USOO956 1231B2

(12) United States Patent (10) Patent No.: US 9,561,231 B2 Hubbard et al. (45) Date of Patent: Feb. 7, 2017

(54) PYRIDINONE AND PYRIDAZINONE (2013.01); A61 K3I/50 (2013.01); A61 K DERVATIVES 31/501 (2013.01); A61K3I/5377 (2013.01); A61K 45/06 (2013.01); C07D 213/30 (71) Applicant: AbbVie Inc., North Chicago, IL (US) (2013.01); C07D 213/64 (2013.01); C07D 213/68 (2013.01); C07D 213/74 (2013.01); (72) Inventors: Robert D. Hubbard, San Diego, CA C07D 213/81 (2013.01); C07D 237/14 (US); Le Wang, Vernon Hills, IL (US); (2013.01); C07D 401/02 (2013.01); C07D Chang H Park, Wadsworth, IL (US); 401/04 (2013.01); C07D 401/10 (2013.01); Chaohong Sun, Gurnee, IL (US); C07D 401/12 (2013.01); C07D 401/14 Keith F McDaniel, Wauconda, IL (US); (2013.01); C07D 403/04 (2013.01); C07D John K Pratt, Kenosha, WI (US); 403/10 (2013.01); C07D 403/12 (2013.01); Todd N Soltwedel, Chicago, IL (US); C07D407/04 (2013.01); C07D 407/12 Michael D Wendt, Vernon Hills, IL (2013.01); C07D 409/04 (2013.01); C07D (US); James H Holms, Gurnee, IL 413/10 (2013.01); C07D 417/04 (2013.01); (US); Dachun Liu, Vernon Hills, IL C07D 417/10 (2013.01); C07D 417/12 (US); George S. Sheppard, Wilmette, (2013.01); C07D 498/04 (2013.01) IL (US) (58) Field of Classification Search None (73) Assignee: AbbVie Inc., North Chicago, IL (US) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. PATENT DOCUMENTS 4,289,774 A 9, 1981 Schacht et al. (21) Appl. No.: 13/796,437 4,397,854 A 8, 1983 Sircar (22) Filed: Mar. 12, 2013 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2013/0331382 A1 Dec. 12, 2013 CN 101910182 A 12/2010 DE 144551.0 A1 3, 1969 (30) Foreign Application Priority Data (Continued)

Jun. 12, 2012 (WO) ...... PCT/CN2012/076748 OTHER PUBLICATIONS (51) Int. Cl. Ach, F. J. Chem. Soc., Abstr. 58, 70-1(1890) (CAS Abstract).* A6 IK 3/54 (2006.01) (Continued) A6 IK3I/50 (2006.01) A6 IK 3/442 (2006.01) Primary Examiner — Timothy R Rozof A6 IK3I/50 I (2006.01) (74) Attorney, Agent, or Firm — Glen Gesicki A 6LX 3/5.377 (2006.01) A6 IK 45/06 (2006.01) (57) ABSTRACT C07D 237/14 (2006.01) CO7D 213/64 (2006.01) The present invention provides for compounds of formula CO7D 40/04 (2006.01) (I) CO7D 40 I/O (2006.01) CO7D 403/04 (2006.01) CO7D 403/0 (2006.01) (I) CO7D 413/10 (2006.01) CO7D 417/10 (2006.01) CO7D 403/2 (2006.01) CO7D 40/4 (2006.01) C07D 213/74 (2006.01) CO7D 213/8 (2006.01) CO7D 40/02 (2006.01) wherein A', A. A. A. J. and X have any of the values CO7D 40/12 (2006.01) defined therefor in the specification, and pharmaceutically CO7D 407/04 (2006.01) acceptable salts thereof, that are useful as agents in the C07D 407/12 (2006.01) treatment of diseases and conditions, including inflamma CO7D 409/04 (2006.01) tory diseases, diabetes, obesity, cancer, and AIDS. Also CO7D 417/04 (2006.01) provided are pharmaceutical compositions comprising one (Continued) or more compounds of formula I. (52) U.S. Cl. CPC ...... A6 IK3I/541 (2013.01); A61 K3I/4412 43 Claims, No Drawings US 9,561,231 B2 Page 2

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(56) References Cited OTHER PUBLICATIONS Yang Z. et al., “Brd4 Recruits P-TEFb to Chromosomes at Late Mitosis to Promote G1 Gene Expression and Cell Cycle Progres sion.” Molecular and Cellular Biology, 2008, vol. 28 (3), pp. 967-976. Zhang G. et al., “Down-regulation of NF-kBTranscriptional Activ ity in HIV-associated Kidney Disease by BRD4. Inhibition.” Journal of Biological Chemistry, 2012, vol. 287 (34), pp. 28840-28851. Zuber J., et al., “RNAi Screen Identifies Brd4 as a Therapeutic Target in Acute Myeloid Leukaemia,” Nature, 2011, vol. 478 (7370), pp. 524-528. Garnier J.M., et al., “BET Bromodomain Inhibitors: A Patent Review.” Expert Opinion on Therapeutic Patents, 2014, vol. 24(2), pp. 185-199. Roberts D.A., et al., "1,2,4-Triazolo 4,3-alpyrazine Derivatives with Human Renin Inhibitory Activity. 1. Synthesis and Biological Properties of Alkyl Alcohol and Statine Derivatives,” Journal of Medicinal Chemistry, 1990, vol. 33 (9), pp. 2326-2334. Supplementary European Search Report for Application No. EP12878861, mailed on Oct. 9, 2015, 8 pages. * cited by examiner US 9,561,231 B2 1. 2 PYRIDINONE AND PYRIDAZINONE SUMMARY DERVATIVES In one aspect, the present invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt thereof, CROSS-REFERENCES TO RELATED 5 APPLICATIONS

This application claims the benefit of PCT Application No. PCT/CN2012/076748, filed on Jun. 12, 2012, the teach ings of which are herein incorporated by reference. 10 s A. A2 s Y BACKGROUND

Bromodomains refer to conserved protein structural folds 15 Wherein J is a group of formula IIa or IIb: which bind to N-acetylated lysine residues that are found in some proteins. The BET family of bromodomain containing (IIa) proteins is comprised of four members (BRD2. BRD3. O BRD4 and BRDt). Each member of the BET family employs R X2a two bromodomains to recognize N-acetylated lysine resi dues found primarily, but not exclusively, on the amino Y terminal tails of histone proteins. These interactions modu s Xla or late gene expression by recruiting transcription factors to 25 specific genome locations within chromatin. For example, (IIb) histone-bound BRD4 recruits the transcription factor O P-TEFb to promoters, resulting in the expression of a subset R. X2b: of genes involved in cell cycle progression (Yang et al., Mol. NN Cell. Biol. 28:967-976 (2008)). BRD2 and BRD3 also 30 l function as transcriptional regulators of growth promoting 1S Y genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BET family members were recently established as being impor tant for the maintenance of several cancer types (Zuber et al., 35 wherein Nature 478: 524-528 (2011); Mertz et al; Proc. Natl. Acad. R" is C-C alkyl, C-C alkylene-OH, or C-C, Sci. 108: 16669-16674 (2011): Delmore et al., Cell 146: haloalkyl: 1-14, (2011); Dawson et al., Nature 478: 529-533 (2011)). Y''' is N or CR", wherein R' is H, halo, C-C alkyl, BET family members have also been implicated in mediat —O—C-C alkyl, C-C haloalkyl, —O—C-C, 40 haloalkyl, aryl, aryl-C-C-alkylene-OH, aryl-C- ing acute inflammatory responses through the canonical Calkylene-heterocycloalkyl, C(O)NR'R'', wherein NF-KB pathway (Huang et al., Mol. Cell. Biol. 29: 1375 heterocycloalkyl of aryl-C-C-alkylene-heterocy 1387 (2009)) resulting in the upregulation of genes associ cloalkyl may be substituted with one to three ated with the production of cytokines (Nicodeme et al., C-C alkyl, Nature 468: 1119-1123, (2010)). Suppression of cytokine 45 R" is H, C-C alkyl, C-C alkylene-OH, or C-C, haloalkyl: induction by BET bromodomain inhibitors has been shown Y' is N or CR, wherein R is heteroaryl, H, halo, to be an effective approach to treat inflammation-mediated C-C alkyl, —O—C-C alkyl, C-C haloalkyl, kidney disease in an animal model (Zhang, et al., J. Biol. —O—C-C haloalkyl, aryl, aryl-C-C-alkylene-OH, Chem. 287: 28840-28851 (2012)). BRD2 function has been 50 aryl-C-C-alkylene-heterocycloalkyl, C(O)NR'R'', linked to predisposition for dyslipidemia or improper regu wherein heterocycloalkyl of aryl-C-C-alkylene-het lation of adipogenesis, elevated inflammatory profiles and erocycloalkyl may be substituted with one to three increased susceptibility to autoimmune diseases (Denis, C-C alkyl; wherein said heteroaryl may be substituted Discovery Medicine 10: 489-499 (2010)). The human with one to three groups selected from the group 55 consisting of C-C alkyl, C-C alkylene-aryl, immunodeficiency virus utilizes BRD4 to initiate transcrip C-C alkylene-heteroaryl, C-C alkylene-heterocy tion of viral RNA from stably integrated viral DNA (Jang et cloalkyl, COOH, and COO C-C alkyl, al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain X* is selected from the group consisting of H, inhibitors have also been shown to reactivate HIV transcrip - NR'R'', halo, OH, - O C-C alkyl, aryl, het tion in models of latent T cell infection and latent monocyte 60 eroaryl, -NR'C(O) C-C alkyl, NR'C(O)O C C alkyl, and NR'S(O). C-C alkyl: infection (Banerjee, et al., J. Leukocyte Biol. doi:10.1189/ X is C-C alkyl, C-C alkylene-OH, or C-C, jlb.0312165). BRDt has an important role in spermatogen haloalkyl: esis that is blocked by BET bromodomain inhibitors (Mat X' and X' are each selected from the group consisting Zuk, et al., Cell 150: 673-684 (2012)). Accordingly, there is 65 of hydrogen, halo, C-C alkyl, C-Chaloalkyl, C-C an ongoing medical need to develop new drugs to treat these alkenyl, —C-C alkenylene-O-C-C alkyl, C-C indications. alkynyl, -C-C alkynylene-N(C-C alkyl).

US 9,561,231 B2 11 12 tetrahydropyranyl, piperidinyl, each of which is optionally In certain embodiments, Substituted). In certain embodiments, G is aryl or C-C, A is CH, A is CR, A is CH, and A is CH: cycloalkyl, wherein G may be substituted with 1 to 3 groups J is formula IIa, independently selected from the group consisting of CN, R'' is methyl, OH, NR'R'', C-C haloalkyl, -SO, C-C alkyl, Y is N or CH, halo, C(O)—C-C-alkyl, O—C-C alkyl, —O—C-C, X* is H or halo, haloalkyl, —C-C, alkyl, NR20C(O)R32, X is L-G wherein L is —O— or —O C-C alkylene-, NRSOOR, NRC(O)NR'R'', and G is phenyl or C-C, cycloalkyl, wherein G is optionally wherein R’ is selected from —C-C alkyl and —C-C, substituted with 1 to 3 halo, haloalkyl, 10 wherein R is selected from C-C alkyl and —C-C, R" is selected from the group consisting of H, haloalkyl, NR'SO, C-C alkyl, and SO C-C alkyl, and wherein R and Rare independently selected from the X" is selected from the group consisting of H, -O-C- group consisting of hydrogen, —C-C alkyl, and Calkyl, -O-C-Chaloalkyl, optionally Substituted phe —C-C haloalkyl. 15 nyl, optionally substituted heteroaryl, and —O—C-C, In certain embodiments, L is —O—, and G is phenyl alkylene-C-C-7 cycloalkyl wherein said C-C, cycloalkyl of substituted with 1 to 3 halo. In certain embodiments, L is —O—C-C alkylene-C-C-7 cycloalkyl is optionally Substi -NR' wherein R is H, and G is C-C, cycloalkyl tuted. which is optionally substituted with 1 to 3 halo. In certain In certain embodiments, a compound of formula (I) is embodiments, L is —O— and G is phenyl substituted with selected from the group consisting of: 1 to 3 fluoro. In certain embodiments, G is 2,4-difluoro N-4-(4-chlorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6- phenyl. In certain embodiments, L is —O-C-C alkyene, dihydropyridin-3-yl)phenylethanesulfonamide: and G is C-C, cycloalkyl. In certain embodiments, L is N-4-(2,4-difluorophenoxy)-3-1-methyl-6-oxo-4-(2.2.2- —NR' C-C alkyene wherein R' is H, and G is C-C, trifluoroethoxy)-1,6-dihydropyridin-3-yl) cycloalkyl or phenyl, each of which is optionally substituted 25 phenylethanesulfonamide: with 1 or 3 halo. In certain embodiments, J is IIa, Y''' is N. N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1, R" is methyl, and X* is hydrogen. In certain embodiments, 6-dihydropyridin-3-yl)phenylethanesulfonamide: J is IIa, Y is CR, wherein R is H, R is methyl, and X? 5-2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl-4- is hydrogen. In certain embodiments, X" is hydrogen. In ethoxy-1-methylpyridin-2(1H)-one: certain embodiments, X" is selected from the group con 30 N-4-(2,4-difluorophenoxy)-3-(4-methoxy-1-methyl-6-oxo sisting of: 1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide: halo, —O C-C alkyl, and aryl, wherein said aryl may N-(3-(4-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihy be substituted with 1 to 3 of R, where R is selected dropyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl)ethane from the group consisting of NR''SO, C-C alkyl, Sulfonamide; —C-C alkylene-NR'R''. —C-C alkylene-hetero 35 N-4-(2,4-difluorophenoxy)-3-1-methyl-4-1-(2-methyl cycloalkyl, wherein said heterocycloalkyl of said C-C, propyl)-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridin-3-yl) alkylene-heterocycloalkyl may be substituted with 1 to phenylethanesulfonamide: 3 groups independently selected from the group con N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-1,6-dihy sisting of C-C alkyl and —CH2-phenyl, wherein said dropyridin-3-yl)phenylmethanesulfonamide; aryl of said C-C alkylene-aryl may be substituted 40 N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1, with 1 to 3 groups independently selected from the 6-dihydropyridin-3-yl)phenyl)methanesulfonamide: group consisting of —C-C alkylene-OH, and hetero N-4-(2,4-difluorophenoxy)-3-1-methyl-4-4-(morpholin cycloalkyl, wherein said heterocycloalkyl may be sub 4-yl)phenyl]-6-oxo-1,6-dihydropyridin-3-yl) stituted with 1-3 substituents independently selected phenylethanesulfonamide: from the group consisting of C-C alkyl, C-C 45 N-4-(2,4-difluorophenoxy)-3-(4-4-(dimethylamino) haloalkyl and aryl. methylphenyl-1-methyl-6-oxo-1,6-dihydropyridin-3- In certain embodiments, J is IIb, R' is hydrogen, X is yl)phenylethanesulfonamide; methyl, Y' is CR', and R' is H. In certain embodiments, N-4-(2,4-difluorophenoxy)-3-1-methyl-4-4-(morpholin X' is hydrogen. In certain embodiments, L is -O-, and G 4-yl)phenyl]-6-oxo-1,6-dihydropyridin-3-yl) is phenyl substituted with 1 to 3 halo. In certain embodi 50 phenyl)methanesulfonamide: ments, G is phenyl substituted with 1 to 3 halo. In certain N-4-(2,4-difluorophenoxy)-3-(1-methyl-4-4-(4-methyl embodiments, G is 2,4-difluoro-phenyl. piperazin-1-yl)methylphenyl-6-oxo-1,6-dihydropyri In certain embodiments, X' is H, and R' is NR'SO.C.- din-3-yl)phenylmethanesulfonamide; C alkyl. N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-1,6-dihy In certain embodiments, 55 dropyridin-3-yl)phenylethanesulfonamide: A is CH, A is CR, A is CH, and A is CH: N-4-(2,4-difluorophenoxy)-3-(4-4-(hydroxymethyl)phe J is formula IIa, nyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl) R'' is methyl, phenylethanesulfonamide: Y is N or CH, N-3-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- X* is H or halo, 60 (2,4-difluorophenoxy)phenylethanesulfonamide; X is L-G wherein L is —O— or —O C-C alkylene-, N-3-(1-methyl-4-4-(4-methylpiperazin-1-yl)methylphe and G is phenyl or C-C, cycloalkyl, wherein G is optionally nyl-6-oxo-1,6-dihydropyridazin-3-yl)-4-phenoxyphe substituted with 1 to 3 halo, and nylmethanesulfonamide; R" is selected from the group consisting of H, 5-2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl-4- NR'SO, C-C alkyl, -NR'SO, C-C haloalkyl, 65 methoxy-1-methylpyridin-2(1H)-one; - SO, NR'R', SO. NR C-C haloalkyl, N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6-dihy —SO C-C alkyl, and —SO C-C haloalkyl. dropyridin-3-yl)phenylethanesulfonamide; and

US 9,561,231 B2 27 28 In another aspect, the present invention relates to phar primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheu maceutical compositions comprising a pharmaceutically matoid arthritis, Scleritis, Sclerosing cholangitis, sepsis sys acceptable excipient and a therapeutically effective amount temic lupus erythematosus, Takayasu's Arteritis, toxic of a compound of formula I, or a pharmaceutically accept shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, able salt thereof. vitiligo, Vasculitis, and Wegener's granulomatosis. In certain In another aspect, the present invention relates to methods embodiments, the methods further comprise administering a of treating cancer in a subject comprising administering a therapeutically effective amount of at least one additional therapeutically effective amount of a compound of formula therapeutic agent. In certain embodiments, the methods (I) or a pharmaceutically acceptable salt thereof, to a subject further comprise administering a therapeutically effective in need thereof. In certain embodiments, the cancer is 10 amount of at least one additional therapeutic agent. selected from the group consisting of acoustic neuroma, In another aspect, the present invention relates to methods acute leukemia, acute lymphocytic leukemia, acute myelo of treating a chronic kidney disease or condition in a subject cytic leukemia (monocytic, myeloblastic, adenocarcinoma, comprising administering a therapeutically effective amount angiosarcoma, astrocytoma, myelomonocytic and promy of a compound of formula (I) or a pharmaceutically accept elocytic), acute t-cell leukemia, basal cell carcinoma, bile 15 able salt thereof, to a subject in need thereof, wherein said duct carcinoma, bladder cancer, brain cancer, breast cancer, disease or condition is selected from the group consisting of bronchogenic carcinoma, cervical cancer, chondrosarcoma, diabetic nephropathy, hypertensive nephropathy, HIV-asso chordoma, choriocarcinoma, chronic leukemia, chronic ciated nephropathy, glomerulonephritis, lupus nephritis, IgA lymphocytic leukemia, chronic myelocytic (granulocytic) nephropathy, focal segmental glomerulosclerosis, membra leukemia, chronic myelogenous leukemia, colon cancer, nous glomerulonephritis, minimal change disease, polycys colorectal cancer, craniopharyngioma, cystadenocarcinoma, tic kidney disease and tubular interstitial nephritis. In certain diffuse large B-cell lymphoma, dysproliferative changes embodiments, the methods further comprise administering a (dysplasias and metaplasias), embryonal carcinoma, endo therapeutically effective amount of at least one additional metrial cancer, endotheliosarcoma, ependymoma, epithelial therapeutic agent. In certain embodiments, the methods carcinoma, erythroleukemia, esophageal cancer, estrogen 25 further comprise administering a therapeutically effective receptor positive breast cancer, essential thrombocythemia, amount of at least one additional therapeutic agent. Ewings tumor, fibrosarcoma, follicular lymphoma, germ In another aspect, the present invention relates to methods cell testicular cancer, glioma, glioblastoma, gliosarcoma, of treating an acute kidney injury or disease or condition in heavy chain disease, hemangioblastoma, hepatoma, hepato a Subject comprising administering a therapeutically effec cellular cancer, hormone insensitive prostate cancer, leio 30 tive amount of a compound of formula (I) or a pharmaceu myosarcoma, leukemia, liposarcoma, lung cancer, lympha tically acceptable salt thereof, to a subject in need thereof, gioendotheliosarcoma, lymphangiosarcoma, lymphoblastic wherein said acute kidney injury or disease or condition is leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), selected from the group consisting of ischemia-reperfusion malignancies and hyperproliferative disorders of the blad induced, cardiac and major Surgery induced, percutaneous der, breast, colon, lung, ovaries, pancreas, prostate, skin and 35 coronary intervention induced, radio-contrast agent induced, uterus, lymphoid malignancies of T-cell or B-cell origin, sepsis induced, pneumonia induced, and drug toxicity leukemia, lymphoma, medullary carcinoma, medulloblas induced. In certain embodiments, the methods further com toma, melanoma, meningioma, mesothelioma, multiple prise administering a therapeutically effective amount of at myeloma, myelogenous leukemia, myeloma, myxosarcoma, least one additional therapeutic agent. In certain embodi neuroblastoma, NUT midline carcinoma (NMC), non-small 40 ments, the methods further comprise administering a thera cell lung cancer, oligodendroglioma, oral cancer, osteogenic peutically effective amount of at least one additional thera sarcoma, ovarian cancer, pancreatic cancer, papillary adeno peutic agent. carcinomas, papillary carcinoma, pinealoma, polycythemia In another aspect, the present invention relates to methods Vera, prostate cancer, rectal cancer, renal cell carcinoma, of treating AIDS in a Subject comprising administering a retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous 45 therapeutically effective amount of a compound of formula gland carcinoma, seminoma, skin cancer, Small cell lung (I) or a pharmaceutically acceptable salt thereof, to a subject carcinoma, Solid tumors (carcinomas and sarcomas), Small in need thereof. In certain embodiments, the methods further cell lung cancer, stomach cancer, Squamous cell carcinoma, comprise administering a therapeutically effective amount synovioma, Sweat gland carcinoma, thyroid cancer, Walden of at least one additional therapeutic agent. ström's macroglobulinemia, testicular tumors, uterine can 50 In another aspect, the present invention relates to methods cer and Wilms tumor. In certain embodiments, the methods of treating obesity in a subject comprising administering a further comprise administering a therapeutically effective therapeutically effective amount of a compound of formula amount of at least one additional therapeutic agent. (I) or a pharmaceutically acceptable salt thereof, to a subject In another aspect, the present invention relates to methods in need thereof. In certain embodiments, the methods further of treating a disease or condition in a Subject comprising 55 comprise administering a therapeutically effective amount administering a therapeutically effective amount of a com of at least one additional therapeutic agent. pound of formula (I) or a pharmaceutically acceptable salt In another aspect, the present invention relates to methods thereof, to a subject in need thereof, wherein said disease or of treating type II diabetes in a subject comprising admin condition is selected from the group consisting of Addison's istering a therapeutically effective amount of a compound of disease, acute gout, ankylosing spondylitis, asthma, athero 60 formula (I) or a pharmaceutically acceptable salt thereof, to Sclerosis, Behcet’s disease, bullous skin diseases, chronic a subject in need thereof. In certain embodiments, the obstructive pulmonary disease (COPD), Crohn's disease, methods further comprise administering a therapeutically dermatitis, eczema, giant cell arteritis, glomerulonephritis, effective amount of at least one additional therapeutic agent. hepatitis, hypophysitis, inflammatory bowel disease, Kawa In another aspect, the present invention relates to methods saki disease, lupus nephritis, multiple Sclerosis, myocarditis, 65 of preventing conception by inhibiting spermatogenesis in a myositis, nephritis, organ transplant rejection, osteoarthritis, Subject comprising administering a therapeutically effective pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, amount of a compound of formula (I) or a pharmaceutically US 9,561,231 B2 29 30 acceptable salt thereof, to a subject in need thereof. In alkylene and alkylenyl include, but are not limited to, certain embodiments, the methods further comprise admin —CH2—, —CH2CH2—, —CH2CHCH . istering a therapeutically effective amount of at least one —CH2CH2CHCH , and —CH2CH(CH)CH . additional therapeutic agent. The term "C-C alkynyl as used herein, means a straight A further aspect of the invention provides the use of a or branched chain hydrocarbon radical containing from 2 to compound of formula (I), alone or in combination with a 4 carbon atoms and containing one carbon-carbon triple second active pharmaceutical agent, in the manufacture of a bond. Representative examples of C-C alkynyl include, medicament for treating or preventing conditions and dis but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, orders disclosed herein, with or without a pharmaceutically 3-butynyl, and 1-butynyl. acceptable carrier. 10 Pharmaceutical compositions comprising a compound of The term "C-C alkynylene' means a divalent radical formula (I), or a pharmaceutically acceptable salt, alone or derived from a straight or branched chain hydrocarbon in combination with a second active pharmaceutical agent, radical containing from 2 to 4 carbon atoms and containing are also provided. one carbon-carbon triple bond. 15 The term "C-C cycloalkyl” (alone or in combination DETAILED DESCRIPTION with another term(s)) means a Saturated cyclic hydrocarbyl Substituent containing from 3 to 14 carbon ring atoms. The a). Definitions term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl groups. It is noted that, as used in this specification and the Examples of monocyclic cycloalkyl groups include, but are intended claims, the singular form “a,” “an,” and “the not limited to, cyclopropyl (cyclopropanyl), cyclobutyl (cy include plural referents unless the context clearly dictates clobutanyl), cyclopentyl (cyclopentanyl), cyclohexyl (cy otherwise. Thus, for example, reference to “a compound clohexanyl), cycloheptyl, cyclooctyl, etc. Unless otherwise includes a single compound as well as one or more of the indicated, the term "C-C monocyclic cycloalkyl refers to same or different compounds, reference to “optionally a 25 monocylic cycloalkyl groups containing from 3 to 8 car pharmaceutically acceptable carrier” refers to a single bons. In certain embodiments, a "C-C cycloalkyl is a optional pharmaceutically acceptable carrier as well as one "C-C monocyclic cycloalkyl or a "C-C-7 monocyclic or more pharmaceutically acceptable carriers, and the like. cycloalkyl.” As used in the specification and the appended claims, In a spirocyclic cycloalkyl group, one atom is common to unless specified to the contrary, the following terms have the 30 two different rings. Examples of spirocyclic cycloalkyls meaning indicated: include spiro2.2 pentanyl. Spiro[2.4]heptanyl, and spiro The term “alkenyl' as used herein, means a straight or 2.5octanyl. Unless otherwise indicated, the term "Cs-Cs branched hydrocarbon chain containing from 2 to 10 car spirocyclic cycloalkyl refers to spirocyclic cycloalkyl bons and containing at least one carbon-carbon double bond. groups containing from 5 to 8 carbons. The term "C-C alkenyl' means an alkenyl group contain 35 In a bridged cycloalkyl, the rings share at least two ing 2-4 carbon atoms. Non-limiting examples of alkenyl common non-adjacent atoms. Examples of bridged include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2- cycloalkyls include bicyclo2.2.1]heptanyl, and adamanta propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, nyl. Unless otherwise indicated, the term “C7-Co bridged 2-methyl-1-heptenyl, and 3-decenyl. cycloalkyl refers to a bridged cycloalkyl groups containing The term “alkenylene' means a divalent group derived 40 from 5 to 10 carbons. from a straight or branched chain hydrocarbon, for example, A bicyclic ring cycloalkyl is a C-C monocyclic of 2 to 10 carbon atoms or of 2 to 6 carbon atoms (C-C, cycloalkyl fused to a monocyclic Cs-C, cycloalkyl ring. alkenylene) or of 2 to 4 carbon atoms (C-C alkenylene), Non-limiting examples of bicyclic cycloalkyls include deca and contains at least one carbon-carbon double bond. Rep hydronaphthalenyl, octahydro-1H-indenyl, octahydropen resentative examples of alkenylene include, but are not 45 talenyl, and decahydroaZulenyl. The bicyclic cycloalkyl limited to, -CH=CH- and CH-CH=CH-. groups may contain one or two alkylene bridges, each The term “alkyl as used herein, means a saturated, consisting of one, two, three, or four carbon atoms in length, straight or branched hydrocarbon chain radical. In some and each bridge links two non-adjacent carbon atoms of the instances, the number of carbon atoms in an alkyl moiety is ring system. Non-limiting examples of bicyclic bridged indicated by the prefix "C-C,”, wherein x is the minimum 50 groups include bicyclo3.1.1 heptanyl, bicyclo2.2.1]hepta and y is the maximum number of carbon atoms in the nyl, bicyclo[2.2.2]octanyl, bicyclo3.2.2 nonanyl, bicyclo substituent. Thus, for example, "C-C alkyl refers to an 3.3.1 nonanyl, and bicyclo4.2.1 nonanyl, tricyclo[3.3. alkyl Substituent containing from 1 to 6 carbon atoms and 1.0 nonanyl(octahydro-2,5-methanopentalenyl or norada "C-C alkyl” refers to an alkyl substituent containing from mantanyl), and tricyclo[3.3.1.1 decanyl(adamantanyl). 1 to 3 carbon atoms. Representative examples of alkyl 55 The term “cycloalkenyl (alone or in combination with include, but are not limited to, methyl, ethyl, n-propyl. another term(s)) means a partially Saturated cycloalkyl Sub iso-propyl. n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, stituent containing from 3 to 14 carbon ring atoms. A isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbu cycloalkenyl may be a monocyclic carbon ring, which tyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl. typically contains from 3 to 8 carbon ring atoms (i.e., a 2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl, 1.2.2- 60 C-Cs cycloalkenyl) and more typically from 4 to 6 carbon trimethylpropyl, 3-methylhexyl, 2,2-dimethylpenty1, 2,3-di ring atoms (i.e., a C-C cycloalkenyl). Examples of single methylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. ring cycloalkenyls include cyclopentenyl, and cyclohexenyl. The term “alkylene' or “alkylenyl' means a divalent A cycloalkenyl may alternatively be bicyclic. Examples of radical derived from a straight or branched, saturated hydro bicyclic cycloalkenyls include bridged and spirocyclic carbon chain, for example, of 1 to 10 carbon atoms or of 1 65 cycloalkyls. to 6 carbon atoms (C-C alkylene) or of 1 to 4 carbon atoms The term "heterocycloalkyl as used herein, means a 3 to or of 1 to 3 carbon atoms (C-C alkylene). Examples of 15 membered non-aromatic monocylic or bicyclic ring radi US 9,561,231 B2 31 32 cal containing carbon atoms and one to three heteroatoms of 7-membered monocyclic heterocycloalkyls include independently selected from O, N, or S. The nitrogen and aZepanyl. 2,3,4,5-tetrahydro-1H-azepinyl, oxepanyl, 2.3.4. Sulfur heteroatoms in the heterocycloalkyl rings may option 5-tetrahydro-1H-oxepinyl, thiepanyl, and 2,3,4,5-tetra ally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, 1.2- hydro-1H-thiepinyl. dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and 5 An “8-membered monocyclic heterocycloalkyl is a the nitrogen atoms may optionally be quarternized. Unless 8-membered, monocyclic cycloalkyl ring having from 5 to otherwise indicated, the foregoing heterocycloalkyls can be 7 carbon atoms and from 1 to 3 heteroatoms selected from C-attached or N-attached where such is possible and which the group consisting of: 1 O; 2 O; 3 O; 1 S; 2 S; 3 S; 1 N: results in the creation of a stable structure. For example, 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 piperidinyl can be piperidin-1-yl (N-attached) or piperidin 10 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. 4-yl (C-attached). Illustrative examples of 8-membered monocyclic heterocy Examples of heterocycloalkyls include 3- to 8-membered cloalkyls include azocanyl, thiocanyl, oxocanyl, 3,4,5,6- monocyclic heterocycloalkyls, 8-12 membered bicyclic het tetrahydro-2H-oxocinyl, etc. erocycloalkyls, a spiro heterocycloalkyl, and 7-15 mem A bicyclic 8-12 membered heterocycloalkyl is a mono bered bridged bicyclic heterocycloalkyls. 15 cyclic 5 to 7 membered heterocycloalkyl fused to a phenyl The phrase “3- to 8-membered monocyclic heterocy group, or a monocyclic 5 to 7 membered heterocycloalkyl cloalkyl means a non-aromatic cyclic group having carbon fused to a monocyclic Cs-C7 cycloalkyl, or a monocyclic 5 atoms and 1 to 3 heteroatoms independently selected from S. to 7 membered heterocycloalkyl fused to a monocyclic 5 to N or O, wherein when two O atoms or one O atom and one 7 membered heterocycloalkyl. Representative examples of Satom are present, the two O atoms or one O atom and one bicyclic heterocycloalkyls include, but are not limited to, Satom are not bonded to each other, respectively. Illustra 2,3-dihydro-1,4-benzodioxin-6-yl, benzopyranyl, benzoth tive examples of 3- to 8-membered monocyclic heterocy iopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothie cloalkyl include aziridin-1-yl, 1-Oxa-cyclobutan-2-yl, tetra nyl, 2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)- hydrofuran-3-yl, morpholin-4-yl, 2-thiacyclohex-1-yl, y1. 2,3,4,6-tetrahydro-1H-pyrido 1,2-alpyrazin-2-yl, 2-oxo-2-thiacyclohex-1-yl, 2.2-dioxo-2-thiacyclohex-1-yl, 25 hexahydropyrano3,4-b 14oxazin-1 (5H)-yl. and 4-methyl-piperazin-2-yl. The monocyclic heterocycloalkyl and the bicyclic hetero A “3-membered monocyclic heterocycloalkyl is a cycloalkyl may contain one or two alkylene bridges or an 3-membered, monocyclic cycloalkyl ring having 2 carbon alkenylene bridge, or mixture thereof, each consisting of no atoms and 1 heteroatom selected from the group consisting more than four carbon atoms and each linking two non of 1 O; 1 S; and 1 N. Illustrative examples of 3-membered 30 adjacent atoms of the ring system. Examples of Such bridged monocyclic heterocycloalkyls include oxiranyl, aziridinyl, heterocycloalkyls include, but are not limited to, azabicyclo and thiranyl. 2.2.1]heptyl (including 2-azabicyclo2.2.1]hept-2-yl), A “4-membered monocyclic heterocycloalkyl is a 8-azabicyclo3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene, 4-membered, monocyclic cycloalkyl ring having 3 carbon hexahydro-2H-2,5-methanocyclopentablfuran, hexahydro atoms and 1 heteroatom selected from the group consisting 35 1H-1,4-methanocyclopentacfuran, aza-admantane (1-aza of 1 O; 1 S; and 1 N. Illustrative examples of 4-membered tricyclo[3.3.1.1 decane), and Oxa-adamantane (2-oxatri monocyclic heterocycloalkyls include oxetanyl, aZetidinyl, cyclo[3.3.1.1 decane). The term “6- to 9-membered and thietanyl. bridged bicyclic heterocycloalkyl refers to a ring radical A “5-membered monocyclic heterocycloalkyl is a which is either saturated or unsaturated, and which is the 5-membered, monocyclic cycloalkyl ring having from 1 to 40 result of the fusion of 5-, 6-, or 7-membered monocyclic 4 carbon atoms and from 1 to 3 heteroatoms selected from heterocycloalkyl to a 3-, 4-, or 5-membered monocyclic the group consisting of: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 heterocycloalkyl; or a 5-, 6-, or 7-membered monocyclic N; 1 S, and 2 N; 1 O and 1 N; and 1 O and 2 N. Illustrative heterocycloalkyl to a Cs-C7-cycloalkyl, wherein the fusion examples of 5-membered monocyclic heterocycloalkyls junctions have 1 to 3 intervening ring atoms. The term “6- include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothie 45 to 9-membered bridged bicyclic heterocycloalkyl includes nyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazoli saturated and unsaturated “6- to 9-membered bridged bicy nyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and 3-pyrroli clic heterocycloalkyls.” “6- to 9-membered bridged bicyclic nyl. heterocycloalkyls' may be substituted as set out above for A “6-membered monocyclic heterocycloalkyl is a alkyl. Examples of “6- to 9-membered bridged bicyclic 6-membered, monocyclic cycloalkyl ring having from 3 to 50 heterocycloalkyls' include 3-azabicyclo4.2.1 nonanyl and 5 carbon atoms and from 1 to 3 heteroatoms selected from 7-azabicyclo[2.2.1]heptanyl. the group consisting of: 1 O; 2 O; 3 O; 1 S; 2 S; 3 S; 1 N: A spiro heterocycloalkyl is a 7 to 15 membered hetero 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 cycloalkyl wherein two substituents on the same carbon S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. atom of a monocyclic 5 to 7 membered heterocycloalkyl Illustrative examples of 6-membered monocyclic heterocy 55 ring together with said carbon atom form a second ring cloalkyls include 5,6-dihydro-4H-1,3-oxazinyl, tetrahydro system selected from a monocyclic cycloalkyl, a bicyclic pyranyl, dihydropyranyl, dioxanyl, 1.3-dioxolanyl, 1,4- cycloalkyl, a monocyclic heterocycloalkyl, or a bicyclic dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, heterocycloalkyl. Examples of spiro heterocycloalkyls piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyra include, but not limited to, 2-azaspiro[3.3 hept-6-yl, Zolinyl, 1.2.3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, 60 6-azaspiro[2.5oct-6-yl, l'H, 4H-spiro 1,3-benzodioxine-2, thiomorpholinyl, thioxanyl, and trithianyl. 4'-piperidin-1-yl, 1'H, 3H-spiro2-benzofuran-1,4'-piperi A "7-membered monocyclic heterocycloalkyl is a din-1-yl, and 1,4-dioxa-8-azaspiro4.5 dec-8-yl. The 7-membered, monocyclic cycloalkyl ring having from 5 or monocyclic, the bicyclic, and the spiro heterocycloalkyls 6 carbon atoms and from 1 to 3 heteroatoms selected from can be unsubstituted or substituted. The monocyclic, the the group consisting of: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 1 S. 65 bicyclic and the spiro heterocycloalkyls are connected to the 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S parent molecular moiety through any carbon atom or any and 2 O; 1 O and 1 N; and 1 O and 2 N. Illustrative examples nitrogen atom contained within the ring systems. The nitro US 9,561,231 B2 33 34 gen and Sulfur heteroatoms in the heterocycloalkyl rings attached is substituted with one or more independently may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothie selected halogen radicals. For example, haloalkyl means an nyl, 1,2-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholi alkyl Substituent in which at least one hydrogen radical is nyl)) and the nitrogenatoms may optionally be quarternized. replaced with a halogen radical. Examples of haloalkyls An aryl group is an aromatic hydrocarbon radical. Fur include chloromethyl, 1-bromoethyl, fluoromethyl, difluo thermore, the term “aryl' includes multicyclic aryl groups, romethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should bicyclic, e.g., naphthyl. Typical aryl groups include phenyl, be recognized that if a substituent is substituted by more than and naphthyl. The term “9- to 12-membered bicyclic aryl' is one halogen radical, those halogen radicals may be identical a ring structure formed by the fusion of a benzene ring to: or different (unless otherwise stated). Examples of haloalkyl (1) a C-C monocyclic cycloalkyl (e.g., indanyl: 1,2,3,4- 10 tetrahydro-naphthalenyl: 6,7,8,9-tetrahydro-5H-benzocy include C-C haloalkyls, which is a halogenated alkyl cloheptenyl, etc.); or (2) another benzene ring (e.g., naph containing from 1 to 3 carbons. thalenyl); wherein the fusion junctions are at adjacent If a moiety is described as “substituted, a non-hydrogen carbons on the benzene ring. radical is in the place of hydrogen radical of any Substitut The term "heteroaryl as used herein, means a monocyclic 15 able atom of the moiety. Thus, for example, a substituted 5 or 6 membered heteroaryland a bicyclic 8 to 12 membered heteroaryl moiety is a heteroaryl moiety in which at least one heteroaryl. non-hydrogen radical is in the place of a hydrogen radical on A “5-membered heteroaryl is a 5-membered, monocy the heterocyclic ring. It should be recognized that if there are clic, aromatic ring radical having from 1 to 4 carbon atoms more than one substitution on a moiety, each non-hydrogen and from 1 to 4 heteroatoms selected from the group radical may be identical or different (unless otherwise consisting of: 1 O; 1 S; 1 N; 2 N; 3 N; 4 N; 1 S and 1 N; 1 stated). S and 2 N; 1 O and 1 N; and 1 O and 2 N. Illustrative If a moiety is described as being “optionally substituted.” examples of 5-membered heteroaryls include, but are not the moiety may be either (1) not substituted or (2) substi limited to, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isox tuted. If a moiety is described as being optionally substituted azolyl, isothiazolyl, oxadiazolyl, oxazolyl pyrazolyl pyrro 25 with up to a particular number of non-hydrogen radicals, that lyl, 2- or 3-pyrrolyl, thienyl, 2-thienyl, 3-thienyl, tetrazolyl, moiety may be either (1) not substituted; or (2) substituted thiazolyl, thiadiazolyl, and triazolyl. by up to that particular number of non-hydrogen radicals or A “6-membered heteroaryl is a 6-membered, monocy by up to the maximum number of Substitutable positions on clic, aromatic ring radical having from 3 to 5 carbon atoms the moiety, whichever is less. Thus, for example, if a moiety and from 1 to 3 heteroatoms selected from the group 30 is described as a heteroaryl optionally substituted with up to consisting of: 1 N; 2 N; and 3 N. Illustrative examples of 3 non-hydrogen radicals, then any heteroaryl with less than 6-membered heteroaryls include, but are not limited to, 3 substitutable positions would be optionally substituted by pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or up to only as many non-hydrogen radicals as the heteroaryl 5-pyrimidinyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, has substitutable positions. To illustrate, tetrazolyl (which 2-pyrazinyl, and triazinyl. 35 has only one substitutable position) would be optionally An “8- to 12-membered bicyclic heteroaryl is a ring Substituted with up to one non-hydrogen radical. To illus structure formed by the fusion of 5- or 6-membered het trate further, if an amino nitrogen is described as being eroaryl to: (1) an independently selected 5-membered het optionally Substituted with up to 2 non-hydrogen radicals, eroaryl; (2) an independently selected 6-membered het then a primary amino nitrogen will be optionally substituted eroaryl (e.g., naphthyridinyl, pteridinyl, phthalazinyl, 40 with up to 2 non-hydrogen radicals, whereas a secondary purinyl, 3,4-dihydro-2H-pyrido3.2-b 14oxazin-7-yl, amino nitrogen will be optionally substituted with up to only etc.); (3) a C-C monocyclic cycloalkyl; (4) a 5- to 7-mem 1 non-hydrogen radical. bered heterocycloalkyl, or (5) a benzene ring (e.g., benz The terms “treat”, “treating, and “treatment” refer to a imidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyra method of alleviating or abrogating a disease and/or its nyl, benzothiadiazine, benzothiazinyl, 2,13 45 attendant symptoms. benzothiadiazol-5-yl, benzothiazolyl, benzothiophenyl, The terms “prevent”, “preventing, and “prevention' benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indoliz refer to a method of preventing the onset of a disease and/or inyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, its attendant symptoms or barring a subject from acquiring quinazolinyl, quinoxalinyl, isoindolyl, and isoquinolinyl), a disease. As used herein, “prevent”, “preventing and wherein the fusion junctions are at adjacent ring atoms. The 50 “prevention' also include delaying the onset of a disease fusion junctions may be at nitrogen (e.g., indolizine) or and/or its attendant symptoms and reducing a subject’s risk carbon atoms in the 5- or 6-membered heteroaryl. of acquiring a disease. The term “hydrogen' (alone or in combination with The phrase “therapeutically effective amount’ means an another term(s)) means a hydrogen radical, and may be amount of a compound, or a pharmaceutically acceptable depicted as —H. 55 salt thereof, sufficient to prevent the development of or to The term “hydroxy” (alone or in combination with alleviate to some extent one or more of the symptoms of the another term(s)) means —OH. condition or disorder being treated when administered alone The term “carboxy” (alone or in combination with another or in conjunction with another pharmaceutical agent or term(s)) means —C(O)—OH. treatment in a particular subject or Subject population. For The term "amino” (alone or in combination with another 60 example in a human or other mammal, a therapeutically term(s)) means —NH. effective amount can be determined experimentally in a The term “halogen' or “halo' (alone or in combination laboratory or clinical setting, or may be the amount required with another term(s)) means a fluorine radical (which may by the guidelines of the United States Food and Drug be depicted as —F), chlorine radical (which may be depicted Administration, or equivalent foreign agency, for the par as —Cl), bromine radical (which may be depicted as —Br). 65 ticular disease and Subject being treated. or iodine radical (which may be depicted as —I). The prefix The term “subject' is defined herein to refer to animals “halo' indicates that the substituent to which the prefix is Such as mammals, including, but not limited to, primates US 9,561,231 B2 35 36 (e.g., humans), cows, sheep, goats, horses, dogs, cats, rab merely to any one tautomeric, geometric, or Stereoisomeric bits, rats, mice and the like. In preferred embodiments, the form utilized within the formula drawings. Subject is a human. Isotope Enriched or Labeled Compounds Compounds Compounds of the invention can exist in isotope-labeled Geometric isomers may exist in the present compounds. or -enriched form containing one or more atoms having an Compounds of this invention may contain carbon-carbon atomic mass or mass number different from the atomic mass double bonds or carbon-nitrogen double bonds in the E or Z or mass number most abundantly found in nature. Isotopes configuration, wherein the term “E” represents higher order can be radioactive or non-radioactive isotopes. Isotopes of Substituents on opposite sides of the carbon-carbon or car atoms Such as hydrogen, carbon, phosphorous, Sulfur, fluo 10 rine, chlorine, and iodine include, but are not limited to, H, bon-nitrogen double bond and the term “Z” represents *H, 13C, 14C, 15 N, 18O, 32p, 35S, 18F 36C1, and 'I. Com higher order substituents on the same side of the carbon pounds that contain other isotopes of these and/or other carbon or carbon-nitrogen double bond as determined by the atoms are within the scope of this invention. Cahn-Ingold-Prelog Priority Rules. The compounds of this In another embodiment, the isotope-labeled compounds invention may also exist as a mixture of “E” and “Z” 15 contain deuterium (H), tritium (H) or ''C isotopes. Iso isomers. Substituents around a cycloalkyl or heterocy tope-labeled compounds of this invention can be prepared cloalkyl may also be designated as being of cis or trans by the general methods well known to persons having configuration. ordinary skill in the art. Such isotope-labeled compounds Compounds of this invention may contain asymmetrically can be conveniently prepared by carrying out the procedures Substituted carbon atoms in the R or S configuration, in disclosed in the Examples disclosed herein and Schemes by which the terms “R” and “S” are as defined by the IUPAC Substituting a readily available isotope-labeled reagent for a 1974 Recommendations for Section E, Fundamental Stereo non-labeled reagent. In some instances, compounds may be chemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds treated with isotope-labeled reagents to exchange a normal having asymmetrically Substituted carbon atoms with equal atom with its isotope, for example, hydrogen for deuterium amounts of R and S configurations are racemic at those 25 can be exchanged by the action of a deuteric acid such as carbon atoms. Atoms with an excess of one configuration DSO/DO. In addition to the above, relevant procedures over the other are assigned the configuration present in the and intermediates are disclosed, for instance, in Lizondo, J higher amount, preferably an excess of about 85%-90%. et al., Drugs Fut, 21 (11), 1116 (1996); Brickner, S J et al., more preferably an excess of about 95%-99%, and still more J Med Chem, 39(3), 673 (1996): Mallesham, B et al., Org preferably an excess greater than about 99%. Accordingly, 30 Lett, 5(7), 963 (2003); PCT publications WO 1997010223, this invention includes racemic mixtures, relative and abso WO2005099353, WO 1995.007271, WO2006008754; U.S. lute stereoisomers, and mixtures of relative and absolute Pat. Nos. 7,538,189: 7,534,814; 7,531,685; 7,528,131: Stereoisomers. 7,521,421; 7,514,068; 7.511,013; and US Patent Application Compounds of formula (I) may contain one or more Publication NoS. 2009.0137457; 20090131485; asymmetrically Substituted atoms. Compounds of formula I 35 20090131363; 2009.0118238; 200901 11840; 20090105338; may also exist as individual stereoisomers (including 20090105307; 20090105147; 20090093.422: 20090088416; enantiomers and diastereomers) and mixtures thereof. Indi and 20090082471, the methods are hereby incorporated by vidual stereoisomers of compounds of formula I may be reference. prepared synthetically from commercially available starting The isotope-labeled compounds of the invention may be materials that contain asymmetric or chiral centers or by 40 used as standards to determine the effectiveness of BET preparation of racemic mixtures followed by resolution of bromodomain inhibitors in binding assays. Isotope contain the individual stereoisomer using methods that are known to ing compounds have been used in pharmaceutical research those of ordinary skill in the art. Examples of resolution are, to investigate the in vivo metabolic fate of the compounds by for example, (i) attachment of a mixture of enantiomers to evaluation of the mechanism of action and metabolic path a chiral auxiliary, separation of the resulting mixture of 45 way of the nonisotope-labeled parent compound (Blake et diastereomers by recrystallization or chromatography, fol al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic lowed by liberation of the optically pure product; or (ii) studies are important in the design of safe, effective thera separation of the mixture of enantiomers or diastereomers on peutic drugs, either because the in vivo active compound chiral chromatographic columns. administered to the patient or because the metabolites pro Compounds of formula I may also include the various 50 duced from the parent compound prove to be toxic or geometric isomers and mixtures thereof resulting from the carcinogenic (Foster et al., Advances in Drug Research Vol. disposition of Substituents around a carbon-carbon double 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. bond, a carbon-nitrogen double bond, a cycloalkyl group, or Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); a heterocycloalkyl group. Substituents around a carbon Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 carbon double bond or a carbon-nitrogen double bond are 55 (1999). designated as being of Z or E configuration and Substituents In addition, non-radio active isotope containing drugs, around a cycloalkyl or heterocycloalkyl are designated as Such as deuterated drugs called "heavy drugs, can be used being of cis or trans configuration. for the treatment of diseases and conditions related to BET Within the present invention it is to be understood that bromodomain activity. Increasing the amount of an isotope compounds disclosed herein may exhibit the phenomenon of 60 present in a compound above its natural abundance is called tautomerism and all tautomeric isomers are included in the enrichment. Examples of the amount of enrichment include Scope of the invention. from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, Thus, the formula drawings within this specification can 33, 37, 42, 46, 50, 54,58, 63, 67, 71, 75, 79, 84, 88,92, 96, represent only one of the possible tautomeric, geometric, or to about 100 mol %. Replacement of up to about 15% of stereoisomeric forms. It is to be understood that the inven 65 normal atom with a heavy isotope has been effected and tion encompasses any tautomeric, geometric, or stereoiso maintained for a period of days to weeks in mammals, meric form, and mixtures thereof, and is not to be limited including rodents and dogs, with minimal observed adverse US 9,561,231 B2 37 38 effects (Czajka D M and Finkel A. J. Ann. N.Y. Acad. Sci. in the presence of a palladium catalyst and a base, and 1960 84: 770; Thomson J. F. Ann. New York Acad. Sci. 1960 optionally in the presence of a ligand, and in a Suitable 84: 736: Czaka D M et al., Am. J. Physiol. 1961 201: 357). solvent at elevated temperature (about 80° C. to about 150° Acute replacement of as high as 15%-23% in human fluids C.). The reaction may be facilitated by microwave irradia with deuterium was found not to cause toxicity (Blagojevic tion. Examples of the palladium catalyst include, but are not N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O limited to, tetrakis(triphenylphosphine)palladium(0), tris Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. (dibenzylideneacetone)dipalladium(0), bis(triphenylphos 125-134; Diabetes Metab. 23: 251 (1997)). phine)palladium(II)dichloride, and palladium(II)acetate. Stable isotope labeling of a drug can alter its physico 10 Examples of suitable bases that may be employed include, chemical properties such as pKa and lipid solubility. These but not limited to, carbonates or phosphates of Sodium, effects and alterations can affect the pharmacodynamic potassium, and cesium, and cesium fluoride. Examples of response of the drug molecule if the isotopic Substitution suitable ligands include, but are not limited to, 1,3,5,7- 15 tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante, affects a region involved in a ligand-receptor interaction. 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl While some of the physical properties of a stable isotope (X-phos), and 1,1'-bis(diphenylphosphanyl)ferrocene. Non labeled molecule are different from those of the unlabeled limiting examples of Suitable solvent include methanol, one, the chemical and biological properties are the same, ethanol, dimethoxyethane, N,N-dimethylformamide, dim with one important exception: because of the increased mass ethylsulfoxide, dioxane, tetrahydropyran, and water, or a of the heavy isotope, any bond involving the heavy isotope mixture thereof. and another atom will be stronger than the same bond Alternatively, compounds of formula (3) may be synthe between the light isotope and that atom. Accordingly, the sized by reaction of boronic acid (4) or a derivative thereof incorporation of an isotope at a site of metabolism or 25 (e.g., pinacol ester) under Suzuki coupling conditions as enzymatic transformation will slow said reactions poten described above with compounds of formula (5) wherein Z tially altering the pharmacokinetic profile or efficacy relative is Br, Cl, I, or triflate. to the non-isotopic compound. Schemes 30 General Synthesis The compounds described herein, including compounds of general formula (I) and specific examples, can be pre Scheme 1 pared by methodologies in the reaction schemes depicted in B(OH)2 35 schemes 1-8. The variables A, A, A, A, R', X', X", L R', X, X, Y, Y', X, L, and G used in the following O G1 Yy schemes have the meanings as set forth in the Summary and R X2a As A2 detailed description sections, unless otherwise noted. 40 (2) Abbreviations used in the descriptions of the schemes and Y. Xla N O the specific examples have the following meanings: Boc for Z Ran X2a Z tert-butoxycarbonyl: DME for 1,2-dimethoxyethane, DMF (1) for dimethylformamide, DMSO for dimethyl sulfoxide, O G - 21 ?' Xla EtOH for ethanol: EtOAc for ethyl acetate; HATU for 45 O-(7-azabenzotriazol-1-yl)-N.N.N',N'-tetramethyluronium RS N X2a As A2 G 1. hexafluorophosphate, HPLC for high performance liquid (5) 4 2 chromatography, MeOH for methanol: mGPBA for 3-chlo YS Xla As A. roperbenzoic acid; NHOAC for ammonium acetate; 50 B(OH)2 (3) Pd(PPh) for tetrakis(triphenylphosphine)palladium(0); PdCl(PPh), for bis(triphenylphosphine)palladium(II)di (4) chloride: PdCl(dppf) for 1,1'-bis(diphenylphosphino)fer rocenedichloropalladium(II): THF for tetrahydrofuran, 55 TFA for trifluoroacetic acid, TLC for thin layer chromatog raphy, and triflate for trifluoromethanesulfonate. Compounds of formula (1) wherein R' is C-C alkyl Compounds of general formula (I) wherein X is L-G and may be may be prepared using synthetic routes Such as, but J is IIa may be prepared using the general procedure as not limited to, those illustrated in Scheme 2. Reaction of 60 compounds of formula (6), wherein Z is Br, Cl, I, with a outlined in Scheme 1. Conversion of (1), wherein Z is Cl, Br, C-C alkyl halide, in the presence of a base such as I, or triflate to compounds of general formula (3) may be carbonate of cesium, Sodium, or potassium and in a solvent achieved by reaction of (1) with a boronic acid of formula such as, but not limited to, dimethylformamide, tetrahydro (2) or derivative thereof (e.g., pinacol ester) under Suzuki furan, or dimethylsulfoxide, provides intermediates of for coupling conditions (N. Miyama and A. Suzuki, Chem. Rev. 65 mula (1) wherein R" is C-C alkyl. The reaction may be 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147 conducted at temperature Such as, but not limited to, about 148). For example, the coupling reaction may be conducted 25° C. to about 60° C. US 9,561,231 B2 40 Scheme 2 pounds of formula (1b). Displacement of the chlorine atom O O by R'R''NH may be accomplished in a solvent such as, H X2a Ra X2a but not limited to, methanol or ethanol, and in the presence NN NN of a base such as, but not limited to, triethylamine or diisopropylethylamine, and at a temperature from about 60° YS| - YS s Xla & Xla C. to about 100° C.

Z Z Utilizing reaction conditions such as those described in Scheme 1, intermediates (1a) and (1b) may be converted to (6) (1) 10 target molecules (3a) and (3.b) respectively by reacting with Compounds of formula (1) wherein X" is C-C alk the appropriate boronic acids or derivatives thereof. enylene-C(O)—O-C-C alkyl, —O-C-C-alkyl, an Alternatively, target molecules (3a) and (3.b) may be optionally substituted heterocycloalkyl or optionally substi synthesized from the reaction of (8) with R'OH and tuted heterocycloalkenyl, wherein said heterocycloalkyl or R'R''NH using reaction conditions discussed above.

Scheme 3

O RaNN X2a I -e- Y s OR 102 O 1 Z Ra X2a (1a) n N Yl, C N O Z Ra X2a (7) NN | He YSs NR101R 103

heterocycloalkenyl is attached to the parent moiety through 50 Compounds of formula (1) wherein X" is aryl, het a nitrogen atom, or X" is NHR' wherein R' is C(O)— eroaryl, or heterocycloalkenyl may be prepared using reac C-C alkyl, -SO, C-C alkyl or —C-C alkylene-C tion conditions described in Scheme 4. Reaction of 5,6- (O)—C-C alkyl, may be prepared using general procedure dichloropyridazin-3 (2H)-ones (9) with boronic acids of as outlined in Scheme 3. Displacement of the chlorine atom 55 formula (10) wherein R'' is aryl, heteroaryl, or heterocy of formula (7) with an alcohol of formula R'OH wherein cloalkenyl, or a derivative thereof (e.g., pinacol ester) under R" is C-C alkyl provides compounds of formula (1a). Suzuki coupling conditions as described in scheme 1 pro Displacement of the chlorine atom may be accomplished in vides intermediates of formula (1c). Utilizing reaction con a solvent Such as, but not limited to, methanol or ethanol, ditions such as those described in Scheme 1, intermediates and in the presence of a base such as, but not limited to, 60 (1c) may be converted to target molecules (3.c) by reacting Sodium or Sodium hydride, and at a temperature from about with the appropriate boronic acids or derivatives thereof. 40°C. to about 80° C. Displacement of the chlorine atom of Alternatively, target molecules (3.c) may be synthesized formula (7) with an amine of formula R'R''NH wherein from the reaction of (8) with boronic acids of formula (10) R' is as defined above and R' is hydrogen, or R', R', 65 wherein R' is aryl, heteroaryl, or heterocycloalkenyl, or a and the nitrogen atom to which they are attached form a derivative thereof (e.g., pinacol ester) under Suzuki coupling heterocycloalkyl or heterocycloalkenyl, provides com conditions using reaction conditions discussed above. US 9,561,231 B2 42

Scheme 4

O O Ra X2a Ra X2a NN NN l -e-RB(OH)2 l -e- a N C N R 104 (10)

(1c)

Compounds of formula (6) wherein X is hydrogen may 2O be prepared using general synthetic scheme as shown in Scheme 5. Hydrolysis of chloride (11) in an acid such as, but not limited to, acetic acid, and at a temperature from about 100° C. to about 150° C. provides compounds of formula (6a). Compounds of formula (6a) may also be prepared by 25 reaction of compounds of formula (12) in the presence of Sodium nitrite and an acid such as, but not limited to, Sulfuric acid in a solvent such as water, and at a temperature from about 0° C. to about 25° C.

Scheme 5 C O NH2

X2b H n X2b X2b N 21 Acetic acid N NaNO2, HSO4. Na Ho a l l X15 S Y X15 S Y N Ylb

Z Z Z (11) (6a) (12)

Compounds of general formula (I) wherein X is L-G and 50 J is IIb may be prepared using general procedure outlined in Scheme 6 Scheme 6. Reaction of boronic acids (12), or a derivative thereof (e.g., pinacol ester) with compounds of formula (5) Z wherein Z is Br, Cl, I, or triflate under Suzuki coupling L conditions as described in Scheme 1 provides compounds of G1 21 ? F formula (14). Hydrolysis of compounds of formula (14) in 4 2 the presence of a base, such as, but not limited to, sodium As A hydroxide or potassium hydroxide, in a solvent Such as N21 (5) water, dioxane, or tetrahydrofuran, or mixtures thereof, and 60 N Ylb Suzuki coupling at temperatures of 80° C. to about 140°C., provides com X15 pounds of formula (15). Hydrolysis of compounds of for mula (14) may also be accomplished by reaction in an acid, (13) Such as but not limited to acetic acid, and water attempera 65 tures of about 80° C. to about 120° C., to provide com pounds of formula (15). US 9,561,231 B2 43 44 -continued a solvent such as dimethylformamide or dimethylsulfoxide, F O and attemperatures ranging from about room temperature to X2b X2b about 100° C. provides compounds of formula (20). Alter N NaOH, HN natively, reaction of phenol (17) with an alcohol of formula l HO l l 2Y l N-Y G-OH in the presence of triphenylphosphine and in the X X presence of diisopropylaZodicarboxylate or diethylazodicar L L boxylate, in a solvent such as tetrahydrofuran or dioxane, G1 21 ? G1 21 ? and attemperatures ranging from about room temperature to 10 ^s.4 A.2 ^s.4 A.2 about 100° C. provides compounds of formula (20). Alternatively, compounds of formula (20) may be (14) (15) obtained by (a) coupling of (1) wherein Z is triflate, Cl, Br, or I, with boronic acid (18) or derivative thereof using Compounds of general formula (I) wherein X is L-G and 15 reaction conditions described in Scheme 1; and (b) displace L is —O— may be prepared as shown in Scheme 7. ment of the fluorine atom of the resulting intermediates (19) Compounds of formula (17) may be prepared from reac with an alcohol of formula G-OH. Displacement of the tion of (1) with a boronic acid of formula (16) or derivatives fluorine atom may be accomplished in a solvent such as, but thereof (e.g. pinacol ester) using Suzuki coupling conditions not limited to, dimethylsulfoxide, dimethylformamide, diox as described in Scheme 1. Treatment of the resulting phenols ane, or tetrahydrofuran and in the presence of a base Such as, of formula (17) with an appropriate halide of formula G-Z but not limited to, carbonate of cesium, potassium, or wherein Z is halogen such as Br, Cl, or F, in the presence of Sodium, or sodium hydride, and at a temperature from about a base Such as carbonate of cesium, potassium or sodium, in 40° C. to about 120° C.

B(OH)2 HO a NA O ^s. s XZa2 (16) | —- 's-n Z

F 21 ? AN, A US 9,561,231 B2 45 46 Compounds of general formula (I) wherein A is CR" and used. Unless otherwise specified, solvents, temperatures and R is NHC(O)R's or NHSORO wherein Rios is C-C, other reaction conditions can be readily selected by one of alkyl, and R' is C-C alkyl, C-C haloalkyl, C-C, ordinary skill in the art. Specific procedures are provided in cycloalkyl, aryl, heteroaryl, C-C alkylene-cycloalkyl, the Examples section. Reactions can be worked up in the C-C alkylene-heterocycloalkyl, C-C alkylene-het conventional manner, e.g. by eliminating the solvent from eroaryl, or C-C alkylene-aryl. the residue and further purified according to methodologies Reduction of the nitro compounds of formula (21) to the generally known in the art such as, but not limited to, anilines of formula (22) may be achieved with iron powder crystallization, distillation, extraction, trituration and chro in the presence of ammonium chloride in a solvent Such as, matography. Unless otherwise described, the starting mate but not limited to, tetrahydrofuran, ethanol, or water, or a 10 rials and reagents are either commercially available or mixture thereof, and at a temperature from about 80° C. to typically can be prepared from commercially available about 120° C. Alternatively the reduction may be carried out materials. with tin chloride in hydrochloric acid at a temperature from Routine experimentations, including appropriate manipu about 80° C. to about 120° C. Transformation of (21) to (22) 15 lation of the reaction conditions, reagents and sequence of may also be conducted in the presence of a catalyst Such as the synthetic route, protection of any chemical functionality platinum oxide or palladium on charcoal, in a solvent Such that can not be compatible with the reaction conditions, and as ethanol or methanol and under hydrogen pressure. Treat deprotection at a suitable point in the reaction sequence of ment of aniline (22) with sulfonyl chlorides of formula the method are included in the scope of the invention. R'SOCl, in the presence of a base such as triethylamine Suitable protecting groups and the methods for protecting or diisopropylethylamine in a solvent such as dichlorometh and deprotecting different Substituents using Such suitable ane or tetrahydrofuran and at a temperature from about 0°C. protecting groups are well known to those skilled in the art; to about 40° C. provides sulfonamides (23). examples of which can be found in T. Greene and P. Wuts, Treatment of aniline (22) with carboxylic acids of formula Protecting Groups in Organic Synthesis (3" ed.), John Wiley R'COOH in the presence of a coupling agent such as 25 & Sons, NY (1999), which is incorporated herein by refer HATU or EDAC and a base such as diisopropylethylaminde ence in its entirety. Synthesis of the compounds of the or triethylamine, and in a solvent such as tetrahydrofuran, invention can be accomplished by methods analogous to dioxane, or dimethylformamide, at a temperature from about those described in the synthetic schemes described herein 0° C. to about 40° C. provides amides of formula (24). above and in specific examples. 30 Starting materials, if not commercially available, can be prepared by procedures selected from standard organic Scheme 8 chemical techniques, techniques that are analogous to the J synthesis of known, structurally similar compounds, or techniques that are analogous to the above described X 21 Al 35 schemes or the procedures described in the synthetic He examples section. When an optically active form of a compound is required, ANn ls NO it typically can be obtained by carrying out one of the (21) procedures described herein using an optically active start J 40 ing material (prepared, for example, by asymmetric induc tion of a Suitable reaction step), or by resolution of a mixture X of the stereoisomers of the compound or intermediates using 21 YA a standard procedure (such as chromatographic separation, A. \/ precipitation, crystallization, or enzymatic resolution). J s N1 NR 102 45 Similarly, when a pure geometric isomer of a compound X 1 is required, it typically can be prepared by carrying out one 21 I (23) of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the A.S. ls N J n NH2 geometric isomers of the compound or intermediates using X 50 a standard procedure Such as chromatographic separation. (22) 21 ? O Compounds of formula I can be used in the form of pharmaceutically acceptable salts. The phrase “pharmaceu A.s ls N l R 102 tically acceptable salt' means those salts which are, within H the scope of Sound medical judgement, Suitable for use in 55 contact with the tissues of humans and lower animals (24) without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk It can be appreciated that the synthetic schemes and ratio. specific examples as illustrated in the synthetic examples Pharmaceutically acceptable salts have been described in section are illustrative and are not to be read as limiting the 60 S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: Scope of the invention as it is defined in the appended claims. 1-19. All alternatives, modifications, and equivalents of the Syn Compounds of formula (I) may contain either a basic or thetic methods and specific examples are included within the an acidic functionality, or both, and can be converted to a Scope of the claims. pharmaceutically acceptable salt, when desired, by using a Optimum reaction conditions and reaction times for each 65 suitable acid or base. The salts may be prepared in situ individual step can vary depending on the particular reac during the final isolation and purification of the compounds tants employed and Substituents present in the reactants of the invention. US 9,561,231 B2 47 48 Examples of acid addition salts include, but are not second active pharmaceutical agent, may be administered to limited to acetate, adipate, alginate, citrate, aspartate, ben the Subjects orally, rectally, parenterally, intracisternally, Zoate, benzenesulfonate, bisulfate, butyrate, camphorate, intravaginally, intraperitoneally, topically (as by powders, camphorsulfonate, digluconate, glycerophosphate, hemisul ointments or drops), bucally or as an oral or nasal spray. The fate, heptanoate, hexanoate, fumarate, hydrochloride, hyd term “parenterally as used herein, refers to modes of robromide, hydroiodide, 2-hydroxyethansulfonate (isothion administration which include intravenous, intramuscular, ate), lactate, malate, maleate, methanesulfonate, nicotinate, intraperitoneal, intrasternal, Subcutaneous and intraarticular 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, per injection and infusion. Sulfate, 3-phenylpropionate, picrate, pivalate, propionate, The term “pharmaceutically acceptable carrier as used Succinate, tartrate, thiocyanate, phosphate, glutamate, bicar 10 bonate, p-toluenesulfonate and undecanoate. Also, the basic herein, means a non-toxic, inert Solid, semi-solid or liquid nitrogen-containing groups can be quaternized with Such filler, diluent, encapsulating material or formulation auxil agents as lower alkyl halides such as, but not limited to, iary of any type. Some examples of materials which can methyl, ethyl, propyl, and butyl chlorides, bromides and serve as pharmaceutically acceptable carriers are Sugars iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and 15 Such as, but not limited to, lactose, glucose and Sucrose; diamyl Sulfates; long chain halides Such as, but not limited starches such as, but not limited to, corn starch and potato to, decyl, lauryl, myristyl and Stearyl chlorides, bromides starch; cellulose and its derivatives such as, but not limited and iodides: arylalkyl halides like benzyl and phenethyl to, sodium carboxymethyl cellulose, ethyl cellulose and bromides and others. Water or oil-soluble or dispersible cellulose acetate; powdered tragacanth; malt, gelatin; talc; products are thereby obtained. Examples of acids which may excipients such as, but not limited to, cocoa butter and be employed to form pharmaceutically acceptable acid addi Suppository waxes; oils such as, but not limited to, peanut tion salts include such inorganic acids as hydrochloric acid, oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn hydrobromic acid, Sulfuric acid, and phosphoric acid and oil and soybean oil; glycols; Such a propylene glycol; esters Such organic acids as acetic acid, fumaric acid, maleic acid, such as, but not limited to, ethyl oleate and ethyl laurate; 4-methylbenzenesulfonic acid, Succinic acid and citric acid. 25 agar, buffering agents such as, but not limited to, magnesium Basic addition salts may be prepared in situ during the hydroxide and aluminum hydroxide; alginic acid; pyrogen final isolation and purification of compounds of this inven free water, isotonic saline; Ringer's solution; ethyl alcohol, tion by reacting a carboxylic acid-containing moiety with a and phosphate buffer Solutions, as well as other non-toxic suitable base such as, but not limited to, the hydroxide, compatible lubricants such as, but not limited to, sodium carbonate or bicarbonate of a pharmaceutically acceptable 30 lauryl Sulfate and magnesium Stearate, as well as coloring metal cation or with ammonia or an organic primary, sec agents, releasing agents, coating agents, Sweetening, flavor ondary or tertiary amine. Pharmaceutically acceptable salts ing and perfuming agents, preservatives and antioxidants include, but are not limited to, cations based on alkali metals can also be present in the composition, according to the or alkaline earth metals such as, but not limited to, lithium, judgment of the formulator. Sodium, potassium, calcium, magnesium and aluminum salts 35 Pharmaceutical compositions for parenteral injection and the like and nontoxic quaternary ammonia and amine comprise pharmaceutically acceptable sterile aqueous or cations including ammonium, tetramethylammonium, tetra nonaqueous Solutions, dispersions, Suspensions or emul ethylammonium, methylamine, dimethylamine, trimethyl sions as well as sterile powders for reconstitution into sterile amine, triethylamine, diethylamine, ethylamine and the like. injectable solutions or dispersions just prior to use. Other examples of organic amines useful for the formation 40 Examples of Suitable aqueous and nonaqueous carriers, of base addition salts include ethylenediamine, etha diluents, solvents or vehicles include water, ethanol, polyols nolamine, diethanolamine, piperidine, piperazine and the (such as glycerol, propylene glycol, polyethylene glycol and like. the like), vegetable oils (such as olive oil), injectable organic The term “pharmaceutically acceptable prodrug or “pro esters (such as ethyl oleate) and suitable mixtures thereof. drug as used herein, represents those prodrugs of the 45 Proper fluidity can be maintained, for example, by the use of compounds of the present invention which are, within the coating materials such as lecithin, by the maintenance of the Scope of Sound medical judgement, Suitable for use in required particle size in the case of dispersions and by the contact with the tissues of humans and lower animals use of Surfactants. without undue toxicity, irritation, allergic response, and the These compositions may also contain adjuvants such as like, commensurate with a reasonable benefit/risk ratio, and 50 preservatives, wetting agents, emulsifying agents and dis effective for their intended use. persing agents. Prevention of the action of microorganisms Compounds described herein can exist in unsolvated as can be ensured by the inclusion of various antibacterial and well as Solvated forms, including hydrated forms, such as antifungal agents, for example, paraben, chlorobutanol, phe hemi-hydrates. In general, the Solvated forms, with pharma nol sorbic acid and the like. It may also be desirable to ceutically acceptable solvents such as water and ethanol 55 include isotonic agents such as Sugars, Sodium chloride and among others are equivalent to the unsolvated forms for the the like. Prolonged absorption of the injectable pharmaceu purposes of the invention. tical form can be brought about by the inclusion of agents, Pharmaceutical Compositions which delay absorption Such as aluminum monostearate and This invention also provides for pharmaceutical compo gelatin. sitions comprising a therapeutically effective amount of a 60 In some cases, in order to prolong the effect of the drug, compound of Formula I, or a pharmaceutically acceptable it is desirable to slow the absorption of the drug from salt thereof together with a pharmaceutically acceptable Subcutaneous or intramuscular injection. This may be carrier, diluent, or excipient therefor. The phrase “pharma accomplished by the use of a liquid Suspension of crystalline ceutical composition” refers to a composition Suitable for or amorphous material with poor water solubility. The rate administration in medical or veterinary use. 65 of absorption of the drug then depends upon its rate of The pharmaceutical compositions that comprise a com dissolution which, in turn, may depend upon crystal size and pound of formula (I), alone or or in combination with a crystalline form. Alternatively, delayed absorption of a par US 9,561,231 B2 49 50 enterally-administered drug form may be accomplished by etc. In general, the dose equivalent of a compound is from dissolving or Suspending the drug in an oil vehicle. about 1 g/kg to 100 mg/kg for a typical Subject. Injectable depot forms are made by forming microencap For administration, compounds of the formula I can be Sule matrices of the drug in biodegradable polymers such as administered at a rate determined by factors that can include, polylactide-polyglycolide. Depending upon the ratio of drug 5 but are not limited to, the LDso of the compound, the to polymer and the nature of the particular polymer pharmacokinetic profile of the compound, contraindicated employed, the rate of drug release can be controlled. drugs, and the side-effects of the compound at various Examples of other biodegradable polymers include poly concentrations, as applied to the mass and overall health of (orthoesters) and poly(anhydrides). Depot injectable formu the Subject. Administration can be accomplished via single lations are also prepared by entrapping the drug in liposomes 10 or divided doses. or microemulsions which are compatible with body tissues. The compounds utilized in the pharmaceutical method of The injectable formulations can be sterilized, for example, the invention can be administered at the initial dosage of by filtration through a bacterial-retaining filter or by incor about 0.001 mg/kg to about 100 mg/kg daily. In certain porating sterilizing agents in the form of sterile Solid com embodiments, the daily dose range is from about 0.1 mg/kg positions which can be dissolved or dispersed in sterile 15 to about 10 mg/kg. The dosages, however, may be varied water or other sterile injectable medium just prior to use. depending upon the requirements of the Subject, the severity Solid dosage forms for oral administration include cap of the condition being treated, and the compound being Sules, tablets, pills, powders and granules. In certain employed. Determination of the proper dosage for a par embodiments, Solid dosage forms may contain from 1% to ticular situation is within the skill of the practitioner. Treat 95% (w/w) of a compound of formula I. In certain embodi ment may be initiated with Smaller dosages, which are less ments, the compound of formula I may be present in the than the optimum dose of the compound. Thereafter, the solid dosage form in a range of from 5% to 70% (w/w). In dosage is increased by Small increments until the optimum Such solid dosage forms, the active compound may be mixed effect under circumstances is reached. For convenience, the with at least one inert, pharmaceutically acceptable excipi total daily dosage may be divided and administered in ent or carrier, Such as Sodium citrate or dicalcium phosphate 25 portions during the day, if desired. and/or a) fillers or extenders such as starches, lactose, Solid compositions of a similar type may also be Sucrose, glucose, mannitol and silicic acid; b) binders such employed as fillers in Soft and hard-filled gelatin capsules as carboxymethylcellulose, alginates, gelatin, polyvinylpyr using Such carriers as lactose or milk Sugar as well as high rolidone, Sucrose and acacia; c) humectants such as glycerol; molecular weight polyethylene glycols and the like. d) disintegrating agents such as agar-agar, calcium carbon 30 The solid dosage forms of tablets, dragees, capsules, pills ate, potato or tapioca Starch, alginic acid, certain silicates and granules can be prepared with coatings and shells Such and sodium carbonate; e) solution retarding agents such as as enteric coatings and other coatings well-known in the paraffin: f) absorption accelerators such as quaternary pharmaceutical formulating art. They may optionally con ammonium compounds; g) wetting agents such as cetyl tain opacifying agents and may also be of a composition alcohol and glycerol monostearate; h) absorbents such as 35 Such that they release the active ingredient(s) only, or kaolin and bentonite clay and i) lubricants such as talc, preferentially, in a certain part of the intestinal tract, option calcium Stearate, magnesium Stearate, Solid polyethylene ally, in a delayed manner. Examples of embedding compo glycols, Sodium lauryl Sulfate and mixtures thereof. In the sitions which can be used include polymeric Substances and case of capsules, tablets and pills, the dosage form may also WaxeS. comprise buffering agents. 40 The active compounds can also be in micro-encapsulated The pharmaceutical composition may be a unit dosage form, if appropriate, with one or more of the above-men form. In such form the preparation is subdivided into unit tioned carriers. doses containing appropriate quantities of the active com Liquid dosage forms for oral administration include phar ponent. The unit dosage form can be a packaged preparation, maceutically acceptable emulsions, Solutions, Suspensions, the package containing discrete quantities of preparation, 45 syrups and elixirs. In addition to the active compounds, the Such as packeted tablets, capsules, and powders in vials or liquid dosage forms may contain inert diluents commonly ampules. Also, the unit dosage form can be a capsule, tablet, used in the art such as, for example, water or other solvents, cachet, or lozenge itself, or it can be the appropriate number solubilizing agents and emulsifiers such as ethyl alcohol, of any of these in packaged form. The quantity of active isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl component in a unit dose preparation may be varied or 50 alcohol, benzyl benzoate, propylene glycol, 1,3-butylene adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg. or glycol, dimethyl formamide, oils (in particular, cottonseed, from 1% to 95% (w/w) of a unit dose, according to the groundnut, corn, germ, olive, castor and sesame oils), glyc particular application and the potency of the active compo erol, tetrahydrofurfuryl alcohol, polyethylene glycols and nent. The composition can, if desired, also contain other fatty acid esters of sorbitan and mixtures thereof. compatible therapeutic agents. 55 Besides inert diluents, the oral compositions may also The dose to be administered to a subject may be deter include adjuvants such as wetting agents, emulsifying and mined by the efficacy of the particular compound employed Suspending agents, Sweetening, flavoring and perfuming and the condition of the subject, as well as the body weight agents. or surface area of the subject to be treated. The size of the Suspensions, in addition to the active compounds, may dose also will be determined by the existence, nature, and 60 contain Suspending agents as, for example, ethoxylated extent of any adverse side-effects that accompany the isostearyl alcohols, polyoxyethylene Sorbitol and Sorbitan administration of a particular compound in a particular esters, microcrystalline cellulose, aluminum metahydroxide, Subject. In determining the effective amount of the com bentonite, agar-agar, tragacanth and mixtures thereof. pound to be administered in the treatment or prophylaxis of Compositions for rectal or vaginal administration are the disorder being treated, the physician can evaluate factors 65 preferably suppositories which can be prepared by mixing Such as the circulating plasma levels of the compound, the compounds of this invention with Suitable non-irritating compound toxicities, and/or the progression of the disease, carriers or carriers such as cocoa butter, polyethylene glycol US 9,561,231 B2 51 52 or a Suppository wax which are solid at room temperature gioma, cystadenocarcinoma, diffuse large B-cell lymphoma, but liquid at body temperature and therefore melt in the dysproliferative changes (dysplasias and metaplasias), rectum or vaginal cavity and release the active compound. embryonal carcinoma, endometrial cancer, endotheliosar Compounds of formula I may also be administered in the coma, ependymoma, epithelial carcinoma, erythroleukemia, form of liposomes. Liposomes generally may be derived esophageal cancer, estrogen-receptor positive breast cancer, from phospholipids or other lipid substances. Liposomes are essential thrombocythemia, Ewing's tumor, fibrosarcoma, formed by mono- or multi-lamellar hydrated liquid crystals follicular lymphoma, germ cell testicular cancer, glioma, which are dispersed in an aqueous medium. Any non-toxic, glioblastoma, gliosarcoma, heavy chain disease, hemangio physiologically acceptable and metabolizable lipid capable blastoma, hepatoma, hepatocellular cancer, hormone insen of forming liposomes can be used. The present compositions 10 sitive prostate cancer, leiomyosarcoma, leukemia, liposar in liposome form may contain, in addition to a compound of coma, lung cancer, lymphagioendotheliosarcoma, formula (I), stabilizers, preservatives, excipients and the lymphangiosarcoma, lymphoblastic leukemia, lymphoma like. Examples of lipids include, but are not limited to, (Hodgkin’s and non-Hodgkin’s), malignancies and hyper natural and synthetic phospholipids and phosphatidyl cho proliferative disorders of the bladder, breast, colon, lung, lines (lecithins), used separately or together. 15 ovaries, pancreas, prostate, skin and uterus, lymphoid malig Methods to form liposomes have been described, see nancies of T-cell or B-cell origin, leukemia, lymphoma, example, Prescott, Ed., Methods in Cell Biology, Volume medullary carcinoma, medulloblastoma, melanoma, menin XIV. Academic Press, New York, N.Y. (1976), p. 33 et seq. gioma, mesothelioma, multiple myeloma, myelogenous leu Dosage forms for topical administration of a compound kemia, myeloma, myxosarcoma, neuroblastoma, NUT mid described herein include powders, sprays, ointments and line carcinoma (NMC), non-Small cell lung cancer, inhalants. The active compound may be mixed under sterile oligodendroglioma, oral cancer, osteogenic sarcoma, ovar conditions with a pharmaceutically acceptable carrier and ian cancer, pancreatic cancer, papillary adenocarcinomas, any needed preservatives, buffers or propellants which may papillary carcinoma, pinealoma, polycythemia Vera, prostate be required. Opthalmic formulations, eye ointments, pow cancer, rectal cancer, renal cell carcinoma, retinoblastoma, ders and solutions are also contemplated as being within the 25 rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, Scope of this invention. seminoma, skin cancer, Small cell lung carcinoma, Solid Methods of Use tumors (carcinomas and sarcomas), Small cell lung cancer, The compounds of formula I, or pharmaceutically accept stomach cancer, squamous cell carcinoma, synovioma, able salts thereof, and pharmaceutical compositions com Sweat gland carcinoma, thyroid cancer, Waldenström's mac prising a compound of formula I, or a pharmaceutically 30 roglobulinemia, testicular tumors, uterine cancer and acceptable salt thereof, can be administered to a subject Wilms tumor. suffering from a bromodomain-mediated disorder or condi Further, compounds of formula I may be used to treat tion. The term “administering refers to the method of inflammatory diseases, inflammatory conditions, and auto contacting a compound with a Subject. Thus, the compounds immune diseases, including, but not limited to: Addison's of formula I can be administered by injection, that is, 35 disease, acute gout, ankylosing spondylitis, asthma, athero intravenously, intramuscularly, intracutaneously, Subcutane Sclerosis, Behcet’s disease, bullous skin diseases, chronic ously, intraduodenally, parentally, or intraperitoneally. Also, obstructive pulmonary disease (COPD), Crohn's disease, the compounds described herein can be administered by dermatitis, eczema, giant cell arteritis, glomerulonephritis, inhalation, for example, intranasally. Additionally, the com hepatitis, hypophysitis, inflammatory bowel disease, Kawa pounds of formula I can be administered transdermally, 40 saki disease, lupus nephritis, multiple Sclerosis, myocarditis, topically, via implantation, transdermally, topically, and via myositis, nephritis, organ transplant rejection, osteoarthritis, implantation. In certain embodiments, the compounds of the pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, formula I may be delivered orally. The compounds can also primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheu be delivered rectally, bucally, intravaginally, ocularly, andi matoid arthritis, Scleritis, Sclerosing cholangitis, sepsis, sys ally, or by insufflation. Bromodomain-mediated disorders 45 temic lupus erythematosus, Takayasu's Arteritis, toxic and conditions can be treated prophylactically, acutely, and shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, chronically using compounds of formula I, depending on the vitiligo, vasculitis, and Wegener's granulomatosis. nature of the disorder or condition. Typically, the host or Compounds of formula I, or pharmaceutically acceptable Subject in each of these methods is human, although other salts thereof, may be used to treat AIDS. In addition, mammals can also benefit from the administration of a 50 compounds of formula I, or pharmaceutically acceptable compound of formula I. salts thereof, may be used to treat obesity. Compounds of A“bromodomain-mediated disorder or condition' is char formula I, or pharmaceutically acceptable salts thereof, may acterized by the participation of one or more bromodomains be used to treat type II diabetes. (e.g., BRD4) in the inception, manifestation of one or more Compounds of formula I, or pharmaceutically acceptable symptoms or disease markers, severity, or progression of a 55 salts thereof, may be used to treat a chronic kidney disease disorder or condition. Accordingly, compounds of formula I or condition including, but are not limited to: diabetic may be used to treat cancer, including, but not limited to nephropathy, hypertensive nephropathy, HIV-associated acoustic neuroma, acute leukemia, acute lymphocytic leu nephropathy, glomerulonephritis, lupus nephritis, IgA neph kemia, acute myelocytic leukemia (monocytic, myeloblas ropathy, focal segmental glomerulosclerosis, membranous tic, adenocarcinoma, angiosarcoma, astrocytoma, myelo 60 glomerulonephritis, minimal change disease, polycystic kid monocytic and promyelocytic), acute t-cell leukemia, basal ney disease and tubular interstitial nephritis. cell carcinoma, bile duct carcinoma, bladder cancer, brain Compounds of formula I, or pharmaceutically acceptable cancer, breast cancer, bronchogenic carcinoma, cervical salts thereof, may be used to treat acute kidney injury or cancer, chondrosarcoma, chordoma, choriocarcinoma, disease or condition including, but are not limited to: isch chronic leukemia, chronic lymphocytic leukemia, chronic 65 emia-reperfusion induced kidney disease, cardiac and major myelocytic (granulocytic) leukemia, chronic myelogenous Surgery induced kidney disease, percutaneous coronary leukemia, colon cancer, colorectal cancer, craniopharyn intervention induced kidney disease, radio-contrast agent US 9,561,231 B2 53 54 induced kidney disease, sepsis induced kidney disease, T-cells when targeted to cancer cells (V. R. Sutton, D. L. pneumonia induced kidney disease, and drug toxicity Vaux and J. A. Trapani, J. of Immunology 1997, 158 (12), induced kidney disease. 5783). Compounds of formula I, or pharmaceutically acceptable SiRNAs are molecules having endogenous RNA bases or salts thereof, may be used to treat obesity, dyslipidemia, chemically modified nucleotides. The modifications do not hypercholesterolemia, Alzheimer's disease, metabolic Syn abolish cellular activity, but rather impart increased stability drome, hepatic steatosis, type II diabetes, insulin resistance, and/or increased cellular potency. Examples of chemical diabetic retinopathy or diabetic neuropathy. modifications include phosphorothioate groups, 2'-deoxy Compounds of formula I, or pharmaceutically acceptable nucleotide, 2'-OCH-containing ribonucleotides, 2'-F-ribo salts thereof, may be used to prevent conception by inhib 10 nucleotides. 2'-methoxyethyl ribonucleotides, combinations iting spermatogenesis in a Subject comprising administering thereof and the like. The siRNA can have varying lengths a therapeutically effective amount of a compound of formula (e.g., 10-200 bps) and structures (e.g., hairpins, single? (I) or a pharmaceutically acceptable salt thereof, to a subject double strands, bulges, nickS/gaps, mismatches) and are in need thereof. processed in cells to provide active gene silencing. A double The compounds of formula I can be co-administered to a 15 stranded siRNA (dsRNA) can have the same number of subject. The term “co-administered” means the administra nucleotides on each strand (blunt ends) or asymmetric ends tion of two or more different pharmaceutical agents or (overhangs). The overhang of 1-2 nucleotides can be present treatments (e.g., radiation treatment) that are administered to on the sense and/or the antisense Strand, as well as present a subject by combination in the same pharmaceutical com on the 5’- and/or the 3'-ends of a given strand. position or separate pharmaceutical compositions. Thus co Multivalent binding proteins are binding proteins com administration involves administration at the same time of a prising two or more antigen binding sites. Multivalent single pharmaceutical composition comprising two or more binding proteins are engineered to have the three or more pharmaceutical agents or administration of two or more antigen binding sites and are generally not naturally occur different compositions to the same subject at the same or ring antibodies. The term “multispecific binding protein’ different times. 25 means a binding protein capable of binding two or more The compounds of the invention can be co-administered related or unrelated targets. Dual variable domain (DVD) with a therapeutically effective amount of one or more binding proteins are tetravalent or multivalent binding pro agents to treat a cancer, where examples of the agents teins binding proteins comprising two or more antigen include, Such as radiation, alkylating agents, angiogenesis binding sites. Such DVDs may be monospecific (i.e., inhibitors, antibodies, antimetabolites, antimitotics, antipro 30 capable of binding one antigen) or multispecific (i.e., liferatives, antivirals, aurora kinase inhibitors, apoptosis capable of binding two or more antigens). DVD binding promoters (for example, Bcl-XL, Bcl-w and Bf-1) inhibi proteins comprising two heavy chain DVD polypeptides and tors, activators of death receptor pathway, Bcr-Abl kinase two light chain DVD polypeptides are referred to as DVD inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, Igs. Each half of a DVD Ig comprises a heavy chain DVD antibody drug conjugates, biologic response modifiers, 35 polypeptide, a light chain DVD polypeptide, and two anti cyclin-dependent kinase inhibitors, cell cycle inhibitors, gen binding sites. Each binding site comprises a heavy chain cyclooxygenase-2 inhibitors, DVDs (dual variable domain variable domain and a light chain variable domain with a antibodies), leukemia viral oncogene homolog (ErbB2) total of 6 CDRs involved in antigen binding per antigen receptor inhibitors, growth factor inhibitors, heat shock binding site. Multispecific DVDs include DVD binding protein (HSP)-90 inhibitors, histone deacetylase (HDAC) 40 proteins that bind DLL4 and VEGF, or C-met and EFGR or inhibitors, hormonal therapies, immunologicals, inhibitors ErbB3 and EGFR. of inhibitors of apoptosis proteins (IAPs), intercalating Alkylating agents include altretamine, AMD-473, antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibi AP-5280, apaziquone, bendamustine, brostallicin, busulfan, tors, mammalian target of rapamycin inhibitors, microR carboquone, carmustine (BCNU), chlorambucil, CLORE NAs, mitogen-activated extracellular signal-regulated 45 TAZINE(R) (laromustine, VNP 401.01M), cyclophosph kinase inhibitors, multivalent binding proteins, non-steroidal amide, decarbazine, estramustine, fotemustine, glufosf anti-inflammatory drugs (NSAIDs), poly ADP (adenosine amide, ifosfamide, KW-2170, lomustine (CCNU), diphosphate)-ribose polymerase (PARP) inhibitors, plati mafosfamide, melphalan, mitobronitol, mitolactol, num chemotherapeutics, polo-like kinase (Plk) inhibitors, nimustine, nitrogen mustard N-oxide, ranimustine, temoZo phosphoinositide-3 kinase (bromodomain) inhibitors, prote 50 lomide, thiotepa, TREANDAR) (bendamustine), treosulfan, oSome inhibitors, purine analogs, pyrimidine analogs, recep rofosfamide and the like. tor tyrosine kinase inhibitors, etinoids/deltoids plant alka Angiogenesis inhibitors include endothelial-specific loids, small inhibitory ribonucleic acids (siRNAs), receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth topoisomerase inhibitors, ubiquitin ligase inhibitors, and the factor receptor (EGFR) inhibitors, insulin growth factor-2 like, and in combination with one or more of these agents. 55 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 BiTE antibodies are bi-specific antibodies that direct (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) T-cells to attack cancer cells by simultaneously binding the inhibitors, platelet-derived growth factor receptor (PDGFR) two cells. The T-cell then attacks the target cancer cell. inhibitors, thrombospondin analogs, vascular endothelial Examples of BiTE antibodies include adecatumumab (Mi growth factor receptor tyrosine kinase (VEGFR) inhibitors cromet MT201), blinatumomab (Micromet MT103) and the 60 and the like. like. Without being limited by theory, one of the mechanisms Antimetabolites include ALIMTAR) (pemetrexed diso by which T-cells elicit apoptosis of the target cancer cell is dium, LY231514, MTA), 5-azacitidine, XELODAR by exocytosis of cytolytic granule components, which (capecitabine), carmofur, LEUSTATR) (cladribine), clofara include perforin and granzyme B. In this regard, Bcl-2 has bine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, been shown to attenuate the induction of apoptosis by both 65 decitabine, deferoxamine, doxifluridine, eflornithine, perforin and granzyme B. These data Suggest that inhibition EICAR (5-ethynyl-1-(3-D-ribofuranosylimidazole-4-car of Bcl-2 could enhance the cytotoxic effects elicited by boxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluo US 9,561,231 B2 55 56 rouracil alone or in combination with leucovorin, Activators of death receptor pathway include TRAIL, GEMZAR(R) (gemcitabine), hydroxyurea, ALKERANR) antibodies or other agents that target TRAIL or death recep (melphalan), mercaptopurine, 6-mercaptopurine riboside, tors (e.g., DR4 and DR5) Such as Apomab, conatumumab, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029, LBY ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, tri 135, PRO-1762 and trastuzumab. apine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, Vidara Kinesin inhibitors include Eg5 inhibitors Such as bine, UFT and the like. AZD4877, ARRY-520; CENPE inhibitors Such as Antivirals include ritonavir, hydroxychloroquine and the GSK923295A and the like. like. JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 10 and INCBO18424 and the like. Aurora kinase inhibitors include ABT-348, AZD-1152, MEK inhibitors include ARRY-142886, ARRY-438.162 MLN-8054, VX-680, Aurora A-specific kinase inhibitors, PD-325901, PD-98.059 and the like. Aurora B-specific kinase inhibitors and pan-Aurora kinase mTOR inhibitors include AP-23573, CCI-779, everoli inhibitors and the like. mus, RAD-001, rapamycin, temsirolimus, ATP-competitive Bcl-2 protein inhibitors include AT-101 ((-)gossypol), 15 TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, GENASENSER (G3139 or oblimersen (Bcl-2-targeting Torin 1 and the like. antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- Non-steroidal anti-inflammatory drugs include chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)- AMIGESICR) (salsalate), DOLOBIDR) (diflunisal), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) MOTRINR) (ibuprofen), ORUDIS(R) (ketoprofen), propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), RELAFENR) (nabumetone), FELDENER) (piroxicam), ibu N-(4-(4-(2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1- profen cream, ALEVER) (naproxen) and NAPROSYNR) en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(mor (naproxen), VOLTARENR) (diclofenac), INDOCINR) (indo pholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- methacin), CLINORIL(R) (sulindac), TOLECTINR) (tolme ((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263). tin), LODINE(R) (etodolac), TORADOL(R) (ketorolac), DAY GX-070 (obatoclax), ABT-199, and the like. 25 PROR) (oxaprozin) and the like. Bcr-Abl kinase inhibitors include DASATINIB(R) (BMS PDGFR inhibitors include C-451, CP-673, CP-868596 354825), GLEEVEC(R) (imatinib) and the like. and the like. CDK inhibitors include AZD-5438, BMI-1040, BMS Platinum chemotherapeutics include cisplatin, ELOXA 032, BMS-387, CVT 2584, flavopyridol, GPC-2861.99, TINR (oxaliplatin) eptaplatin, lobaplatin, medaplatin, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, 30 PARAPLATINR (carboplatin), satraplatin, picoplatin and R-roscovitine), ZK-304709 and the like. the like. COX-2 inhibitors include ABT-963, ARCOXIAR (etori Polo-like kinase inhibitors include BI-2536 and the like. coxib), BEXTRAR (valdecoxib), BMS347070, CEL Phosphoinositide-3 kinase (PI3K) inhibitors include wort EBREXR (celecoxib), COX-189 (lumiracoxib), CT-3, mannin, LY294.002, XL-147, CAL-120, ONC-21, AEZS DERAMAXX(R) (deracoxib), JTE-522, 4-methyl-2-(3,4-di 35 127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, methylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663 XL765 and the like. (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, Thrombospondin analogs include ABT-510, ABT-567, SD-8381, SVT-2016, S-2474, T-614, VIOXX(R) (rofecoxib) ABT-898, TSP-1 and the like. and the like. VEGFR inhibitors include AVASTINR) (bevacizumab), EGFR inhibitors include EGFR antibodies, ABX-EGF, 40 ABT-869, AEE-788, ANGIOZYMETM (a ribozyme that anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, ERBITUX(R) (cetuximab), HR3, IgA antibodies, IRESSAR) Colo.) and Chiron, (Emeryville, Calif.)), axitinib (AG (gefitinib), TARCEVAR) (erlotinib or OSI-774), TP-38, 13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pe EGFR fusion protein, TYKERB(R) (lapatinib) and the like. gaptamib), NEXAVAR(R) (sorafenib, BAY43-9006), ErbB2 receptor inhibitors include CP-724-714, CI-1033 45 pazopanib (GW-786034), Vatalanib (PTK-787, ZK-222584), (canertinib), HERCEPTINR) (trastuzumab), TYKERB(R) (la SUTENTR) (sunitinib, SU-11248), VEGF trap, ZAC patinib), OMNITARG(R) (2C4, petuzumab), TAK-165, TIMATM (vandetanib, ZD-6474), GA101, ofatumumab, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, ABT-806 (mAb-806), ErbB3 specific antibodies, BSG2 spe dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti cific antibodies, DLL4 specific antibodies and C-met spe HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 tri 50 cific antibodies, and the like. functional bispecific antibodies, maB AR-209, maB 2B-1 Antibiotics include intercalating antibiotics aclarubicin, and the like. actinomycin D, amrubicin, annamycin, adriamycin, BLE Histone deacetylase inhibitors include depsipeptide, NOXANE(R) (bleomycin), daunorubicin, CAELYX(R) or LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic MYOCETR) (liposomal doxorubicin), elsamitrucin, epirbu acid (SAHA), TSA, valproic acid and the like. 55 cin, glarbuicin, ZAVEDOSR) (idarubicin), mitomycin C, HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF nemorubicin, neocarzinostatin, peplomycin, pirarubicin, 101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI rebeccamycin, stimalamer, streptozocin, VALSTAR(R) (val 504, KOS-953, MYCOGRABR (human recombinant anti rubicin), Zinostatin and the like. body to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, Topoisomerase inhibitors include aclarubicin, 9-amin SNX-2112, STA-9090 VER49009 and the like. 60 ocamptothecin, amonafide, amsacrine, becatecarin, belote Inhibitors of inhibitors of apoptosis proteins include can, BN-80915, CAMPTOSAR(R) (irinotecan hydrochlo HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 ride), camptothecin, CARDIOXANER) (dexrazoxine), and the like. diflomotecan, edotecarin, ELLENCE(R) or PHARMORUBI Antibody drug conjugates include anti-CD22-MC CINR (epirubicin), etoposide, exatecan, 10-hydroxycamp MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, 65 tothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, CR-0, 1-vcMMAE, PSMA-ADC, MEDI-547, SGN-19 Am pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, SGN-35, SGN-75 and the like tafluposide, topotecan and the like. US 9,561,231 B2 57 58 Antibodies include AVASTINR) (bevacizumab), CD40 GEMZAR(R) (gemcitabine), TOMUDEX(R) (ratitrexed), specific antibodies, chTNT-1/B, denosumab, ERBITUX(R) TROXATYLTM (triacetyluridine troxacitabine) and the like. (cetuximab), HUMAX-CD4(R) (Zanolimumab), IGF1R-spe Purine analogs include LANVISR) (thioguanine) and cific antibodies, lintuzumab, PANOREXR (edrecolomab), PURI-NETHOLR) (mercaptopurine). RENCAREXR (WX G250), RITUXANR) (rituximab), Antimitotic agents includebatabulin, epothilone D (KOS ticilimumab, trastuzimab, CD20 antibodies types I and II 862), N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4- and the like. methoxybenzenesulfonamide, ixabepilone (BMS 247550), Hormonal therapies include ARIMIDEXOR (anastrozole), paclitaxel, TAXOTERE(R) (docetaxel), PNU100940 AROMASINR) (exemestane), arzoxifene, CASODEX(R) (bi (109881), patupilone, XRP-9881 (larotaxel), vinflunine, calutamide), CETROTIDE(R) (cetrorelix), degarelix, 10 ZK-EPO (synthetic epothilone) and the like. deslorelin, DESOPANR) (trilostane), dexamethasone, DRO Ubiquitin ligase inhibitors include MDM2 inhibitors, GENIL(R) (flutamide), EVISTAR (raloxifene), AFEMATM such as nutlins, NEDD8 inhibitors such as MLN4924 and (fadrozole), FARESTONR) (toremifene), FASLODEX(R) the like. (fulvestrant), FEMARAR) (letrozole), formestane, glucocor Compounds of this invention can also be used as radio ticoids, HECTOROL(R) (doxercalciferol), RENAGEL(R) 15 sensitizers that enhance the efficacy of radiotherapy. (sevelamer carbonate), lasofoxifene, leuprolide acetate, Examples of radiotherapy include external beam radio MEGACE(R) (megesterol), MIFEPREXR (mifepristone), therapy, teletherapy, brachytherapy and sealed, unsealed NILANDRONTM (nilutamide), NOLVADEX(R) (tamoxifen Source radiotherapy and the like. citrate), PLENAXISTM (abarelix), prednisone, PROPE Additionally, compounds having Formula (I) may be CIAR (finasteride), rilostane, SUPREFACTR) (buserelin), combined with other chemotherapeutic agents such as TRELSTARR) (luteinizing hormone releasing hormone ABRAXANETM (ABI-007), ABT-100 (farnesyl transferase (LHRH)), VANTAS(R) (Histrelin implant), VETORYL(R) inhibitor), ADVEXINR (Ad5CMV-p53 vaccine), ALTO (trilostane or modrastane), ZOLADEXR (fosrelin, goser CORR) or MEVACORR (lovastatin), AMPLIGENR) (poly elin) and the like. I:poly C12U, a synthetic RNA), APTOSYNR) (exisulind), Deltoids and retinoids include seocalcitol (EB1089, 25 AREDIAR (pamidronic acid), arglabin, L-asparaginase, CB1093), lexiacalcitrol (KH1060), fenretinide, PANRE atameStane (1-methyl-3,17-dione-androsta-1,4-diene), TINR) (aliretinoin), ATRAGENR) (liposomal tretinoin), AVAGE(R) (tazarotene), AVE-8062 (combreastatin deriva TARGRETINR) (bexarotene), LGD-1550 and the like. tive) BEC2 (mitumomab), cachectin or cachexin (tumor PARP inhibitors include ABT-888 (veliparib), olaparib, necrosis factor), canvaxin (vaccine), CEAVAC(R) (cancer KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, 30 vaccine), CELEUKOR (celmoleukin), CEPLENER) (hista INO-1001, ONO-2231 and the like. mine dihydrochloride), CERVARIX(R) (human papillomavi Plant alkaloids include, but are not limited to, Vincristine, rus vaccine), CHOPR (C: CYTOXANR) (cyclophosph vinblastine, vindesine, vinorelbine and the like. amide); H: ADRIAMYCINR (hydroxydoxorubicin); O: Proteasome inhibitors include VELCADE(R) (bort Vincristine (ONCOVINR); P: prednisone), CYPATTM (cy ezomib), MG132, NPI-0052, PR-171 and the like. 35 proterone acetate), combrestatin A4P, DAB(389)EGF (cata Examples of immunologicals include interferons and lytic and translocation domains of diphtheria toxin fused via other immune-enhancing agents. Interferons include inter a His-Ala linker to human epidermal growth factor) or feron alpha, interferon alpha-2a, interferon alpha-2b, inter TransMID-107RTM (diphtheria toxins), dacarbazine, dac feron beta, interferon gamma-1a, ACTIMMUNER) (inter tinomycin, 5,6-dimethylxanthenone-4-acetic acid feron gamma-1b) or interferon gamma-nl, combinations 40 (DMXAA), eniluracil, EVIZONTM (squalamine lactate), thereof and the like. Other agents include ALFAFERONER, DIMERICINE(R) (T4N5 liposome lotion), discodermolide, (IFN-C), BAM-002 (oxidized glutathione), BEROMUNR) DX-8951f (exatecan mesylate), enzastaurin, EPO906 (epi (tasonermin), BEXXAR(R) (to situmomab), CAMPATHR) thilone B), GARDASILR) (quadrivalent human papilloma (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4). virus (Types 6, 11, 16, 18) recombinant vaccine), decarbazine, denileukin, epratuzumab, GRANOCYTER 45 GASTRIMMUNER), GENASENSER), GMK (ganglioside (lenograstim), lentinan, leukocyte alpha interferon, imiqui conjugate vaccine), GVAX(R) (prostate cancer vaccine), mod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitu halofuginone, histerelin, hydroxycarbamide, ibandronic momab, molgramostim, MYLOTARGTM (gemtuzumab ozo acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin gamicin), NEUPOGENR (filgrastim), OncoVAC-CL, besudotox), IL-13-pseudomonas exotoxin, interferon-C. OVAREXR (oregovomab), pemtumomab (Y-muHMFG1), 50 interferon-Y, JUNOVANTM or MEPACTTM (mi?amurtide), PROVENGER (sipuleucel-T), sargaramostim, sizofilan, lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine teceleukin, THERACYS(R) (Bacillus Calmette-Guerin), (hexadecylphosphocholine), NEOVASTATR (AE-941), ubenimex, VIRULIZINR) (immunotherapeutic, Lorus Phar NEUTREXINR) (trimetrexate glucuronate), NIPENTR) maceuticals), Z-100 (Specific Substance of Maruyama (pentostatin), ONCONASE(R) (a ribonuclease enzyme), (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PRO 55 ONCOPHAGE(R) (melanoma vaccine treatment), ONCO LEUKINR) (aldesleukin), ZADAXINR) (thymalfasin), VAX(R) (IL-2 Vaccine), ORATHECINTM (rubitecan), ZENAPAX(R) (daclizumab), ZEVALINR) (90Y-Ibritumomab OSIDEMR) (antibody-based cell drug), OVAREX(R) MAb tiuxetan) and the like. (murine monoclonal antibody), paclitaxel, PANDIMEXTM Biological response modifiers are agents that modify (aglycone Saponins from ginseng comprising 200S)pro defense mechanisms of living organisms or biological 60 topanaxadiol (aPPD) and 200S)protopanaxatriol (aPPT)), responses, such as Survival, growth or differentiation of panitumumab, PANVAC(R)-VF (investigational cancer vac tissue cells to direct them to have anti-tumor activity and cine), pegaspargase, PEG Interferon A, phenoXodiol, pro include krestin, lentinan, sizofiran, picibanil PF-3512676 carbazine, rebimastat, REMOVAB(R) (catumaxomab), REV (CpG-8954), ubenimex and the like. LIMID(R) (lenalidomide), RSR13 (efaproxiral), Pyrimidine analogs include cytarabine (ara C or Arabino 65 SOMATULINE(R) LA (lanreotide), SORIATANER) (acitre side C), cytosine arabinoside, doxifluridine, FLUDARAR tin), staurosporine (Streptomyces staurospores), tallabostat (fludarabine), 5-FU (5-fluorouracil), floxuridine, (PT100), TARGRETINR) (bexarotene), TAXOPREXINR) US 9,561,231 B2 59 60 (DHA-paclitaxel), TELCYTAR (canfosfamide, TLK286), (I) of the invention may be co-administered include the temilifene, TEMODARR) (temozolomide), tesmilifene, tha following: budenoside; epidermal growth factor, corticos lidomide, THERATOPER (STn-KLH), thymitaq (2-amino teroids; cyclosporin, Sulfasalazine; aminosalicylates; 6-mer 3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline captopurine; azathioprine; metronidazole; lipoxygenase dihydrochloride), TNFERADETM (adenovector: DNA car inhibitors; mesalamine; olSalazine; balsalazide; antioxi rier containing the gene for tumor necrosis factor-C), TRA dants; thromboxane inhibitors; IL-1 receptor antagonists; CLEER(R) or ZAVESCAR (bosentan), tretinoin (Retin-A), anti-IL-13 monoclonal antibodies; anti-IL-6 monoclonal tetrandrine, TRISENOX(R) (arsenic trioxide), VIRULIZINR, antibodies; growth factors; elastase inhibitors; pyridinyl ukrain (derivative of alkaloids from the greater celandine imidazole compounds; antibodies to or antagonists of other plant), vitaxin (anti-alphavbeta3 antibody), XCYTRINR) 10 human cytokines or growth factors, for example, TNF, LT, (motexafin gadolinium), XINLAYTM (atrasentan), XYO IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, TAXTM (paclitaxel poliglumex), YONDELIS(R) (trabect EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules edin), ZD-6126, ZINECARDR) (dexrazoxane), ZOMETAR) such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, (Zolendronic acid), Zorubicin and the like. CD45, CD69, CD90 or their ligands; methotrexate: The compounds of the invention can also be co-admin 15 cyclosporine; FK506: rapamycin; mycophenolate mofetil: istered with a therapeutically effective amount of one or leflunomide: NSAIDs, for example, ibuprofen; corticoster more agents to treat an inflammatory disease or condition, or oids such as prednisolone; phosphodiesterase inhibitors; autoimmune disease, where examples of the agents include, adenosine agonists; antithrombotic agents; complement Such as methotrexate, tofacitinib, 6-mercaptopurine, aza inhibitors; adrenergic agents; agents which interfere with thioprine SulphaSalazine, mesalazine, olsalazine chloroqui signalling by proinflammatory cytokines such as TNFC. or nine/hydroxychloroquine, pencillamine, aurothiomalate (in IL-1 (e.g. NIK, IKK, or MAP kinase inhibitors); IL-1B tramuscular and oral), azathioprine, cochicine, converting enzyme inhibitors; TNFC. converting enzyme corticosteroids (oral, inhaled and local injection), beta-2 inhibitors; T-cell signalling inhibitors such as kinase inhibi adrenoreceptor agonists (salbutamol, terbutaline, Salme tors; metalloproteinase inhibitors; SulfaSalazine, azathio teral), Xanthines (theophylline, aminophylline), cromogly 25 prine; 6-mercaptopurines; angiotensin converting enzyme cate, nedocromil, ketotifen, ipratropium and oxitropium, inhibitors; soluble cytokine receptors and derivatives thereof cyclosporin, FK506, rapamycin, mycophenolate mofetil, (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, SIL-1RII, leflunomide, NSAIDs, for example, ibuprofen, corticoster SIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, oids Such as prednisolone, phosphodiesterase inhibitors, IL-11, IL-13 and TGFB. Preferred examples of therapeutic adensosine agonists, antithrombotic agents, complement 30 agents for Crohn's disease with which a compound of inhibitors, adrenergic agents, agents which interfere with Formula (I) can be combined include the following: TNF signalling by proinflammatory cytokines such as TNFC. or antagonists, for example, anti-TNF antibodies, D2E7 (adali IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1B mumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, converting enzyme inhibitors, T-cell signalling inhibitors (p75TNFRIgG (etanercept) and p55TNFRIgG (LENER Such as kinase inhibitors, metalloproteinase inhibitors, Sul 35 CEPTTM) inhibitors and PDE4 inhibitors. A compound of fasalazine, 6-mercaptopurines, angiotensin converting Formula (I) can be combined with corticosteroids, for enzyme inhibitors, Soluble cytokine receptors and deriva example, budenoside and dexamethasone; Sulfasalazine, tives thereof (e.g. soluble p55 or p75 TNF receptors and the 5-aminosalicylic acid; olsalazine; and agents which interfere derivatives p75TNFRIgG (etanercept) and p55TNFRIgG with synthesis or action of proinflammatory cytokines Such (Lenercept), sIL-1RI, SIL-1RII, SIL-6R), antiinflammatory 40 as IL-1, for example, IL-1B converting enzyme inhibitors cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFB, cele and IL-1 ra; T cell signaling inhibitors, for example, tyrosine coxib, folic acid, hydroxychloroquine Sulfate, rofecoxib, kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; etanercept, infliximab, adalimumab, certolizumab, tocili prednisone; azathioprine; mercaptopurine; infliximab, meth Zumab, abatacept, naproxen, Valdecoxib, Sulfasalazine, ylprednisolone sodium Succinate; diphenoxylate/atrop Sul methylprednisolone, meloxicam, methylprednisolone 45 fate; loperamide hydrochloride; methotrexate; omeprazole; acetate, gold sodium thiomalate, aspirin, triamcinolone folate; ciprofloxacin/dextrose-water; hydrocodone bitar acetonide, propoxyphene napsylate/apap, folate, nabume tratefapap; tetracycline hydrochloride; fluocinonide; met tone, diclofenac, piroXicam, etodolac, diclofenac sodium, ronidazole; thimerosal/boric acid; cholestyramine? sucrose; oxaprozin, oxycodone HCl, hydrocodone bitartratefapap, ciprofloxacin hydrochloride; hyoscyamine Sulfate; meperi diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol 50 dine hydrochloride; midazolam hydrochloride; oxycodone HCl, Salsalate, Sulindac, cyanocobalamin/fa/pyridoxine, HCl/acetaminophen; promethazine hydrochloride; sodium acetaminophen, alendronate Sodium, prednisolone, corti phosphate; sulfamethoxazole/trimethoprim; celecoxib; Sone, betamethasone, morphine Sulfate, lidocaine hydro polycarbophil; propoxyphene napsylate; hydrocortisone; chloride, indomethacin, glucosamine Sulf chondroitin, ami multivitamins; balsalazide disodium; codeine phosphate/ triptyline HCl, Sulfadiazine, oxycodone HCl/ 55 apap; colesevelam HCl, cyanocobalamin; folic acid; levo acetaminophen, olopatadine HCl misoprostol, naproxen floxacing methylprednisolone; natalizumab and interferon Sodium, omeprazole, cyclophosphamide, rituximab, IL-1 gamma. TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, Non-limiting examples of therapeutic agents for multiple BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflu sclerosis with which a compound of Formula (I) may be milast, IC-485, CDC-801, S1P1 agonists (such as FTY720), 60 co-administered include the following: corticosteroids; PKC family inhibitors (such as Ruboxistaurin or AEB-071) prednisolone; methylprednisolone; azathioprine; cyclophos and Mesopram. In certain embodiments, combinations phamide; cyclosporine; methotrexate, 4-aminopyridine; include methotrexate or leflunomide and in moderate or tizanidine; interferon-B1a (AVONEXR); Biogen); inter severe rheumatoid arthritis cases, cyclosporine and anti feron-B1b (BETASERONR); Chiron/Berlex); interferon TNF antibodies as noted above. 65 C.-n3) (Interferon Sciences/Fujimoto), interferon-C. (Alfa Non-limiting examples of therapeutic agents for inflam Wassermann/J&J), interferon B1A-IF (Serono/Inhale Thera matory bowel disease with which a compound of Formula peutics), Peginterferon C. 2b (Enzon/Schering-Plough), US 9,561,231 B2 61 62 Copolymer 1 (Cop-1: COPAXONE(R); Teva Pharmaceutical pseudoephed, phenylephrine/cod/promethazine, codeine/ Industries, Inc.); hyperbaric oxygen; intravenous immuno promethazine, cefprozil, dexamethasone, guaifenesin/pseu globulin, cladribine; antibodies to or antagonists of other doephedrine, chlorpheniramine/hydrocodone, nedocromil human cytokines or growth factors and their receptors, for Sodium, terbutaline Sulfate, epinephrine, methylpredniso example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, 5 lone, anti-IL-13 antibody, and metaproterenol Sulfate. IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A Non-limiting examples of therapeutic agents for COPD compound of Formula (I) can be combined with antibodies with which a compound of Formula (I) may be co-admin to cell surface molecules such as CD2, CD3, CD4, CD8, istered include the following: albuterol sulfate/ipratropium, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, ipratropium bromide, salmeterol/fluticaSone, albuterol, Sal CD80, CD86, CD90 or their ligands. A compound of For 10 meterol Xinafoate, fluticaSone propionate, prednisone, the mula (I) may also be combined with agents such as metho ophylline anhydrous, methylprednisolone sodium Succinate, trexate, cyclosporine, FK506, rapamycin, mycophenolate montelukast sodium, budesonide, formoterol fumarate, tri mofetil, leflunomide, an S1P1 agonist, NSAIDs, for amcinolone acetonide, levofloxacin, guaifenesin, azithromy example, ibuprofen, corticosteroids such as prednisolone, cin, beclomethasone dipropionate, levalbuterol HCl, fluni phosphodiesterase inhibitors, adensosine agonists, anti 15 Solide, ceftriaxone sodium, amoxicillin trihydrate, thrombotic agents, complement inhibitors, adrenergic gatifloxacin, Zafirlukast, amoxicillin/clavulanate, flunisol agents, agents which interfere with signalling by proinflam ide/menthol, chlorpheniramine/hydrocodone, metaprotere matory cytokines such as TNFC. or IL-1 (e.g., NIK, IKK, nol sulfate, methylprednisolone, mometasone furoate, p38 or MAP kinase inhibitors), IL-1B converting enzyme p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephed inhibitors, TACE inhibitors, T-cell signaling inhibitors such rine/loratadine, terbutaline sulfate, tiotropium bromide, as kinase inhibitors, metalloproteinase inhibitors, sulfasala (R,R)-formoterol, TgAAT. cilomilast and roflumilast. Zine, azathioprine, 6-mercaptopurines, angiotensin convert Non-limiting examples of therapeutic agents for psoriasis ing enzyme inhibitors, Soluble cytokine receptors and with which a compound of Formula (I) may be co-admin derivatives thereof (e.g. soluble p55 or p75 TNF receptors, istered include the following: calcipotriene, clobetasol pro sIL-1RI, SIL-1RII, SIL-6R) and antiinflammatory cytokines 25 pionate, triamcinolone acetonide, halobetasol propionate, (e.g. IL-4, IL-10, IL-13 and TGFB. tazarotene, methotrexate, fluocinonide, betamethasone A compound of Formula (I) may also be co-administered diprop augmented, fluocinolone acetonide, acitretin, tar with agents, such as alemtuzumab, dronabinol, daclizumab, shampoo, betamethasone Valerate, mometasone furoate, mitoxantrone, Xaliproden hydrochloride, fampridine, glati ketoconazole, pramoxine/fluocinolone, hydrocortisone val ramer acetate, natalizumab, Sinnabidol, C.-immunokine 30 erate, flurandrenolide, urea, betamethasone, clobetasol pro NNSO3, ABR-215062, AnergiX.MS, chemokine receptor pionate/emoll, fluticasone propionate, azithromycin, hydro antagonists, BBR-2778, calagualine, CPI-1189, LEM (lipo cortisone, moisturizing formula, folic acid, desonide, some encapsulated mitoxantrone), THC.CBD (cannabinoid pimecrolimus, coal tar, diflorasone diacetate, etanercept agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA folate, lactic acid, methoXSalen, he/bismuth Subgal/ZnOX/ 715, anti-IL-6 receptor antibody, neurovax, pirfenidone 35 resor, methylprednisolone acetate, prednisone, Sunscreen, allotrap 1258 (RDP-1258), sTNF-R1, talampanel, terifluno halcinonide, Salicylic acid, anthralin, clocortolone pivalate, mide, TGF-beta2, tiplimotide, VLA-4 antagonists (for coal extract, coal tar/salicylic acid, coal tarisalicylic acid/ example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/ Sulfur, desoximetasone, diazepam, emollient, fluocinonide/ Biogen), interferon gamma antagonists and IL-4 agonists. emollient, mineral oil/castor oil/na lact, mineral oil/peanut Non-limiting examples of therapeutic agents for ankylo 40 oil, petroleum/isopropyl myristate, psoralen, Salicylic acid, sing spondylitis with which a compound of Formula (I) can soap/tribromsalan, thimerosal/boric acid, celecoxib, inflix be co-administered include the following: ibuprofen, imab, cyclosporine, alefacept, efalizumab, tacrolimus, pime diclofenac, misoprostol, naproxen, meloxicam, indometha crolimus, PUVA, UVB, sulfasalazine, ABT-874 and usteki cin, diclofenac, celecoxib, rofecoxib, SulfaSalazine, metho namab. trexate, azathioprine, minocyclin, prednisone, and anti-TNF 45 Non-limiting examples of therapeutic agents for psoriatic antibodies, D2E7 (HUMIRAR), CA2 (infliximab), CDP arthritis with which a compound of Formula (I) may be 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL(R) and co-administered include the following: methotrexate, etan p55TNFRIgG (LENERCEPTR). ercept, rofecoxib, celecoxib, folic acid, Sulfasalazine, Non-limiting examples of therapeutic agents for asthma naproxen, leflunomide, methylprednisolone acetate, indo with which a compound of Formula (I) may be co-admin 50 methacin, hydroxychloroquine Sulfate, prednisone, Sulindac, istered include the following: albuterol, salmeterol/flutica betamethasone diprop augmented, infliximab, methotrexate, Sone, montelukast Sodium, fluticasone propionate, budes folate, triamcinolone acetonide, diclofenac, dimethylsulfox onide, prednisone, salmeterol Xinafoate, levalbuterol HCl, ide, piroXicam, diclofenac sodium, ketoprofen, meloxicam, albuterol Sulfate?ipratropium, prednisolone sodium phos methylprednisolone, nabumetone, tolmetin Sodium, calci phate, triamcinolone acetonide, beclomethasone dipropi 55 potriene, cyclosporine, diclofenac sodium/misoprostol, fluo onate, ipratropium bromide, azithromycin, pirbuterol cinonide, glucosamine Sulfate, gold sodium thiomalate, acetate, prednisolone, theophylline anhydrous, methylpred hydrocodone bitartratefapap, ibuprofen, risedronate Sodium, nisolone sodium Succinate, clarithromycin, Zafirlukast, for sulfadiazine, thioguanine, Valdecoxib, alefacept, D2E7 moterol fumarate, influenza virus vaccine, amoxicillin tri (adalimumab), and efalizumab. hydrate, flunisolide, allergy injection, cromolyn Sodium, 60 Preferred examples of therapeutic agents for SLE (Lupus) fexofenadine hydrochloride, flunisolide/menthol, amoxicil with which a compound of Formula (I) may be co-admin lin/clavulanate, levofloxacin, inhaler assist device, guaife istered include the following: NSAIDS, for example, nesin, dexamethasone sodium phosphate, moxifloxacin HCl, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; doxycycline hyclate, guaifenesin/d-methorphan, p-ephed COX2 inhibitors, for example, celecoxib, rofecoxib, Valde rine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, 65 coxib; anti-malarials, for example, hydroxychloroquine; Ste mometasone furoate, salmeterol Xinafoate, benzonatate, roids, for example, prednisone, prednisolone, budenoside, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HC1/ dexamethasone; cytotoxics, for example, azathioprine, US 9,561,231 B2 63 64 cyclophosphamide, mycophenolate mofetil, methotrexate; that inhibit dipeptidyl-peptidase IV such as vildagliptin, inhibitors of PDE4 or purine synthesis inhibitor, for example Sitagliptin, saxagliptin, linagliptin, allogliptin and septaglip Cellcept(R). A compound of Formula (I) may also be com tin, agents that bind to the peroxisome proliferator-activated bined with agents such as Sulfasalazine, 5-aminosalicylic receptor gamma Such as rosiglitaZone and pioglitaZone; acid, olSalazine, Imuran R and agents which interfere with agents that decrease insulin resistance Such as metformin; synthesis, production or action of proinflammatory cytok agents that reduce glucose absorbance in the Small intestine ines such as IL-1, for example, caspase inhibitors like IL-1B Such as acarbose, miglitol and Voglibose. converting enzyme inhibitors and IL-1 ra. A compound of The compounds of the invention can be co-administered Formula (I) may also be used with T cell signaling inhibi with a therapeutically effective amount of one or more tors, for example, tyrosine kinase inhibitors; or molecules 10 agents to prevent or treat acute kidney disorders and chronic that target T cell activation molecules, for example, CTLA kidney diseases, where examples of the agents include, but 4-IgG or anti-B7 family antibodies, anti-PD-1 family anti are not limited to, dopamine, diuretics such as furosemide, bodies. A compound of Formula (I) can be combined with bumetanide, thiazide and the like, mannitol, calcium glu IL-11 or anti-cytokine antibodies, for example, fonotoli conate, sodium bicarbonate, albuterol, paricalcitol, doxer Zumab (anti-IFNg antibody), or anti-receptor receptor anti 15 calciferol, and cinacalcet. bodies, for example, anti-IL-6 receptor antibody and anti The following Examples may be used for illustrative bodies to B-cell surface molecules. A compound of Formula purposes and should not be deemed to narrow the scope of (I) may also be used with UP 394 (abetimus), agents that the invention. deplete or inactivate B-cells, for example, Rituximab (anti CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (adali EXAMPLES mumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) and p55TNFRIgG (LENER Example 1 CEPTTM). A compound of Formula (I) may also be co-administered 25 with insulin for the treatment of type I diabetes. 2-methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one The compounds of the invention can also be co-admin istered with a therapeutically effective amount of one or Example 1A more agents used in the prevention or treatment of AIDS, where examples of the agents include, HIV reverse tran 30 scriptase inhibitors, HIV protease inhibitors, immunomodu 6-chloro-2-methylpyridazin-3 (2H)-one lators, and other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, aba A mixture of 6-chloropyridazin-3(2H)-one (5.04 g. 38.6 cavir, adefovir, didanosine, dipivoxil delavirdine, efavirenz, mmol) and iodomethane (2.88 mL, 46.3 mmol) in dimeth emitricitabine, lamivudine, nevirapine, rilpivirine, stavudine, 35 ylformamide (30 mL) was treated with CsCO (15.10 g, tenofovir, Zalcitabine, and Zidovudine. Examples of protease 46.3 mmol) at ambient temperature. The reaction mixture inhibitors include, but are not limited to, amprenavir, ata was stirred at ambient temperature for 4 hours. The reaction Zanavir, darunavir, indinavir, foSamprenavir, lopinavir, nel mixture was partitioned between water and ethyl acetate. finavir, ritonavir, Saquinavir, and tipranavir. Examples of The aqueous layer was extracted with additional ethyl other retroviral drugs include, but are not limited to, elvite 40 acetate three times. The combined organic layers were gravir, enfuVirtide, maraviroc and raltegravir. washed with brine, dried over MgSO, filtered, and concen The compounds of the invention can also be co-admin trated. The residue was purified by flash column chroma istered with a therapeutically effective amount of one or tography on silica gel eluting with 20% ethyl acetate in more agents used in the treatment of obesity, where hexanes to give 4.55 g (82%) of the title compound. examples of the agents include orlistat. 45 The compounds of the invention can also be co-admin Example 1B istered with a therapeutically effective amount of one or more agents used in the treatment of type II diabetes, where examples of the agents include, alpha glucosidase inhibitors, 2-methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one insulin, metformin, Sulfonylureas (e.g., carbutamide, aceto 50 hexamide, chlorpropamide, glibenclamide, glibornuride, A mixture of Example 1A (29 mg 0.20 mmol), 2-phe gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, noxyphenylboronic acid (0.056 g., 0.260 mmol. 1.3 equiva glyclopyramide, tolbutamide, and tolaZamide), nonsulfony lents), Pd(PPh) (0.011 g, 5 mol %) and cesium fluoride lureas (e.g., nateglinide, and repaglinide), and thiazolidin (0.091 g, 0.6 mmol) in DME (2 mL) and methanol (1 mL) ediones (e.g., pioglitaZone). 55 was heated under microwave condition (120° C., 40 min The compounds of the invention can be co-administered utes). The reaction mixture was partitioned between water with a therapeutically effective amount of one or more and ethyl acetate. The aqueous layer was extracted with agents to prevent or treat type II diabetes, hepatic Steatosis, additional ethyl acetate three times. The combined organic insulin resistance, metabolic syndrome and related disor layers were washed with brine, dried over MgSO filtered, ders, where examples of the agents include, but are not 60 and concentrated. The residue was purified by flash column limited to, insulin and insulins that have been modified to chromatography on silica gel eluting with 30% ethyl acetate improve the duration of action in the body; agents that in hexanes to give the title compound (0.041 g, 74% yield). stimulate insulin secretion Such as acetohexamide, chlorpro H NMR (500 MHz, DMSO-d) & 7.75 (d. J=9.77 Hz, 1H), pamide, glyburide, glimepiride, glipizide, glicazide, glyco 7.66 (dd, J=7.78, 1.68 hz, 1H), 7.45-749 (m, 1H), 7.35-7.40 pyramide, gliquidone, rapaglinide, nataglinide, tolaZamide 65 (m. 2H), 7.26-7.30 (m, 2H), 7.11-7.15 (m, 1H), 6.97-7.01 and tolbutamide; agents that are glucagon-like peptide ago (m, 3H), 6.94 (d. J=9.77 Hz, 1H), 3.68 (s, 3H). MS (ESI+) nists such as exanatide, liraglutide and taspoglutide; agents m/z 279.0 (M+H)". US 9,561,231 B2 65 66 Example 2 Example 5 N-4-(2,4-difluorophenoxy)-3-1-methyl-6-oxo-4- 6-2-(benzyloxy)phenyl)-2-methylpyridazin-3 (2H)- (trifluoromethyl)-1,6-dihydropyridin-3-yl) O phenyl)methanesulfonamide Example 2 was prepared according to the procedure used Example 5A for the preparation of Example 1B, substituting 2-(benzy loxy)phenylboronic acid for 2-phenoxyphenylboronic acid, 5-bromo-1-methyl-4-(trifluoromethyl)pyridin-2(1H)- to provide the title compound. "H NMR (500 MHz, DMSO 10 O d) & 7.78 (d. J=9.77 Hz, 1H), 7.49 (dd, J=748, 1.68 hz, 1H), 7.30-7.46 (m, 6H), 7.25 (d. J=7.63 Hz, 1H), 7.06 (t, J=7.02 Example 5A was prepared according to the procedure HZ, 1H), 6.92 (d. J=9.46 Hz, 1H), 5.19 (s. 2H), 3.70 (s, 3H). used for the preparation of Example 1A, Substituting MS (ESI+) m/z 293.1 (M+H)". 5-bromo-4-(trifluoromethyl)-1,2-dihydropyridin-2-ol for 15 6-chloropyridazin-3 (2H)-one, to provide the title compound. Example 3 Example 5B

4-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene phenoxybenzonitrile 2-Bromo-1-fluoro-4-nitrobenzene (15g, 68.2 mmol), 2,4- difluorophenol (7.82 ml, 82 mmol), and cesium carbonate A mixture of 6-(2-hydroxyphenyl)-2-methylpyridazin-3 (26.7 g 82 mmol) were combined in DMSO (75 mL) then (2H)-one (0.100 g, 0.495 mmol) (prepared according to the heated to 110° C. for 1 hour. After cooling, to the reaction procedure reported in Synthetic Communications, 2002, 32. 25 mixture was added water (1000 mL) and brine (1000 mL), and the mixture was extracted with ethyl acetate (3x200 1675), 4-fluorobenzonitrile (0.072 g, 0.593 mmol), and mL). The combined organics were washed with brine, dried sodium hydride (14.2 mg, 0.593 mmol) in N-methylpyr (MgSO), filtered, and concentrated under reduced pressure rolodone (4 mL) was heated at 130° C. for 16 hours. The to give a crude Solid which was used in the next step without reaction mixture was cooled to ambient temperature, taken 30 additional purification. up in ethyl acetate, and washed with 1 Naqueous sodium hydroxide solution followed by brine. The organic layer was Example 5C separated, dried over anhydrous sodium Sulfate, filtered, and 3-bromo-4-(2,4-difluorophenoxy)aniline evaporated under reduced pressure. The residue was purified 35 by flash chromatography (silica gel, 30-100% ethyl acetate/ A mixture of Example 5B (22.5 g. 68.2 mmol), iron hexane) to provide the title compound. "H NMR (300 MHz, powder (19.0 g, 341 mmol), and ammonium chloride (7.30 DMSO-d) & 7.77-7.87(m. 2H) 7.71-7.76 (m, 1H) 7.66-7.71 g, 136 mmol) in tetrahydrofuran (117 ml), ethanol (117 ml), (m. 1H) 7.52-7.61 (m, 1H) 736-7.47 (m, 1H) 722 (d. J=7.93 and water (39.0 ml) was refluxed at 100° C. for 2 hours. The HZ, 1H) 7.02-7.10 (m, 2H) 6.89-6.97 (m. 1H)3.60 (s, 3H). 40 mixture was cooled just below reflux, filtered through Celite. The filter cake was washed with warm MeOH (3x50 mL). MS (ESI+) m/z 304.3 (M+H)". The solution was concentrated under reduced pressure, neutralized to a pH of 8 with saturated NaHCO (150 mL), Example 4 and extracted with ethyl acetate (3x100 mL). The combined 45 organics were washed with brine, dried (MgSO), filtered, concentrated, and purified by flash chromatography (silica 6-2-(cyclopentyloxy)phenyl-2-methylpyridazin-3 gel, 0-15% ethyl acetate/hexane gradient) to provide the title (2H)-one compound (8.1 g, 85%).

A mixture of 6-(2-hydroxyphenyl)-2-methylpyridazin-3 50 Example 5D (2H)-one (0.120g, 0.593 mmol) (prepared according to the procedure reported in Synthetic Communications, 2002, 32. 4-(2,4-difluorophenoxy)-3-(4.4.5.5-tetramethyl-1,3, 1675), 4-bromocyclopentane (0.097 g., 0.653 mmol), and 2-dioxaborolan-2-yl)aniline sodium hydride (17.1 mg, 0.712 mmol) in N-methylpyr rolodone (4 mL) was stirred at ambient temperature for 72 55 Example 5C (14.3 g, 47.7 mmol), 4.4.4.4.5.5.5',5'-oc h. The reaction mixture was taken up in ethyl acetate, and tamethyl-2,2'-bi(1,3,2-dioxaborolane) (24 g, 95 mmol), washed with 1 N aqueous sodium hydroxide solution fol potassium acetate (10.3 g, 105 mmol), 1,3,5,7-tetramethyl lowed by brine. The organic layer was separated, dried over 6-phenyl-2,4,8-trioxa-6-phosphaadamantane (1.39 g, 4.77 anhydrous sodium Sulfate, filtered, and evaporated under mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.31 reduced pressure. The residue was purified by flash chro 60 g, 1.43 mmol) were degassed under argon for 30 minutes. matography (silica gel, 10-30% ethyl acetate/hexane) to Dioxane (200 mL), degassed with argon for 30 minutes, was provide the title compound. H NMR (300 MHz, DMSO-d) then added by cannula transfer and the reaction mixture 8 7.68 (d. J=9.49 Hz, 1H) 7.47 (dd, J=7.80, 1.70 Hz, 1H) heated at 80° C. for 22 hours. The cooled mixture was 7.35-7.44 (m, 1H) 7.12 (d. J=7.80 Hz, 1H) 7.01 (t, J=6.95 vacuum filtered through Celite, rinsed with ethyl acetate HZ, 1H) 6.94 (d. J=9.49 Hz, 1H)4.85-4.95 (m. 1H)3.70 (s, 65 (100 mL), and washed with brine (150 mL) and water (150 3H) 1.82-197 (m, 2H) 1.52-1.77 (m, 6H). MS (ESI+) m/z mL). The aqueous phase was extracted with ethyl acetate 271.3 (M+H)". (3x150 mL). The combined organics were washed with US 9,561,231 B2 67 68 brine, dried (MgSO), gravity filtered, then concentrated 7.53-7.60 (m, 1H) 7.38-744 (m, 1H) 7.21 (dd, J=8.14, 1.02 under reduced pressure. Purification by flash chromatogra HZ, 1H) 7.10-7.17 (m, 2H) 6.94 (d. J=9.49 Hz, 1H)3.61 (s, phy (silica gel, 0-25% ethyl acetate/hexane gradient) 3H) 3.17 (s, 3H). MS (ESI+) m/z. 357.2 (M+H)". afforded the title compound (14.2 g 88%). Example 9 Example 5E 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-1- 2-methyl-6-(5-nitro-2-phenoxyphenyl)pyridazin-3 methyl-4-(trifluoromethyl)pyridin-2(1H)-one (2H)-one 10 Example 5E was prepared according to the procedure Example 9A used for the preparation of Example 1B, substituting Example 5D for 2-phenoxyphenylboronic acid, and Example 5A for Example 1A, respectively, to provide the 6-(2-fluoro-5-nitrophenyl)-2-methylpyridazin-3 (2H)- title compound. 15 O Example 5F Example 1A (0.145 g, 1 mmol), 2-fluoro-5-nitrophenyl boronic acid (0.294 g, 1.1 mmol), Pd(PPh) (0.058 g., 0.05 N-4-(2,4-difluorophenoxy)-3-1-methyl-6-oxo-4- mmol) and sodium carbonate (0.212 g, 2.0 mmol) were (trifluoromethyl)-1,6-dihydropyridin-3-yl) combined in toluene (4 mL), ethanol (1 mL), and water (1 phenyl)methanesulfonamide mL) and the mixture was degassed and left under nitrogen. The reaction mixture was heated at 90° C. overnight, and Example 5F was prepared according to the procedure then cooled to room temperature. The mixture was parti used for the preparation of Example 22, Substituting tioned between ethyl acetate and water. The organic layer Example 5E for Example 20O to provide the title compound. 25 was washed with brine, dried (MgSO), filtered and con H NMR (300 MHz, DMSO-d) & 9.74 (s, 1H), 7.93 (s, 1H), centrated. The crude product was purified by flash chroma 7.46-7.31 (m. 1H), 7.31-7.00 (m, 4H), 6.89-6.75 (m, 2H), tography (silica gel, 20-50% ethyl acetate in hexanes) to 3.47 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 475.3 (M+H)". provide 0.19 g (76%) of the title compound. Example 6 30 Example 9B 2-methyl-6-2-(pyridin-2-yloxy)phenylpyridazin-3 (2H)-one 2-methyl-6-(5-nitro-2-phenoxyphenyl)pyridazin-3 (2H)-one Example 6 was prepared according to the procedure used 35 for the preparation of Example 3, substituting 2-fluoropyri Phenol (0.045 g, 0.48 mmol). Example 9A (0.1 g, 0.4 dine for 4-fluorobenzonitrile, to provide the title compound. mmol) and cesium carbonate (0.130 g, 0.4 mmol) were "H NMR (300 MHz, DMSO-d) & 8.08 (dd, J=5.35, 1.78 Hz, combined in DMSO (2 mL) and heated at 100° C. for 2 1H) 7.79-7.88 (dd, J=6.74, 1.59 Hz, 1H) 7.63-7.68 (m. 1H) hours. The reaction mixture was partitioned between ethyl 7.63 (d. J=9.52 Hz, 1H) 747-7.55 (m. 1H) 7.32-7.39 (m, 1H) 40 acetate and water and pH was adjusted to pH 7. The organic 7.20 (dd, J=8.33, 1.19 Hz, 1H) 707-7.12 dd, J=4.76, 0.79 layer was washed with brine, dried (NaSO), filtered and HZ, 1H) 7.02 (d. J=8.33 Hz, 1H) 6.89 (d. J=9.52 Hz, 1H) concentrated. Purification by flash chromatography (silica 3.60 (s, 3H). MS (ESI+) m/z 280.2 (M+H)". gel, 60% ethyl acetate in hexanes) afforded 0.09 g (70%) of Example 7 45 the title compound. "H NMR (500 MHz, DMSO-d) & 8.47 (d. J=2.75 Hz, 1H), 8.28 (dd, J=9.15, 2.75 Hz, 1H), 7.94 (d. 2-methyl-6-2-4-(trifluoromethyl)phenoxy J=9.46 Hz, 1H), 7.49-7.53 (m, 2H), 7.31 (t, J=7.48 Hz, 1H), 7.26 (d. J=7.63 Hz, 2H), 7.04 (d. J=9.46 HZ), 6.98 (d. J=9.16 phenylpyridazin-3 (2H)-one HZ, 1H), 3.76 (s, 3H). MS (DCI+) m/z 324.1 (M+H)". Example 7 was prepared according to the procedure used 50 for the preparation of Example 3, substituting 1-fluoro-4- Example 10 (trifluoromethyl)benzene for 4-fluorobenzonitrile, to pro vide the title compound. "H NMR (300 MHz, DMSO-d) & 7.66-7.76 (m, 4H) 7.51-7.59 (m, 1H) 7.36-7.43 (m, 1H) 7.19 6-(5-amino-2-phenoxyphenyl)-2-methylpyridazin-3 (dd, J=8.13, 0.99 Hz, 1H) 7.11 (d. J=8.33 Hz, 2H)6.94 (d. 55 (2H)-one J=9.52 Hz, 1H)3.62 (s.3H). MS (ESI+) m/z 347.0 (M+H)". Example 9B (0.08 g., 0.247 mmol) and 10% palladium on Example 8 carbon (0.023 g, 0.025 mmol) in ethyl acetate (10 mL) was treated with a balloon of hydrogen overnight. The solid was 2-methyl-6-2-4-(methylsulfonyl)phenoxy 60 removed by filtration. The filtrate was concentrated under phenylpyridazin-3 (2H)-one reduced pressure. The residue was purified by reverse phase HPLC (C18, CHCN/water (0.1% TFA), 0-100%) to afford Example 8 was prepared according to the procedure used the title compound (0.066 g, 90%). "H NMR (500 MHz, for the preparation of Example 3, substituting 1-fluoro-4- DMSO-d) & 7.72 (d. J=9.77 Hz, 1H), 7.31-7.36 (m, 2H), (methylsulfonyl)benzene for 4-fluorobenzonitrile, to pro 65 7.23 (d. J=2.75 Hz, 1H), 7.31 (t, J–7.08 Hz, 1H), 7.03 (dd, vide the title compound. 'H NMR (300 MHz, DMSO-d) & J=8.85, 2.75 Hz, 1H), 6.92-6.94 (m, 4H), 3.67 (s, 3H). MS 7.86-7.93 (m, 2H) 7.71-7.77 (m. 1H) 7.70 (d. J=9.49 Hz, 1H) (DCI+) m/z 294.0 (M+H)". US 9,561,231 B2 69 70 Example 11 ane (3 mL) and water (1 mL) was heated at 90° C. for 2 hours. After cooling to room temperature, the reaction 4-methyl-N-3-(1-methyl-6-oxo-1,6-dihydro mixture was partitioned between water and ethyl acetate. pyridazin-3-yl)-4-phenoxyphenylbenzenesulfona The aqueous layer was neutralized to pH 5 using 10% HC1. mide It was then extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, A mixture of Example 10 (0.03 g, 0.102 mmol), 4-meth dried over MgSO, filtered, and concentrated. The residue ylbenzene-1-sulfonyl chloride (0.019 g, 0.102 mmol) and was purified by reverse phase HPLC (C18, CHCN/water triethylamine (0.022 g, 0.204 mmol) in dichloromethane (2 (0.1%TFA), 0-100%) to afford the title compound. "H NMR mL) was stirred for 2 hours. The solvent was removed under (500 MHz, DMSO-d) & 8.17 (d. J–2.14 Hz, 1H), 8.03 (br reduced pressure. The residue was purified by reverse phase 10 s, 1H), 7.94 (dd, J=8.54, 2.44 Hz, 1H), 7.82 (d. J=9.77 Hz, HPLC (C18, CHCN/water (0.1% TFA), 0-100%) to afford 1H), 7.40-7.45 (m, 3H), 7.20 (t, J–7.32 Hz, 1H), 7.08-7.11 the title compound (0.037 g. 80%). H NMR (500 MHz, (m 2H), 6.98 (d. J=9.77 Hz, 1H), 6.94 (d. J=8.54 Hz, 1H), DMSO-d) & 10.30 (s, 1H), 7.66-7.69 (m,3H), 7.31-7.36 (m, 3.72 (s, 3H). MS (DCI+) m/z 322.1 (M+H)". 2H), 7.31-7.39 (m, 5H), 7.16 (dd, J=8.85, 2.75 Hz, 1H), 7.09 (t, J=7.32 Hz, 1H), 6.89-6.92 (m, 4H), 3.66 (s, 3H), 2.35 (s, 15 Example 15 3H). MS (DCI+) m/z 448.2 (M+H)". 3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- Example 12 phenoxybenzoic acid N-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- The title compound was isolated as a by-product during phenoxyphenyl)acetamide the preparation of Example 14. "H NMR (500 MHz, DMSO d) & 13.04 (brs, 1H), 8.20 (d. J–2.14 Hz, 1H), 7.98 (dd. Example 12 was prepared according to the procedure used J=8.7, 2.29 Hz, 1H), 7.86 (d. J=9.77 Hz, 1H), 7.44-7.48 (m, for the preparation of Example 10, substituting acetic chlo 2H), 7.24 (t, J=7.48 Hz, 1H), 7.13-7.17 (m 2H), 6.99 (d. ride for 4-methylbenzene-1-sulfonyl chloride, to provide the 25 J=9.77 Hz, 1H), 6.93 (d. J=8.54 Hz, 1H), 3.74 (s, 3H). MS title compound. 'H NMR (500 MHz, DMSO-d) & 10.11 (s, (DCI+) m/z 323.1 (M+H)". 1H), 7.89 (d. J=2.75 Hz, 1H), 7.67-7.72 (m, 2H), 7.32-7.36 (m. 2H), 7.08 (t, J=7.32 Hz, 1H), 7.00 (d. J=8.85 Hz, 1H), Example 16 6.92-6.95 (m,3H), 3.67 (s.3H), 2.05 (s.3H). MS (ESI+) m/z 336.2 (M+H)". N-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- 30 phenoxybenzyl)acetamide Example 13 Example 1.6A 3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- phenoxybenzonitrile 6-(5-(aminomethyl)-2-phenoxyphenyl)-2-methyl 35 pyridazin-3 (2H)-one Example 13A Example 13B (0.1 g, 0.330 mmol) and solvent 7M NH 4-fluoro-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3- methanol (10 mL) were added to Ra-Ni 2800, water slurry yl)benzonitrile (0.200 g, 3.41 mmol) in a 50 mL pressure bottle and stirred 40 for 16 hours at 30 psi and room temperature. The mixture Example 13A was prepared according to the procedure was filtered through a nylon membrane and the filtrate was used for the preparation of Example 9A, substituting concentrated. The residue was purified by reverse phase 4-fluoro-3-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) HPLC (C18, CHCN/water (0.1% TFA), 0-100%) to afford benzonitrile for 2-fluoro-5-nitrophenylboronic acid, to pro the title compound. vide the title compound. 45 Example 16B Example 13B N-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- 3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- phenoxybenzyl)acetamide phenoxybenzonitrile 50 Example 16B was prepared according to the procedure Example 13B was prepared according to the procedure used for the preparation of Example 11, Substituting acetic used for the preparation of Example 9B, substituting chloride for 4-methylbenzene-1-sulfonyl chloride, and Example 13A for Example 9A, to provide the title com Example 16A for Example 10, respectively, to provide the pound. "H NMR (500 MHz, DMSO-d) & 8.10 (d. J=2.14 55 title compound. "H NMR (500 MHz, DMSO-d) & 8.41 (t, HZ, 1H), 7.86-7.89 (m, 2H), 7.45-749 (m, 2H), 7.27 (t, J=5.65, 1H), 7.72 (d. J=9.77 Hz, 1H), 7.53 (d. J=2.14 Hz, J=7.48 Hz, 1H), 7.18-7.21 (m, 2H), 7.01 (d. J=9.46 Hz, 1H), 1H), 7.34-7.38 (m, 3H), 7.11 (t, J=7.32 Hz, 1H), 6.93-6.97 6.95 (d. J=8.85 Hz, 1H), 3.73 (s.3H). MS (DCI+) m/z 3.04.1 (m, 4H), 4.28 (d. J=6.1 Hz, 2H), 3.68 (s, 3H), 1.88 (s, 3H). (M+H)". MS (ESI+) m/z. 350.1 (M+H)". 60 Example 14 Example 17 3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- 2.2.2-trifluoro-N-3-(1-methyl-6-oxo-1,6-dihydro phenoxybenzamide pyridazin-3-yl)-4-phenoxybenzyl)acetamide 65 A mixture of Example 13B (0.030 g, 0.1 mmol) and The title compound was isolated as a by-product during lithium hydroxide monohydrate (0.042 g, 1 mmol) in diox the preparation of Example 16B. "H NMR (500 MHz, US 9,561,231 B2 71 72 DMSO-d) & 10.5 (t, J=5.65, 1H), 7.75 (d. J=9.46 Hz, 1H), was filtered through a 0.45 um Nylon filter disk to remove 7.59 (d. J=2.14 Hz, 1H), 7.35-7.39 (m, 3H), 7.13 (t, J=7.48 solids and the filtrate was partitioned between ethyl acetate HZ, 1H), 6.94-7.01 (m, 4H), 4.43 (d. J=5.8 Hz, 2H), 3.69 (s. and brine. The organic layer was separated and concentrated. 3H). MS (ESI+) m/z 404.1 (M+H)". Purification by reverse phase HPLC (C18, 0-100% CHCN/ water (0.1% TFA)) afforded the title compound (0.048 g. Example 18 52%) 'H NMR (300 MHz, DMSO-d) & 9.84 (s, 1H) 7.50 (s, 1H) 7.33-744 (m, 2H) 722-7.31 (m, 1H)6.43 (s, 1H) 3.83 5-methoxy-2-methyl-6-(2-phenoxyphenyl)pyridazin (s, 3H) 3.65 (s, 3H) 3.00 (s, 3H). MS (ESI+) m/z. 310 3(2H)-one (M+H)". 10 Example 18A Example 20 5,6-dichloropyridazin-3 (2H)-one 6-(5-amino-2-phenoxyphenyl)-5-methoxy-2-methyl pyridazin-3 (2H)-one 3,4,6-Trichloropyridazine (12 g. 65.4 mmol) in acetic acid 15 (45 mL) was heated at 130° C. for two hours. After cooling to room temperature, the reaction mixture was poured into Example 20A ice water (200 mL). The solid was collected by filtration to give 3.7 g of the title compound. 6-(2-fluoro-5-nitrophenyl)-5-methoxy-2-methyl pyridazin-3 (2H)-one Example 18B Example 20A was prepared according to the procedure 5,6-dichloro-2-methylpyridazin-3 (2H)-one used for the preparation of Example 9A, substituting Example 18C for Example 1A, to provide the title com Example 18B was prepared according to the procedure 25 pound. used for the preparation of Example 1A, Substituting Example 18A for 6-chloropyridazin-3(2H)-one, to provide the title compound. Example 20B Example 18C 30 5-methoxy-2-methyl-6-(5-nitro-2-phenoxyphenyl) pyridazin-3 (2H)-one 6-chloro-5-methoxy-2-methylpyridazin-3(2H)-one Example 20B was prepared according to the procedure Methanol (80 mL) was cooled to 0°C. To this solvent was used for the preparation of Example 9B, substituting added sodium (0.804 g., 35.0 mmol). All sodium was dis 35 Example 20A for Example 9A, to provide the title com solved completely within 1 hour. To this solution was added pound. Example 18B (6.2g, 34.5 mmol). The reaction mixture was stirred at 50° C. for 2 hours. The solvent was removed, and Example 20O the residue was triturated with water. The solid was collected 40 by filtration to give 5.41 g (89%) of the title compound. 6-(5-amino-2-phenoxyphenyl)-5-methoxy-2-methyl Example 18D pyridazin-3 (2H)-one 5-methoxy-2-methyl-6-(2-phenoxyphenyl)pyridazin Example 20O was prepared according to the procedure 3(2H)-one 45 used for the preparation of Example 10, substituting Example 20B for Example 9B, to provide the title com Example 18D was prepared according to the procedure pound. "H NMR (500 MHz, DMSO-d) & 7.23-7.26 (m, used for the preparation of Example 1B, substituting 2H), 6.95 (t, J=7.93 Hz, 1H), 6.76-6.81 (m, 3H), 6.64-6.67 Example 18C for Example 1A, to provide the title com (m. 1H), 6.56 (d. J=2.75 Hz, 1H), 6.21 (s, 1H), 5.11 (s. 2H), pound. "H NMR (500 MHz, DMSO-d) & 7.60-7.64 (m, 50 3.51 (s, 3H), 3.50 (s, 3H). MS (DCI+) m/z 324.1 (M+H)". 1H), 7.40-7.47 (m, 2H), 7.32-7.38 (m, 2H), 7.21-7.25 (m, 1H), 7.10 (t, J=7.32 Hz, 1H), 6.91-6.98 (m, 3H), 6.29 (s. Example 21 1H), 3.61 (s, 3H), 3.57 (s, 3H). MS (DCI+) m/z 309.1 (M+H)". 55 N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro Example 19 pyridazin-3-yl)-4-phenoxyphenyl)acetamide N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro Example 21 was prepared according to the procedure used pyridazin-3-yl)phenylmethanesulfonamide for the preparation of Example 11, Substituting acetic chlo 60 ride for 4-methylbenzene-1-sulfonyl chloride, and substitut A mixture of the product from Example 18C (0.053 g, ing Example 20O for Example 10, respectively, to provide 0.30 mmol), 3-(methylsulfonylylamino)phenylboronic acid the title compound. "H NMR (500 MHz, DMSO-d) & 10.05 (Combi-Blocks 0.084 g. 0.390 mmol), tetrakis(tiriphenyl (s, 1H), 7.67 (d. J=2.44 Hz, 1H), 7.59 (dd, J=8.85, 2.44 Hz, phosphine)palladium(0) (0.017 g., 0.015 mmol) and sodium 1H), 7.29-7.34 (m, 2H), 7.06 (t, J=7.48 Hz, 1H), 6.97 (d. carbonate (2M, 0.300 mL, 0.600 mmol) in toluene (1.0 mL), 65 J=8.85 Hz, 1H), 6.86-6.92 (m, 2H), 6.28 (s, 1H), 3.58 (s, ethanol (0.25 mL), and water (0.5 mL) was heated by 3H), 3.56 (s, 3H), 2.04 (s, 3H). MS (DCI+) m/z. 366.0 microwave at 110° C. for 30 minutes. The reaction mixture (M+H)". US 9,561,231 B2 73 74 Example 22 ride for propanesulfonyl chloride to afford the title com pound (0.040 g, 71%). H NMR (300 MHz, DMSO-d) & N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro 10.46 (s, 1H) 7.29-7.38 (m,3H) 7.25 (d. J=2.38 Hz, 1H) 7.09 pyridazin-3-yl)-4-phenoxyphenylmethanesulfona (t, J–7.34 Hz, 1H) 6.99 (d. J=8.73 Hz, 1H) 6.92 (d. J=7.54 mide Hz, 2H) 6.30 (s, 1H)4.56 (q, J=9.78 Hz, 2H)3.60 (s, 3H) A mixture of Example 20O (0.03 g, 0.093 mmol), meth 3.56 (s, 3H). MS (ESI+) m/z 470 (M+H)". anesulfonyl chloride (0.021 g, 0.186 mmol), and triethyl amine (0.036 g., 0.36 mmol) in dichloromethane (1 mL) was Example 26 stirred at room temperature for 1 hour. The solvent was removed, and the residue was taken up in dioxane (2 mL) 10 N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro and 1.0 N NaOH (1 mL). The reaction mixture was heated pyridazin-3-yl)-4-phenoxyphenylcyclopentanesulfo at 90° C. for 1 hour. The solvents were partially removed, namide and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl A mixture of the product from Example 20 (0.049 g, 0.15 and extracted with additional ethyl acetate twice. The com 15 mmol) cyclopentanesulfonyl chloride (0.03 g, 0.18 mmol) bined organic layers were washed with brine, dried over and cesium carbonate (0.073 g, 0.225 mmol) in dimethyl MgSO filtered, and concentrated under reduced pressure. formamide (0.75 mL) was heated at 80° C. for 30 minutes The residue was purified by reverse phase HPLC (C18, and partitioned between ethyl acetate and brine adjusting the CHCN/water (0.1%TFA), 0-100%) to afford 0.025 g (68%) pH to 2 with 1M HC1. The organic layer was separated and of the title compound. "H NMR (500 MHz, DMSO-d) & concentrated. Purification by reverse phase HPLC (C18, 9.77 (s, 1H), 7.29-7.35 (m, 1H), 7.22 (d. J=2.75 Hz, 1H), 0-100% CHCN/water (0.1% TFA)) afforded the title com 7.08 (t, J=7.32 Hz, 1H), 6.99 (d. J=8.85 Hz, 1H), 6.91-6.93 pound (0.006g, 8%). "H NMR (300 MHz, DMSO-d) & 9.77 (m. 2H), 6.29 (s, 1H), 3.60 (s.3H), 3.56 (s.3H), 3.02 (s.3H). (s, 1H) 7.26-7.37 (m, 3H) 722 (d. J=2.78 Hz, 1H) 7.07 (t, MS (DCI+) m/z 402.2 (M+H)". J=7.34 Hz, 1H) 6.98 (d. J=9.12 Hz, 1H) 6.90 (d. J=7.54 Hz, Example 23 25 2H) 6.29 (s, 1H)3.59 (s.3H)3.55 (s.3H) 1.81-1.98 (m, 4H) N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro 1.48-1.75 (m, 4H). MS (ESI+) m/z 456 (M+H)". pyridazin-3-yl)-4-phenoxyphenyl-N-methylmeth Example 27 anesulfonamide 30 N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro The product from Example 22 (0.06 g., 0.149 mmol), pyridazin-3-yl)-4-phenoxyphenyl-1-phenylmethane potassium carbonate (0.027 g., 0.194 mmol) and methyl sulfonamide iodide (0.014 mL, 0.224 mmol) in dimethylformamide (0.7 mL) was stirred for 1 hour and partitioned between ethyl Example 27 was prepared according to the procedure of acetate and brine. The organic layer was separated and 35 concentrated. Purification by reverse phase HPLC (C18, Example 26 substituting alpha-toluenesulfonyl chloride for 0-100% CHCN/water (0.1% TFA)) afforded the title com cyclopentanesulfonyl chloride to afford the title compound pound (0.030 g, 48%). H NMR (300 MHz, DMSO-d) & (0.025 g, 43%). "H NMR (300 MHz, DMSO-d) & 9.88 (s, 7.43-7.51 (m, 2H) 7.30-7.41 (m, 2H) 7.13 (t, J=7.29 Hz, 1H) 1H) 7.30-7.40 (m, 7H) 7.26 (dd, J=8.73, 2.78 Hz, 1H) 7.13 6.89-7.04 (m, 3H) 6.32 (s, 1H)3.64 (s.3H)3.58 (s.3H)3.24 (d. J=2.78 Hz, 1H) 7.08 (t, J=7.34 Hz, 1H) 6.95 (d. J=8.73 (s, 3H) 2.98 (s, 3H). MS (ESI+) m/z 416 (M+H)". 40 HZ, 1H) 6.91 (d. J–7.54 Hz, 2H) 6.29 (s, 1H) 4.49 (s. 2H) Example 24 3.61 (s, 3H) 3.57 (s, 3H). MS (ESI+) m/z 478 (M+H)". N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro Example 28 pyridazin-3-yl)-4-phenoxyphenylpropane-1-sulfo 45 3,3,3-trifluoro-N-3-(4-methoxy-1-methyl-6-oxo-1, namide 6-dihydropyridazin-3-yl)-4-phenoxyphenylpropane The product from Example 20 (0.039 g, 0.12 mmol) and 1-sulfonamide triethylamine (0.025 mL, 0.18 mmol) in dichloromethane (0.5 mL) were treated with propanesulfonyl chloride (0.015 Example 28 was prepared according to the procedure of mL, 0.13 mmol) stirred for 3 hours and partitioned between 50 Example 24 substituting 3,3,3-trifluoropropane-1-sulfonyl ethyl acetate and brine. The organic layer was separated and chloride for propanesulfonyl chloride. Purification by chro concentrated. Purification by reverse phase HPLC (C18, matography (silica gel, 0-100% ethyl acetate in hexane) 0-100% CHCN/water (0.1% TFA)) afforded the title com afforded the title compound (0.30 g, 41%). to afford the title pound (0.023 g, 44%). "H NMR (300 MHz, DMSO-d) & compound (0.040 g, 71%). "H NMR (300 MHz, DMSO-d) 9.84 (s, 1H) 7.26-7.41 (m, 3H) 7.21 (d. J=2.38 Hz, 1H) 7.08 55 & 10.04 (s, 1H) 7.29-7.38 (m, 3H) 7.25 (d. J=2.71 Hz, 1H) (t, J=7.34 Hz, 1H) 6.98 (d. J=8.73 Hz, 1H) 6.91 (d. J=7.54 7.09 (t, J=746 Hz, 1H) 6.99 (d. J=8.82 Hz, 1H) 6.91 (d. Hz, 2H) 6.30 (s, 1H)3.59 (s.3H)3.56 (s, 3H)3.02-3.13 (m, J=7.80 Hz, 2H) 6.29 (s, 1H) 3.60 (s, 3H) 3.56 (s, 3H) 2H) 1.63-1.81 (m, 2H) 0.96 (t, J=7.34 Hz, 3H). MS (ESI+) 3.33-3.40 (m, 2H) 2.67-2.85 (m, 2H). MS (ESI+) m/z, 484 m/Z 430 (M+H)". (M+H)". Example 25 60 Example 29 2.2.2-trifluoro-N-3-(4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl)-4-phenoxyphenylethane ethyl 3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro Sulfonamide pyridazin-3-yl)-4-phenoxyphenylcarbamate 65 Example 25 was prepared according to the procedure of A mixture of Example 20O (0.03 g, 0.093 mmol), ethyl Example 24 substituting 2.2.2-trifluoroethanesulfonyl chlo carbonochloridate (0.015 g, 0.139 mmol), and triethylamine US 9,561,231 B2 75 76 (0.028 g., 0.278 mmol) in dichloromethane (1 mL) was Example 32A for phenol, and substituting 4-fluorobenzoni stirred at room temperature for 1 hour. The solvent was trile for Example 9A, respectively, to provide crude material. removed, and the residue was purified by reverse phase The crude mixture was purified by reverse phase HPLC HPLC (C18, CHCN/water (0.1% TFA), 0-100%) to afford 0.030 g (81%) of the title compound. 'H NMR (500 MHz, s (C18, CHCN/water (0.1%TFA), 0-100%) to afford the title DMSO-d) & 9.71 (s, 1H), 748-7.51 (m, 2H), 7.29-7.33 (m, compound. "H NMR (500 MHz, DMSO-d) & 7.79-782 (m, 2H), 7.05 (t, J–7.48 Hz, 1H), 6.96 (d. J=8.85 Hz, 1H), 6.88 2H), 7.54-7.58 (m, 1H), 7.50 (dd, J=7.78, 1.68 Hz, 1H), (d. J=7.63 Hz, 2H), 6.27 (s, 1H), 4.12 (q, J=7.02 Hz, 2H), 7.35-7.38 (m, 1H), 7.20 (d. J=8.24 Hz, 1H), 7.03-7.06 (m, 3.57 (s, 3H), 3.55 (s, 3H), 1.24 (t, J=7.02 Hz, 3H). MS 2H), 6.28 (s, 1H), 3.53 (s.3H), 3.51 (s.3H). MS (ESI+) m/z (DCI+) m/z 396.2 (M+H)". 10 334.2 (M+H)". Example 30 Example 33 1-ethyl-3-3-(4-methoxy-1-methyl-6-oxo-1,6-dihy 6-2-(4-fluorophenoxy)phenyl-5-methoxy-2-meth dropyridazin-3-yl)-4-phenoxyphenylurea 15 ylpyridazin-3(2H)-one A mixture of Example 20O (0.03 g, 0.093 mmol), iso A mixture of Example 32A (0.035 g, 0.015 mmol), cyanatoethane (0.019 g, 0.269 mmol), and triethylamine 4-fluorophenylboronic acid (0.042 g, 0.03 mmol), copper (0.027 g., 0.269 mmol) in dichloromethane (1 mL) was (II) acetate (0.027 g., 0.015 mmol), triethylamine (0.076 g. stirred at 43° C. overnight. The solvent was removed, and the residue was purified by reverse phase HPLC (C18, 0.750 mmol) and molecular sieves 4 A (0.05 g) in dichlo CHCN/water (0.1%TFA), 0-100%) to afford 0.019 g (51%) romethane (2 mL) was stirred overnight. The solid was of the title compound. "H NMR (500 MHz, DMSO-d) & removed by filtration, and the filtrate was concentrated. The 8.54 (s, 1H), 7.52 (d. J=2.44 Hz, 1H), 7.38 (dd, J=8.85, 2.75 residue was purified by reverse phase HPLC (C18, CHCN/ HZ, 1H), 728-7.31 (m, 2H), 7.03 (t, J-7.32 Hz, 1H), 6.90 (d. water (0.1% TFA), 0-100%) to afford 0.019 g (31%) of the J=8.54 Hz, 1H), 6.87 (d. J=7.63 Hz, 2H), 6.26 (s, 1H), 3.56 25 title compound. 'H NMR (500 MHz, DMSO-d) & 7.40-7.47 (s.3H), 3.55 (s.3H), 3.10 (q, J=7.22 Hz, 2H), 1.05 (t, J=7.17 (m. 2H), 7.17-7.24 (m, 3H), 6.97-7.00 (m, 2H), 6.92 (d. Hz, 3H). MS (DCI+) m/z 395.2 (M+H)". J=7.32 Hz, 1H), 6.31 (s, 1H), 3.64 (s, 3H), 3.58 (s, 3H). MS (ESI+) m/z 327.1 (M+H)". Example 31 30 Example 34 N'-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydro pyridazin-3-yl)-4-phenoxyphenyl-N,N-dimethylsul 6-2-(3-chloro-4-fluorophenoxy)phenyl-5-methoxy furic diamide 2-methylpyridazin-3(2H)-one Example 31 was prepared according to the procedure of 35 Example 34 was prepared according to the procedure used Example 26 substituting dimethylsulfamoyl chloride for for the preparation of Example 33, substituting 4-fluoro3 cyclopentanesulfonyl chloride to afford the title compound chlorophenylboronic acid for 4-fluorophenylboronic acid, to (0.013 g, 25%). "H NMR (300 MHz, DMSO-d) 89.92 (s, provide the title compound. "H NMR (500 MHz, DMSO-d) 1H) 7.26-7.35 (m, 3H) 7.20 (d. J=2.78 Hz, 1H) 7.06 (t, 8 737-7.52 (m, 3H), 7.26-7.30 (m. 1H), 7.14 (dd, J=6.26, J=7.34 Hz, 1H)6.97 (d. J=8.72 Hz, 1H) 6.89 (d. J=7.54 Hz, 40 2.9 Hz, 1H), 7.06 (d. J=7.32 Hz, 1H), 6.93-6.97 (m, 1H), 2H) 6.28 (s, 1H)3.59 (s.3H)3.55 (s, 3H) 2.73 (s, 6H). MS 6.31 (s, 1H), 3.62 (s.3H), 3.57 (s.3H). MS (ESI+) m/z. 361.1 (ESI+) m/z. 432 (M+H)". (M+H)". Example 32 Example 35 45 4-2-(4-methoxy-1-methyl-6-oxo-1,6-dihydro 5-methoxy-6-2-(4-methoxyphenoxy)phenyl-2- pyridazin-3-yl)phenoxybenzonitrile methylpyridazin-3 (2H)-one Example 32A Example 35 was prepared according to the procedure used 50 for the preparation of Example 33, substituting 4-methoxy 6-(2-hydroxyphenyl)-5-methoxy-2-methylpyridazin phenylboronic acid for 4-fluorophenylboronic acid, to pro 3(2H)-one vide the title compound. "H NMR (500 MHz, DMSO-d) & 7.36-7.42 (m, 3H), 7.13-7.17 (m. 1H), 6.93 (s, 4H), 6.80 (d. Example 32A was prepared according to the procedure J=8.24 Hz, 1H), 6.32 (s, 1H), 3.73 (s.3H), 3.69 (s.3H), 3.60 used for the preparation of Example 9A, substituting 55 (s, 3H). MS (ESI+) m/z 339.1 (M+H)". Example 18C for Example 1A, and substituting 2-(4.4.5.5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenol for 2-fluoro-5- Example 36 nitrophenylboronic acid, respectively, to provide the title compound. 6-2-(3-fluorophenoxy)phenyl-5-methoxy-2-meth 60 ylpyridazin-3(2H)-one Example 32B Example 36 was prepared according to the procedure used 4-2-(4-methoxy-1-methyl-6-oxo-1,6-dihydro for the preparation of Example 33, substituting 3-fluorophe pyridazin-3-yl)phenoxybenzonitrile nylboronic acid for 4-fluorophenylboronic acid, to provide 65 the title compound. H NMR (500 MHz, DMSO-d) & Example 32B was prepared according to the procedure 7.44-7.52 (m, 2H), 7.34-7.40 (m, 1H), 7.29 (t, J=7.48 Hz, used for the preparation of Example 9B, substituting 1H), 7.08 (d. J=8.24 Hz, 1H), 6.91-6.95 (m, 1H), 6.76 (dd. US 9,561,231 B2 77 78 J=9, 1.37 Hz, 2H), 6.32 (s, 1H), 3.59 (s.3H), 3.56 (s, 3H). Example 39 MS (DCI+) m/z 327.2 (M+H)". 6-2-(cyclohexyloxy)phenyl-5-methoxy-2-methyl Example 37 pyridazin-3 (2H)-one 6-2-(4-chlorophenoxy)phenyl-5-methoxy-2-meth A mixture of the product from Example 32A (0.046g, 0.2 mmol), cyclohexanol (0.022 mL, 0.210 mmol) and triph ylpyridazin-3(2H)-one enylphosphine (0.055 g, 0.210 mmol) in tetrahydrofuran (0.1 mL) was sonicated until the solids dissolved. With A mixture of Example 32A (0.035 g, 0.15 mmol), 10 continued Sonication, diisopropyl azodicarboxylate (0.041 1-chloro-4-iodobenzene (0.054 g., 0.225 mmol), copper(I) mL, 0.210 mmol) was added and sonication continued for 20 iodide (0.007 14 g., 0.0038 mmol), picolinic acid (0.00923 g, minutes. Purification by chromatography (silica gel, 0-70% 0.075 mmol) and tripotassium phosphate (0.064 g., 0.30 ethyl acetate in hexane) afforded the title compound (0.030 mmol) in toluene (1 mL) was degassed and back-filled with g, 48%). "H NMR (300 MHz, DMSO-d) & 7.33-7.41 (m, nitrogen three times. The reaction mixture was heated at 15 1H) 7.21 (dd, J–7.54, 1.59 Hz, 1H) 7.06 (d. J=8.33 Hz, 1H) 110° C. overnight. After cooling, the reaction mixture was 6.95 (t, J=6.94 Hz, 1H) 6.33 (s, 1H)4.28-4.44 (m. 1H)3.72 partitioned between water and ethyl acetate. The aqueous (s, 3H)3.60 (s.3H) 1.69-1.86 (m, 2H) 1.49-1.62 (m, J=8.93, layer was extracted with additional ethyl acetate twice. The 6.15 Hz, 2H) 1.16-1.49 (m, 6H). MS (ESI+) m/z. 315 combined organic layers were washed with brine, dried over (M+H)". MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18, Example 40 CHCN/water (0.1%TFA), 0-100%) to afford 0.038 g (75%) of the title compound. "H NMR (500 MHz, DMSO-d) & 5-methoxy-2-methyl-6-2-(pyridin-2-ylmethoxy) 737-7.50 (m, 1H), 7.24-728 (m, 1H), 7.04 (d. J=8.24 Hz, phenylpyridazin-3 (2H)-one 1H), 6.94-6.98 (m, 2H), 6.30 (s, 1H), 3.60 (s, 3H), 3.57 (s, 25 3H). MS (DCI+) m/z 343.2 (M+H)". The product from Example 32A (0.046 g., 0.2 mmol), 2-(bromomethyl)pyridine hydrobromide (0.066 g., 0.260 Example 38 mmol), and potassium carbonate (0.069 g, 0.500 mmol) were combined in dimethylformamide (1.0 mL) and stirred 30 for 16 hours. The reaction mix was partitioned between ethyl methyl-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- acetate and water. The organic layer was separated and dihydropyridazin-4-yl)oxyacetate concentrated. Purification by chromatography (silica gel. 0-4% methanol in dichloromethane) afforded the title com Example 38A pound (0.030 g, 46%). H NMR (300 MHz, DMSO-d) & 35 8.55 (d. J=3.97 Hz, 1H) 7.78-7.87(m. 1H) 737-7.45 (m, 1H) ethyl 2-(3-chloro-1-methyl-6-oxo-1,6-dihydro 7.22-7.35 (m, 3H) 7.14 (d. J=7.93 Hz, 1H) 7.04 (t, J=7.54 pyridazin-4-yloxy)acetate HZ, 1H) 6.36 (s, 1H) 5.18 (s. 2H)3.69 (s.3H)3.61 (s.3H). MS (ESI+) m/z 324 (M+H)". Ethyl 2-hydroxyacetate (0.208 g, 2.0 mmol) in tetrahy 40 Example 41 drofuran (5 mL) was treated with sodium hydride (0.080 g, 2.0 mmol. 60% dispersion in mineral oil) for 5 minutes. To 6-2-(1H-indazol-5-ylmethoxy)phenyl-5-methoxy this solution was added Example 18B (0.179 g, 1.0 mmol). 2-methylpyridazin-3(2H)-one The reaction mixture was stirred at room temperature over night. The reaction mixture was partitioned between water 45 Example 41 was prepared according to the procedure of and ethyl acetate. The aqueous layer was extracted with Example 40 substituting 5-(bromomethyl)-1H-indazole additional ethyl acetate twice. The combined organic layers hydrobromide for 2-(bromomethyl)pyridine hydrobromide. were washed with brine, dried over MgSO, filtered, and Purification by reverse phase HPLC (C18, 0-100% CHCN/ concentrated under reduced pressure. The residue was puri water (0.1% TFA)) afforded the title compound (0.007 g. fied by flash column chromatography on silica gel eluting 50 10%). H NMR (300 MHz, DMSO-d) & 13.07 (s, 1H) 8.05 with 70% ethyl acetate in hexanes to afford 0.128 g (52%) (s, 1H) 7.70 (s, 1H) 7.53 (d. J=8.72 Hz, 1H) 737-7.46 (m, of the title compound. 1H) 7.18-7.30 (m, 3H) 7.01 (t, J=6.94 Hz, 1H) 6.32 (s, 1H) 5.19 (s. 2H)3.72 (s, 3H) 3.58 (s, 3H). MS (ESI+) m/z. 363 Example 38B (M+H)". 55 Example 42 methyl-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- dihydropyridazin-4-ylloxyacetate 6-2-(2-cyclohexylethoxy)phenyl-5-methoxy-2- methylpyridazin-3 (2H)-one Example 38B was prepared according to the procedure 60 used for the preparation of Example 1B, substituting Example 42 was prepared according to the procedure of Example 38A for Example 1A, to provide the title com Example 40, substituting (2-bromoethyl)cyclohexane for pound. "H NMR (500 MHz, DMSO-d) & 7.60-7.64 (m, 2-(bromomethyl)pyridine hydrobromide and heating the 1H), 7.40-7.47 (m, 2H), 7.32-7.38 (m, 2H), 7.21-7.25 (m, reaction mixture at 50° C. for 6 hours. Purification by 1H), 7.10 (t, J=7.32 Hz, 1H), 6.91-6.98 (m, 3H), 6.39 (s. 65 chromatography (silica gel, 0-100% ethyl acetate in hexane) 1H), 4.82 (s. 2H), 3.66 (s.3H), 3.53 (s.3H). MS (ESI+) m/z afforded the title compound (0.038 g. 63%). "H NMR (300 367.1 (M+H)". MHz, DMSO-d) & 7.35-7.45 (m, 1H) 7.21 (dd, J=7.54, 1.59

US 9,561,231 B2 81 82 1H), 4.02-4.07 (s. 2H), 3.46 (s, 3H), 3.02-3.17 (m, 5H), Example 51A for Example 1A, to provide the title com 1.84-2.08 (m, 2H), 1.13 (t, J=7.02 Hz, 3H). MS (DCI+) m/z pound. "H NMR (500 MHz, DMSO-d) & 7.54 (dd, J=7.63, 420.2 (M+H)". 1.83 Hz, 1H), 7.46-7.49 (m. 1H), 7.31-7.35 (m, 2H), 7.28 (t, J=7.63 Hz, 1H), 7.1 (t, J=7.32 Hz, 1H), 7.01 (d. J=8.24 Hz, Example 50 1H), 6.98-6.91 (m, 2H), 6.14 (s, 1H), 3.51 (s, 3H), 3.34 (br s, 2H), 3.09 (br 2, 2H), 2.93 (brs, 2H), 2.78 (s, 3H). MS methyl N-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1, (ESI+) m/z 391.1 (M+H)". 6-dihydropyridazin-4-yl)glycinate Example 52 Example 50A 10 6-(biphenyl-2-yl)-2-methylpyridazin-3(2H)-one methyl 2-(3-chloro-1-methyl-6-oxo-1,6-dihydro pyridazin-4-ylamino)acetate Example 52A A mixture of Example 18B (0.179 g, 1.0 mmol), 2-amino 2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl N-methylacetamide, hydrochloric acid (0.374 g., 3 mmol), 15 trifluoromethanesulfonate and triethylamine (0.506 g. 5.0 mmol) in ethanol (10 mL) was heated under reflux for 16 hours. After cooling, more A mixture of 6-(2-hydroxyphenyl)-2-methylpyridazin-3 2-amino-N-methylacetamide, hydrochloric acid (0.374 g. 3 (2H)-one (1.24 g. 6.13 mmol), 1,1,1-trifluoro-N-phenyl-N- mmol), and triethylamine (0.506 g. 5.0 mmol) were added. (trifluoromethylsulfonyl)methanesulfonamide (2.41 g, 6.75 The reaction mixture was heated under reflux overnight. The mmol), and triethylamine (0.745 g, 7.36 mmol) in dichlo Solvent was removed, and the residue was taken up to ethyl romethane (35 mL) was stirred at ambient temperature for acetate. It was washed with water. The aqueous layer was 16 h. The reaction mixture was concentrated under reduced extracted with additional ethyl acetate three times. The pressure, and the residue purified by flash chromatography combined organic layers were washed with brine, dried over (silica gel, 10-30% ethyl acetate/hexane gradient) to provide MgSO filtered, and concentrated. The residue was purified the title compound. by flash column chromatography on silica gel eluting with 25 40-80% ethyl acetate in hexanes to afford 0.135 g (55%) of Example 52B the title compound. 6-(biphenyl-2-yl)-2-methylpyridazin-3(2H)-one Example 50B 30 A mixture of Example 52A (0.232 g, 0.694 mmol), methyl N-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1, phenylboronic acid (0.102 g, 0.833 mmol) and PdCl2(dppf) 6-dihydropyridazin-4-yl)glycinate (0.025 g, 0.035 mmol) in dioxane (4 mL) and 2M aqueous sodium carbonate (2 mL) was heated at 70° C. for 4 hours. Example 50B was prepared according to the procedure The reaction mixture was cooled to ambient temperature, used for the preparation of Example 1B, substituting 35 partitioned between ethyl acetate and brine, and the organic Example 50A for Example 1A, to provide the title com layer separated, dried (anhydrous sodium Sulfate), filtered, pound. "H NMR (500 MHz, DMSO-d) & 7.47-7.50 (m, and concentrated. The residue was purified by flash chro 2H), 7.40 (dd, J=7.63, 1.83 Hz, 1H), 7.33-7.36 (m, 2H), matography (silica gel, 10-50% ethyl acetate/hexane gradi 7.24-7.27 (m. 1H), 7.12 (t, J–7.32 Hz, 1H), 705-7.06 (m, ent) to provide the title compound. "H NMR (300 MHz, 3H), 6.92 (d. J=7.63 Hz, 1H), 5.96 (t, J=6.26, HZ, 1H), 5.62 40 DMSO-d) & 743-7.63 (m, 4H) 7.30-7.39 (m,3H) 7.18-7.26 (s, 1H), 3.90 (d. J=5.8 Hz, 1H), 3.59 (s.3H), 3.47 (s, 3H). (m. 2H) 6.83 (d. J=9.51 Hz, 1H) 6.67 (d. J=9.51 Hz, 1H) MS (DCI+) m/z 366.2 (M+H)". 3.64 (s, 3H). MS (ESI+) m/z 263.1 (M+H)". Example 51 Example 53 2-methyl-5-(4-methyl-3-oxopiperazin-1-yl)-6-(2- 45 2'-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)biphe phenoxyphenyl)pyridazin-3(2H)-one nyl-3-carbonitrile Example 51A Example 53 was prepared according to the procedure used for the preparation of Example 52B, substituting 3-cyano 6-chloro-2-methyl-5-(4-methyl-3-oxopiperazin-1-yl) 50 phenylboronic acid for phenylboronic acid, to provide the pyridazin-3 (2H)-one title compound. 'H NMR (300 MHz, DMSO-d) & 7.78-7.83 (m. 1H) 7.75 (t, J=1.53 Hz, 1H) 7.43-7.66 (m, 6H) 7.04 (d. A mixture of Example 18B (0.179 g, 1.0 mmol), 1-meth J=9.49 Hz, 1H) 6.76 (d. J=9.49 Hz, 1H) 3.57 (s, 3H). MS ylpiperazin-2-one, hydrochloric acid (0.301 g, 2 mmol), and (ESI+) m/z 288.3 (M+H)". triethylamine (0.405 g 4.0 mmol) in ethanol (10 mL) was 55 heated under reflux for 16 hours. The solvent was removed, Example 54 and the residue was purified by flash column chromatogra phy on silica gel eluting with 1-5% methanol in ethyl acetate 5-(2-fluoropyridin-4-yl)-2-methyl-6-(2-phenoxyphe to afford 0.21 g (82%) of the title compound. nyl)pyridazin-3 (2H)-one 60 Example 51B Example 54A 2-methyl-5-(4-methyl-3-oxopiperazin-1-yl)-6-(2- 6-chloro-5-(2-fluoropyridin-4-yl)-2-methyl phenoxyphenyl)pyridazin-3(2H)-one pyridazin-3 (2H)-one 65 Example 50B was prepared according to the procedure Example 54A was prepared according to the procedure used for the preparation of Example 1B, substituting used for the preparation of Example 9A, substituting US 9,561,231 B2 83 84 Example 18B for Example 1A, and substituting 2-fluoro (d. J=5.19 Hz, 1H), 7.61 (dd, J=7.63, 1.83 Hz, 1H), 7.35 pyridin-4-ylboronic acid for 2-fluoro-5-nitrophenylboronic 7.39 (m, 1H), 7.21-7.27 (m, 3H), 7.08 (t, J–7.32 Hz, 1H), acid, respectively, to provide the title compound. 7.03 (s, 1H), 6.70 (dd, J=5.19, 1.53 Hz, 1H), 6.56-6.62 (m, 2H), 6.36-6.40 (m, 2H), 3.76 (s, 3H), 3.72 (s, 3H). MS Example 54B (DCI+) m/z. 386.2 (M+H)". 5-(2-fluoropyridin-4-yl)-2-methyl-6-(2-phenoxyphe Example 58 nyl)pyridazin-3 (2H)-one N-3-4-(2-methoxypyridin-4-yl)-1-methyl-6-oxo-1, Example 54B was prepared according to the procedure 10 6-dihydropyridazin-3-yl)-4- used for the preparation of Example 9A, substituting phenoxyphenyl)methanesulfonamide Example 54A for Example 1A, and Substituting 2-phenoxy phenylboronic acid for 2-fluoro-5-nitrophenylboronic acid, Example 58A respectively, to provide the title compound. "H NMR (500 MHz, DMSO-d) & 8.13 (d. J=5.13 Hz, 1H), 7.64 (dd. 15 6-chloro-5-(2-methoxypyridin-4-yl)-2-methyl J=7.51, 1.65 Hz, 1H), 737-7.41 (m, 2H), 7.24-7.27 (m, 3H), pyridazin-3 (2H)-one 7.07-7.10 (m, 2H), 6.99 (s, 1H), 6.63 (d. J=8.43 Hz, 1H), 6.38-6.39 (m, 2H), 3.73 (s, 3H). MS (ESI+) m/z. 374.1 Example 58A was prepared according to the procedure (M+H)". used for the preparation of Example 57, substituting Example 54A for Example 54B, to provide the title com Example 55 pound. 2-methyl-5-(2-oxo-1,2-dihydropyridin-4-yl)-6-(2- Example 58B phenoxyphenyl)pyridazin-3(2H)-one 25 6-(2-fluoro-5-nitrophenyl)-5-(2-methoxypyridin-4- Example 54B (0.032 g, 0.086 mmol) in acetic acid (4 mL) yl)-2-methylpyridazin-3(2H)-one and water (1 mL) was heated at 100° C. overnight. The solvents were removed under reduced pressure. The residue Example 54B was prepared according to the procedure was purified by reverse phase HPLC (C18, CHCN/water used for the preparation of Example 9A, substituting (0.1% TFA), 0-100%) to afford 0.028 g (88%) of the title 30 Example 58A for Example 1A, to provide the title com compound. "H NMR (500 MHz, DMSO-d) & 7.56 (dd. pound. J=7.63, 1.53 Hz, 1H), 737-741 (m, 1H), 7.27-7.29 (m, 2H), 7.21-7.25 (m, 2H), 7.10 (t, J=7.48 Hz, 1H), 6.98 (s, 1H), Example 58C 6.70 (d. J=7.32 Hz, 1H), 6.93-6.95 (m, 2H), 6.07 (d. J=1.22 HZ, 1H), 5.92 (dd, J=6.71, 1.83 Hz, 1H), 3.69 (s.3H). MS 35 5-(2-methoxypyridin-4-yl)-2-methyl-6-(5-nitro-2- (DCI+) m/z. 372.2 (M+H)". phenoxyphenyl)pyridazin-3(2H)-one Example 56 Example 54B was prepared according to the procedure used for the preparation of Example 9B, substituting 2-methyl-5-(1-methyl-2-oxo-1,2-dihydropyridin-4- 40 Example 58B for Example 9A, to provide the title com yl)-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one pound. Example 56 was prepared according to the procedure used Example 58D for the preparation of Example 1A, substituting Example 55 for 6-chloropyridazin-3 (2H)-one, except that the crude prod 45 6-(5-amino-2-phenoxyphenyl)-5-(2-methoxypyridin uct was purified by reverse phase HPLC (C18, CHCN/ 4-yl)-2-methylpyridazin-3 (2H)-one water (0.1% TFA), 0-100%) to provide the title compound. H NMR (500 MHz, DMSO-d) & 7.58 (dd, J=7.63, 1.53 Hz, Example 58D was prepared according to the procedure 1H), 7.51 (d. J=7.02 Hz, 1H), 7.38-741 (m, 1H), 7.23-7.30 used for the preparation of Example 10, substituting (m, 3H), 7.08 (t, J–7.32 Hz, 1H), 6.98 (s, 1H), 6.74 (d. 50 Example 58D for Example 9B, to provide the title com J=7.32 Hz, 1H), 6.59-6.61 (m, 2H), 6.10 (d. J=1.83 Hz, 1H), pound. 5.94 (dd, J=6.71, 1.83 Hz, 1H), 3.70 (s, 3H), 3.35 (s, 3H). MS (DCI+) m/z 386.2 (M+H)". Example 58E

Example 57 55 N-3-4-(2-methoxypyridin-4-yl)-1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl)-4- 5-(2-methoxypyridin-4-yl)-2-methyl-6-(2-phenoxy phenoxyphenyl)methanesulfonamide phenyl)pyridazin-3 (2H)-one Example 58D was prepared according to the procedure Methanol (2 mL) was cooled to 0°C. To this solvent was 60 used for the preparation of Example 22, Substituting added sodium (0.0248 g, 1.08 mmol). All sodium was Example 58E for Example 20O, to provide the title com dissolved completely within 10 minutes. To this solution pound. "H NMR (500 MHz, DMSO-d) & 9.76 (s, 1H), 8.04 was added Example 54B (0.08 g., 0.216 mmol). The reaction (d. J=5.19 Hz, 1H), 7.43 (d. J=2.75 Hz, 1H), 7.19-7.24 (m, mixture was stirred at 60° C. for 10 hours. The solvent was 3H), 7.05 (t, J=7.32 Hz, 1H), 7.02 (s, 1H), 6.72 (dd, J=5.34, removed, and the residue was purified by reverse phase 65 1.37 Hz, 1H), 6.68 (d. J=8.85 Hz, 1H), 6.57 (s, 1H), 6.40 (d. HPLC (C18, CHCN/water (0.1%TFA), 0-100%) to provide J=7.63 Hz, 2H), 3.77 (s.3H), 3.70 (s, 3H), 2.99 (s.3H). MS the title compound. "H NMR (500 MHz, DMSO-d) & 8.03 (ESI+) m/z 479.0 (M+H)". US 9,561,231 B2 85 86 Example 59 (4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pip erazine for 1-methyl-3-(4-(4.4.5.5-tetramethyl-1,3,2-dioxa ethyl 3-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- borolan-2-yl)benzyl)piperazine, to provide the title dihydropyridazin-4-ylbenzoate compound as TFA salt. H NMR (500 MHz, DMSO-d) & 7.59 (dd, J=7.63, 1.83 Hz, 1H), 7.31-7.35 (m, 1H), 7.14-7.24 Example 18B (0.090 g, 0.5 mmol), 3-(ethoxycarbonyl) (m, 7H), 7.07 (t, J–7.48 Hz, 1H), 6.91 (s, 1H), 6.51 (d. phenylboronic acid (0.107 g., 0.55 mmol), Pd(PPh) (0.058 J=8.24 Hz, 1H), 6.31 (d. J=8.54 Hz, 2H), 3.71 (s.3H), 3.40 g, 0.05 mmol) and sodium carbonate (0.106 g, 1.0 mmol) (brs, 2H), 2.96 (brs, 4H), 2.77 (s.3H). MS (ESI) m/z 467.1 were combined in toluene (4 mL), ethanol (1 mL) and water (M+H)". (1 mL) and the mixture was degassed and left under nitro gen. The reaction mixture was heated at 90° C. for 2 hours, 10 Example 62 and then cooled to room temperature. To this solution was he added 2-phenoxyphenylboronic acid (0.150 g, 1.4 mmol). N-3-(1-methyl-4-4-(4-methylpiperazin-1-yl) The reaction mixture was heated under reflux overnight. methylphenyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- After cooling to room temperature, the mixture was parti phenoxyphenylmethanesulfonamide tioned between ethyl acetate and water. The aqueous layer 15 was extracted with additional ethyl acetate twice. The com Example 62A bined organic layers were washed with brine, dried (MgSO), filtered and concentrated. The crude product was 6-chloro-2-methyl-5-(4-(4-methylpiperazin-1-yl) purified by flash chromatography (silica gel, 20-50% ethyl methyl)phenyl)pyridazin-3 (2H)-one acetate in hexanes) to provide crude material, which was further purified by reverse HPLC (C18, CHCN/water (0.1% Example 62A was prepared according to the procedure TFA), 0-100%) to afford 0.11 g (52%) of the title compound. used for the preparation of Example 9A, substituting "H NMR (500 MHz, DMSO-d) & 7.90-7.92 (m, 1H), 7.67 Example 18B for Example 1A, and substituting 1-methyl (s, 1H), 7.61 (dd, J=7.63, 1.83 Hz, 1H), 7.40-746 (m, 2H), 4-(4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) 7.19-7.24 (m, 3H), 7.32-7.35 (m, 1H), 7.17-7.23 (m, 3H), 25 7.03 (t, J=7.32 Hz, 1H), 7.00 (s, 1H), 6.56 (d. J=8.24 Hz, piperazine for 2-fluoro-5-nitrophenylboronic acid, respec 1H), 6.32 (d. J=7.63 Hz, 2H), 4.21 (q, J=7.12 Hz, 2H), 3.73 tively, to provide the title compound. (s, 3H), 1.23 (t, J=7.02 Hz, 3H). MS (DCI+) m/z 427.1 (M+H)". Example 62B Example 60 30 6-(2-fluoro-5-nitrophenyl)-2-methyl-5-(4-((4-meth ylpiperazin-1-yl)methyl)phenyl)pyridazin-3 (2H)-one 2-methyl-5-3-(4-methylpiperazin-1-yl)methyl phenyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one Example 62B was prepared according to the procedure used for the preparation of Example 9A, substituting Syntheses were performed using a Personal Chemistry 35 Example 62A for Example 1A, to provide the title com Ermy's optimizer microwave. Each microwave tube was pound. charged with a stir bar and 0.1 equivalent of PdCl2(PPh.) (15 mg). In the microwave tube, a solution of Example 18B Example 62C (39 mg, 0.22 mmol) dissolved in dioxane (1.0 mL) was added, followed by the addition of 1-methyl-4-(3-(4.4.5.5- 40 2-methyl-5-(4-(4-methylpiperazin-1-yl)methyl)phe tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (82 nyl)-6-(5-nitro-2-phenoxyphenyl)pyridazin-3(2H)- mg, 0.26 mmol) in dioxane (0.7 mL). Then, 434 uL of 1M O aqueous Solution of CSCO was added. The resulting mix ture was heated in the microwave for 1800 seconds at 150° Example 62C was prepared according to the procedure C. In the microwave vial with the previous mixture a 45 used for the preparation of Example 9B, substituting Solution of 2-phenoxyphenylboronic acid (26 mg, 0.12 Example 62B for Example 9A, to provide the title com mmol) in dioxane (0.5 mL), was added, along with 0.1 pound. equivalent of PdCl2(PPh) (9 mg) and 246 uL of 1M aqueous Solution of CSCO. This was capped and placed Example 62D back in the microwave to heat for 1800 seconds at 150° C. 50 The reaction mixture was filtered, and concentrated to 6-(5-amino-2-phenoxyphenyl)-2-methyl-5-(4-((4- dryness. The residues were dissolved in 1:1 DMSO/MeOH. methylpiperazin-1-yl)methyl)phenyl)pyridazin-3 Purification by reverse phase HPLC (C18, CHCN/water (2H)-one (0.1% TFA), 0-100% gradient) provided the title compound as TFA salt. "H NMR (500 MHz, DMSO-d) & 7.67 (dd, 55 Example 58D was prepared according to the procedure J=7.63, 1.53 Hz, 1H), 7.29-7.39 (m, 4H), 7.22-7.26 (m, 3H), used for the preparation of Example 10, substituting 7.01-7.15 (m, 3H), 6.94 (s, 1H), 6.91 (s, 1H), 6.54 (d. J=7.93 Example 62D for Example 9B, to provide the title com HZ, 1H), 6.32 (d. J=7.63 Hz, 1H), 3.73 (s.3H), 3.52 (s. 2H), pound. 2.77 (s, 3H). MS (ESI) m/z 467 (M+H)". 60 Example 62E Example 61 N-3-(1-methyl-4-4-(4-methylpiperazin-1-yl) 2-methyl-5-4-(4-methylpiperazin-1-yl)methyl methylphenyl-6-oxo-1,6-dihydropyridazin-3-yl)-4- phenyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one phenoxyphenylmethanesulfonamide 65 Example 61 was prepared according to the procedure used Example 62E was prepared according to the procedure for the preparation of Example 60, substituting 1-methyl-4- used for the preparation of Example 22, Substituting US 9,561,231 B2 87 88 Example 62D for Example 20O, to provide the title com nitrogen for 15 minutes and heated at 90° C. for 16 hours pound. 'H NMR (500 MHz, DMSO-d) & 9.74 (s, 1H), 7.38 under nitrogen. The reaction mixture was partitioned (d. J=2.75 Hz, 1H), 7.14-7.25 (m, 7H), 7.05 (t, J=7.32 Hz, between ethyl acetate and water. The ethyl acetate layer was 1H), 6.91 (s, 1H), 6.59 (d. J=8.85 Hz, 1H), 6.36 (d. J=7.63 washed with brine, dried (NaSO), treated with mercapto Hz, 2H), 4.21 (q, J–7.12 Hz, 2H), 3.69 (s.3H), 3.64 (s. 2H), propyl silica gel for 30 minutes, filtered and concentrated. 2.97 (brs, 4H), 2.77 (s.3H). MS (ESI+) m/z 560.2 (M+H)". Purification by chromatography (silica gel, 20-70% ethyl acetate in hexane) afforded the title compound (1.2g, 64%). Example 63 MS (APCI+) m/z 249 (M+H)". N-3-1-methyl-4-(4-methylphenyl)-6-oxo-1,6-dihy 10 Example 65B dropyridazin-3-yl)-4- phenoxyphenyl)methanesulfonamide 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy dropyridazin-4-ylbenzaldehyde Example 63A 15 The product from Example 65A (0.249 g, 1.0 mmol), 6-(5-amino-2-phenoxyphenyl)-2-methyl-5-p- 2-phenoxyphenylboronic acid (0.257 g, 1.2 mmol), bis(tri tolylpyridazin-3 (2H)-one phenylphosphine)palladium(II)chloride (0.035 g, 0.05 mmol) and sodium carbonate (1.0 mL, 2.0 mmol) were The title compound was isolated as a by-product in combined in 1,2-dimethoxyethane (4.0 mL), sparged with preparation of Example 62D. argon for 15 minutes and heated at 120° C. for 60 minutes under argon. The mixture was cooled and partitioned Example 63B between ethyl acetate and water. The organic layer was washed with brine, dried (NaSO), treated with mercapto N-3-1-methyl-4-(4-methylphenyl)-6-oxo-1,6-dihy propyl silica gel for twenty minutes, filtered and concen dropyridazin-3-yl)-4- 25 trated. Purification by chromatography (silica gel, 0-70% phenoxyphenyl)methanesulfonamide ethyl acetate in hexane) afforded the title compound (0.38g. 94%). "H NMR (300 MHz, DMSO-d) & 9.98 (d. 1H) 7.76 Example 63B was prepared according to the procedure (d. J=8.48 Hz, 2H) 7.62 (dd, J=746, 1.70 Hz, 1H) 7.34-7.39 used for the preparation of Example 22, Substituting (m, 3H) 7.15-7.26 (m, 3H) 7.05 (d. J=7.12 Hz, 1H) 7.01 (s, Example 63A for Example 20O, to provide the title com 30 1H) 6.56 (d. J=8.14 Hz, 1H) 6.32 (d. J=7.80 Hz, 2H) pound. 'H NMR (500 MHz, DMSO-d) & 9.72 (s, 1H), 7.36 3.71-3.73 (m, 3H). MS (ESI+) m/z 383 (M+H)". (d. J=2.75 Hz, 1H), 7.16-7.22 (m, 3H), 7.02-7.08 (m, 5H), 6.87 (s, 1H), 6.61 (d. J=8.85 Hz, 1H), 6.35 (d. J=7.63 Hz, Example 66 2H), 3.86 (s.3H), 2.95 (s. 2H), 2.29 (s.3H). MS (ESI+) m/z 462.1 (M+H)". 35 2-methyl-5-4-(morpholin-4-ylmethyl)phenyl]-6-(2- phenoxyphenyl)pyridazin-3(2H)-one Example 64 A mixture of the product from Example 65B (0.048 g. 5-(3-amino-4-methylphenyl)-2-methyl-6-(2-phe 0.125 mmol), morpholine (0.016 mL, 0.188 mmol) and noxyphenyl)pyridazin-3(2H)-one 40 acetic acid (7.16 ul, 0.125 mmol) in dichloroethane (0.625 mL) was treated with sodium triacetoxyborohydride (0.034 Example 64 was prepared according to the procedure used g, 0.163 mmol) and stirred for two hours. The reaction for the preparation of Example 60, substituting 3-amino-4- mixture was partitioned between ethyl acetate and 5% methylphenylboronic acid for 1-methyl-3-(4-(4,4,5,5-te aqueous Sodium bicarbonate. The organic layer was sepa tramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, to 45 rated, dried (NaSO) and concentrated. Purification by provide the title compound as TFA salt. H NMR (500 MHz, reverse phase HPLC (C18, 0-100% CHCN/water (0.1% DMSO-d) & 7.57 (dd, J=7.63, 1.53 Hz, 1H) 733-7.40 (m, TFA)) afforded the title compound as the trifluoroacetic acid 1H) 7.20-7.26 (m,3H) 7.00-7.11 (m, 2H) 6.90 (d. J=1.53 Hz, salt (0.050 g., 70%). "H NMR (300 MHz, DMSO-d) & 9.87 1H) 6.86 (s, 1H) 6.68 (dd, J=7.93, 1.53 Hz, 1H) 6.59 (d. (s, 1H) 7.61 (dd, J=7.46, 1.70 Hz, 1H) 7.34-7.40 (m, 3H) J=7.63 Hz, 1H) 6.38 (d. J=7.63 Hz, 2H)3.70 (s.3H) 2.19 (s. 50 7.17-729 (m, 5H) 7.07 (t, J=746 Hz, 1H) 6.94 (s, 1H) 6.55 3H). MS (ESI) m/z 384 (M+H)". (d. J=8.14 Hz, 1H) 6.35 (d. J–7.80 Hz, 2H) 4.33 (s. 2H) 3.90-4.04 (m, 2H)3.71 (s, 3H)3.55-3.67 (m, 2H)3.02-3.27 Example 65 (m, 4H). MS (ESI+) m/z 454 (M+H)".

4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy 55 Example 67 dropyridazin-4-ylbenzaldehyde 2-methyl-6-(2-phenoxyphenyl)-5-4-(piperidin-1- Example 65A ylmethyl)phenylpyridazin-3 (2H)-one

4-(3-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4- 60 Example 67 was prepared according to the procedure of yl)benzaldehyde Example 66 substituting piperidine for morpholine. Purifi cation by reverse phase HPLC (C18, 0-100% CHCN/water 4-formylphenylboronic acid (1.18 g, 7.88 mmol), (0.1% TFA)) afforded the title compound as the trifluoro Example 18B (1.34g, 7.5 mmol), bis(triphenylphosphine) acetic acid salt (0.050 g, 71%). H NMR (300 MHz, palladium(II) chloride (0.26 g., 0.375 mmol) and sodium 65 DMSO-d) & 9.30 (s, 1H) 7.61 (dd, J–7.80, 1.70 Hz, 1H) carbonate (7.50 mL, 15.00 mmol) were combined in 1,2- 7.31-7.40 (m, 3H) 7.18-728 (m, 5H) 7.08 (t, J=7.46 Hz, 1H) dimethoxyethane (18 mL) and water (12 mL), sparged with 6.95 (s, 1H) 6.53 (d. J=8.14 Hz, 1H) 6.36 (d. J=746 Hz, 2H) US 9,561,231 B2 89 90 4.27 (d. J=5.09 Hz, 2H)3.75-3.77 (s, 3H) 3.28 (d. J=11.87 6.32 (d. J=7.54 Hz, 2H)3.82 (s, 1H)3.71 (s.3H)3.19 (s, 4H) Hz, 2H)2.81-2.95 (m, 2H) 1.75-1.90 (m, 2H) 1.50-1.74 (m, 2.80 (s, 4H). MS (ESI+) m/z 453 (M+H)". 3H) 1.26-1.45 (m, 1H). MS (ESI+) m/z 452 (M+H)". Example 71 Example 68 2-methyl-6-(2-phenoxyphenyl)-5-4-(pyrrolidin-1- 2-methyl-5-4-(4-methylpiperidin-1-yl)methyl ylmethyl)phenylpyridazin-3 (2H)-one phenyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one Example 71 was prepared according to the procedure of Example 68 was prepared according to the procedure of 10 Example 66 substituting pyrrolidine for morpholine. Puri Example 66 substituting 4-methylpiperidine for morpholine. fication by reverse phase HPLC (C18, 0-100% CHCN/ Purification by reverse phase HPLC (C18, 0-100% CHCN/ water (0.1% ammonium acetate)) afforded the title com water (0.1% TFA)) afforded the title compound as the pound (0.048 g., 87%). H NMR (300 MHz, DMSO-d) & trifluoroacetic acid salt (0.050 g. 69%). "H NMR (300 MHz, 9.27 (s, 1H) 7.58 (dd, J=746, 1.70 Hz, 1H) 7.27-7.37 (m, DMSO-d) & 9.24 (s, 1H) 7.61 (dd, J–7.54, 1.59 Hz, 1H) 15 1H) 7.15-7.23 (m, 5H) 7.04-7.12 (m, 3H) 6.90 (s, 1H) 6.46 7.31-742 (m, 3H) 7.18-7.28 (m, 5H) 7.08 (t, J=7.34 Hz, 1H) (d. J=746 Hz, 1H) 6.28 (d. J=7.46 Hz, 2H, 3.71 (s. 2H)3.55 6.95 (s, 1H) 6.53 (d. J=8.33 Hz, 1H) 6.35 (d. J=7.54 Hz, 2H) (s, 3H)2.42 (s, 4H) 1.67-1.74 (m, 4H). MS (ESI+) m/z 438 4.26 (d. J=4.76 Hz, 2H)3.72 (s, 3H) 3.29 (d. J=11.90 Hz, (M+H)". 2H)2.83-3.00 (m, 2H) 1.18-187(m, 5H) 0.91 (d. J=6.35 Hz, Example 72 3H). MS (ESI+) m/z 466 (M+H)". 5-4-(1-hydroxyethyl)phenyl)-2-methyl-6-(2-phe Example 69 noxyphenyl)pyridazin-3(2H)-one 5-4-(diethylamino)methylphenyl)-2-methyl-6-(2- 25 To a solution of the product of Example 65B (0.09 g, phenoxyphenyl)pyridazin-3(2H)-one 0.235 mmol) in tetrahydrofuran (10 mL) was added drop wise methylmagnesium bromide (0.26 mL of a 1M solution Example 69 was prepared according to the procedure of in tetrahydrofuran, 0.26 mmol). The reaction mixture was Example 66 substituting diethylamine for morpholine. Puri stirred at ambient temperature for 3 hours under nitrogen fication by reverse phase HPLC (C18, 0-100% CHCN/ 30 gas. The reaction mixture was quenched by the addition of water (0.1% TFA)) afforded the title compound as the ethyl acetate and then washed with Saturated aqueous trifluoroacetic acid salt (0.048 g. 69%). "H NMR (300 MHz, sodium chloride solution. The organic phase was dried with DMSO-d) & 9.27 (s, 1H) 7.60 (dd, J–7.54, 1.98 Hz, 1H) anhydrous NaSO and filtered. The solvent was evaporated 7.30-7.44 (m, 3H) 7.18-7.29 (m, 5H) 7.08 (t, J=7.34 Hz, 1H) under reduced pressure, and the resulting residue was puri 6.96 (s, 1H) 6.54 (d. J=7.93 Hz, 1H) 6.37 (d. J=7.54 Hz, 2H) 35 fied by flash chromatography (silica gel. 0-100% ethyl 4.30 (d. J=5.16 Hz, 2H)3.71 (s.3H)3.00-3.09 (m, 4H) 1.21 acetate/hexane gradient) to provide the title compound (t, J=7.14 Hz, 6H). MS (ESI+) m/z 440 (M+H)". (0.030g, 18% yield). "H NMR (400 MHz, DMSO-d) & 7.53 (d. J=7.6 Hz, 1H), 7.26-7.01 (m, 9H), 6.88 (s, 1H), 6.53 (d. Example 70 J=7.6 Hz, 1H), 6.29 (d. J=7.6 Hz, 2H), 4.88 (q, J=6.4 Hz, 40 1H), 3.87 (s, 3H), 1.50 (d. J=6.4 Hz, 3H). MS (ESI+): m/z 2-methyl-6-(2-phenoxyphenyl)-5-4-(piperazin-1- 399.2 (M+H). ylmethyl)phenylpyridazin-3 (2H)-one Example 73 Example 70A 45 5-4-(1-hydroxy-2-methylpropyl)phenyl)-2-methyl tert-butyl 4-(4-(1-methyl-6-oxo-3-(2-phenoxyphe 6-(2-phenoxyphenyl)pyridazin-3 (2H)-one nyl)-1,6-dihydropyridazin-4-yl)benzyl)piperazine-1- carboxylate Example 73 was prepared according to the procedure used for the preparation of Example 72, Substituting isopropyl Example 70A was prepared according to the procedure of 50 magnesium bromide for methylmagnesium bromide, to pro Example 66 substituting 1-Boc-piperazine for morpholine vide the title compound. "H NMR (400 MHz, DMSO-d) & and used in the next step without further purification (0.052 7.57 (dd, J=7.6, 1.6, HZ, 1H), 7.30 (t, J=6.4 Hz, 1H), g, 75%). 723-7.16 (m, 5H), 7.11-7.08 (m, 3H), 6.90 (s, 1H), 6.44 (d. J=8.4 Hz, 1H), 6.31 (d. J=7.6 Hz, 2H), 5.14 (d. J–4.8 Hz, Example 70B 55 1H), 4.24 (t, J–4.2 Hz, 1H), 3.71 (s.3H), 1.79 (q, J–6.4 Hz, 1H), 0.83 (d. J=6.4 Hz, 3H), 0.77 (d. J=6.8 Hz, 3H). MS 2-methyl-6-(2-phenoxyphenyl)-5-4-(piperazin-1- (ESI+) m/z 427.1 (M+H). ylmethyl)phenylpyridazin-3 (2H)-one Example 74 The product from Example 70A (0.052 g, 0.094 mmol) 60 and trifluoroacetic acid (0.5 mL) in dichloromethane (1 mL) 5-(4-cyclopentyl(hydroxy)methylphenyl-2- was stirred for 1 h and concentrated. Purification by reverse methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one phase HPLC (C18, 0-100% CHCN/water (0.1% TFA)) afforded the title compound as the bis-trifluoroacetic acid Example 74 was prepared according to the procedure used salt (0.024g, 37%). "H NMR (300 MHz, DMSO-d) & 8.70 65 for the preparation of Example 72, Substituting cyclopen (s. 2H) 7.59 (dd, J=7.54, 1.59 Hz, 1H) 7.14-7.38 (m, 8H) tylmagnesium bromide for methylmagnesium bromide, to 7.06 (t, J=7.34 Hz, 1H) 6.90 (s, 1H) 6.53 (d. J=8.33 Hz, 1H) provide the title compound. "H NMR (400 MHz, CDC1) & US 9,561,231 B2 91 92 7.51 (dd, J=7.6, 1.6 Hz, 1H), 7.26-7.02 (m, 8H), 6.90 (s, 1H), Example 78 6.52 (d. J=7.6 Hz, 1H), 6.35 (d. J=7.6 Hz, 2H), 4.39 (d. J=7.6 HZ, 1H), 3.86 (s.3H), 2.22-2.16 (m, 1H), 1.87-1.82 (m, 2H), 5-4-(methoxymethyl)phenyl)-2-methyl-6-(2-phe 1.65-141 (m, 5H), 1.19-1.14 (m. 1H). MS (ESI) m/z 453.1 noxyphenyl)pyridazin-3(2H)-one (M+H). Example 78A Example 75 6-chloro-5-(4-(methoxymethyl)phenyl)-2-methyl pyridazin-3 (2H)-one 5-4-(1-hydroxypropyl)phenyl-2-methyl-6-(2-phe 10 noxyphenyl)pyridazin-3(2H)-one A mixture of Example 18B (121 mg, 0.726 mmol), 4-(methoxymethyl)phenylboronic acid, (100 mg 0.559 mmol), Pd(Ph-P) (32 mg, 0.028 mmol) and sodium car Example 75 was prepared according to the procedure used bonate (118 mg, 1.12 mmol) in toluene (4 mL), ethanol (1 for the preparation of Example 72, Substituting ethylmag 15 mL) and water (1 mL) was stirred at 85°C. for 16 hours. The nesium bromide for methylmagnesium bromide, to provide reaction mixture was concentrated and purified by prepara the title compound. "H NMR (400 MHz, DMSO-d) & 7.58 tory-thin layer chromatography (silica, 3:1 petroleum ether/ (dd, J-7.6., 1.9 HZ, 1H), 7.29 (dd, J=7.6, 1.6 Hz, 1H), ethyl acetate) to afford the title compound (107 mg, 0.404 7.22-7.18 (m, 5H), 7.10-7.07 (m, 3H), 6.90 (s, 1H), 6.43 (d. mmol, 72.4% yield). MS (ESI+) m/z. 265 (M+H)". J=8.0 Hz, 1H), 6.26 (d. J=8.0 Hz, 2H). 5.15 (brs, 1H), 4.43 (t, J=6.4 Hz, 1H), 3.71 (s.3H), 1.63-1.56 (dt, J–7.2, 14.0 Hz, Example 78B 2H), 0.85 (t, J–7.2 Hz, 3H). MS (ESI+) m/z 412.9 (M). 5-4-(methoxymethyl)phenyl)-2-methyl-6-(2-phe noxyphenyl)pyridazin-3(2H)-one Example 76 25 A mixture of 2-phenoxyphenylboronic acid (323 mg. 5-4-hydroxy(phenyl)methylphenyl-2-methyl-6- 1.511 mmol). Example 78A (100 mg 0.378 mmol), potas (2-phenoxyphenyl)pyridazin-3(2H)-one sium carbonate (157 mg, 1.133 mmol) and Pd(dppf)Cl. (30.9 mg, 0.038 mmol) in 1,4-dioxane (2 mL) and water (0.5 30 mL) was heated in a microwave reactor at 100° C. for 1 hour. Example 76 was prepared according to the procedure used The mixture was diluted with ethyl acetate (100 mL) and for the preparation of Example 72, Substituting phenylmag washed with brine (4x30 mL). The organic layer was dried nesium bromide for methylmagnesium bromide, to provide over anhydrous NaSO4, filtered, and concentrated in vacuo. the title compound. "H NMR (400 MHz, DMSO-d) & 7.57 The residue was purified by preparative-TLC (silica, 100/1 (d. J=6.0 Hz, 1H), 7.39 (d. J=7.2 Hz, 2H), 7.35-7.16 (m, 7H), 35 dichloromethane/methanol) followed by preparative HPLC 7.07 (d. J=8.0 Hz, 2H), 7.02-7.00 (m, 3H), 6.87 (s, 1H), 6.39 (C18, water (10 mM NHHCO)/acetonitrile, 35-75% gra (d. J–7.6 Hz, 1H), 6.16 (dd, J=6.4, 2.4 Hz, 2H), 5.92 (d. dient) to afford the title compound (73 mg, 49% yield). "H J=44 Hz, 1H), 5.68 (d. J=4.0 Hz, 1H), 3.70 (s, 3H). MS NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 (s, 1H), (ESI) m/z 461.2 (M+H). 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 (m, 40 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 399 Example 77 (M+H)". Example 79 5-4-(1-hydroxybut-3-en-1-yl)phenyl-2-methyl-6- 45 (2-phenoxyphenyl)pyridazin-3(2H)-one 5-4-(hydroxymethyl)phenyl-2-methyl-6-(2-phe noxyphenyl)pyridazin-3(2H)-one To a solution of the product of Example 65B (0.2g, 0.523 mmol) in dimethylformamide (10 mL) was added indium Example 79A (0.523 mmol, 0.060 g), and to the mixture was added 50 dropwise 3-bromoprop-1-ene (0.070 g., 0.575 mmol). The 6-chloro-5-(4-(hydroxymethyl)phenyl)-2-methyl reaction mixture was stirred at ambient temperature for 2 pyridazin-3 (2H)-one days under nitrogen gas. The reaction mixture was quenched by the addition of ethyl acetate and then washed with Example 79A was prepared according to the procedure saturated aqueous sodium chloride solution. The organic 55 used for the preparation of Example 78A, substituting 4-(hy phase was dried with anhydrous NaSO and filtered. The droxymethyl)phenylboronic acid for 4-(methoxymethyl) Solvent was evaporated under reduced pressure, and the phenylboronic acid, to provide the title compound. resulting residue was purified by reverse phase HPLC (C18, Example 79B CHCN/water (10 mM NHCO), 35-7.5%) to provide the 60 title compound (0.30 g., 39% yield). H NMR (400 MHz, 5-4-(hydroxymethyl)phenyl-2-methyl-6-(2-phe DMSO-d) & 7.57 (d. J–5.6 Hz, 1H), 7.32 (t, J=6.8 Hz, 1H), noxyphenyl)pyridazin-3(2H)-one 7.22-7.13 (m, 5H), 7.11-7.06 (m, 3H), 6.89 (s, 1H), 6.47 (d. J=5.6 Hz, 1H), 6.27 (d. J=8.0 Hz, 2H), 5.78-5.74 (m, 1H), Example 79B was prepared according to the procedure 5.29 (d. J–4.8 Hz, 1H), 5.04-5.00 (m, 2H), 4.58-4.56 (m, 65 used for the preparation of Example 78B, substituting 1H), 3.71 (s.3H), 2.38-2.35 (m, 2H). MS (ESI+) m/Z 425.2 Example 79A for Example 78A, to provide the title com (M+H). pound. 'H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 US 9,561,231 B2 93 94 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 sium carbonate (127 mg, 0.921 mmol) and Pd(dppf)Cl. (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), (25.1 mg, 0.031 mmol) in dioxane (3 mL) and water (0.75 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 385 mL) was heated under microwave conditions at 130° C. for (M+H)". 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (2x10 mL). The organic Example 80 layer was dried over anhydrous NaSO filtered, and con centrated under reduced pressure. The residue was purified 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy by flash chromatography (silica gel, 6:1 to 3:1 gradient, dropyridaZin-4-ylbenzyl acetate petroleum ether?ethyl acetate) to afford the title compound 10 (0.070 g, 47% yield). "H NMR (400 MHz, CDC1) & 7.42 (d. Example 80A J=7.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.18 (t, J–7.2 Hz, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.87 (t, J–7.2 Hz, 3H), 6.73 (s, 1H), 4-(3-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4- 5.56 (s, 1H), 3.81-3.77 (m, 5H), 3.38 (s. 2H), 2.09 (s. 2H), yl)benzyl acetate 1.46 (s, 9H). MS (ESI+) m/z 460.0 (M+H)". 15 Example 80A was prepared according to the procedure Example 82 used for the preparation of Example 78A, substituting 4-(ac etoxymethyl)phenylboronic acid for 4-(methoxymethyl) 2-methyl-6-(2-phenoxyphenyl)-5-(1,2,3,6-tetrahy phenylboronic acid, to provide the title compound. dropyridin-4-yl)pyridazin-3(2H)-one Example 80B Example 81B (0.3 g, 0.650 mmol) was dissolved in the solution of HCl in dioxane (2M, 10 mL) and the mixture was 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy stirred at room temperature for 2 hours. The solvent was dropyridaZin-4-ylbenzyl acetate evaporated under reduced pressure. The crude material was 25 purified via flash chromatography (Redi-Sep C-18 column, Example 80B was prepared according to the procedure 0-100% acetonitrile/Water (NHOAc buffer) to provide the used for the preparation of Example 78B, substituting title compound. "H NMR (400 MHz. CDOD) & 7.51-7.44 Example 80A for Example 78A, to provide the title com (m. 2H), 7.33-7.26 (m, 3H), 7.08 (t, J–7.2 Hz, 1H), 7.01 (d. pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 J=8.4 Hz, 1H), 6.91-6.89 (m, 2H), 6.81 (s, 1H), 5.69 (s, 1H), (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 30 3.72 (s, 3H), 3.39-3.38 (m, 2H), 2.94 (t, J=5.6 Hz, 2H), (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 2.24-2.23 (m, 2H). MS (ESI+) m/z 360.1 (M+H)". 2.25 (s, 3H), 2.04 (s, 3H), 2.03 (s.3H). MS (ESI+) m/z 427 (M+H)". Example 83 Example 81 35 2-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one tert-butyl 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)- 1,6-dihydropyridazin-4-yl)-3,6-dihydropyridine-1 Sodium cyanoborohydride (0.027 g., 0.422 mmol) was (2H)-carboxylate added to a solution of Example 82 (0.070 g, 0.18 mmol), 40 formaldehyde (37% solution) (0.131 mL, 1.759 mmol) and Example 81A acetic acid (0.013 mL, 0.229 mmol) in methanol (2 mL) and the reaction mixture was stirred at ambient temperature for tert-butyl 4-(3-chloro-1-methyl-6-oxo-1,6-dihydro 16 hours. The reaction mixture was neutralized with aqueous pyridazin-4-yl)-5,6-dihydropyridine-1 (2H)-carboxy saturated aqueous sodium bicarbonate Solution, and metha late 45 nol was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2x25 A mixture of tert-butyl 4-(4.4.5.5-tetramethyl-1,3,2-di mL). The combined organic layers were combined, dried oxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate over anhydrous NaSO filtered, and concentrated under (1.73 g, 5.59 mmol), 5,6-dichloro-2-methylpyridazin-3 (2H)- reduced pressure. The crude product was purified by pre one (1.00 g, 5.59 mmol), Pd(PhP) (0.323 g, 0.279 mmol), 50 parative-TLC (silica, 15:1 CHCl/Me?oH) to provide the and Sodium carbonate (1.18 g., 11.2 mmol) in toluene (40 title compound. 'H NMR (400 MHz, CDOD) & 7.37-7.31 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° (m. 2H), 7.21-7.12 (m, 3H), 6.96 (t, J–7.2 Hz, 1H), 6.85 (d. C. for 16 hours. The reaction mixture was diluted with ethyl J=8.4 Hz, 1H), 6.80-6.77 (m, 2H), 6.68 (s, 1H), 5.52-5.51 acetate (10 mL), filtered through Celite and concentrated (m. 1H), 3.61 (s, 3H), 2.82-2.81 (m, 2H), 2.38 (t, J=5.6 Hz, under reduced pressure. The resulting residue was purified 55 2H), 2.19 (s.3H), 2.15-2.14 (m, 2H). MS (ESI+) m/z. 373.9 by flash chromatography (silica gel. 2:1, petroleum ether/ (M+H)". ethyl acetate) to afford the title compound (1.4 g 74% yield). Example 84

Example 81B 60 5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2- methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one tert-butyl 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)- 1,6-dihydropyridazin-4-yl)-3,6-dihydropyridine-1 Acetyl chloride (0.021 g, 0.264 mmol) was added to a (2H)-carboxylate solution of Example 82 (0.070 g., 0.18 mmol) and triethyl 65 amine (0.049 mL, 0.35 mmol) in tetrahydrofuran (2 mL). A mixture of 2-phenoxyphenylboronic acid (197 mg, The reaction mixture was stirred at ambient temperature for 0.921 mmol). Example 81A (100 mg, 0.307 mmol), potas 16 hours. The crude reaction mixture was diluted with ethyl US 9,561,231 B2 95 96 acetate (20 mL) and washed with water (15 mL) and brine Example 88 (15 mL), filtered and concentrated. The crude residue was purified by preparative-TLC (silica gel. 20:1 dichlorometh 2-methyl-5-(1-methylpiperidin-4-yl)-6-(2-phenoxy ane/methanol) to afford the title compound. H NMR (400 phenyl)pyridazin-3 (2H)-one MHz, CDC1,) & 7.45-7.27 (m, 4H), 7.20 (t, J–7.2 Hz, 1H), 7.08 (d. J–7.2 Hz, 1H), 6.92-6.83 (m, 3H), 6.74 (s, 1H), Sodium cyanoborohydride (0.027 g., 0.422 mmol) was 5,60-5.55 (m, 1H), 3.99-3.98 (m. 1H), 3.86-3.85 (m, 1H), added to a solution of Example 87 (0.070 g, 0.18 mmol), 3.78-3.77 (m, 3H), 3.60-3.57 (m, 1H), 3.40 (t, J=5.6 Hz, formaldehyde (37% solution) (0.131 mL, 1.759 mmol) and 1H), 2.15-2.13 (m, 2H), 2.06-2.05 (m, 3H). MS (ESI+) m/z acetic acid (0.013 mL, 0.229 mmol) in methanol (2 mL) and 462.0 (M+H)". 10 the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was neutralized with aqueous Example 85 saturated Sodium bicarbonate solution, and methanol was evaporated under reduced pressure. The residue was diluted 2-methyl-5-1-(methylsulfonyl)-1,2,3,6-tetrahydro with water and extracted with ethyl acetate (2x25 mL). The pyridin-4-yl)-6-(2-phenoxyphenyl)pyridazin-3 (2H)- 15 combined organic layers were dried over anhydrous O Na2SO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica, Methanesulfonyl chloride (0.026 g., 0.226 mmol) was 15:1 dichloromethane/methanol) to afford the title com added to a solution of Example 82 (0.06 g., 0.15 mmol) and pound (38 mg, 57.5% yield). H NMR (400 MHz. CDOD) triethylamine (0.042 mL, 0.30 mmol) in tetrahydrofuran (2 & 7.52-742 (m, 2H), 7.35-7.27 (m, 3H), 7.12-7.08 (m. 1H), mL). The reaction mixture was stirred at ambient tempera 7.05-7.03 (m, 1H), 6.92-6.88 (m, 2H), 6.87 (s, 1H), 3.71 (s, ture for 16 h. The crude reaction mixture was diluted with 3H), 2.99-2.87 (n, 2H), 2.48-2.41 (m, 1H), 2.29 (s, 3H), ethyl acetate (20 mL), washed with water (15 mL) and brine 2.00-1.48 (m, 6H). MS (ESI+) m/z. 376.0 (M+H)". (15 mL), filtered and concentrated. The crude material was 25 purified by preparative TLC (silica gel. 20:1 dichlorometh Example 89 ane/methanol) to afford the title compound. H NMR (400 MHz, CDC1) & 743-7.27 (m, 4H), 7.21-7.17 (m, 1H, 7.09 5-(1-acetylpiperidin-4-yl)-2-methyl-6-(2-phenoxy (t, J=7.6 Hz, 1H), 6.92-6.89 (m, 3H), 6.73 (s, 1H), 5.60-5.59 phenyl)pyridazin-3 (2H)-one (m. 1H), 3.78 (s.3H), 3.70–3.69 (m, 2H), 3.27 (t, J=5.6 Hz, 30 2H), 2.76 (s.3H), 2.23-2.22 (m, 2H). MS (ESI+) m/z 438.0 Acetyl chloride (0.021 g, 0.264 mmol) was added to a (M+H)". solution of Example 87 (0.070 g, 0.18 mmol) and Et N Example 86 (0.049 mL, 0.352 mmol) in tetrahydrofuran (2 mL). The 35 reaction mixture was stirred at ambient temperature for 16 tert-butyl 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)- hours. The crude material was diluted with ethyl acetate (20 1,6-dihydropyridazin-4-yl)piperidine-1-carboxylate mL), washed with water (15 mL) and brine (15 mL), filtered and concentrated. The crude residue was purified by pre To a solution of Example 81B (0.090 g, 0.20 mmol) in parative TLC (silica gel. 20:1 dichloromethane/1 methanol) methanol (4 mL) was added Pd/C (0.021 g, 0.020 mmol) 40 to afford the title compound. (49 mg, 0.121 mmol. 69.0% under argon, and the reaction was degassed with hydrogen yield). "HNMR (400 MHz, CDOD) & 7.45-7.25 (m, 5H), three times and stirred under an atmosphere of hydrogen at 7.11-7.08 (m, 1H), 7.01 (d. J=8.0 Hz, 1H), 6.91-6.89 (m, 20° C. for 6 hours. The reaction mixture was filtered through 2H), 6.74 (s, 1H), 4.74-4.61 (m. 1H), 3.88-3.79 (m. 1H), Celite and concentrated to afford the title compound (0.09 g, 3.74 (s, 3H), 2.96-2.81 (m, 1H), 2.62-2.55 (m. 1H), 2.43 100% yield). "H NMR (400 MHz, CDC1,) & 743-7.27 (m, 45 2.25 (m. 1H), 2.07 (d. J=5.2 Hz, 3H), 1.93-1.83 (m, 1H), 4H), 7.24-7.21 (m, 1H), 7.09 (t, J=7.6 Hz, 1H), 6.98 (d. 1.63-1.53 (m, 2H), 1.32-1.24 (m, 1H). MS (ESI+) m/z 404.0 J=7.6 Hz, 1H), 6.91-6.89 (m, 2H), 6.76 (s, 1H), 4.15-4.07 (M+H)". (m. 2H), 3.74 (s.3H), 2.58–2.45 (m, 3H), 1.77-147 (m, 4H), 1.44 (s, 9H). MS (ESI+) m/z 406.0 (M+H)". Example 90 50 Example 87 2-methyl-5-1-(methylsulfonyl)piperidin-4-yl)-6-(2- phenoxyphenyl)pyridazin-3(2H)-one 2-methyl-6-(2-phenoxyphenyl)-5-(piperidin-4-yl) pyridazin-3 (2H)-one Methanesulfonyl chloride (0.026 g., 0.226 mmol) was 55 added to a solution of Example 87 (0.060 g, 0.15 mmol) and Example 86 (0.3 g, 0.650 mmol) was dissolved in the triethylamine (0.042 mL, 0.302 mmol) in tetrahydrofuran (2 solution of HCl in dioxane (2M, 10 mL) and the reaction mL). The reaction mixture was stirred at ambient tempera mixture was stirred at ambient temperature for 2 hours. The ture for 16 hours. The crude material was diluted with ethyl Solvent was evaporated under reduced pressure and the acetate (20 mL), washed with water (15 mL) and brine (15 residue was purified by flash chromatography (Redi-Sep 60 mL), filtered and concentrated. The crude material was C-18 column, 0-100% acetonitrile/water (NHOAc buffer) purified by preparative TLC (silica gel. 20:1 dichlorometh to provide the title compound. 'H NMR (400 MHz, CDC1) ane/methanol) to afford the title compound (46 mg, 69.4% & 7.52-743 (m, 2H), 7.35-7.27 (m, 3H), 7.10 (t, J=7.2 Hz, yield). H NMR (400 MHz, CDOD) & 7.46-7.44 (m, 1H), 1H), 7.04 (d. J=8.4 Hz, 1H), 6.93-6.91 (m, 2H), 6.87 (s, 1H), 7.38-7.36 (m, 1H), 7.32-7.23 (m, 3H), 7.09 (t, J=7.6 Hz, 3.71 (s, 3H), 3.35-3.32 (m, 1H), 3.16-3.06 (m, 2H), 2.64 65 1H), 7.02 (d. J=8.0 Hz, 1H), 6.89-6.87(m, 2H), 6.79 (s, 1H), 2.44 (m, 3H), 1.77-1.67 (m, 3H), 1.45-141 (m, 1H). MS 3.91-3.76 (m, 2H), 3.73 (s.3H), 2.76 (s, 3H), 2.50-2.42 (m, (ESI+) m/z. 362.0 (M+H)". 2H), 1.94-1.48 (m, 5H). MS (ESI+) m/z 440.0 (M+H)". US 9,561,231 B2 97 98 Example 91 4-benzylphenylboronic acid for 4-(methoxymethyl)phenyl boronic acid, to provide the title compound. 2-methyl-5-4-(5-methyl-1,3,4-oxadiazol-2-yl)phe nyl-6-(2-phenoxyphenyl)pyridazin-3(2H)-one Example 93B Example 91A 5-(4-benzylphenyl)-2-methyl-6-(2-phenoxyphenyl) pyridazin-3 (2H)-one 6-chloro-2-methyl-5-(4-(5-methyl-1,3,4-oxadiazol-2- yl)phenyl)pyridazin-3 (2H)-one Example 93B was prepared according to the procedure used for the preparation of Example 78B, substituting Example 91A was prepared according to the procedure 10 Example 93A for Example 78A, to provide the title com used for the preparation of Example 78A, substituting 4-(5- pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid for (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 4-(methoxymethyl)phenylboronic acid, to provide the title (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), compound. 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 445 Example 91B 15 (M+H)". 2-methyl-5-4-(5-methyl-1,3,4-oxadiazol-2-yl)phe Example 94 nyl-6-(2-phenoxyphenyl)pyridazin-3(2H)-one {4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy Example 91B was prepared according to the procedure dropyridazin-4-yl)phenyl)acetonitrile used for the preparation of Example 78B, substituting Example 91A for Example 78A, to provide the title com Example 94A pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 2-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 pyridazin-4-yl)phenyl)acetonitrile (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 25 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 437 Example 94A was prepared according to the procedure (M+H)". used for the preparation of Example 78A, substituting Example 92 4-(cyanomethyl)phenylboronic acid for 4-(methoxymethyl) phenylboronic acid, to provide the title compound. methyl 3-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)- 30 1,6-dihydropyridazin-4-yl)phenylpropanoate Example 94B Example 92A {4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6-dihy dropyridazin-4-yl)phenyl)acetonitrile methyl 3-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro 35 pyridaZin-4-yl)phenyl)propanoate Example 94B was prepared according to the procedure used for the preparation of Example 78B, substituting Example 92A was prepared according to the procedure Example 94A for Example 78A, to provide the title com used for the preparation of Example 78A, substituting 4-(3- pound. 'H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 methoxy-3-oxopropyl)phenylboronic acid for 40 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 4-(methoxymethyl)phenylboronic acid, to provide the title (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), compound. 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 394 Example 92B (M+H)". methyl 3-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)- 45 Example 95 1,6-dihydropyridazin-4-yl)phenylpropanoate 5-4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl-2- Example 92B was prepared according to the procedure methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one used for the preparation of Example 78B, substituting Example 92A for Example 78A, to provide the title com 50 Example 95A pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 6-chloro-5-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phe (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), nyl)-2-methylpyridazin-3 (2H)-one 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 441 (M+H)". 55 Example 95A was prepared according to the procedure Example 93 used for the preparation of Example 78A, substituting 4-(5. 6-dihydro-4H-1,3-oxazin-2-yl)phenylboronic acid for 5-(4-benzylphenyl)-2-methyl-6-(2-phenoxyphenyl) 4-(methoxymethyl)phenylboronic acid, to provide the title pyridazin-3 (2H)-one compound. 60 Example 93A Example 95B 5-(4-benzylphenyl)-6-chloro-2-methylpyridazin-3 5-4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl-2- (2H)-one methyl-6-(2-phenoxyphenyl)pyridazin-3 (2H)-one 65 Example 93A was prepared according to the procedure Example 95B was prepared according to the procedure used for the preparation of Example 78A, substituting used for the preparation of Example 78B, substituting US 9,561,231 B2 99 100 Example 95A for Example 78A, to provide the title com (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 441 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 (M+H)". (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 438 Example 98 (M+H)". Example 96 N-(4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- dihydropyridazin-4-yl)benzylmethanesulfonamide 2-methyl-5-4-(2-methylpropyl)phenyl]-6-(2-phe 10 noxyphenyl)pyridazin-3(2H)-one Example 98A

Example 96A N-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro 15 pyridazin-4-yl)benzyl)ethanesulfonamide 6-chloro-5-(4-isobutylphenyl)-2-methylpyridazin-3 (2H)-one Example 98A was prepared according to the procedure used for the preparation of Example 78A, substituting Example 96A was prepared according to the procedure 4-(ethylsulfonamidomethyl)phenylboronic acid for used for the preparation of Example 78A, substituting 4-(methoxymethyl)phenylboronic acid, to provide the title 4-isobutylphenylboronic acid for 4-(methoxymethyl)phe compound. nylboronic acid, to provide the title compound. Example 98B Example 96B 25 N-(4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- 2-methyl-5-4-(2-methylpropyl)phenyl]-6-(2-phe dihydropyridazin-4-yl)benzylmethanesulfonamide noxyphenyl)pyridazin-3(2H)-one 30 Example 98B was prepared according to the procedure Example 96B was prepared according to the procedure used for the preparation of Example 78B, substituting used for the preparation of Example 78B, Substituting Example 98A for Example 78A, to provide the title com Example 96A for Example 78A, to provide the title com pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 35 (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 462 2.25 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 411 (M+H)". (M+H)". Example 99 Example 97 40 ethyl-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- N-(4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- dihydropyridazin-4-yl)phenyl)acetate dihydropyridazin-4-yl)benzyl)acetamide 45 Example 97A Example 99A ethyl 2-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro N-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro pyridaZin-4-yl)benzyl)acetamide pyridaZin-4-yl)phenyl)acetate 50 Example 97A was prepared according to the procedure Example 99A was prepared according to the procedure used for the preparation of Example 78A, substituting 4-(2- used for the preparation of Example 78A, substituting 4-(ac ethoxy-2-oxoethyl)phenylboronic acid for 4-(methoxym etamidomethyl)phenylboronic acid for 4-(methoxymethyl) ethyl)phenylboronic acid, to provide the title compound. 55 phenylboronic acid, to provide the title compound. Example 97B Example 99E ethyl-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- N-(4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- dihydropyridazin-4-yl)phenyl)acetate 60 dihydropyridazin-4-yl)benzyl)acetamide Example 97B was prepared according to the procedure Example 99E3 was prepared according to the procedure used for the preparation of Example 78B, substituting used for the preparation of Example 78B, substituting Example 97A for Example 78A, to provide the title com 65 Example 99A for Example 78A, to provide the title com pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 US 9,561,231 B2 101 102 (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), 4-(methoxycarbonyl)phenylboronic acid in 1,4-dioxane for 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 426 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) (M+H)". acetamide, to provide the title compound. %). H NMR (500 MHz, DMSO-d/DO) & 7.81 (d. J=8.24 Hz, 2H) 7.62 (dd, Example 100 J=7.63, 1.53 Hz, 1H) 7.36-7.40 (m. 1H) 724-7.32 (m, 3H) N-(2-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- 7.20 (t, J=7.93 Hz, 2H) 7.06 (t, J–7.48 Hz, 1H) 7.01 (s, 1H) dihydropyridazin-4-yl)phenyl)ethyl)acetamide 6.58 (d. J=8.24 Hz, 1H) 6.32 (d. J=7.63 Hz, 2H)3.86 (s.3H) 3.74 (s, 3H) MS (ESI+) m/z 413.3 (M+H)". Example 100A 10 Example 103 N-(4-(3-chloro-1-methyl-6-oxo-1,6-dihydro pyridazin-4-yl)phenethyl)acetamide 2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(2-phe noxyphenyl)pyridazin-3(2H)-one Example 100A was prepared according to the procedure used for the preparation of Example 78A, substituting 4-(2- 15 Example 103 was prepared according to the procedure acetamidoethyl)phenylboronic acid for 4-(methoxymethyl) used for the preparation of Example 105, substituting phenylboronic acid, to provide the title compound. 1-methyl-4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole for N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Example 100B lan-2-yl)phenyl)acetamide, to provide the title compound. "H NMR (500 MHz, DMSO-d/DO) & 7.58 (s, 1H) 7.44 N-(2-4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- 7.54 (m, 2H) 7.26-7.33 (m, 3H) 7.08-7.13 (m, 1H) 7.00 (s, dihydropyridazin-4-yl)phenyl)ethyl)acetamide 1H)6.96 (s, 1H)6.79 (d. J=8.24 Hz, 1H)6.49-6.59 (m, 2H) Example 100B was prepared according to the procedure 3.75 (s, 3H)3.65 (s, 3H). MS (ESI+) m/z. 359.2 (M+H)". used for the preparation of Example 78B, substituting Example 100A for Example 78A, to provide the title com 25 Example 104 pound. "H NMR (400 MHz, DMSO-d) & 1.80 (s, 1H), 8.64 (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 2-methyl-6-(2-phenoxyphenyl)-5-(pyridin-4-yl) (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), pyridazin-3 (2H)-one 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z 440 30 Example 104 was prepared according to the procedure (M+H)". used for the preparation of Example 105, substituting pyri Example 101 din-4-yl-boronic acid for N-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetamide, to provide the title 5-4-(3-hydroxypropyl)phenyl-2-methyl-6-(2-phe compound. "H NMR (500 MHz, DMSO-d/DO) & 7.67 (dd. noxyphenyl)pyridazin-3(2H)-one 35 J=7.48, 1.68 Hz, 1H) 7.52 (d. J=6.10 Hz, 1H) 7.43 (d. J=6.41 Hz, 3H) 7.23-7.34 (m, 4H) 7.12 (s, 1H) 707-7.11 (m, 1H) Example 101A 6.63 (d. J=8.24 Hz, 1H) 6.38 (d. J=7.93 Hz, 2H)3.75 (s.3H) MS (ESI+) m/z. 356.2 (M+H)". 6-chloro-5-(4-(3-hydroxypropyl)phenyl)-2-methyl pyridazin-3 (2H)-one 40 Example 105 Example 101A was prepared according to the procedure N-(4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- used for the preparation of Example 78A, substituting 4-(3- dihydropyridazin-4-yl)phenyl)acetamide hydroxypropyl)phenylboronic acid for 4-(methoxymethyl) phenylboronic acid, to provide the title compound. 45 A 4 mL microwave vial was charged with a stir bar, a solution of Example 18B (40 mg, 0.22 mmol) in dioxane (1 Example 101B mL), a solution of N-(4-(4.4.5.5-tetramethyl-1,3,2-dioxa borolan-2-yl)phenyl)acetamide monomer (87 mg, 1.5 5-4-(3-hydroxypropyl)phenyl-2-methyl-6-(2-phe equivalents, 0.34 mmol) in dioxane (1 mL), cesium carbon noxyphenyl)pyridazin-3(2H)-one 50 ate (145 mg, 2 eq, 0.44 mmol) in water (0.45 mL) with Silicat resin (82 mg, 0.1 eq, 0.27 loading). This was placed Example 101B was prepared according to the procedure in parallel dual model microwave system Anton Parr and used for the preparation of Example 78B, substituting was allowed to heat at 135° C. for 30 minutes. Upon Example 101A for Example 78A, to provide the title com completion, the crude material was filtered, dried, and pound. "H NMR (400 MHz, DMSO-d) & 11.80 (s, 1H), 8.64 55 purified by reverse phase HPLC (C18, 0-100% CHCN/ (s, 1H), 8.63 (d. J–4.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.34-7.43 water (0.1% TFA)) to afford N-(4-(3-chloro-1-methyl-6- (m. 2H), 6.70 (brs, 1H), 6.25-6.28 (m, 1H), 3.46 (s, 3H), OXO-1,6-dihydropyridazin-4-yl)phenyl)acetamide interme 2.25 (s.3H), 2.04 (s, 3H), 2.03 (s, 3H). MS (ESI+) m/z. 413 diate (35 mg, 0.13 mmol) which was then dissolved in (M+H)". dioxane (1 mL) to which was added excess 2-pheoxyphenyl 60 boronic acid (45 mg, 1.6 equivalents, 0.20 mmol) in diox Example 102 ane, cesium carbonate (41 mg, 1 equivalent, 0.12 mmol) in water (0.130 mL) and with Silicat resin (93 mg 0.2 eq, 0.27 methyl 4-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- loading). This was again placed in parallel dual model dihydropyridazin-4-ylbenzoate microwave system Anton Parr and was allowed to heat at 65 135° C. for 30 minutes. Upon completion, the crude material Example 102 was prepared according to the procedure was filtered, dried, and purified by reverse phase HPLC used for the preparation of Example 105, substituting (C18, 0-100% CHCN/water (0.1% TFA)) to afford the title

US 9,561,231 B2 131 132 raphy on silica gel eluting with 10% ethyl acetate in hexanes Example 18B for Example 1A, and substituting (E)-ethyl to give 0.15 g (25%) of the title compound. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate for 2-fluoro-5-nitrophenylboronic acid, respectively, to provide Example 217B the title compound. 5-butyl-2-methyl-6-(2-phenoxyphenyl)pyridazin-3 Example 219B (2H)-one Example 217B was prepared according to the procedure methyl (2E)-3-1-methyl-6-oxo-3-(2-phenoxyphe used for the preparation of Example 1B, substituting nyl)-1,6-dihydropyridazin-4-yl)prop-2-enoate Example 217A for Example 1A, to provide the title com 10 pound. "H NMR (500 MHz, DMSO-d) & 7.32-7.50 (m, Example 219B was prepared according to the procedure 4H), 7.24-7.28 (m, 1H), 7.11 (t, J-7.32 Hz, 1H), 6.98 (d. used for the preparation of Example 1B, substituting J=7.32 Hz, 1H), 6.92 (d. J=7.63 Hz, 2H), 6.77 (s, 1H), 3.57 Example 219A for Example 1A, to provide the title com (s, 3H), 2.23-2.26 (m, 2H), 1.33-1.38 (m, 2H), 0.72 (t, pound. "H NMR (500 MHz, DMSO-d) & 7.44-7.53 (m, J=7.32 Hz, 3H). MS (DCI+) m/z. 355.2 (M+H)". 15 3H), 7.26-7.36 (m, 3H), 7.11-7.15 (m, 2H), 6.89-6.92 (m, 3H), 6.73 (d. J=16.17 Hz, 1H), 3.69 (s.3H), 3.67 (s.3H). MS Example 218 (DCI+) m/z. 363.1 (M+H)". methyl 1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- dihydropyridazine-4-carboxylate Example 220 methyl 3-1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- Example 218A dihydropyridaZin-4-ylpropanoate methyl 3-chloro-6-oxo-1,6-dihydropyridazine-4-carboxylate Example 219B was prepared according to the procedure 25 used for the preparation of Example 10, substituting Methyl 3,6-dichloropyridazine-4-carboxylate (12 g, 58.0 Example 219B for Example 9B, to provide the title com mmol) in acetic acid (45 mL) was heated at 130° C. for two pound. "H NMR (500 MHz, DMSO-d) & 7.46-7.50 (m, hours. After cooling to room temperature, the solvent was 1H), 7.43 (dd, J–7.48, 1.68 Hz, 1H), 7.34-7.37 (m, 2H), 7.26 removed under reduced pressure to give a white Solid (10g), (t, J=7.48 Hz, 1H), 7.13 (t, J=7.48 hz, 1H), 6.93-6.97 (m, which contained 45% of the desired product. The crude 30 3H), 6.80 (s, 1H), 3.58 (s, 3H), 3.54 (s, 3H), 2.55-2.63 (m product was used directly for the next step. 4H). MS (DCI+) m/z. 365.1 (M+H)". Example 218B Example 221 methyl 3-chloro-1-methyl-6-oxo-1,6-dihydro 35 5-acetyl-2-methyl-6-(2-phenoxyphenyl)pyridazin-3 pyridazine-4-carboxylate (2H)-one Example 218B was prepared according to the procedure Example 221A used for the preparation of Example 1A, Substituting Example 218A for 6-chloropyridazin-3 (2H)-one, to provide 40 6-chloro-5-(1-ethoxyvinyl)-2-methylpyridazin-3 the title compound. (2H)-one Example 218C Example 218C was prepared according to the procedure methyl 1-methyl-6-oxo-3-(2-phenoxyphenyl)-1,6- used for the preparation of Example 217A, substituting dihydropyridazine-4-carboxylate 45 tributyl(1-ethoxyvinyl)stannane for (E)-ethyl 3-(tributyl Stannyl)acrylate, to provide the title compound. Example 218C was prepared according to the procedure used for the preparation of Example 1B, substituting Example 221B Example 218B for Example 1A, to provide the title com pound. "H NMR (500 MHz, DMSO-d) & 7.56 (dd, J=7.63, 50 5-(1-ethoxyvinyl)-2-methyl-6-(2-phenoxyphenyl) 1.83 Hz, 1H), 7.42-746 (m, 1H), 7.33-7.38 (m, 2H), 7.24 pyridazin-3 (2H)-one 7.28 (m, 1H), 7.23 (s, 1H), 7.13 (t, J=7.48 Hz, 1H), 6.87 6.89 (m, 3H), 3.71 (s, 3H), 3.63 (s, 3H). MS (DCI+) m/z Example 221B was prepared according to the procedure 337.1 (M+H)". used for the preparation of Example 1B, substituting 55 Example 221A for Example 1A, to provide the title com Example 219 pound. methyl (2E)-3-1-methyl-6-oxo-3-(2-phenoxyphe Example 221C nyl)-1,6-dihydropyridazin-4-yl)prop-2-enoate 60 5-acetyl-2-methyl-6-(2-phenoxyphenyl)pyridazin-3 Example 219A (2H)-one (E)-ethyl 3-(3-chloro-1-methyl-6-oxo-1,6-dihydro Example 221B (0.11g, 0.316 mmol) in tetrahydrofuran (5 pyridaZin-4-yl)acrylate mL) was treated with 1.0 NHCl (1.3 mL, 1.3 mmol). The 65 reaction mixture was heated at 60° C. for one hour. The Example 219A was prepared according to the procedure solvent was removed, and the residue was purified by used for the preparation of Example 9A, substituting reverse phase HPLC (C18, CHCN/water (0.1% TFA), US 9,561,231 B2 133 134 0-100%) to provide 0.085 g (84%) of the title compound. H Example 225 NMR (500 MHz, DMSO-d) & 7.54 (dd, J=7.63, 1.83 Hz, 1H), 7.36-7.42 (m, 4H), 7.22-7.26 (m. 1H), 7.16 (t, J=7.32 methyl 3-(1-methyl-6-oxo-1,6-dihydropyridin-3- HZ, 1H), 6.90 (d. J=7.63 Hz, 2H), 6.75 (d. J=8.24 Hz, 1H), yl)-4-phenoxyphenylsulfamoyl)acetate 3.71 (s, 3H), 2.41 (s, 3H). MS (DCI+) m/z 321.0 (M+H)". Example 225A Example 222 5-(2-fluoro-5-nitrophenyl)-1-methylpyridin-2(1H)- O 6-(2-benzylphenyl)-2-methylpyridazin-3 (2H)-one 10 Example 225A was prepared according to the procedure used for the preparation of Example 9A, substituting 5-bromo-1-methylpyridin-2(1H)-one for Example 1A, to A mixture of 2-(1-methyl-6-oxo-1,6-dihydropyridazin-3- provide the title compound. yl)phenyl trifluoromethanesulfonate (0.232 g, 0.694 mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.182 g, 15 Example 225B 0.833 mmol), cesium fluoride (0.211, 1.39 mmol) and PdCl (dppf) (0.025 g, 0.035 mmol) in dioxane (5 mL) was heated 1-methyl-5-(5-nitro-2-phenoxyphenyl)pyridin-2 at 75° C. for 16 hours. The reaction mixture was cooled to (1H)-one ambient temperature and concentrated under reduced pres sure. The residue was purified by flash chromatography Example 225B was prepared according to the procedure used for the preparation of Example 9B, substituting (silica gel, 10-50% ethyl acetate/hexane gradient) to provide Example 225A for Example 9A, to provide the title com the title compound. "H NMR (300 MHz, DMSO-d) & pound. 7.29-7.46 (m, 5H) 7.15-7.23 (m, 2H) 7.07-7.15 (m, 1H) 6.94-7.00 (m, 2H) 6.89 (d. J=9.49 Hz, 1H)4.09 (s. 2H)3.65 Example 225C (s, 3H). MS (ESI+) m/z 277.3 (M+H)". 25 5-(5-amino-2-phenoxyphenyl)-1-methylpyridin-2 Example 223 (1H)-one Example 225B was prepared according to the procedure 1-methyl-5-(2-phenoxyphenyl)pyridin-2(1H)-one 30 used for the preparation of Example 10, substituting Example 225B for Example 9B, to provide the title com pound. Example 223 was prepared according to the procedure used for the preparation of Example 1B, substituting Example 225D 5-bromo-1-methylpyridin-2(1H)-one for Example 1A, to 35 provide the title compound. "H NMR (500 MHz, DMSO-d) methyl 3-(1-methyl-6-oxo-1,6-dihydropyridin-3- & 7.91 (d. J=2.44 Hz, 1H), 7.63 (dd, J=9.31, 2.59 Hz, 1H), yl)-4-phenoxyphenylsulfamoyl)acetate 7.48 (dd, J=7.63, 1.83 Hz, 1H), 7.232-7.37 (m, 3H), 7.23 7.27 (m, 1H), 7.08 (t, J=7.48 Hz, 1H), 6.92-6.98 (m, 3H), A mixture of Example 225C (0.04 g., 0.137 mmol), 40 2.2.2-trifluoroethanesulfonyl chloride (0.062 g, 0.342 3.44 (s, 3H). MS (DCI+) m/z 278.1 (M+H)". mmol), and triethylamine (0.055 g, 0.4 mmol) in dichlo romethane (3 mL) was stirred at room temperature for 1 Example 224 hour. The solvent was removed, and the residue was taken up in dioxane (1 mL), methanol (1 mL) and 1.0 N NaOH (1 45 mL). The reaction mixture was heated at 90° C. for 1 hour. N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- The solvents were partially removed under reduced pres phenoxyphenylmethanesulfonamide Sure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2di HCl and extracted with additional ethyl acetate twice. The oxaborolan-2-yl)-1H-pyridine-2-one (Synchem Inc. 0.056 g. 50 combined organic layers were washed with brine, dried over 0.24 mmol), the product from Example 261C (0.068 g., 0.2 MgSO4, filtered, and concentrated under reduced pressure. mmol), tetrakis(tiriphenylphosphine)palladium(0) (0.012 g, The residue was purified by reverse phase HPLC (C18, 0.01 mmol) and sodium carbonate 2M (0.2 mL, 0.40 mmol) CHCN/water (0.1%TFA), 0-100%) to afford 0.026 g (19%) in toluene (1 mL), ethanol (0.25 mL) and water (0.5 mL) was of the title compound. "H NMR (500 MHz, DMSO-d) & heated by microwave at 110°C. for 30 minutes. The reaction 55 10.18 (s, 1H), 7.88 (d. J–2.44 Hz, 1H), 7.56 (dd, J=9.31, mixture was filtered through a 0.45 um Nylon filter disk to 2.59 Hz, 1H), 7.29-7.36 (m, 3H), 7.20 (dd, J=8.7, 2.59 Hz, 1H), 7.06 (t, J=7.32 Hz, 1H), 7.01 (d. J=8.54 Hz, 1H), 6.91 remove solids and the filtrate was partitioned between ethyl (d. J=7.93 Hz, 2H), 6.39 (d. J=9.46 Hz, 1H), 4.30 (s. 2H), acetate and brine. The organic layer was separated and 3.67 (s, 3H), 3.44 (s, 3H). MS (ESI+) m/z 429.1 (M+H)". concentrated. Purification by reverse phase HPLC (C18, 60 0-100% CHCN/water (0.1% TFA)) afforded the title com Example 226 pound (0.028 g., 37%). H NMR (300 MHz, DMSO-d) & 9.73 (s, 1H) 7.88 (d. J=2.38 Hz, 1H) 7.56 (dd, J=9.52, 2.78 {3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- HZ, 1H) 728-7.36 (m, 2H) 7.26 (d. J=2.78 Hz, 1H) 7.16 phenoxyphenylsulfamoyl)acetic acid 7.22 (m, 1H) 7.05 (t, J=7.34 Hz, 1H) 7.00 (d. J=8.73 Hz, 1H) 65 6.90 (d. J=7.93 Hz, 2H) 6.35-6.40 (m. 1H)3.44 (s.3H)3.03 Example 226 was obtained as a by-product in the Syn (s, 3H). MS (ESI+) m/z. 371 (M+H)". thesis of Example 225D. "H NMR (500 MHz, DMSO-d) &

US 9,561,231 B2 137 138 rophenol for phenol, and substituting Example 225A for HZ, 1H), 6.95-6.88 (m, 2H), 6.38 (d. J=9.4 Hz, 1H), 3.44 (s, Example 9A, respectively, to provide the title compound. 3H), 3.04 (s, 3H). MS (ESI+) m/z 405.0 (M+H)" Example 232B Example 234 5-(5-amino-2-(4-fluorophenoxy)phenyl)-1-methyl N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- pyridin-2(1H)-one (pyridin-3-yloxy)phenylmethanesulfonamide

Example 232B was prepared according to the procedure 10 Example 234A used for the preparation of Example 10, substituting Example 232A for Example 9B, to provide the title com pound. 1-methyl-5-(5-nitro-2-(pyridin-3-yloxy)phenyl)pyri din-2(1H)-one Example 232C 15 Example 234A was prepared according to the procedure used for the preparation of Example 9B, substituting pyrin N-4-(4-fluorophenoxy)-3-(1-methyl-6-oxo-1,6-di din-3-ol for phenol, and substituting Example 225A for hydropyridin-3-yl)phenyl)methanesulfonamide Example 9A, respectively, to provide the title compound. Example 232C was prepared according to the procedure Example 234B used for the preparation of Example 22, Substituting Example 232B for Example 20O, to provide the title com pound. 'H NMR (300 MHz, DMSO-d) & 9.72 (s, 1H), 7.89 5-(5-amino-2-(pyridin-3-yloxy)phenyl)-1-methyl (d. J=2.6 Hz, 1H), 7.57 (dd, J=9.4, 2.6 Hz, 1H), 7.29-7.06 pyridin-2(1H)-one (m, 4H), 7.00-6.91 (m, 3H), 6.39 (d. J=9.3 Hz, 1H), 3.45 (s, 25 3H) 3.02 (s, 3H). MS (ESI+) m/z 389.1 (M+H)" Example 234A (340.4 mg, 1.053 mmol), iron (294 mg. 5.26 mmol), and ammonium chloride (113 mg, 2.106 mmol) Example 233 were combined in ethanol (12 mL), tetrahydrofuran (12 mL), and water (4 mL), then allowed to reflux at 100° C. for 30 2 hours. The mixture was cooled just below reflux, vacuum N-4-(4-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- filtered through diatomaceous earth, the filter cake was dihydropyridin-3-yl)phenyl)methanesulfonamide washed with warm methanol (3x35 mL). The filtrate was concentrated under reduced pressure and the residue was Example 233A partitioned between saturated aqueous NaHCO, and ethyl 35 acetate. The combined organics were washed with brine, 5-(2-(4-chlorophenoxy)-5-nitrophenyl)-1-methyl dried (MgSO4), gravity filtered, and concentrated to give the pyridin-2(1H)-one title compound.

Example 233A was prepared according to the procedure 40 Example 234C used for the preparation of Example 9B, substituting 4-chlo rophenol for phenol, and substituting Example 225A for N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- Example 9A, respectively, to provide the title compound. (pyridin-3-yloxy)phenylmethanesulfonamide Example 233B 45 Example 234C was prepared according to the procedure used for the preparation of Example 22, Substituting Example 234B for Example 20O, to provide the title com 5-(5-amino-2-(4-chlorophenoxy)phenyl)-1-methyl pound. "H NMR (300 MHz, DMSO-d) & 9.79 (s, 1H), pyridin-2(1H)-one 8.37-8.24 (m, 2H), 7.89 (d. J=2.6 Hz, 1H), 7.56 (dd, J=9.4, 50 2.6 Hz, 1H), 743-7.17 (m, 4H), 7.10 (d. J=8.6 Hz, 1H), 6.38 Example 233B was prepared according to the procedure (d. J=9.6 Hz, 1H), 3.44 (s.3H), 3.05 (s.3H). MS (ESI+) m/z used for the preparation of Example 10, substituting 372.1 (M+H)" Example 233A for Example 9B, to provide the title com pound. 55 Example 235 Example 233C N-4-(2-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenylmethanesulfonamide N-4-(4-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenylmethanesulfonamide 60 Example 235A Example 233C was prepared according to the procedure used for the preparation of Example 22, Substituting 5-(2-(2-chlorophenoxy)-5-nitrophenyl)-1-methyl Example 233B for Example 20O, to provide the title com pyridin-2(1H)-one pound. "H NMR (300 MHz, DMSO-d) & 9.76 (s, 1H), 7.87 65 (d. J=2.6 Hz, 1H), 7.45 (dd. 1H), 7.39-7.32 (m, 2H), 7.26 (d. Example 235A was prepared according to the procedure J=2.6 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 7.05 (d. J=8.7 used for the preparation of Example 9B, substituting 2-chlo US 9,561,231 B2 139 140 rophenol for phenol, and substituting Example 225A for (m,3H), 7.07 (d. J=8.7 Hz, 1H), 6.80 (d. J=8.4 Hz, 1H), 6.36 Example 9A, respectively, to provide the title compound. (d. J=9.3 Hz, 1H), 3.41 (s.3H), 3.06 (s.3H). MS (ESI+) m/z 439.1 (M+H)" Example 235B 5-(5-amino-2-(2-chlorophenoxy)phenyl)-1-methyl Example 237 pyridin-2(1H)-one N-4-(2-cyanophenoxy)-3-(1-methyl-6-oxo-1,6-di Example 235B was prepared according to the procedure hydropyridin-3-yl)phenyl)methanesulfonamide used for the preparation of Example 234B, substituting 10 Example 235A for Example 234A, to provide the title Example 237A compound. Example 235C 2-(2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- 15 nitrophenoxy)benzonitrile N-4-(2-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenylmethanesulfonamide Example 237A was prepared according to the procedure used for the preparation of Example 9B, substituting 2-hy Example 235C was prepared according to the procedure droxybenzonitrile for phenol, and substituting Example used for the preparation of Example 22, Substituting 225A for Example 9A, respectively, to provide the title Example 235B for Example 20O, to provide the title com compound. pound. 'H NMR (300 MHz, DMSO-d) & 9.75 (s, 1H), 7.91 (d. J–2.6 Hz, 1H), 7.59 (dd, J=9.4, 2.6 Hz, 1H), 7.53 (dd. J=7.9, 1.6 Hz, 1H), 7.31-7.21 (m, 2H), 7.19 (dd, J=8.7, 2.7 Example 237B HZ, 1H), 7.16-7.06 (m, 1H), 6.94 (d. J=8.7 Hz, 1H), 6.88 25 (dd, J=8.1, 1.5 Hz, 1H), 6.39 (d. J=9.4 Hz, 1H), 3.45 (s.3H), 2-(4-amino-2-(1-methyl-6-oxo-1,6-dihydropyridin 3.03 (s, 3H). MS (ESI+) m/z 405.1 (M+H)" 3-yl)phenoxy)benzonitrile Example 236 30 Example 237B was prepared according to the procedure N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- used for the preparation of Example 234B, substituting 2-(trifluoromethyl)phenoxy Example 237A for Example 234A, to provide the title phenyl)methanesulfonamide compound. Example 236A 35 Example 237C 1-methyl-5-(5-nitro-2-(2-(trifluoromethyl)phenoxy) phenyl)pyridin-2(1H)-one N-4-(2-cyanophenoxy)-3-(1-methyl-6-oxo-1,6-di hydropyridin-3-yl)phenyl)methanesulfonamide Example 236A was prepared according to the procedure 40 used for the preparation of Example 9B, substituting 2-(tri Example 237C was prepared according to the procedure fluoromethyl)phenol for phenol, and substituting Example used for the preparation of Example 22, Substituting 225A for Example 9A, respectively, to provide the title Example 237B for Example 20O, to provide the title com compound. pound. 'H NMR (300 MHz, DMSO-d) & 9.89 (s, 1H), 7.88 45 (d. J=2.6 Hz, 1H), 7.82 (dd, J–7.7, 1.7 Hz, 1H), 7.61-7.45 Example 236B (m. 2H), 7.30 (dd, J–2.2, 0.9 HZ, 1H), 7.27-7.06 (m, 3H), 5-(5-amino-2-(2-(trifluoromethyl)phenoxy)phenyl)- 6.78 (d. J=8.0 Hz, 1H), 6.36 (d. J=9.3 Hz, 1H), 3.43 (s, 3H), 1-methylpyridin-2(1H)-one 3.07 (s, 3H). MS (ESI+) m/z 396.1 (M+H)". 50 Example 236B was prepared according to the procedure Example 238 used for the preparation of Example 234B, substituting Example 236A for Example 234A, to provide the title N-4-(2-methoxyphenoxy)-3-(1-methyl-6-oxo-1,6- compound. dihydropyridin-3-yl)phenylmethanesulfonamide 55 Example 236C Example 238A N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- 2-(trifluoromethyl)phenoxy phenyl)methanesulfonamide 60 5-(2-(2-methoxyphenoxy)-5-nitrophenyl)-1-methyl pyridin-2(1H)-one Example 23.6C was prepared according to the procedure used for the preparation of Example 22, Substituting Example 238A was prepared according to the procedure Example 236B for Example 20O, to provide the title com used for the preparation of Example 9B, substituting pound. "H NMR (300 MHz, DMSO-d) & 9.83 (s, 1H), 7.84 65 2-methoxyphenol for phenol, and Substituting Example (d. J–2.6 Hz, 1H), 7.72 (dd, J=7.8, 1.6 Hz, 1H), 7.56 (dd. 225A for Example 9A, respectively, to provide the title J=8.0, 1.6 Hz, 1H), 7.50 (dd, J=9.4, 2.6 Hz, 1H), 7.32-7.17 compound. US 9,561,231 B2 141 142 Example 238B J=8.7 Hz, 1H), 6.41 (d. J=9.3 Hz, 1H), 3.46 (s.3H), 3.02 (s, 3H). MS (ESI+) m/z 389.1 (M+H)". 5-(5-amino-2-(2-methoxyphenoxy)phenyl)-1-meth Example 240 ylpyridin-2(1H)-one N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-1,6- Example 238B was prepared according to the procedure dihydropyridin-3-yl)phenylmethanesulfonamide used for the preparation of Example 234B, substituting Example 238A for Example 234A, to provide the title Example 240A compound. 10 5-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-1-methyl pyridin-2(1H)-one Example 238C Example 239A was prepared according to the procedure used for the preparation of Example 9B, substituting 2,4- N-4-(2-methoxyphenoxy)-3-(1-methyl-6-oxo-1,6- 15 difluorophenol for phenol, and substituting Example 225A dihydropyridin-3-yl)phenylmethanesulfonamide for Example 9A, respectively, to provide the title compound. Example 238C was prepared according to the procedure Example 240B used for the preparation of Example 22, Substituting Example 238B for Example 20O, to provide the title com 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-1-meth pound. 'H NMR (300 MHz, DMSO-d) & 9.58 (s, 1H), 7.93 ylpyridin-2(1H)-one (d. J–2.6 Hz, 1H), 7.69 (dd, J=9.4, 2.6 Hz, 1H), 7.21 (d. Example 240B was prepared according to the procedure J=2.6 Hz, 1H), 7.18-7.05 (m, 3H), 6.99-6.88 (m, 2H), 6.67 used for the preparation of Example 234B, substituting (d. J=8.7 Hz, 1H), 6.42 (d. J=9.3 Hz, 1H), 3.76 (s.3H), 3.47 Example 240A for Example 234A, to provide the title (s, 3H), 2.99 (s.3H). MS (ESI+) m/z 401.1 (M+H)" 25 compound. Example 239 Example 240C N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-1,6- N-4-(2-fluorophenoxy)-3-(1-methyl-6-oxo-1,6-di 30 dihydropyridin-3-yl)phenylmethanesulfonamide hydropyridin-3-yl)phenyl)methanesulfonamide Example 240C was prepared according to the procedure used for the preparation of Example 22, Substituting Example 239A Example 240B for Example 20O, to provide the title com 35 pound. 'H NMR (300 MHz, DMSO-d) & 9.69 (s, 1H), 7.90 5-(2-(2-fluorophenoxy)-5-nitrophenyl)-1-methyl (d. J=2.6 Hz, 1H), 7.60 (dd, J=9.4, 2.6 Hz, 1H), 7.49-7.38 pyridin-2(1H)-one (m. 1H), 7.24 (d. J–2.6 Hz, 1H), 7.19-7.01 (m, 3H), 6.88 (d. J=8.7 Hz, 1H), 6.43 (d. J=9.3 Hz, 1H), 3.47 (s.3H)3.01 (s, Example 239A was prepared according to the procedure 3H). MS (ESI+) m/z 407.1 (M+H)" used for the preparation of Example 9B, substituting 2-fluo 40 Example 241 rophenol for phenol, and substituting Example 225A for Example 9A, respectively, to provide the title compound. N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenyl]ethanesulfonamide Example 239B 45 Example 241 was prepared according to the procedure used for the preparation of Example 22, Substituting ethane 5-(5-amino-2-(2-fluorophenoxy)phenyl)-1-methyl sulfonyl chloride for methanesulfonyl chloride, and substi pyridin-2(1H)-one tuting Example 240B for Example 20O, respectively, to provide the title compound. "H NMR (300 MHz, DMSO-d) Example 239B was prepared according to the procedure 50 & 9.77 (s, 1H), 7.89 (d. J=2.6 Hz, 1H), 7.59 (dd, J=9.3, 2.6 used for the preparation of Example 234B, substituting HZ, 1H), 7.43 (ddd, J=11.3, 8.7, 2.8 Hz, 1H), 7.24 (d. J=2.7 Example 239A for Example 234A, to provide the title HZ, 1H), 7.19-7.01 (m, 3H), 6.87 (d. J=8.7 Hz, 1H), 6.43 (d. compound. J=9.3 Hz, 1H), 3.46 (s.3H), 3.11 (q, J=7.3 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 421.1 (M+H)". 55 Example 239C Example 242 N-4-(3,5-difluorophenoxy)-3-(1-methyl-6-oxo-1,6- N-4-(2-fluorophenoxy)-3-(1-methyl-6-oxo-1,6-di dihydropyridin-3-yl)phenylmethanesulfonamide hydropyridin-3-yl)phenyl)methanesulfonamide 60 Example 242A Example 239C was prepared according to the procedure used for the preparation of Example 22, Substituting 5-(2-(3,5-difluorophenoxy)-5-nitrophenyl)-1-methyl Example 239B for Example 20O, to provide the title com pyridin-2(1H)-one pound. "H NMR (300 MHz, DMSO-d) & 9.71 (s, 1H), 7.90 65 (d. J=2.6 Hz, 1H), 7.59 (dd, J=9.4, 2.6 Hz, 1H), 7.38-7.23 Example 242A was prepared according to the procedure (m. 2H), 7.20-7.09 (m, 3H), 7.06-6.96 (m, 1H), 6.92 (d. used for the preparation of Example 9B, substituting 3.5- US 9,561,231 B2 143 144 difluorophenol for phenol, and substituting Example 225A Example 244 for Example 9A, respectively, to provide the title compound. N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- Example 242B 3-(trifluoromethyl)phenoxy phenyl)methanesulfonamide 5-(5-amino-2-(3,5-difluorophenoxy)phenyl)-1-meth ylpyridin-2(1H)-one Example 244A Example 242B was prepared according to the procedure 1-methyl-5-(5-nitro-2-(3-(trifluoromethyl)phenoxy) used for the preparation of Example 234B, substituting 10 phenyl)pyridin-2(1H)-one Example 242A for Example 234A, to provide the title compound. Example 244A was prepared according to the procedure used for the preparation of Example 9B, substituting 3-(tri Example 242C fluoromethyl)phenol for phenol, and substituting Example 15 225A for Example 9A, respectively, to provide the title N-4-(3,5-difluorophenoxy)-3-(1-methyl-6-oxo-1,6- compound. dihydropyridin-3-yl)phenylmethanesulfonamide Example 244B Example 242C was prepared according to the procedure used for the preparation of Example 22, Substituting 5-(5-amino-2-(3-(trifluoromethyl)phenoxy)phenyl)- Example 242B for Example 20O, to provide the title com 1-methylpyridin-2(1H)-one pound. "H NMR (300 MHz, DMSO-d) & 9.83 (s, 1H), 7.87 Example 244B was prepared according to the procedure (d. J=2.6 Hz, 1H), 7.52 (dd, J=9.4, 2.6 Hz, 1H), 7.30-7.19 used for the preparation of Example 234B, substituting (m. 2H), 7.16 (d. J=8.6 Hz, 1H), 6.91 (tt, J=9.3, 2.3 Hz, 1H), 25 Example 244A for Example 234A, to provide the title 6.67-6.57 (m, 2H), 6.39 (d. J=9.3 Hz, 1H), 3.44 (s.3H), 3.06 compound. (s, 3H). MS (ESI+) m/z 407.1 (M+H)" Example 244C Example 243 30 N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- N-4-(3-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- 3-(trifluoromethyl)phenoxy dihydropyridin-3-yl)phenylmethanesulfonamide phenyl)methanesulfonamide Example 243A Example 244C was prepared according to the procedure 35 used for the preparation of Example 22, Substituting 5-(2-(3-chlorophenoxy)-5-nitrophenyl)-1-methyl Example 244B for Example 20O, to provide the title com pyridin-2(1H)-one pound. "H NMR (300 MHz, DMSO-d) & 9.82 (s, 1H), 7.90 (d. J=2.6 Hz, 1H), 7.58-748 (m, 2H), 7.44-7.36 (m. 1H), Example 243A was prepared according to the procedure 7.28 (d. J–2.6 Hz, 1H), 7.26-7.08 (m, 4H), 6.37 (d. J=9.3 Hz, used for the preparation of Example 9B, substituting 3-chlo 40 1H), 3.44 (s, 3H), 3.05 (s, 3H). MS (ESI+) m/z. 439.1 rophenol for phenol, and substituting Example 225A for (M+H)". Example 9A, respectively, to provide the title compound. Example 245 Example 243B 45 N-4-(3-cyanophenoxy)-3-(1-methyl-6-oxo-1,6-di 5-(5-amino-2-(3-chlorophenoxy)phenyl)-1-methyl hydropyridin-3-yl)phenyl)methanesulfonamide pyridin-2(1H)-one Example 245A Example 243B was prepared according to the procedure used for the preparation of Example 234B, substituting 50 3-(2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- Example 243A for Example 234A, to provide the title nitrophenoxy)benzonitrile compound. Example 245A was prepared according to the procedure Example 243C used for the preparation of Example 9B, substituting 3-hy 55 droxybenzonitrile for phenol, and substituting Example N-4-(3-chlorophenoxy)-3-(1-methyl-6-oxo-1,6- 225A for Example 9A, respectively, to provide the title dihydropyridin-3-yl)phenylmethanesulfonamide compound. Example 243C was prepared according to the procedure Example 245B used for the preparation of Example 22, Substituting 60 Example 243B for Example 20O, to provide the title com 3-(4-amino-2-(1-methyl-6-oxo-1,6-dihydropyridin pound. "H NMR (300 MHz, DMSO-d) & 9.80 (s, 1H), 7.89 3-yl)phenoxy)benzonitrile (d. J=2.6 Hz, 1H), 7.54 (dd, J=9.4, 2.7 Hz, 1H), 7.33 (t, J=8.1 HZ, 1H), 7.27 (d. J=2.6 Hz, 1H), 7.21 (dd, J=8.6, 2.7 Hz, Example 245B was prepared according to the procedure 1H), 7.14-7.05 (m, 2H), 6.97 (t, J=2.2 Hz, 1H), 6.85 (ddd, 65 used for the preparation of Example 234B, substituting J=8.3, 2.4, 0.9 HZ, 1H), 6.38 (d. J=9.3 Hz, 1H), 3.44 (s.3H), Example 245A for Example 234A, to provide the title 3.05 (s, 3H). MS (ESI+) m/z 405.1 (M+H)" compound. US 9,561,231 B2 145 146 Example 245C mixture was stirred at ambient temperature for 1 hour. Example 225A (100 mg, 0.403 mmol) was added and the N-4-(3-cyanophenoxy)-3-(1-methyl-6-oxo-1,6-di mixture heated to 50° C. for 2 hours. Cold water (10 mL) hydropyridin-3-yl)phenyl)methanesulfonamide was added and the aqueous extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO), Example 245C was prepared according to the procedure filtered, and concentrated to give the title compound. used for the preparation of Example 22, Substituting Example 245B for Example 20O, o provide the title com Example 247B pound. "H NMR (300 MHz, DMSO-d) & 9.81 (s, 1H), 7.88 (d. J=2.6 Hz, 1H), 7.57-7.46 (m, 3H), 7.39-7.34 (m, 1H), 10 5-(5-amino-2-(cyclohexyloxy)phenyl)-1-methylpyri 7.30-7.18 (m, 3H), 7.10 (d. J=8.6 Hz, 1H), 6.37 (d. J=9.3 Hz, din-2(1H)-one 1H), 3.44 (s, 3H), 3.05 (s, 3H). MS (ESI+) m/z 396.1 (M+H)". Example 247B was prepared according to the procedure used for the preparation of Example 234B, substituting Example 246 15 Example 247A for Example 234A, to provide the title compound. N-4-(3-fluorophenoxy)-3-(1-methyl-6-oxo-1,6-di hydropyridin-3-yl)phenyl)methanesulfonamide Example 247C Example 246A N-4-(cyclohexyloxy)-3-(1-methyl-6-oxo-1,6-dihy dropyridin-3-yl)phenyl)methanesulfonamide 5-(2-(3-fluorophenoxy)-5-nitrophenyl)-1-methyl pyridin-2(1H)-one Example 247C was prepared according to the procedure used for the preparation of Example 22, Substituting Example 246A was prepared according to the procedure 25 Example 247B for Example 20O, to provide the title com used for the preparation of Example 9B, substituting 3-fluo pound. "H NMR (300 MHz, DMSO-d) "H NMR 9.40 (s, rophenol for phenol, and substituting Example 225A for 1H), 7.83 (d. J=2.6 Hz, 1H), 7.61 (dd, J=9.3, 2.6 Hz, 1H), Example 9A, respectively, to provide the title compound. 7.15-7.04 (m, 3H), 6.42 (d. J=9.3 Hz, 1H), 4.39-4.27 (m, 1H), 3.48 (s, 3H), 2.94 (s, 3H), 1.96-1.20 (m. 10H). MS Example 246B 30 (ESI+) m/z. 377.1 (M+H)". 5-(5-amino-2-(3-fluorophenoxy)phenyl)-1-methyl Example 248 pyridin-2(1H)-one N-4-(cyclopentyloxy)-3-(1-methyl-6-oxo-1,6-dihy Example 246B was prepared according to the procedure 35 dropyridin-3-yl)phenyl)methanesulfonamide used for the preparation of Example 234B, substituting Example 246A for Example 234A, to provide the title Example 248A compound. 5-(2-(cyclopentyloxy)-5-nitrophenyl)-1-methylpyri Example 246C 40 din-2(1H)-one N-4-(3-fluorophenoxy)-3-(1-methyl-6-oxo-1,6-di Example 248A was prepared according to the procedure hydropyridin-3-yl)phenyl)methanesulfonamide used for the preparation of Example 247A, substituting cyclopentanol for cyclohexanol, to provide the title com Example 246C was prepared according to the procedure 45 pound. used for the preparation of Example 22, Substituting Example 246B for Example 20O, to provide the title com Example 248B pound. 'H NMR (300 MHz, DMSO-d) 9.79 (s, 1H), 7.88 (d. J–2.6 Hz, 1H), 7.54 (dd, J=9.4, 2.6 Hz, 1H), 7.34 (td, 5-(5-amino-2-(cyclopentyloxy)phenyl)-1-methyl J=8.1, 6.8 Hz, 1H), 7.27 (d. J=2.6 Hz, 1H), 7.21 (dd, J=8.6, 50 pyridin-2(1H)-one 2.6 Hz, 1H), 7.10 (d. J–8.6 Hz, 1H), 6.88 (tdd, J=8.5, 2.4,0.9 HZ, 1H), 6.79-6.67 (m, 2H), 6.38 (d. J=9.3 Hz, 1H), 3.43 (s, Example 248B was prepared according to the procedure 3H) 3.05 (s, 3H). MS (ESI+) m/z 389.1 (M+H)". used for the preparation of Example 234B, substituting Example 248A for Example 234A, to provide the title Example 247 55 compound. N-4-(cyclohexyloxy)-3-(1-methyl-6-oxo-1,6-dihy Example 248C dropyridin-3-yl)phenylmethanesulfonamide N-4-(cyclopentyloxy)-3-(1-methyl-6-oxo-1,6-dihy Example 247A 60 dropyridin-3-yl)phenyl)methanesulfonamide 5-(2-(cyclohexyloxy)-5-nitrophenyl)-1-methylpyri Example 248C was prepared according to the procedure din-2(1H)-one used for the preparation of Example 22, Substituting Example 248B for Example 20O, to provide the title com Cyclohexanol (48.4 mg. 0.483 mmol) and sodium hydride 65 pound. 'H NMR (300 MHz, DMSO-d) 9.39 (s, 1H), 7.80 (56.4 mg, 1.410 mmol) were combined in anhydrous tetra (d. J=2.6 Hz, 1H), 7.55 (dd, J=9.3, 2.6 Hz, 1H), 7.16-7.09 hydrofuran (5 mL). Bubbling occurred and the opaque (m. 2H), 7.08-7.01 (m. 1H), 6.41 (d. J=9.3 Hz, 1H), 4.83 US 9,561,231 B2 147 148 4.75 (m, 1H), 3.47 (s, 3H), 2.93 (s, 3H), 1.90-1.75 (m, 2H), Example 250B 1.76-1.35 (m, 6H). MS (ESI+) m/z. 363.1 (M+H)". 5-(5-amino-2-((tetrahydro-2H-pyran-4-yl)methoxy) Example 249 phenyl)-1-methylpyridin-2(1H)-one Example 250B was prepared according to the procedure N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- used for the preparation of Example 234B, substituting (tetrahydrofuran-3-yloxy)phenyl)methanesulfona Example 250A for Example 234A, to provide the title mide compound. 10 Example 249A Example 250C N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- 1-methyl-5-(5-nitro-2-(tetrahydrofuran-3-yloxy)phe (tetrahydro-2H-pyran-4-ylmethoxy)phenylmethane nyl)pyridin-2(1H)-one 15 Sulfonamide Example 249A was prepared according to the procedure Example 250C was prepared according to the procedure used for the preparation of Example 247A, substituting used for the preparation of Example 22, Substituting tetrahydrofuran-3-ol for cyclohexanol, to provide the title Example 250B for Example 20O, to provide the title com compound. pound. 'H NMR (300 MHz, DMSO-d) 9.41 (s, 1H), 7.83 (d. J=2.6 Hz, 1H), 7.57 (dd, J=9.3, 2.6 Hz, 1H), 7.17-7.03 Example 249B (m,3H), 6.42 (d. J=9.3 Hz, 1H), 3.87 (d. J=4.0 Hz, 2H), 3.83 (d. J=6.1 Hz, 2H), 3.47 (s, 3H), 3.41-3.17 (m, 2H), 2.93 (s, 3H), 2.04-1.86 (m, 1H), 1.64-1.54 (m, 2H), 1.39-1.20 (m, 5-(5-amino-2-(tetrahydrofuran-3-yloxy)phenyl)-1- 25 2H). MS (ESI+) m/z 393.1 (M+H)". methylpyridin-2(1H)-one Example 251 Example 249B was prepared according to the procedure used for the preparation of Example 234B, substituting N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- Example 249A for Example 234A, to provide the title 30 phenoxyphenyl)-1H-pyrrole-2-carboxamide compound. A mixture of 1H-pyrrole-2-carboxylic acid (0.018 g. 0.164 mmol), oxalyl chloride (0.035 g, 0.274 mmol) and Example 249C dimethylformamide (1 drop) in dichloromethane (3 mL) was 35 stirred at ambient temperature for 1 hour. The solvent was N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- evaporated under reduced pressure and the residue treated (tetrahydrofuran-3-yloxy)phenyl)methanesulfona with toluene (2 mL) and then evaporated under reduced mide pressure. The residue was dissolved in dichloromethane (2 mL) and was then added to a solution of Example 225C Example 249C was prepared according to the procedure 40 (0.040 g, 0.137 mmol) and triethylamine (0.055 g, 0.547 used for the preparation of Example 22, Substituting mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction Example 249B for Example 20O, to provide the title com mixture was concentrated under reduced pressure. The resi pound. 'H NMR (300 MHz, DMSO-d) 9.43 (s, 1H), 7.82 due was purified by reverse phase HPLC (C18, CHCN/ (d. J=2.6 Hz, 1H), 7.57 (dd, J=9.4, 2.6 Hz, 1H), 7.21-7.09 45 water (0.1% TFA), 0-100%) to afford the title compound (m. 2H), 7.09-7.02 (m. 1H), 6.42 (d. J=9.3 Hz, 1H), 5.06 (0.035 g. 66%). "H NMR (500 MHz, DMSO-d) & 10.64 (s, 4.98 (m, 1H), 3.89-3.76 (m, 4H), 3.47 (s, 3H), 2.95 (s, 3H), 1H), 9.85 (s, 1H), 7.90 (d. J=2.75 Hz, 1H), 7.82 (d. J=2.75 2.30-2.10 (m. 1H), 2.00-1.87 (n, 1H). MS (ESI+) m/z,365.1 HZ, 1H), 7.76 (dd, J=8.85, 2.75 Hz, 1H), 7.60 (dd, J=9.31, (M+H)". 2.59 Hz, 1H), 7.29-7.33 (m, 2H), 6.97-7.01 (m, 3H), 6.97 50 6.98 (m, 1H), 6.89 (d. J=7.63 Hz, 2H), 6.38 (d. J=9.46 Hz, Example 250 1H), 6.17-6.19 (m. 1H), 3.44 (s, 3H). MS (ESI+) m/z 386.1 (M+H)". N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- (tetrahydro-2H-pyran-4-ylmethoxy)phenylmethane Example 252 55 Sulfonamide tert-butyl (2-3-(1-methyl-6-oxo-1,6-dihydropyri din-3-yl)-4-phenoxyphenyl)amino)-2-oxoethyl)car Example 250A bamate

60 The product from Example 225C (0.058 g., 0.2 mmol), 1-methyl-5-(5-nitro-2-((tetrahydro-2H-pyran-4-yl) Boc-glycine (0.042 g, 0.240 mmol), triethylamine (0.098 methoxy)phenyl)pyridin-2(1H)-one mL, 0.70 mmol) and HATU (0.091 g, 0.240 mmol) were combined in DMSO (1.2 mL), stirred for 1 hour and Example 250A was prepared according to the procedure partitioned between ethyl acetate and brine. The organic used for the preparation of Example 247A, substituting 65 layer was separated and concentrated. Purification by chro (tetrahydro-2H-pyran-4-yl)methanol for cyclohexanol, to matography (silica gel. 1-4% methanol in dichloromethane) provide the title compound. afforded the title compound (0.071 g, 79%). "H NMR (300 US 9,561,231 B2 149 150 MHz, DMSO-d) & 10.00 (s, 1H) 7.86 (d. J=2.71 Hz, 1H) water (2 mL) dropwise at 0°C. The solution was stirred at 7.70 (d. J=2.37 Hz, 1H) 748-7.59 (m, 2H) 7.27-7.34 (m, 2H) 0° C. for three hours. To the SO, containing solution was 6.97-7.08 (m, 3H) 6.87 (d. J=7.80 Hz, 2H) 6.37 (d. J=9.49 added copper(I)chloride (0.020 g, 0.205 mmol). Then, to this HZ, 1H)3.72 (d. J=6.10 Hz, 2H)3.43 (s, 3H) 1.40 (s, 9H). solution was added the diazotized Example 225C at 0° C. MS (ESI+) m/z 448 (M+H)". The solution was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The solvent was Example 253 removed, and the residue was taken up into tetrahydrofuran which was used directly for the next reaction. N-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- phenoxyphenylglycinamide 10 Example 255B The product from Example 252 (0.071 g, 0.158 mmol) N-ethyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3- and trifluoroacetic acid (0.5 mL) in dichloromethane (1 mL) yl)-4-phenoxybenzenesulfonamide was stirred for 1 h and concentrated. Purification by reverse phase HPLC (C18, 0-100% CHCN/water (0.1% TFA)) 15 A quater of tetrahydrofuran solution containing Example afforded the title compound as the trifluoroacetic acid salt (0.060 g, 81%). "H NMR (300 MHz, DMSO-d) & 10.49 (s. 255A was treated with excess ethyl amine in tetrahydro 1H) 8.08 (s. 2H) 7.86 (d. J=2.37 Hz, 1H) 7.63 (d. J=2.37 Hz, furan. The solution was stirred at ambient temperature for 1H) 7.51-7.58 (m, 2H) 7.29-7.36 (m, 2H) 6.99-7.10 (m, 2H) three hours. The solvent was removed, and the residue was 6.89 (d. J=746 Hz, 2H) 6.39 (d. J=9.49 Hz, 1H) 3.79 (q, purified by reverse phase HPLC (C18, CHCN/water (0.1% J=5.54 Hz, 2H) 3.44 (s, 3H). MS (ESI+) m/z. 350 (M+H)". TFA), 0-100%) to afford 0.010 g of the title compound. H NMR (500 MHz, DMSO-d) & 8.00 (d. J=2.44 Hz, 1H), 7.82 Example 254 (d. J=2.44 Hz, 1H), 7.71 (dd, J=2.59, 1.37 Hz, 1H), 7.69 (d. J=2.14 Hz, 1H), 7.51 (t, J=5.8 Hz, 1H), 741-7.45 (m, 3H), 1-methyl-5-2-phenoxy-5-(pyridin-2-ylamino)phe 25 7.21 (t, J=7.32 Hz, 1H), 7.11 (d. J=7.63 Hz, 2H), 6.99 (d. nylpyridin-2(1H)-one J=8.54 Hz, 1H), 6.44 (d. J=9.46 Hz, 1H), 3.49 (s. 3H), 2.77-2.84 (m, 2H), 1.00 (t, J=7.17 Hz, 3H). MS (ESI+) m/z A mixture of Example 225C (0.035 g, 0.120 mmol), 385.2 (M+H)". 2-bromopyridine (0.023 g, 0.144 mmol), 2-(dicyclohexyl phosphino)-N,N-dimethylbiphenyl-2-amine (0.0071 g, 30 Example 256 0.018 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0055 g, 0.006 mmol), and CsCO, (0.055 g, 0.168 mmol) 3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phe in dioxane (1 mL) was degassed and back-filled with nitro noxybenzenesulfonamide gen several times. The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the reac 35 A quarter of tetrahydrofuran solution containing Example tion mixture was partitioned between ethyl acetate and 255A was treated with excess concentrated ammonium water. The aqueous layer was extracted with additional ethyl hydroxide. The solution was stirred at for three hours. The acetate twice. The combined organic layers were washed solvent was removed, and the residue was purified by with brine, dried over MgSO, filtered, and concentrated. reverse phase HPLC (C18, CHCN/water (0.1% TFA), The residue was purified by reverse phase HPLC (C18, 40 0-100%) to afford 0.010 g of the title compound. "H NMR CHCN/water (0.1%TFA), 0-100%) to afford 0.019 g (33%) (500 MHz, DMSO-d) & 7.98 (d. J=2.75 Hz, 1H), 7.88 (d. of the title compound as a TFA salt. H NMR (500 MHz, J=2.44 Hz, 1H), 7.74 (dd, J=8.7, 2.29 HZ, 1H), 7.6 (dd. DMSO-d) & 10.46 (s, 1H), 9.86 (brs, 1H), 8.08 (dd, J=5.49. J=9.46, 2.75 Hz, 1H), 7.40-7.44 (m, 2H), 7.34 (s. 2H), 7.20 1.22 Hz, 1H), 7.91 (d. J=2.44 Hz, 1H), 7.75 (t, J=7.02 Hz, (t, J=7.32 Hz, 1H), 7.08 (d. J=7.63 Hz, 2H), 7.00 (d. J=8.54 1H), 7.67 (d. J=2.75 Hz, 1H), 7.61 (dd, J=9.46, 2.75 Hz, 45 HZ, 1H), 6.45 (d. J=9.46 Hz, 1H), 3.49 (s.3H). MS (ESI+) 1H), 7.57 (dd, J=8.7, 2.59 Hz, 1H), 7.30-7.35 (m, 2H), m/z. 357.2 (M+H)". 7.02-7.07 (m, 2H), 6.98 (d. J=8.54 Hz, 1H), 6.90 (d. J=7.93 Hz, 2H), 6.84-6.87 (m. 1H), 6.38 (d. J=9.46 Hz, 1H), 3.43 Example 257 (s, 3H). MS (ESI+) m/z 370.2 (M+H)". 50 N-2-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin Example 255 3-yl)-4-phenoxyphenylmethanesulfonamide N-ethyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3- Example 257A yl)-4-phenoxybenzenesulfonamide 55 5-(2-fluoro-4-methyl-5-nitrophenyl)-1-methylpyri Example 255A din-2(1H)-one 3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phe 4-bromo-5-fluoro-2-nitrotoluene (Aldrich, 0.234 g, 1.0 noxybenzene-1-sulfonyl chloride mmol), 1-methyl-5-(4.4.5.5-tetramethyl-1,3,2dioxabo 60 ralan-2-yl)-1H-pyridin-2-one (Synchem, Inc. 0.235 g, 1.0 Under ice-cooling, thionyl chloride (2 mL) was added mmol), bis(triphenylphosphine)palladium(II) chloride dropwise over 20 minutes to water (8 mL). The mixture was (0.035 g, 0.05 mmol) and sodium carbonate 2M (1.5 mL, 3.0 stirred overnight for 12 hours to give a SO containing mmol) were combined in DME (4 mL) and water (4.0 mL), solution. Separately, Example 225C (0.3 g, 1.026 mmol) was sparged with nitrogen and heated by microwave at 120° C. added to concentrated HCl (8 mL) and dioxane (6 mL) at 0° 65 for 30 minutes. The reaction mixture was partitioned C. The solution was stirred for 5 minutes. To this suspension/ between ethyl acetate and water. The ethyl acetate layer was solution was added sodium nitrite (0.078 g, 1.129 mmol) in washed with brine, dried (NaSO), treated with mercapto US 9,561,231 B2 151 152 propyl silica gel for 30 minutes, filtered and concentrated to solution was added sodium hydride (0.254 g. 21.81 mmol). afford the title compound (0.262 g, 99%). After the end of bubbling, iodomethane (3.1 g, 21.81 mmol) was added to the solution. The solution was stirred for 6 Example 257B hours at room temperature. The reaction mixture was par titioned between water and ethyl acetate. The aqueous layer 1-methyl-5-(4-methyl-5-nitro-2-phenoxyphenyl) was extracted with additional ethyl acetate three times. The pyridin-2(1H)-one combined organic layers were washed with brine, dried over MgSO filtered, and concentrated. The residue was purified The product from Example 257A (0.262 g, 1.0 mmol), by flash chromatography on silica gel eluting with 40% ethyl phenol (0.104 g, 1.1 mmol) and cesium carbonate (0.358 g. 10 acetate in hexanes to afford 0.2 g (6.6%) of the title 1.1 mmol) were combined in DMSO (5 mL) and heated at compound. 100° C. for 30 minutes under nitrogen. The reaction mixture was partitioned between ethyl acetate and water. The organic Example 258B layer was washed with brine, dried (NaSO), filtered and concentrated to afford the title compound (0.31 g, 92%). 15 4-methoxy-1-methyl-5-(2-phenoxyphenyl)pyridin-2 (1H)-one Example 257C A mixture of Example 258A (0.035 g, 0.2 mmol), 2-phe 5-(5-amino-4-methyl-2-phenoxyphenyl)-1-methyl noxyphenylboronic acid (0.064 g., 0.30 mmol), 2-(dicyclo pyridin-2(1H)-one hexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.016 g. 0.040 mmol), palladium(II)acetate (0.0045 g, 0.02 mmol) The product from Example 257B (0.336 g, 1.0 mmol), and CsP (0.091 g, 0.6 mmol) in dioxane (1 mL) in a 4 mL iron (0.279 g, 5.0 mmol), and ammonium chloride (0.080 g, vial was degassed and back-filled with nitrogen four times. 1.5 mmol) were combined in a solvent mixture of ethanol (9 The reaction mixture was heated at 90° C. overnight. The mL), tetrahydrofuran (9 mL) and water (3 mL) and heated 25 mixture was filtered through a pad of filtering agent. The at 95°C. with vigorous stirring for 1.5 hours. The mixture filtrate was concentrated. The residue was then purified by was cooled, filtered through Celite and the Celite was rinsed reverse HPLC (C18, CHCN/water (0.1%TFA), 0-100%) to repeatedly with methanol and tetrahydrofuran. The filtrate afford 0.030 g (48%) of the title compound. "H NMR (500 was concentrated and the residue partitioned between ethyl MHz, DMSO-d) & 7.57 (m, 1H), 7.30-7.37 (m, 4H), 7.16 acetate and water. The ethyl acetate layer was washed with 30 7.20 (m. 1H), 7.07 (t, J=7.32 Hz, 1H), 6.90-6.92. (m, 3H), brine, dried (NaSO), filtered and concentrated. Purification 5.79 (s, 1H), 3.54 (s.3H), 3.34 (s.3H). MS (ESI+) m/z 308.1 by chromatography (silica gel, 0-4% methanol in dichlo (M+H)". romethane) afforded the title compound (0.186 g. 61%). Example 259 Example 257D 35 N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyri N-2-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin din-3-yl)-4-phenoxyphenylmethanesulfonamide 3-yl)-4-phenoxyphenylmethanesulfonamide Example 259A A solution of the product from Example 257C (0.060 g, 40 0.196 mmol) and triethylamine (0.068 mL, 0.49 mmol) in 5-(2-fluoro-5-nitrophenyl)-4-methoxy-1-methylpyri dichloromethane (3 mL) was treated with methanesulfonyl din-2(1H)-one chloride (0.035 mL, 0.45 mmol), stirred for 2 hours and concentrated. The residue was dissolved in a mixture of Example 259A was prepared according to the procedure dioxane (2 mL) and 1M sodium hydroxide (2 mL) and 45 used for the preparation of Example 258B, substituting heated for 1 hour at 90° C. The mixture was cooled, diluted 2-fluoro-5-nitrophenylboronic acid for 2-phenoxyphenylbo with ethyl acetate, brought to pH 7 with 1 M HCl and the ronic acid, to provide the title compound. organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel. Example 259B 0-4% methanol in dichloromethane) afforded the title com 50 pound (0.039 g, 52%). "H NMR (300 MHz, DMSO-d) & 4-methoxy-1-methyl-5-(5-nitro-2-phenoxyphenyl) 9.11 (s, 1H) 7.86 (d. J=2.78 Hz, 1H) 7.58 (dd, J=9.52, 2.78 pyridin-2(1H)-one HZ, 1H) 7.29-7.39 (m, 3H) 7.08 (t, J=7.34 Hz, 1H) 6.93 (d. J=7.93 Hz, 2H) 6.87 (s, 1H) 6.37 (d. J=9.52 Hz, 1H)3.44 (s, Example 259B was prepared according to the procedure 3H)3.03 (s, 3H) 2.27 (s.3H). MS (ESI+) m/z 385 (M+H)". 55 used for the preparation of Example 9B, substituting Example 259A for Example 9A, to provide the title com Example 258 pound. 4-methoxy-1-methyl-5-(2-phenoxyphenyl)pyridin-2 Example 259C (1H)-one 60 5-(5-amino-2-phenoxyphenyl)-4-methoxy-1-methyl Example 258A pyridin-2(1H)-one 5-chloro-4-methoxy-1-methylpyridin-2(1H)-one Example 259C was prepared according to the procedure 65 used for the preparation of Example 10, substituting 5-Chloro-4-hydroxypyridin-2(1H)-one (1.27 g, 8.73 Example 259B for Example 9B, to provide the title com mmol) in dimethylformamide was cooled to 0°C. To this pound. US 9,561,231 B2 153 154 Example 259D with brine, dried (MgSO), gravity filtered then concentrated to afford the title compound (2.86, 93%). N-3-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyri din-3-yl)-4-phenoxyphenylmethanesulfonamide Example 261C Example 259D was prepared according to the procedure used for the preparation of Example 22, Substituting N-(3-bromo-4-phenoxyphenyl)methanesulfonamide Example 259C for Example 20O, to provide the title com pound. "H NMR (500 MHz, DMSO-d) & 9.70 (s, 1H), 7.58 Example 261B (2.86 g. 10.8 mmol) and triethylamine (s, 1H), 7.29-7.33 (m, 2H), 7.20 (dd, J=8.85, 2.75 Hz, 1H), 10 7.13 (d. J=2.75 Hz, 1H), 7.04 (t, J–7.48 Hz, 1H), 6.94 (d. (6.03 mL, 43.3 mmol) were stirred in dichloromethane (48.1 J=8.85 Hz, 1H), 6.88 (d. J=7.63 Hz, 2H), 5.79 (s, 1H), 3.53 mL) at ambient temperature. Methanesulfonyl chloride (s, 3H), 3.33 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z 401.0 (2.53 mL, 32.4 mmol) was added dropwise and the solution (M+H)". stirred at ambient temperature for 1 hour. The reaction 15 mixture was concentrated under reduced pressure, dioxane Example 260 (24 mL) and sodium hydroxide (10% w/v. 12 mL, 0.427 mmol) were added, and the solution was heated to 70° C. for 3-methyl-5-(2-phenoxyphenyl)pyridin-2(1H)-one 1 hour. The solution was neutralized to a pH of 7 with saturated aqueous NHCl (200 mL). The aqueous phase was 2-Phenoxylphenylboronic acid (0.072 g, 0.335 mmol), extracted with ethyl acetate (3x125 mL). The combined 5-bromo-3-methylpyridin-2(1H)-one (0.060 g, 0.319 organics were washed with brine, dried (MgSO), filtered, mmol), bis(triphenylphosphine)palladium(II) chloride then concentrated. The residue was purified by flash chro (0.009 g, 0.013 mmol) and 2M sodium carbonate (0.64 mL, matography (silica gel, 0-25% ethyl acetate/hexane gradi 1.28 mmol) were combined in 1,2-dimethoxyethane (1.6 ent) to afford the title compound (2.79 g, 75%). mL) and ethanol (1.6 mL), sparged with nitrogen for 15 25 minutes and heated by microwave at 120° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate Example 261D and water. The ethyl acetate layer was washed with brine, dried (NaSO), filtered and concentrated. Purification by N-(3-(6-fluoro-5-methylpyridin-3-yl)-4-phenoxyphe reverse phase HPLC (C18, 0-100% CHCN/water (0.1% 30 nyl)methanesulfonamide TFA)) afforded the title compound as the trifluoroacetic acid salt (0.020 g, 23%). H NMR (300 MHz, DMSO-d) & 11.60 (s, 1H) 6.75-7.63 (m, 11H) 1.97 (m, 3H) MS (APCI+) m/z A mixture of 2-fluoro-3-methylpyridine-5-boronic acid 278 (M+H)". (Combi-Blocks 0.088 g. 0.566 mmol), the product from 35 Example 261C (0.149 g, 0.435 mmol), tetrakis(tiriphenyl Example 261 phosphine)palladium(0) (0.025 g, 0.022 mmol) and sodium carbonate (0.435 mL, 0.871 mmol) in toluene (2.4 mL), N-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- ethanol (0.62 mL) and water (1.24 mL) was heated by phenoxyphenylmethanesulfonamide microwave at 110° C. for 30 minutes. The reaction mixture 40 was filtered through a 0.45 um Nylon filter disk to remove Example 261A solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. 2-bromo-4-nitro-1-phenoxybenzene Purification by chromatography (silica gel, 0–60% ethyl acetate in hexane) afforded the title compound (0.133 g, 2-Bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), 45 phenol (1.28 g, 13.6 mmol), and cesium carbonate (4.44 g. 82%). MS (ESI+) m/z. 373 (M+H)". 13.6 mmol) were combined in dimethylsulfoxide (140 mL) and heated to 110° C. for 1 hour. The reaction mixture was Example 261E partitioned between ethyl acetate and brine. The combined organics were washed with brine, dried (MgSO), filtered 50 and concentrated to afford the title compound (3.43 g, N-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- quantitative yield). phenoxyphenylmethanesulfonamide Example 261B The product from Example 261D (0.12 g, 0.322 mmol) 55 and sodium hydroxide (1M, 6.0 mL, 6.00 mmol) were 3-bromo-4-phenoxyaniline combined in dioxane (1.611 mL) and heated at 140° C. for 3 hours. The reaction mixture was partitioned into ethyl Example 261A (3.43 g, 11.7 mmol), iron powder (3.26 g. acetate and water adjusting the pH to 6. The ethyl acetate 58.4 mmol), and ammonium chloride (1.25 g, 23.4 mmol) layer was washed with brine, dried (NaSO), filtered and were combined in ethanol (50 mL), tetrahydrofuran (50 60 concentrated. Purification by reverse phase HPLC (C18, mL), and water (16.7 mL), and heated at 100° C. for 2 hours. 0-100% CHCN/water (0.1% TFA)) afforded the title com The reaction mixture was cooled to just below reflux, pound (0.027 g, 22%). "H NMR (300 MHz, DMSO-d) & vacuum filtered through diatomaceous earth, the filter cake 11.60 (s, 1H) 9.70 (s, 1H) 7.48 (s, 1H) 7.36 (s, 1H) 7.31 (t, washed with warm methanol (3x35 mL), and the filtrate J=7.93 Hz, 2H) 7.25 (d. J=2.38 Hz, 1H) 7.14-7.20 (m. 1H) concentrated under reduced pressure. The residue was par 65 7.04 (t, J=7.34 Hz, 1H) 6.99 (d. J=8.73 Hz, 1H) 6.88 (d. titioned between saturated aqueous NaHCO and ethyl J=7.93 Hz, 2H)3.02 (s, 3H) 1.95 (s, 3H). MS (ESI+) m/z acetate (3x125 mL). The combined organics were washed 371 (M+H)". US 9,561,231 B2 155 156 Example 262 2-bromo-1-fluoro-4-nitrobenzene for Example 9A, and sub stituting 2,4-difluorophenol for phenol, respectively, to pro N-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- vide the title compound. phenoxyphenyl)acetamide Example 263B Example 262A 3-bromo-4-(2,4-difluorophenoxy)aniline Example 263B was prepared according to the procedure 3-(6-fluoro-5-methylpyridin-3-yl)-4-phenoxyaniline used for the preparation of Example 234B, substituting 10 Example 263A for Example 234A, to provide the title compound. The product from Example 261B (0.792 g, 3.0 mmol), 2-fluoro-3-methylpyridine-5-boronic acid (Combi-Blocks Example 263C 0.604 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium (0) (0.173 g, 0.15 mmol) and sodium carbonate (4.50 mL. 15 4-(2,4-difluorophenoxy)-3-(6-fluoro-5-methylpyri 9.0 mmol) were combined in toluene (10 mL), ethanol (2.5 din-3-yl)aniline mL) and water (2.5 mL), sparged with nitrogen for 10 minutes and heated by microwave at 120° C. for 60 minutes. Example 263C was prepared according to the procedure The reaction mixture was partitioned between ethyl acetate used for the preparation of Example 9A, substituting and brine. The organic layer was separated, dried (Na2SO4), Example 263B for Example 1A, and substituting 6-fluoro filtered and concentrated. Purification by chromatography 5-methylpyridin-3-ylboronic acid for 2-fluoro-5-nitrophe (silica gel, 0–60% ethyl acetate in hexane) afforded the title nylboronic acid, respectively, to provide the title compound. compound (0.742 g, 84%). Example 263D Example 262B 25 N-(4-(2,4-difluorophenoxy)-3-(6-fluoro-5-methyl pyridin-3-yl)phenyl)methanesulfonamide N-(3-(6-fluoro-5-methylpyridin-3-yl)-4-phenoxyphe Example 263C was prepared according to the procedure nyl)acetamide used for the preparation of Example 22, Substituting 30 Example 263C for Example 20O, to provide the title com The product from Example 262A (0.059 g, 0.2 mmol) in pound. acetic anhydride (0.5 mL) was heated by microwave at 100° C. for 20 minutes and concentrated. Purification by chro Example 263E matography (silica gel, 0-4% methanol in dichloromethane) afforded the title compound (0.050 g, 72%). 35 N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6- dihydropyridin-3-yl)phenylmethanesulfonamide Example 262C Example 263E was prepared according to the procedure used for the preparation of Example 55, substituting N-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4- 40 Example 263D for Example 54B, to provide the title com phenoxyphenyl)acetamide pound. "H NMR (500 MHz, DMSO-d) & 11.63 (brs, 1H), 9.68 (s, 1H), 7.51-7.53 (m, 1H), 7.40-7.46 (m, 2H), 7.24 (d. J=2.75 Hz, 1H), 7.01-7.15 (m, 3H), 6.89 (d. J=8.54 Hz, 1H), The product from Example 262B (0.045 g, 0.134 mmol) 3.01 (s, 3H), 1.99 (s.3H). MS (DCI+) m/z 407.0 (M+H)". in acetic acid (1.4 mL)/water (0.35 mL) was heated at 100° C. for 16 hours and concentrated. Purification by reverse 45 Example 264 phase HPLC (C18, 0-100% CHCN/water (0.1% TFA)) afforded the title compound (0.030 g. 66%). "H NMR (300 N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6- MHz, DMSO-d) & 11.56 (s, 1H) 10.01 (s, 1H) 7.67 (d. dihydropyridin-3-yl)phenyl]ethanesulfonamide J=2.78 Hz, 1H) 7.52 (dd, J=8.73, 2.78 Hz, 1H) 7.44-7.48 (m, J=1.59 Hz, 1H) 7.26-7.35 (m, 3H) 7.02 (t, J=7.34 Hz, 1H) 50 Example 264A 6.96 (d. J=8.73 Hz, 1H) 6.84 (d. J–7.54 Hz, 2H)2.05 (s.3H) N-(4-(2,4-difluorophenoxy)-3-(6-fluoro-5-methyl 1.95 (s, 3H). MS (ESI+) m/z 335 (M+H)". pyridin-3-yl)phenyl)ethanesulfonamide

Example 263 55 Example 264A was prepared according to the procedure used for the preparation of Example 22, Substituting N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6- Example 263C for Example 20O, and substituting ethane dihydropyridin-3-yl)phenylmethanesulfonamide sulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound. 60 Example 263A Example 264B N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6- 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene dihydropyridin-3-yl)phenyl]ethanesulfonamide 65 Example 263A was prepared according to the procedure Example 264B was prepared according to the procedure used for the preparation of Example 9B, substituting used for the preparation of Example 55, substituting US 9,561,231 B2 157 158 Example 264A for Example 54B, to provide the title com Example 266E pound. "H NMR (500 MHz, DMSO-d) & 11.67 (brs, 1H), 9.75 (s, 1H), 7.49-7.51 (m. 1H), 7.41-7.46 (m, 1H), 7.38 (d. N-4-(4.4-difluorocyclohexyl)oxy-3-(5-methyl-6- J=2.44 Hz, 1H), 7.23 (d. J=2.44 Hz, 1H), 7.14 (dd, J=8.85, oxo-1,6-dihydropyridin-3-yl) 2.75 Hz, 1H), 7.01-7.10 (m, 2H), 6.88 (d. J=8.85 Hz, 1H), phenyl)methanesulfonamide 3.11 (q, J–7.32 Hz, 2H), 1.21 (t, J=7.32 Hz, 3H). MS (DCI+) m/Z 421.0 (M+H)". Example 266E was prepared according to the procedure Example 265 used for the preparation of Example 55, substituting Example 266D for Example 54B, to provide the title com N-4-(2,4-difluorophenoxy)-3-(5-methyl-6-oxo-1,6- 10 pound. "H NMR (300 MHz, DMSO-d) & 11.63 (bs, 1H), dihydropyridin-3-yl)phenyl)acetamide 9.42 (s, 1H), 7.52 (dd, J=2.6, 1.1 Hz, 1H), 7.34 (d. J=2.2 Hz, 1H), 7.257.00 (m, 3H), 4.57 (d. J=3.3 Hz, 1H), 2.94 (s.3H), Example 265 was prepared according to the procedure 2.00 (s, 3H), 1.98-1.74 (m, 8H). MS (ESI+) m/z 413.1 used for the preparation of Example 55, substituting (M+H)". Example 263C for Example 54B, to provide the title com 15 pound. "H NMR (500 MHz, DMSO-d) & 11.63 (brs, 1H), Example 267 10.00 (s, 1H), 7.65 (d. J=2.44 Hz, 1H), 7.46-7.50 (m, 2H), 7.39-7.44 (m. 1H), 7.36 (d. J=2.44 Hz, 1H), 701-7.04 (m, 2H), 6.87 (d. J=8.85 Hz, 1H), 2.04 (s.3H), 1.98 (s.3H). MS N-4-(4.4-difluorocyclohexyl)oxy-3-(5-methyl-6- oxo-1,6-dihydropyridin-3-yl) (DCI+) m/z. 371.1 (M+H)". phenylethanesulfonamide Example 266 N-4-(4.4-difluorocyclohexyl)oxy-3-(5-methyl-6- Example 267A oxo-1,6-dihydropyridin-3-yl) 25 phenyl)methanesulfonamide N-(4-(4,4-difluorocyclohexyloxy)-3-(6-fluoro-5- methylpyridin-3-yl)phenyl)ethanesulfonamide Example 266A Example 267A was prepared according to the procedure 2-bromo-1-(4,4-difluorocyclohexyloxy)-4-nitroben 30 used for the preparation of Example 22, Substituting Zee Example 266C for Example 20O, and substituting ethane Example 266A was prepared according to the procedure sulfonyl chloride for methanesulfonyl chloride, respectively, used for the preparation of Example 247A, substituting to provide the title compound. 2-bromo-1-fluoro-4-nitrobenzene for Example 225A, and 35 Substituting 4.4-difluorocyclohexanol for cyclohexanol, Example 267B respectively, to provide the title compound. Example 266B N-4-(4.4-difluorocyclohexyl)oxy-3-(5-methyl-6- oxo-1,6-dihydropyridin-3-yl) 3-bromo-4-(4,4-difluorocyclohexyloxy)aniline 40 phenylethanesulfonamide Example 266B was prepared according to the procedure Example 267B was prepared according to the procedure used for the preparation of Example 10, substituting used for the preparation of Example 55, substituting Example 266A for Example 9B, and substituting platinum 45 Example 267A for Example 54B, to provide the title com on carbon for palladium on carbon, respectively, to provide pound. "H NMR (300 MHz, DMSO-d) & 11.62 (bs, 1H), the title compound. 9.51 (s, 1H), 7.50 (dd, J=2.5, 1.1 Hz, 1H), 7.33 (d. J=2.1 Hz, 1H), 7.12 (s.3H), 4.56 (d. J=3.2 Hz, 1H), 3.04 (q, J–74 Hz, Example 266C 2H), 2.00 (s.3H), 1.95 1.70 (m, 8H), 1.20 (t, J=7.3 Hz, 3H). 4-(4,4-difluorocyclohexyloxy)-3-(6-fluoro-5-methyl 50 MS (ESI+) m/z 427.1 (M+H)". pyridin-3-yl)aniline Example 268 Example 266C was prepared according to the procedure used for the preparation of Example 9A, substituting N-4-(2,4-difluorophenoxy)-3-1-methyl-6-oxo-4- Example 266B for Example 1A, and substituting 6-fluoro 55 (trifluoromethyl)-1,6-dihydropyridin-3-yl) 5-methylpyridin-3-ylboronic acid for 2-fluoro-5-nitrophe phenylethanesulfonamide nylboronic acid, respectively, to provide the title compound. Example 266D Example 268 was prepared according to the procedure 60 used for the preparation of Example 22, Substituting ethane N-(4-(4,4-difluorocyclohexyloxy)-3-(6-fluoro-5- sulfonyl chloride for methanesulfonyl chloride, and substi methylpyridin-3-yl)phenyl)methanesulfonamide tuting Example 5E for Example 20O, respectively, to pro vide the title compound. "H NMR (300 MHz, DMSO-d) Example 266D was prepared according to the procedure 81H, 9.82 (s, 1H), 7.93 (s, 1H), 7.46-7.34 (m, 1H), 7.34-7.12 used for the preparation of Example 22, Substituting 65 (m. 2H), 7.13-6.95 (m, 2H), 6.85 (d. J=8.8 Hz, 2H), 3.47 (s, Example 266C for Example 20O, to provide the title com 3H), 3.06 (q, J=7.4 Hz, 2H), 1.19 (t, J=7.3 Hz, 3H). MS pound. (ESI+) m/z. 489.1 (M+H)". US 9,561,231 B2 159 160 Example 269 Example 270 N-4-(2,4-difluorophenoxy)-3-(4-methoxy-1-methyl N-3-(4-chloro-1-methyl-6-oxo-1,6-dihydropyridin 6-oxo-1,6-dihydropyridin-3-yl)phenyl)methanesulfo 3-yl)-4-(2,4-difluorophenoxy)phenylmethanesulfo namide namide Example 270A Example 269A 5-bromo-4-methoxy-1-methylpyridin-2(1H)-one 10 5-bromo-4-chloropyridin-2-ol Example 270A was prepared according to the procedure used for the preparation of Example 18C, substituting 5-Bromo-4-chloropyridin-2-amine (2.01 g, 9.69 mmol) Example 269B for Example 18B, to provide the title com pound. was dissolved in 75% (v/v) sulfuric acid (40.2 ml, 566 15 mmol) and then chilled in an ice bath. Sodium nitrite (2.21 Example 270B g, 32.0 mmol) dissolved in water (20.1 ml, 1116 mmol) was 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-4- added dropwise and the reaction mixture was then stirred for methoxy-1-methylpyridin-2(1H)-one 3 hours. The mixture was concentrated under reduced pres Sure and aqueous ammonia (15 mL) was added dropwise. Example 270B was prepared according to the procedure The resulting white precipitate was collected via vacuum used for the preparation of Example 1B, substituting Example 5D for 2-phenoxyphenylboronic acid, and filtration and the filter cake washed with cold water (100 Example 270A for Example 1A, respectively, to provide the mL) then dried in a vacuum oven for 24 hours to give 1.94 25 title compound. g (95%) of the title compound. Example 270C Example 269B N-4-(2,4-difluorophenoxy)-3-(4-methoxy-1-methyl 30 6-oxo-1,6-dihydropyridin-3-yl)phenyl)methanesulfo 5-bromo-4-chloro-1-methylpyridin-2(1H)-one namide Example 270C was prepared according to the procedure Example 269B was prepared according to the procedure used for the preparation of Example 22, substituting 270B used for the preparation of Example 1A, Substituting 35 for Example 20O. "H NMR (300 MHz, DMSO-d) & 9.69 (s. Example 269A for 6-chloropyridazin-3 (2H)-one, to provide 1H), 7.62 (s, 1H), 743-7.32 (m, 1H), 7.18 (dd, J=8.7, 2.7 Hz, the title compound. 1H), 7.15-6.97 (m, 3H), 6.88 (d. J–8.7 Hz, 1H), 5.82 (s, 1H), 3.60 (s, 3H), 3.36 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 437.1 (M+H)". Example 269C 40 Example 271 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-4- chloro-1-methylpyridin-2(1H)-one N-4-(2,4-difluorophenoxy)-3-(4-methoxy-1-methyl 6-oxo-1,6-dihydropyridin-3-yl)phenylethanesulfo 45 namide Example 269C was prepared according to the procedure used for the preparation of Example 1B, substituting Example 271 was prepared according to the procedure Example 5D for 2-phenoxyphenylboronic acid, and used for the preparation of Example 22, Substituting Example 269B for Example 1A, respectively, to provide the Example 27OB for Example 20O and substituting ethane 50 sulfonyl chloride for methanesulfonyl chloride, respectively title compound. to provide the title compound. "H NMR (300 MHz, DMSO d) & 9.76 (s, 1H), 7.62 (s, 1H), 7.43-7.32 (m. 1H), 7.18 (dd. Example 269D J=8.7, 2.7 Hz, 1H), 7.14-6.96 (m, 3H), 6.87 (d. J=8.7 Hz, 1H), 5.81 (s, 1H), 3.60 (s, 3H), 3.36 (s, 3H), 3.10 (q, J–7.3 55 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 451.1 N-3-(4-chloro-1-methyl-6-oxo-1,6-dihydropyridin (M+H)". 3-yl)-4-(2,4-difluorophenoxy)phenylmethanesulfo namide Example 272

60 N-4-(2,4-difluorophenoxy)-3-(4-4-(hydroxym Example 269D was prepared according to the procedure ethyl)phenyl-1-methyl-6-oxo-1,6-dihydropyridin-3- used for the preparation of Example 22, Substituting ylphenyl)methanesulfonamide Example 269C for Example 20O, to provide the title com pound. "H NMR (300 MHz, DMSO-d) & 9.82-9.74 (m, Example 272 was prepared according to the procedure 1H), 7.93 (s, 1H), 748-7.35 (m. 1H), 727-7.01 (m, 4H), 65 used for the preparation of Example 1B, substituting 4-(hy 6.90 (d. J=8.8 Hz, 1H), 6.65-6.44 (m. 1H), 3.46-3.41 (m, droxymethyl)phenylboronic acid for 2-phenoxyphenylbo 3H), 3.01 (s, 3H). MS (ESI+) m/z. 441.1 (M+H)". ronic acid, and Example 269D for Example 1A, respectively. US 9,561,231 B2 161 162 The reaction mixture was heated at 140°C., instead of 120° washed with brine, dried over MgSO, filtered, and concen C., to provide the title compound. "H NMR (300 MHz, trated to provide the title compound (4.35 g, 98% yield). DMSO-d) & 9.62 (s, 1H), 7.87-7.76 (m, 1H), 743-729 (m, 1H), 7.21-6.94 (m, 6H), 6.96-6.85 (m. 1H), 6.63-6.54 (m, Example 275B 1H), 6.45-6.25 (m, 1H), 6.14 (td, J=9.2, 5.6 Hz, 1H), 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene 4.48-4.42 (m, 2H), 3.49 (s, 3H), 2.87-2.76 (m, 3H). MS (ESI+) m/z 513.1 (M+H)". Example 275A (4.4 g. 18.7 mmol) in dichloromethane (300 mL) was treated with mCPBA (10.2g, 41.2 mmol). The Example 273 reaction was stirred at ambient temperature for 6 hours. The 10 Solvent was removed under reduced pressure, and the resi N-4-(2,4-difluorophenoxy)-3-(1-methyl-4-4-(4- due was taken up into ethyl acetate and was washed with methylpiperazin-1-yl)methylphenyl-6-oxo-1,6- saturated aqueous NaHCO solution (150 mL). The aqueous dihydropyridin-3-yl)phenylmethanesulfonamide layer was then extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, Example 273 was prepared according to the procedure 15 dried over MgSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl used for the preparation of Example 1B, substituting acetate in hexane to afford the title compound (4.4g, 88% 1-methyl-4-(4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2- yield). yl)benzyl)piperazine for 2-phenoxyphenylboronic acid, and substituting Example 269D for Example 1A, respectively. Example 275C The reaction mixture was heated at 140°C., instead of 120° C., to provide the title compound. "H NMR (300 MHz, 2-bromo-1-(cyclopropylmethoxy)-4-(ethylsulfonyl) DMSO-d) & 9.66 (s, 1H), 7.83 (s, 1H), 7.41-7.28 (m. 1H), benzene 7.20 (d. J=8.3 Hz, 2H), 7.13 (d. J=2.8 Hz, 1H), 7.09 (d. J=8.7 Example 275C was prepared according to the procedure Hz, 2H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 6.99-6.87 (im, 1H), 25 used for the preparation of Example 247A, substituting 6.57 (d. J=8.7 Hz, 1H), 6.37 (s, 1H), 6.31 (td, J=9.2, 5.8 Hz, Example 275B for Example 225A, and substituting cyclo 1H), 3.58 (m, 2H), 3.49 (s.3H), 3.45-3.21 (m, 4H), 2.87 (s, propylmethanol for cyclohexanol, respectively, to provide 3H), 2.74 (s.3H), 2.43-2.27 (m, 4H). MS (ESI+) m/z 595.1 the title compound. (M+H)" 30 Example 275D Example 274 2-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phe N-4-(2,4-difluorophenoxy)-3-1-methyl-4-4-(mor nyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane pholin-4-yl)phenyl]-6-oxo-1,6-dihydropyridin-3-yl phenyl)methanesulfonamide 35 Example 275D was prepared according to the procedure used for the preparation of Example 5D, substituting Example 274 was prepared according to the procedure Example 275C for Example 5C, to provide the title com used for the preparation of Example 1B, substituting 4-mor pound. pholinophenyl boronic acid for 2-phenoxyphenylboronic acid, and substituting Example 269D for Example 1A, 40 Example 275E respectively. The reaction mixture was heated at 140° C. 5-2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phe instead of 120° C., to provide the title compound. "H NMR nyl-4-methoxy-1-methylpyridin-2(1H)-one (300 MHz, DMSO-d) & 9.62 (s, 1H), 7.75 (s, 1H), 7.40-7.28 (m. 1H), 7.13 (d. J=2.7 Hz, 1H), 7.07 (dd, J=8.7, 2.7 Hz, Example 275E was prepared according to the procedure 1H), 6.97 (s, 1H), 6.96-6.86 (m, 2H), 6.88-6.74 (m, 2H), 45 used for the preparation of Example 1B, substituting 6.62 (d. J–8.7 Hz, 1H), 6.34-6.24 (m, 2H), 3.75-3.66 (m, Example 275D for 2-phenoxyphenylboronic acid, and sub 4H), 3.47 (s, 3H), 3.13-3.06 (m, 4H), 2.86 (s, 3H). MS stituting Example 270A for Example 1A, respectively, to (ESI+) m/z 568.2 (M+H)" provide the title compound. "H NMR (300 MHz, DMSO-d) & 7.79 (dd, J=8.6, 2.4 Hz, 1H), 7.61 (d. J=2.4 Hz, 2H), 7.23 Example 275 50 (d. J=8.7 Hz, 1H), 5.89 (s, 1H), 3.93 (d. J=6.7 Hz, 2H), 3.67 (s, 3H), 3.39 (s.3H), 3.25 (q, J–7.3 Hz, 2H), 1.20-1.06 (m, 5-2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phe 4H), 0.61-0.44 (m, 2H), 0.37-0.24 (m, 2H). MS (ESI+) m/z nyl-4-methoxy-1-methylpyridin-2(1H)-one 378.1 (M+H)".

Example 275A 55 Example 276 (3-bromo-4-fluorophenyl)(ethyl)sulfane 5-(2-(2,4-difluorophenoxy)-5-[(methylsulfonyl) aminolphenyl-N,1-dimethyl-2-oxo-1,2-dihydro A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.8 pyridine-4-carboxamide mmol) and 5.0 M sodium hydroxide (3.95 mL, 19.7 mmol) 60 in methanol (50 mL) was stirred at 0°C. for 10 minutes. To Example 276A this solution was added iodoethane (1.80 mL. 22.5 mmol). The reaction mixture was stirred at ambient temperature for methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyri 6 hours. The solvent was removed under reduced pressure, dine-4-carboxylate and the residue was partitioned between water and ethyl 65 acetate. The aqueous layer was extracted with additional Example 276A was prepared according to the procedure ethyl acetate three times. The combined organic layers were used for the preparation of Example 1A, Substituting methyl US 9,561,231 B2 163 164 5-bromo-2-hydroxyisonicotinate for 6-chloropyridazin-3 Example 278 (2H)-one, to provide the title compound. N-4-(2,4-difluorophenoxy)-3-(4-4-(hydroxym Example 276B ethyl)phenyl-1-methyl-6-oxo-1,6-dihydropyridin-3- yl)phenyl)ethanesulfonamide Methyl 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)- 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate Example 278A Example 276B was prepared according to the procedure N-(3-(4-chloro-1-methyl-6-oxo-1,6-dihydropyridin used for the preparation of Example 1B, substituting 10 3-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfona Example 5D for 2-phenoxyphenylboronic acid, and mide Example 276A for Example 1A, respectively, to provide the title compound. Example 278A was prepared according to the procedure used for the preparation of Example 22, Substituting ethane Example 276C 15 sulfonyl chloride for methanesulfonyl chloride, and Example 269C for Example 20O, respectively to provide the 5-(2-(2,4-difluorophenoxy)-5-(methylsulfonamido) title compound. phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-car boxylic acid Example 278B N-4-(2,4-difluorophenoxy)-3-(4-4-(hydroxym Example 276C was prepared according to the procedure ethyl)phenyl-1-methyl-6-oxo-1,6-dihydropyridin-3- used for the preparation of Example 22, Substituting yl)phenyl)ethanesulfonamide Example 276B for Example 20O to provide the title com pound. 25 Example 278B was prepared according to the procedure used for the preparation of Example 1B, substituting 4-(hy Example 276D droxymethyl)phenylboronic acid for 2-phenoxyphenylbo ronic acid, and substituting Example 278A for Example 1A, 5-2-(2,4-difluorophenoxy)-5-[(methylsulfonyl) respectively. The reaction mixture was heated at 140° C. aminolphenyl-N,1-dimethyl-2-oxo-1,2-dihydro 30 instead of 120° C., to provide the title compound. "H NMR pyridine-4-carboxamide (300 MHz, DMSO-d) & 9.72-9.65 (m, 1H), 7.82-7.76 (m, 1H), 743-729 (m. 1H), 7.21-7.11 (m, 2H), 7.12-6.82 (m, Example 276C (23 mg 0.051 mmol) and oxalyl chloride 5H), 6.59 (d. J=8.6 Hz, 1H), 6.44-6.34 (m. 1H), 6.25 (td, (8.94 uL, 0.102 mmol) were combined in dichloromethane J=9.3, -5.6 Hz, 1H), 4.49-442 (m, 2H), 3.49 (s.3H), 2.88 (5 mL) and 1 drop of dimethylformamide. After stirring at 35 (q, J=7.3 Hz, 2H), 1.13 (t, J–7.3 Hz, 3H). MS (ESI+) m/z ambient temperature for 2 hours, the Solution was concen 527.1 (M+H)". trated under reduced pressure. The residue was treated with 2.0 N methylamine in tetrahydrofuran (0.383 mL, 0.766 Example 279 mmol) and stirred at ambient temperature for 1 hour. To this mixture was added 1:1 brine/water (20 mL) and the mixture 40 N-4-(2,4-difluorophenoxy)-3-(1-methyl-4-4-(4- was extracted with ethyl acetate. The combined organics methylpiperazin-1-yl)methylphenyl-6-oxo-1,6- were washed with brine, dried (MgSO), filtered, and con dihydropyridin-3-yl)phenyl]ethanesulfonamide centrated. Purification by reverse phase chromatography Example 279 was prepared according to the procedure (C18, CHCN/water 0.1% TFA) afforded 18.8 mg (79%) of used for the preparation of Example 1B, substituting the title compound. "H NMR (300 MHz, DMSO-d) & 9.67 1-methyl-4-(4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2- (s, 1H), 8.39-8.32 (m. 1H), 7.78 (s, 1H), 7.46-7.34 (m. 1H), yl)benzyl)piperazine for 2-phenoxyphenylboronic acid, and 7.17-7.00 (m, 4H), 6.73 (d. J=8.6 Hz, 1H), 6.45 (s, 1H), 3.47 substituting Example 278A for Example 1A, respectively. (s, 3H), 2.99 (s.3H). MS (ESI+) m/z 464.1 (M+H)". The reaction mixture was heated at 140° C. instead of 120° 50 C., to provide the title compound. "H NMR (400 MHz, Example 277 pyridine-ds) & 7.51 (d. J=1.6 Hz, 1H) 7.43 (dd, J=8.7, 2.7 HZ, 1H), 7.33-7.25 (m, 4H), 7.05 (ddd, J=11.0, 8.3, 2.8 Hz, N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- 1H), 6.90-6.81 (m, 1H), 6.73 (t, J–4.4 Hz, 2H), 6.68 (td, oxo-1,6-dihydropyridin-3-yl)phenylmethanesulfo J=5.5 Hz, 2H), 3.51 (s.3H), 3.47 (s. 2H), 3.18 (q, J=7.3 Hz, namide 55 2H), 2.72 (m, 4H), 2.59 (m, 4H), 2.42 (s.3H), 1.35 (t, J–7.3 Hz, 3H). MS (ESI+) m/z. 609.1 (M+H)". Example 277 was prepared according to the procedure used for the preparation of Example 18C, substituting Example 280 Example 269D for Example 18B, and substituting ethanol for methanol, respectively. Purification by flash chromatog 60 N-4-(2,4-difluorophenoxy)-3-(4-4-(dimethyl raphy (SiO, 0-2% methanol/dichloromethane gradient) amino)methylphenyl-1-methyl-6-oxo-1,6-dihydro afforded 25 mg (49%) of the title compound. 'H NMR (300 pyridin-3-yl)phenylethanesulfonamide MHz, DMSO-d) & 9.69 (s, 1H), 7.61 (s, 1H), 7.43-7.31 (m, 1H), 7.21-7.11 (m, 2H), 7.08-6.96 (m, 2H), 6.90 (d. J=8.6 Example 280 was prepared according to the procedure HZ, 1H), 5.79 (s, 1H), 3.92 (q, J–7.0 Hz, 2H), 3.35 (s, 3H), 65 used for the preparation of Example 1B, substituting 4-((di 3.00 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI+) m/z 451.1 methylamino)methyl)phenylboronic acid for 2-phenoxyphe (M+H)" nylboronic acid, and substituting Example 278A for US 9,561,231 B2 165 166 Example 1A, respectively. The reaction mixture was heated 7.31-7.12 (m, 3H), 7.13-7.02 (m, 1H), 6.88 (d. J–8.7 Hz, at 140°C. instead of 120° C., to provide the title compound. 1H), 3.56 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z. 441.1 H NMR (300 MHz, DMSO-d) & 9.68 (s, 1H), 9.54 (bs, (M+H)". 1H), 7.81 (s, 1H), 7.40-7.26 (m, 3H), 7.21-7.14 (m, 2H), 7.12 (d. J=2.6 Hz, 1H), 7.04 (dd, J=8.7, 2.7 Hz, 1H), Example 283 6.97-6.86 (m. 1H), 6.55 (d. J–8.7 Hz, 1H), 6.48-6.31 (m, N-3-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin 2H), 4.25-4.18 (m, 2H), 3.47 (s.3H), 2.96 (q, J–7.3 Hz, 2H), 3-yl)-4-(2,4-difluorophenoxy)phenylethanesulfona 2.69 (d. J=4.3 Hz, 6H), 1.14 (t, J=7.3 Hz, 3H). MS (ESI+) mide m/z 554.0 (M+H)". 10 Example 283 was prepared according to the procedure Example 281 used for the preparation of Example 22, Substituting Example 282A for Example 20O and substituting ethane 3-chloro-1-methyl-5-(2-phenoxyphenyl)pyridin-2 sulfonyl chloride for methanesulfonyl chloride, respectively, (1H)-one to provide the title compound. "H NMR (300 MHz, DMSO 15 d) & 9.78 (s, 1H), 7.98-7.88 (m, 2H), 7.50-7.39 (m, 1H), 7.28-7.12 (m, 3H), 7.13-7.02 (m, 1H), 6.87 (d. J–8.7 Hz, Example 281A 1H), 3.56 (s, 3H), 3.12 (q, J=7.3 Hz, 2H), 1.22 (t, J–7.3 Hz, 5-bromo-3-chloro-1-methylpyridin-2(1H)-one 3H). MS (ESI+) m/z 455.1 (M+H)". Example 284 Example 281A was prepared according to the procedure used for the preparation of Example 1A, Substituting N-4-(2,4-difluorophenoxy)-3-1-methyl-4-4-(mor 5-bromo-3-chloropyridin-2(1H)-one for 6-chloropyridazin pholin-4-yl)phenyl]-6-oxo-1,6-dihydropyridin-3-yl 3(2H)-one, to provide the title compound. phenylethanesulfonamide 25 Example 281B Example 284 was prepared according to the procedure used for the preparation of Example 1B, substituting 4-mor pholinophenyl boronic acid for 2-phenoxyphenylboronic 3-chloro-5-(2-phenoxyphenyl)pyridin-2(1H)-one acid, and substituting Example 278A for Example 1A, respectively. The reaction mixture was heated at 140° C. Example 281B was prepared according to the procedure 30 instead of 120° C., to provide the title compound. "H NMR used for the preparation of Example 1B, substituting (300 MHz, DMSO-d) & 9.67 (s, 1H), 7.75 (s, 1H), 7.40-7.28 Example 281 A for Example 1A to provide the title com (m. 1H), 7.13 (d. J=2.7 Hz, 1H), 7.07 (dd, J=8.7, 2.7 Hz, pound. "H NMR (300 MHz, DMSO-d) & 7.98 (d. J=2.4 Hz, 1H), 6.97 (s, 1H), 6.96-6.86 (m, 2H), 6.88-6.74 (m, 2H), 1H), 7.93 (d. J=2.4 Hz, 1H), 7.51 (dd, J=7.6, 1.8 Hz, 1H), 6.62 (d. J=8.7 Hz, 1H), 6.34-6.24 (m, 2H), 3.75-3.66 (m, 7.43-729 (m, 3H), 7.25 (td, J-7.5, 1.3 Hz, 1H), 7.15-7.05 35 4H), 3.46 (s, 3H), 3.13-3.06 (m, 4H), 2.88 (q, J=7.46 Hz, (m. 1H), 7.01-6.91 (m, 3H), 3.54 (s, 3H). MS (ESI+) m/z 2H), 1.12 (t, J=746 Hz, 3H). MS (ESI+) m/z 582.2 (M+H)". 312.3 (M+H)". Example 285 Example 282 N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- 40 oxo-1,6-dihydropyridin-3-yl)phenylethanesulfona N-3-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin mide 3-yl)-4-(2,4-difluorophenoxy)phenylmethanesulfo namide A mixture of Example 278a (0.050 g, 0.110 mmol) and sodium ethoxide (0.187 g, 2.75 mmol) in ethanol (2 mL) was Example 282A 45 heated at 65° C. for 72 hours. The reaction mixture was cooled to ambient temperature and quenched with water. 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-3- The mixture was extracted with ethyl acetate, and the organic layer was washed with Saturated aqueous sodium chloro-1-methylpyridin-2(1H)-one chloride, dried over anhydrous magnesium sulfate, filtered, 50 and evaporated. The residue was purified by flash chroma Example 282A was prepared according to the procedure tography (silica gel, 0-2% methanol/dichloromethan gradi used for the preparation of Example 1B, substituting ent) to provide the title compound (0.025 g, 49% yield). H Example 5D for 2-phenoxyphenylboronic acid, and substi NMR (300 MHz, DMSO-d) & 9.75 (s, 1H), 7.60 (s, 1H), tuting Example 281 A for Example 1A, respectively, to 7.36 (ddd, J=11.2, 8.7, 2.7 Hz, 1H), 7.17 (dd, J=8.7, 2.7 Hz, provide the title compound. 55 1H), 7.12 (d. J=2.7 Hz, 1H), 7.05-6.94 (m, 2H), 6.88 (d. J=8.7 Hz, 1H), 5.78 (s, 1H), 3.90 (q, J=7.0 Hz, 2H), 3.34 (s, Example 282B 1H), 3.10 (q, J–7.0 Hz, 2H), 1.21 (t, J=7.3 Hz, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI+) m/z 465.1 (M+H)". N-(3-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin 3-yl)-4-(2,4-difluorophenoxy)phenyl)methanesulfo 60 Example 286 namide N-4-(2,4-difluorophenoxy)-3-1-methyl-4-2-(mor Example 282B was prepared according to the procedure pholin-4-yl)ethoxy-6-oxo-1,6-dihydropyridin-3-yl used for the preparation of Example 22, Substituting phenylethanesulfonamide Example 282A for Example 20O, to provide the title com 65 pound. 'H NMR (300 MHz, DMSO-d) & 9.70 (s, 1H), 7.97 To a slurry of sodium hydride (16.23 mg, 0.440 mmol) in (d. J=2.4 Hz, 1H), 7.92 (d. J=2.4 Hz, 1H), 7.50-7.39 (m, 1H), anhydrous dioxane (2 mL) was added portion-wise 2-mor

US 9,561,231 B2 169 170 60% in oil). The solution was stirred at ambient temperature Example 294E for 10 minutes. To this solution was added Example 269B (2.5g, 11.24 mmol). The reaction mixture was heated at 90° 4-(4-amino-2-(1-methyl-6-oxo-4-(2.2.2-trifluoroeth C. for three hours. The solvent was evaporated, and the oxy)-1,6-dihydropyridin-3-yl)phenoxy)benzonitrile residue was subjected re-dissolved in ethyl acetate, washed with water, and partitioned. The aqueous layer was extracted Example 294E was prepared according to the procedure used for the preparation of Example 1B, substituting with additional ethyl acetate three times. The combined Example 294D for 2-phenoxyphenylboronic acid, and organic layers were washed with Saturated aqueous sodium Example 294A for Example 1A, respectively, to provide the chloride, dried over anhydrous magnesium sulfate, filtered title compound. and concentrated. The residue was purified by flash column 10 chromatography on silica gel eluting with 60% ethyl acetate Example 294F in hexanes to afford the title compound (3.06 g. 10.70 mmol. 95% yield). 4-4-(ethylsulfonyl)amino-2-1-methyl-6-oxo-4-(2, 2.2-trifluoroethoxy)-1,6-dihydropyridin-3-yl) Example 294B 15 phenoxybenzamide Example 294F was prepared according to the procedure 4-(2-bromo-4-nitrophenoxy)benzonitrile used for the preparation of Example 22, Substituting Example 294D for Example 20O, and ethanesulfonyl chlo ride for methanesulfonyl chloride, respectively, to provide A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.20 g, 10 the title compound. The title product was isolated as a minor mmol), 4-hydroxybenzonitrile (1.31 g, 11 mmol), and product. "H NMR (500 MHz, DMSO-d) & 9.87 (s, 1H), cesium carbonate (3.58 g, 11 mmol) in dimethyl sulfoxide 7.85 (s, 1H), 7.78 (d. J=8.54 Hz, 2H), 7.65 (s, 1H), 7.24-7.27 (20 mL) was heated at 90° C. for 2 hours. After cooling, the (m. 2H), 7.17 (d. J=2.44 Hz, 1H), 7.07 (d. J=8.85 Hz, 1H), reaction mixture was partitioned between water and ethyl 6.79 (d. J=8.85 Hz, 2H), 5.99 (s, 1H), 4.69 (q, J=8.65 Hz, acetate. The aqueous layer was extracted three times with 25 2H), 3.32 (s, 3H), 3.11 (q, J-7.32 Hz, 2H), 1.22 (t, J–7.32 ethyl acetate. The combined organic layers were washed Hz, 3H). MS (ESI+) m/z 526.1 (M+H)". with Saturated aqueous Sodium chloride, dried over anhy drous magnesium sulfate, filtered, and concentrated to give Example 295 3.19 g (110%) of the title compound. N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- 30 oxo-1,6-dihydropyridin-3-yl)phenyl)-2-oxo-1-phe Example 294C nylpyrrolidine-3-carboxamide 4-(4-amino-2-bromophenoxy)benzonitrile A solution of Example 406B and diisopropylethylamine (0.182 M and 0.52 M in dimethyl acetamide, respectively, 35 221 uL, 0.40 mmol Example 406B (1.0 equivalent) and 1.21 Example 294 B (3.21 g, 10.06 mmol) and tetrahydrofuran mmol diisopropylethylamine (3.0 equivalents)), O-(7- (70 mL) were added to platinum(IV)oxide (0.642 g, 2.83 aZabenzotriazol-1-yl)-N.N.N',N'-tetramethyluronium mmol) in a 250 mL stainless steel pressure bottle and stirred hexafluorophosphate (HATU) (0.182 M in dimethyl acet for 45 minutes at 30 psi of hydrogen at ambient temperature. amide, 221 uL, 0.40 mmol. 1 equivalent) and 2-oxo-1- The solid was filtered off, and the filtrate was concentrated. 40 phenylpyrrolidine-3-carboxylic acid (0.40 M in dimethyl The residue was purified by flash chromatography on silica acetamide, 151 uL, 0.60 mmol. 1.5 equivalents) were mixed gel eluting with 30% ethyl acetate in hexanes to give 1.75 g through a perfluoroalkoxy mixing tube (0.2 mm inner diam (60%) of the title compound. eter), and loaded into an injection loop. The reaction seg ment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C. Example 294D 45 and passed through the reactor at 180 uL per minute (10 minute residence time). Upon exiting the reactor, the solu 4-(4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboro tion was loaded directly into an injection loop and purified lan-2-yl)phenoxy)benzonitrile by preparative HPLC on a Phenomenex Luna C8(2) 5um 50 100 A AXIA column (50 mmx21.2 mm) eluting with a A mixture of Example 294C (1.75 g. 6.05 mmol), 4.4.4, gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in 4.5.5.5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.07 g. water (B) at a flow rate of 30 mL/min (0-0.5 min 5% A, 12.11 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- 0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, phosphaadamantane (0.159 g, 0.545 mmol), tris(diben 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to Zylideneacetone)dipalladium(0) (0.166 g., 0.182 mmol), and 55 provide the title compound. "H NMR (400 MHz, DMSO potassium acetate (1.307 g. 13.32 mmol) in dioxane (30 mL) d/DO) & 7.71-7.55 (m, 5H), 747-728 (m, 3H), 7.24-7.16 was degassed and back-filled with nitrogen several times. (m. 1H), 7.07-6.96 (m, 2H), 6.92 (d. J=8.7 Hz, 1H), 5.83 (s, The reaction mixture was heated at 80° C. for 20 hours. The 1H), 4.03-3.85 (m, 4H), 3.37 (s, 3H), 2.46-2.32 (m, 2H), Solvent was evaporated, and the residue was partitioned 1.15 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 560.0 (M+H)". between water and ethyl acetate. The aqueous layer was 60 Example 296 extracted with additional ethyl acetate three times. The combined organic layers were washed with Saturated aque N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- ous sodium chloride, dried over anhydrous magnesium oxo-1,6-dihydropyridin-3-yl)phenyl-3,3-dimeth sulfate, filtered, and concentrated. The crude product was ylbutanamide purified by flash chromatography (silica gel, 40-70% ethyl 65 acetate in hexanes) to provide 2.0 g (98%) of the title Example 296 was prepared according to the procedure compound. used for the preparation of Example 295, substituting 3.3-

US 9,561,231 B2 173 174 7.10-6.99 (m, 2H), 6.95 (d. J=8.5 Hz, 1H), 5.85 (s, 1H), 3.96 set at 50° C., and passed through the reactor at 180 uL per (q, J=6.9 Hz, 2H), 3.39 (s.3H), 1.17 (t, J=6.9 Hz, 3H). MS minute (10 minute residence time). Upon exiting the reactor, (APCI+) m/z 552.9 (M+H)". the reaction mixture was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Example 305 Luna C8(2) 5um 100 A AXIA column (50 mmx21.2 mm) eluting with a gradient of acetonitrile (A) and 0.1% trifluo 5-2-(2,4-difluorophenoxy)-5-[(2,2-dimethylpropyl) roacetic acid in water (B) at a flow rate of 30 mL/min (0-0.5 aminolphenyl)-4-ethoxy-1-methylpyridin-2(1H)-one min 5% A, 0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 A solution of Example 406B and acetic acid (0.152 Mand 10 min 5% A) to provide the title compound. "H NMR (400 1.4 M in methanol, respectively, 265 uL, 0.40 mmol Example 406B (1.0 equivalent) and 4 mmol acetic acid (10 MHz, DMSO-d/DO) & 8.16-8.09 (m. 2H), 8.02-7.96 (m, equivalents)), sodium cyanoborohydride (0.2 M in metha 2H), 7.45 (s, 1H), 7.36-7.27 (m, 1H), 7.07 (dd, J=8.7, 2.7 Hz, nol, 294 uL, 0.6 mmol. 1.5 equivalents) and 2,2-dimethyl 1H), 7.06-6.91 (m, 3H), 6.85-6.79 (m. 1H), 5.80 (s, 1H), propanal (0.40 M in dimethyl acetamide, 121 uL, 0.48 15 3.89 (q, J=7.0 Hz, 2H), 3.35 (s.3H), 3.27 (s.3H), 1.26-1.06 mmol. 1.2 equivalents) were mixed through a perfluoro (m, 3H). MS (APCI+) m/z 590.9 (M+H)". alkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected Example 308 into the flow reactor (Hastelloy coil, 0.75 mm inner diam N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- eter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 uL per minute (10 minute resi oxo-1,6-dihydropyridin-3-yl)phenyl)-4-(trifluo dence time). Upon exiting the reactor, the reaction mixture romethoxy)benzenesulfonamide was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Example 308 was prepared according to the procedure A AXIA column (50 mmx21.2 mm) eluting with a gradient 25 used for the preparation of Example 307, substituting 4-(tri of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) fluoromethoxy)benzenesulfonyl chloride for 4-(methylsul at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6.5 min fonyl)benzenesulfonyl chloride. "H NMR (400 MHz, linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min DMSO-d/DO) & 7.91-7.85 (m, 2H), 7.60-7.54 (m, 2H), linear gradient 100-5% A, 9.0-10 min 5% A) to provide the 7.46 (s, 1H), 7.38-7.27 (m, 1H), 7.11-6.89 (m, 4H), 6.82 (d. title compound as the trifluoroacetate salt. H NMR (400 30 J=8.7 Hz, 1H), 5.80 (s, 1H), 3.89 (q, J=7.0 Hz, 2H), 3.35 (s, MHz, DMSO-d/DO) & 7.48 (s, 1H), 7.23 (ddd, J=11.4, 8.6, 3H), 1.09 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 596.9 2.9 Hz, 1H), 6.98-6.88 (m, 1H), 6.85-6.76 (m, 2H), 6.65 (dd. (M+H)". J=8.7, 2.9 Hz, 1H), 6.55 (d. J–2.9 Hz, 1H), 5.76 (s, 1H), 3.87 (q, J–7.0 Hz, 2H), 3.33 (s, 3H), 2.80 (s. 2H), 1.10 (t, J=6.9 Example 309 Hz, 3H), 0.96 (s, 9H). MS (APCI+) m/z 443.1 (M+H)". 35 N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- Example 306 oxo-1,6-dihydropyridin-3-yl)phenylbiphenyl-4- 5-2-(2,4-difluorophenoxy)-5-[(3.3-dimethylbutyl) Sulfonamide aminolphenyl)-4-ethoxy-1-methylpyridin-2(1H)-one 40 Example 309 was prepared according to the procedure Example 306 was prepared according to the procedure used for the preparation of Example 307, substituting 4-phe used for the preparation of Example 305, substituting 3.3- nylbenzenesulfonyl chloride for 4-(methylsulfonyl)benze dimethylbutanal for 2,2-dimethylpropanal. "H NMR (400 nesulfonyl chloride. "H NMR (400 MHz, DMSO-d/DO) & MHz, DMSO-d/DO) & 7.48 (s, 1H), 7.23 (ddd, J=11.4, 8.6, 45 7.91-7.85 (m, 2H), 7.87-7.80 (m, 2H), 7.73 (d. J=1.6 Hz, 2.9 HZ, 1H), 6.98-6.89 (m. 1H), 6.85-6.76 (m, 2H), 6.58 (dd. 1H), 7.52 (t, J=7.5 Hz, 2H), 7.46 (d. J=7.2 Hz, 2H), J=8.7, 2.9 Hz, 1H), 6.47 (d. J–2.8 Hz, 1H), 5.77 (s, 1H), 3.87 7.46-7.42 (m, 2H), 7.30 (ddd, J=11.2, 8.6, 2.8 Hz, 1H), 7.11 (q, J–7.0 Hz, 2H), 3.33 (s.3H), 3.02-2.94 (m, 2H), 1.52-1.44 (dd, J=8.7, 2.7 Hz, 1H), 7.05-6.89 (m, 3H), 6.83 (d. J=8.7 (m. 2H), 1.12 (t, J=6.9 Hz, 3H), 0.94 (s, 9H) MS (APCI+) HZ, 1H), 5.79 (s, 1H), 3.87 (q, J–7.0 Hz, 2H), 3.31 (s, 3H), m/z 457.1 (M+H)". 50 1.06 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 588.9 (M+H)". Example 307 Example 310 N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- oxo-1,6-dihydropyridin-3-yl)phenyl)-4-(methylsul 55 oxo-1,6-dihydropyridin-3-yl)phenyl-1-(1S,4R)-7,7- fonyl)benzenesulfonamide dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesul fonamide A stock solution of Example 406B and diisopropylethyl amine (0.11 M and 0.2 M in dimethyl acetamide, respec Example 310 was prepared according to the procedure tively, 375 uL, 0.40 mmol Example 406B (1.0 equivalent) 60 used for the preparation of Example 307, substituting 1-(1S, and 0.80 mmol diisopropylethylamine (2 equivalents)) and 4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methane 4-(methylsulfonyl)benzenesulfonyl chloride (0.40 M in sulfonyl chloride for 4-(methylsulfonyl)benzenesulfonyl dimethyl acetamide, 232 uL, 0.92 mmol. 2.3 equivalents) chloride. "H NMR (400 MHz, DMSO-d/DO) & 7.57 (s, were mixed through a perfluoroalkoxy mixing tube (0.2 mm 1H), 737-7.27 (m, 1H), 7.20-7.12 (m, 2H), 7.06-6.96 (m, inner diameter), and loaded into an injection loop. The 65 2H), 6.92-6.86 (m. 1H), 5.82 (s, 1H), 3.96-3.88 (m, 2H), reaction segment was injected into the flow reactor (Hastel 3.37 (s, 4H), 3.20-2.93 (m, 1H), 2.43-2.29 (m, 3H), 2.09 loy coil, 0.75 mm inner diameter, 1.8 mL internal volume) 2.03 (m. 1H), 1.99-1.87 (im, 2H), 1.66 (s, 4H), 1.57-1.47 (m, US 9,561,231 B2 175 176 1H), 1.45-1.35 (m. 1H), 1.19-1.13 (m, 2H), 1.13 (d. J=6.9 Example 312C Hz, 3H), 1.00 (s, 3H), 0.77 (s.3H). MS (APCI+) m/z 587.0 (M+H)". 5-(4-bromo-3-(cyclopropylmethoxy)phenyl)-3- methyl-1H-pyrazole Example 311 Example 312B (1.50 g, 4.82 mmol) and hydrazine (0.159 N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- mL, 5.06 mmol) were combined in ethanol (20 mL). The oxo-1,6-dihydropyridin-3-yl)phenyl)-1-phenylmeth reaction mixture was stirred at ambient temperature for 1 anesulfonamide hour and concentrated to provide the title compound (1.48g. 10 100%). A flask with stirbar was charged with Example 406B (0.173 g, 0.465 mmol), phenylmethanesulfonyl chloride Example 312D (0.23 g, 1.206 mmol) and triethylamine (0.30 mL, 2.152 mmol) in dichloromethane (6.00 mL) and the solution was 5-2-(cyclopropylmethoxy)-4-(3-methyl-1H-pyrazol stirred at ambient temperature for 18 hours. The mixture was 15 5-yl)phenyl-1-methylpyridin-2(1H)-one stripped down by rotovap, then 1 M sodium hydroxide (2 mL, 2.000 mmol) and tetrahydrofuran (4.00 mL) were added Example 312C (61.4 mg., 0.200 mmol), 1-methyl-5-(4.4, and the mixture was heated at 60° C. for 1 hour. The mixture 5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one was cooled and partitioned between 60 mL each of ethyl (47.0 mg, 0.200 mmol), cesium fluoride (91 mg, 0.60 mmol) acetate and aqueous ammonium chloride. The organics were and tetrakis(triphenylphosphine)palladium(0) (11.6 mg, dried over anhydrous Sodium sulfate, filtered, and concen 10.0 umol) were combined in the mixture of dimethoxy trated. The residues chromatographed on a 12 g silica ethane (2 mL) and methanol (1 mL). The reaction mixture cartridge eluting with 0-10% methanol/dichloromethane to was purged with nitrogen for 15 minutes and heated in a provide the title compound. 1H NMR (400 MHz, DMSO-d) microwave reactor at 130° C. for 80 minutes. The reaction & 12.04 (s, 1H), 9.85 (s, 1H), 7.40-7.24 (m, 9H), 7.17 (dd. 25 mixture was partitioned with ethyl acetate and water. The J=8.8, 2.7 Hz, 1H), 7.09-6.95 (m, 2H), 6.91 (d. J=8.8 Hz, organic layer was washed with Saturated aqueous sodium 1H), 6.26 (t, J–2.2 Hz, 1H), 4.50 (s. 2H), 3.54 (s, 3H). MS chloride, dried with anhydrous sodium sulfate, treated with (ESI) 522.1 (M+H+). 3-mercaptopropyl functionalized silica gel, filtered, and con centrated. The residue was purified by flash chromatography Example 312 30 (silica gel, 2-6% methanol in dichloromethane) to provide the title compound (36 mg, 54%). "H NMR (300 MHz, 5-2-(cyclopropylmethoxy)-4-(3-methyl-1H-pyrazol DMSO-d) & 12.53 (s, 1H) 7.93 (s, 1H) 7.71 (dd, J=9.49, 5-yl)phenyl-1-methylpyridin-2(1H)-one 2.71 Hz, 1H) 7.09-7.45 (m, 3H) 6.35-6.57 (m, 2H)3.93 (d. J=6.44 Hz, 2H)3.49 (s.3H) 2.27 (s, 3H) 1.13-1.31 (m, 1H) Example 312A 35 0.48-0.60 (m, 2H) 0.27-0.40 (m, 2H). MS (ESI+) m/z 336 (M+H)". 1-(4-bromo-3-(cyclopropylmethoxy)phenyl)ethanone Example 313 1-(4-bromo-3-hydroxyphenyl)ethanone (2.04 g. 9.50 mmol), (bromomethyl)cyclopropane (1.01 mL, 10.5 mmol) 40 5-2-[2-(but-3-en-1-yn-1-yl)phenoxy-5-(ethylsulfo and potassium carbonate (1.58 g., 11.4 mmol) were com nyl)phenyl)-4-hydroxy-1-methylpyridin-2(1H)-one bined in dimethylsulfoxide (10 mL). The reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was Example 313A partitioned with ethyl acetate and water. The organic layer was washed with Saturated aqueous sodium chloride, dried 45 2-(5-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetram with anhydrous sodium sulfate, filtered, and concentrated. ethyl-1,3,2-dioxaborolane The residue was purified by flash chromatography (silica gel, 10-20% ethyl acetate in heptanes) to provide the title Example 313A was prepared according to the procedure compound (2.05 g, 80%). used for the preparation of Example 5D, substituting 50 Example 275B for Example 5C, to provide the title com Example 312B pound. (Z)-1-(4-bromo-3-(cyclopropylmethoxy)phenyl)-3- Example 313B hydroxybut-2-en-1-one 55 4-chloro-5-(5-(ethylsulfonyl)-2-fluorophenyl)-1- Example 312A (1.66 g. 6.17 mmol), sodium ethoxide methylpyridin-2(1H)-one (0.504g, 7.40 mmol) and anhydrous ethyl acetate (2.42 mL, 24.7 mmol) were combined and stirred at ambient tempera A mixture of Example 269B (1.112 g, 5 mmol). Example ture for 18 hours. To this reaction mixture was added sodium 313A (1.571 g, 5 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4, ethoxide (0.840 mg, 1.23 mmol) again and stirred at ambient 60 8-trioxa-6-phosphaadamantane (0.171 g, 0.585 mmol), tris temperature for another 4 hours. The reaction mixture was (dibenzylideneacetone)dipalladium(0) (0.137 g., 0.150 partitioned with ethyl acetate and 1M HCl. The organic layer mmol), and potassium phosphate (2.65 g, 12.50 mmol) in was washed with Saturated aqueous sodium chloride, dried dioxane (16 mL) and water (4.00 mL) was degassed and with anhydrous sodium sulfate, filtered, and concentrated. back-filled with nitrogen several times. The reaction mixture The residue was purified by flash chromatography (silica 65 was heated at 60° C. for 16 hours. The reaction mixture was gel, 0-10% ethyl acetate in heptanes) to provide the title partitioned between water and ethyl acetate. The aqueous compound (1.57 g. 82%). layer was extracted with additional ethyl acetate three times. US 9,561,231 B2 177 178 The combined organic layers were washed with saturated 3.34 (s, 3H), 3.28 (q, J-7.32 Hz, 2H), 1.11 (t, J=7.32 Hz, aqueous sodium chloride, dried over anhydrous magnesium 3H). MS (ESI+) m/z 436.1 (M+H)". sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with Example 314 60% ethyl acetate in hexanes to give the title compound (0.72 g, 2.183 mmol, 43.7% yield). 4-chloro-5-5-(ethylsulfonyl)-2-[2-(3-hydroxyprop 1-yn-1-yl)phenoxyphenyl-1-methylpyridin-2(1H)- Example 313C O 4-chloro-5-(5-(ethylsulfonyl)-2-(2-iodophenoxy) 10 Example 314 was prepared according to the procedure phenyl)-1-methylpyridin-2(1H)-one used for the preparation of Example 313D, substituting prop-2-yn-1-ol for but-3-yn-1-ol, to provide the title com A mixture of Example 313B (0.46 g, 1.395 mmol), pound. "H NMR (500 MHz, DMSO-d) & 7.99 (s, 1H), 2-iodophenol (0.307 g. 1.395 mmol), and cesium carbonate 7.87-7.89 (m, 1H), 7.86 (d. J=2.44 Hz, 1H), 7.52 (dd, (0.454g, 1.395 mmol) in dimethyl sulfoxide (10 mL) was 15 J–7.78, 1.68 Hz, 1H), 7.42-746 (m, 1H), 7.24-728 (m. 1H), heated at 100° C. overnight. After cooling, the reaction 7.11 (d. J=7.32 Hz, 1H), 6.93 (d. J=8.85 Hz, 1H), 6.86 (s, mixture was partitioned between water and ethyl acetate. 1H), 4.17 (s, 1H), 3.46 (s.3H), 3.32 (q, J=7.32 Hz, 2H), 1.13 The aqueous layer was separarred and extracted with addi (t, J-7.32 Hz, 3H). MS (ESI+) m/z 457.9 (M+H)". tional ethyl acetate twice. The combined organic layers were washed with Saturated aqueous sodium chloride, dried over Example 315 anhydrous magnesium Sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica N-4-(2,4-difluorophenoxy)-3-(1-methyl-4-4-(mor gel eluting 1:1 ethyl acetate/hexanes to give the title com pholin-4-ylmethyl)benzyloxy-6-oxo-1,6-dihydro pound (0.46g, 0.868 mmol, 62.2% yield). pyridin-3-yl)phenylethanesulfonamide 25 Example 313D The trifluoroacetic acid salt of Example 315 was prepared according to the procedure used for the preparation of 4-chloro-5-(5-(ethylsulfonyl)-2-(2-(4-hydroxybut-1- Example 286, substituting (4-(morpholinomethyl)phenyl) yn-1-yl)phenoxy)phenyl)-1-methylpyridin-2(1H)- methanol for 2-morpholinoethanol. H NMR (300 MHz, O 30 DMSO-d) 89.82 (s, 1H), 7.66 (s, 1H), 7.34-7.46 (m, 5H), 7.17-7.20 (m, 2H), 6.90-6.95 (m, 3H), 5.85 (s, 1H), 5.12 (s, A mixture of Example 313C (0.106 g., 0.2 mmol), but-3- 2H), 4.33 (s. 2H), 3.94 (s. 2H), 3.34 (s, 3H), 3.05-3.24 (m, yn-1-ol (0.028 g., 0.400 mmol), copper(I) iodide (7.62 mg, 1OH), 1.19 (t, J=7.32 Hz, 3H). MS (ESI+) m/z. 626.1 0.040 mmol), bis(triphenylphosphine)palladium(II) chloride (M+H)". (0.014 g., 0.020 mmol), and triethylamine (0.573 mL, 4.00 35 mmol) in dimethylformamide (2 mL) was heated at 80° C. Example 316 for 2 hours. After cooling, the reaction mixture was parti tioned between water and ethyl acetate. The aqueous layer N-4-(2,4-difluorophenoxy)-3-1-methyl-4-(oxetan was separarred and extracted with additional ethyl acetate 3-yloxy)-6-oxo-1,6-dihydropyridin-3-yl) twice. The combined organic layers were washed with 40 phenylethanesulfonamide saturated aqueous Sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue Example 316 was prepared according to the procedure was purified by flash chromatography on silica gel eluting used for the preparation of Example 286, substituting 4:1 ethyl acetate/hexanes to give the title compound (0.078 oxetan-3-ol for 2-morpholinoethanol. H NMR (500 MHz, g, 0.165 mmol, 83% yield). 45 DMSO-d) & 9.80 (s, 1H), 7.70 (s, 1H), 7.36-7.42 (m. 1H), 7.18-7.22 (m, 2H), 7.01-7.11 (m, 2H), 6.91 (d. J=8.54 Hz, Example 313E 1H), 5.48 (s, 1H), 5.15-5.21 (m. 1H), 4.80 (t, J=6.87 Hz, 2H), 4.33 (dd, J–7.63, 4.88 Hz, 2H), 3.36 (s, 3H), 3.12 (q, 5-2-[2-(but-3-en-1-yn-1-yl)phenoxy-5-(ethylsulfo J=7.32 Hz, 2H), 1.23 (t, J=7.32 Hz, 3H). MS (ESI+) m/z nyl)phenyl)-4-hydroxy-1-methylpyridin-2(1H)-one 50 493.1 (M+H)". A mixture of Example 313D (0.078 g., 0.165 mmol) and Example 317 sodium hydride (0.043 g, 0.662 mmol. 60% in oil) in dioxane (5 mL) was heated at 85° C. overnight. After 4-(2,4-difluorophenoxy)-5-[2-(2,4-difluorophenoxy)- cooling, the reaction mixture was partitioned between water 55 5-(ethylsulfonyl)phenyl-1-methylpyridin-2(1H)-one and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate twice. The combined A mixture of Example 313B (0.330 g, 1 mmol), 2,4- organic layers were washed with Saturated aqueous sodium difluorophenol (0.195 g, 1.500 mmol), and cesium carbonate chloride, dried over anhydrous magnesium sulfate, filtered, (0.489 g, 1.500 mmol) in dimethyl sulfoxide (8 mL) was and concentrated. The residue was purified by reverse phase 60 heated at 100° C. overnight. After cooling, the reaction HPLC (C18, CH,CN/water (0.1% TFA), 0-100%) to give mixture was partitioned between water and ethyl acetate. (0.036 g., 0.083 mmol, 50.0% yield). "H NMR (500 MHz, The aqueous layer was separarred and extracted with addi DMSO-d) & 10.89 (s, 1H), 7.81 (d. J=2.14 Hz, 1H), 7.78 tional ethyl acetate twice. The combined organic layers were (dd, J=8.54, 2.44 Hz, 1H), 7.73 (s, 1H), 7.53 (dd, J=7.78, washed with Saturated aqueous Sodium chloride, dried over 1.68 Hz, 1H), 742-7.45 (m, 1H), 7.23 (t, J=7.48 Hz, 1H), 65 anhydrous magnesium Sulfate, filtered, and concentrated. 7.10 (d. J=7.63 Hz, 1H), 6.93 (d. J=8.54 Hz, 1H), 6.00 (dd, The residue was purified by reverse phase HPLC (C18, J=17.39, 11.29 Hz, 1H), 5.22 (s, 1H), 5.50-5.57 (m, 2H), CHCN/water (0.1% TFA), 0-100%) to give the title com

US 9,561,231 B2 181 182 3H), 5.80 (s, 1H), 3.87 (d. J=11.9 Hz, 2H), 3.74 (d. J=6.41 mixture was adsorbed on silica gel and chromatographed on Hz, 2H), 3.33 (s, 3H), 3.07 (q, J=7.32 Hz, 2H), 2.46 (brs, a 40 g silica cartridge eluting with 0-100% ethyl acetate/ 2H), 1.73-1.77 (m, 1H), 1.54 (d. J=10.99 Hz, 2H), 1.37 (s, heptane to give the title compound. 9H), 1.22 (t, J=7.32 Hz, 3H), 0.95-1.05 (m, 2H). MS (ESI+) m/z 633.9 (M+H)". 5 Example 327C Example 325 N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4.4.5, tert-butyl 6-(5-2-(2,4-difluorophenoxy)-5-[(ethyl 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Sulfonyl)aminolphenyl-1-methyl-2-oxo-1,2-dihy 10 dropyridin-4-yl)oxy-2-azaspiro3.3 heptane-2-car Example 327C was prepared according to the procedure boxylate used for the preparation of Example 5D, substituting Example 327B for Example 5C. Example 325 was prepared according to the procedure used for the preparation of Example 286, substituting tert 15 Example 327D butyl 6-hydroxy-2-azaspiro3.3 heptane-2-carboxylate for 2-morpholinoethanol. "H NMR (500 MHz, DMSO-d) & 4-chloro-5-(2-(cyclopropylmethyl)amino)-5-(meth 9.79 (s, 1H), 7.62 (s, 1H), 7.38-7.43 (m, 1H), 7.17-7.20 (m, ylsulfonyl)phenyl)-1-methylpyridin-2(1H)-one 1H), 7.12 (d. J=2.75 Hz, 1H), 6.99-7.08 (m, 2H), 6.93 (d. J=8.85 Hz, 1H), 5.67 (s, 1H), 4.49-4.56 (m, 1H), 3.83 (s. 20 Example 327C (0.793 g, 2.258 mmol), Example 269B 2H), 3.65 (s. 2H), 3.36 (s, 3H), 3.17 (q, J–7.32 Hz, 2H), (0.521 g, 2.342 mmol), tris(dibenzylidineacetone)dipalla 2.56-2.60 (m, 2H), 1.89-194 (m, 2H), 1.35 (s, 9H), 1.23 (t, dium(0) (0.089 g, 0.097 mmol), 1,3,5,7-tetramethyl-6-phe J=7.32 Hz, 3H). MS (APCI+) m/z 632.2 (M+H)". nyl-2,4,8-trioxa-6-phosphaadamantane (0.079 g, 0.270 Example 326 25 mmol) and tris-potassium phosphate (1.41 g, 6.64 mmol) were combined in a sealed 20 mL microwave tube with stir N-3-4-(2-azaspiro[3.3]hept-6-yloxy)-1-methyl-6- bar and sparged with nitrogen for 15 minutes. A degassed oxo-1,6-dihydropyridin-3-yl)-4-(2,4-difluorophe mixture of 4:1 dioxane/water (12.5 mL) was added by noxy)phenylethanesulfonamide syringe into the reaction vessel which was heated to 100° C. 30 for 30 minutes, then cooled to ambient temperature. The The trifluoroacetic acid salt of Example 326 was prepared reaction mixture was shaken in a separatory funnel with 150 according to the procedure used for the preparation of mL ethyl acetate and 100 mL saturated aqueous sodium Example 322, substituting Example 325 for Example 319. chloride. The organics were washed with Saturated aqueous H NMR (500 MHz, DMSO-d) & 9.80 (s, 1H), 8.62 (s. 2H), sodium chloride and dried over anhydrous sodium sulfate. 7.64 (s, 1H), 7.38-7.43 (m, 1H), 7.17-7.20 (m. 1H), 7.13 (d. 35 After filtration and solvent removal the residues were chro J=2.44 Hz, 1H), 6.99-7.07 (m, 2H), 6.92 (d. J=8.54 Hz, 1H), matographed on a 40 g silica cartridge eluting with 0-100% 5.69 (s, 1H), 4.49-4.56 (m, 1H), 3.98 (t, J=5.95 Hz, 2H), ethyl acetate?heptane to provide the title compound. 3.81 (t, J=6.1 Hz, 2H), 3.35 (s.3H), 3.12 (q, J–743 Hz, 2H), 2.64-2.69 (m, 2H), 1.97-2.02 (m, 2H), 1.23 (t, J–7.32 Hz, Example 327E 3H). MS (ESI+) m/z 532.3 (M+H)". 40 5-2-(cyclopropylmethyl)amino-5-(methylsulfo Example 327 nyl)phenyl)-4-(E)-2-ethoxyethenyl-1-methylpyri 5-2-(cyclopropylmethyl)amino-5-(methylsulfo din-2(1H)-one nyl)phenyl)-4-(E)-2-ethoxyethenyl-1-methylpyri- 45 din-2(1H)-one A 5 mL microwave vessel with stirbar was charged with Example 327D (0.199 g, 0.542 mmol), tris-potassium phos Example 327A phate (1.17 g, 5.51 mmol), tris(dibenzylidineacetone)dipal ladium(0) (0.0315 g, 0.034 mmol), and 1,3,5,7-tetramethyl 2-bromo-1-fluoro-4-(methylsulfonyl)benzene 50 6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.0314 g. 0.107 mmol), sealed and swept with nitrogen for 15 minutes. To a solution of 1-fluoro-4-(methylsulfonyl)benzene A solution of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3, (25.04 g. 144 mmol) in sulfuric acid (140 mL) was added 2-dioxaborolane (1.0 g, 5.05 mmol) in degassed dioxane N-bromosuccinimide (28.48 g. 160 mmol). The mixture was (2.000 mL)/water (0.5 mL) was added and the mixture stirred for 16 hours and then poured into ice water. A white 55 stirred in a 90° C. oil bath for 22 hours. The mixture was finely divided solid was collected by decanting and filtra cooled and partitioned between ethyl acetate and Saturated tion, washed repeatedly with water and dried to constant aqueous Sodium chloride. The organics were dried over mass providing the title compound. anhydrous sodium sulfate, filtered and concentrated, then the residues were chromatographed on a 40 g silica cartridge Example 327B 60 eluting with 0-7% methanol/dichloromethane to provide the title compound. "H NMR (300 MHz, DMSO-d) & 7.91 (s, 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl) 1H), 7.66 (m. 1H), 7.52 (s, 1H), 7.34 (d. J=2.4 Hz, 1H), 7.27 aniline (d. J=12.6 Hz, 1H), 6.82 (d. J=8.8 Hz, 1H), 6.55 (s, 1H), 5.56 (m. 1H), 5.07 (d. J=12.6 Hz, 1H), 3.74 (q, J=7.1 Hz, 2H), A mixture of Example 327A (1.28 g. 5.06 mmol) and 65 3.40 (s, 3H), 3.08 (s, 3H), 3.03 (d. J=2.4 Hz, 2H), 1.17 (t, cyclopropylmethanamine (1.10 g, 15.47 mmol) in dioxane J=7.0 Hz, 3H), 1.05 (m, 1H), 0.39 (dd, J=2.0, 8.5 Hz, 2H), (12 mL) was heated at 100° C. overnight. The crude reaction 0.16 (dd, J=1.7, 4.8 Hz, 2H). MS (ESI+) 403.2.

US 9,561,231 B2 185 186 g, 2.70 mmol. 60% in oil) at ambient temperature. The (Z)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro reaction mixture was stirred for 10 minutes. To this solution lane for (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-di was added Example 269B (0.2g, 0.899 mmol). The reaction oxaborolane. "H NMR (300 MHz, DMSO-d) & 7.66 (dd. mixture was then heated at 85°C. for 4 hours. After cooling, J=2.4, 8.8 Hz, 1H), 7.49 (s, 1H), 7.32 (d. J–2.4 Hz, 1H), 7.06 5 (s, 1H), 6.82 (d. J=8.8 Hz, 1H), 6.52 (d. J=7.0 Hz, 1H), 5.52 the reaction mixture was partitioned between water and (t, J=6.1 Hz, 1H), 4.48 (d. J=7.0 Hz, 1H), 4.03 (m, 2H), 3.39 ethyl acetate. The aqueous layer was separarred and (s, 3H), 3.08 (s, 3H), 3.04 (m, 2H), 1.26 (t, J=7.1 Hz, 3H), extracted with additional ethyl acetate three times. The 1.13 (m, 1H), 0.41 (m, 2H), 0.17 (m, 2H). MS (ESI+) 403.1. combined organic layers were washed with Saturated aque ous sodium chloride, dried over anhydrous magnesium Example 338 sulfate, filtered, and concentrated. The residue was purified 10 by flash chromatography on silical ge eluting with 4:1 ethyl ethyl-5-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl) acetate/hexanes to give the title compound (0.195 g, 0.633 phenyl-1-methyl-2-oxo-1,2-dihydropyridin-3- mmol. 70.4% yield). yl)carbamate Example 335B 15 Example 338 was prepared according to the procedure used for the preparation of Example 11, substituting ethyl 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-4-((2.2- carbonochloridate for 4-methylbenzene-1-sulfonyl chloride, difluoro-1-methylcyclopropyl)methoxy)-1-methyl and Example 357 for Example 10, to provide the title pyridin-2(1H)-one compound. "H NMR (300 MHz, DMSO-d) & 8.19 (d. J–2.3 HZ, 1H), 8.16 (s, 1H), 7.79 (dd, J=8.6, 2.4 Hz, 1H), 7.74 (d. Example 335B was prepared according to the procedure J=2.3 Hz, 1H), 7.69 (d, J-2.4 Hz, 1H), 7.30 (d. J=8.7 Hz, used for the preparation of Example 1B, substituting 1H), 4.14 (q, J=7.1 Hz, 2H), 4.02 (d. J=6.9 Hz, 2H), 3.58 (s, Example 5D for 2-phenoxyphenylboronic acid, and 3H), 3.27 (q, J–7.3 Hz, 2H), 1.23 (t, J=7.1 Hz, 4H), 1.11 (t, Example 335A for Example 1A, respectively, to provide the J–7.3 Hz, 3H), 0.58 (m, 2H), 0.36 (m, 2H). MS (ESI+) m/z title compound. 25 435.0 (M+H)". Example 339 Example 335C N-5-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl) N-3-4-(2,2-difluoro-1-methylcyclopropyl) phenyl-1-methyl-2-oxo-1,2-dihydropyridin-3- methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- 30 yl)methanesulfonamide 4-(2,4-difluorophenoxy)phenylethanesulfonamide Example 339 was prepared according to the procedure Example 335C was prepared according to the procedure used for the preparation of Example 11, Substituting meth used for the preparation of Example 22, Substituting anesulfonyl chloride for 4-methylbenzene-1-sulfonyl chlo Example 335B for Example 20O, and ethanesulfonyl chlo 35 ride, and Example 357 for Example 10, to provide the title ride for methanesulfonyl chloride, respectively, to provide compound. "H NMR (300 MHz, DMSO-d) & 8.80 (s, 1H), the title compound. "H NMR (500 MHz, DMSO-d) & 9.80 7.73-7.83 (m, 3H), 7.71 (d. J=2.4 Hz, 1H), 7.29 (d. J=8.6 Hz, (s, 1H), 7.61 (s, 1H), 7.30-7.36 (m. 1H), 7.22 (dd, J=8.85, 1H), 4.00 (d. J=70 Hz, 2H), 3.59 (s.3H), 3.27 (q, J=7.3 Hz, 2.75 Hz, 1H), 7.14 (d. J=2.75 Hz, 1H), 6.93-6.98 (m, 2H), 2H), 3.09 (s.3H), 1.26 (m, 1H), 1.12 (t, J=7.3 Hz, 3H), 0.56 6.83-6.90 (m, 1H), 5.80 (s, 1H), 3.96 (d. J=10.38 Hz, 1H), 40 (m. 2H), 0.35 (m, 2H). MS (ESI+) m/z 440.9 (M+H)". 3.84 (d. J=10.68 Hz, 1H), 3.34 (s, 3H), 3.08 (q, J=7.32 Hz, 2H), 1.42-1.47 (m. 1H), 1.27-1.31 (m, 1H), 1.20 (t, J=7.32 Example 340 Hz, 3H), 1.11 (s, 3H). MS (ESI+) m/z 541.0 (M+H)". 5-2-(cyclopropylmethyl)amino-5-(methylsulfo Example 336 45 nyl)phenyl-4-ethoxy-1-methylpyridin-2(1H)-one N-4-2-fluoro-4-(oxetan-3-yloxy)phenoxy-3-1- Example 340 was prepared according to the procedure methyl-4-(oxetan-3-yloxy)-6-oxo-1,6-dihydropyri used for the preparation of Example 327D, substituting din-3-ylphenylethanesulfonamide Example 368B for Example 327C and Example 327B for 50 Example 269B, respectively. Purification by reverse phase The title compound was isolated as a minor product HPLC (C18, CHCN/water (0.1% TFA), 10-100%) afforded during the preparation of Example 318B. "H NMR (500 the title compound as the trifluoroacetic acid salt. "H NMR MHz, DMSO-d) & 9.72 (s, 1H), 7.73 (s, 1H), 7.15-7.20 (m, (300 MHz, DMSO-d) & 7.62 (dd, J=2.3, 8.8 Hz, 1H), 7.57 2H), 6.93 (dd, J=8.85, 5.8 Hz, 1H), 6.81 (d. J=8.85 Hz, 1H), (s, 1H), 7.35 (d. J=2.3 Hz, 1H), 6.76 (d. J=8.8 Hz, 1H), 5.90 6.69-6.78 (m, 2H), 6.83-6.90 (m, 1H), 5.49 (s, 1H), 5.18 55 (s, 1H), 3.99 (q, J–7.0 Hz, 2H), 3.38 (s, 3H), 3.07 (s, 3H), 5.27 (m. 1H), 4.81-4.86 (m, 4H), 4.36-4.41 (m, 4H), 3.36 (s. 3.04 (d. J=6.1 Hz, 2H), 1.18 (t, J–7.0 Hz, 3H), 1.05 (m. 1H), 3H), 3.08 (q, J=7.32 Hz, 2H), 1.22 (t, J=7.32 Hz, 3H). MS 0.42 (dd, J-2.1, 6.0 Hz, 2H), 0.19 (m, 2H). MS (ESI+) (ESI+) m/z 547.2 (M+H)". 377.1.

Example 337 60 Example 341 5-2-(cyclopropylmethyl)amino-5-(methylsulfo 5-2-(cyclopropylmethyl)amino-5-(methylsulfo nyl)phenyl)-4-(Z)-2-ethoxyethenyl-1-methylpyri nyl)phenyl)-4-(3-hydroxy-2,3-dimethylbutan-2-yl) din-2(1H)-one oxy-1-methylpyridin-2(1H)-one 65 Example 337 was prepared according to the procedure Example 341 is prepared according to the procedure used used for the preparation of Example 327E, substituting for the preparation of Example 286, substituting 1.1.2.2-

US 9,561,231 B2 189 190 pylsulfonyl chloride for 4-(methylsulfonyl)benzenesulfonyl Example 352C chloride. "H NMR (400 MHz, DMSO-d/DO) & 7.59 (s. 1H), 737-7.28 (m. 1H), 7.20-7.09 (m, 2H), 7.07-6.95 (m, N-4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6- 2H), 6.90 (d. J=8.7 Hz, 1H), 5.82 (s, 1H), 3.93 (q, J–7.0 Hz, oxo-1,6-dihydropyridin-3-yl)phenylethanesulfona 2H), 3.37 (s, 3H), 3.09-3.02 (m, 2H), 1.75-1.65 (m, 3H), 1.15 (t, J=6.9 Hz, 3H), 0.96 (t, J–7.4 Hz, 3H). MS (APCI+) mide m/z 479.0 (M+H)". Example 352C was prepared according to the procedure Example 350 used for the preparation of Example 22, Substituting 10 Example 352B for Example 20O, and ethanesulfonyl chlo ride for methanesulfonyl chloride, respectively, to provide 1-(2-chloro-5-fluorophenyl)-N-4-(2,4-difluorophe the title compound. "H NMR (500 MHz, DMSO-d) & 9.79 noxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyri (s, 1H), 7.79 (d. J=2.2 Hz, 1H), 7.60 (dd, J=11.1, 2.3 Hz, din-3-yl)phenylmethanesulfonamide 1H), 7.45 (ddd, J=11.2, 8.6, 2.8 Hz, 1H), 7.26 (d. J=2.7 Hz, 15 1H), 7.13-7.24 (m, 2H), 7.04-7.12 (m. 1H), 6.86 (d. J=8.7 Example 350 was prepared according to the procedure HZ, 1H), 3.55 (s.3H), 3.12 (q, J=7.3 Hz, 2H), 1.22 (t, J=7.3 used for the preparation of Example 311, substituting Hz, 3H). MS (ESI+) m/z. 439.1 (M+H)". 2-chloro-5-fluorophenylmethanesulfonyl chloride for phe nylmethanesulfonyl chloride. "H NMR (300 MHz, DMSO Example 353 d) & 10.96 (m, 1H), 9.79 (bds, 1H), 7.50 (s, 1H), 7.44-7.25 (m, 7H), 7.12-6.99 (m, 3H), 6.91 (dd, J=7.0, 5.7 Hz, 1H), N-3-4-(cyclopropylmethyl)amino-1-methyl-6- 6.85 (d. J=8.7 Hz, 1H), 6.55 (dd, J=7.0, 1.2 Hz, 1H), 4.47 (s, oxo-1,6-dihydropyridin-3-yl)-4-(2,4-difluorophe 2H), 4.09 (s.3H). MS (ESI) 522.1 (M+H+). noxy)phenylethanesulfonamide Example 351 25 Example 353A N-4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6- oxo-1,6-dihydropyridin-3-yl)phenyl)-1-(2-fluorophe 5-bromo-4-((cyclopropylmethyl)amino)-1-methyl nyl)methanesulfonamide 30 pyridin-2(1H)-one Example 351 was prepared according to the procedure A mixture of Example 269B (0.044 g., 0.2 mmol) and used for the preparation of Example 311, substituting 2-fluo cyclopropylmethanamine (0.043 g, 0.600 mmol) in dioxane rophenylmethanesulfonyl chloride for phenylmethanesulfo (1 mL) was heated at 100° C. for 2 days. The solvent was nyl chloride. "H NMR (500 MHz, DMSO-d) & 10.00 (s, 35 evaporated, and the residue was purified by flash chroma 1H), 7.56 (s, 1H), 7.45-7.35 (m, 3H), 7.25-7.17 (m, 2H), tography on silica gel to give the title compound (0.042 g, 7.14 (dd, J=8.7, 2.7 Hz, 1H), 7.10 (d. J=2.7 Hz, 1H), 7.05 0.163 mmol. 82% yield). (m. 1H), 6.98 (td, J=9.1, 5.5 Hz, 1H), 6.89 (d. J=8.8 Hz, 1H), 5.80 (s, 1H), 4.53 (s. 2H), 3.93 (q, J=6.9 Hz, 2H), 3.36 (s, Example 353B 3H), 1.15 (t, J=6.9 Hz, 3H). MS (ESI) 545.1 (M+H+). 40 Example 352 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-4-((cy clopropylmethyl)amino)-1-methylpyridin-2(1H)-one N-4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6- 45 Example 353B was prepared according to the procedure oxo-1,6-dihydropyridin-3-yl)phenylethanesulfona used for the preparation of Example 1B, substituting mide Example 5D for 2-phenoxyphenylboronic acid, and Example 353A for Example 1A, respectively, to provide the Example 352A 50 title compound. Example 352A was prepared according to the procedure Example 353C used for the preparation of Example 1A, Substituting 5-bromo-3-fluoropyridin-2-ol for 6-chloropyridazin-3(2H)- one, to provide the title compound. 55 N-3-4-(cyclopropylmethyl)amino-1-methyl-6- oxo-1,6-dihydropyridin-3-yl)-4-(2,4-difluorophe Example 352B noxy)phenylethanesulfonamide Example 353C was prepared according to the procedure 5-(5-amino-2-(2,4-difluorophenoxy)phenyl)-3- 60 used for the preparation of Example 22, Substituting fluoro-1-methylpyridin-2(1H)-one Example 353B for Example 20O, and ethanesulfonyl chlo ride for methanesulfonyl chloride, respectively, to provide Example 352B was prepared according to the procedure the title compound. "H NMR (500 MHz, DMSO-d) & 9.68 used for the preparation of Example 1B, substituting (s, 1H), 7.37 (s, 1H), 7.22-7.26 (m, 1H), 7.06-7.11 (m, 2H), Example 5D for 2-phenoxyphenylboronic acid, and 65 6.94 (d. J=2.75 Hz, 1H), 6.89-6.93 (m. 1H), 6.83-6.90 (m, Example 352A for Example 1A, respectively, to provide the 1H), 6.75 (d. J=8.85 Hz, 1H), 5.74 (s, 1H), 5.42 (s.3H), 3.23 title compound. (s, 3H), 2.97 (q, J=7.32 Hz, 2H), 2.77 (d. J=5.96 Hz, 2H), US 9,561,231 B2 191 192 1.07 (t, J=7.32 Hz, 3H), 0.78-0.83 (m. 1H), 0.22 (t, J=7.32 (s, 3H), 2.14 (m, 3H), 1.08 (m. 1H), 0.46 (m. 2H), 0.22 (m, Hz, 3H). MS (ESI+) m/z 490.1 (M+H)". 2H). MS (DCI+) m/z 270.0 (M+H)". Example 354 Example 357 N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-4- 3-amino-5-2-(cyclopropylmethoxy)-5-(ethylsulfo propoxy-1,6-dihydropyridin-3-yl)phenylethanesul nyl)phenyl-1-methylpyridin-2(1H)-one fonamide The trifluoroacetic acid salt of Example 357 was prepared Example 354 was prepared according to the procedure 10 according to the procedure used for the preparation of used for the preparation of Example 286, substituting pro Example 1B, substituting Example 275D for 2-phenoxyphe pan-1-ol for 2-morpholinoethanol, to provide the title com nylboronic acid, and 3-amino-5-bromo-1-methylpyridin-2 pound H NMR (300 MHz, DMSO-d) & 9.76 (s, 1H), 7.59 (1H)-one for Example 1A, respectively. "H NMR (400 MHz, (s, 1H), 7.26-7.40 (m, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 7.13 DMSO-d) & 7.75 (dd, J=2.4, 6 Hz, 1H) 7.71 (d. J–2 Hz, (d. J=2.7 Hz, 1H), 6.83-7.04 (m,3H), 5.78 (s, 1H), 3.72-3.89 15 1H), 7.42 (d. J=1.6 Hz, 1H), 7.28 (d. J=8.8 Hz, 1H), 6.93 (d. (t, J=7.3 Hz, 2H), 3.46 (s.3H), 2.97-3.24 (q, J=7.3 Hz, 2H), J=2.4 Hz, 1H), 3.95 (d. J=6.8 Hz, 2H), 3.46 (s.3H), 3.66 (q, 141-1.69 (sextet, J–7.3 Hz, 2H), 1.12-1.30 (t, J=7.3 Hz, J=7.3 Hz, 2H), 1.19-135 (m. 1H), 1.04 (t, J=7.3 Hz, 3H), 3H), 0.72-0.90 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 479.0 0.47-0.66 (m, 2H), 0.24-0.46 (m, 2H). MS (ESI+) m/z. 363.1 (M+H)". (M+H)". Example 355 Example 358 N-4-(2,4-difluorophenoxy)-3-1-methyl-6-oxo-4-(2, N-4-(4-cyanophenoxy)-3-(4-ethoxy-1-methyl-6- 2.2-trifluoroethoxy)-1,6-dihydropyridin-3-yl) oxo-1,6-dihydropyridin-3-yl)phenylethanesulfona phenylethanesulfonamide 25 mide Example 355 was prepared according to the procedure Example 358A used for the preparation of Example 286, substituting 2.2, 2-trifluoroethanol for 2-morpholinoethanol, to provide the 4-(4-amino-2-(4-ethoxy-1-methyl-6-oxo-1,6-dihy title compound "H NMR (300 MHz, DMSO-d) & 9.77 (s, 30 dropyridin-3-yl)phenoxy)benzonitrile 1H), 7.69 (s, 1H), 7.30-7.41 (m, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 7.13 (d. J=2.7 Hz, 1H), 6.86-7.05 (m, 3H), 6.03 (s, 1H), Example 358A was prepared according to the procedure 4.70 (q, J=8.8 Hz, 2H), 3.37 (s, 3H), 3.07 (q, J=7.3 Hz, 2H), used for the preparation of Example 1B, substituting 1.20 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 519.0 (M+H)". Example 294D for 2-phenoxyphenylboronic acid, and 35 Example 368A for Example 1A, respectively, to provide the Example 356 title compound. 5-2-(cyclopropylmethoxy)-6-methylphenyl)-1- Example 358B methylpyridin-2(1H)-one 40 N-4-(4-cyanophenoxy)-3-(4-ethoxy-1-methyl-6- Example 356A. 2-bromo-1-(cyclopropylmethoxy)-3- oxo-1,6-dihydropyridin-3-yl)phenylethanesulfona methyl-4-nitrobenzene. A flask with stirbar was charged mide with 2-bromo-3-methyl-4-nitrophenol (1.15g, 4.96 mmol), (bromomethyl)cyclopropane (0.60 mL, 6.19 mmol) and Example 358B was prepared according to the procedure cesium carbonate (2.65 g, 8.13 mmol) in dimethylforma 45 used for the preparation of Example 22, Substituting mide (16 mL). The mixture was stirred overnight at ambient Example 358A for Example 20O, and ethanesulfonyl chlo temperature. The mixture was then heated to 50° C. in an oil ride for methanesulfonyl chloride, respectively, to provide bath for 3 hours, cooled and shaken in a separatory funnel the title compound. "H NMR (300 MHz, DMSO-d) & 9.88 with 100 mL each of ethyl acetate and saturated aqueous (s, 1H), 7.71-7.78 (m, 2H), 7.55 (s, 1H), 7.26 (dd, J=8.7, 2.7 sodium chloride. The organics were washed twice with 50 HZ, 1H), 7.18 (d. J=2.6 Hz, 1H), 7.15 (d. J=8.7 Hz, 1H), saturated aqueous sodium chloride and dried over anhydrous 6.92-6.99 (m, 2H), 5.74 (s, 1H), 3.84 (q, J=7.0 Hz, 2H), 3.30 sodium sulfate. Filtration and solvent removal provided the (s, 3H), 3.15 (q, J–7.3 Hz, 2H), 1.24 (t, J–7.3 Hz, 3H), 1.06 title compound. (t, J=6.9 Hz, 3H). MS (ESI+) m/z 454.0 (M+H)".

Example 356B 55 Example 359 5-2-(cyclopropylmethoxy)-6-methylphenyl)-1- N-4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-4- methylpyridin-2(1H)-one propyl-1,6-dihydropyridin-3-yl)phenylethanesulfo namide Example 356B was prepared according to the procedure 60 used for the preparation of Example 327D, substituting Example 329 (0.056 g., 0.122 mmol) and palladium on 1-methyl-5-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) carbon (0.013 g, 0.122 mmol) were stirred in ethyl acetate pyridin-2(1H)-one for Example 327C and Example 356A for (10 mL) then subjected to hydrogen gas for 22 hours. The Example 269B, respectively, to provide the title compound. mixture was filtered through diatomaceous earth then con H NMR (300 MHz, DMSO-d) 8 ppm 7.59 (d. J=2.0 Hz, 65 centrated under reduced pressure. The residue was purified 1H), 7.29 (dd, J=9.2, 2.4 Hz, 1H), 7.16 (m, 1H), 6.87 (d. by reverse phase HPLC (C18, CHCN/water (0.1% TFA), J=8.5 Hz, 1H), 6.41 (d. J=9.8 Hz, 1H), 3.77 (m, 2H), 3.46 0-100%) to afford 4.1 mg (7%) of the title compound. H