® CL, Polyplasdone® XL-10, and Povidone® sodium caseinate, soy lecithin, sodium ·chloride, tricalcium K-12), larch arabogalactan, Vecgum®, polyethylene glycol, phosphate, dipotassium phosphate, sodium stearoyllactylate, waxes, sodimn alginate, and the like. carrageenan, monoglyceride, diglyceride, pregelatinized 15 In general, binder levels of 20-70% are used in powder- starch, hydroxypropylmethylcellulose, hydroxypropylmeth filled gelatin capsule formulations. Binder usage level in tab ylcellulose acetate stearate, sucrose, microcrystalline cellu let formulations varies whether direct compression, wet lose, lactose, mannitol and the like. granulation, roller compaction, or usage of other excipients Suitable filling agents for use in the solid dosage forms such as fillers which itself can act as moderate binder. For- described herein include, but are not limited to, lactose, cal 20 mulators skilled in art can determine the binder level for the cium carbonate, calcium phosphate, dibasic calcium phos formulations, but binder usage level of up to 70% in tablet phate, calcium sulfate, microcrystalline cellulose, cellulose formulations is common. powder, dextrose, dextrates, dextran, starches, pregelatinized Suitable lubricants or glidants for use in the solid dosage starch, hydroxypropylmethycellulose (HPMC), hydroxypro forms described herein include, but are not limited to, stearic pylmethycellulose phthalate, hydroxypropylmethylcellulose 25 acid, calcium hydroxide, talc, com starch, sodium stearyl acetate stearate (HPMCAS), sucrose, xylitol, lactitol, manni fumerate, alkali-metal and alkaline earth metal salts, such as tol, sorbitol, sodium chloride, polyethylene glycol, and the aluminum, calcium, magnesium zinc, stearic acid, sodium like. stearates, magnesium stearate, zinc stearate, waxes, In order to release the compound of any of Formula (A), Stearowet®, boric acid, sodium benzoate, sodium acetate, Formula (B), Formula (C), or Formula (D), from a solid 30 sodium chloride, leucine, a polyethylene glycol or a meth dosage form matrix as efficiently as possible, disintegrants oxypolyethylene glycol such as Carbowax™, PEG 4000, are often used in the formulation, especially when the dosage PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyc forms are compressed with binder. Disintegrants help ruptur eryl behenate, glyceryl palmitostearate, glyceryl benzoate, ing the dosage form matrix by swelling or capillary action magnesium or sodium lauryl sulfate, and the like. when moisture is absorbed into the dosage form. Suitable 35 Suitable diluents for use in the solid dosage forms disintegrants for use in the solid dosage forms described described herein include, but are not limited to, sugars (in herein include, but are not limited to, natural starch such as cluding lactose, sucrose, and dextrose), polysaccharides (in com starch or potato starch, a pregelatinized starch such as cluding dextrates andmaltodextrin), polyols (including man National1551 or Amijel®, or sodium starch glycolate such as nitol, xylitol, and sorbitol), cyclodextrins and the like. Promogel® or Explotab®, a cellulose such as a wood prod- 40 The term "non water-soluble diluent" represents com- uct, methylcrystalline cellulose, e.g., Avicel®, Avicel® pounds typically used in the formulation of pharmaceuticals, PHIOI, Avice!® PH102, Avicel® PH105, Elcema® PlOD, such as calcium phosphate, calcium sulfate, starches, modi Emcocel®, Vivace!®, Ming Tia®, and Solka-Floc®, methyl fied starches and microcrystalline cellulose, and microcellu 3 cellulose, croscarmellose, or across-linked cellulose, such as lose (e.g., having a density of about 0.45 glcm , e.g. Avicel, cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), 45 powdered cellulose), and talc. cross-linked carboxymethylcellulose, or cross-linked cros Suitable wetting agents for use in the solid dosage forms carmellose, a cross-linked starch such as sodium starch gly described herein include, for example, oleic acid, glyceryl colate, a cross-linked polymer such as crospovidone, a cross monostearate, sorbitan monooleate, sorbitan monolaurate, linked polyvinylpyrrolidone, alginate such as alginic acid or triethanolamine oleate, polyoxyethylene sorbitan a salt of alginic acid such as sodium alginate, a clay such as so monooleate, polyoxyethylene sorbitan monolaurate, quater Veegum® HV (magnesium aluminum silicate), a gum such as nary ammonium compounds (e.g., Polyquat l():JJ)), sodium agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a docusate, triacetin, vitamin E TPGS and the like. resin such as a cation-exchange resin, citrus pulp, sodium Suitable surfactants for use in the solid dosage forms lauryl sulfate, sodium lauryl sulfate in combination starch, 55 described herein include, for example, sodium lauryl sulfate, and the like. sorbitan monooleate, polyoxyethylene sorbitan monooleate, Binders impart cohesiveness to solid oral dosage form polysorbates, polaxomers, bile salts, glyceryl monostearate, formulations: for powder filled capsule formulation, they aid copolymers of ethylene oxide and propylene oxide, e.g., Plu in plug formation that can be filled into soft or hard shell ronic® (BASF), and the like. Suitable suspending agents for capsules and for tablet formulation, they ensure the tablet 60 use in the solid dosage forms described here include, but are remaining intact after compression and help assure blend not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrroli uniformity prior to a compression or fill step. Materials suit done Kl2, polyvinylpyrrolidone Kl7, polyvinylpyrrolidone able for usc as binders in the solid dosage forms described K25, or polyvinylpyrrolidone 1<30, polyethylene glycol, e.g., herein include, but are not limited to, carboxymethylcellu the polyethylene glycol can have a molecular weight of about lose, methylcellulose (e.g., Methocel®), hydroxypropylm 65 300 to about 6000, orabout3350 to about4000, or about 7000 ethylcellulose (e.g. Hypromellose USP Pharmacoat-603, to about 5400, vinyl pyrrolidone/vinyl acetate copolymer hydroxypropylmethylcellulose acetate stearate {Aqoate HS- (S630), sodium carboxymethylcellulose, methylcellulose, US 8,008,309 B2 71 72 hydroxy-propylmethylcellulose, polysorbate-SO, hydroxy 55 minutes, or Jess than about 60 minutes, after oral admin ethylcellulose, sodium alginate, gums, such as, e.g., gum istration, thereby releasing the formulation into the gas tragacanth and gum acacia, guar gum, xanthans, including trointestinal fluid. xanthan gum, sugars, cellulosics, such as, e.g., sodium car In another aspect, dosage forms may include microencapM boxymethylcellulose, methylcellulose, sodium carboxym- 5 sulated formulations. In some embodiments, one or more ethylcellulose, hydroxypropylmethylcellulose, hydroxyeth other compatible materials are present in the microencapsu ylce11ulose, polysorbate-80, sodium alginate, lation material. Exemplary materials include, but are not lim- polyethoxylated sorbitan monolaurate, polyethoxylated sor ited to, pH modifiers, erosion facilitators, antiMfoaming bitan monolaurate, poVidone and the like. agents, antioxidants, flavoring agents, and carrier materials Suitable antioxidants for use in the solid dosage forms 10 such as binders, suspending agents, disintegration agents, described herein include, for example, e.g., butylated filling agents, surfactants, solubilizers, stabilizers, lubricants, hydroxytoluene (BHT), sodium ascorbate, and tocopherol. wetting agents, and diluents. It should be appreciated that there is considerable overlap Materials useful for the microencapsulation described between additives used in the solid dosage forms described herein include materials compatible with compounds of any herein. Thus, the above-listed additives should be taken as rs of Formula (A), Formula (B), Formula (C), or Formula (D), merely exemplary, and not limiting, of the types of additives which sufficiently isolate the compound of any of Formula that can be included in solid dosage forms described herein. (A), Formula (B), Formula (C), or Formula (D), from other The amounts of such additives can be readily detennined by nonMcompatible excipients. Materials compatible with com one skilled in the art, according to the particular properties pounds of any of Formula (A), Formula (B), Formula (C), or desired. 20 Formula (D), are those that delay the release of the com In other embodiments, one or more layers of the phannaM pounds of any of Formula (A), Formula (B), Formula (C), or ceutical formulation are plasticized. Illustratively, a plasti Formula (D), in vivo. cizer is generally a high boiling point solid or liquid. Suitable Exemplary microencapsulation materials useful for delay plasticizers can be added from about 0.01% to about 500/o by ing the release of the formulations including compounds weight (w/w) of the coating composition. Plasticizers 25 described herein, include, but are not limited to, hydroxypro include, but are not limited to, diethyl phthalate, citrate esters, pyl cellulose ethers (HPC) such as K.lucel® or Nissa HPC, polyethylene glycol, glycerol, acetylated glycerides, triaceM low-substituted hydroxypropyl cellulose ethers (L-HPC), tin, polypropylene glycol, polyethylene glycol, triethyl citM hydroxypropyl methyl cellulose ethers (HPMC) such as Sep rate, dibutyl sebacate, stearic acid, stearol, stearate, and castor pifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, oil. 30 Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, Compressed tablets are solid dosage forms prepared by methylcellulose polymers such as Methocel®-A, hydrox compacting the bulk blend of the formulations described ypropylmethylcellulose acetate stearate Aqoat (HFMLS, HF above. In various embodiments, compressed tablets which LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mix- are designed to dissolve in the mouth wi1l include one or more tures thereof such as E461, Ethocel®, Aqualon®-EC, flavoring agents. In other embodiments, the compressed tabM 35 Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, lets will include a film surrounding the final compressed hydroxyethylcelluloses such as Natrosol®, carboxymethyl- tablet. In some embodiments, the film coating can provide a celhdoses and salts of carboxymethylceliuloses (CMC) such delayed release of the compound of any of Formula (A), as Aqualon®-CMC, polyvinyl alcohol and polyethylene gly Formula (B), Formula (C), or Formula (D), from the formu col co-polymers such as Kollicoat IR®, monoglycerides lation. In other embodiments, the film coating aids in patient 40 (Myverol), triglycerides (KLX), polyethylene glyools, modi compliance (e.g., Opachy® coatings or sugar coating). Film fied food starch, acrylic polymers and mixtures of acrylic coatings including Opad.ry® typically range from about 1% polymers with cellulose ethers such as Eudragit® EPO, to about 3% of the tablet weight. In other embodiments, the Eudragit® L30D-55, Eudragit® FS 30D Eudragit® LI00-55, compressed tablets include one or more excipients. Eudragit® LIOO, Eudragit® SlOO, Eudragit® RDIOO, A capsule may be prepared, for example, by placing the 45 Eudragit® EIOO, Eudragit® Ll2.5, Eudragit® Sl2.5, bulk blend of the formulation of the compound of any of Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate Formula (A), Formula (B), Formula (C), or Formula (D), phthalate, sepifilms such as mixtures of HPMC and stearic described above, inside of a capsule. In some embodiments, acid, cyclodextrins, and mixtures of these materials. the formulations (non-aqueous suspensions and solutions) In still other embodiments, plasticizers such as polyethyl are placed in a soft gelatin capsule. In other embodiments, the so ene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, formulations are placed in standard gelatin capsules or nonM PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic gelatin capsules such as capsules comprising HPMC. In other acid, and triacetin are incorporated into the microencapsula- embodiments, the formulation is placed in a sprinkle capsule, tion material. In other embodiments, the microencapsulating wherein the capsule may be swallowed whole or the capsule material useful for delaying the release of the pharmaceutical may be opened and the contents sprinkled on food prior to 55 compositions is from the USP or the National Formulary eating. In some embodiments, the therapeutic dose is split (NF). In yet other embodiments, the microencapsulation into multiple (e.g., two, three, or four) capsules. In some material is Klucel. In still other embodiments, the microen embodiments, the entire dose of the formulation is delivered capsulation material is methocel. in a capsule form. Microencapsulated compounds of any of Formula (A), In various embodiments, the particles of the compound of 60 Formula (B), Formula (C), or Formula (D), may be formu any of Formula (A), Formula (B), Formula (C), or Formula lated by methods known by one of ordinary skill in the art. (D), and one or more excipients are dry blended and com Such known methods include, e.g., spray drying processes, pressed into a mass, such as a tablet, having a hardness suf spinning disk-solvent processes, hot melt processes, spray ficient to provide a pharmaceutical composition that substan chilling methods, fluidized bed, electrostatic deposition, cen tial1y disintegrates within less than about 30 minutes, less 65 trifugal extrusion, rotational suspension separation, polymer than about 35 minutes, less than about 40 minutes, less than ization at liquid-gas or solid-gas interface, pressure extrusion, about 45 minutes, less than about 50 minutes, less than about or spraying solvent extraction bath. In addition to these, sev- US 8,008,309 B2 73 74 eral chemical techniques, e.g., complex coacervation, solvent to, for example, U.S. Pat. Nos. 4,151,273, 5,281,420, and evaporation, polymer-polymer incompatibility, interfacial 6,083,518, each of which is specifically incorporated by ref polymerization in liquid media, in situ polymerization, in erence. liquid drying, and desolvation in liquid media could also be The pharmaceutical solid oral dosage forms including for used. Furthermore, other methods such as roller compaction, 5 mulations described herein, which include a compound of extrusionlspheronization, coacervation, or nanoparticle coat any of Formula (A), Formula (B), Formula (C), or Formula ing may also be used. (D), can be further formulated to provide a controlled release In one embodiment, the particles of compounds of any of ofthe compound ofFormula (A). Controlled release refers to Formula (A), Formula (B), Formula (C), or Formula (D), are the release of the compound of any of Formula (A), Formula microencapsulated prior to being formulated into one of the 10 (B), Formula (C), or Formula (D), from a dosage form in above forms. Instill another embodiment, some or most of the which it is incorporated according to a desired profile over an particles are coated prior to being further formulated by using extended period oftime. Controlled release profiles include, standard coating procedures, such as those described in Rem for example, sustained release, prolonged release, pulsatile ington's Pharmaceutical Sciences, 20th Edition (2000). release, and delayed release profiles. In contrast to immediate In other embodiments, the solid dosage formulations of the 15 release compositions, controlled release compositions al1ow compounds ofany ofFormu1a (A), Formula (B), Formula (C), delivery of an agent to a subject over an extended period of or Formula (D), are plasticized (coated) with one or more time according to a predetermined profile. Such release rates layers. Illustratively, a plasticizer is generally a high boiling can provide therapeutically effective levels of agent for an point solid or liquid. Suitable plasticizers can be added from extended period of time and thereby provide a longer period about 0.01% to about 50% by weight (w/w) of the coating 20 of pharmacologic response while minimizing side effects as composition. Plasticizers include, but are not limited to, compared to conventional rapid release dosage forms. Such diethyl phthalate, citrate esters, polyethylene glycol, glyc longer periods of response provide for many inherent benefits erol, acetylated glycerides, triacetin, polypropylene glycol, that are not achieved with the corresponding short acting, polyethylene glycol triethyl citrate, dibutyl sebacate, stearic immediate release preparations. acid, stearol, stearate, and castor oil. 25 In some embodiments, the solid dosage forms described In other embodiments, a powder including the formula herein can be formulated as enteric coated delayed release tions with a compound of any of Formula (A), Formula (B), oral dosage forms, i.e., as an oral dosage form of a pharma Formula (C), or Formula (D), described herein, may be for ceutical composition as described herein which utilizes an mulated to include one or more pharmaceutical excipients enteric coating to affect release in the small intestine of the and flavors. Such a powder may be prepared, for example, by 30 gastrointestinal tract. The enteric coated dosage form may be mixing the formulation and optional pharmaceutical excipi a compressed or molded or extruded tablet/mold (coated or ents to form a bu1k blend composition. Additional embodi uncoated) containing granules, powder, pellets, beads or par ments also include a suspending agent and/or a wetting agent. ticles of the active ingredient and/or other composition com This bulk blend is uniformly subdivided into unit dosage ponents, which are themselves coated or uncoated. The packaging or multi-dosage packaging units. 35 enteric coated oral dosage form may also be a capsule (coated In still other embodiments, effervescent powders are also or uncoated) containing pellets, beads or granules of the solid prepared in accordance with the present disclosure. Efferves carrier or the composition, which are themselves coated or cent salts have been used to disperse medicines in water for uncoated. oral administration. Effervescent salts are granules or coarse The term "delayed release" as used herein refers to the powders containing a medicinal agent in a dry mixture, usu- 40 delivery so that the release can be accomplished at some ally composed of sodium bicarbonate, citric acid and/or tar generally predictable location in the intestinal tract more taric acid. When salts of the compositions described herein distal to that which would have been accomplished if there are added to water, the acids and the base react to liberate had been no delayed release alterations. In some embodi carbon dioxide gas, thereby causing "effervescence". ments the method for delay ofrelease is coating. Any coatings Examples of effervescent salts include, e.g., the following 45 should be applied to a sufficient thickness such that the entire ingredients: sodium bicarbonate or a mixture of sodium coating does not dissolve in the gastrointestinal fluids at pH bicarbonate and sodium carbonate, citric acid and/or tartaric below about 5, but does dissolve at pH about 5 and above. It acid. Any acid-base combination that results in the liberation is expected that any anionic polymer exhibiting a pH-depen of carbon dioxide can be used in place of the combination of dent solubility profile can be used as an enteric coating in the sodium bicarbonate and citric and tartaric acids, as long as the 50 methods and compositions described herein to achieve deliv ingredients were suitable for pharmaceutical use and result in ery to the lower gastrointestinal tract. In some embodiments a pH of about 6.0 or higher. the polymers described herein are anionic carboxylic poly In other embodiments, the formulations described herein, mers. In other embodiments, the polymers and compatible which include a compound of Formula (A), are solid disper mixtures thereof, and some of their properties, include, but sions. Methods of producing such solid dispersions are 55 are not limited to: known in the art and include, but are not limited to, for Shellac, also called purified lac, a refined product obtained example, U.S. Pat. Nos. 4,343, 789, 5,340,591, 5,456,923, from the resinous secretion of an insect. This coating dis 5,700,485, 5,723,269, and U.S. Pub. Appl 2004/0013734, solves in media of pH>7; each of which is specifica11y incorporated by reference. In Acrylic polymers. The performance of acrylic polymers still other embodiments, the formulations described herein 60 (primarily their solubility in biological fluids) can vary based are solid solutions. Solid solutions incorporate a substance on the degree and type of substitution. Examples of suitable together with the active agent and other excipients such that acrylic polymers include methacrylic acid copolymers and heating the mixture results in dissolution of the drug and the ammonium methacrylate copolymers. The Eudragit series E, resulting composition is then cooled to provide a solid blend L, S, RL, RS and NE (Rohm Pharma) are available as solu which can be further formulated or directly added to a capsule 65 bilized in organic solvent, aqueous dispersion, or dry pow or compressed into a tablet. Methods ofproducing such solid ders. The Eudragit series~ NE, and RS are insoluble in the solutions are known in the art and include, but are not limited gastrointestinal tract but are permeable and are used primarily US 8,008,309 B2 75 76 for colonic targeting. The Eudragit series E dissolve in the 5,837,284, all of which are specifically incorporated by ref stomach. The Eud.ragit series L, L~30D and S are insoluble in erence. In one embodiment, the controlled release dosage stomach and dissolve in the intestine; form is pulsatile release solid oral dosage form including at Cellulose Derivatives. Examples of suitable cellulose least two groups of particles, (i.e. multiparticulate) each con- derivatives are: ethyl cellulose; reaction mixtures of partial s taining the formulation described herein. The frrst group of acetate esters of cellulose with phthalic anhydride. The per particles provides a substantially immediate dose of the com formance can vary based on the degree and type of substitu pound of any of Formula (A), Formula (B), Formula (C), or tion. Cellulose acetate phthalate (CAP) dissolves in pH>6. Formula (D), upon ingestion by a mammal. The first group of Aquateric (FMC) is an aqueous based system and is a spray particles can be either lUlcoated or include a coating and/or dried CAP psuedolatex with particles <1 Jllll· Other compo 10 sealant. The second group of particles includes coated par Tweens, and acety nents inAquateric can include pluronics, ticles, which includes from about 2% to about 75%, from lated monoglycerides. Other suitable cellulose derivatives about 2.5% to about 700/o, or from about 40% to about 70%, include; cellulose acetate tritne11itate (Eastman); methylcel by weight ofthe total dose ofthe compolUld of any ofFormula lulose (Pharmacoat, Methocel); hydroxypropylmethyl cellu {A), Formula (B), Formula {C), or Formula (D), in said for lose phthalate (HPMCP); hydroxypropylmethyl cellulose 15 succinate (HPMCS); and hydroxypropylmethy!cellulose mulation, in admixture with one or more binders. The coating acetate succinate (e.g., AQOAT (Shin Etsu)). The perfor includes a pharmaceutically acceptable ingredient in an mance can vary based on the degree and type of substitution. amount sufficient to provide a delay of from about 2 hours to For example, HPMCP such as, HP-50, HP-55, HP-SSS, a bout 7 hours following ingestion before release ofthe second HP-SSF grades are suitable. The performance can vary based 20 dose. Suitable coatings include one or more differentially on the degree and type of substitution. For example, suitable degradable coatings such as, by way of example only, pH grades of hydroxypropylmethylcellulose acetate succinate sensitive coatings (enteric coatings) such as acrylic resins include, but are not limited to, AS-LG (LF), which dissolves (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS at pH 5,AS-MG{MF), which dissolves at pH 5.5, andAS-HG 30D Eudragit® LI00-55, Eudragit® L!OO, Eudragit® SIOO, (HF), which dissolves at higher pH. Jbese polymers are 25 Eudragit® RDIOO, Eudragit® EIOO, Eudragit® L 12.5, offered as granules, or as fine powders for aqueous disper Eudragit® S812.5, and Eudragit® NE30D, Eudragit® NE sions; 400®) either alone or blended with cellulose derivatives, Poly Vmyl Acetate Phthalate (PVAP). PVAP dissolves in e.g., ethylcellulose, or non~enteric coatings having variable pH>S, and it is much less permeable to water vapor and thickness to provide differential release of the formulation gastric fluids. 30 that includes a compound of any of Formu1a (A), Formula In some embodiments, the coating can, and usually does, {B), Formula (C), or Formula (D). contain a plasticizer and possibly other coating excipients Many other types of controlled release systems known to such as colorants, talc, and/or magnesium stearate, which are those of ordinary skill in the art and are suitable for use with well known in the art. Suitable plasticizers include triethyl the formulations described herein. Examples of such delivery citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl tri 35 systems include, e.g., polymerMbased systems, such as poly~ ethyl citrate (Citroftec A2), Carbowax 400 (polyethylene gly lactic and polyglycolic acid, polyanhyd.rides and polycapro col 400), diethyl phthalate, tributyl citrate, acetylated lactone; porous matrices, nonpolymer-based systems that are monoglycerides, glycerol, fatty acid esters, propylene glycol, lipids, including sterols, such as cholesterol, cholesterol and dibutyl phthalate. In particular, anionic carboxylic acrylic esters and fatty acids, or neutral fats, such as mono-, di- and polymers usually will contain 10M25% by weight of a plastiM 40 triglycerides; hydrogel release systems; silastic systems; pep cizer, especially dibutyl phthalate, polyethylene glycol, triM tide-based systems; wax coatings, bioerodible dosage forms, ethyl citrate and triacetin. Conventional coating techniques compressed tablets using conventional binders and the like. such as spray or pan coating are employed to apply coatings. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 The coating thickness must be sufficient to ensure that the oral Ed., Vol.!, pp. 209-214 (1990); Singh eta!., Encyclopedia of dosage form remains intact until the desired site of topical 45 Pharmaceutical Technology, znd Ed., pp. 751~753 (2002); delivery in the intestinal tract is reached. U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, Colorants, detackifiers, surfactants, antifoaming agents, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, lubricants (e.g., carnuba wax or PEG) may be added to the 5,977,175, 6,465,014 and 6,932,983, each of which is spe- coatings besides plasticizers to solubilize or disperse the coatM cifically incorporated by reference. ing material, and to improve coating performance and the 50 In some embodiments, pharmaceutical formulations are coated product. provided that include particles of the compounds of any of In other embodiments, the fOrmulations described herein, Formula (A), Formula (B), Formula {C), or Formula {D), which include a compound of Formula (A), are delivered described herein and at least one dispersing agent or suspend using a pulsatile dosage form A pulsatile dosage form is ing agent for oral administration to a subject. The formula- capable of providing one or more immediate release pulses at 55 tions may be a powder and/or granules for suspension, and predetermined time points after a controlled Jag time or at upon admixture with water, a substantially uniform suspen specific sites. Pulsatile dosage forms including the formulaM sion is obtained. tions described herein, which include a compound of any of Liquid formulation dosage forms for oral administration Formula (A), Formula {B), Formula {C), or Formula (D), may can be aqueous suspensions selected from the group includ be administered using a variety of pulsatile formulations 60 ing, but not limited to, pharmaceutically acceptable aqueous known in the art. For example, such formulations include, but oral dispersions, emulsions, solutions, elixirs, gels, and syr- are not limited to, those described in U.S. Pat. Nos. 5,011,692, ups. See, e.g., Singh et al., Encyclopedia ofpharmaceutical 5,017,381, 5,229,135, and 5,840,329, each of which is spe Technology, 2"d Ed., pp. 754-757 (2002). In addition to the cifically incorporated by reference. Other pulsatile release particles of compound of Formula (A), the liquid dosage dosage forms suitable for use with the present formulations 65 forms may include additives, such as: (a) disintegrating include, but are not limited to, for example, U.S. Pat. Nos. agents; (b) dispersing agents; (c) wetting agents; (d) at least 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and one preservative, (e) viscosity enhancing agents, (t) at least US 8,008,309 B2 77 78 one sweetening agent, and (g) at least one flavoring agent. In vinylpyrrolidone (PVP); hydroxypropylcellulose and some embodiments, the aqueous dispersions can further hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and include a crystalline inhibitor. HPC-L); hydroxypropyl methylcellulose and hydroxypropyl The aqueous suspensions and dispersions described herein methylcellulose ethers (e.g. HPMC KlOO, HPMC K4M, can remain in a homogenous state, as defined in The USP s HPMC K15M, HPMC Kl OOM, and Pharmacoat® USP 2910 Pharmacists' Pharmacopeia (2005 edition, chapter 905), for (Shin-Etsu)); carboxymethylcellulose sodium; methylcellu at least 4 hours. The homogeneity should be determined by a lose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose sampling method consistent with regard to determining phthalate; hydroxypropylmethyl-cellulose acetate stearate; homogeneity of the entire composition. In one embodiment, non-crystalline cellulose; magnesium aluminum si1icate; tri- an aqueous suspension can be re~suspended into a homog 10 ethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetram enous suspension by physical agitation lasting less than 1 ethylbutyl)-phenol polymer with ethylene oxide and formal minute. In another embodiment, an aqueous suspension can dehyde; poloxamers (e.g., Pluronics F68®, F88®, and be re-suspended into a homogenous suspension by physical F 108®, which arc block copolymers of ethylene oxide and agitation lasting less than 45 seconds. In yet another embodi propylene oxide); or poloxamines (e.g., Tetronic 908®, also ment) an aqueous suspension can be re-suspended into a 15 known as Poloxamine 908®). homogenous suspension by physical agitation lasting less Wetting agents suitable for the aqueous suspensions and than 30 seconds. In still another embodiment, no agitation is dispersions described herein are known in the art and include, necessary to maintain a homogeneous aqueous dispersion. but are not limited to, cetyl alcohol, glycerol monostearate, Examples of disintegrating agents for use in the aqueous polyoxyethylene sorbitan fatty acid esters (e.g., the commer- suspensions and dispersions include, but are not limited to, a 20 cially available Tweens® such as e.g., Tween 20® and Tween starch, e.g., a natural starch such as corn starch or potato 80® (!Cl Specialty Chemicals)), and polyethylene glycols starch, a pregelatinized starch such as National 1551 or (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® Amijel®, or sodium starch glycolate such as Promogel® or (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan Explotab®; a cellulose such as a wood product, methylcrys monooleate, sorbitan monolaurate, triethanolamine oleate, talline ce1lulose, e.g., Avice!®, Avicel® PI-1101, 25 polyoxyethylene sorbitan monooleate, polyoxyethylene sor Avicel®PH102,Avicel® P-105, Elcema® PlOO, Emcocel®, bitan monolaurate, sodium oleate, sodium lauryl sulfate, VJVacel®, Ming Tia®, and Solka-Floc®, methylcellulose, sodium docusate, triacetin, vitamin E TPGS, sodium tauro croscarmellose, or a cross-linked cellulose, such as cross cholate, simethicone, phosphotidylcholine and the like linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross Suitable preservatives for the aqueous suspensions or dis- linked carboxymethylcellulose, or cross-linked croscarmel 30 persions described herein include, for example, potassium lose; a cross-linked starch such as sodium starch glycolate; a sorbate, parabens (e.g., methylparaben and propylparaben), cross-linked polymer such as crospovidone; a cross-linked benzoic acid and its salts, other esters of parahydroxybenzoic polyvinylpyrrolidone; alginate such as alginic acid or a salt of acid such as butylparaben, alcohols such as ethyl alcohol or alginic acid such as sodium alginate; a clay such as Veegum® benzyl alcohol, phenolic compounds such as phenol, or qua- HV (magnesium aluminum silicate); a gum such as agar, 35 ternary compounds such as benzalkonium chloride. Preser guar, locust bean, Karaya, pectin, or tragacanth; sodium vatives, as used herein, are incorporated into the dosage form starch glycolate; bentonite; a natural sponge; a surfactant; a at a concentration sufficient to inhibit microbial growth. resin such as a cation-exchange resin; citrus pulp; sodium Suitable viscosity enhancing agents for the aqueous sus lauryl sulfate; sodium Iaury! sulfate in combination starch; pensions or dispersions described herein include, but are not and the like. 40 limited to, methyl cellulose, xanthan gum, carboxymethyl In some embodiments, the dispersing agents suitable for cellulose, hydroxypropyl cellulose, hydroxypropylmethyl the aqueous suspensions and dispersions described herein are cellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, known in the art and include, for example, hydrophilic poly alginates, acacia, chitosans and combinations thereof. The mers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrroli concentration of the viscosity enhancing agent will depend done (PVP; commercially known as Plasdone®), and the 45 upon the agent selected and the viscosity desired. carbohydrate-based dispersing agents such as, for example, Examples of sweetening agents suitable for the aqueous hydroxypropylcellulose and hydroxypropyl cellulose ethers suspensions or dispersions described herein include, for (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcel example, acacia syrup, acesulfame K, alitame, anise, apple, lulose andhydroxypropyl methylcellulose ethers (e.g. HPMC aspartame, banana, Bavarian cream, berry) black currant, but- K!OO, HPMC K4M, HPMC Kl5M, and HPMC KlOOM), 50 terscotch, calcium citrate, camphor, caramel, cherry, cherry carboxymethylcellulose sodium, methylcellulose, hydroxy cream, chocolate, cinnamon, bubble gum, citrus, citrus ethylcellulose, hydroxypropylmethyl-ce11ulose phthalate, punch, citrus cream cotton candy, cocoa, cola, cool cherry, hydroxypropylmethyl-cellulose acetate stearate, noncrystal cool citrus, cyclamate, cylamate, dextrose, eucalyptus, line cellulose, magnesium aluminum silicate, triethanola eugenol, fructose, fruit punch, ginger, glycyrrhetinate, gly- mine, polyvinyl alcohol (PVA), polyvinylpyrrolidonelvinyl 55 cyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, acetate copolymer (Plasdone®, e.g., S-630), 4-(1,1,3,3-tet lemon, lime, lemon cream, monoammonium glyrrhlzinate ramethylbutyl)-phenol polymer with ethylene oxide and (MagnaSweet®), maltol, mannitol, maple, marshmallow, formaldehyde (also known as tyloxapol), poloxamers (e.g., menthol, mint cream, mixed berry, neohesperidine DC, Pluronics F68®, F88®, and Fl 08®, which are block copoly neotame, orange, pear, peach, peppermint, peppermint mers of ethylene oxide and propylene oxide); and poloxam 60 cream, Prosweet® Powder, raspberry, root beer, rum, saccha ines (e.g., Tetronic 908®, also known as Poloxamine 908®, rin, sa.frole, sorbitol, spearmint, spearmint cream, strawberry, which is a tetrafunctional block copolymer derived from strawberry cream, stevia, sucralose, sucrose, sodium saccha sequential addition of propylene oxide and ethylene oxide to rin, saccharin, aspartame, acesulfame potassium, mannitol, ethylenediamine (BASF Corporation, Parsippany, N.J.)). In talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, other embodiments, the dispersing agent is selected from a 65 thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild group not comprising one of the following agents: hydro cherry, wintergreen, xyJitol, or any combination of these fla philic polymers; electrolytes; Tween® 60 or 80; PEG; poly- voring ingredients, e.g., anise-menthol, cherry-anise, cinna- US 8,008,309 B2 79 80 man-orange, cherry-cinnamon, chocolate-mint, honey known in the art. See, for example, Ansel, H. C. et al., Phar lemon, lemon-lime, lemon-mint, menthol-eucalyptus, maceutical Dosage Forms and Drug Delivery Systems, Sixth orange-cream, vanilla-mint, and mixtures thereof. In one Ed. (1995). Preferably these compositions and formulations embodiment, the aqueous liquid dispersion can comprise a are prepared with suitable nontoxic pharmaceutically accept sweetening agent or flavoring agent in a concentration rang able ingredients. These ingredients are known to those skilled ing from about 0.001% to about 1.0% the volume of the in the preparation of nasal dosage fOrms and some of these aqueous dispersion. In another embodiment, the aqueous liq can be found in REMINGTON: THE SCIENCE AND uid dispersion can comprise a sweetening agent or flavoring PRACTICE OF PHARMACY, 21 st edition, 2005, a standard agent in a concentration ranging from about 0.005% to about reference in the field. The choice of suitable carriers is highly 0.5% the volume of the aqueous dispersion. In yet another 10 dependent upon the exact nature of the nasal dosage form embodiment, the aqueous liquid dispersion can comprise a desired, e.g., solutions, suspensions, ointments, or gels. Nasal sweetening agent or flavoring agent in a concentration rang dosage forms generally contain large amounts of water in ing from about 0.01% to about 1.0% the volume of the aque addition to the active ingredient. Minor amounts of other ous dispersion. ingredients such as pH adjusters, emulsifiers or dispersing In addition to the additives listed above, the liquid formu- 15 agents, preservatives, surfactants, gelling agents, or buffering lations can also include inert diluents commonly used in the and other stabilizing and solubilizing agents may also be art, such as water or other solvents, solubilizing agents, and present. The nasal dosage form should be isotonic with nasal emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopro secretions. pyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, For administration by inhalation, the compounds of any of benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dim- 20 Formula (A), Formula (B), Formula (C), or Formula (D), ethylformamide, sodium lauryl sulfate, sodium doccusate, described herein may be in a form as an aerosol, a mist or a cholesterol, cholesterol esters, taurocholic acid, phosphoti powder. Pharmaceutical compositions described herein are dylcholine, oils, such as cottonseed oil, grmmdnut oil, corn conveniently delivered in the form of an aerosol spray pre germ oil, olive oil, castor oil, and sesame oil, glycerol, tet sentation from pressurized packs or a nebuliser, with the use rahydrofurfuryl a1cohol, polyethylene glycols, fatty acid 25 of a suitable propellant, e.g., dicblorodifluoromethane, esters of sorbitan, or mixtures of these substances, and the tricblorofluoromethane, dicblorotetrafluoroethane, carbon like. dioxide or other suitable gas. In the case of a pressurized In some embodiments, the pharmaceutical formulations aerosol, the dosage unit may be determined by providing a described herein can be self-emulsifying drug delivery sys valve to deliver a metered amount. Capsules and cartridges of, tems (SEODS). Emulsions are dispersions of one inmiscible 30 such as, by way of example only, gelatin for use in an inhaler phase in another, usually in the form of droplets. Generally, or insufflator may be formulated containing a powder mix of emulsions are created by vigorous mechanical dispersion. the compound described herein and a suitable powder base SEDDS, as opposed to emulsions or microemulsions, spon such as lactose or starch. taneously form emulsions when added to an excess of water Buccal Formulations without any external mechanical dispersion or agitation. An 35 Buccal formulations that include compounds of any of advantage ofSEODS is that only gentle mixing is required to Formula (A), Formula (B), Formula (C), or Formula (D), may distribute the droplets throughout the solution. Additionally, be administered using a variety of formulations known in the water or the aqueous phase can be added just prior to admin art. For example, such formulations include, but are not lim istration, which ensures stability of an unstable or hydropho- ited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and bic active ingredient. Thus, the SEODS provides an effective 40 5,739,136, each of which is specifically incorporated by ref delivery system for oral and parenteral delivery ofhydropho erence. In addition, the buccal dosage forms described herein bic active ingredients. SEDDS may provide improvements in can further include a bioerodible (hydrolysable) polymeric the bioavailability of hydrophobic active ingredients. Meth carrier that also serves to adhere the dosage form to the buccal ods of producing self-emulsifying dosage forms are known in mucosa. The buccal dosage form is fabricated so as to erode the art and include, but are not limited to, for example, U.S. 45 gradually over a predetermined time period, wherein the Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which delivery of the compound of any of Formula (A), Formula is specifically incorporated by reference. (B), Formula (C), or Formula (D), is provided essentially It is to be appreciated that there is overlap between the throughout. Bucca1 drug delivery, as will be appreciated by above-listed additives used in the aqueous dispersions or those skilled in the art, avoids the disadvantages encountered suspensions described herein, since a given additive is often 50 with oral drug administration, e.g., slow absorption, degrada classified differently by different practitioners in the field, or tion ofthe active agent by fluids present in the gastrointestinal is commonly used for any ofseveral different functions. Thus, tract and/or first-pass inactivation in the liver. With regard to the above-listed additives should be taken as merely exem the bioerodible (hydrolysable) polymeric carrier, it will be plary, and not limiting, of the types of additives that can be appreciated that virtually any such carrier can be used, so long included in formulations described herein. The amounts of 55 as the desired drug release profile is not compromised, and the such additives can be readily determined by one skilled in the carrier is compatible with the compound of any of Formula art, according to the particular properties desired. (A), Formula (B), Formula (C), or Formula (D), and any other Intranasal Formulations components that may be present in the buccal dosage unit. Intranasal formulations are known in the art and are Generally, the polymeric carrier comprises hydrophilic (wa described in, for example, U.S. Pat. Nos. 4,476,116, 5,116, 60 ter-soluble and water-swellable) polymers that adhere to the 817 and 6,391 ,452, each of which is specifically incorporated wet surface of the bucca1 mucosa. Examples of polymeric by reference. Formulations that include a compound of any of carriers useful herein include acrylic acid polymers and co, Formula (A), Formula (B), Formula (C), or Formula (D), e.g., those known as "carbomers" (Carbopol®, which may be which are prepared according to these and other techniques obtained from B.F. Goodrich, is one such polymer). Other well-known in the art are prepared as solutions in saline, 65 components may also be incorporated into the bucca] dosage employing benzyl alcohol or other suitable preservatives, forms described herein include, but are not limited to, disin fluorocarbons, and/or other solubilizing or dispersing agents tegrants, diluents, binders, lubricants, flavoring, colorants, us 8,008,309 82 81 82 preservatives, and the like. For buccal or sublingual adminM maintained, for example, by the use of a coating such as istration, the compositions may take the form of tablets, lozM lecithin, by the maintenance of the required particle size in the enges, or gels formulated in a conventional manner. case of dispersions, and by the use of surfactants. Formula- Transdermal Formulations tions suitable for subcutaneous injection may also contain Transdermal formulations described herein may be admin~ s additives such as preserving, wetting, emulsifying, and dis istered using a variety of devices which have been described pensing agents. Prevention of the growth of microorganisms in the art. For example, such devices include, but are not can be ensured by various antibacterial and antifungal agents, limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, such as parabens, chlorobutanol, phenol, sorbic acid, and the 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, like. It may also be desirable to include isotonic agents, such 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 10 as sugars, sodium chloride, and the like. Prolonged absorp 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, tion of the injectable pharmaceutical form can be brought 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, about by the use of agents delaying absorption, such as alu~ 6,923,983, 6,929,801 and 6,946,144, each of which is spe minum monostearate and gelatin. cifically incorporated by reference in its entirety. For intravenous injections, compounds described herein The transdermal dosage forms described herein may incor- 15 may be formulated in aqueous solutions, preferably in physi porate certain pharmaceutically acceptable excipients which ologically compatible buffers such as Hank's solution, Ring are conventional in the art. In one embodiments, the transder er's solution, or physiological saline buffer. Fortransmucosal mal formulations described herein include at least three com administration, penetrants appropriate to the barrier to be ponents: (1) a formulation of a compound of any of Formula permeated are used in the formulation. Such penetrants are (A), Formula (B), Formula (C), or Formula (D); (2) a pen- 20 generally known in the art. For other parenteral injections, ctration enhancer; and (3) an aqueous adjuvant. In addition, appropriate formulations may include aqueous or nonaque~ transdermal formulations can include additional components ous solutions, preferably with physiologically compatible such as, but not limited to, gelling agents, creams and oint buffers or excipients. Such excipients are generally known in ment bases, and the like. In some embodiments, the transder the art. mal formulation can further include a woven or non-woven 25 Parenteral injections may involve bolus injection or con~ backing material to enhance absorption and prevent the tinuous infusion. Formulations for injection may be presented removal of the transdermal formulation from the skin. In in unit dosage form, e.g., in ampoules or in multi-dose con other embodiments, the transdennal formulations described tainers, with an added preservative. The pharmaceutical com herein can maintain a saturated or supersaturated state to position described herein may be in a form suitable for promote diffusion into the skin. 30 parenteral injection as a sterile suspensions, solutions or Formulations suitable for transdermal administration of emulsions in oily or aqueous vehicles, and may contain for- compounds described herein may employ transdermal deliv mulatory agents such as suspending, stabilizing and/or dis ery devices and transdermal delivery patches and can be persing agents. Pharmaceutical formulations for parenteral lipophilic emulsions or buffered, aqueous solutions, dis administration include aqueous solutions of the active com solved and/or dispersed in a polymer or an adhesive. Such 35 pounds in water-soluble form. Additionally, suspensions of patches may be constructed for continuous, pulsatile, or on the active compounds may be prepared as appropriate oily demand delivery of pharmaceutical agents. Still further, injection suspensions. Suitable lipophilic solvents or vehicles transdermal delivery of the compounds described herein can include fatty oils such as sesame oil, or synthetic fatty acid be accomplished by means of iontophoretic patches and the esters, such as ethyl oleate or triglycerides, or liposomes. like. Additionally, transdennal patches can provide con- 40 Aqueous injection suspensions may contain substances trolled delivery of the compounds of any of Formula (A), which increase the viscosity of the suspension, such as Formula (B), Formula (C), or Formula (D). The rate of sodium carboxymethyl cellulose, sorbitol, or dextran. absorption can be slowed by using rate-controlling mem Optionally, the suspension may also contain suitable stabiliz branes or by trapping the compound within a polymer matrix ers or agents which increase the solubility of the compounds or gel. Conversely, absorption enhancers can be used to 45 to allow for the preparation of highly concentrated solutions. increase absorption. An absorption enhancer or carrier can Alternatively, the active ingredient may be in powder form for include absorbable pharmaceuticaUy acceptable solvents to constitution with a suitable vehicle, e.g., sterile pyrogen-free assist passage through the skin. For example, transdermal water, before use. devices are in the form of a bandage comprising a backing Other Formulations member, a reservoir containing the compound optionally 50 In certain embodiments, delivery systems for pharmaceu- with carriers, optionally a rate controlling barrier to deliver tical compounds may be employed, such as, for example, the compound to the skin of the host at a controlled and liposomes and emulsions. In certain embodiments, composi predetermined rate over a prolonged period of time, and tions provided herein can also include an mucoadbesive poly means to secure the device to the skin. mer, selected from among, for example, carboxymethylcel- Injectable Formulations 55 lulose, carbomer (acrylic acid polymer), poly Formulations that include a compound of any of Formula (methylmethacrylate), polyacrylamide, polycarbophil, (A), Formula (B), Formula (C), or Formula (D), suitable for acrylic acid/butyl acrylate copolymer, sodium alginate and intramuscular, subcutaneous, or intravenous injection may dextran. include physiologically acceptable sterile aqueous or non In some embodiments, the compounds described herein aqueous solutions, dispersions, suspensions or emulsions, 60 may be administered topically and can be formulated into a and sterile powders for reconstitution into sterile injectable variety of topically administrable compositions, such as solu solutions or dispersions. Examples of suitable aqueous and tions, suspensions, lotions, gels, pastes, medicated sticks, non-aqueous carriers, diluents, solvents, or vehicles includ- balms, creams or ointments. Such pharmaceutical com ing water, ethanol, polyols (propyleneglycol, polyethylene pounds can contain solubilizers, stabilizers, tonicity enhanc glycol, glycerol, cremophor and the like), suitable mixtures 65 ing agents, buffers and preservatives. thereof, vegetable oils (such as olive oil) and injectable The compounds described herein may also be formulated organic esters such as ethyl oleate. Proper fluidity can be in rectal compositions such as enemas, rectal gels, rectal us 8,008,309 82 83 84 foams, rectal aerosols, suppositories, jelly suppositories, or days, !50 days, 180 days, 200 days, 250 days, 280 days, 300 retention enemas, containing conventional suppository bases days, 320 days, 350 days, or 365 days. The dose reduction such as cocoa butter or other glycerides, as well as synthetic during a drug holiday may be from 10%-100%, including, by polymers such as polyvinylpyrrolidone, PEG, and the like. In way of example only, 10%, 15%, 20%, 25%, 300/o, 35%, 40%, suppository fOrms of the compositions, a low-melting wax s 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, such as, but not limited to, a mixture of fatty acid glycerides, 95%, or 100%. optionally in combination with cocoa butter is first melted. Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Examples of Methods of Dosing and Treatment Subsequently, the dosage or the frequency of administration, Regimens 10 or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is The compounds described herein can be used in the prepa retained. Patients can, however, require intermittent treat ration of medicaments for the inhibition ofBtk or a homolog ment on a long-term basis upon any recurrence of symptoms. thereof or for the treatment of diseases or conditions that The amount of a given agent that will correspond to such an would benefit, at least in part, from inhibition of Btk or a 15 amount will vary depending upon factors such as the particu homolog thereof. In addition, a method for treating any of the lar compound, disease or condition and its severity, the iden~ diseases or conditions described herein in a subject in need of tity (e.g., weight) of the subject or host in need of treatment, such treatment, involves administration of pharmaceutical but can nevertheless be routinely determined in a manner compositions containing at least one compound of any of known in the art according to the particular circumstances Formula (A), Formula (B), Formula (C), or Formula (D), 20 surrounding the case, incJuding, e.g., the specific agent being described herein, or a pharmaceutically acceptable salt, phar administered, the route of administration, the condition being maceutically acceptable N-oxide, pharmaceutically active treated, and the subject or host being treated. In general, metabolite, pharmaceutically acceptable pro drug, or pharma however, doses employed for adult human treatment will ceutically acceptable solvate thereof, in therapeutically effec typically be in the range of 0.02-5000 mg per day, or from tive amounts to said subject. 25 about 1-1500 mg per day. The desired dose may conveniently The compositions containing the compound(s) described be presented in a single dose or as divided doses administered herein can be administered for prophylactic and/or therapeu- simultaneously (or over a short period of time) or at appro tic treatments. In therapeutic applications, the compositions priate intervals, for example as two, three, four or more sub- are administered to a patient already suffering from a disease doses per day. or condition, in an amount sufficient to cure or at least par- 30 The pharmaceutical composition described herein may be tia1ly arrest the symptoms of the disease or condition. in unit dosage forms suitable for single administration of Amounts effective for this use will depend on the severity and precise dosages. In unit dosage form the formulation is course of the disease or condition, previous therapy, the divided into unit doses containing appropriate quantities of patient's health status, weight, and response to the drugs, and one or more compound. The unit dosage may be in the form the judgment of the treating physician. It is considered we11 35 of a package containing discrete quantities ofthe formulation. within the skill of the art for one to determine such therapeu Non-limiting examples are packaged tablets or capsules, and tically effective amounts by routine experimentation (includ powders in vials or ampoules. Aqueous suspension composi ing, but not limited to, a dose escalation clinical trial). tions can be packaged in single-dose non-reclosable contain In prophylactic applications, compositions containing the ers. Alternatively, multiple~dose reclosable containers can be compounds described herein are administered to a patient 40 used, in whlch case it is typical to include a preservative in the susceptible to or otherwise at risk of a particular disease, composition. By way of example only, formulations for disorder or condition. Such an amount is defined to be a parenteral injection may be presented in unit dosage form, "prophylactically effective amount or dose". In this use, the which include, but are not limited to ampoules, or in multi- precise amounts also depend on the patient's state of health, dose containers, with an added preservative. weight, and the like. It is considered well within the skill of 45 The foregoing ranges are merely suggestive, as the number the art for one to determine such prophylactically effective of variables in regard to an individual treatment regime is amounts by routine experimentation (e.g., a dose escalation large, and considerable excursions from these recommended clinical trial). When used in a patient, effective amounts for values are not uncommon. Such dosages may be altered this use will depend on the severity and course of the disease, depending on a number ofvariables, not limited to the activity disorder or condition, previous therapy, the patient's health 50 of the compound used, the disease or condition to be treated, status and response to the drugs, and the judgment of the the mode of administration, the requirements of the indi- treating physician. vidual subject, the severity of the disease or condition being In the case wherein the patient's condition does not treated, and the judgment of the practitioner. improve, upon the doctor's discretion the administration of Toxicity and therapeutic efficacy of such therapeutic regi the compounds may be administered cbronicaJly, that is, for 55 mens can be determined by standard pharmaceutical proce an extended period of time, including throughout the duration dures in cell cultures or experimental animals, including, but of the patient's life in order to ameliorate or otherwise control not limited to, the determination of the LD50 (the dose lethal or limit the symptoms of the patient's disease or condition. to 50% of the population) and the ED)50 (the dose therapeu In the case wherein the patient's status does improve, upon tically effective in 50% of the population). The dose ratio the doctor's discretion the administration of the compounds 60 between the toxic and therapeutic effects is the therapeutic may be given continuously; alternatively, the dose of drug index and it can be expressed as the mtio between LD50 and being administered may be temporarily reduced or tempo ED50• Compounds exhibiting high therapeutic indices are rarily suspended for a certain length of time (i.e., a "drug preferred. The data obtained from cell culture assays and holiday"). The length of the drug holiday can vary between 2 animal studies can be used in formulating a range of dosage days and I year, including by way of example only, 2 days, 3 65 for use in human. The dosage of such compounds lies pref days, 4 days, 5 days, 6 days, 7 days, lOdays, 12 days, 15 days, erably within a range of circulating concentrations that 20 days, 28 days, 35 days, 50 days, 70 days, I 00 days, I 20 include the ED5 0 with minimal toxicity. The dosage may vary US 8,008,309 B2 85 86 within this range depending upon the dosage form employed on the type of co~drug employed, on the specific drug and the route of administration utilized. employed, on the disease or condition being treated and so Combination Treatments forth. In addition, when co-administered with one or more The irreversible Btk inhibitor compositions described biologically active agents, the compound provided herein herein can also be used in combination with other well known 5 may be adnrinistered either simultaneously with the biologi therapeutic reagents that are selected for their therapeutic cally active agents), or sequentially. If administered sequen value for the condition to be treated. ln general, the compo tially, the attending physician will decide on the appropriate sitions described herein and, in embodiments where combi sequence of administering protein in combination with the national therapy is employed, other agents do not have to be biologically active agent(s). administered in the same pbatmaceutical composition, and 1o In any case, the multiple therapeutic agents (one of which may, because of different physical and chemical characteris is a compound of Formula (A), (B), (C), or (D) described tics, have to be administered by different routes. The deter herein) may be administered in any order or even simulta mination of the mode of administration and the advisability of neously. If simultaneously, the multiple therapeutic agents administration, where possible, in the same pharmaceutical may be provided ina single, unified form, orin multiple forms composition, is well within the knowledge of the skilled 15 (by way of example only, either as a single pill or as two clinician. The initial administration can be made according to separate pills). One of the therapeutic agents may be given in established protocols known in the art, and then, based upon multiple doses, or both may be given as multiple doses. Ifnot the observed effects, the dosage, modes of administration and simultaneous, the timing between the multiple doses may times of administration can be modified by the skilled clini~ vary from more than zero weeks to less than four weeks. In cian. 20 addition, the combination methods, compositions and formu~ In certain instances, it may be appropriate to administer at lations are not to be limited to the use of only two agents; the least one irreversible Btk inhlbitor compound described use of multiple therapeutic combinations are also envisioned. herein in combination with another therapeutic agent. By way It is understood that the dosage regimen to treat, prevent, or of example only, if one of the side effects experienced by a ameliorate the condition(s) for which relief is sought, can be patient upon receiving one of the irreversible Btk inhlbitor 25 modified in accordance with a variety of factors. These fac compounds described herein is nausea, then it may be appro~ tors include the disorder from which the subject suffers, as priate to administer an anti~nausea agent in combination with well as the age, weight, sex, diet, and medical condition ofthe the initial therapeutic agent. Or, by way of example only, the subject. Thus, the dosage regimen actually employed can therapeutic efii::ctiveness of one of the compounds described vary widely and therefore can deviate from the dosage regi- herein may be enhanced by administration of an adjuvant 30 mens set forth herein. (i.e., by itself the adjuvant may have minimal therapeutic The pharmaceutical agents which make up the combina benefit, but in combination with another therapeutic agent, tion therapy disclosed herein may be a combined dosage form the overall therapeutic benefit to the patient is enhanced). Or, or in separate dosage forms intended for substantially simul by way of example only, the benefit experienced by a patient taneous administration. The pharmaceutical agents that make may be increased by administering one of the compounds 35 up the combination therapy may also be administered sequen described herein with another therapeutic agent (which also tially, with either therapeutic compound being administered includes a therapeutic regimen) that also has therapeutic ben by a regimen calling for two~step administration. The two efit. In any case, regardless of the disease, disorder or condi step administration regimen may call for sequential adminis tion being treated, the overall benefit experienced by the tration of the active agents or spaced-apart administration of patient may simply be additive of the two therapeutic agents 40 the separate active agents. The time period between the mul or the patient may experience a synergistic benefit. tiple administration steps may range from, a few minutes to The particular choice of compounds used will depend upon several hours, depending upon the properties of each phar the diagnosis of the attending physicians and their judgment maceutical agent, such as potency, solubility, bioavailability, of the condition of the patient and the appropriate treatment plasma half-life and kinetic profile of the pharmaceutical protocol. The compounds may be administered concurrently 45 agent. Circadian variation of the target molecule concentra (e.g., simultaneously, essentially simultaneously or within tion may also determine the optimal dose interval. the same treatment protocol) or sequentially, depending upon In addition, the compounds described herein also may be the nature of the disease, disorder, or condition, the condition used in combination with procedures that may provide addi of the patient, and the actual choice of compounds used. The tional or synergistic benefit to the patient. By way ofexample determination of the order of administration, and the number 50 only, patients are expected to find therapeutic and/orprophy~ of repetitions of administration of each therapeutic agent lactic benefit in the methods described herein, wherein phar during a treatment protocol, is well within the knowledge of maceutical composition ofa compound disclosed herein and/ the skilled physician after evaluation of the disease being or combinations with other therapeutics are combined with treated and the condition of the patient. genetic testing to determine whether that individual is a car- It is known to those of skill in the art that therapeutically~ 55 rier of a mutant gene that is known to be correlated with effective dosages can vary when the drugs are used in treat certain diseases or conditions. ment combinations. Methods for experimentally determining The compounds described herein and combination thera therapeutically~effective dosages of drugs and other agents pies can be administered before, during or after the occur for use in combination treatment regimens are described in rence of a disease or condition, and the timing of ad.minister- the literature. For example, the use of metronomic dosing, 60 ing the composition containing a compound can vary. Thus, i.e., providing more frequent, lower doses in order to mini for example, the compounds can be used as a prophylactic and mize toxic side effects, has been described extensively in the can be administered continuously to subjects with a propen literature Combination treatment further includes periodic sity to develop conditions or diseases in order to prevent the treatments that start and stop at various times to assist with the occurrence of the disease or condition. The compounds and clinical management of the patient. 65 compositions can be administered to a subject during or as For combination therapies described herein, dosages of the soon as possible after the onset of the symptoms. The admin~ co~administered compounds will of course vary depending istration of the compounds can be initiated within the first 48 us 8,008,309 82 87 88 hours of the onset of the symptoms, within the first 6 hours of SB239063, SP600125, BAY 43-9006, wortmannin, or the onset of the symptoms, or within 3 hours of the onset of LY294002; Syk inhibitors; mTOR inhibitors; and antibodies the symptoms. The initial administration can be via any route (e.g., rituxan). practical, such as, for example, an intravenous injection, a Other anti-cancer agents that can be employed in combi bolus injection, infusion over 5 minutes to about 5 hours, a 5 nation with an irreversible Btk inhibitor compound include pill, a capsule, transdermal patch, buccal delivery, and the Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cispl like, or combination thereof. A compound should be admin atin, acivicin; aclarubicin; acodazole hydrochloride; aero- istered as soon as is practicable after the onset of a disease or nine; adozelesin; aldesleukin; altretamine; ambomycin; condition is detected or suspected, and for a length of time ametantrone acetate; aminoglutethimide; amsacrine; anastro necessary for the treatment of the disease, such as, for 10 zole; antbramycin; asparaginase; asperlin; azacitidine; example, from about 1 month to about 3 months. The length azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; of treatment can vary for each subject, and the length can be bleomycin sulfate; brequinar sodium; bropirimine; busulfan; determined using the known criteria. For example, the com cactinomycin; calusterone; caracemide; carbetimer; carbopl pound or a formulation containing the compound can be 15 atin; cannustine; carubicin hydrochloride; car.£elesin; cedef administered for at least 2 weeks, between about 1 month to ingol; chlorambucil; cirolemycin; cladribine; crisnatol mesy- about 5 years, or from about 1 month to about 3 years. late; cyclophosphamide; cytarabine; dacarbazine; Exemplary Therapeutic Agents for Use in Combination with daunorubicin hydrochloride; decitabine; dexoramplatin; an Irreversible Btk Inhibitor Compound dezaguanine; dezaguanine mesylate; diaziquone; doxorubi Where the subject is suffering from or at risk of suffering 20 cin; doxorubicin hydrochloride; droloxifene; droloxifene cit from an autoimmune disease, an inflammatory disease, or an rate; dromostanolone propionate; duazomycin; edatrexate; allergy disease, an irreversible Btk inhibitor compound can be eflornithine hydrochloride; elsamitrucin; enloplatin; enpro used in with one or more of the following therapeutic agents mate; epipropidine; epirubicin hydrochloride; erbulozole; in any combination: immunosuppressants (e.g., tacrolimus, esorubicin hydrochloride; estramustine; estramustine phos cyclosporin, rapamicin, methotrexate, cyclophosphamide, 25 phate sodium; etanidazole; etoposide; etoposide phosphate; azathioprine, mercaptopurine, mycophenolate, or FTY720), etoprine; fadrozole hydrochloride; fazarabine; fenretinide; glucocorticoids (e.g., prednisone, cortisone acetate, pred floxuridine; ftudarabine phosphate; fluorouracil; fluorocitab nisolone, methylprednisolone, dexamethasone, betametha ine; fosquidone; fostriecin sodium; gemcitabine; gemcitab sone, triamcinolone, beclometasone, fludrocortisone acetate, ine hydrochloride; hydroxyurea; idarubicin hydrochloride; deoxycorticosterone acetate, aldosterone), non-steroidal 30 ifosfamide; iimofosine; interleukin 11 (including recombi anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, nant interleukin ll, or riL2), interferon alfa-2a; interferon 2-arylpropionic acids, N-arylanthranilic acids, oxicams, cox alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon ibs, or sulphonanilides), Cox-2-specific inhibitors (e.g., val beta-I a; interferon gamma-I b; iproplatin; irinotecan hydro decoxlb, celecoxib, or rofecoxib), leflunomide, gold thioglu- chloride; lanreotide acetate; letrozole; Ieuprolide acetate; cose, gold thiomalate, aurofin, sulfasalazine, 35 liarozole hydrochloride; lometrexol sodium; lomustine; hydroxychlotoquinine, minocycline, TNF-a binding proteins losoxantrone hydrochloride; masoprocol; maytansine; (e.g., infliximab, etanercept, or adalimumab), abatacept, mechlorethamine hydrochloride; megestrol acetate; anakinra, interferon-~, interferon-y, interleukin-2, allergy melengestrol acetate; melphalan; menogaril; mercaptopu vaccines, antihistamines, antileukotrienes, beta-agonists, rine; methotrexate; methotrexate sodium; metoprine; meture- theophylline, or anticholinergics. 40 depa; mitindomide; mitocarcin; mitocromin; mitogillin; Where the subject is suffering from or at risk of suffering mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone from a B-cell proliferative disorder (e.g., plasma cell hydrochloride; mycophenolic acid; nocodazoie; nogalamy myeloma), the subjected can be treated with an irreversible cin; ormaplatin; oxisuran; pegaspargase; peliomycin; penta- Btk inhibitor compound in any combination with one or more mustine; peplomycin sulfate; perfosfamide; pipobroman; other anti-cancer agents. In some embodiments, one or more 45 piposu]fan; piroxantrone hydrochloride; plicamycin; plom of the anti-cancer agents are proapoptotic agents. Examples estane; porfimer sodium; por.firomycin; prednimustine; proof anti-cancer agents include, but are not limited to, any of the carbazine hydrochloride; puromycin; puromycin hydrochlo following: gossyphol, genasense, polyphenol E, Chlorofusin, ride; pyrazofurin; riboprine; rogletimide; safingol; safingol all trans-retinoic acid (ATRA), bryostatin, tumor necrosis hydrochloride; semustine; simtrazene; sparfosate sodium; 1 factor-related apoptosis-inducing ligand (TRAlL), 5-aza-2 - so sparsomycin; spirogermanium hydrochloride; spiromustine; deoxycytidine, all trans retinoic acid, doxorubicin, vincris spiroplatin; streptonigrin; streptozocin; sulofenur; talisomy- tine, etoposide, gemcitabine, imatinib (Gleevec®), geldana cin; tecogalan sodium; tegafur; teloxantrone hydrochloride; mycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17- temoporfin; teniposide; teroxlrone; testolactone; thiamiprine; AAG), flavopiridol, LY294002, bortezomib, trastuzumab, thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene BAY 11-7082, PKC412, or PD184352, TaxoJTM, also referred 55 citrate; trestolone acetate; triciribine phosphate; trimetrexate; to as "paclitaxel", which is a well-known anti-cancer drug trimetrexate glucuronate; triptorelin; tubulozole hydrochlo- which acts by enhancing and stabilizing microtubule fonna ride; uracil mustard; uredepa; vapreotide; verteporfin; vin tion, and analogs ofTaxol™, such as Taxotere™. Compounds blastine sulfate; vincristine sulfate; vindesine; vindesine sul that have the basic taxane skeleton as a common structure fate; vinepidine sulfate; vinglycinate sulfate; vinleurosine feature, have also been shown to have the ability to arrest cells 60 sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine in the G2-M phases due to stabilized microtubules and may be sulfate; vorozole; zeniplalin; zinostatin; zorubicin hydrochlo useful for treating cancer in combination with the compounds ride. described herein. Other anti-cancer agents that can be employed in combi Further examples of anti-cancer agents for use in combi nation with an irreversible Btk inhibitor compound include: nation with an irreversible Btk inhibitor compound include 65 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abirater inhibitors ofmitogen-activated protein kinase signaling, e.g., one; aclarubicin; acylfulvene; adecypenol; adozelesin; U0126, PD98059, PD184352, PD0325901, ARRY-142886, aldesleukin; ALL-TK antagonists; altretamine; ambamus- us 8,008,309 82 89 90 tine; amidox; amifostine; aminolevulinic acid; amrubicin; tumor suppressor 1-based therapy; mustard anticancer agent; amsacrine; anagrelide; anastrozole; andrographolide; angio mycaperoxide B; mycobacterial cell wall extract; myriapor genesis inhibitors; antagonist D; antagonistG; antarelix; anti one; N-acetyldinaline; N-substituted benzamides; nafarelin; dorsalizing morphogenetic protein-); antiandrogen, prostatic nagrestip; naJoxone+pentazocine; napavin; naphterpin; nar carcinoma; antiestrogen; antineoplaston; antisense oligo- s tograstim; nedaplatin; nemorubicin; neridronic acid; neutral nucleotides; aphidicolin glycinate; apoptosis gene modula endopeptidase; nilutamide; nisamycin; nitric oxide modula tors; apoptosis regulators; apurinic acid; ara-CDP-DL tors; nitroxideantioxidant; nitrullyn; 06-benzylguanine; oct PTBA; arginine deam.inase; asulacrine; atamestane; reotide; okicenone; oligonucleotides; onapristone; atrimustine; axinastatin 1; ax.inastatin 2; axinastatin 3; aza ondansetron; ondansetron; oracin; oral cytokine inducer; setron; azatoxin; azatyrosine; baccatin III derivatives; hal- 10 ormaplatin; osaterone; oxaliplatin; oxaunomycin; palaua anal; batimastat; BCRIABLantagonists; benzochlorins; ben mine; palmitoylrhizoxin; pamidronic acid; panaxytriol; pan zoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta orifene; parabactin; pazelliptine; pegaspargase; peldesine; mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene pentosan polysulfate sodium; pentostatin; pentrozole; perflu A; bizelesin; breflate; bropirimine; budotitane; buthionine 15 bron; perfosfamide; perillyl alcohol; phenazinomycin; phe sulfoximine; calcipotriol; calphostin C; camptothecin deriva nylacetate; phosphatase inhibitors; picibanil; pilocarpine tives; canarypox IL-2; capecitabine; carboxamide-amino hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; triazole; carboxyamidotriazole; CaR est M3; CARN 700; car plasminogen activator inhibitor; platinum complex; platinum tilage derived inhibitor; carzelesin; casein kinase inhibitors compounds; platinum-triamine complex; porfimer sodium; (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; 20 porfiromycin; prednisone; propyl bis~acridone; prostaglan chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; din J2; proteasome inhibitors; protein A-based immune cladribine; clomifene analogues; clot imazole; collismycin modulator; protein kinase C inhibitor; protein kinase C A; collismycin B; combretastatin A4; combretastatin ana inhibitors, microalgal; protein tyrosine phosphatase inhibi logue; conagenin; crambescidin 816; crisnatol; cryptophycin tors; purine nucleoside phosphorylase inhibitors; purpurins; 8; cryptophycin A derivatives; curacin A; cyclopentan- 25 pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyl thraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; erie conjugate; raf antagonists; raltitrexed; ramosetron; ras cytolytic factor; cytostatin; dacliximab; decitabine; dehy farnesyl protein transferase inhibitors; ras inhibitors; ras drodidemnin B; deslorelin; dexamethasone; dexifosfamide; GAP inhibitor; retelliptine demethylated; rhenium Re 186 dexrazoxane; dexverapamil; diaziquone; didermnin B; etidronate; rhizoxin; ribozymes; RJI retinamide; rogletimide; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxa- JO rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; mycin; diphenyl spiromustine; docosanol; dolasetron; doxi safingol; saintopin; SarCNU; sarcophytol A; sargramostim; fluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; Sdi 1 mimetics; semustine; senescence derived inhibitor I; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; sense oligonucleotides; signal transduction inhibitors; signal estrogen agonists; estrogen antagonists; etanidazole; etopo- 35 transduction modulators; single chain antigen-binding pro side phosphate; exemestane; fadrozole; fazarabine; fenretin tein; sizofiran; sobuzoxane; sodium borocaptate; sodium phe ide; filgrastim; finasteride; flavopiridol; flezelastine; fluaster nylacetate; solverol; somatomedin binding protein; saner one; fludarabine; fluorodaunorunicin hydrochloride; min; sparfosic acid; spicamycin D; spiromustine; forfenimex; formestane; fostriecin; fotemustine; gadolinium splenopentin; spongistatin 1; squalamine; stem cell inhibitor; texaphyrin; gallium nitrate; galocitabine; ganirelix; gelati- 40 stem-cell division inhibitors; stipiamide; stromelysin inhibi nase inhibitors; gemcitabine; glutathione inhibitors; hepsul tors; sulfinosine; superactive vasoactive intestinal peptide fam; heregulin; hexamethylene bisacetamide; hypericin; antagonist; suradista; suramin; swainsonine; synthetic gly ibandronic acid; idarubicin; idoxifene; idramantone; ilmo cosaminoglycans; tallimustine; tamoxifenmethiodide; tauro fosine; ilomastat; imidazoacridones; imiquimod; immuno mustine; tazarotene; tecogalan sodium; tegafur; tellurapyry stimulant peptides; insulin-like growth factor-1 receptor 45 lium; telomerase inhibitors; temoporfin; temozolomide; inhibitor; interferon agonists; interferons; interleukins; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; thiocoraline; thrombopoietin; thrombopoietin mimetic; thy irsogladine; isobengazole; isohomohalicondrin B; itasetron; malfasin; thymopoietin receptor agonist; thymotrinan; thy jasplakinolide; kahalalide F; lamellarin-N triacetate; lan roid stimulating hormone; tin ethyl etioprupurin; tira reotide; leinamycin; lenograstim; lenrinan sulfate; leptolsta- 50 pazamine; titanocene bichloride; topsentin; toremifene; tin; letrozole; leukemia inhibiting factor; leukocyte alpha totipotent stem cell factor; translation inhibitors; tretinoin; interferon; leuprolide+estrogen+progesterone; leuprorelin; triacetyluridine; triciribine; trimetrexate; triptorelin; tro levamirsole; liarozole; linear polyamine analogue; lipophilic pisetron; turosteride; tyrosine kinase inhibitors; tyiphostins; disaccharide peptide; lipophilic platinum compounds; lisso UBC inhibitors; ubenimex; urogenital sinus-derived growth clinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; 55 inhibitory factor; urokinase receptor antagonists; vapreotide; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium variolin B; vector system, erythrocyte gene therapy; texaphyrin; lysofyl1ine; lytic peptides; maitansine; mannosta velaresol; verdmine; verdins; verteporfin; vinorelbine; vinx tinA; marimastat; masoprocol; maspin; matrilysin inhibitors; altine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; matrix metalloproteinase inhibitors; menogaril; merbarone; and zinostatin stimalamer. meterelin; methioninase; metoclopramide; MIF inhibitor; 60 Yet other anticancer agents that can be employed in com mifepristone; miltefosine; mirimostim; mismatched double bination with an irreversible Btk inhibitor compound include stranded RNA; mitoguazone; mitolactol; mitomycin ana alkylating agents, antimetabolites, natural products, or hor logues; mitonafide; mitotoxin fibroblast growth factor-sa mones, e.g., nitrogen mustards (e.g., mechloroethiamine, porin; mitoxantrone; mofarotene; molgramostim; mono cyclophosphamide, chlorambucil, etc.), alkyl sulfonates clonal antibody, human chorionic gonadotrophin; 65 (e.g., busulfan), nitrosorueas (e.g., carmustine, lomusitne, monophosphoryllipid A+myobacterium cell wall sk; mopi ete.), or triazenes (decarbazine, etc.). Examples of antime damol; multiple drug resistance gene inhlbitor; multiple tabolites include but are not limited to folic acid analog (e.g., US 8,008,309 B2 91 92 methotrexate), or pyrimidine analogs (e.g., Cytarabine), (BASF, also known as ILX-651 and LU-223651), purine analogs (e.g., mercaptopurine, thioguanine, pentosta SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), tin). AM-97 (Armad/Kyowa Hakko),AM-132 (Armad), AM-138 Examples of nanrral products useful in combination with (Arrad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 an irreversible Btk inhibitor compound include but are not (also known as LY-355703), AC-7739 (Ajinomoto, also limited to vinca alkaloids (e.g., vinblastin, vincristine), epi known as AVE-8063A and CS-39.1-lCl), AC-7700 (Ajino podophyllotoxins (e.g., etoposide), antibiotics (e.g., dauno moto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser rubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparagi .HCI, and RPR-258062A), Vitilevuamide, Tubulysin A, nase), or biological response modifiers (e.g., interferon Canadensol, Centaureiclin (also known as NSC~106969), alpha). 10 T-138067 (Tularik, also known as T-67, TL-138067 and Examples of alkylating agents that can be employed in TI-138067), COBRA-I (Parker Hughes Institute, also known combination an irreversible Btk inhibitor compound include, as DDE-261 and WHl-261), HlO (Kansas State University), but are not limited to, nitrogen mustards (e.g., mechloroet Hl6 (Kansas State University), OncocidinAI (also known as hamine, cyclophosphamide, chlorambucil, meiphalan, etc.), BT0-956 and DIME), DDE-313 (Parker Hughes Institute), ethylenimine and methylmelamines (e.g., hexamethly- 15 Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), melamine, thiotepa), alkyl sulfonates (e.g., busulfan), SPA-t (Parker Hughes Institute, also known as SPIKET-P), nitrosoureas (e.g., carmustine, lomusitne, semustine, strepto 3-IAABU (Cytoskeleton!Mt. Sinai School of Medicine, also zocin, etc.), or triazenes (decarbazine, ete.). Examples of known as .MF-569), Narcosine (also known as NSC-5366), antimetabolites include, but are not limited to folic acid ana Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), log (e.g., methotrexate), or pyrimidine analogs (e.g., fiuorou- 20 Hemiaster1i~ 3-BAABU (Cytoskeleton!Mt. Sinai School of racil, floxouridine, Cytarabine ), purine analogs (e.g., mercap Medicine, also known as .MF-191), TMPN (Arizona State topurine, thioguanine, pentostatin. University), Vanadocene acetylacetonate, T-138026 (Tu Examples ofhormones and antagonists useful in combina larik), Monsatrol, Inanocine (also known as NSC-698666), tion with an irreversible Btk inhibitor compound include, but 3-lAABE (Cytoskeleton/MI. Sinai School of Medicine), are not limited to, adrenocorticosteroids (e.g., prednisone), 25 A-204197 (Abbott), T-607 (Tuiarik, also known as progestins (e.g., hydroxyprogesterone caproate, megestrol T-900607), RPR-115781 (Aventis), Eleutherobins (such as acetate, medroxyprogesterone acetate), estrogens (e.g., Desmethyleleutherobin, Desaetyleleutherobin, Isoeleuther~ diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., obin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, tamoxifen), androgens (e.g., testosterone propionate, ftu Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta oxymesterone ), antiandrogen (e.g., ftutamide ), gonadotropin 30 Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 releasing hormone analog (e.g., leuprolide ). Other agents that (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 can be used in the methods and compositions described (Abbott), Diozostatin, (-)-Phenylahistin (also known as herein for the treatment or prevention of cancer incJude plati NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta num coordination complexes (e.g., cisplatin, carboblatin), Medica), Myoseverin B, D-43411 (Zentaris, also known as anthracenedione (e.g., uitoxantrone), substituted urea (e.g., 35 D-81862),A-289099 (Abbott),A-318315 (Abbott), HTI-286 hydroxyurea), methyl hydrazine derivative (e.g., procarba (also known as SPA-110, triftuoroacetate salt) (Wyeth), zine), adrenocortical suppressant (e.g., mitotane, aminoglu D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), tethimide). Resverastatin phosphate sodium, BPR~OY-007 (National Examples ofanti-cancer agents which act by arresting cells Health Research Institutes), and SSR-250411 (Sanofi). in the G2-M phases due to stabilized microtubules and which 40 Where the subject is suffering from or at risk of suffering can be used in combination with an irreversible Btk inhibitor from a thromboembolic disorder (e.g., stroke), the subject can compound include without limitation the foJlowingmarketed be treated with an irreversible Btk inhibitor compound in any drugs and drugs in development: Erbulozole (also known as combination with one or more other anti-thromboembolic R-55104), Dolastatin 10 (also known as DLS-10 and NSC- agents. Examples of anti-thromboembolic agents include, but 376128), Mivobulin isethionate (also known as CI-980), Vm- 45 are not limited any of the following: thrombolytic agents cristine, NSC-639829, Discodermolide (also known as NVP (e.g., alteplase anistreplase, streptokinase, urokinase, or tis- XX-A-296), ABT-751 (Abbott, also known as E-7010), sue plasminogen activator), heparin, tinzaparin, warfarin, Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), dabigatran (e.g., dabigatran etexilate ), factor Xa inhibitors Spongistatins (such as Spongistatin 1, Spongistatin 2, Spong (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, istatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, so otarixaban, LY517717, orYM150), ticlopidine, clopidogrel, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cema CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048. dotinhydrochloride (also known as LU-103793 and NSC-D- Kits/Articles of Manufacture 669356), Epothilones (such as Epothilone A, Epothilone B, For use in the therapeutic applications described herein, Epothilone C (also known as desoxyepothiloneA or dEpoA), kits and articles of manufacture are also described herein. Epothilone 0 (also referred to as KOS-862, dEpoB, and des- 55 Such kits can include a carrier, package, or container that is oxyepothilone B), Epothilone E, Epothilone F, Epothilone B compartmentalized to receive one or more containers such as N-oxide, Epothilone A N-oxide, 16-aza~epothilone B, vials, tubes, and the like, each of the container(s) including 21-aminoepothilone B (also known as BMS-310705), 21-hy one of the separate elements to be used in a method described droxyepothilone D (also known as Dcsoxycpothilone F and herein. Suitable containers include, for example, bottles, dEpoF), 26-ftuoroepothilone), Auristatin PE (also known as 60 vials, syringes, and test tubes. The containers can be formed NSC-654663), Soblidotin (also known as TZT-1027), from a variety of materials such as glass or plastic. LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 The articles of manufacture provided herein contain pack- (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), aging materials. Packaging materials for use in packaging LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine pharmaceutical products are well known to those of skill in sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also 65 the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and known as WS-9885B), Gs-164 (Takeda), GS-198 (Takeda), 5,033,252. Examples of pharmaceutical packaging materials KAR-2 (Hungarian Academy of Sciences), BSF-223651 include, but are not limited to, blister packs, bottles, tubes, us 8,008,309 82 93 94 inhalers, pumps, bags, vials, containers, syringes: bottles, and found by searching the internet. Reference thereto evidences any packaging material suitable for a selected fonnulation the availability and public dissemination of such information. and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions Example I provided herein are contemplated as are a variety of treat ments for any disease, disorder, or condition that would ben Synthesis of Compounds efit by inhibition of Btk, or in which Btk is a mediator or contributor to the symptoms or cause. Preparation of 4-Amino-3-(4-phenoxyphenyl)-IH For example, the containers) can include one or more com pyrazolo[3,4-d]pyrimidine (Intermediate 2) pmmds described herein, optionally in a composition or in 1o combination with another agent as disclosed herein. The con 4-Amino-3-(4- phenoxyphenyl)-I H -pyrazolo [3 ,4-d]pyri tainer(s) optionally have a sterile access port (for example the midine (Intermediate 2) is prepared as disclosed in Interna~ container can be an intravenous solution bag or a vial having tiona! Patent Publication No. WO 01/019829. Briefly, 4-phe~ a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying 15 noxybenzoic acid ( 48 g) is added to thionyl chloride (I 00 mL) description or label or instructions relating to its use in the and heated under gentle reflux for 1 hour. Thionyl chloride is methods described herein. removed by distillation, the residual oil dissolved in toluene A kit will typically may include one or more additional and volatile material removed at 80° CJ20 mbar. The result containers, each with one or more of various materials (such ing acid chloride is dissolved in toluene (200 m.L) and tet as reagents, optional1y in concentrated form, and/or devices) 20 rahydrofuran (35 mL). Malononitrile (14.8 g) is added and desirable from a commercial and user standpoint for use of a the solution and stirred at -10° C. while adding diisopropyl- compound described herein. Non~limiting examples of such materials include, but not limited to, buffers, diluents, filters, ethylethylamine (57.9 gi in toluene (150 mL), while main needles, syringes; carrier, package, container, vial and/or tube taining the temperature below 0° C. After 1 hour at 0° C., the labels listing contents ancVor instructions for use, and pack~ 25 mixture is stirred at 20° C. overnight. Amine hydrochloride is age inserts with instructions for use. A set of instructions will removed by filtration and the filtrate evaporated in vacuo. The also typically be included. residue is taken up in ethyl acetate and washed with 1.25 M A label can be on or associated with the container. A label sulphuric acid, then with brine and dried over sodium sulfate. can be on a container when letters, numbers or other charac~ ters forming the label are attached, molded or etched into the 30 Evaporation ofthe solvents gives a semisolid residue which is container itself; a label can be associated with a container treated with a little ethyl acetate to give 4.1 g of 1,1~dicyano~ when it is present within a receptacle or carrier that also holds 2-hydroxy-2-(4-phenoxyphenyl)ethene as a white solid (m.p. the container, e.g., as a package insert. A label can be used to 160-162' C.). The filtrate on evaporation gives 56.58 (96%) indicate that the contents are to be used for a specific thera of l,l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a peutic application. The label can also indicate directions for 35 grey~brown solid, which is sufficiently pure for further use. use of the contents, such as in the methods described herein. I , 1-Dicyano-2-hydroxy-2-(4-phenoxypheny l)ethene In certain embodiments, the pharmaceutical compositions can be presented in a pack or dispenser device which can (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is contain one or more unit dosage forms containing a com~ stirred under nitrogen at 0° C. while adding diisopropylethy~ pound provided herein. The pack can for example contain 40 !amine (52.5 mL) followed by 2M trimethylsilyldiaz metal or plastic foil, such as a blister pack. The pack or omethane (150 mL) in THF. The reaction is stirred for 2 days dispenser device can be accompanied by instructions for at 20° C., and then2 g ofsilica is added (for chromatography). administration. The pack or dispenser can also be accompa The brown~red solution is evaporated in vacuo, the residue nied with a notice associated with the container in form pre scribed by a governmental agency regulating the manufac 45 dissolved in ethyl acetate and washed well with water then ture, use, or sale of pharmaceuticals, which notice is reflective brine, dried and evaporated. The residue is extracted with of approval by the agency of the form of the drug for human diethyl ether (3x250 mL), decanting from insoluble oil. or veterinary administration. Such notice, for example, can be Evaporation of the ether extracts gives 22.5 g of 1,1 ~dicyano~ the labeling approved by the U.S. Food and Drug Adminis 2~methoxy-2~(4~phenoxyphenyl)ethene as a pale orange 50 tration for prescription drugs, or the approved product insert. solid. The insoluble oil is purified by flash chromatography to Compositions containing a compound provided herein for~ give 15.0 g of a red~orange oil. mutated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for 1,1-Dicyano-2~methoxy~2~(4-phenoxyphenyl)ethene treatment of an indicated condition. (22.5 g) and 1, -dicyano-2-methoxy-2-(4-phenoxyphenyl) 55 ethene oil (15 g) are treated with a solution of hydrazine EXAMPLES hydrate (18 mL) in ethanol (25 mL) and heated on the steam bath for 1 hour. Ethanol (15 ml) is added followed by water The following specific and non-limiting examples are to be (10 rot). The precipitated solid is collected and washed with construed as merely illustrative, and do not limit the present ethanol:water (4: 1) and then dried in air to give 3-amino~4~ disclosure in any way whatsoever. Without further elabora 60 cyano~S-( 4~phenoxyphenyl)pyrazole as a pale orange solid. tion, it is believed that one skilled in the art can, based on the 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) description herein, utilize the present disclosure to its fullest is suspended in formamide (300 mL) and heated under nitro~ extent. All publications cited herein are hereby incorporated gen at 180° C. for 4 hours. The reaction mixture is cooled to by reference in their entirety. Where reference is made to a 30' C. and water (300 mL) is added. The solid is collected, URL or other such identifier or address, it is understood that 65 washed well with water, then with methanol and dried in air to such identifiers can change and particular information on the give of 4-amino-3-(4-phenoxyphenyl)-IH-pyrazolo[3,4-d] internet can come and go, but equivalent information can be pyrimidine. US 8,008,309 B2 95 96 Example la Compounds described herein were synthesized by follow ing the steps outlined in Scheme 1. A detailed illustrative example of the reaction conditions shown in Scheme 1 is Synthesis of 1-(3-(4-amino-3-( 4-phenoxyphenyl)- described for the synthesis of 1-(3-(4-amino-3-(4-phenox- 1H-pyrazolo[3,4- ]pyrimidin-1-yl)piperidin-1-yl) 5 yphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl) prop-2-en-1-one (Compound 4) prop-2-en-1-one (Compound 4).

101 mg of 4-amino-3-( 4-phenoxyphenyl)-IH-pyrazolo[3,

Scbcme 1. 10 4-d]pyrimid.ine and 330 mg of polymer-bound triphenylphos phine (TPP) (polymerlab) were mixed together with 5 mL of tetrahydrofuran (THF). tert-Butyl 3-hydroxypiperidine-1- carboxylate (200 mg; 2.0 equivalents) was added to the mix o--0 ture followed by the addition of diisopropyl diazodicarboxy~ 15 late (0.099 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to '\ OH ' remove the resins and the reaction mixture was concentrated NH, and purified by flash chromatography (pentane/ethyl acetate=l/1) to give intermediate 3 (55 mg). 20 N """" Intermediate 3 (48.3 mg) was treated with I mL of 4N 1-ICI l""N 6yt in dioxane for 1 hour and then concentrated to dryness. The residue was dissolved in dichloromethane 2 and triethylamine 25 (0.042mL) was added followed by aery! chloride (O.O!OmL). The reaction was stopped after 2 hours. The reaction mixture was washed with 5% by weight aqueous citric acid and then with brine. The organic layer was dried with MgS0 , and o--0 4 concentrated. Flash chromatography (with CH2 CI/ '\ 30 Me0H=25/l) gave 22 mg ofcompound 4 as a white solid. MS (M+l): 441.2; 'H-NMR(400 MHz): 8.26, s, IH, 7.65,m, 2H, NH, 7.42, m, 2H, 7.1~7.2, m, 5H, 6.7-6.9, m, lH, 6.1, in lH, b 5.5-5.7, m lH; 4.7, m, lH, 4.54, m, 0.5H, 4.2, m, lH, 4.1, m, 0.5H,3.7,m,0.5H, 3.2, m, lH, 3.0,m,0.5H, 2.3,m, lH; 2.1, N """" ~N - 35 m, 1H, 1.9, m, IH, 1.6, m, lH. / l""N N

Example lb C)--(-t 40 0 Synthesis of !-(! R)-3-(4-amino-3-( 4-phenoxyphe nyl)-1 H-pyrazolo[3,4-d]pyrhnidin-l-yI)piperidin-1- yl)prop-2-en-1-ooe (Compound 13)

45 0 --0 '\ 50 NH,

~N /

N / O-r::0 4

Syntbc~is of~ompound 4; ~)polymer-bound b:iphcnylp!JO'lpbiuc (IPP), dii~opropyl dinzodicarbo}()'lntc (DIAD), tctrahydrofuron (THF); b) HCVdio.unc; then acryloyl chloride, triethylamine (lEA). 65 6-r0 us 8,008,309 82 97 98 The synthesis of compound 13 was accomplished using a The synthesis of this compound was accomplished using a procedure analogous to that described in Example Ia. EM procedure analogous to that described for Example la EM (calc.): 440.2; MS (ESI) rnle (M+!Hj+: 441.1, (M-IH)-: (calc.): 426.18; MS (ESI) rnle (M+IH)+: 427.2, (M-IH)-: 439.2. 425.2. 5 Example le Example lc

Synthesis of 1-((R)-3-(4-amino-3-(4-phenoxyphe Synthesis of l((S)-3-(4-amino-3-( 4-phenoxyphenyl)- ny I)-1 H -pyrazolo[3 ,4-d]pyrimidin-1-y l)pyrrol idin-1- 1H -pyrazolo[3 ,4-d] pyrimidin-1-yl )piperidin-1-y I) 10 yl)prop-2-en-1-one (Compound II) prop~2~en-1-one (Compound 14)

~N / } 25 N

30 b-r0 ~0

The synthesis of compound 14 was accomplished using a The synthesis of this compound was accomplished using a procedure analogous to that described for Example 1a. EM 35 procedure analogous to that described for Example 1a. EM (calc.): 440.2; MS (ESI) rnle (M+IH)+: 441.5, (M-IH)-: (calc.): 426.18; MS (ESI) rnle (M+IH)-: 427.2. 439.2. Example If Example ld 40 Synthesis of N -((! s,4s )-4-( 4-amino-3-(4-phenox ypheny I)-I H -pyrazolo[3 ,4-d]pyrimidin-1-yl)cyclo Syntl1esis of 1-((S)-3-(4-amino-3-( 4-phenoxyphenyl- hexyl)acrylamide (Compound 10) 1 H -pyrazolo [3 ,4-d]pyrimidin-1-y l)pyrrolidin-1-yl) prop-2-en-1-one (Compound 12) 45

65 us 8,008,309 82 99 100 The synthesis of this compound was accomplished using a The synthesis of compound 8 was accomplished using a procedure analogous to that described for Example 1a. EM procedure analogous to that described for Example 1a. EM (calc.): 454.21; MS (ESI) m/e (M+IH)+: 455.1, (M-IH)-: (calc.): 438.18; MS (ESI) m/e (M+IHt: 439.2) (M-IHt: 453.1. 437.2. 5 Example li Example lg Syuthesis of (E)-C-(3-( 4-amino-3-( 4-phenoxyphe Synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)- nyl)-1 H -pyrazolo[3,4-d]pyrimidin-1-y l)piperidin-1- 1 H -pyrazolo[3 ,4-d] pyrimidin-1-yl )piperidin-1-yl) 10 yl)-4-( dimethylamino )but-2-en-1-one (Compound sulfonylethene (Compound 6) 15)

The synthesis of compound 15 was accomplished using a 1be synthesis of compound 6 was accomplished using a 35 procedure analogous to that described for Example la. EM procedure analogous to that described for Example la. EM (calc.): 497.25; MS (EST) m/e (M+IHt: 498.4, M-IHf: (calc.): 476.16; MS (ESI) m/e (M+IHt: 478.0, (M-IHf: 496. 475.3. Example2 Example lh 40 Btk In Vitro Inhibitory Activity

Synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)- The Btk IC50s of compounds disclosed herein was deter 1 H -pyrazolo[3 ,4-d] pyrimidin-1-yl )piperidin-1-y I) mined in both an acellular kinase assay and in a cellular prop-2-yn-1-one (Compound 8) 45 functional assay of BCR-induced calcium flux as described below. Btk kinase activity was determined using a time-resolved fluorescence resonance energy transfer (fR-FRET) method ology. Measurements were performed in a reaction volume of 5o 50 ).lL using 96-well assay plates. Kinase enzyme, inhibitor, ATP (at the Km for the kinase), and I fiM peptide substrate (Biotin-AVLESEEELYSSARQ-NH,) were incubated in a reaction buffer composed of 20 mM Tris, 50 mM NaCl, MgCI2 (5-25 mM depending on the kinase), MnCI2 (0-10 55 mM), 1 mM DTT, 0.1 mM EDTA, 0.01% bovine serum albumin, 0.005% Tween-20, and 10% DMSO at pl-1 7.4 for one hour. The reaction was quenched by the addition of 1.2 equivalents ofEDTA (relative to divalent cation) in 25 J.iL of lx Lance buffer (Perkin-Elmer). Streptavidin-APC (Perkin- 60 Elmer) and Eu-Jabeled p-TyrlOO antibody (Perkin-Elmer) in lx Lance buffer were added in a 25 f.LL volume to give fmal concentrations of 100 nM and 2.5 nM, respectively, and the mixture was allowed to incubate for one hour. The TR-FRET signal was measured on a multimode plate reader with an 65 excitation wavelength (A.Ex) of330 nm and detection wave lengths (1-Em of 615 and 665 nm. Activity was determined by the ratio of the fluorescence at 665 nm to that at 615 nm. For US 8,008,309 B2 101 102 each compound, enzyme activity was measured at various washed andre-plated in low serum medium at approximately concentrations ofcompound. Negative control reactions were 5x1 05 cells per 100 j.!l perweii ina 96-well plate. Compounds performed in the absence of inhibitor in replicates of six, and to be assayed were dissolved in DMSO and then diluted in two no-enzyme controls were used to determine baseline low serum medium to final concentrations ranging from 0 to fluorescence levels. Inhibition constants, K,(app), were 5 10 j.!M (at a dilution factor of0.3). The diluted compounds obtained using the program BatchK1 (Kuzmic et al. (2000), were then added to each well (final DMSO concentration was Anal. Biochem. 286:45-50). IC50swereobtainedaccording to 0.01%) and incubated at 37 degree in 5% C02 incubator for the equation: one hour. Afterwards, 100 111 of a calcium-sensitive dye (from IC5e'"" {Ki(app )/( 1+{ATP ]IK,,/11) }+[EJ,"'a/2; the Calcium 3 assay kit, Molecular Devices) was added to 10 For all kinases, [ATP]=K"'AT.P, [Btk]wtaz=0.5 nM and each well and incubated for an additional hour. The com [Lck Jww/~6 nM. pound-treated cells were stimulated with a goat anti-human Calcium flux florescence-based assays were performed in a IgM antibody (80 ug/ml; JacksonimmunoResearch) an dread FlexStation II384 fl.uorometric imaging plate reader (Mo in the FlexStation 11384 using a f...ex =485 nm and f.. Em =538 nm lecular Devices) according to manufacturer instructions. In for 200 seconds. The relative fluorescence unit (RFU) and the 15 brief, actively growing Ramos cells (ATCC) in RPMl IC50 were recorded and analyzed using a built-in SoftMax medium supplemented with 10% FBS (Invitrogen) were program (Molecular devices). TABLE2

Assay data for representative compounds o--0

Ramos Cell Ca Flux

Compound No. R Btk IC50 {nM) ICso(nM)

4 0.72 10

OY'0

5 20 89 0~ 0

6 0.52 92

Ov-.#~ 0 0 US 8,008,309 B2 103 104 TABLE 2-conlinued

Assn;t datil. for reeresentative compounds o--0

NH,

N l """... N

Ramos Cell Ca Flu~ Compound No. R Btk IC50 (nM) IC50 (nM)

7 0.58 9

0'00 8 Oy 0.72 9 0 9 0 3.6 48 0~ 10 Q 0.58 3 !mY' 0 11 0 1.6 24 0~ us 8,008,309 82 105 106 TABLE 2-continued

Assay data for representative compounds o--0

Ramos Cell Ca Flux Compound No. R Btk IC50 (nM) IC~;o {nM) 12 T 1.9 90 0 0~ 13 OY" <0.5 10 0

14 1.4 7 OY' 0

15 2.5 36

0~"/o I

Two lines of evidence demonstrated irreversible inhibition Of note, we found that three types of Michael acceptors, ofBtk by these compounds. First, after recombinant Btkwas 55 acrylamide, vinyl sulfonamide and propargylamide, exhib pretreated with compounds, its activity was not recovered by ited strong interactions with Btk. Adding a trans-oriented repeat washing with inhibitor-free medium (see, e.g., J. B. methyl group to the vinyl group decreased potency as shown Smaill, et al.,J. Med. Chem. 1999, 42, 1803). Second, a major by compound 5, which was 28-fold less potent than 4. This mass peak was observed by mass spectrometry correspond presumably relates to the reduced electrophilicity ofthe more ing to the molecular weight of a 1:1 covalent complex 60 substituted olefin. Compound 15 with a tertiary amine group between compound 4 and Btk (Compound4: 440 Da, recom gained back some potency compared to 5, even though it still binant Btk kinase domain: 33,487 Da; Complex: expected suffered a potency drop relative to compound 13. Compound 33,927 Da, observed 33,927 Da). 1Owas about 6-foldmore potent than 9, presumably due to the These compounds are highly potent inhibitors of Btk difference in the electrophile orientation. Finally, R configu- kinase activity with IC50s in the sub-nanomolarto single digit 65 ration was determined as the slightly preferred absolute ste nanomolarrangeforin vitro kinase activity. Their IC50s in the reochemistry configuration by two sets ofenantiomers (11 vs. 2 (Ramos cell) Ca + flux assay ranged from 3 to 92 mM. 12 and 13 vs. 14). US 8,008,309 B2 107 108 Example3 TABLE4

Dose n.nd Time Dependence ofComoound 4 Concentration in Plasma Inhibition ofBtk Cone (uM) 5

We further characterized the properties of these com Dose (mglkglday) Collection Time (h) Me~ SD pounds by assaying a number of cellular biochemical and 0.5 0.0657 0.0153 functional endpoints. In particular, we sought to assess the 2 0.0485 0.0200 selectivity of these compounds for inhibition of Btk versus 3 0.5 0.250 0.019 the closely related protein kinases Lck, Lyn, and Syk. In to 2 0.135 0.059 anti-IgM-stimulated Ramos 10 0.5 0.635 0.053 cells (a human B cell line), we 2 0.670 0.190 assayed Btk-dependent phosphorylation of PLC-y 1; Lyn and 30 0.5 1.72 0.15 Syk-dependent phosphorylation of tyrosine 551 on Btk; and 2 LlO 0.19 BCR-activated calcium flux. We also measured the effect of 15 comp::mnd 4 on Jurkat cells, a human T celll ine in which Lck Inhibition of arthritis by compound 4 was dose~dependent, and Itk, but not Btk are required forT cell receptor mediated with a maximum effect (>95% inhibition) at dose levels of 10 2 Ca + flux. As shown in Table 3, compound 4 exhibited sig and 30 mglkg. The plasma concentrationsOf compound 4 that nificant selectivity for Btk in cellular assays. In anti-IgM induced this maximum effect were in the 0.6-1.7 f.LM range at Tma:c (2 hr) and did not stimulated Ramos cells, compound 4 inhibited the phospho~ need to be sustained at high levels for 20 24 hours to achieve efficacy, which is not surprising for an rylation ofPLC~y 1 with aniC50~.0 14 ).lM, while the Lyn and irreversible inhibitor. Based on sequence analysis Syk~dependent phosphorylation of tyrosine 551 on Btk was and molecular modeling, the irreversible inhibitors described inhibited more weakly (IC >7.5 J.!M). Thus, compound 4 50 herein are proposed to form a covalent bond with Cys 481 of exhibits a >500-fold selectivity between Btk. and Lyn or Syk Btk (e.g., the Michael reaction acceptor portion of the com- in cells. Further, compound 4 was 11-fold less active in inhib~ 2 25 pounds described herein react with the Cys 481 residue of iting Ca + flux than in Ramos cells, supporting the expected Btk). Based on sequence homology analysis (FIG. 1), the selectivity for B versus T cells. compounds presented herein are also expected to act as irre~ versible inhibitors ofk.inases having a Cys 481 or a homolo~ TABLE3 gous cysteine residue, but to bind reversibly with k.inases 30 having a different amino acid at the 481 position within a Cellular assay data for compound 4 catalytic domain sequence that is otherwise homologous to that ofBtk. See, e.g., the sequences listed in FIG. 1. See also Ramos Jurkat the sequence alignments of tyrosine kinases (TK) published on the world wide web at kinase.comlhuman/kinomelphylog~ Btk" Lck:" Lyn" Btk p551b pPLC·ylb Ca Flux!' Ca Fluxb 35 eny.html. Cmpd (nM) (nM) (<>M) (,.M) (pM) ij>M) (pM) Example5 4 0.72b 97 14 >7.5 0.014 0.0405 0.466 Inhibition of Mast Cell Degranulation "Ki (~pp) 40 itCso Human CD34+ cells differentiated to mast cells by 9 weeks in culture in the presence of 1 nglml IL~3, 50 nglml IL-6, 100 nglmJ SCF. Cells were incubated with lgE+IL~4 for 4 days and then degranulation was induced by cross~linking Example4 with 45 anti-IgE. Degranulation quantitated using hexosaminidase assay. Compound did not inhibit degranulation induced by Use of Compound 4 to Treat Rheumatoid Arthritis the Ca++ ionophore ionomycin and did not affect cell viabil ity as determined by Alamar Blue assay. Compound 4 has an IC in MC degranulation less than 100 nanomolar. As such, The in vivo efficacy of compound 4 was evaluated in a 50 so compounds described herein can be used for the treatment of mouse model of rheumatoid arthritis. Arthritis was induced in inflammatory diseases, such as asthma. Balb/c mice by administration ofanti-collagen antibodies and lipopolysaccharide (LPS). See Nandakumar et a!. (2003), Example6 Am. J. ?athol 163:1827-1837. 55 Pharmaceutical Compositions Female Balb/c mice were treated with 100 mglkg of Chemicon mAb cocktail to Type II collagen intravenously on The compositions described below are presented with a compound ofFormula Day 0 and 1.25 mglkg of LPS intraperitoneally on Day I. (A) for illustrative purposes; any ofthe compounds of any of Formulas (A), (B), (C), or (D) can be Compound 4 was administered orally in a methylcellulose~ 60 used in such pharmaceutical compositions. based aqueous suspension formulation at 1, 3, 10 and 30 mglkg once daily starting on Day 2 through Day 12. Blood Example6a samples were collected at 0.5 and 2 hours post dose of com~ pound 4 administration on Day 12 (see Table 4). The serum Parenteral Composition concentrations of compound 4 were quantified by LC/MS/ 65 MS. Twenty four hours post dose, levels of compound 4 were To prepare a parenteral pharmaceutical composition suit below the level of quantitation. able for administration by injection, 100 mg of a water- us 8,008,309 82 109 110 soluble salt of a compound of Formula (A) is dissolved in rated into ophthalmic delivery units, such as eye drop con DMSO and then mixed with 10 mL of0.9% sterile saline. The tainers, which are suitable for ophthalmic administration. mixture is incorporated into a dosage unit fonn suitable for It is understood that the examples and embodiments administration by injection. described herein are for illustrative purposes only and that 5 various modifications or changes in light thereof will be sug Example 6b gested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of Oral Composition the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by refer- To prepare a pharmaceutical composition for oral delivery, to ence in their entirety for all purposes. 100 mg of a compound of Formula (A) is mixed with 750 mg What is claimed is: of starch. The mixture is incorporated into an oral dosage unit 1. A compound of Formula (D) having the structure: for, such as a hard gelatin capsule, which is suitable for oral administration. 15 Fonnula(D) Example 6c

Sublingual (Hard Lozenge) Composition

1b prepare a pharmaceutical composition for buccal deliv- 20 ery, such as a hard lozenge, mix 100 mg of a compound of Formula (A), with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. ~N The mixture is gently blended and poured into a / mold to form a lozenge suitable for buccal administration. 25 N I Example 6d "'-z Ro Inhalation Composition 30 Rs>=< R, To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (A) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0. 9% sodium wherein: chloride solution. The mixture is incorporated into an inha La is CH2 , 0, NH or S; lation delivery unit, such as a nebulizer, which is suitable for 35 Ar is a substituted orunsubstituted aryl, or a substituted or inhalation administration. unsubstituted heteroaryl; Y is an optionally substituted group selected from among Example 6e alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Rectal Gel Composition 40 Z is C(=O), OC(==O), NRC(=O), C(=S), S(==O)., OS( 0)", NRS(==O)", where X is 1 or 2; To prepare a pham1aceutical composition for rectal deliv ~and R8 are each H; or ery, 100 mg of a compound of Formula (A) is mixed with 2.5 R7 and R8 taken together form a bond; g ofmethylcelluose (1500 mPa), 100 mgofmethylparapen, 5 R6 isH; g of glycerin and I 00 mL of purified water. The resulting gel 45 R is H or C1-C6alky1; or pharmaceutically acceptable salts mixture is then incorporated into rectal delivery units, such as thereof. syringes, which are suitable for rectal administration. 2. The compound of claim 1, wherein La is 0. 3. The compound ofc1aim 2, whereinAr is phenyl. Example 6f 4. The compound of claim 3, wherein: 50 Z is C( 0), NHC(=O), or S(==0)2 • Topical Gel Composition 5. The compound of claim 4, wherein: Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or To prepare a pharmaceutical topical gel composition, 100 Y is a 4-, 5-, 6-, or ?-membered heterocycloalkyl ring. m.g of a compound of Formula (A) is mixed with 1.75 g of 6. The compound of claim 1 selected from among: hydroxypropyl celJuose, 10 mL ofpropylene glycol, 10 mL of 55 1-(3-(4-amino-3-(4-phenoxyphenyl)-JH-pyrozolo [3,4-d] isopropyl myristate and 100 mL of purified alcohol USP. The pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one; N-(( ls, resulting gel mixture is then incorporated into containers, 4s )-4-(4-amino- 3-(4- phenoxyphenyl )-1 H -pyrazol o[3, such as tubes, which are suitable for topic administration. 4-d]pyrimidin-1-yl)cyclohexyl)propiolamide; 1-(3-(4- amino-3-(4-phenoxyphenyl )-1 H-pyrazolo[3 ,4-d] Example 6g 60 pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-yn-1-one; 1-(4- (4-amino- 3-(4-phenoxypheny 1)-1 H -pyrazolo [3, 4-d] Ophthalmic Solution Composition pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one ;N-(2- (4-amino-3-( 4-phenoxyphenyl)-1 H-pyrazolo [3,4-d] To prepare a pharmaceutical opthalmic solution composi pyrimidin -1-yl)ethyl )propiolamide;N -(2-(4-amino- 3- tion, 100 mg of a compoundofFormula (A) is mixed with 0.9 65 (4-phenoxypheoyl )-1 H -pyrazolo[3,4-d]pyrimidin-1-yl) g ofNaCl in 100 mL of purified water and filtered using a 0.2 ethy 1)-N -methy lpropiolamide; 1-(3-( 4-amino-3 -( 4- micron filter. The resulting isotonic solution is then incorpo- phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-l-yl) us 8,008,309 82 111 112 piperidin-1-y1)prop-2-en-1-one; 1-(3-(4-amino-3-( 4- phenoxyphenyl)-1 H -pyrazolo [3, 4-d]pyrimi din-1-y I) phenoxyphenyl)-1 H-pyrazo1o (3,4-d]pyrimidin-1-yl) ethyl)-N-methylethenesulfonamide. piperidin-1-y1)sulfonylethene; 1-( 4-( 4-amino-3-(4- 7. A pharmaceutical composition comprising a therapeuti phenoxypheny 1)-1 H -pyrazo lo [3 ,4-d]pyrimidin-1-y 1) cally effective amount of a compound of claim 1, and a piperidin-1-y1)prop-2-en-1-one; N-((1s,4s )-4-(4- s pharmaceutically acceptable excipient. amino-3-( 4-pbenoxypbeny1 )-1 H-pyrazolo[3,4-d] 8. The compound of claim 1 having the formula 1-( 4-( 4- pyrimidin-1-y1)eyclobexyl)aery1amide; 1-((R)-3-(4- amino-3 -( 4-phenoxypbeny 1)-1 H-pyrazolo (3,4-d]pyrimidin- amino-3-(4-pbenoxypbeny1)-1H-pyrazolo (3,4-d] 1-yl)piperidin-1-y1)prop-2-en-1-one. pyrimidinw 1-yl)pyrrolidin-1-yl)prop-2-en-1-one; 9. The compound of claim 1 having the formula N-((ls, 1o 4s )-4-( 4-amino-3-( 1-( (S)-3-( 4-amino-3-(4-phenoxypheny1)-1 H-pyrazolo 4-phenoxyphenyl)-1 H -pyrazolo[3,4-d] (3,4-d]pyrimidin-1-y1)pyrrolidin-1-yl)prop-2-en-1- pyrimidini -1-y l)eyclohexyl )aery!amide. 10. The compound of claim 1 having one; 1-((R)-3-(4-amino-3-( 4-pbenoxyphenyl)-1 the formula 1-(R)-3- H ( 4-amino- 3-(4-phenoxyph pyrazolo enyl )-1 H -pyrazol o [3 ,4 -d ]pyrimi [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2- din-1-yl)piperidin-1-yl)prop-2-en-1-one. en-1-one; 1-( (S )-3-( 4-amino-3-(4- phenoxypbenyl)-1 H ts 11. The compound of claim 1 having the formula 1-(R)-3- pyrazolo[3, 4-d]pyrimidin -1-y l)piperidin -1-y I)prop- 2- (4-amino- 3-(4-phenoxypheny I)-1 H-pyrazolo[3 ,4-d]pyrimi en-1-one; N-((1 s,4s )-4-(4-amino-3-( 4- din-1-yl)pyrrolidin-1-yl)prop-2-en-1-one. pbenoxypbenyl)-1 H-pyrazolo (3,4-d]pyrimidin-1-yl) 12. A pharmaceutical composition comprising a therapeu cye1ohexyl)ethenesulfonamide; 1-(3-( 4-amino-3-( 4- tically effective amount of the compound of phenoxyphenyl)-1H-pyrazolo claim 8, and a [3,4-d] pyrimidin-1-yl) 20 pharmaceutically acceptable excipient. pyrrolidin-1-yl)prop-2-en-1-one ;3-(4- 13. A pharmaceutical composition comprising a therapeu phenoxypbeny 1)-1-( 1-(viny lsulfony I)pyrrolidin- 3 -y l)- tically effective ammmt of the compound of 1H-pyrazolo claim 9, and a (3,4-d]pyrimidin-4-amine ;3-(4- pharmaceutically acceptable excipient. phenoxypheny 1)-1-( 1-(vinylsulfonyl)piperidin-4- y 1)- 14.A pharmaceutical composition comprising a therapeu- 1 H-pyrazol o (3, 4-d ]pyrimidin-4-amine;N -(2-(4-amino- 25 tically effective amount ofthe compound of claim 3 -( 4-phenoxyphenyl 10, and a )-1 H -pyrazolo[3 ,4 -d]pyrimidin -1- pharmaceutically acceptable excipient. y1)ethy 1)-N -methy !aery lamide;N -(2-( 4-amino-3-( 4- 15. A pharmaceutical composition comprising a therapeu phenoxypheny 1)-1 H -pyrazo1o (3, 4-d]pyrimidin-1-y I) tically effective amount of the compound of claim ethy I)aery1amide;N 11, and a -(2 -( 4-amino-3 -( 4- pharmaceutically acceptable excipient. phenoxypheny I)-1 H-pyrazo1o (3, 4-d]pyrimidin-1-y I) ethyl)ethenesulfonamide; and N-(2-(4-amino-3-(4- * * * * * Exhibit 4 Copy of Terminal Disclaimer filed for U.S. Patent No. 8.008.309

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In reApplication ot. Lee Honig berg, et al.

Application No.: 12/499,005

filed: July 7. 2009

for: INHIBITORS OF BRUTON'S TYROSINE KINASE

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4277684_1.DOC Exhibit 5 Claims of U.S. Patent No. 8,008,309 That Cover the Anproved Product

What is claimed is: Claim 1: The chemical structure of ibrutinib 1. A compound of Formula (D) having the structure: is:

Formula (D)

~,N CN-r 0 Claim 1 reads on the approved product when: L, is 0, Ar is an unsubstituted aryl, Y is a heterccycloalkyl, Z is C(=O), R7 and R8 are each H, and R6 is H. Claim 1 covers ibrutinib. wherein:

La is CH2 , 0, NH or S; Ar is a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl; Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Z is C(=O), OC(=O), NRC(-0), CC-S), S(=O).,, OS(=O)x, NRS(=O), where xis 1 or 2; R., and R8 are each H; or R7 and R8 taken together form a bond; R6 isH; R isH or C1 -C6 alkyl; or pharmaceutically acceptable salts thereof.

13 2. The compound of claim 1, wherein L" is 0. Claim 2: The chemical structure of ibrutinib is:

N "": ~ lt_ --< ,N

N ~~)-r 0 Claim 2 reads on the approved product when: L, is 0, Ar is an unsubstituted aryl, Y is a heterocycloalkyl, Z is C(=O), R7 and R8 are each H, and R6 is H. Claim 2 covers ibrutinib.

3. The compoundo~claim2, wherein AI is phenyl. Claim 3: The chemical structure of ibrutinib is:

~,N ~~)-r 0 Claim 3 reads on the approved product when: L, is 0, Ar is phenyl, Y is a heterocycloalkyl, Z is C(=O), R7 and Rs are each H, and R6 is H. Claim 3 covers ibrutinib.

14 4. The compound of claim 3, wherein: Claim 4: The chemical structure of ibrutinib

Z is C(=O), NHC(=O), or S(=0)2• is:

~ ~r: ,N N CN-r 0 Claim 4 reads on the approved product when: L, is 0, Ar is phenyl, Y is a heterocycloalkyl, Z is C(=O), R7 and R8 are each H, and R6 is H. Claim 4 covers ibrutinib.

. ,. . ·- 5. The compound of claim 4, wherein: Claim 5: The chemical structure of ibrutinib Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or is: Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

~,N CN-r 0 Claim 5 reads on the approved product when: L, is 0, Ar is phenyl, Y is a 6- membered heterocycloalkyl ring, Z is C(=O), R7 and Rs are each H, and R6 is H. Claim 5 covers ibrutinib.

15 6. The compound of claim 1 selected from among: Claim 6: The chemical name for ibrutinib is 1-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4-d] 1-((R)-3-(4-amino-3-( 4-phenoxyphenyl) pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one; N-((1s, lH-pyrazolo[3 ,4-d]pyrimidin-1- 4s )-4-( 4-amino-3-(4-phenoxyphenyi)-1H-pyrazolo[3, yl)piperidin-1-y1)prop-2-en-l-one. 4-d]pyrimidin-1-yl)cyclohexyl)propiolamide; 1-(3-(4- Claim 6 covers ibrutinib. amino-3-(4-phenoxyphenyi)-1H-pyrazolo[3,4-d] pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-yn-1-one; 1-(4- (4-amino-3-( 4-phenoxyphenyl)-1 H-pyrazolo [3,4-d] pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one ;N-(2- (4-amino- 3 -(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d] pyrimidin-1-yl)ethy1)propiolamide;N-(2-(4-amino-3- (4-phenoxypheny 1)-1 H -pyrazolo[3, 4-d]pyrimidin-1-yl) ethyi)-N -methylpropiolamide;1-(3-( 4-amino-3-(4- phenoxypheny1)-1 H -pyrazolo [3 ,4-d]pyrimidin-1-y1) piperidin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-( 4- phenoxypheny 1)-1 H -pyrazolo [3 ,4-d]pyrimidin-1-yl) piperidin-1-y1)sulfonylethene; 1-(4-( 4-amino-3-(4- phenoxypheny1)-1 H-pyrazolo [3,4-d]pyrimidin-1-y 1) piperidin-1-y1)prop-2-en-1-one; N-((ls,4s)-4-( 4- amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d] pyrimidin -1-y l)cyclohexyl)acry1amide; 1-((R)-3-(4- amino-3-(4-phenoxypheny1)-1 H -pyrazo1o [3 ,4-d] pyrimidin-1-y1)pyrrolidin-1-y1)prop-2-en-l-one; 1-( (S)-3-(4-amino- 3-(4-phenoxyphenyl)-1 H-pyrazo1o [3,4-d]pyrimidin-l-y1)pyrrolidin-l-y!)prop- 2-en-1- one; 1-((R)-3-( 4-amino-3 -( 4-phenoxypheny 1)-1 H pyrazolo [3,4-d]pyrimidin-1-y l)piperidin-1-yl)prop-2- en-1-one;I-((S)-3-(4-amino-3-( 4-phenoxypheny1)-1H pyrazo1o[3,4-d]pyrimidin -l-y1)piperidin -I-yl)prop-2- en-1-one; N-((1 s,4s )-4-(4-amino-3-(4- phenoxyphenyl)-IH-pyrazo1o [3 ,4-d]pyrimidin-1-yl) cyclohexy1)ethenesulfonamide; 1-(3-(4-amino-3-( 4- phenoxypheny1)-1H-pyrazolo [3,4-d] pyrimidin-1-y1) pyrrolidin-1-yl)prop-2-en-1-one ;3-(4- phenoxyphenyl)-1-(l-(viny1su1fony1)pyrrolidin-3-y1)- IH-pyrazo1o [3,4-d]pyrimidin-4-amine ;3-(4- phenoxypheny 1)-1-( 1-(viny1su1fony1 )piperidin-4-y 1)- 1H -pyrazolo [3,4-d]pyrimidin-4-amine;N-(2-(4-amino- 3 -(4-phenoxyphenyl )-1 H -pyrazolo[3 ,4-d]pyrimidin-1- y l)ethy1)-N -methylacrylamide;N -(2-( 4-amino-3-(4- phenoxypheny 1)-1 H-pyrazolo [3 ,4-d]pyrimidin-1-y I) ethyl)acry1amide;N-(2-( 4-amino-3 -( 4- phenoxyphenyl)-1 H -pyrazolo[3,4-d]pyrimidin-1-y I) ethyl)ethenesu1fonamide; and N-(2-(4-amino-3-(4- phenoxyphenyl)-1 H-pyrazolo[3 ,4-d]pyrimidin -1-yl) ethy 1)-N -methy lethenesulfonamide.

16 7. A pharmaceutical composition comprising a therapeuti Claim 7 reads on the approved product cally effective amount of a compound of claim 1, and a when: L, is 0, Ar is an unsubstituted aryl, Y pharmaceutically acceptable excipient. is a heterocycloal.kyl, Z is C(=O), R7 and R8 are each H, and R6 is H. Claim 7 covers ibrutinib and a pharmaceuticaUy acceptable excipient.

8. The compound of claim 1 having the formula 1-(4-( 4- Claim 8 does not cover ibrutinib. amino-3-(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin- 1-yl)piperidin-1-yl)prop-2-en-1-one.

9. The compound of claim 1 having the formula N-((ls, Claim 9 does not cover ibrutinib. 4s)-4-( 4-amino-3-(4-phenoxyphenyl)-1 H -pyrazolo[3,4-d] pyrimidini -1-yl)cyclohexyl)acry !amide.

10. The compound of claim 1 having the formula 1-(R)-3- Claim 10: The chemical name for ibrutinib (4-amino-3-( 4-phenoxypheny 1)-1 H -pyrazolo [3,4-d]pyrimi is 1-(R)-3-(4-amino-3-( 4-phenoxyphenyl) din-1-yl)piperidin-1-yl)prop-2-en-1-one. lH-pyrazolo[3,4-d]pyrimidin-1- yl)piperidin-1-yl)prop-2-en-1-one. Claim 10 covers ibrutinib. 11. The compound of claim 1 having the formula 1-(R)-3- (4-amino-3-( 4-phenoxypheny 1)-1 H -pyrazolo[3,4-d]pyrimi Claim 11 does not cover ibrutinib. din-1-yl)pyrrolidin-1-yl)prop-2-en-1-one.

12. A pharmaceutical composition comprising a therapeu Claim 12 does not cover ibrutinib. tically effective amount of the compound of claim 8, and a pharmaceutically acceptable excipient.

- - 13. A pharmaceutical composition comprising a therapeu- Claim 13 does not cover ibrutinib. tically effective am01mt of the compound of claim 9, and a phannaceuticaUy acceptable excipient. - - - 14. A pharmaceutical composition comprising a therapeu- Claim 14: The chemical name for ibrutinib tically effective amount of the compound of claim 10, and a pharmaceutically acceptable excipient. is 1-((R)-3-(4-amino-3-( 4-phenoxyphenyl) lH -pyrazolo[3,4-d]pyrimidin-1- yl)piperidin-1-yl)prop-2-en-1-one. Claim 14 covers ibrutinib and a pharmaceutically acceptable excipient. 15. A pharmaceutical composition comprising a therapeu tically effective amount ofthe compound of claim 11, and a Claim 15 does not cover ibrutinib. pharmaceutically acceptable excipient.

17 Exhibit 6 Description of Significant Activities of Applicant During Regulatory Review

18 IND-102,688/NDA 205552 IMBRUVICA TM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

9-08-2008 0000 Oliginal IND Submission Letter 9-12-2008 .. from FDA acknowledging IND Submission 10-10-2008 0001 Protocol Amendment

10-31-2008 0002 15 Day IND Safety Report

11-05-2008 0003 15 Day IND Safety Report

12-12-2008 0004 Protocol Amendment

2-11-2009 0005 Investigator update

5-11-2009 0006 Protocol Amendment

7-13-2009 0007 Information Amendment (CMC) 1. Investigator Update 8-12-2009 0008 2. Clinical and Non-Clinical lnfmmation Amendment 9-16-2009 0009 Investigator Update

10-30-2009 0010 Information Amendment

11-19-2009 .. Initial 7-Day IND Safety Report

11-25-2009 0011 Initial15 Day IND Safety Report 1. Protocol Amendment 12-3-2009 0012 2. New Investigator Update 3. Information Amendment: CMC 12-16-2009 0013 1. Follow-up 15 Day IND Safety Repmt 2. New Investigator Update 1-19-2010 0014 Initial 15 Day IND Safety Repmt

2-11-2010 0015 Follow-up 15 Day IND Safety Report Follow-up 3-09-2010 0016 1. 15 Day IND Safety Repmt 2. New Investigator Update 1. Protocol Amendment 3-31-2010 0017 2. New Protocol Submission 3. Infmmation Amendment 4-02-2010 0018 Information Amendment: CMC Update

4-21-2010 0019 Protocol Amendment

6-18-2010 0020 Follow-up 15 Day IND Safety Report

Submission Selia! Nos. following the letter "N" refer to NDA submissions IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

8-03-2010 0021 1. Initial 15 Day IND Safety Report 2. New Investigator Update 1. Initial and Follow-up 15 Day IND Safety 8-31-2010 0022 Report 2. New Investigator Update 9-17-2010 0023 Follow-up 15 Day IND Safety Report

9-24-2012 0024 Initial 15 Day IND Safety Report 1. Protocol Amendment 10-05-2010 0025 2. New Protocol Submission 3. Information Amendment 10-05-2010 0026 Initial15 Day IND Safety Report

10-13-2010 0027 1. Follow-up 15 Day IND Safety Report 2. New Protocols 10-20-2010 0028 Follow-up 15 Day IND Safety Report

10-21-2010 0029 Initial15 Day IND Safety Report

10-28-2010 0030 Follow-up 15 Day IND Safety Report

12-02-2010 0031 Information Amendment: CMC

12-02-2010 0032 Annual Report 2010 1. Protocol Amendment 1-20-2011 0033 2. New Protocol Submission 3. Information Amendment 2-01-2011 0034 New Protocol Submission

3-15-2011 0035 Form FDA 3674 Submission

4-01-2011 0036 Protocol Amendment

5-16-2011 0037 1. Protocol Amendment 2. New Investigator Update 5-19-2011 0038 General Correspondence: Cross Reference Authorization Letter 7-15-2011 0039 1. Protocol Amendment 2. New Investigator Update 7-07-2011 0040 Initial15 Day IND Safety Report

8-19-2011 0041 1. Protocol Amendment 2. New Investigators Update 8-24-2011 0042 1. New Investigators Update 2. Information Amendment

Page 2 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type 3. Transfer of Obligations Meeting Request: 9-06-2011 0043 Type B- EOP 2/Pre-Phase-3 1. Information Amendment- CMC 10-14-2011 0044 2. Non-Clinical Study Reports General Correspondence: 10-14-2011 0045 Cross Reference Authorization Letter General Correspondence: 10-17-2011 0046 Cross Reference Authorization Letter 1. Protocol Amendment 10-19-2011 0047 2. New Investigator Update Meeting Package Submission: 10-31-2011 0048 Type B- EOP 2/Pre-Phase-3

General Correspondence: 11-4-2011 0049 Cross Reference Authorization Letter 11-22-2011 0050 lnitial15 Day IND Safety Repmt

11-23-2011 0051 Initial15 Day IND Safety Report

11-29-2011 0052 Protocol Amendment

12-02-2011 0053 Annual Report 2011 General Correspondence: 12-01-2011 0054 Cross Reference Authorization Letter 1. Protocol Amendment 12-05-2011 0055 2. New Investigator Update 1. Protocol Amendment 12-08-2011 0056 2. New Protocol Submission 3. Information Amendment Meeting Request - 12-20-2011 0057 Type B - EOP 2/Pre-Phase-3 1-10-2012 0058 Initial 7-Day IND Safety Report 1. Protocol Amendment 1-18-2012 0059 2. New Investigator Update 1-18-2012 0060 Follow-up to a 7-Day IND Safety Report. Meeting Brief Submission - Type B - EOP 2-06-2012 0061 2/Pre-Phase-3 1. New Investigator Update 2-29-2012 0062 2. General Correspondence General Correspondence: 2-10-2012 0063 Cross Reference Authorization Letter

Page 3 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type Meeting Request- 2-15-2012 0064 Type B -EOP 2/Pre-Phase-3

1. New Protocol Submission 4-19-2012 0065 2. Protocol Amendment 3. Other: Supporting material for EOP2 Meeting questions 3-12-2012 0066 General Correspondence: Cross Reference Authorization Letter 3-16-2012 0067 Meeting Package submission Type B -EOP 2/Pre-Phase -3 4-20-2012 0068 General CoiTespondence: !RB Waiver Request 4-24-2012 0069 General Correspondence

4-25-2012 0070 Initial 7-Day IND Safety Report

4-27-2012 0071 Protocol Amendment

4-27-2012 0072 CLL Final Response to FDA

5-02-2012 0073 Initial15 Day IND Safety Repmt

5-03-2012 0074 Follow-up to a 7 -Day IND Safety Report.

5-07-2012 0075 Meeting Request- Type B -EOP 2/Pre- Phase -3 lnf01mation Amendment - 6-04-2012 0076 l.CMC 2. Investigator Brochure update 6-11-2012 0077 New Investigator update

6-14-2012 0078 Meeting Package submission - Type B - EOP 2/Pre-Phase -3 6-15-2012 0079 Protocol Amendment

6-15-2012 0080 Protocol Amendment

6-21-2012 0081 Information Amendment- CMC

6-21-2012 0082 Information Amendment- CMC

6-22-2012 0083 1. Initial15 Day IND Safety Report 2. New Protocol Submission 6-26-2012 0084 1. Protocol Amendment 2. Investigator Brochure

Page 4of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

6-29-2012 0085 Follow-up 15 Day IND Safety Rep01t Information Amendment: Clinical 6-29-2012 0086 Pharmacology Meeting Request - 6-29-2012 0087 TypeB -EOP2 Meeting 7-06-2012 0088 Request- Type B CMC-EOP2 7-06-2012 0089 Initial 15 Day IND Safety Report Information Amendment: Pharmacology- 7-06-2012 0090 Toxicology 7-11-2012 0091 lnf01mation Amendment - CMC

7-11-2012 0092 General Correspondence: Transfer of Obligations and NCT number 7-12-2012 0093 General CotTespondence: Request for DSUR submission 7-16-2012 0094 Follow-up 15 Day IND Safety Report lnf01mation 7-17-2012 0095 Amendment: Pharmacology- Toxicology 1. Response 7-18-2012 0096 to Request for Information 2. Information Amendment 7-18-2012 0097 New Investigator Update

7-20-2012 0098 Follow-up 15 Day IND Safety Report

7-23-2012 0099 Information Amendment: Clinical 1. Protocol 7-23-2012 0100 Amendment 2. New Investigator Update 7-23-2012 0101 Initial 15 Day IND Safety Report

7-23-2012 0102 Initial 7 Day IND Safety Report 1. New Protocol Submission 7-31-2012 0103 2. New Investigator Update 3. Protocol Amendment 7-31-2012 0104 Follow-up 15 Day IND Safety Report

8-03-2012 0105 Follow-up 15 Day IND Safety Report

8-07-2012 0106 Follow-up 15 Day IND Safety Rep01t 1. New 8-10-2012 0107 Protocol Submission 2. New Investigator Update

Page 5 of20 IND-102,688/NDA 205552 IMBRUVICA™ (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type 3. Information Amendment 8-10-2012 0108 Follow-up 15 Day IND Safety Report New and updated Investigator information - 8-10-2012 0109 PCYC Meeting Request: Type B -EOP 1/ Pre- 8-10-2012 0110 Phase 2 8-14-2012 0111 Follow-up 15 Day IND Safety Repmt

8-14-2012 0112 Initial 7 Day IND Safety Report Meeting Request- Type B -EOP 2/Pre- 8-16-2012 0113 Phase-3 8-17-2012 0114 Follow-up 15 Day IND Safety Repmt

8-17-2012 0115 Meeting Package- Type B CMC -EOP 2 Information Amendment: Response to 8-20-2012 0116 Clinical Information Request 8-20-2012 0117 lnitiall5 Day IND Safety Report

8-20-2012 0118 Meeting Package- Type B -EOP 2 (dell7p)

8-27-2012 0119 Follow-up 15 Day IND Safety Report Request for Special Protocol Assessment for 8-27-2012 0120 PCYC-1115-CA 8-30-2012 0121 New and Updated Investigator Information Initial and Follow-up 15 Day IND Safety 9-05-2012 0122 Report Information Amendment: Correction of 9-06-2012 0123 ModuleS 9-06-2012 0124 Fast Tack Designation Request Initial and Follow-up 15 Day IND Safety 9-06-2012 0125 Report Initial and Follow-up 15 Day IND Safety 9-11-2012 0126 Report 9-11-2012 0127 Protocol Amendment General Conespondence: Letter of 9-11-2012 0128 Authorization Meeting Package: Type B Clinical End of 9-17-2012 0129 Phase 1 9-18-2012 0130 Follow-up 15 Day IND Safety Report

Page 6 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

9-24-2012 0131 Follow-up 15 Day IND Safety Report

9-26-2012 0132 Initial 7-Day Safety Repmt Follow-up 15 Day IND Safety Report 9-27-2012 0133 New and Updated Investigator Infmmation- JNJ &PCYC 9-28-2012 0134 Initial 7-Day Safety Repmt Follow-up 15 Day IND Safety Report 10-02-2012 0135 Follow-up 15 Day IND Safety Report

10-03-2012 0136 Response to Request for Information - SPA - PCYC-1115-CA 10-09-2012 0137 Initial 7 Day IND Safety Repmt Follow-up 15 Day IND Safety Report 10-12-2012 0138 Information Amendment: Orphan Drug Application 10-15-2012 0139 Follow-up 15 Day IND Safety Report

10-16-2012 0140 Annual Report (DSUR Format)

10-17-2012 0141 Follow-up 15 Day IND Safety Report

10-19-2012 0142 Protocol Amendment

10-24-2012 0143 Follow-up 15 Day IND Safety Report

10-25-2012 0144 Meeting Package: Type B Clinical End of Phase2 10-29-2012 0145 Initial and Follow-up 15 Day IND Safety Report 10-31-2012 0146 Information Amendment: CMC

11-01-2012 0147 Initiall5 Day IND Safety Repmt General 11-01-2012 0148 Con·espondence: Letter of Authorization 11-01-2012 0149 New and Updated Investigator Information

11-06-2012 0150 1. New Protocol Submission 2. Protocol Amendment 11-06-2012 0151 Initiall5 Day IND Safety Report

11-08-2012 0152 Fast Tack Designation Request for MCL Responses 11-13-2012 0153 to FDA Preliminary Comments for Type B EOP 1 Meeting

Page 7 of20 IND-102,688/NDA 205552 IMBRUVICA™ (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type Initial and Follow-up 15 Day IND Safety 11-13-2012 0154 Report Inf01mation Amendment: Safety 11-16-2012 0155 Infotmation Update Meeting Request: 11-16-2012 0156 Type B Clinical Pharmacology 11-20-2012 0157 Protocol Amendment Information Amendment: Response to FDA 11-20-2012 0158 request for Information - Protocol Synopsis Initial and Follow-up 15 Day IND Safety 11-20-2012 0159 Report 1. New Protocol Submission 11-20-2012 0160 2. New Investigator Update 11-21-2012 0161 Follow-up 15 Day IND Safety Report Meeting Request: 11-21-2012 0162 TypeBEOP2 11-26-2012 0163 Initial 7 Day IND Safety Report

11-28-2012 0164 Follow-up 15 Day IND Safety Report 1. New Protocol Submission 11-28-2012 0165 2. New Investigator Update Initial and Follow-up 15 Day IND Safety 11-28-2012 0166 Report New and Updated Investigator Information- 11-29-2012 0167 JNJ &PCYC 12-05-2012 0168 Initiall5 Day IND Safety Rep01t

12-10-2012 0169 Follow-up 15 Day IND Safety Report Initial and Follow-up 15 Day IND Safety 12-12-2012 0170 Report 1. New Protocol Submission 12-14-2012 0171 2. New Investigator Update Inf01mation Amendment: Response to FDA 12-17-2012 0172 Request for Information dated 06 Dec 2012 12-18-2012 0173 Follow-up 15 Day IND Safety Report Initial and Follow-up 15 Day IND Safety 12-20-2012 0174 Rep01t 12-21-2012 0175 Protocol Amendment Request for Breakthrough Therapy 12-21-2012 0176 designation

Page 8 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

12-26-2012 0177 Initial and Follow-up 15 Day IND Safety Repott 12-28-2012 0178 New and updated Investigator infmmation

12-28-2012 0179 Request for Breakthrough Therapy designation 12-28-2012 0180 Initial and Follow-up 15 Day IND Safety Report 1-03-2013 0181 Initial and Follow-up 15 Day IND Safety Report 1-04-2013 0182 Meeting Package: Type C EOP2 - Clinical Phrumacology 1-04-2013 0183 Meeting Package: Type B EOP2 -Clinical 1-09-2013 0184 Initial and Follow-up 15 Day IND Safety Report 1-10-2013 0185 Study PCI-32765CLL1007 submission with revised synopsis 1-15-2013 0186 Initial and Follow-up 15 Day IND Safety Repmt 1-16-2013 0187 lnitia115 Day IND Safety Rep01t

1-17-2013 0188 1. Protocol Amendment 2. New Protocols Submission 1-22-2013 0189 Initial and Follow-up 15 Day IND Safety Repmt 1-24-2013 0190 Follow-up 15 Day IND Safety Rep01t

1-28-2013 0191 1. Protocol Amendment 2. General Correspondence 1-28-2013 0192 Meeting Request: Type B, EOP2/Pre-P3 DLBCL Meeting 1-29-2013 0193 Follow-up 15 Day IND Safety Report

1-31-2013 0194 New and updated Investigator infmmation

2-01-2013 0195 Request for Breakthrough Therapy Designation 2-05-2013 0196 Initial and Follow-up 15 Day IND Safety Report 2-05-2013 0197 Information Amendment: Phrumacology- Toxicology 2-05-2013 0198 New and updated Investigator infmmation

2-06-2013 0199 Response to Request for lnfmmation: CMC

Page 9 of20 IND-102,688/NDA 205552 IMBRUVICA™ (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

2-06-2013 0200 Protocol Amendment

2-07-2013 0201 Protocol Amendment

2-07-2013 0202 Initial and Follow-up 15 Day IND Safety Report 2-08-2013 0203 Meeting Request: Type B, Pre-NDA Clinical/Non-Clinical 2-08-2013 0204 Meeting Request: Type B, Pre-NDA CMC Initial 2-12-2013 0205 and Follow-up 15 Day IND Safety Report 2-14-2013 0206 Follow-up 15 Day IND Safety Report

2-20-2013 0207 Initial and Follow-up 15 Day IND Safety Report 2-22-2013 0208 Request for Proprietary Name Review:

2-22-2013 0209 Information Amendment: CMC

2-22-2013 0210 Initial and Follow-up 15 Day IND Safety Report 2-25-2013 0211 Initial 7 Day IND Safety Report Meeting Package: 2-26-2013 0212 Type B Clinical EOP 2/Pre-Phase 3 DLBCL 2-26-2013 0213 Protocol Amendment

2-26-2013 0214 Initial and Follow-up 15 Day IND Safety Report 2-28-2013 0215 Meeting Package: Type B Pre-NDA CMC 2-28-2013 0216 Follow-up 15 Day IND Safety Report

3-01-2013 0217 Meeting Package: Type B Clinical/Nonc!inical Pre-NDA 3-01-2013 0218 Protocol Amendment: Response to FDA Request 3-01-2013 0219 New Protocol Submission: New Principal Investigator Submission 3-04-2013 0220 Initial and Follow-up 15 Day IND Safety Report 3-04-2013 -- NDA number requested 3-05-2013 0221 New and updated Investigator information Page 10of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

3-05-2013 0222 Follow-up 15 Day IND Safety Report 3-05-2013 .. NDA number received; informed FDA that NDA 205552 refers to IND 102688 3-07-2013 0223 New and updated Investigator information

3-08-2013 0224 Follow-up 15 Day IND Safety Report

3-11-2013 0225 Protocol Amendment

3-13-2013 0226 1. Protocol Amendment 2. Information Amendment Initial 7-Day Safety Report- IND report 3-13-2013 0227 Initial and Follow-up 15-day IND Safety Reports 3-18-2013 0228 Initial and Follow-up 15 Day IND Safety Report 3-21-2013 0229 Initial 7-Day IND Safety Reports Follow-up 15-day IND Safety Report 3-22-2013 0230 Information Amendment

3-25-2013 0231 General Correspondence Follow-up 7-Day IND Safety Repmt 3-26-2013 0232 Initial and Follow-up 15-day IND Safety Reports 3-27-2013 0233 Follow-up 15 Day IND Safety Report

3-28-2013 0234 Follow-up 15 Day IND Safety Report Information Request: Additional 3-29-2013 0235 information for Type B pre-NDA CMC Briefing Document 3-29-2013 .. NDC Labe1er code submitted to FDA

4-01-2013 .. Labeler code approved by FDA

4-02-2013 0236 New and updated Investigator information 4-02-2013 0237 1. Protocol Amendment 2. General Correspondence 4-02-2013 0238 Initial and Follow-up 15 Day IND Safety Report 4-05-2013 0239 Follow-up 15 Day IND Safety Report 4-05-2013 0240 Information Amendment: Request for submission of portions of application

Page 11 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

4-08-2013 0241 New and updated Investigator infmmation Initial 7-Day IND 4-11-2013 0242 Safety Report Follow-up 15-day IND Safety Repmt 4-11-2013 0243 General Co!Tespondence

4-15-2013 -- SPL Labeler code resubmitted to FDA Initial and Follow-up 4-16-2013 0244 15 Day IND Safety Report Initial 4-18-2013 0245 7-Day IND Safety Report Follow-up 15-day IND Safety Report 4-19-2013 0246 General CmTespondence

4-24-2013 0247 Protocol Amendment Initial 7-Day IND Safety Report 4-25-2013 0248 Initial and Follow-up 15-day IND Safety Repmt 4-25-2013 NOOOO Oliginal NDA Submission 4-30-2013 0249 New and updated Investigator infmmation Initial 4-30-2013 0250 and Follow-up 15 Day IND Safety Report 5-01-2013 0251 General Correspondence lnitial7-Day 5-02-2013 0252 IND Safety Report Follow-up 15-day IND Safety Repmt Information 5-06-2013 0253 Amendment: Response to FDA Advice/Information Requested 5-06-2013 N0001 Amendment Submission Initial 5-07-2013 0254 7-Day IND Safety Report Initial and Follow-up 15-day IND Safety Repmt 5-10-2013 0255 New and updated Investigator information

5-10-2013 0256 Information Amendment- CMC Initial 5-13-2013 0257 and Follow-up 15 Day IND Safety Repmt 5-13-2013 N0002 Amendment Submission Follow-up 7-Day IND Safety Repmt 5-16-2013 0258 Initial and Follow-up 15-day IND Safety Report Information 5-20-2013 0259 Amendment - Phannacology and Toxicology

Page 12 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

5-21-2013 0260 Initial and Follow-up 15 Day IND Safety Report 5-21-2013 0261 Initial 7-Day IND Safety Report Follow-up 15-day IND Safety Report 5-28-2013 0262 General Correspondence

5-28-2013 0263 Protocol Amendment

5-30-2013 0264 Initial and Follow-up 15 Day IND Safety Report 5-31-2013 N0003 Amendment Submission

6-03-2013 0265 New and updated Investigator infmmation 6-05-2013 0266 2013 Development Safety Update Report (DSUR) 6-05-2013 0267 Initial and Follow-up 15 Day IND Safety Report 6-06-2013 N0004 Amendment Submission

6-07-2013 0268 Initial and Follow-up 15 Day IND Safety Report 6-10-2013 0269 New and updated Investigator information 6-10-2013 0270 Information Amendment - Response to FDA Request for Information 6-14-2013 0271 Initial and Follow-up 15 Day IND Safety Repmt Expanded Access Submission: Early Access 6-17-2013 0272 Treatment Protocol PCYC-1120-CA 6-17-2013 0273 lnfmmation Amendment: Request for information 6-20-2013 0274 Follow-up 15 Day IND Safety Report 6-20-2013 N0005 Amendment Submission

6-21-2013 0275 Protocol Amendment

6-24-2013 0276 Protocol Amendment

6-26-2013 0277 Meeting Request: Type B EOP2 FLR3001 meeting 6-26-2013 0278 Initial and Follow-up 15 Day IND Safety Rep_ort 6-27-2013 0279 Information Amendment: PCYC-1117-CA update Page 13 of20 IND-102,688/NDA 205552 IMBRUVICA TM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

6-28-2013 0280 Follow-up 15 Day IND Safety Repo1t 6-28-2013 N0006 Amendment Submission 6-28-2013 -- NDA Acknowledgement letter from FDA 7-02-2013 0281 lnitial7-Day IND Safety Report Initial and Follow-up 15-day IND Safety Report 7-03-2013 0282 New and updated Investigator information 7-09-2013 0283 Initial and Follow-up 15 Day IND Safety Report Information Amendment - Pharmacology 7-09-2013 0284 and Toxicology Final Study Reports & Final Publications 7-11-2013 0285 Initial 7-Day IND Safety Report Follow-up 15-day IND Safety Repmt 7-12-2013 0286 New and updated Investigator infmmation

7-12-2013 0287 Protocol Amendment 7-12-2013 0288 General Correspondence: Withdrawal of Proprietary Name Review Request 7-12-2013 N0007 Proptietary Name Review Submission

7-16-2013 0289 Initial and Follow-up 15 Day IND Safety Report 7-19-2013 0290 Initial and Follow-up 15 Day IND Safety Report 7-24-2013 0291 Initial and Follow-up 15 Day IND Safety Report Amendment Submission-Response 7-24-2013 N0008 to clinical information request from FDA

Amendment Submission-Response 7-25-2013 N0009 to clinical information request from FDA

Amendment Submission-Response 7-26-2013 N0010 to clinical infmmation request from FDA 7-29-2013 0292 1. Other Correspondence: 2. TOO for Protocol PCYC-1104-CA 7-30-2013 0293 Initial and Follow-up 15 Day IND Safety Repmt Amendment Submission-- Response 7-30-2013 NOOll to clinical information request from FDA

Page 14 of20 IND-102,688/NDA 205552 IMBRUVICA TM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

Amendment Submission-- Response to 7-30-2013 N0012 clinical information request from FDA

8-01-2013 0294 Protocol Amendment: New and Updated Investigator Information 8-01-2013 Establishment Registration submitted to -- include FEI number 8-01-2013 Amendment Submission-response to N0013 infmmation request

8-02-2013 0295 Meeting Package: Type C Clinical EOP2/Pre-Phase 3 Meeting 8-02-2013 Amendment Submission-response to N0014 infmmation request

8-04-2013 Amendment Submission-response to N0015 information request

8-05-2013 Amendment Submission-response to N0016 information request

8-07-2013 0296 Response to FDA Request for Information

8-07-2013 0297 Initial 7-Day IND Safety Report Initial and Follow-up_15-day IND Safety_ Report Amendment Submission-- Response to 8-07-2013 N0017 clinical information request from FDA

8-09-2013 0298 New and updated Investigator information

8-09-2013 0299 Protocol Amendment

8-09-2013 Amendment Submission-response to N0018 CMC information request

8-09-2013 Amendment Submission-response to N0019 information request

8-12-2013 0300 Initial and Follow-up 15 Day IND Safety Report 8-12-2013 Amendment Submission-- response to N0020 information request

8-13-2013 0301 Protocol Amendment

8-13-2013 Amendment Submission-response to N0021 CMC infmmation request

Page 15 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

8-14-2013 0302 Initial and Follow-up 15-Day IND Safety Reports Amendment Submission-- 8-14-2013 N0022 response to information request

8-16-2013 0303 Initial and Follow-up 15-Day IND Safety Reports 8-16-2013 Amendment Submission-- response to N0023 information request

Amendment Submission-provide 8-16-2013 N0024 NDA safety update

8-20-2013 0304 Initial and Follow"up 15-Day IND Safety Reports Amendment Submission-response to FDA 8-20-2013 N0025 request for revised draft container and carton labeling

8-22-2013 0305 Protocol Amendment Amendment Submission-provide 8-21-2013 N0026 errata to the NDA safety update

8-23-2013 0306 Information Amendment: General Correspondence:

8-23-2013 0307 Information Amendment: Clinical Amendment Submission-response 8-23-2013 N0027 to FDA request for Quality information

Amendment Submission-response 8-26-2013 N0028 to infmmation request

8-27-2013 0308 Initial and Follow-up 15-Day IND Safety Reports 8-28-2013 Conespondence and Amendment N0029 Submission

8-29-2013 0309 Protocol Amendment Investigator Information 8-29-2013 0310 Meeting Request 8-30-2013 0311 New and Updated Investigator Information

Page 16 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

Amendment Submission-- response to 8-29-2013 N0030 information request Initial and Follow-up 15-Day IND Safety 8-30-2013 0312 Reports Con·espondence Submission-response to 8-30-2013 N0031 information request Response to FDA Advice/Information 9-04-2013 0313 Request- Statistical Design for Study PCYC-1112-CA Initial 7-Day Safety Report 9-04-2013 0314 Initial and Follow-up 15-Day IND Safety Reports 9-05-2013 0315 Special Protocol Assessment- Amendment

9-09-2013 0316 Meeting Request Initial 7-Day Safety Report 9-09-2013 0317 Initial and Follow-up 15-Day IND Safety Reports 9-09-2013 N0032 Amendment Submission-- response to information request 9-10-2013 N0033 Amendment Submission-- response to information request 9-11-2013 0318 New and updated Investigator information Initial 7-Day Safety Repmt 9-12-2013 0319 Initial and Follow-up 15-Day IND Safety Reports 9-12-2013 N0034 Amendment Submission-submission of revised draft container and carton labeling 9-16-2013 N0035 Amendment Submission-- response to information request 9-16-2013 N0036 Amendment Submission-- response to information request Initial 7-Day Safety Report 9-18-2013 0320 Initial and Follow-up 15-Day IND Safety Reports 9-18-2013 N0037 Amendment Submission-- response to information request 9-19-2013 0321 Protocol Amendment

9-23-2013 N0038 Amendment Submission-- response to Page 17 of20 IND-102,688/NDA 205552 IMBRUVICA TM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type information request Initial 7-Day Safety Rep01t 9-24-2013 0322 Initial and Follow-up 15-Day IND Safety Reports 9-24-2013 0323 Protocol Amendment

9-24-2013 N0039 Amendment Submission-provide revised draft container and carton labeling 9-25-2013 N0040 Amendment Submission-- response to information request 9-27-2013 0324 Initial and Follow-up 15-Day IND Safety Reports 9-27-2013 0325 Meeting Package

9-27-2013 N0041 Amendment Submission-- response to inf01mation request 10-01-2013 0326 Response to FDA Guidance 10-01-2013 0327 Protocol Amendment 10-01-2013 0328 Protocol Amendment 10-01-2013 0329 Pre-sNDA Questions 10-02-2013 0330 New and Updated Investigator Information 10-02-2013 0331 Initial and Follow-up 15-Day IND Safety Reports 10-02-2013 N0042 Amendment Submission-- response to inf01mation request 10-04-2013 0332 Protocol Amendment 10-04-2013 0333 Initial and Follow-up 15-Day IND Safety Reports 10-07-2013 N0043 Amendment Submission-- response to information request 10-09-2013 0334 Initial and Follow-up 15-Day IND Safety Reports 10-09-2013 0335 New Investigator information

10-11-2013 N0044 Amendment Submission-- response to information request 10-14-2013 0336 Initial and Follow-up 15-Day IND Safety Reports

Page 18 of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

10-14-2013 0337 Information Amendment- CMC

10-15-2013 N0045 Amendment Submission to Original #2

10-16-2013 N0046 Amendment Submission to Original #1

10-16-2013 N0047 Amendment Submission to Original #2 Follow-up 7-Day 10-17-2013 0338 Initial and Follow-up 15-Day IND Safety Reports 10-17-2013 0339 Information Amendment- CMC

10-18-2013 0340 General Correspondence

10-18-2013 N0048 Amendment Submission to Original #2 10-21-2013 0341 General Con·espondence

10-21-2013 0342 Meeting Package

10-22-2013 0343 Initial and Follow-up 15-Day IND Safety Reports 10-23-2013 N0049 Amendment Submission to Original #1 and #2-- response to infmmation request 10-23-2013 N0050 Amendment Submission to Original #1 10-25-2013 0344 Initial and Follow-up 15-Day IND Safety Reports 10-25-2013 0345 Protocol Amendment

10-29-2013 0346 Initial and Follow-up 7-Day Follow-uo 15-Dav IND Safety Reports Amendment Submission 10-29-2013 N0051 Original #2-- response to information request Follow-up 7-Day 11-01-2013 0347 Initial and Follow-up 15-Day lND Safety Reports 11-01-2013 0348 Information Amendment Protocol Amendment 11-05-2013 0349 New and Updated Investigator Information General Conesoondence Initial 11-06-2013 0350 and Follow-up 15-Day IND Safety Repmts

Page 19of20 IND-102,688/NDA 205552 IMBRUVICATM (ibrutinib) (*also known internally as PCI-32765) US Submission Log

Date Submission Serial No. Type

11-06-2013 0350 General Correspondence

11-08-2013 0352 Initial and Follow-up 15-Day IND Safety Reports 11-08-2013 0353 New and Updated Investigator information General Con·espondence Amendment Submission 11-11-2013 N0052 Original # 1-labeling and patient information Amendment Submission-submission of 11-13-2013 N0053 final agreed upon container and carton labeling 11-13-2013 N0054 Amendment Submission-submission of final agreed upon PMC/PMR information 11-13-2013 -- Signed NDA Approval letter for Imbruvica from FDA

Page 20of20 Exhibit 7 Statement that applicant is eligible for extension and length of extension claimed

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

Patent No.: 8,008,309 Issued: August 30, 2011 Expiration Date: December 28, 2026

Inventors: Lee Honigberg, Erik Verner, and Zhengying Pan.

Title: INHIBITORS OF BRUTON'S TYROSINE KINASE

Mail Stop Patent Extension Commissioner for Patents P.O. Box 1450 Alexandria, VA 22303-1450

Statement of Eligibility for Extension of Patent Term Dne to Regulatory Review

I, Michael J. Hostetler, represent that I am the attorney of record duly appointed by the assignee of the entire right, title and interest in the patent identified above, and do state on behalf of the Applicant as follows:

To the best of my knowledge, U.S. Patent No. 8,008,309 (the '309 Patent) meets all the eligibility criteria set forth in 37 C.F.R § I. 710 and 1. 720 for extension of patent term.

The '309 patent claims a "product" as that term is defined in 37 C.F.R §1.710, specifically the active ingredient ibrutinib of a new human drug IMBRUVICA TM. 37 C.F.R § 1.720(a).

The term of the '309 Patent has never been previously extended. 37 C.F.R §1.720(b).

An application for extension of the term of the '309 Patent in compliance with 37 C.F.R §1.740 is herewith submitted. 37 C.F.R §1.720(c).

The approved product, IMBRUVICA TM, has been subject to a regulatory review period as defined in 35 U.S.C. §156(g). 37 C.F.R §1.720(d).

The approved product, IMBRUVICA TM, has received permission for commercial marketing or use and the permission for the commercial marketing or use of the product is the first received permission for commercial marketing or use under the provision of law under which the applicable regulatory review occurred. 37 C.F.R §1.720(e).

The application for extension of the term of the '309 Patent submitted herewith is submitted within the sixty day period beginning on the date the product first received permission for commercial marketing or use under the provision oflaw under which the applicable regulatory review period occurred. 37 C.F.R §1.720(!). 19 The term of the '309 Patent, including any interim extension issued pursuant to 37 C.F.R §1.790, has not expired before the submission of an application in compliance with 37 C.F.R §1.741. 37 C.F.R § 1.720(g).

No other patent term has been extended for the same regulatory review period for the approved product, IMBRUVICA TM 37 C.F.R §1.720(h).

The extension claimed is 320 days, setting the patent to expire on November 13, 2027. The following are the calculations, made in accordance with 37 C.F.R §1.775, that result in the claimed extension:

(I) The testing phase began on September 8, 2008 (the effective date of the IND) and ended on June 28, 2013 (submission date of the NDA.)

(2) The approval phase began on June 28, 2013 (day of receipt by the FDA of the NDA) and approval was granted on November 13, 2013.

(3) The total number of days in the testing phase (from and including September 8, 2008 to and including June 28, 2013) is 1755 days from the start date to the end date, end date included.

(4) The patent issued on August 30, 2011, after the regulatory approval process began. The period of the testing phase that occurred prior to the issuance of the '309 Patent (from and including September 8, 2008 to August 30, 2011) is 1086 days. Thus, 1086 days must be subtracted from the 1755 day testing phase, resulting in a post-issuance phase of 669 days. One-half of the post-issuance testing phase is 334 days.

(5) The total number of days in the approval phase (from and including June 28, 2013 up to November 13, 2013) is 138 days from the start date to the end date.

(6) Applicant acted with due diligence throughout the entire regulatory review period.

(7) The sum of the (a) one-half of the number of days in the testing phase occurring after the issuance of the '309 Patent (334), and (b) number of days in the approval phase (138) is: 472 days.

(8) The original expiration date of the patent is December 28, 2026.

(9) Addition of the extension of 472 days to the original expiration date of the patent extends the expiration date of the patent to April 13, 2028.

(10) Fourteen years from the approval date of the product (November 13, 2013) is November 13,2027.

(11) Pursuant to 35 U.S.C. 5156(c)(3), the extended term of the patent cannot exceed 14 years from the date of product approval. This "fourteen year cap" applies since the extension of 472 days sets the patent to expire on April13, 2028, which is a date that is after 14 years post-approval (November 13, 2027).

(12) Pursuant to 35 U.S.C. §156(g)(6)(A), the extension period is subject to a five year limitation (for patents issued after September 24, 1984). The five year limitation does not apply since the extension of 472 days is less than five years.

20 (13) In light of the conclusions set forth above, the extended expiration date of the '309 Patent is believed to be November 13,2027, a total of320 days.

I hereby declare that all the statements made herein of my own knowledge are true, and that all the statements made on information and belief are believed to be true; and further, that these statement are made with the knowledge that willful false statements, and the like so made, are punishable by fine or imprisonment or both, under section 1001, Title 18 of the United States Code, and that such willful false statements may jeopardize the validity of the application or any patent issuing thereon.

Date: December 23, 2013 /Michael Hostetler/

Signature of Practitioner Reg. No.: 47,664 Michael J. Hostetler, Esq. Tel. No.: 858-350-2306 Wilson Sonsini Goodrich & Rosati Customer No.: 116469 12235 El Camino Real, Suite 200 San Diego, CA 92130

21 Electronic Acknowledgement Receipt

EFSID: 17749014

Application Number: 12499005

International Application Number:

Confirmation Number: 9452

Title of Invention: INHIBITORS OF BRUTON'S TYROSINE KINASE

First Named Inventor/Applicant Name: Lee HONIGBERG

Customer Number: 116469

Filer: Michael J. Hostetler/UT/ Lora Kim

Filer Authorized By: Michael J. Hostetler

Attorney Docket Number: 25922-750.403

Receipt Date: 23-DEC-2013

Filing Date: 07-JUL-2009

TimeStamp: 19:25:19

Application Type: Utility under 35 USC 111 (a) Payment information:

Submitted with Payment yes

Payment Type Deposit Account Payment was successfully received in RAM $1120 RAM confirmation Number 7344 Deposit Account 232415 Authorized User File Listing:

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New Applications Under 35 U.S.C. 111 If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR 1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this Acknowledgement Receipt will establish the filing date of the application.

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New International Application Filed with the USPTO as a Receiving Office If a new international application is being filed and the international application includes the necessary components for an international filing date (see PCT Article 11 and MPEP 181 0), a Notification of the International Application Number and of the International Filing Date (Form PCT/R0/1 05) will be issued in due course, subject to prescriptions concerning national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of the application. Electronic Patent Application Fee Transmittal

Application Number: 12499005

Filing Date: 07-Jul-2009

Title of Invention: INHIBITORS OF BRUTON'S TYROSINE KINASE

First Named Inventor/Applicant Name: Lee HONIGBERG

Filer: Michael J. HostetlerJUT/ Lora Kim

Attorney Docket Number: 25922-750.403

Filed as large Entity

Utility under 35 USC 111 (a) Filing Fees

Sub-Total in Description Fee Code Quantity Amount USD($)

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Pages:

Claims:

Miscellaneous-Filing:

Petition:

Extension ofTerm of Patent 1457 1 1120 1120

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ExtensionMof-Time: Sub-Total in Description Fee Code Quantity Amount USD($)

Miscellaneous:

Total in USD ($) 1120