US 20160361298A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0361298 A1 Novick et al. (43) Pub. Date: Dec. 15, 2016

(54) METHODS AND COMPOSITIONS FOR A63/496 (2006.01) TREATING CANCER A 6LX 39/395 (2006.01) (71) Applicant: Globavir BioSciences, Inc., Los Altos, A63/496 (2006.01) CA (US) A63L/452 (2006.01) A6II 45/06 (2006.01) (72) Inventors: Paul Novick, San Francisco, CA (US); C07K 6/28 (2006.01) Jonathan Choy, Lafayette, CA (US); A6II 3/478 (2006.01) Sumit Mahajan, Foster City, CA (US); Ritika Prasad, Mountain View, CA A6II 3/167 (2006.01) (US); Shalabh Gupta, Mountain View, (52) U.S. Cl. CA (US) CPC ...... A61K 31/4174 (2013.01); A61K 31/41 78 (2013.01); A61K 31/4184 (2013.01); A61 K (21) Appl. No.: 15/179,764 3 1/496 (2013.01); A61K 31/167 (2013.01); (22) Filed: Jun. 10, 2016 A61K 31/4196 (2013.01); A61K 31/4152 (2013.01); A61K 45/06 (2013.01); C07K Related U.S. Application Data 16/2818 (2013.01); A61K 39/3955 (2013.01); (60) Provisional application No. 62/174,430, filed on Jun. A6 IK 2039/505 (2013.01) 11, 2015, provisional application No. 62/174,424, filed on Jun. 11, 2015, provisional application No. (57) ABSTRACT 62/188.413, filed on Jul. 2, 2015, provisional appli cation No. 62/195,750, filed on Jul. 22, 2015. Described are compositions and methods for treating cancer. Some methods comprise the administration of an effective Publication Classification amount of at least one inhibitor of tryptophan 2,3-dioxy (51) Int. Cl. genase (TDO) and/or indoleamine 2,3-dioxygenase (IDO), A6 IK 3/474 (2006.01) optionally combined with one or more additional anti-cancer A6 IK3I/484 (2006.01) agents. Patent Application Publication Dec. 15, 2016 Sheet 1 of 7 US 2016/0361298 A1

FIG.

-- on M

w * ioconazole X :1 * Deferasiox - or Nicosanide ^x to 8x Etrorro ag

orcentration.

-1 * Suicorazoie - Cocorazoie * - * vicaras2& 20 Coacetratio: vi Patent Application Publication Dec. 15, 2016 Sheet 2 of 7 US 2016/0361298 A1

FG 2 Wiate CD4+ T Cels

u-- r Eltrombopag

at 1M * Nicosamide Deferasirox * Tioconazole

Concentiation at

e : () on M s * Suiconazole S3 * Coconazole * Miconazole

Concentratifs ... if Patent Application Publication Dec. 15, 2016 Sheet 3 of 7 US 2016/0361298 A1

FIG. 3 C88CO4- Ces

-1 Eitrombopag / * Tioconazole

5 1 * Deferasirax . - Nicosamide - - - 1MT

2 Concentration - if

t x -" * Miconazole - * Sulconazole 11 Cioconazole

s 3.

s Concertrait a Patent Application Publication Dec. 15, 2016 Sheet 4 of 7 US 2016/0361298 A1

FG, 4. C7-CD4+ T Ces

r Eltrombopag /* Tioconazole 5 - * Deferasirox

- * Nicosamide - or M 2} 40 Concentration -- ty

as x - * Nicoagie r

a (e Sulconazole s 50 Š r - Coconazole st n 9. 4- the Mi

20 40 6 Concentration -- Patent Application Publication Dec. 15, 2016 Sheet 5 of 7 US 2016/0361298 A1

F.G. 5 Wiate C3 Ces

A at Mr * Nicosamide * Deferasirox ?2 ioconazole - Etrombopag 2. forcentratief -- tal

s É

e - she s S. 1 + Cocorazos XX - * Suiconazole 8 -- * Miconazole . Concentration w ti Patent Application Publication Dec. 15, 2016 Sheet 6 of 7 US 2016/0361298 A1

E.G. 6 CS-58 is

& - Fioconazole

k1 - * Deferasirox " + Nicosamide

-- Eitrombopagy 2 Concertation a

1- * iconazole - Suiconazole - Cioconazole

43 (Concentration or us Patent Application Publication Dec. 15, 2016 Sheet 7 of 7 US 2016/0361298 A1

FG. 7 CB7-08 Ces

- -* Tioconazole - * Deferasiox - * Nicosamide s r Eltrombopag

28 43 Concentratic

t s *-* iconazole " * Suiconazole 3. 4- Coconazole

e s 5 Š ae wet n 3.

Concentratio -- i. US 2016/0361298 A1 Dec. 15, 2016

METHODS AND COMPOSITIONS FOR tered to the individual. In some embodiments, miconazole or TREATING CANCER a pharmaceutically acceptable salt or Solvate of miconazole is administered to the individual. In some embodiments, CROSS-REFERENCE TO RELATED Sertaconazole or a pharmaceutically acceptable salt or Sol APPLICATIONS vate of sertaconazole is administered to the individual. In 0001. This application claims the benefit of U.S. Provi Some embodiments, tioconazole or a pharmaceutically sional Application No. 62/174,430 filed Jun. 11, 2015; U.S. acceptable salt or Solvate oftioconazole is administered to Provisional Application No. 62/174,424 filed Jun. 11, 2015: the individual. In some embodiments, fenticonazole or a U.S. Provisional Application No. 62/188,413 filed Jul. 2, pharmaceutically acceptable salt or Solvate offenticonazole is administered to the individual. In some embodiments, 2015; and U.S. Provisional Application No. 62/195,750 filed liaroZole or a pharmaceutically acceptable salt or Solvate of Jul. 22, 2015; the entirety of which are incorporated by liarozole is administered to the individual. In some embodi reference herein. ments, cloconazole or a pharmaceutically acceptable salt or BACKGROUND solvate of cloconazole is administered to the individual. In Some embodiments, itraconazole or a pharmaceutically 0002 Immuno-oncology focuses on the development and acceptable salt or Solvate of itraconazole is administered to delivery of therapies that improve a body's intrinsic poten the individual. In some embodiments, niclosamide or a tial for generating an effective immune response against pharmaceutically acceptable salt or Solvate of niclosamide is cancer. Immuno-oncology therapies often target the immune administered to the individual. In some embodiments, system and not the cancer, providing the potential to treat deferasiroX or a pharmaceutically acceptable salt or Solvate cancer across a variety of tumor types. Manipulation of of deferasirox is administered to the individual. In some T-cell modulation is one method of augmenting the immune embodiments, eltrombopag or a pharmaceutically accept system to treat cancer. able salt or solvate of eltrombopag is administered to the individual. In some embodiments, the cancer comprises SUMMARY OF THE INVENTION colon cancer, pancreatic cancer, cutaneous T-cell lymphoma, 0003. The immune system has an intrinsic potential for glioma, head and neck cancer, hepatocarcinoma, leukemia, recognizing and eliminating tumor cells. However, tumors glioblastoma, colorectal cancer, gallbladder, mastocytoma, can adapt and circumvent the immune system by disrupting acute myeloid leukemia, adrenocortical cancer, bladder T-cell checkpoint pathways. An approach to disrupt tumor urothelial cancer, brain tumor, brain lower grade glioma, inhibition of the immune system involves the targeted block breast cancer, breast invasive cancer, cervical cancer, cho of checkpoint pathways Immune checkpoint pathway targets langiocarcinoma, cutaneous melanoma, diffuse large B-cell for activating therapeutic antitumor immunity include pro lymphoma, endometrial cancer, glioblastoma multiform, grammed cell death protein (PD-1) and its ligand PD-L1, H&N squamous cell carcinoma, hepatocellular carcinoma, indoleamine 2,3-dioxygenase (IDO), and cytotoxic T-lym kidney chromophobe carcinoma, lung cancer, lung adeno phocyte antigen 4 (CTLA-4). IDO is a heme-containing carcinoma, lung Squamous cell carcinoma, mesothelioma, enzyme that catalyzes the oxidation of L-tryptophan to ovarian serous cystadenocarcinoma, pancreatic adenocarci N-formyl-L-kynurenine. Another heme-containing enzyme noma, pheochromocytoma and paraganglioma, prostate that also catalyzes tryptophan degradation is tryptophan adenocarcinoma, prostate cancer, rectum adenocarcinoma, 2,3-dioxygenase (TDO). TDO has been found to be rectum cancer, renal cell cancer, renal papillary cell cancer, expressed in many tumors and this expression prevents sarcoma, testicular germ cell tumors, thymoma, thyroid tumor rejection by locally depleting tryptophan. Develop cancer, uterine carcinosarcoma, melanoma, uveal mela ment of TDO inhibitors for the treatment of tumors is an noma, or a combination thereof. In some embodiments, the active area of drug development. As the active sites of both effective amount is from about 5 mg to about 5,000 mg. In IDO and TDO enzymes are structurally similar, various Some embodiments, the individual is administered an addi inhibitors of TDO and IDO have activity against one tional active agent comprising a PD-1/PD-L pathway inhibi another. Provided in this disclosure are compounds and tor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a compositions comprising TDO inhibitors, IDO inhibitors, combination thereof. In some embodiments, the individual is and inhibitors of both TDO and IDO for active stimulation administered an additional active agent comprising BMS of the immune system. In various aspects, provided are TDO 936559, MEDI4736, MPDL3280A, MSB0010718C, AMP inhibitors, IDO inhibitors, and inhibitors of both TDO and 224, nivolumab, pembrolizumab, pidilizumab, BMS IDO that are useful for the treatment of cancer. 98.6016, MDX1105-01, avelumab, indoximod, F001287, 0004. In one aspect, provided herein is a method of NLG919, INCB024360, ipilimumab, tremelimumab, anti treating cancer comprising administering to an individual in body clone 9H10, antibody clone BNI3, Del 60, M9-14 del need thereof an effective amount of econazole, Sulconazole, 55, or a salt, solvate or combination thereof. In some isoconazole, miconazole, Sertaconazole, tioconazole, fenti embodiments, the method further comprises treating the conazole, liarozole, cloconazole, itraconazole, niclosamide, individual with an immunotherapy. In some embodiments, deferasiroX, eltrombopag, or a pharmaceutically acceptable the method further comprises treating the individual with a salt, Solvate, or combination thereof. In some embodiments, chimeric antigen receptor (CAR) T-cell therapy. In some econazole or a pharmaceutically acceptable salt or Solvate of embodiments, the method further comprises treating the econazole is administered to the individual. In some individual with a stem cell therapy. embodiments, Sulconazole or a pharmaceutically acceptable 0005. In one aspect, provided herein is a method of salt or solvate of Sulconazole is administered to the indi inhibiting tryptophan 2,3-dioxygenase (TDO), indoleamine vidual. In some embodiments, isoconazole or a pharmaceu 2,3-dioxygenase (IDO), or both TDO and IDO in an indi tically acceptable salt or Solvate of isoconazole is adminis vidual in need thereof, the method comprising administering US 2016/0361298 A1 Dec. 15, 2016

to the individual an effective amount of an antifungal agent, AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS antiparasitic agent, iron chelator, thrombopoietin (TPO) 98.6016, MDX1105-01, avelumab, indoximod, F001287, receptor agonist, or a combination thereof. In some embodi NLG919, INCB024360, ipilimumab, tremelimumab, anti ments, the antifungal agent comprises tioconazole, liarozole, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del Sertaconazole, econazole, Sulconazole, miconazole, isocon 55, or a salt, solvate or combination thereof. azole, itraconazole, fenticonazole, cloconazole; or a phar maceutically acceptable salt, Solvate or combination thereof. 0007. In one aspect, provided herein is a method of In some embodiments, the antiparasitic agent comprises treating cancer comprising administering to an individual in niclosamide or a pharmaceutically acceptable salt or Solvate need thereof an effective amount of a compound of Formula of niclosamide. In some embodiments, the iron chelator (VIII), or a pharmaceutically acceptable salt or solvate comprises deferasiroX or a pharmaceutically acceptable salt thereof: or solvate of deferasirox. In some embodiments, the TPO receptor agonist comprises eltrombopag or a pharmaceuti

cally acceptable salt or Solvate of eltrombopag. In some Formula (VIII) embodiments, the individual has cancer. In some embodi ments, the cancer comprises colon cancer, pancreatic cancer, cutaneous T-cell lymphoma, glioma, head and neck cancer, hepatocarcinoma, leukemia, glioblastoma, colorectal cancer, gallbladder, mastocytoma, acute myeloid leukemia, adreno cortical cancer, bladder urothelial cancer, brain tumor, brain lower grade glioma, breast cancer, breast invasive cancer, cervical cancer, cholangiocarcinoma, cutaneous melanoma, diffuse large B-cell lymphoma, endometrial cancer, glioblas toma multiform, H&N squamous cell carcinoma, hepatocel 0008 wherein lular carcinoma, kidney chromophobe carcinoma, lung can cer, lung adenocarcinoma, lung Squamous cell carcinoma, 0009 each are independently a single bond or a double mesothelioma, ovarian serous cystadenocarcinoma, pancre bond provided that they are not both double bonds; atic adenocarcinoma, pheochromocytoma and paragan 0.010 Ring A is optionally substituted aryl, or option glioma, prostate adenocarcinoma, prostate cancer, rectum ally substituted heteroaryl; adenocarcinoma, rectum cancer, renal cell cancer, renal papillary cell cancer, sarcoma, testicular germ cell tumors, 0011 X is O or S, when is; or thymoma, thyroid cancer, uterine carcinosarcoma, mela 0012 X is N, when is: noma, uveal melanoma, or a combination thereof. In some embodiments, the effective amount is from about 5 mg to 0013 R71 is hydrogen or optionally substituted C1-C6 about 5,000 mg. In some embodiments, the individual is alkyl: administered an additional active agent comprising a PD-1/ 0.014 R72 is —(C1-C6 alkylene) (optionally substi PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, tuted aryl), —(C1-C6 alkylene) (optionally substituted CTLA-4 inhibitor, or a combination thereof. In some heteroaryl), —(C1-C6 alkylene)-O-(optionally substi embodiments, the individual is administered an additional active agent comprising BMS-936559, MEDI4736, tuted aryl), or —O—(C1-C6 alkylene) (optionally sub MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem stituted aryl), provided that when R2 is —O—(C1-C6 brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave alkylene) (optionally substituted aryl), then X is N. lumab, indoximod, F001287, NLG919, INCB024360, ipili 0015. In some embodiments, the compound of Formula mumab, tremelimumab, antibody clone 9H10, antibody (VIII) or a pharmaceutically acceptable salt or solvate clone BNI3, Del 60, M9-14 del 55, or a salt, solvate or thereof comprises: combination thereof. In some embodiments, the method further comprises treating the individual with an immuno therapy. In some embodiments, the method further com prises treating the individual with a chimeric antigen recep tor (CAR) T-cell therapy. In some embodiments, the method further comprises treating the individual with a stem cell therapy. O, Cy 0006. In another aspect, provided herein is a composition comprising: (a) an antifungal agent, antiparasitic agent, iron chelator, thrombopoietin (TPO) receptor agonist, or a com bination thereof, and (b) an anti-cancer agent. In some embodiments, the anti-cancer agent is a component of an immunotherapy. In some embodiments, the anti-cancer agent is a component of a chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the anti-cancer agent C comprises a PD-1/PD-L pathway inhibitor, IDO inhibitor, (econazole) TDO inhibitor, CTLA-4 inhibitor, or a combination thereof. In some embodiments, the anti-cancer agent comprises BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, US 2016/0361298 A1 Dec. 15, 2016

-continued -continuedC - a C

O C

C Cl, (fenticonazole) (sulconazole) or a combination thereof. 0016. In some embodiments, the compound of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof comprises econazole. In some embodiments, the compound of Formula (VIII) or a pharmaceutically accept able salt or Solvate thereof comprises Sulconazole. In some embodiments, the compound of Formula (VIII) or a phar C C Cl, maceutically acceptable salt or Solvate thereof comprises (isoconazole) isoconazole. In some embodiments, the compound of For mula (VIII) or a pharmaceutically acceptable salt or solvate thereof comprises miconazole. In some embodiments, the compound of Formula (VIII) or a pharmaceutically accept able salt or Solvate thereof comprises Sertaconazole. In some embodiments, the compound of Formula (VIII) or a phar C O maceutically acceptable salt or Solvate thereof comprises tioconazole. In some embodiments, the compound of For C mula (VIII) or a pharmaceutically acceptable salt or solvate thereof comprises fenticonazole. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is cutaneous T-cell lymphoma. In some embodiments, the C cancer is a glioma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is (miconazole) hepatocarcinoma, leukemia, glioblastoma, colorectal carci noma, gallbladder, mastocytoma, acute myeloid leukemia, adrenocortical carcinoma, bladder urothelial carcinoma, brain tumor, brain lower grade glioma, breast carcinoma, Cl, breast invasive carcinoma, cervical carcinoma, cholangio carcinoma, cutaneous melanoma, diffuse large B-cell lym phoma, endometrial carcinoma, glioblastoma multiform, H&N squamous cell carcinoma, hepatocellular carcinoma, C kidney chromophobe carcinoma, lung carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothe lioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, prostate carcinoma, rectum adenocarcinoma, rectum carcinoma, renal cell carcinoma, renal papillary cell carcinoma, sarcoma, testicular germ cell (sertaconazole) tumors, thymoma, thyroid carcinoma, uterine carcinosar N coma, melanoma, uveal melanoma, or a combination thereof. In some embodiments, the individual is adminis tered an additional active agent. In some embodiments, the additional active agent is an anti-cancer agent. In some embodiments, the additional active agent comprises a PD-1/ PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a combination thereof. In some embodiments, the additional cancer agent comprises an Cl, antifungal agent, antiparasitic agent, iron chelator, throm (tioconazole) bopoietin (TPO) receptor agonist, or a combination thereof. In some embodiments, the additional active agent comprises BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS US 2016/0361298 A1 Dec. 15, 2016

98.6016, MDX1105-01, avelumab, indoximod, F001287, I0024) R' is —(C-C alkylene) (optionally substituted NLG919, INCB024360, ipilimumab, tremelimumab, anti aryl), —(C-C alkylene) (optionally Substituted het body clone 9H10, antibody clone BNI3, Del 60, M9-14 del eroaryl), —(C-C alkylene)-O-(optionally substituted 55, or salts, solvates or combinations thereof. In some aryl), or—O—(C-C alkylene) (optionally substituted embodiments, the method further comprises treating the aryl), provided that when R is —O (C-C alkylene) individual with an immunotherapy. In some embodiments, (optionally substituted aryl), then X is N: the method further comprises treating the individual with a 0.025 and chimeric antigen receptor (CAR) T-cell therapy. In some 0026 (b) an additional active agent. embodiments, the method further comprises treating the 0027. In some embodiments, the compound of Formula individual with a stem cell therapy. (VIII) or a pharmaceutically acceptable salt or solvate 0017. In one aspect, provided herein is a combination thereof comprises: comprising (a) a compound of Formula (VIII), or a phar maceutically acceptable salt or solvate thereof:

Formula (VIII) Ol C Or 0.018 wherein (0019 each r are independently a single bond or a C double bond provided that they are not both double bonds; (econazole) 0020 Ring A is optionally substituted aryl, or option ally substituted heteroaryl; 0021 X is O or S, when

Wy C Cl,

(sulconazole) is

O C C Cl, 0022 X is N, when (isoconazole) Wy C C O is C ). Wy

I0023 R' is hydrogen or optionally substituted C-C, (miconazole) alkyl: US 2016/0361298 A1 Dec. 15, 2016

-continued 0028. In some embodiments, the compound of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof comprises econazole. In some embodiments, the CN compound of Formula (VIII) or a pharmaceutically accept Cl, able salt or Solvate thereof comprises Sulconazole. In some embodiments, the compound of Formula (VIII) or a phar maceutically acceptable salt or Solvate thereof comprises isoconazole. In some embodiments, the compound of For C mula (VIII) or a pharmaceutically acceptable salt or solvate thereof comprises miconazole. In some embodiments, the compound of Formula (VIII) or a pharmaceutically accept able salt or Solvate thereof comprises Sertaconazole. In some embodiments, the compound of Formula (VIII) or a phar maceutically acceptable salt or Solvate thereof comprises C tioconazole. In some embodiments, the compound of For (sertaconazole) mula (VIII) or a pharmaceutically acceptable salt or solvate N thereof comprises fenticonazole. In some embodiments, the s additional active agent is an anti-cancer agent. In some embodiments, the additional active agent comprises a PD-1/ Cl C PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a combination thereof. In some embodiments, the additional cancer agent comprises an antifungal agent, antiparasitic agent, iron chelator, throm bopoietin (TPO) receptor agonist, or a combination thereof. In some embodiments, the additional active agent comprises an immunotherapy agent, a stem cell therapy agent, a CAR (tioconazole) T-cell therapy agent, BMS-936559, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave ( N ) - a lumab, indoximod, F001287, NLG919, INCB024360, ipili mumab, tremelimumab, antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, solvates or combinations thereof. 0029. In one aspect, provided herein is a method of treating cancer comprising administering to an individual in (fenticonazole) need thereof an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof, the or a combination thereof. compound comprising:

C

HC

NH X s C O O N (liarozole) (cloconazole) US 2016/0361298 A1 Dec. 15, 2016

-continued

C

(itraconazole)

HO

O N No. C N H C OH OH HO

(niclosamide) (deferasirox) OH H3C O 2 N NNE O N \ 2 OH H3C N CH3 (eltrombopag)

0030. In some embodiments, the compound comprises melanoma, diffuse large B-cell lymphoma, endometrial car liaroZole. In some embodiments, the compound comprises cinoma, glioblastoma multiform, H&N squamous cell car cloconazole. In some embodiments, the compound com cinoma, hepatocellular carcinoma, kidney chromophobe prises itraconazole. In some embodiments, the compound carcinoma, lung carcinoma, lung adenocarcinoma, lung comprises niclosamide. In some embodiments, the com squamous cell carcinoma, mesothelioma, ovarian serous pound comprises deferasiroX. The compound comprises cystadenocarcinoma, pancreatic adenocarcinoma, pheochro eltrombopag. In some embodiments, the cancer is colon mocytoma and paraganglioma, prostate adenocarcinoma, cancer. In some embodiments, the cancer is pancreatic prostate carcinoma, rectum adenocarcinoma, rectum carci cancer. In some embodiments, the cancer is cutaneous T-cell noma, renal cell carcinoma, renal papillary cell carcinoma, lymphoma. In some embodiments, the cancer is a glioma. In sarcoma, testicular germ cell tumors, thymoma, thyroid Some embodiments, the cancer is head and neck cancer. In carcinoma, uterine carcinosarcoma, melanoma, uveal mela Some embodiments, the cancer is hepatocarcinoma, leuke noma, or a combination thereof. In some embodiments, the mia, glioblastoma, colorectal carcinoma, gallbladder, mas individual is administered an additional active agent. In tocytoma, acute myeloid leukemia, adrenocortical carci Some embodiments, the additional active agent is an anti noma, bladder urothelial carcinoma, brain tumor, brain cancer agent. In some embodiments, the additional active lower grade glioma, breast carcinoma, breast invasive car agent comprises a PD-1/PD-L pathway inhibitor, IDO cinoma, cervical carcinoma, cholangiocarcinoma, cutaneous inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a combina US 2016/0361298 A1 Dec. 15, 2016

tion thereof. In some embodiments, the additional cancer 0032. In one aspect, provided herein is a method of agent comprises an antifungal agent, antiparasitic agent, iron treating cancer comprising administering to an individual in chelator, thrombopoietin (TPO) receptor agonist, or a com need thereof an effective amount of liarozole or a pharma bination thereof. In some embodiments, the additional active ceutically acceptable salt or solvate thereof. In some agent comprises BMS-936559, MEDI4736, MPDL3280A, embodiments, the cancer is colon cancer. In some embodi MSB0010718C, AMP-224, nivolumab, pembrolizumab, ments, the cancer is pancreatic cancer. In some embodi pidilizumab, BMS-98.6016, MDX1105-01, avelumab, ments, the cancer is cutaneous T-cell lymphoma. In some indoximod, F001287, NLG919, INCB024360, ipilimumab, embodiments, the cancer is a glioma. In some embodiments, tremelimumab, antibody clone 9H10, antibody clone BNI3, the cancer is head and neck cancer. In some embodiments, Del 60, M9-14 del 55, or salts, solvates or combinations the cancer is hepatocarcinoma, leukemia, glioblastoma, col thereof. In some embodiments, the method further com orectal carcinoma, gallbladder, mastocytoma, acute myeloid prises treating the individual with an immunotherapy. In leukemia, adrenocortical carcinoma, bladder urothelial car Some embodiments, the method further comprises treating cinoma, brain tumor, brain lower grade glioma, breast the individual with a chimeric antigen receptor (CAR) T-cell carcinoma, breast invasive carcinoma, cervical carcinoma, therapy. In some embodiments, the method further com cholangiocarcinoma, cutaneous melanoma, diffuse large prises treating the individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma 0031. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount oftioconazole or a phar noma, lung adenocarcinoma, lung Squamous cell carcinoma, maceutically acceptable salt or Solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. embodiments, the additional cancer agent comprises an 0033. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of sertaconazole or a In some embodiments, the additional active agent comprises pharmaceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma US 2016/0361298 A1 Dec. 15, 2016

multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. embodiments, the additional cancer agent comprises an 0035. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of sulconazole or a phar In some embodiments, the additional active agent comprises maceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma 0034. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount of econazole or a pharma noma, lung adenocarcinoma, lung Squamous cell carcinoma, ceutically acceptable salt or solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. US 2016/0361298 A1 Dec. 15, 2016

0036. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount of miconazole or a phar noma, lung adenocarcinoma, lung Squamous cell carcinoma, maceutically acceptable salt or Solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. embodiments, the additional cancer agent comprises an 0038. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of itraconazole or a phar In some embodiments, the additional active agent comprises maceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma 0037. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount of isoconazole or a phar noma, lung adenocarcinoma, lung Squamous cell carcinoma, maceutically acceptable salt or Solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some US 2016/0361298 A1 Dec. 15, 2016

embodiments, the additional cancer agent comprises an 0040. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of deferasirox or a phar In some embodiments, the additional active agent comprises maceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma 0039. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount of niclosamide or a phar noma, lung adenocarcinoma, lung Squamous cell carcinoma, maceutically acceptable salt or Solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. embodiments, the additional cancer agent comprises an 0041. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of fenticonazole or a In some embodiments, the additional active agent comprises pharmaceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma US 2016/0361298 A1 Dec. 15, 2016

multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. embodiments, the additional cancer agent comprises an 0043. In one aspect, provided herein is a method of antifungal agent, antiparasitic agent, iron chelator, throm treating cancer comprising administering to an individual in bopoietin (TPO) receptor agonist, or a combination thereof. need thereof an effective amount of eltrombopag or a In some embodiments, the additional active agent comprises pharmaceutically acceptable salt or Solvate thereof. In some BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, embodiments, the cancer is colon cancer. In some embodi AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS ments, the cancer is pancreatic cancer. In some embodi 98.6016, MDX1105-01, avelumab, indoximod, F001287, ments, the cancer is cutaneous T-cell lymphoma. In some NLG919, INCB024360, ipilimumab, tremelimumab, anti embodiments, the cancer is a glioma. In some embodiments, body clone 9H10, antibody clone BNI3, Del 60, M9-14 del the cancer is head and neck cancer. In some embodiments, 55, or salts, solvates or combinations thereof. In some the cancer is hepatocarcinoma, leukemia, glioblastoma, col embodiments, the method further comprises treating the orectal carcinoma, gallbladder, mastocytoma, acute myeloid individual with an immunotherapy. In some embodiments, leukemia, adrenocortical carcinoma, bladder urothelial car the method further comprises treating the individual with a cinoma, brain tumor, brain lower grade glioma, breast chimeric antigen receptor (CAR) T-cell therapy. In some carcinoma, breast invasive carcinoma, cervical carcinoma, embodiments, the method further comprises treating the cholangiocarcinoma, cutaneous melanoma, diffuse large individual with a stem cell therapy. B-cell lymphoma, endometrial carcinoma, glioblastoma 0042. In one aspect, provided herein is a method of multiform, H&N squamous cell carcinoma, hepatocellular treating cancer comprising administering to an individual in carcinoma, kidney chromophobe carcinoma, lung carci need thereof an effective amount of cloconazole or a phar noma, lung adenocarcinoma, lung Squamous cell carcinoma, maceutically acceptable salt or Solvate thereof. In some mesothelioma, ovarian serous cystadenocarcinoma, pancre embodiments, the cancer is colon cancer. In some embodi atic adenocarcinoma, pheochromocytoma and paragan ments, the cancer is pancreatic cancer. In some embodi glioma, prostate adenocarcinoma, prostate carcinoma, rec ments, the cancer is cutaneous T-cell lymphoma. In some tum adenocarcinoma, rectum carcinoma, renal cell embodiments, the cancer is a glioma. In some embodiments, carcinoma, renal papillary cell carcinoma, sarcoma, testicu the cancer is head and neck cancer. In some embodiments, lar germ cell tumors, thymoma, thyroid carcinoma, uterine the cancer is hepatocarcinoma, leukemia, glioblastoma, col carcinosarcoma, melanoma, uveal melanoma, or a combi orectal carcinoma, gallbladder, mastocytoma, acute myeloid nation thereof. In some embodiments, the individual is leukemia, adrenocortical carcinoma, bladder urothelial car administered an additional active agent. In some embodi cinoma, brain tumor, brain lower grade glioma, breast ments, the additional active agent is an anti-cancer agent. In carcinoma, breast invasive carcinoma, cervical carcinoma, Some embodiments, the additional active agent comprises a cholangiocarcinoma, cutaneous melanoma, diffuse large PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, B-cell lymphoma, endometrial carcinoma, glioblastoma CTLA-4 inhibitor, or a combination thereof. In some multiform, H&N squamous cell carcinoma, hepatocellular embodiments, the additional cancer agent comprises an carcinoma, kidney chromophobe carcinoma, lung carci antifungal agent, antiparasitic agent, iron chelator, throm noma, lung adenocarcinoma, lung Squamous cell carcinoma, bopoietin (TPO) receptor agonist, or a combination thereof. mesothelioma, ovarian serous cystadenocarcinoma, pancre In some embodiments, the additional active agent comprises atic adenocarcinoma, pheochromocytoma and paragan BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, glioma, prostate adenocarcinoma, prostate carcinoma, rec AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS tum adenocarcinoma, rectum carcinoma, renal cell 98.6016, MDX1105-01, avelumab, indoximod, F001287, carcinoma, renal papillary cell carcinoma, sarcoma, testicu NLG919, INCB024360, ipilimumab, tremelimumab, anti lar germ cell tumors, thymoma, thyroid carcinoma, uterine body clone 9H10, antibody clone BNI3, Del 60, M9-14 del carcinosarcoma, melanoma, uveal melanoma, or a combi 55, or salts, solvates or combinations thereof. In some nation thereof. In some embodiments, the individual is embodiments, the method further comprises treating the administered an additional active agent. In some embodi individual with an immunotherapy. In some embodiments, ments, the additional active agent is an anti-cancer agent. In the method further comprises treating the individual with a Some embodiments, the additional active agent comprises a chimeric antigen receptor (CAR) T-cell therapy. In some PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, embodiments, the method further comprises treating the CTLA-4 inhibitor, or a combination thereof. In some individual with a stem cell therapy. US 2016/0361298 A1 Dec. 15, 2016

0044. In one aspect, provided herein is a method of 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, treating cancer comprising administering to an individual in Solvates or combinations thereof. In some embodiments, the need thereof an effective amount of an antifungal agent method further comprises treating the individual with an comprising tioconazole, liarozole, Sertaconazole, econazole, immunotherapy. In some embodiments, the method further Sulconazole, miconazole, isoconazole, itraconazole, fenti comprises treating the individual with a chimeric antigen conazole, cloconazole, or salts, Solvates or combinations receptor (CAR) T-cell therapy. In some embodiments, the thereof. In some embodiments, the antifungal agent com method further comprises treating the individual with a stem prises tioconazole or a pharmaceutically acceptable salt or cell therapy. Solvate thereof. In some embodiments, the antifungal agent 0045. In one aspect, provided herein is a method of comprises liarozole or a pharmaceutically acceptable salt or treating cancer comprising administering to an individual in Solvate thereof. In some embodiments, the antifungal agent need thereof an effective amount of an antiparasitic agent. In comprises Sertaconazole or a pharmaceutically acceptable Some embodiments, the antiparasitic agent comprises niclos salt or Solvate thereof. In some embodiments, the antifungal amide or a pharmaceutically acceptable salt or Solvate agent comprises econazole or a pharmaceutically acceptable thereof. In some embodiments, the cancer is colon cancer. In salt or Solvate thereof. In some embodiments, the antifungal Some embodiments, the cancer is pancreatic cancer. In some agent comprises Sulconazole or a pharmaceutically accept embodiments, the cancer is cutaneous T-cell lymphoma. In able salt or solvate thereof. In some embodiments, the Some embodiments, the cancer is a glioma. In some embodi antifungal agent comprises miconazole or a pharmaceuti ments, the cancer is head and neck cancer. In some embodi cally acceptable salt or solvate thereof. In some embodi ments, the cancer is hepatocarcinoma, leukemia, glioblas ments, the antifungal agent comprises isoconazole or a toma, colorectal carcinoma, gallbladder, mastocytoma, acute pharmaceutically acceptable salt or Solvate thereof. In some myeloid leukemia, adrenocortical carcinoma, bladder embodiments, the antifungal agent comprises itraconazole urothelial carcinoma, brain tumor, brain lower grade glioma, or a pharmaceutically acceptable salt or Solvate thereof. In breast carcinoma, breast invasive carcinoma, cervical car Some embodiments, the antifungal agent comprises fenti cinoma, cholangiocarcinoma, cutaneous melanoma, diffuse conazole or a pharmaceutically acceptable salt or Solvate large B-cell lymphoma, endometrial carcinoma, glioblas thereof. In some embodiments, the antifungal agent com toma multiform, H&N squamous cell carcinoma, hepatocel prises cloconazole or a pharmaceutically acceptable salt or lular carcinoma, kidney chromophobe carcinoma, lung car Solvate thereof. In some embodiments, the cancer is colon cinoma, lung adenocarcinoma, lung Squamous cell cancer. In some embodiments, the cancer is pancreatic carcinoma, mesothelioma, ovarian serous cystadenocarci cancer. In some embodiments, the cancer is cutaneous T-cell noma, pancreatic adenocarcinoma, pheochromocytoma and lymphoma. In some embodiments, the cancer is a glioma. In paraganglioma, prostate adenocarcinoma, prostate carci Some embodiments, the cancer is head and neck cancer. In noma, rectum adenocarcinoma, rectum carcinoma, renal cell Some embodiments, the cancer is hepatocarcinoma, leuke carcinoma, renal papillary cell carcinoma, sarcoma, testicu mia, glioblastoma, colorectal carcinoma, gallbladder, mas lar germ cell tumors, thymoma, thyroid carcinoma, uterine tocytoma, acute myeloid leukemia, adrenocortical carci carcinosarcoma, melanoma, uveal melanoma, or a combi noma, bladder urothelial carcinoma, brain tumor, brain nation thereof. In some embodiments, the individual is lower grade glioma, breast carcinoma, breast invasive car administered an additional active agent. In some embodi cinoma, cervical carcinoma, cholangiocarcinoma, cutaneous ments, the additional active agent is an anti-cancer agent. In melanoma, diffuse large B-cell lymphoma, endometrial car Some embodiments, the additional active agent comprises a cinoma, glioblastoma multiform, H&N squamous cell car PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, cinoma, hepatocellular carcinoma, kidney chromophobe CTLA-4 inhibitor, or a combination thereof. In some carcinoma, lung carcinoma, lung adenocarcinoma, lung embodiments, the additional cancer agent comprises an squamous cell carcinoma, mesothelioma, ovarian serous antifungal agent, a second antiparasitic agent, an iron chela cystadenocarcinoma, pancreatic adenocarcinoma, pheochro tor, a thrombopoietin (TPO) receptor agonist, or a combi mocytoma and paraganglioma, prostate adenocarcinoma, nation thereof. In some embodiments, the additional active prostate carcinoma, rectum adenocarcinoma, rectum carci agent comprises BMS-936559, MEDI4736, MPDL3280A, noma, renal cell carcinoma, renal papillary cell carcinoma, MSB0010718C, AMP-224, nivolumab, pembrolizumab, sarcoma, testicular germ cell tumors, thymoma, thyroid pidilizumab, BMS-98.6016, MDX1105-01, avelumab, carcinoma, uterine carcinosarcoma, melanoma, uveal mela indoximod, F001287, NLG919, INCB024360, ipilimumab, noma, or a combination thereof. In some embodiments, the tremelimumab, antibody clone 9H10, antibody clone BNI3, individual is administered an additional active agent. In Del 60, M9-14 del 55, or salts, solvates or combinations Some embodiments, the additional active agent is an anti thereof. In some embodiments, the method further com cancer agent. In some embodiments, the additional active prises treating the individual with an immunotherapy. In agent comprises a PD-1/PD-L pathway inhibitor, IDO Some embodiments, the method further comprises treating inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a combina the individual with a chimeric antigen receptor (CAR) T-cell tion thereof. In some embodiments, the additional cancer therapy. In some embodiments, the method further com agent comprises a second antifungal agent, an antiparasitic prises treating the individual with a stem cell therapy. agent, an iron chelator, a thrombopoietin (TPO) receptor 0046. In one aspect, provided herein is a method of agonist, or a combination thereof. In some embodiments, the treating cancer comprising administering to an individual in additional active agent comprises BMS-93.6559, need thereof an effective amount of an iron chelator. In some MEDI4736, MPDL3280A, MSB0010718C, AMP-224, embodiments, the iron chelator comprises deferasiroX or a nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, pharmaceutically acceptable salt or Solvate thereof. In some MDX1105-01, avelumab, indoximod, F001287, NLG919, embodiments, the cancer is colon cancer. In some embodi INCB024360, ipilimumab, tremelimumab, antibody clone ments, the cancer is pancreatic cancer. In some embodi US 2016/0361298 A1 Dec. 15, 2016

ments, the cancer is cutaneous T-cell lymphoma. In some adenocarcinoma, pheochromocytoma and paraganglioma, embodiments, the cancer is a glioma. In some embodiments, prostate adenocarcinoma, prostate carcinoma, rectum the cancer is head and neck cancer. In some embodiments, adenocarcinoma, rectum carcinoma, renal cell carcinoma, the cancer is hepatocarcinoma, leukemia, glioblastoma, col renal papillary cell carcinoma, sarcoma, testicular germ cell orectal carcinoma, gallbladder, mastocytoma, acute myeloid tumors, thymoma, thyroid carcinoma, uterine carcinosar leukemia, adrenocortical carcinoma, bladder urothelial car coma, melanoma, uveal melanoma, or a combination cinoma, brain tumor, brain lower grade glioma, breast thereof. In some embodiments, the individual is adminis carcinoma, breast invasive carcinoma, cervical carcinoma, tered an additional active agent. In some embodiments, the cholangiocarcinoma, cutaneous melanoma, diffuse large additional active agent is an anti-cancer agent. In some B-cell lymphoma, endometrial carcinoma, glioblastoma embodiments, the additional active agent comprises a PD-1/ multiform, H&N squamous cell carcinoma, hepatocellular PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, carcinoma, kidney chromophobe carcinoma, lung carci CTLA-4 inhibitor, or a combination thereof. In some noma, lung adenocarcinoma, lung Squamous cell carcinoma, embodiments, the additional cancer agent comprises an mesothelioma, ovarian serous cystadenocarcinoma, pancre antifungal agent, an antiparasitic agent, an iron chelator, a atic adenocarcinoma, pheochromocytoma and paragan second thrombopoietin (TPO) receptor agonist, or a combi glioma, prostate adenocarcinoma, prostate carcinoma, rec nation thereof. In some embodiments, the additional active tum adenocarcinoma, rectum carcinoma, renal cell agent comprises BMS-936559, MEDI4736, MPDL3280A, carcinoma, renal papillary cell carcinoma, sarcoma, testicu MSB0010718C, AMP-224, nivolumab, pembrolizumab, lar germ cell tumors, thymoma, thyroid carcinoma, uterine pidilizumab, BMS-98.6016, MDX1105-01, avelumab, carcinosarcoma, melanoma, uveal melanoma, or a combi indoximod, F001287, NLG919, INCB024360, ipilimumab, nation thereof. In some embodiments, the individual is tremelimumab, antibody clone 9H10, antibody clone BNI3, administered an additional active agent. In some embodi Del 60, M9-14 del 55, or salts, solvates or combinations ments, the additional active agent is an anti-cancer agent. In thereof. In some embodiments, the method further com Some embodiments, the additional active agent comprises a prises treating the individual with an immunotherapy. In PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, Some embodiments, the method further comprises treating CTLA-4 inhibitor, or a combination thereof. In some the individual with a chimeric antigen receptor (CAR) T-cell embodiments, the additional cancer agent comprises an therapy. In some embodiments, the method further com antifungal agent, an antiparasitic agent, a second iron chela prises treating the individual with a stem cell therapy. tor, a thrombopoietin (TPO) receptor agonist, or a combi 0048. In one aspect, provided herein is a combination nation thereof. In some embodiments, the additional active comprising: (a) tioconazole; and (b) an anti-cancer agent. In agent comprises BMS-936559, MEDI4736, MPDL3280A, another aspect, provided herein is a combination compris MSB0010718C, AMP-224, nivolumab, pembrolizumab, ing: (a) tioconazole; and (b) a PD-1/PD-L pathway inhibitor, pidilizumab, BMS-98.6016, MDX1105-01, avelumab, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com indoximod, F001287, NLG919, INCB024360, ipilimumab, bination thereof. In another aspect, provided herein is a tremelimumab, antibody clone 9H10, antibody clone BNI3, combination comprising (a) tioconazole; and (b) an antifun Del 60, M9-14 del 55, or salts, solvates or combinations gal agent, an antiparasitic agent, an iron chelator, a throm thereof. In some embodiments, the method further com bopoietin (TPO) receptor agonist, or a combination thereof. prises treating the individual with an immunotherapy. In In another aspect, provided herein is a combination com Some embodiments, the method further comprises treating prising (a) tioconazole; and (b) BMS-936559, MEDI4736, the individual with a chimeric antigen receptor (CAR) T-cell MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem therapy. In some embodiments, the method further com brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave prises treating the individual with a stem cell therapy. lumab, indoximod, F001287, NLG919, INCB024360, ipili 0047. In one aspect, provided herein is a method of mumab, tremelimumab, antibody clone 9H10, antibody treating cancer comprising administering to an individual in clone BNI3, Del 60, M9-14 del 55, or salts, solvates or need thereof an effective amount of a thrombopoietin (TPO) combinations thereof. In another aspect, provided herein is receptor agonist. In some embodiments, the TPO receptor a combination comprising: (a)tioconazole; and (b) liarozole, agonist comprises eltrombopag or a pharmaceutically Sertaconazole, econazole, Sulconazole, miconazole, isocon acceptable salt or solvate thereof. In some embodiments, the azole, itraconazole, niclosamide, deferasiroX, fenticonazole, cancer is colon cancer. In some embodiments, the cancer is cloconazole, eltrombopag, or salts, Solvates, or combina pancreatic cancer. In some embodiments, the cancer is tions thereof. In some embodiments, the combination is a cutaneous T-cell lymphoma. In some embodiments, the composition. In some embodiments, the anti-cancer agent is cancer is a glioma. In some embodiments, the cancer is head a component of an immunotherapy. In some embodiments, and neck cancer. In some embodiments, the cancer is the anti-cancer agent is a component of a CAR T-cell hepatocarcinoma, leukemia, glioblastoma, colorectal carci therapy. In some embodiments, the anti-cancer agent is a noma, gallbladder, mastocytoma, acute myeloid leukemia, component of a stem cell therapy. adrenocortical carcinoma, bladder urothelial carcinoma, 0049. In one aspect, provided herein is a combination brain tumor, brain lower grade glioma, breast carcinoma, comprising: (a) liarozole; and (b) an anti-cancer agent. In breast invasive carcinoma, cervical carcinoma, cholangio another aspect, provided herein is a combination compris carcinoma, cutaneous melanoma, diffuse large B-cell lym ing: (a) liarozole; and (b) a PD-1/PD-L pathway inhibitor, phoma, endometrial carcinoma, glioblastoma multiform, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com H&N squamous cell carcinoma, hepatocellular carcinoma, bination thereof. In another aspect, provided herein is a kidney chromophobe carcinoma, lung carcinoma, lung combination comprising (a) liarozole; and (b) an antifungal adenocarcinoma, lung Squamous cell carcinoma, mesothe agent, an antiparasitic agent, an iron chelator, a thrombopoi lioma, ovarian serous cystadenocarcinoma, pancreatic etin (TPO) receptor agonist, or a combination thereof. In US 2016/0361298 A1 Dec. 15, 2016

another aspect, provided herein is a combination comprising isoconazole, itraconazole, niclosamide, deferasirox, fenti (a) liarozole; and (b) BMS-936559, MEDI4736, conazole, cloconazole, eltrombopag, or salts, Solvates, or MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem combinations thereof. In some embodiments, the combina brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave tion is a composition. In some embodiments, the anti-cancer lumab, indoximod, F001287, NLG919, INCB024360, ipili agent is a component of an immunotherapy. In some mumab, tremelimumab, antibody clone 9H10, antibody embodiments, the anti-cancer agent is a component of a clone BNI3, Del 60, M9-14 del 55, or salts, solvates or CART-cell therapy. In some embodiments, the anti-cancer combinations thereof. In another aspect, provided herein is agent is a component of a stem cell therapy. a combination comprising: (a) liarozole; and (b) tioconazole, 0052. In one aspect, provided herein is a combination Sertaconazole, econazole, Sulconazole, miconazole, isocon comprising: (a) Sulconazole; and (b) an anti-cancer agent. In azole, itraconazole, niclosamide, deferasiroX, fenticonazole, another aspect, provided herein is a combination compris cloconazole, eltrombopag, or salts, Solvates, or combina ing: (a) sulconazole; and (b) a PD-1/PD-L pathway inhibitor, tions thereof. In some embodiments, the combination is a IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com composition. In some embodiments, the anti-cancer agent is bination thereof. In another aspect, provided herein is a a component of an immunotherapy. In some embodiments, combination comprising (a) Sulconazole; and (b) an anti the anti-cancer agent is a component of a CAR T-cell fungal agent, an antiparasitic agent, an iron chelator, a therapy. In some embodiments, the anti-cancer agent is a thrombopoietin (TPO) receptor agonist, or a combination component of a stem cell therapy. thereof. In another aspect, provided herein is a combination 0050. In one aspect, provided herein is a combination comprising (a) sulconazole; and (b) BMS-93.6559, comprising: (a) Sertaconazole; and (b) an anti-cancer agent. MEDI4736, MPDL3280A, MSB0010718C, AMP-224, In another aspect, provided herein is a combination com nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, prising: (a) sertaconazole; and (b) a PD-1/PD-L pathway MDX1105-01, avelumab, indoximod, F001287, NLG919, inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, INCB024360, ipilimumab, tremelimumab, antibody clone or a combination thereof. In another aspect, provided herein 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, is a combination comprising (a) sertaconazole; and (b) an Solvates or combinations thereof. In another aspect, pro antifungal agent, an antiparasitic agent, an iron chelator, a vided herein is a combination comprising: (a) Sulconazole; thrombopoietin (TPO) receptor agonist, or a combination and (b) tioconazole, liarozole, Sertaconazole, econazole, thereof. In another aspect, provided herein is a combination miconazole, isoconazole, itraconazole, niclosamide, defera comprising (a) sertaconazole; and (b) BMS-936559, sirox, fenticonazole, cloconazole, eltrombopag, or salts, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, Solvates, or combinations thereof. In some embodiments, the nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, combination is a composition. In some embodiments, the MDX1105-01, avelumab, indoximod, F001287, NLG919, anti-cancer agent is a component of an immunotherapy. In INCB024360, ipilimumab, tremelimumab, antibody clone Some embodiments, the anti-cancer agent is a component of 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, a CART-cell therapy. In some embodiments, the anti-cancer Solvates or combinations thereof. In another aspect, pro agent is a component of a stem cell therapy. vided herein is a combination comprising: (a) sertaconazole; 0053. In one aspect, provided herein is a combination and (b) tioconazole, liarozole, econazole, Sulconazole, comprising: (a) miconazole; and (b) an anti-cancer agent. In miconazole, isoconazole, itraconazole, niclosamide, defera another aspect, provided herein is a combination compris Sirox, fenticonazole, cloconazole, eltrombopag, or salts, ing: (a) miconazole; and (b) a PD-1/PD-L pathway inhibitor, Solvates, or combinations thereof. In some embodiments, the IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com combination is a composition. In some embodiments, the bination thereof. In another aspect, provided herein is a anti-cancer agent is a component of an immunotherapy. In combination comprising (a) miconazole; and (b) an antifun Some embodiments, the anti-cancer agent is a component of gal agent, an antiparasitic agent, an iron chelator, a throm a CART-cell therapy. In some embodiments, the anti-cancer bopoietin (TPO) receptor agonist, or a combination thereof. agent is a component of a stem cell therapy. In another aspect, provided herein is a combination com 0051. In one aspect, provided herein is a combination prising (a) miconazole; and (b) BMS-936559, MEDI4736, comprising: (a) econzole; and (b) an anti-cancer agent. In MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem another aspect, provided herein is a combination compris brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave ing: (a) econzole; and (b) a PD-1/PD-L pathway inhibitor, lumab, indoximod, F001287, NLG919, INCB024360, ipili IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com mumab, tremelimumab, antibody clone 9H10, antibody bination thereof. In another aspect, provided herein is a clone BNI3, Del 60, M9-14 del 55, or salts, solvates or combination comprising (a) econzole; and (b) an antifungal combinations thereof. In another aspect, provided herein is agent, an antiparasitic agent, an iron chelator, a thrombopoi a combination comprising: (a) miconazole; and (b) tiocon etin (TPO) receptor agonist, or a combination thereof. In azole, liarozole, Sertaconazole, econazole, Sulconazole, iso another aspect, provided herein is a combination comprising conazole, itraconazole, niclosamide, deferasiroX, fenticon (a) econzole; and (b) BMS-93.6559, MEDI4736, azole, cloconazole, eltrombopag, or salts, Solvates, or MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem combinations thereof. In some embodiments, the combina brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave tion is a composition. In some embodiments, the anti-cancer lumab, indoximod, F001287, NLG919, INCB024360, ipili agent is a component of an immunotherapy. In some mumab, tremelimumab, antibody clone 9H10, antibody embodiments, the anti-cancer agent is a component of a clone BNI3, Del 60, M9-14 del 55, or salts, solvates or CART-cell therapy. In some embodiments, the anti-cancer combinations thereof. In another aspect, provided herein is agent is a component of a stem cell therapy. a combination comprising: (a) econzole; and (b) tiocon 0054. In one aspect, provided herein is a combination azole, liarozole, Sertaconazole, Sulconazole, miconazole, comprising: (a) isoconazole; and (b) an anti-cancer agent. In US 2016/0361298 A1 Dec. 15, 2016 another aspect, provided herein is a combination compris nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, ing: (a) isoconazole; and (b) a PD-1/PD-L pathway inhibitor, MDX1105-01, avelumab, indoximod, F001287, NLG919, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com INCB024360, ipilimumab, tremelimumab, antibody clone bination thereof. In another aspect, provided herein is a 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, combination comprising (a) isoconazole; and (b) an anti Solvates or combinations thereof. In another aspect, pro fungal agent, an antiparasitic agent, an iron chelator, a vided herein is a combination comprising: (a) niclosamide; thrombopoietin (TPO) receptor agonist, or a combination and (b) tioconazole, liarozole, Sertaconazole, econazole, thereof. In another aspect, provided herein is a combination Sulconazole, miconazole, isoconazole, itraconazole, defera comprising (a) isoconazole; and (b) BMS-93.6559, SiroX, fenticonazole, cloconazole, eltrombopag, or salts, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, Solvates, or combinations thereof. In some embodiments, the nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, combination is a composition. In some embodiments, the MDX1105-01, avelumab, indoximod, F001287, NLG919, anti-cancer agent is a component of an immunotherapy. In INCB024360, ipilimumab, tremelimumab, antibody clone Some embodiments, the anti-cancer agent is a component of 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, a CART-cell therapy. In some embodiments, the anti-cancer Solvates or combinations thereof. In another aspect, pro agent is a component of a stem cell therapy. vided herein is a combination comprising: (a) isoconazole; 0057. In one aspect, provided herein is a combination and (b) tioconazole, liarozole, Sertaconazole, econazole, comprising: (a) deferasiroX, and (b) an anti-cancer agent. In Sulconazole, miconazole, itraconazole, niclosamide, defera another aspect, provided herein is a combination compris Sirox, fenticonazole, cloconazole, eltrombopag, or salts, ing: (a) deferasirox; and (b) a PD-1/PD-L pathway inhibitor, Solvates, or combinations thereof. In some embodiments, the IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com combination is a composition. In some embodiments, the bination thereof. In another aspect, provided herein is a anti-cancer agent is a component of an immunotherapy. In combination comprising (a) deferasiroX, and (b) an antifun Some embodiments, the anti-cancer agent is a component of gal agent, an antiparasitic agent, an iron chelator, a throm a CART-cell therapy. In some embodiments, the anti-cancer bopoietin (TPO) receptor agonist, or a combination thereof. agent is a component of a stem cell therapy. In another aspect, provided herein is a combination com 0055. In one aspect, provided herein is a combination prising (a) deferasirox; and (b) BMS-936559, MEDI4736, comprising: (a) itraconazole; and (b) an anti-cancer agent. In MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem another aspect, provided herein is a combination compris brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave ing: (a) itraconazole; and (b) a PD-1/PD-L pathway inhibi lumab, indoximod, F001287, NLG919, INCB024360, ipili tor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a mumab, tremelimumab, antibody clone 9H10, antibody combination thereof. In another aspect, provided herein is a clone BNI3, Del 60, M9-14 del 55, or salts, solvates or combination comprising (a) itraconazole; and (b) an anti combinations thereof. In another aspect, provided herein is fungal agent, an antiparasitic agent, an iron chelator, a a combination comprising: (a) deferasiroX, and (b) tiocon thrombopoietin (TPO) receptor agonist, or a combination azole, liarozole, Sertaconazole, econazole, Sulconazole, thereof. In another aspect, provided herein is a combination miconazole, isoconazole, itraconazole, niclosamide, fenti comprising (a) itraconazole; and (b) BMS-93.6559, conazole, cloconazole, eltrombopag, or salts, Solvates, or MEDI4736, MPDL3280A, MSB0010718C, AMP-224, combinations thereof. In some embodiments, the combina nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, tion is a composition. In some embodiments, the anti-cancer MDX1105-01, avelumab, indoximod, F001287, NLG919, agent is a component of an immunotherapy. In some INCB024360, ipilimumab, tremelimumab, antibody clone embodiments, the anti-cancer agent is a component of a 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, CART-cell therapy. In some embodiments, the anti-cancer Solvates or combinations thereof. In another aspect, pro agent is a component of a stem cell therapy. vided herein is a combination comprising: (a) itraconazole; 0058. In one aspect, provided herein is a combination and (b) tioconazole, liarozole, Sertaconazole, econazole, comprising: (a) fenticonazole; and (b) an anti-cancer agent. Sulconazole, miconazole, isoconazole, niclosamide, defera In another aspect, provided herein is a combination com Sirox, fenticonazole, cloconazole, eltrombopag, or salts, prising: (a) fenticonazole; and (b) a PD-1/PD-L pathway Solvates, or combinations thereof. In some embodiments, the inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, combination is a composition. In some embodiments, the or a combination thereof. In another aspect, provided herein anti-cancer agent is a component of an immunotherapy. In is a combination comprising (a) fenticonazole; and (b) an Some embodiments, the anti-cancer agent is a component of antifungal agent, an antiparasitic agent, an iron chelator, a a CART-cell therapy. In some embodiments, the anti-cancer thrombopoietin (TPO) receptor agonist, or a combination agent is a component of a stem cell therapy. thereof. In another aspect, provided herein is a combination 0056. In one aspect, provided herein is a combination comprising (a) fenticonazole; and (b) BMS-93.6559, comprising: (a) niclosamide; and (b) an anti-cancer agent. In MEDI4736, MPDL3280A, MSB0010718C, AMP-224, another aspect, provided herein is a combination compris nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, ing: (a) niclosamide; and (b) a PD-1/PD-L pathway inhibi MDX1105-01, avelumab, indoximod, F001287, NLG919, tor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a INCB024360, ipilimumab, tremelimumab, antibody clone combination thereof. In another aspect, provided herein is a 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, combination comprising (a) niclosamide; and (b) an anti Solvates or combinations thereof. In another aspect, pro fungal agent, an antiparasitic agent, an iron chelator, a vided herein is a combination comprising: (a) fenticonazole; thrombopoietin (TPO) receptor agonist, or a combination and (b) tioconazole, liarozole, Sertaconazole, econazole, thereof. In another aspect, provided herein is a combination Sulconazole, miconazole, isoconazole, itraconazole, niclos comprising (a) niclosamide; and (b) BMS-93.6559, amide, deferasiroX, cloconazole, eltrombopag, or salts, Sol MEDI4736, MPDL3280A, MSB0010718C, AMP-224, Vates, or combinations thereof. In some embodiments, the US 2016/0361298 A1 Dec. 15, 2016

combination is a composition. In some embodiments, the anti-cancer agent is a component of an immunotherapy. In Formula (I) Some embodiments, the anti-cancer agent is a component of OH a CART-cell therapy. In some embodiments, the anti-cancer R4 agent is a component of a stem cell therapy. 1N 0059. In one aspect, provided herein is a combination (R), H- N comprising: (a) cloconazole; and (b) an anti-cancer agent. In 2 R11 NR2 another aspect, provided herein is a combination compris ing: (a) cloconazole; and (b) a PD-1/PD-L pathway inhibitor, 0062 wherein IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a com I0063 R' and Rare each independently selected from bination thereof. In another aspect, provided herein is a hydrogen or C-C alkyl; combination comprising (a) cloconazole; and (b) an anti I0064 each Rare independently selected from hydro fungal agent, an antiparasitic agent, an iron chelator, a gen, halogen, —OH, C-C alkyl, or C-C alkoxy; thrombopoietin (TPO) receptor agonist, or a combination I0065) R' is hydrogen, halogen, or C-C alkyl; and thereof. In another aspect, provided herein is a combination 0066 n is 1, 2, 3, or 4. comprising (a) cloconazole; and (b) BMS-93.6559, 0067. In another aspect, provided herein is a method of MEDI4736, MPDL3280A, MSB0010718C, AMP-224, treating cancer comprising administering to a patient in need nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, thereof an effective amount of a compound of Formula (II), MDX1105-01, avelumab, indoximod, F001287, NLG919, or a pharmaceutically acceptable salt or Solvate thereof: INCB024360, ipilimumab, tremelimumab, antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, Solvates or combinations thereof. In another aspect, pro Formula (II) vided herein is a combination comprising: (a) cloconazole; and (b) tioconazole, liarozole, Sertaconazole, econazole, s OH Sulconazole, miconazole, isoconazole, itraconazole, niclos : A amide, deferasiroX, fenticonazole, eltrombopag, or salts, ---- O Solvates, or combinations thereof. In some embodiments, the combination is a composition. In some embodiments, the anti-cancer agent is a component of an immunotherapy. In 0068 wherein Some embodiments, the anti-cancer agent is a component of 0069. Ring A is optionally substituted aryl or option a CART-cell therapy. In some embodiments, the anti-cancer ally substituted heteroaryl. agent is a component of a stem cell therapy. 0070. In some embodiments, the compound of Formula (II) is of Formula (IIa): 0060. In one aspect, provided herein is a combination comprising: (a) eltrombopag; and (b) an anti-cancer agent. In another aspect, provided herein is a combination com prising: (a) eltrombopag; and (b) a PD-1/PD-L pathway Formula (IIa) inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, or a combination thereof. In another aspect, provided herein N OH is a combination comprising (a) eltrombopag; and (b) an R10-l antifungal agent, an antiparasitic agent, an iron chelator, a 2 O thrombopoietin (TPO) receptor agonist, or a combination thereof. In another aspect, provided herein is a combination comprising (a) eltrombopag; and (b) BMS-93.6559, (0071 wherein MEDI4736, MPDL3280A, MSB0010718C, AMP-224, 0072 R is X R'': nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, 0.073 X is -O-, -CH-, -(C=O) , or MDX1105-01, avelumab, indoximod, F001287, NLG919, —CH=; and INCB024360, ipilimumab, tremelimumab, antibody clone 0074) R' is optionally substituted aryl, optionally sub 9H10, antibody clone BNI3, Del 60, M9-14 del 55, or salts, stituted cycloalkyl, optionally substituted heteroaryl, or Solvates or combinations thereof. In another aspect, pro optionally substituted heterocycloalkyl. vided herein is a combination comprising: (a) eltrombopag: 0075. In another aspect, provided herein is a method of and (b) tioconazole, liarozole, Sertaconazole, econazole, treating cancer comprising administering to a patient in need Sulconazole, miconazole, isoconazole, itraconazole, niclos thereof an effective amount of a compound of Formula (III), amide, deferasiroX, fenticonazole, cloconazole, or salts, Sol or a pharmaceutically acceptable salt or Solvate thereof: Vates, or combinations thereof. In some embodiments, the combination is a composition. In some embodiments, the anti-cancer agent is a component of an immunotherapy. In Formula (III) Some embodiments, the anti-cancer agent is a component of : B a CART-cell therapy. In some embodiments, the anti-cancer Y O - - agent is a component of a stem cell therapy. N-N a 0061. In one aspect, provided herein is a method of e? y -/ treating cancer comprising administering to a patient in need 4N | thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or Solvate thereof: US 2016/0361298 A1 Dec. 15, 2016

0076 wherein heteroaryl, optionally Substituted heteroaralkyl, option 0077 Ring B is an optionally substituted heteroaryl; ally substituted cycloalkyl, optionally substituted 0078 Y is —CH or - N -; and cycloalkylalkyl, or -(CH2) S-R': I0079) R' is hydrogen, halogen, C-C alkyl, C-C, 0093 each R" is independently hydrogen, halogen, alkoxy, or C-C haloalkoxy. C-C alkyl, C-C alkoxy, or —S(=O)NH2, 0080. In some embodiments, the compound of Formula I0094) R' is C-C alkyl, C-C haloalkyl, or option (III) is of Formula (IIIa): ally substituted aralkyl; and (0.095 q is 1, 2, 3, or 4. 0096. In some embodiments, the compound of Formula f Formula (IIIa) (V) is of Formula (Va): Formula (Va) H

s C O 21 N O R41 -NS S DOC SM

0081 wherein I0082 each R is independently hydrogen, C-C, alkyl, C-C haloalkyl, C-C alkoxy, alkoxy 0097. In another aspect, provided herein is a method of C-Calkoxy, or C-C haloalkoxy; and treating cancer comprising administering to a patient in need I0083 p is 1, 2, 3, or 4. thereof an effective amount of a compound of Formula (VI), 0084. In another aspect, provided herein is a method of or a pharmaceutically acceptable salt or Solvate thereof: treating cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula (IV), Formula (VI) or a pharmaceutically acceptable salt or Solvate thereof: RI H y S Formula (IV) O O OH N R3 s O NN 21 ', OH H C O N 1Ns - /MV \, 0098 wherein I0099 R is optionally substituted aryl, optionally sub 0085 wherein stituted heteroaryl, or -CHR'R'': I0086) R' is an optionally substituted aryl or an option 0100 R is C-C alkyl; and ally substituted heteroaryl; and I0101 R is optionally substituted aryl, optionally sub I0087 Ring C is an optionally substituted aryl or an stituted heteroaryl, or optionally substituted aryloxy. optionally substituted heteroaryl. 0102. In some embodiments, the compound of Formula 0088. In another aspect, provided herein is a method of (VI) is of Formula (Vla): treating cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt or Solvate thereof: Formula (VIa) N R55 / N O Formula (V) le H R56 S O N O OH O 0089 wherein start is a single bond or a double bond; 0090 R' is hydrogen or C-C alkyl when it is a (0103 wherein single bond; or 0104 R is C-C alkyl; and 0091) R' is absent when it is a double bond; 0105 R is optionally substituted aryl. 0092 R is C-C alkyl, optionally substituted aryl, 0106. In another aspect, provided herein is a method of optionally substituted aralkyl, optionally substituted treating cancer comprising administering to a patient in need US 2016/0361298 A1 Dec. 15, 2016

thereof an effective amount of a compound of Formula 0.115. In some embodiments, a method of treating cancer (VII), or a pharmaceutically acceptable salt or solvate further comprises administering to the patient an effective thereof: amount of at least one PD-1/PD-L pathway inhibitor, at least one IDO inhibitor, at least one CTLA-4 inhibitor, at least one TDO inhibitor, at least one anti-cancer agent, or a combi Formula (VII) nation thereof. R62 R61 0116. In one aspect of the disclosure, provided herein is R3 a method of inhibiting TDO, IDO, or both TDO and IDO in a patient comprising administering to the patient an effective OH amount of an antimicrobial agent. In some embodiments, the R64 antimicrobial agent is an antibacterial agent. In some embodiments, the antibacterial agent comprises cloxiduine, O O betamipronum, chloroxine, nalidixic acid, paZufloxacin, propicillin, besifloxacin, oxacillin Sodium, moxifloxacin, 01.07 wherein cloxacillin, dicloxacillin, or a salt, Solvate or combination 0108) R' is C-C alkyl or cycloalkyl: thereof. In some embodiments, the antimicrobial agent is an I0109) R' is halogen, C-C alkyl, or C-C alkoxy; or antifungal agent. In some embodiments, the antifungal agent (0.110) R' and R taken together with the atoms to comprises tioconazole, liarozole, Sertaconazole, econazole, which they are attached form an optionally substituted Sulconazole, miconazole, isoconazole, itraconazole, fenti heterocycloalkyl: conazole, cloconazole, acrisorcinum, climbazole, crocon 10111) R' is optionally substituted cycloalkyl or azole, diphenylimidazole, exalamide, lanoconazole, oxicon optionally substituted heterocycloalkyl; and azole, bifonazole, thiabendazole, butoconazole, I0112 R is halogen, C-C alkyl, or C-C alkoxy. clotrimazole, ketoconazole, luliconazole, albaconazole, efi 0113. In some embodiments, the compound of Formula naconazole, epoxiconazole, fluconazole, isaVuconazole, (I) is a TDO inhibitor, IDO inhibitor, or both a TDO and IDO posaconazole, propiconazole, ravuconazole, terconazole, inhibitor. In some embodiments, the compound of Formula Voriconazole, abafungin, omoconazole, phenoxyacetic acid, (II) is a TDO inhibitor, IDO inhibitor, or both a TDO and naftifine, tolindate, tolnaftate, butenafine, o-(5,6,7,8-tetra IDO inhibitor. In some embodiments, the compound of hydro-2-naphthyl)-6-methoxy-n-methylthio-2-pyridinecar Formula (III) is a TDO inhibitor, IDO inhibitor, or both a bamate, or a salt, Solvate or combination thereof. In some TDO and IDO inhibitor. In some embodiments, the com embodiments, the antimicrobial agent is an antiparasitic pound of Formula (IV) is a TDO inhibitor, IDO inhibitor, or agent. In some embodiments, the antiparasitic agent com both a TDO and IDO inhibitor. In some embodiments, the prises praziquantel, chloroquine, epsiprantel, niclosamide, compound of Formula (V) is a TDO inhibitor, IDO inhibitor, hydroxychloroquin, or a salt, Solvate or combination thereof. or both a TDO and IDO inhibitor. In some embodiments, the In some embodiments, the antimicrobial agent is an anti compound of Formula (VI) is a TDO inhibitor, IDO inhibi septic. In some embodiments, the antiseptic comprises iod tor, or both a TDO and IDO inhibitor. In some embodiments, ochlorohydroxyquinoline, euresol, acrisorcinum, benzyl the compound of Formula (VII) is a TDO inhibitor, IDO peroxide, benzoyl peroxide, benzoxiquine, ethacridine lac inhibitor, or both a TDO and IDO inhibitor. In some embodi tate, or a salt, Solvate or combination thereof. In some ments, the compound of Formula (VIII) is a TDO inhibitor, embodiments, the antimicrobial agent comprises an antiviral IDO inhibitor, or both a TDO and IDO inhibitor. agent. In some embodiments, the antiviral agent comprises 0114. In some embodiments, a method of treating cancer imiquimod, efavirenz, or a salt, Solvate or combination comprises administering to a patient in need thereof an thereof. In some embodiments, the antimicrobial agent com effective amount of a compound of Formula (I), or a prises chlorquinaldol, or a salt or Solvate thereof. In some pharmaceutically acceptable salt or Solvate thereof, an effec embodiments, the patient has cancer and the antimicrobial tive amount of a compound of Formula (II), or a pharma agent is administered for the treatment of cancer. In some ceutically acceptable salt or solvate thereof; an effective embodiments, the method further comprises administering amount of a compound of Formula (III), or a pharmaceuti to the patient an effective amount of an anti-cancer agent. In cally acceptable salt or solvate thereof; an effective amount Some embodiments, the method further comprises adminis of a compound of Formula (IV), or a pharmaceutically tering to the patient an effective amount of an additional acceptable salt or solvate thereof an effective amount of a antimicrobial agent, adrenergic agent, serotonergic agent, compound of Formula (V), or a pharmaceutically acceptable NSAID, sulfonamide, phosphodiesterase inhibitor, proton salt or Solvate thereof an effective amount of a compound pump inhibitor, or a combination thereof. In some embodi of Formula (VI), or a pharmaceutically acceptable salt or ments, the method further comprises treating the individual solvate thereof; an effective amount of a compound of with an immunotherapy. In some embodiments, the method Formula (VII), or a pharmaceutically acceptable salt or further comprises treating the individual with a chimeric solvate thereof; an effective amount of a compound of antigen receptor (CAR) T-cell therapy. In some embodi Formula (VIII), or a pharmaceutically acceptable salt or ments, the method further comprises treating the individual solvate thereof, or a combination thereof. In some embodi with a stem cell therapy. ments, the method further comprises treating the individual 0117. In one aspect of the disclosure, provided herein is with an immunotherapy. In some embodiments, the method a method of inhibiting TDO, IDO, or both TDO and IDO in further comprises treating the individual with a chimeric a patient comprising administering to the patient an effective antigen receptor (CAR) T-cell therapy. In some embodi amount of an adrenergic agent. In some embodiments, the ments, the method further comprises treating the individual adrenergic agent comprises octopamine, ephedrine, epi with a stem cell therapy. nephrine, levonordefrin, norfenefrine, methoxamine, mir US 2016/0361298 A1 Dec. 15, 2016

tazapine, norpseudoephedrine, pseudophedrine, norepineph I0120 In one aspect of the disclosure, provided herein is rine, adrenochrome, ameZinium, clobenzorex, mirtazapine, a method of inhibiting TDO, IDO, or both TDO and IDO in or a salt, Solvate or combination thereof. In some embodi a patient comprising administering to the patient an effective ments, the patient has cancer and the adrenergic agent is amount of an NSAID. In some embodiments, the NSAID administered for the treatment of cancer. In some embodi comprises glucosamine, nabumetone, fenoprofen, loxopro ments, the method further comprises administering to the fen, diflunisal, ketoprofen, dexketoprofen, fenbufen, patient an effective amount of an anti-cancer agent. In some nepafenac, tolmetin, pelubiprofen, tiaprofenic acid, Supro embodiments, the method further comprises administering fen, metiazinic acid, carprofen, clidanac, etodolac, Zaltopro to the patient an effective amount of an antimicrobial agent, fen, nifenaZone, rofecoxib, protizinic acid, methyl salicylate, additional adrenergic agent, serotonergic agent, NSAID, piroXicam, meloxicam, diacerein, lornoxicam, glafenine, or a salt, Solvate, or combination thereof. In some embodi Sulfonamide, phosphodiesterase inhibitor, proton pump ments, the patient has cancer and the NSAID is administered inhibitor, or a combination thereof. In some embodiments, for the treatment of cancer. In some embodiments, the the method further comprises treating the individual with an method further comprises administering to the patient an immunotherapy. In some embodiments, the method further effective amount of an anti-cancer agent. In some embodi comprises treating the individual with a chimeric antigen ments, the method further comprises administering to the receptor (CAR) T-cell therapy. In some embodiments, the patient an effective amount of an antimicrobial agent, adren method further comprises treating the individual with a stem ergic agent, serotonergic agent, additional NSAID, Sulfona cell therapy. mide, phosphodiesterase inhibitor, proton pump inhibitor, or 0118. In one aspect of the disclosure, provided herein is a combination thereof. In some embodiments, the method a method of inhibiting TDO, IDO, or both TDO and IDO in further comprises treating the individual with an immuno a patient comprising administering to the patient an effective therapy. In some embodiments, the method further com amount of a serotonergic agent. In some embodiments, the prises treating the individual with a chimeric antigen recep serotonergic agent comprises 1-tryptophan, froVatriptan Suc tor (CAR) T-cell therapy. In some embodiments, the method cinate, ramosetron, mazindol, ondansetron, itasetron, indis further comprises treating the individual with a stem cell etron, naratriptan, or a salt, Solvate or combination thereof. therapy. In some embodiments, the patient has cancer and the sero I0121. In one aspect of the disclosure, provided herein is tonergic agent is administered for the treatment of cancer. In a method of inhibiting TDO, IDO, or both TDO and IDO in some embodiments, the method further comprises adminis a patient comprising administering to the patient an effective tering to the patient an effective amount of an anti-cancer amount of a phosphodiesterase inhibitor. In some embodi agent. In some embodiments, the method further comprises ments, the phosphodiesterase inhibitor comprises theophyl administering to the patient an effective amount of an line, ibudilast, anagrelide, doxofylline, rolipram, cilomilast, antimicrobial agent, adrenergic agent, additional serotoner Vinpocetine, or a salt, Solvate or combination thereof. In gic agent, NSAID, Sulfonamide, phosphodiesterase inhibi Some embodiments, the patient has cancer and the phos tor, proton pump inhibitor, or a combination thereof. In some phodiesterase inhibitor is administered for the treatment of embodiments, the method further comprises treating the cancer. In some embodiments, the method further comprises individual with an immunotherapy. In some embodiments, administering to the patient an effective amount of an the method further comprises treating the individual with a anti-cancer agent. In some embodiments, the method further chimeric antigen receptor (CAR) T-cell therapy. In some comprises administering to the patient an effective amount embodiments, the method further comprises treating the of an antimicrobial agent, adrenergic agent, serotonergic individual with a stem cell therapy. agent, NSAID, sulfonamide, additional phosphodiesterase 0119. In one aspect of the disclosure, provided herein is inhibitor, proton pump inhibitor, or a combination thereof. In a method of inhibiting TDO, IDO, or both TDO and IDO in Some embodiments, the method further comprises treating a patient comprising administering to the patient an effective the individual with an immunotherapy. In some embodi amount of a Sulfonamide. In some embodiments, the Sulfo ments, the method further comprises treating the individual namide is a Sulfonamide diuretic. In some embodiments, the with a chimeric antigen receptor (CAR) T-cell therapy. In Sulfonamide diuretic comprises furosemide, chlorthalidone, Some embodiments, the method further comprises treating indapamide, cyclopenthiazide, alilusem, benzthiazide, poly the individual with a stem cell therapy. thiazide, or a salt, Solvate or combination thereof. In some I0122. In one aspect of the disclosure, provided herein is embodiments, the patient has cancer and the Sulfonamide is a method of inhibiting TDO, IDO, or both TDO and IDO in administered for the treatment of cancer. In some embodi a patient comprising administering to the patient an effective ments, the method further comprises administering to the amount of a proton pump inhibitor. In some embodiments, patient an effective amount of an anti-cancer agent. In some the proton pump inhibitor comprises esomeprazole, omepra embodiments, the method further comprises administering Zole, tenatoprazole, rabeprazole, lanSoprazole, pantoprazole, to the patient an effective amount of an antimicrobial agent, or a salt, Solvate or combination thereof. In some embodi adrenergic agent, serotonergic agent, NSAID, additional ments, the patient has cancer and the proton pump inhibitor Sulfonamide, phosphodiesterase inhibitor, proton pump is administered for the treatment of cancer. In some embodi inhibitor, or a combination thereof. In some embodiments, ments, the method further comprises administering to the the method further comprises treating the individual with an patient an effective amount of an anti-cancer agent. In some immunotherapy. In some embodiments, the method further embodiments, the method further comprises administering comprises treating the individual with a chimeric antigen to the patient an effective amount of an antimicrobial agent, receptor (CAR) T-cell therapy. In some embodiments, the adrenergic agent, serotonergic agent, NSAID, Sulfonamide, method further comprises treating the individual with a stem phosphodiesterase inhibitor, additional proton pump inhibi cell therapy. tor, or a combination thereof. In some embodiments, the US 2016/0361298 A1 Dec. 15, 2016 20 method further comprises treating the individual with an droperidol, benperidol, pantoprazole, benzlhydrochlorothi immunotherapy. In some embodiments, the method further azide, cyclothiazide, abiraterone acetate, alilusem, besi comprises treating the individual with a chimeric antigen floxacin, (2S,3r,4r,5r,6r)-3-((3S.4s.5r,6s)-6-carboxy-3,4-di receptor (CAR) T-cell therapy. In some embodiments, the hydroxy-5-methoxytetrahydro-2h-pyran-2-yloxy)-4,5- method further comprises treating the individual with a stem dihydroxy-6-methoxytetrahydro-2h-pyran-2-carboxylic cell therapy. acid, Sunitinib, oxacillin sodium, moxifloxacin, aceto phenazine, noscapine, carfenazine, domperidone, benzthiaz 0123. In one aspect, provided herein is a method of ide, cloxacillin, polythiazide, pimozide, dicloxacillin, thi inhibiting TDO in a patient comprising administering to the abendazole, Zonisamide, bendazac, alosetron, dolasetron, patient an effective amount of a composition comprising timiperone, iodochlorohydroxyquinoline, bifonazole, buto econazole, Sulconazole, isoconazole, miconazole, Sertacon conazole, clotrimazole, ketoconazole, luliconazole, albacon azole, tioconazole, fenticonazole, liarozole, cloconazole, azole, efinaconazole, epoxiconazole, fluconazole, isavucon itraconazole, niclosamide, deferasiroX, eltrombopag, azole, posaconazole, propiconazole, ravuconazoie, allopurinol, indium in-111 oxyquinoline, coumarin, lutine, terconazole, Voriconazole, abafungin, omoconazole, lano phenoxyacetic acid, mesalazine, euresol, norpseudoephed conazole, nimustine, climbazole, nedocromil, pemirolast, rine, octopamine, norfenefrine, allantoin, sodium phenylbu granisetron, methysergide, Sorbinil, tolazoline, metronida tyrate, (r)-3-(methoxymethyl)-2,3-dihydro-1h-pyrrolo2,3- Zole, dexmedetomidine, ornidazole, diphenylimidazole, bipyridine, 2-(dimethylamino)-1-phenylethanol, tinidazole, Sulfamethoxazole, pyrrolnitrin, benznidazole, edrophonium, ephedrine, pseudophedrine, pyridoxine, chlo nevirapine, rizatriptan, mebhydroline, niturtatel, Zolmitrip rZoxazone, norepinephrine, edaravone, cantabiline, tan, nitazoxanide, alcaftadine, Sulfaphenazole, fexbuXostat, methoxycinnamate, cloxiquine, glucose, theophylline, glu protirelin, bromhexine, rivaroxaban, letrozole, hydroben cosamine, adrenochrome, fludeoxyglucose, epinephrine, Zole, OZagrel, procainamide, Sulfisoxazole, Sulfamethizole, levonordefrin, dibenzothiophene, betamipronum, Sodium chlorpropamide, anastroZole, flumazenil, Sulfadimethoxine, ferulic, caffeine, acrisorcinum, tacrine, ameZinium, 1-tryp succinylsulfathiazole, At-7519, rebamipide, taltirelin, sita tophan, trapidil, alphalipoic acid, lipoic acid, caldibasic gliptin, eZetimibe, bicalutamide, or a salt, Solvate or com phosphate, methoxamine, benzyl nicotinate, chloroxine, bination thereof. In some embodiments, the method further benzyl peroxide, methoXSalen, Santoquin, n-acetylman comprises treating the individual with an immunotherapy. In nosamine, (1)-isomer, hydrocotarnine, guaiac, dithranol, Some embodiments, the method further comprises treating hydroxyethyltheophylline, chlorquinaldol, nabumetone, the individual with a chimeric antigen receptor (CAR) T-cell ibudilast, diazoxide, acitazanolast, nalidixic acid, melatonin, eptazocine, 4-methoxy-2-(5-methoxy-3-methyl-1h-pyrazol therapy. In some embodiments, the method further com 1-yl)-6-methyl-pyrimidine, rufinamide, 1,8-dihydroxyan prises treating the individual with a stem cell therapy. thraquinone, benzyl cinnamate, (Z)-3-((3,5-dimethyl-1h 0.124. In some embodiments, the patient has cancer and pyrrol-2-yl)methylene)indolin-2-one, felbinac ethyl ester, the composition is administered for the treatment of cancer. imiquimod, methocarbamol, fenoprofen, benzoyl peroxide, In some embodiments, the method further comprises admin (e)-2-(isoxazol-3(2h)-ylidene)-2,6,7,9-tetrahydroimidazo[4, istering to the patient an effective amount of an anti-cancer 5-dipyrano 4.3-bipyridine, huperzine a, froVatriptan Succi agent. In some embodiments, the method further comprises nate, loxoprofen, chlorphenesin carbamate, tolperisone, administering to the patient an effective amount of an erdosteine, diflunisal, benzoxiquine, 5-(dimethylamino) antimicrobial agent, adrenergic agent, serotonergic agent, naphthalene-2-sulfonic acid, 2-(4-morpholino)thiobenzothi NSAID, sulfonamide, phosphodiesterase inhibitor, proton azole, menadione, menadione sodium bisulfite, ketoprofen, pump inhibitor, or a combination thereof. In some embodi dexketoprofen, fenbufen, nepafenac, ethacridine lactate, tol ments, the method further comprises administering to the metin, petoxil, anagrelide, pelubiprofen, tiaprofenic acid, patient a CTLA-4 inhibitor. In some embodiments, the suprofen, 1-(3,4-dihydro-1h-pyrido 3,4-bindol-2(9h)-yl)-3- CTLA-4 inhibitor comprises ipilimumab, tremelimumab, mercaptopropan-1-one, clobenzorex, hexylcaine, n-cyclo antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 hexyl-2-benzothiaZylsulfenamide, doxofylline, mirtazapine, del 55, or a combination thereof. In some embodiments, the emodin, metiazinic acid, carprofen, perisoxalum, Zelando method further comprises administering to the patient an pam, rolipram, cyclandelate, clidanac, Venlafaxine, phen effective amount of a PD-1/PD-L pathway inhibitor. In some procoumon, esonarimod, ramosetron, insc-4911, mazindol, embodiments, the PD-1/PD-L pathway inhibitor comprises etodolac, naftifine, lobenzarit, ondansetron, leucogen, Zal BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, toprofen, tolindate, ampholyt g. itasetron, chlorambucil, AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS Zaleplon, pirenoXine, tolnaftate, nifenaZone, cycotiamine, 98.6016, MDX1105-01, avelumab, or a salt, solvate, or d-panthenol, trenbolone acetate, praziquantel, rofecoxib, combination thereof. In some embodiments, the method protizinic acid, indisetron, efavirenz, nateglinide, choline further comprises administering to the patient an effective fenofibrate, paZufloxacin, butenafine, (r)-(5-(3-aminophe amount of an IDO pathway inhibitor. In some embodiments, nyl)-1h-pyrrolo2,3-bipyridin-3-yl)(5-methyl-4,5-dihy the IDO inhibitor comprises indoximod (D-1MT), F001287, droisoxazol-3-yl)methanone, methyl salicylate, chloro NLG919, INCB024360, or a salt, solvate or combination quine, glabridin, epsiprantel, cyclic adenosine thereof. monophosphate, o-(5,6,7,8-tetrahydro-2-naphthyl)-6- 0.125. In another aspect, provided herein is a method of methoxy-n-methylthio-2-pyridinecarbamate, furosemide, inhibiting IDO in a patient comprising administering to the piroXicam, mitomycin, berberine, naratriptan, hydroxychlo patient an effective amount of a composition comprising roquine, chlorthalidone, cilomilast, esomeprazole, omepra econazole, Sulconazole, isoconazole, miconazole, Sertacon Zole, tenatoprazole, meloxicam, Vinpocetine, repirinast, azole, tioconazole, fenticonazole, liarozole, cloconazole, rabeprazole, indapamide, diacerein, blonanserin, lanSopra itraconazole, niclosamide, deferasiroX, eltrombopag, Zole, lornoxicam, glafenine, propicillin, cyclopenthiazide, allopurinol, indium in-111 oxyquinoline, coumarin, lutine, US 2016/0361298 A1 Dec. 15, 2016

phenoxyacetic acid, mesalazine, euresol, norpseudoephed terconazole, Voriconazole, abafungin, omoconazole, lano rine, octopamine, norfenefrine, allantoin, sodium phenylbu conazole, nimustine, climbazole, nedocromil, pemirolast, tyrate, (r)-3-(methoxymethyl)-2,3-dihydro-1h-pyrrolo2,3- granisetron, methysergide, Sorbinil, tolazoline, metronida bipyridine, 2-(dimethylamino)-1-phenylethanol, Zole, dexmedetomidine, ornidazole, diphenylimidazole, edrophonium, ephedrine, pseudophedrine, pyridoxine, chlo tinidazole, Sulfamethoxazole, pyrrolnitrin, benznidazole, rZoxazone, norepinephrine, edaravone, cantabiline, nevirapine, rizatriptan, mebhydroline, niturtatel, Zolmitrip methoxycinnamate, cloxiquine, glucose, theophylline, glu tan, nitazoxanide, alcaftadine, Sulfaphenazole, fexbuXostat, cosamine, adrenochrome, fludeoxyglucose, epinephrine, protirelin, bromhexine, rivaroxaban, letrozole, hydroben levonordefrin, dibenzothiophene, betamipronum, Sodium Zole, OZagrel, procainamide, Sulfisoxazole, Sulfamethizole, chlorpropamide, anastroZole, flumazenil, Sulfadimethoxine, ferulic, caffeine, acrisorcinum, tacrine, ameZinium, 1-tryp succinylsulfathiazole, At-7519, rebamipide, taltirelin, sita tophan, trapidil, alphalipoic acid, lipoic acid, caldibasic gliptin, eZetimibe, bicalutamide, or a salt, Solvate or com phosphate, methoxamine, benzyl nicotinate, chloroxine, bination thereof. In some embodiments, the method further benzyl peroxide, methoXSalen, Santoquin, n-acetylman comprises treating the individual with an immunotherapy. In nosamine, (1)-isomer, hydrocotarnine, guaiac, dithranol, Some embodiments, the method further comprises treating hydroxyethyltheophylline, chlorquinaldol, nabumetone, the individual with a chimeric antigen receptor (CAR) T-cell ibudilast, diaZoxide, acitaZanolast, nalidixic acid, melatonin, therapy. In some embodiments, the method further com eptazocine, 4-methoxy-2-(5-methoxy-3-methyl-1h-pyrazol prises treating the individual with a stem cell therapy. 1-yl)-6-methyl-pyrimidine, rufinamide, 1,8-dihydroxyan I0126. In some embodiments, the patient has cancer and thraquinone, benzyl cinnamate, (Z)-3-((3,5-dimethyl-1h the composition is administered for the treatment of cancer. pyrrol-2-yl)methylene)indolin-2-one, felbinac ethyl ester, In some embodiments, the method further comprises admin imiquimod, methocarbamol, fenoprofen, benzoyl peroxide, istering to the patient an effective amount of an anti-cancer (e)-2-(isoxazol-3(2h)-ylidene)-2,6,7,9-tetrahydroimidazo[4, agent. In some embodiments, the method further comprises 5-dipyrano 4.3-bipyridine, huperzine a, froVatriptan Succi administering to the patient an effective amount of an nate, loxoprofen, chlorphenesin carbamate, tolperisone, antimicrobial agent, adrenergic agent, serotonergic agent, erdosteine, diflunisal, benzoxiquine, 5-(dimethylamino) NSAID, sulfonamide, phosphodiesterase inhibitor, proton naphthalene-2-sulfonic acid, 2-(4-morpholino)thiobenzothi pump inhibitor, or a combination thereof. In some embodi azole, menadione, menadione sodium bisulfite, ketoprofen, ments, the method further comprises administering to the dexketoprofen, fenbufen, nepafenac, ethacridine lactate, tol patient a CTLA-4 inhibitor. In some embodiments, the metin, petoxil, anagrelide, pelubiprofen, tiaprofenic acid, CTLA-4 inhibitor comprises ipilimumab, tremelimumab, suprofen, 1-(3,4-dihydro-1h-pyrido 3,4-bindol-2(9h)-yl)-3- antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 mercaptopropan-1-one, clobenzorex, hexylcaine, n-cyclo del 55, or a combination thereof. In some embodiments, the hexyl-2-benzothiaZylsulfenamide, doxofylline, mirtazapine, method further comprises administering to the patient an emodin, metiazinic acid, carprofen, perisoxalum, Zelando effective amount of a PD-1/PD-L pathway inhibitor. In some pam, rolipram, cyclandelate, clidanac, Venlafaxine, phen embodiments, the PD-1/PD-L pathway inhibitor comprises procoumon, esonarimod, ramosetron, insc-4911, mazindol, BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, etodolac, naftifine, lobenzarit, ondansetron, leucogen, Zal AMP-224, nivolumab, pembrolizumab, pidilizumab, BMS toprofen, tolindate, ampholyt g. itasetron, chlorambucil, 98.6016, MDX1105-01, avelumab, or a salt, solvate, or Zaleplon, pirenoXine, tolnaftate, nifenaZone, cycotiamine, combination thereof. In some embodiments, the method d-panthenol, trenbolone acetate, praziquantel, rofecoxib, further comprises administering to the patient an effective protizinic acid, indisetron, efavirenz, nateglinide, choline fenofibrate, paZufloxacin, butenafine, (r)-(5-(3-aminophe amount of an IDO pathway inhibitor. In some embodiments, nyl)-1h-pyrrolo2,3-bipyridin-3-yl)(5-methyl-4,5-dihy the IDO inhibitor comprises indoximod (D-1MT), F001287, droisoxazol-3-yl)methanone, methyl salicylate, chloro NLG919, INCB024360, or a salt, solvate or combination quine, glabridin, epsiprantel, cyclic adenosine thereof. monophosphate, o-(5,6,7,8-tetrahydro-2-naphthyl)-6- methoxy-n-methylthio-2-pyridinecarbamate, furosemide, BRIEF DESCRIPTION OF THE FIGURES piroXicam, mitomycin, berberine, naratriptan, hydroxychlo I0127. The novel and inventive features of the subject roquine, chlorthalidone, cilomilast, esomeprazole, omepra matter described herein are set forth with particularity in the Zole, tenatoprazole, meloxicam, Vinpocetine, repirinast, appended claims. A better understanding of the features and rabeprazole, indapamide, diacerein, blonanserin, lanSopra advantages of the present invention will be obtained by Zole, lornoxicam, glafenine, propicillin, cyclopenthiazide, reference to the following detailed description that sets forth droperidol, benperidol, pantoprazole, benzylhydrochlorothi illustrative embodiments, in which the principles of the azide, cyclothiazide, abiraterone acetate, alilusem, besi invention are utilized, and accompanying drawings of floxacin, (2S,3r,4r,5r,6r)-3-((3S,4s.5r,6s)-6-carboxy-3,4-di which: hydroxy-5-methoxytetrahydro-2h-pyran-2-yloxy)-4,5- I0128 FIG. 1 shows plots of viable CT26 murine colon dihydroxy-6-methoxytetrahydro-2h-pyran-2-carboxylic cancer cells as a percent of total cells versus concentration acid, Sunitinib, oxacillin Sodium, moxifloxacin, aceto of TDO/IDO inhibitor test compounds. The graph of panel phenazine, noscapine, carfenazine, domperidone, benzthiaz A shows the effect of test compounds tioconazole, niclos ide, cloxacillin, polythiazide, pimozide, dicloxacillin, thi amide, eltrombopag, deferasiroX, and control compound abendazole, Zonisamide, bendazac, alosetron, dolasetron, 1MT on CT26 viability. The graph of panel B shows the timiperone, iodochlorohydroxyquinoline, bifonazole, buto effect of test compounds Sulconazole, cloconazole, micon conazole, clotrimazole, ketoconazole, luliconazole, albacon azole, and control compound 1MT on C26 viability. azole, efinaconazole, epoxiconazole, fluconazole, isavucon I0129 FIG. 2 shows plots of percent viable CD4+ cells azole, posaconazole, propiconazole, ravuconazole, versus concentration of TDO/IDO inhibitor test compounds. US 2016/0361298 A1 Dec. 15, 2016 22

The graph of panel A shows the effect of test compounds cancer. In various aspects, a TDO inhibitor is provided that tioconazole, niclosamide, eltrombopag, deferasiroX, and also functions as an inhibitor of IDO, and vice versa. In control compound 1MT on CD4+ viability. The graph of some embodiments, the TDO and/or IDO inhibitor compo panel B shows the effect of test compounds sulconazole, sitions provided herein are useful for the treatment of cloconazole, miconazole, and control compound 1MT on non-cancerous diseases or conditions, for example, infec CD430 viability. tious diseases. In some embodiments, the TDO and/or IDO 0130 FIG. 3 shows plots of percent viable CD69+CD4+ inhibitors provided herein are useful in immunotherapy, cells versus concentration of TDO/IDO inhibitor test com stem cell therapy, and/or CART-cell therapy. pounds. The graph of panel A shows the effect of test 0.136. In the following description, certain specific details compounds tioconazole, niclosamide, eltrombopag, defera are set forth in order to provide a thorough understanding of sirox, and control compound 1MT on CD4+ viability. The various embodiments. However, one skilled in the art will graph of panel B shows the effect of test compounds understand that the embodiments provided may be practiced Sulconazole, cloconazole, miconazole, and control com without these details. In some instances, well-known struc pound 1MT on CD430 viability. tures have not been shown or described in detail to avoid 0131 FIG. 4 shows plots of percent viable CD71+CD4+ unnecessarily obscuring descriptions of the embodiments. cells versus concentration of TDO/IDO inhibitor test com Unless the context requires otherwise, throughout the speci pounds. The graph of panel A shows the effect of test fication and claims which follow, the word “comprise' and compounds tioconazole, niclosamide, eltrombopag, defera variations thereof. Such as, "comprises and "comprising sirox, and control compound 1MT on CD4+ viability. The are to be construed in an open, inclusive sense, that is, as graph of panel B shows the effect of test compounds “including, but not limited to.” As used in this specification Sulconazole, cloconazole, miconazole, and control com and the appended claims, the singular forms “a,” “an,” and pound 1MT on CD430 viability. “the include plural referents unless the content clearly (0132 FIG. 5 shows plots of percent viable CD8+ cells dictates otherwise. It should also be noted that the term 'or' versus concentration of TDO/IDO inhibitor test compounds. is generally employed in its sense including “and/or unless The graph of panel A shows the effect of test compounds tioconazole, niclosamide, eltrombopag, deferasiroX, and the content clearly dictates otherwise. Further, headings control compound 1MT on CD8+ viability. The graph of provided herein are for convenience only and do not inter panel B shows the effect of test compounds sulconazole, pret the scope or meaning of the claimed embodiments. cloconazole, miconazole, and control compound 1MT on 0.137 The terms below, as used herein, have the follow CD830 viability. ing meanings, unless indicated otherwise: 0.133 FIG. 6 shows plots of percent viable CD69+CD8+ 0.138 “Oxo' refers to the =O substituent. cells versus concentration of TDO/IDO inhibitor test com pounds. The graph of panel A shows the effect of test 0.139. “Thioxo’ refers to the =S substituent. compounds tioconazole, niclosamide, eltrombopag, defera 0140 “Alkyl refers to a straight or branched hydrocar sirox, and control compound 1MT on CD8+ viability. The bon chain radical, having from one to twenty carbon atoms, graph of panel B shows the effect of test compounds and which is attached to the rest of the molecule by a single Sulconazole, cloconazole, miconazole, and control com bond. An alkyl comprising up to 10 carbon atoms is referred pound 1MT on CD830 viability. to as a C-Co alkyl, likewise, for example, an alkyl com 0134 FIG. 7 shows plots of percent viable CD71+CD8+ prising up to 6 carbon atoms is a C-C alkyl. Alkyls (and cells versus concentration of TDO/IDO inhibitor test com other moieties defined herein) comprising other numbers of pounds. The graph of panel A shows the effect of test carbon atoms are represented similarly Alkyl groups compounds tioconazole, niclosamide, eltrombopag, defera include, but are not limited to, C-C alkyl, C-C alkyl, sirox, and control compound 1MT on CD8+ viability. The C-Cs alkyl, C-C, alkyl, C-C alkyl, C-C alkyl, C-C, graph of panel B shows the effect of test compounds alkyl, C-C alkyl, C-C alkyl, C-Cs alkyl, C-C alkyl and Sulconazole, cloconazole, miconazole, and control com C-Cs alkyl. Representative alkyl groups include, but are not pound 1MT on CD830 viability. limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-bu DETAILED DESCRIPTION OF THE tyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the INVENTION like. In some embodiments, the alkyl is methyl, ethyl, 0135 Immunotherapeutic approaches for treating cancer s-butyl, or 1-ethyl-propyl. Unless stated otherwise specifi often comprise the manipulation of the immune systems cally in the specification, an alkyl group may be optionally T-cell response by disrupting mechanisms by which tumor substituted as described below. “Alkylene' or “alkylene cells evade the immune system. One method of reducing chain” refers to a straight or branched divalent hydrocarbon tumor cell evasion involves the use of immune checkpoint chain linking the rest of the molecule to a radical group. In inhibitors to potentiate the antitumor T-cell response. An Some embodiments, the alkylene is —CH2—, exemplary immune checkpoint inhibitor for the treatment of —CH2CH2—, or —CH2CHCH-. In some embodiments, cancer is indoleamine 2,3-dioxygenase (IDO). The enzy the alkylene is —CH2—. In some embodiments, the alky matic activity of IDO is similar to that of tryptophan lene is —CH2CH2—. In some embodiments, the alkylene is 2,3-dioxygenase (TDO) and studies have implicated TDO in —CH2CH2CH2—. the development of cancer in a similar manner to IDO. 0.141. “Alkoxy' refers to a radical of the formula —OR Disclosed herein, in various aspects, are compositions com where R is an alkyl radical as defined. Unless stated other prising TDO and/or IDO inhibitors and optionally one or wise specifically in the specification, an alkoxy group may more additional agents, such as one or more additional be optionally substituted as described below. Representative immune checkpoint inhibitors, useful for the treatment of alkoxy groups include, but are not limited to, methoxy, US 2016/0361298 A1 Dec. 15, 2016

ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the -continued alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy. l-O e v v 0142 “Heteroalkylene' refers to an alkyl radical as X=O, N, | 2N described above where one or more carbon atoms of the N M A alkyl is replaced with a O, N, or S atom. “Heteroalkylene’ H or "heteroalkylene chain” refers to a straight or branched OH OH divalent heteroalkyl chain linking the rest of the molecule to O a radical group. Unless stated otherwise specifically in the O specification, the heteroalkyl or heteroalkylene group may N be optionally substituted as described below. Representative M s OH, heteroalkyl groups include, but are not limited to –OCHOMe, –OCHCHOMe, O OH O —OCHCHOCH2CH-NH. Representative heteroalkylene groups include, but are not limited to —OCH2CH2O , and the like. –OCHCHOCHCHO , O 0147 “Cycloalkyl refers to a monocyclic or polycyclic –OCHCHOCHCHOCH2CHO non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may 0143 “Alkylamino” refers to a radical of the formula be saturated, or partially unsaturated. Cycloalkyls may be —NHR or —NRR where each R is, independently, an alkyl fused with an aromatic ring (in which case the cycloalkyl is radical as defined above. Unless stated otherwise specifi bonded through a non-aromatic ring carbon atom). cally in the specification, an alkylamino group may be Cycloalkyl groups include groups having from 3 to 10 ring optionally substituted as described below. atoms. Representative cycloalkyls include, but are not lim 0144. The term “aromatic' refers to a planar ring having ited to, cycloakyls having from three to ten carbon atoms, a delocalized L-electron system containing 4n+2 at electrons, from three to eight carbon atoms, from three to six carbon where n is an integer. Aromatics can be optionally Substi atoms, or from three to five carbon atoms. Monocyclic tuted. The term 'aromatic' includes both aryl groups (e.g., cycicoalkyl radicals include, for example, cyclopropyl. phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and quinolinyl). cyclooctyl. In some embodiments, the monocyclic cyci coalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclo 0145 "Aryl refers to an aromatic ring wherein each of hexyl. Polycyclic radicals include, for example, adamantyl, the atoms forming the ring is a carbon atom. Aryl groups can norbornyl, decalinyl, and 3,4-dihydronaphthalen-1 (2H)-one. be optionally substituted. Examples of aryl groups include, Unless otherwise Stated specifically in the specification, a but are not limited to phenyl and naphthalenyl. In some cycloalkyl group may be optionally Substituted. embodiments, the aryl is phenyl. Depending on the struc 0148 “Fused refers to any ring structure described ture, an aryl group can be a monoradical or a diradical (i.e., herein which is fused to an existing ring structure. When the an arylene group). Unless stated otherwise specifically in the fused ring is a heterocyclyl ring or a heteroaryl ring, any specification, the term “aryl' or the prefix "ar-' (such as in carbon atom on the existing ring structure which becomes “aralkyl) is meant to include aryl radicals that are option part of the fused heterocyclyl ring or the fused heteroaryl ally substituted. ring may be replaced with a nitrogen atom. 0146 “Carboxy' refers to —COH. In some embodi 0149) “Halo' or “halogen” refers to bromo, chloro, ments, carboxy moieties may be replaced with a "carboxylic fluoro, or iodo. acid bioisostere', which refers to a functional group or 0150 “Haloalkyl refers to an alkyl radical, as defined moiety that exhibits similar physical and/or chemical prop above, that is substituted by one or more halo radicals, as erties as a carboxylic acid moiety. A carboxylic acid bio defined above, e.g., trifluoromethyl, difluoromethyl, fluo isostere has similar biological properties to that of a car romethyl, trichloromethyl, 2.2.2-trifluoroethyl, 1,2-difluoro boxylic acid group. A compound with a carboxylic acid ethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the moiety can have the carboxylic acid moiety exchanged with like. Unless stated otherwise specifically in the specification, a carboxylic acid bioisostere and have similar physical a haloalkyl group may be optionally Substituted. and/or biological properties when compared to the carbox 0151. “Haloalkoxy' refers to an alkoxy radical, as ylic acid-containing compound. For example, in one defined above, that is substituted by one or more halo embodiment, a carboxylic acid bioisostere would ionize at radicals, as defined above, e.g., trifluoromethoxy, difluo physiological pH to roughly the same extent as a carboxylic romethoxy, fluoromethoxy, trichloromethoxy. 2.2.2-trifluo acid group. Examples of bioisosteres of a carboxylic acid roethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, include, but are not limited to: 1,2-dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted. e N 0152 “Heterocycloalkyl or "heterocyclyl or “hetero OH CN \ cyclic ring refers to a stable 3- to 14-membered non 1." 1." ^ aromatic ring radical comprising 2 to 13 carbon atoms and H from one to 6 heteroatoms selected from the group consist ing of nitrogen, oxygen, and Sulfur. Unless Stated otherwise specifically in the specification, the heterocycloalkyl radical US 2016/0361298 A1 Dec. 15, 2016 24 may be a monocyclic, or bicyclic ring system, which may benzofuran, benzothiophene, indazole, benzimidazole, include fused (when fused with an aryl or a heteroaryl ring, purine, quinolizine, quinoline, isoquinoline, cinnoline, the heterocycloalkyl is bonded through a non-aromatic ring phthalazine, quinazoline, quinoxaline, 1.8-naphthyridine, atom) or bridged ring systems. The nitrogen, carbon or and pteridine. In some embodiments, heteroaryl is pyridinyl, sulfur atoms in the heterocyclyl radical may be optionally pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or oxidized. The nitrogen atom may be optionally quaternized. furyl. In some embodiments, a heteroaryl contains 0-4 N The heterocycloalkyl radical is partially or fully saturated. atoms in the ring. In some embodiments, a heteroaryl Examples of such heterocycloalkyl radicals include, but are contains 1-4N atoms in the ring. In some embodiments, a not limited to, dioxolanyl, thienyl 1.3dithianyl, decahy heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S droisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidi atoms in the ring. In some embodiments, a heteroaryl nyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahy contains 1-4N atoms, 0-1 O atoms, and 0-1 Satoms in the droisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, ring. In some embodiments, heteroaryl is a C-C heteroaryl. 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, In some embodiments, monocyclic heteroaryl is a C-Cs 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, heteroaryl. In some embodiments, monocyclic heteroaryl is thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, a 5-membered or 6-membered heteroaryl. In some embodi thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, ments, a bicyclic heteroaryl is a C-C heteroaryl. and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl 0154) The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one also includes all ring forms of carbohydrates, including but or more additional group(s) individually and independently not limited to monosaccharides, disaccharides, and oligosac selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, charides. Unless otherwise noted, heterocycloalkyls have heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio. from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, some embodiments, heterocycloalkyls have from 2 to 8 —CN, alkyne, C-C alkylalkyne, halogen, acyl, acyloxy, carbons in the ring and 1 or 2 Natoms. It is understood that —COH, -CO alkyl, nitro, and amino, including mono when referring to the number of carbon atoms in a hetero and di-substituted amino groups (e.g. —NH2, —NHR, cycloalkyl, the number of carbon atoms in the heterocy —N(R)), and the protected derivatives thereof. In some cloalkyl is not the same as the total number of atoms embodiments, optional Substituents are independently (including the heteroatoms) that make up the heterocy selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, cloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). —CN, NH, —NH(CH), N(CH), —OH, -COH, Unless stated otherwise specifically in the specification, a and CO-alkyl. In some embodiments, optional substitu heterocycloalkyl group may be optionally Substituted. ents are independently selected from fluoro, chloro, bromo, iodo, —CH, —CH2CH, -CF, —OCH, and —OCF. In 0153. “Heteroaryl” refers to an aryl group that includes Some embodiments, Substituted groups are Substituted with one or more ring heteroatoms selected from nitrogen, oxy one or two of the preceding groups. In some embodiments, gen, and Sulfur. The heteroaryl is monocyclic or bicyclic. an optional Substituent on an aliphatic carbon atom (acyclic Illustrative examples of monocyclic heteroaryls include or cyclic, Saturated or unsaturated carbon atoms, excluding pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, aromatic carbon atoms) includes oxo (=O). pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, 0.155. A “tautomer' refers to a proton shift from one atom oxazolyl, isothiazolyl pyrrolyl pyridazinyl, triazinyl, of a molecule to another atom of the same molecule. The oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, ben compounds presented herein may exist as tautomers. Tau Zofuran, benzothiophene, indazole, benzimidazole, purine, tomers are compounds that are interconvertible by migration quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, of a hydrogen atom, accompanied by a Switch of a single quinazoline, quinoxaline, 1.8-naphthyridine, and pteridine. bond and adjacent double bond. In bonding arrangements Illustrative examples of monocyclic heteroaryls include where tautomerization is possible, a chemical equilibrium of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, the tautomers will exist. All tautomeric forms of the com pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, pounds disclosed herein are contemplated. The exact ratio of oxazolyl, isothiazolyl pyrrolyl pyridazinyl, triazinyl, the tautomers depends on several factors, including tem oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative perature, solvent, and pH. Some examples of tautomeric examples of bicyclic heteroaryls include indolizine, indole, interconversions include:

OH O O OH

vXH =s vaH. H. vXh sh vs. x

O OH NH2 NH Ji N N

vs. vs. vs. X. s-s vX N) sh NX V H US 2016/0361298 A1 Dec. 15, 2016

-continued

N N N Hh- N =s N Hh- NH NNN M HN- / H

0156. In one aspect, the compounds disclosed herein therapeutic advantages resulting from greater metabolic possess one or more stereocenters and each stereocenter stability, such as, for example, increased in vivo half-life or exists independently in either the R or S configuration. The reduced dosage requirements. compounds presented herein include all diastereomeric, (0160. In additional or further embodiments, the com enantiomeric, and epimeric forms as well as the appropriate pounds described herein are metabolized upon administra mixtures thereof. The compounds and methods provided tion to an organism in need to produce a metabolite that is herein include all cis, trans, syn, anti, entgegen (E), and then used to produce a desired effect, including a desired Zusammen (Z) isomers as well as the appropriate mixtures therapeutic effect. thereof. In certain embodiments, compounds described 0.161 “Pharmaceutically acceptable' as used herein, herein are prepared as their individual stereoisomers by refers a material. Such as a carrier or diluent, which does not reacting a racemic mixture of the compound with an opti abrogate the biological activity or properties of the com cally active resolving agent to form a pair of diastereoiso pound, and is relatively nontoxic, i.e., the material may be meric compounds/salts, separating the diastereomers and administered to an individual without causing undesirable recovering the optically pure enantiomers. In some embodi biological effects or interacting in a deleterious manner with ments, resolution of enantiomers is carried out using cova any of the components of the composition in which it is lent diastereomeric derivatives of the compounds described contained. herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences 0162 The term “pharmaceutically acceptable salt” refers in solubility. In other embodiments, separation of stereoiso to a formulation of a compound that does not cause signifi mers is performed by chromatography or by the forming cant irritation to an organism to which it is administered and diastereomeric salts and separation by recrystallization, or does not abrogate the biological activity and properties of chromatography, or any combination thereof. Jean Jacques, the compound. In some embodiments, pharmaceutically Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates acceptable salts are obtained by reacting a compound of and Resolutions”, John Wiley And Sons, Inc., 1981. In one Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) aspect, Stereoisomers are obtained by Stereoselective Syn with acids. Pharmaceutically acceptable salts are also thesis. obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) with a base to form a salt. 0157. In some embodiments, sites on the aromatic ring 0163 Compounds described herein may be formed as, portion of compounds described herein are susceptible to and/or used as, pharmaceutically acceptable salts. The type various metabolic reactions Therefore incorporation of of pharmaceutical acceptable salts, include, but are not appropriate Substituents on the aromatic ring structures will limited to: (1) acid addition salts, formed by reacting the free reduce, minimize or eliminate this metabolic pathway. In base form of the compound with a pharmaceutically accept specific embodiments, the appropriate Substituent to able: inorganic acid, such as, for example, hydrochloric acid, decrease or eliminate the Susceptibility of the aromatic ring hydrobromic acid, Sulfuric acid, phosphoric acid, metaphos to metabolic reactions is, by way of example only, a halogen phoric acid, and the like; or with an organic acid, such as, for or an alkyl group. example, acetic acid, propionic acid, hexanoic acid, cyclo 0158. In another embodiment, the compounds described pentanepropionic acid, glycolic acid, pyruvic acid, lactic herein are labeled isotopically (e.g. with a radioisotope) or acid, malonic acid. Succinic acid, malic acid, maleic acid, by another other means, including, but not limited to, the use fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, of chromophores or fluorescent moieties, bioluminescent benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic labels, or chemiluminescent labels. acid, mandelic acid, methanesulfonic acid, ethanesulfonic 0159 Compounds described herein include isotopically acid, 1.2-ethanedisulfonic acid, 2-hydroxyethanesulfonic labeled compounds, which are identical to those recited in acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphtha the various formulae and structures presented herein, but for lenesulfonic acid, 4-methylbicyclo-2.2.2]oct-2-ene-1-car the fact that one or more atoms are replaced by an atom boxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hy having an atomic mass or mass number different from the droxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, atomic mass or mass number usually found in nature. trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric Examples of isotopes that can be incorporated into the acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, present compounds include isotopes of hydrogen, carbon, salicylic acid, Stearic acid, muconic acid, butyric acid, nitrogen, oxygen, Sulfur, fluorine and chlorine. Such as, for phenylacetic acid, phenylbutyric acid, valproic acid, and the example, H, H, C, C, N, O, 7O, S, F, C1. In like; (2) salts formed when an acidic proton present in the one aspect, isotopically-labeled compounds described parent compound is replaced by a metal ion, e.g., an alkali herein, for example those into which radioactive isotopes metalion (e.g. lithium, Sodium, potassium), an alkaline earth such as H and ''C are incorporated, are useful in drug ion (e.g. magnesium, or calcium), or an aluminum ion. In and/or Substrate tissue distribution assays. In one aspect, Some cases, compounds described herein may coordinate substitution with isotopes such as deuterium affords certain with an organic base, such as, but not limited to, etha US 2016/0361298 A1 Dec. 15, 2016 26 nolamine, diethanolamine, triethanolamine, tromethamine, a TDO/IDO inhibitor has in vitro and/or in vivo activity for N-methylglucamine, dicyclohexylamine, tris(hydroxymeth the inhibition of IDO and little or no measurable activity for yl)methylamine. In other cases, compounds described herein the inhibition of TDO. may form salts with amino acids Such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases (0167. In some embodiments, a TDO/IDO inhibitor is a used to form salts with compounds that include an acidic small molecule. In some embodiments, a TDO/IDO inhibi proton, include, but are not limited to, aluminum hydroxide, tor is a peptide. In some cases, a TDO/IDO inhibitor is not calcium hydroxide, potassium hydroxide, sodium carbonate, an immunoglobulin or immunoglobulin derived protein. In sodium hydroxide, and the like. some embodiments, a TDO/IDO inhibitor directly or indi rectly inhibits TDO, IDO, or both TDO and IDO. In some 0164. It should be understood that a reference to a embodiments, a TDO/IDO inhibitor refers to a compound pharmaceutically acceptable salt includes the solvent addi that targets TDO, IDO, or both TDO and IDO. In some tion forms, particularly Solvates. Solvates contain either instances, a TDO/IDO inhibitor targets one or more proteins Stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with in a signaling cascade comprising TDO, IDO, or both TDO pharmaceutically acceptable solvents such as water, ethanol, and IDO. In some instances, a TDO/IDO inhibitor inhibits and the like. Hydrates are formed when the solvent is water, TDO, IDO, or both TDO and IDO expression. In some or alcoholates are formed when the solvent is alcohol. embodiments, a composition comprising one or more TDO/ Solvates of compounds described herein can be conve IDO inhibitors provided herein further comprises or is niently prepared or formed during the processes described combined with one or more additional active agents. In some herein. In addition, the compounds provided herein can exist cases, an additional active agent is a PD-1 inhibitor. PD-1 in unsolvated as well as Solvated forms. In general, the inhibitors include any inhibitors of the PD-1/PD-L pathway. Solvated forms are considered equivalent to the unsolvated In some instances, an additional active agent is an IDO forms for the purposes of the compounds and methods inhibitor or an additional IDO inhibitor. In some instances, provided herein. an additional active agent is a CTLA-4 inhibitor. In some instances, an additional active agent is an IDO inhibitor or Compounds and Compositions another TDO inhibitor. In some cases, an additional active agent is an anti-cancer agent. In some cases, the anti-cancer (0165. In one aspect, provided herein are compounds and agent is a PD-1 inhibitor. In some cases, the anti-cancer compositions comprising one or more TDO inhibitors, IDO agent is an IDO inhibitor. In some cases, the anti-cancer inhibitors, and/or inhibitors of both TDO and IDO. In some agent is a CTLA-4 inhibitor. In some cases, the anti-cancer embodiments, a TDO inhibitor is also an inhibitor of IDO, agent is a TDO inhibitor. In various embodiments, an and vice versa. In some cases wherein a TDO inhibitor is anti-cancer agent is an agent that modulates the immune also an inhibitor of IDO, the TDO inhibitory activity is system to treat cancer. For example, in order exploit the greater than the IDO inhibitory activity. In some cases intrinsic potential of the immune system to recognize and/or wherein a TDO inhibitor is also an inhibitor of IDO, the IDO eliminate tumor cells. inhibitory activity is greater than the TDO inhibitory activ ity. In some cases wherein an IDO inhibitor is also an (0168 Non-limiting examples of TDO inhibitors, IDO inhibitor of TDO, the IDO inhibitory activity is greater than inhibitors, or inhibitors of both TDO and IDO are provided the TDO inhibitory activity. In some cases wherein an IDO in Table 1 and include salts and solvates of the compounds inhibitor is also an inhibitor of TDO, the TDO inhibitory of Table 1. Additional examples of TDO inhibitors, IDO activity is greater than the IDO inhibitory activity. In some inhibitors, or inhibitors of both TDO and IDO include, cases wherein a TDO inhibitor is also an inhibitor of IDO, the TDO inhibitory activity is comparable to that of the IDO without limitation, indoximod (D-1MT), F001287, inhibitory activity. For example, comparable includes activ NLG919, INCB024360, and salts, solvates and combina ity values as measured by any in vitro and/or in vitro tions thereof. method(s) known in the art that are within 30%, 25%, 20%, (0169. The compositions and TDO/IDO inhibitors pro 15%, 10%, 5%, 1% or less of one another. In some embodi vided herein, in various aspects, are useful for the treatment ments, a TDO inhibitor provided herein has little or no of cancer. In some embodiments, the TDO/IDO inhibitors measurable activity for inhibiting TDO and has measurable provided herein are useful in immunotherapy, stem cell activity for inhibiting IDO. In some embodiments, an IDO therapy, and/or CART-cell therapy. In some embodiments, inhibitor provided herein has little or no measurable activity a composition comprising one or more TDO/IDO inhibitors for inhibiting IDO and has measurable activity for inhibiting described herein is useful for the treatment of cancer. In TDO. Some embodiments, provided herein are methods of treating 0166 In some embodiments, inhibitors of TDO, IDO, or cancer comprising administering one or more TDO/IDO both TDO and IDO are referred to as TDO/IDO inhibitors. inhibitors provided herein, for example, one or more com In some cases, a TDO/IDO inhibitor has in vitro and/or in pounds of Table 1, or salts or solvates of one or more vivo activity for the inhibition of TDO. In some cases, a compounds of Table 1. In some cases, a composition for TDO/IDO inhibitor has in vitro and/or in vivo activity for treating cancer comprises 2, 3, 4, or 5 TDO/IDO inhibitors. the inhibition of IDO. In some cases, a TDO/IDO inhibitor For example, a composition comprises 1, 2, 3, 4, or 5 has in vitro and/or activity for the inhibition of TDO and TDO/IDO inhibitors from Table 1, or salts or solvates IDO. In some cases, a TDO/IDO inhibitor has in vitro and/or thereof, and optionally 1 or more additional TDO/IDO in vivo activity for the inhibition of TDO and little or no inhibitors, such as indoximod (D-1MT), F001287, NLG919, measurable activity for the inhibition of IDO. In some cases, INCB024360, or salts or solvates thereof. US 2016/0361298 A1 Dec. 15, 2016 27

TABLE 1. TABLE 1-continued

TDOIDO Inhibitors. TDOIDO Inhibitors. TDO/IDO Inhibitor Compound Name TDO/IDO Inhibitor Compound Name (2s,3r,4r,5r,6r)-3-((3S.4s,5r,6s)-6-carboxy-3,4-dihydroxy-5- coumarin methoxytetrahydro-2h-pyran-2-yloxy)-4,5-dihydroxy-6- cyclandelate methoxytetrahydro-2h-pyran-2-carboxylic acid cyclic adenosine monophosphate (e)-2-(isoxazol-3(2h)-ylidene)-2,6,7,9-tetrahydroimidazo[4,5-dipyrano.4.3- cyclopenthiazide bipyridine cyclothiazide (r)-(5-(3-aminophenyl)-1h-pyrrolo[2,3-bipyridin-3-yl)(5-methyl-4,5- cycotiamine dihydroisoxazol-3-yl)methanone deferasirox (r)-3-(methoxymethyl)-2,3-dihydro-1h-pyrrolo[2,3-bipyridine dexketoprofen (Z)-3-((3,5-dimethyl-1h-pyrrol-2-yl)methylene)indolin-2-one dexmedetomidine 1-(3,4-dihydro-1h-pyrido 3,4-bindol-2(9h)-yl)-3-mercaptopropan-1-one diacerein 1,8-dihydroxyanthraquinone diazoxide 2-(4-morpholino)thiobenzothiazole dibenzothiophene 2-(dimethylamino)-1-phenylethanol dicloxacillin 4-methoxy-2-(5-methoxy-3-methyl-1h-pyrazol-1-yl)-6-methyl-pyrimidine diflunisal 5-(dimethylamino)naphthalene-2-sulfonic acid diphenylimidazole abafungin dithranol abiraterone acetate dolasetron acetophenazine domperidone acitazanolast doxofylline acrisorcinum d-panthenol adrenochrome droperidol albaconazole econazole alcaftadine (C88WOile alilusem edrophonium allantoin efavirenz allopurinol efinaconazole alosetron eltrombopag alphalipoic acid emodin amezinium ephedrine ampholytg epinephrine anagrellide epoxiconazole anastrozole epsiprantel at-7519 eptazocine bendazac erdosteine benperidol esomeprazole benZnidazole esonarimod benzoxiquine ethacridine lactate benzoyl peroxide etodolac benzthiazide euresol benzyl cinnamate ezetimibe benzyl nicotinate felbinac ethyl ester benzyl peroxide fenbufen benzylhydrochlorothiazide fenoprofen berberine fenticonazole besifloxacin fexbuxostat betamipronum fluconazole bicalutamide fludeoxyglucose bifonazole flumazenil blonanserin froVatriptan Succinate brom hexine furosemide butenafine glabridin butoconazole glafenine caffeine glucosamine caldibasic phosphate glucose cantabiline granisetron carfenazine guaiac carprofen hexylcaine hlorambucil huperzine a hloroquine hydrobenzole hloroxine hydrocotarnine hlorphenesin carbamate hydroxychloroquine hlorpropamide hydroxyethyltheophylline hlorquinaldol ibudilast hlorthalidone imiquimod hlorZoxazone indapamide holine fenofibrate indisetron ilomilast indium in-111 oxyquinoline idanac iodochlorohydroxyquinoline imbazole isaVuconazole obenzorex isoconazole oconazole itasetron otrimazole itraconazole oxacillin ketoconazole oxiduine ketoprofen US 2016/0361298 A1 Dec. 15, 2016 28

TABLE 1-continued TABLE 1-continued

TDOIDO Inhibitors. TDOIDO Inhibitors. TDO/IDO Inhibitor Compound Name TDO/IDO Inhibitor Compound Name lanoconazole posaconazole lansoprazole praziquantel letrozole procainamide leucogen propicillin levonordefrin propiconazole liarozole protirelin lipoic acid protizinic acid lobenzarit pseudophedrine lornoxicam pyridoxine loxoprofen pyrrolnitrin 1-tryptophan rabeprazole luliconazole ranOSetron lutine raVuconazole mazindol rebamipide mebhydroline repirinast melatonin rivarOxaban meloxicam rizatriptan menadione rofecoxib menadione sodium bisulfite rolipram meSalazine rufinamide methocarbamol Santoquin methoxamine Sertaconazole methoXSalen Sitagliptin methoxycinnamate Sodium ferulic methyl salicylate Sodium phenylbutyrate methysergide sorbinil metiazinic acid Succinylsulfathiazole metronidazole Sulconazole miconazole sulfadimethoxine mirtazapine sulfamethizole mitomycin Sulfamethoxazole moxifloxacin Sulfaphenazole nabumetone Sulfisoxazole n-acetylmannosamine (1)-isomer Sunitinib naftifine Suprofen nalidixic acid acrine naratriptan altirelin nateglinide enatoprazole n-cyclohexyl-2-benzothiazylsulfenamide erconazole nedocromil heophylline nepafenac hiabendazole nevirapine iaprofenic acid niclosamide imiperone nifenaZone inidazole nimustine ioconazole nitazoxanide olazoline niturtate olindate norepinephrine ometin norfenefrine olinaftate norpseudoephedrine olperisone noscapine trapidil insc-4911 trenbolone acetate o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n-methylthio-2- venlafaxine pyridinecarbamate vinpocetine octopamine Voriconazole omeprazole Zaleplon omoconazole Zaltoprofen Ondansetron Zelandopam ornidazole Zolmitriptan oxacillin Sodium Zonisamide oxiconazole oZagrel pantoprazole paZufloxacin 0170 In various aspects, compositions comprising one or pelubiprofen more TDO/IDO inhibitors (e.g., 1, 2, 3, 4, 5, or more) further pemirolast perisoxalum comprise and/or are administered with one or more PD-1 petoxil inhibitors (e.g., 1, 2, 3, 4, 5, or more). In some embodiments, phenoxyacetic acid the compositions comprising one or more TDO/IDO inhibi phenprocoumon tors and one or more PD-1 inhibitors are useful for the pimozide pirenoxine treatment of cancer. In some embodiments, the compositions piroxicam comprising one or more TDO/IDO inhibitors administered polythiazide with one or more PD-1 inhibitors are useful for the treatment of cancer. As used herein, PD-1 inhibitors include inhibitors US 2016/0361298 A1 Dec. 15, 2016 29 of the PD-1 ligand pathway. Non-limiting examples of PD-1 TABLE 2-continued inhibitors include BMS-93.6559, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, nivolumab, pembrolizumab, PD-1 PD-1L Inhibitors. pidilizumab, BMS-98.6016, MDX1105-01, avelumab, and PD-1/PD-1 L Inhibitor Compound Name salts and solvates thereof. Additional examples of PD-1 cefixine inhibitors include, without limitation, the compounds listed cefibiramide in Table 2, and salts, Solvates and combinations thereof. In ce?tezole Some instances, the compositions comprising one or more his TDO/IDO inhibitors and one or more PD-1 inhibitors further ceftizoxime comprise one or more additional active agents. In some ceftriaxone instances, the compositions comprising one or more TDO/ ceruroxime IDO inhibitors administered with one or more PD-1 inhibi- SE axetil tors are further administered with one or more additional chlamphenicol active agents. Additional active agents include, without chloprocaine limitation, anti-cancer agents, IDO inhibitors (e.g., Table 1). chlpropamide TDO inhibitors (e.g., Table 1), CTLA-4 inhibitors (e.g., stymine Table 3), and combinations thereof. In some cases, the cisapride anti-cancer agent is an IDO inhibitor. In some cases, the citicoline anti-cancer agent is a TDO inhibitor. In some cases, the clindamycin anti-cancer agent is a CTLA-4 inhibitor. clinofibratecocarboxylase cycotiamine TABLE 2 dasatinib deferasirox PD-1 PD-1L Inhibitors. desoxycticosterone PD-1/PD-1 L Inhibitor Compound Name dibucaine diphenylcyclopropenone 2-phenylbenzamidazole-5-sulfonic acid dipivefrin 2-propanediol dicarbanilate ester dobutamine abacavir docarpamine aceclofenac doxazosin acemetacin enalapril acetohexamide ergometrine acetyltyrosine esomeprazole acreoZast faropenem alacepril fenoldopam alvimopan fenoterol aminoglutethimide floctafenine amisulpride fluconazole amprenavir formoterol amsacrine gadodiamide aprepitant gastrodin airformoterol genistin aspartame glafenine aspoxicillin gliclazide astemizole glutathione azlocillin glybuzole aztreonan glyclopyramide bacampecillin glycodiazine benserazide gusperimus bentiromide ifenprodil benzoxiquine imatibin benzyl benzoate imidurea benzyl nicotinate isoXSuprine benzylparaben kalmegh benzylpenicilloyl polylysine lansoprazole beraprost lenampicillin beta-d-glucopyranoside leucogen betiatide levosulpride bisacodyl lidofenin boceprevir lisdexamfetamine butoctamide lodoxamide butyl aminobenzoate lofepramine butylparaben masoprocol butyl-sympatol mefrusida calcitriol mesiidazine calcium alginate methotrexate carfecillin methyl salicyalate carindacillin methylergonovine C8O8. methysergide cefanide metyrapone cefathiamidine micizine cefatrizine midodrine cefazolin mizolastine celetallet monobenzone US 2016/03 61298 A1 Dec. 15, 2016 30

TABLE 2-continued TABLE 2-continued

PD-1 PD-1L Inhibitors. PD-1 PD-1L Inhibitors. PD-1/PD-1 L Inhibitor Compound Name PD-1/PD-1 L Inhibitor Compound Name montirelin ubenimex mosapride villazodone nafanostat naratriptan n-cyclohexyl-2-benzothiazylsulfenamide nebivolol 0171 In various aspects, compositions comprising one or nelfinavir more TDO/IDO inhibitors (e.g., 1, 2, 3, 4, 5, or more) further nibentan nicardipine comprise and/or are administered with one or more IDO nylidrin inhibitors (e.g., 1, 2, 3, 4, 5, or more). In some embodiments, OSutidine the compositions comprising one or more TDO/IDO inhibi Oxamniquine tors and one or more IDO inhibitors are useful for the panipenem pentamidine treatment of cancer. In some embodiments, the compositions phenyl aminosalicylate comprising one or more TDO/IDO inhibitors administered piperacillin with one or more IDO inhibitors are useful for the treatment pivampicillin podophyllum resin of cancer. Non-limiting examples of IDO inhibitors useful in procainamide the compositions described herein include indoximod, procaine F001287, NLG919, INCB024360, and salts and solvates proglumide propafenone thereof. Additional non-limiting examples of IDO inhibitors propyl paraben include the compounds listed in Table 1, and salts, Solvates protirelin and combinations thereof. In some instances, the composi protokylol quatenium 73 tions comprising one or more TDO/IDO inhibitors and one quinapril or more IDO inhibitors further comprise one or more racecadotril additional active agents. In some instances, the compositions rafoxanide raloxifene comprising one or more TDO/IDO inhibitors administered regadenoson with one or more IDO inhibitors are further administered riboflavin with one or more additional active agents. Additional active rilmazafone ritodrine agents include, without limitation, anti-cancer agents, PD-1 Sarpogrelate inhibitors (e.g., Table 2), TDO inhibitors (e.g., Table 1), Seratrodast CTLA-4 inhibitors (e.g., Table 3), and combinations thereof. Sitagliptin sitaxentan In some cases, the anti-cancer agent is a PD-1 inhibitor. In SO ium picosulphate Some cases, the anti-cancer agent is a TDO inhibitor. In Succinylsulfathiazole Some cases, the anti-cancer agent is a CTLA-4 inhibitor. Sl alfadiazine Sl abenzamide 0172 In various aspects, compositions comprising one or Sl acetamide more TDO/IDO inhibitors (e.g., 1, 2, 3, 4, 5, or more) further Sl acytine comprise and/or are administered with one or more CTLA-4 Sl adimethoxine Sl adoxine inhibitors (e.g., 1, 2, 3, 4, 5, or more). In some embodiments, Sl amerazine the compositions comprising one or more TDO/IDO inhibi Sl alleter tors and one or more CTLA-4 inhibitors are useful for the Sl amethizole treatment of cancer. Non-limiting examples of CTLA-4 Sl amethoxazole inhibitors include ipilimumab, tremelimumab, antibody Sl amethoxypyridazine Sl ametomidine clone 9H10, antibody clone BNI3, Del 60, and M9-14 del Sl amonomethoxine 55. Additional non-limiting examples of CTLA-4 inhibitors Sl anilamide are provided in Table 3, and include salts, solvates, and Sl aphenazole Sl apyridine combinations of the compounds of Table 3. In some embodi Sl aquinoxaline ments, the compositions comprising one or more TDO/IDO Sl atolamide inhibitors administered with one or more CTLA-4 inhibitors Sl isomidine are useful for the treatment of cancer. In some instances, the Sl isoxazole compositions comprising one or more TDO/IDO inhibitors Sl isoxazole acetyl Sl phaguanidine and one or more CTLA-4 inhibitors further comprise one or Sl piride more additional active agents. In some instances, the com Sl opride positions comprising one or more TDO/IDO inhibitors SuxibuZone talampicillin administered with one or more CTLA-4 inhibitors are fur tal irelin ther administered with one or more additional active agents. tec hnetium (tc-99m) mebrofenin Additional active agents include, without limitation, anti tetragastrin cancer agents, IDO inhibitors (e.g., Table 1), PD-1 inhibitors thiothixene tirofiban (e.g., Table 2), TDO inhibitors (e.g., Table 1), and combi tocofersolanum nations thereof. In some cases, the anti-cancer agent is an tolbutamide IDO inhibitor. In some cases, the anti-cancer agent is a PD-1 tranilast inhibitor. In some cases, the anti-cancer agent is a TDO inhibitor. US 2016/0361298 A1 Dec. 15, 2016 31

TABLE 3 TABLE 3-continued

CTLA-4 Inhibitors. CTLA-4 Inhibitors. CTLA-4 Inhibitor Compound Name CTLA-4 Inhibitor Compound Name 1-(2-(2-methyl-4-(-o-tolyldiazenyl)phenyl)hydrazono)naphthalen-2(1h)- fenbutrazate Ole firocoxib 1-(2-(naphth-2-yl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,5,6- feroxacin tetrahydropyridine flumazenil y-23023, 2-(dimethylamino)-2-oxoethyl 2-(2-methyl-5H-chromeno2,3- flupirtine bipyridin-7-yl)propanoate flurbiprofen 6-(2-(naphthalen-1-yl)hydrazono)-5-oxo-5,6-dihydronaphthalene-1- flurbiprofen axetil Sulfonic acid fluvastatin abiraterone folic acid abiraterone acetate fp 83 acemetacin gefitinib acetohexamide gemifloxacin alosetron gemifloxacin mesylate amyltricresol gimatecan apafant grepafloxacin aZaperone he-11 (nibentan) azelastine indapamide balofloxacin indigo balsalazide ipriflavone bendroflumethiazide irinotecan benzoyl peroxide isoconazole benzydamine israpafant benzylhydrochlorothiazide lenalidomide berberine levofloxacin bicalutamide linezolid brotizolam liranaftate bufogenin lomefloxacin carbamazepine lornoxicam carfecillin marbofloxacin carindacillin mebhydrolin celecoxib meloxicam cepae ext mepitiostane cetirizine methyl polysilox cga 184699 (lufenuron) miconazole cilomilast mosapramine ciprofloxacin moxifloxacin clemizole mycophenolic acid clopamide nadifloxacin cloxacillin nandrolone cyclohexylpropionate coumarin nandrolone phenylpropionate crizotinib naratriptain cyclomethycaine nebivolol cyclopenthiazide nedocromil aidzein nevirapine antrolene nichicaine apiprazole niclosamide asatinib nifenaZone eferasirox nitazoxanide eracoxib norfloxacin esoxycorticosterone Oestradiol benzoate icloxacillin ofatumumab ifloxacin ofloxacin olasetron olanzapine olasetron meSylate omoconazole Omperidone Ondansetron onepezil orbifloxacin oxazosin o-tolylazo-o-tolylazo-beta-naphthol oxorubicin Oxabolone roperidol Oxaprozin yclonine oxcarbazepine econazole oxiconazole efloxate oxitriptan eltrombopag papaverine emedastine perisoxal enoxacin pioglitaZone ensulizole pipemidic acid epsiprantel piperidolate eslicarbazepine piperine estr-4-en-3-one, 17-(3-(2-furanyl)-1-oxopropoxy)-(17beta)-)estr-4-en-3- pirenoxine Ole piromidic acid etizolam piroxicam etravirine polythiazide fabesetron pranlukast fenbufen praziquantel US 2016/0361298 A1 Dec. 15, 2016 32

TABLE 3-continued cases, the one or more additional active agents is a TDO/ IDO inhibitor. In some cases, the one or more additional CTLA-4 Inhibitors. active agents is a CTLA-4 inhibitor, PD-1 inhibitor, IDO CTLA-4 Inhibitor Compound Name inhibitor, TDO inhibitor, or a combination thereof. prazosin 0.175. In various aspects of the disclosure, provided are procarbazine protokylol compositions comprising one or more (e.g., 1, 2, 3, 4, 5 or prulifloxacin more) TDO/IDO inhibitors comprising a compound of Table rafoxanide 1, or a salt, Solvate or combination thereof. In some ranolazine instances, the composition is administered with 1, 2, 3, or regadenoson more additional TDO and/or IDO inhibitors. In some repirinast rivaroXaban instances, the composition further comprises 1, 2, 3, or more rubitecan additional TDO and/or IDO inhibitors. In some cases, the Seratrodast composition is administered with 1, 2, 3, or more PD-1 Sertaconazole silybin inhibitors. In some cases, the composition further comprises simetride 1, 2, 3, or more PD-1 inhibitors. In some instances, the Sulbentinum composition is administered with 1, 2, 3, or more CTLA-4 Sulconazole inhibitors. In some instances, the composition further com Sulthiame Sunitinib prises 1, 2, 3, or more CTLA-4 inhibitors. In some embodi tamibaroteine ments, the composition further comprises one or more PD-1 terazosin inhibitors, IDO inhibitors, TDO inhibitors, CTLA-4 inhibi tiagabine tors, or any combination thereof. In some embodiments, the tiaprofenic acid timacoxib composition is useful for the treatment of cancer. In some tinoridine embodiments, the composition is useful for treating an tometin infectious disease. In some embodiments, the composition tolvaptain further comprises and/or is administered with one or more toSufloxacin troglitaZone anti-cancer agents, wherein an anti-cancer agent optionally vandetanib comprises a PD-1 inhibitor, IDO inhibitor, CTLA-4 inhibi Vesnarinone tor, TDO inhibitor, or combinations thereof. y-23023 y-3642 0176 Provided herein, in various aspects, are composi Zaleplon tions comprising one or more TDO/IDO inhibitors, wherein Zaltoprofen one or more of the TDO/IDO inhibitors are useful for the Zolmitriptan treatment and/or prevention of one or more diseases or conditions in addition to those described herein. For example, one or more TDO/IDO inhibitors are useful for the 0173 The compositions and TDO/IDO compounds treatment of cancer and one or more additional diseases or described herein, in various aspects, are useful for the conditions. In another example, one or more TDO/IDO treatment of a disease or condition. Non-limiting examples inhibitors are useful for the treatment of an infectious of diseases or conditions include cancer and infectious disease and one or more additional diseases or conditions. In diseases. In some embodiments, a composition comprising a some embodiments, one or more TDO/IDO inhibitors are TDO/IDO inhibitor inhibits tumor cell survival and/or pro useful in compositions and methods that do not involve motes tumor cell death when administered to a patient TDO/IDO inhibition. having cancer. In some embodiments, a composition com 0177. In some instances, one or more TDO/IDO inhibi prising a TDO/IDO inhibitor prevents and/or attenuates tors of a composition herein are antimicrobial agents and are tumor cell growth when administered to a patient having useful for the treatment of cancer. In some instances, one or cancer. In some embodiments, a composition comprising a more TDO/IDO inhibitors of a composition herein are TDO/IDO inhibitor prevents and/or attenuates tumor cell antibacterial agents and are useful for the treatment of invasion when administered to a patient having cancer. In cancer and/or non-bacterial infectious disease. In some some embodiments, a composition comprising a TDO/IDO instances, one or more TDO/IDO inhibitors of a composition inhibitor prevents and/or attenuates tumor cell metastasis herein are antifungal agents and are useful for the treatment when administered to a patient having cancer. of cancer and/or non-fungal infectious disease. In some 0.174. In some embodiments, a composition provided instances, one or more TDO/IDO inhibitors of a composition herein comprises one or more TDO/IDO inhibitors and one herein are antiparasitic agents and are useful for the treat or more additional active agents. In other or additional ment of cancer and/or non-parasitic infectious disease. In embodiments, a composition provided herein comprising some instances, one or more TDO/IDO inhibitors of a one or more TDO/IDO inhibitors is co-administered with composition herein are antiseptics and are useful for the one or more additional active agents. In some embodiments, treatment of cancer. In some instances, one or more TDO/ the composition is useful in a method of treating cancer, the IDO inhibitors of a composition herein are antiviral agents method comprising administering the composition compris and are useful for the treatment of cancer and/or non-viral ing the one or more TDO/IDO inhibitors and one or more infectious disease. In some instances, one or more TDO/IDO additional active agents to a Subject in need thereof. In some inhibitors of a composition herein are Sulfonamides, for embodiments, the compositions is useful in a method of example, diuretic and/or nonsteroidal anti-inflammatory Sul treating cancer, the method comprising co-administering the fonamides, and are useful for the treatment of cancer and/or composition comprising the one or more TDO/IDO inhibi infectious disease. In some instances, one or more TDO/IDO tors with the one or more additional active agents. In some inhibitors of a composition herein are nonsteroidal anti US 2016/0361298 A1 Dec. 15, 2016

inflammatory drugs (NSAIDs) and are useful for the treat cillin, besifloxacin, oxacillin Sodium, moxifloxacin, ment of cancer and/or infectious disease. In some instances, cloxacillin, dicloxacillin, or a salt, Solvate or combination one or more TDO/IDO inhibitors of a composition herein are thereof. In some embodiments, the antimicrobial agent com adrenergic agents and are useful for the treatment of cancer prises an antifungal agent. In some embodiments, the anti and/or infectious disease. In some instances, one or more fungal agent comprises tioconazole, liarozole, Sertacon TDO/IDO inhibitors of a composition herein are serotoner azole, econazole, Sulconazole, miconazole, isoconazole, gic agents and are useful for the treatment of cancer and/or itraconazole, fenticonazole, cloconazole, acrisorcinum, infectious disease. In some instances, one or more TDO/IDO climbazole, croconazole, diphenylimidazole, exalamide, inhibitors of a composition herein are phosphodiesterase lanoconazole, oxiconazole, bifonazole, luliconazole, thi inhibitors and are useful for the treatment of cancer and/or abendazole, butoconazole, clotrimazole, ketoconazole, luli infectious disease. In some instances, one or more TDO/IDO conazole, albaconazole, efinaconazole, epoxiconazole, flu inhibitors of a composition herein are proton pump inhibi conazole, isavuconazole, posaconazole, propiconazole, tors and are useful for the treatment of cancer and/or ravuconazole, terconazole, Voriconazole, abafungin, omo infectious disease. In some instances, one or more TDO/IDO conazole, phenoxyacetic acid, naftifine, tolindate, tolnaftate, inhibitors of a composition herein are acetocholinesterase butenafine, o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n- inhibitors, adrogenic agents, coumarins, anti-inflammatory methylthio-2-pyridinecarbamate, or a salt, Solvate or com drugs, antipsychotic agents, dopamenergic agents, GABA bination thereof. In some embodiments, the antimicrobial modulators, laxatives, muscle relaxants, sigmaergic agents, agent comprises an antiparasitic agent. In some embodi vasodilators, vitamins, antioxidants, or combinations ments, the antiparasitic agent comprises praziquantel, chlo thereof, and are useful for the treatment of cancer and/or roquine, epsiprantel, niclosamide, hydroxychloroquin, or a infectious disease. In some instances, one or more TDO/IDO salt, Solvate or combination thereof. In some embodiments, inhibitors of a composition herein also function as inhibitors the antimicrobial agent comprises an antiseptic. In some of a PD-1 pathway. In some instances, one or more TDO/ embodiments, the antiseptic comprises iodochlorohydroxy IDO inhibitors of a composition herein also function as quinoline, euresol, acrisorcinum, benzyl peroxide, benzoyl CTLA-4 inhibitors. Non-limiting examples of TDO/IDO peroxide, benzoxiduine, ethacridine lactate, or a salt, Solvate inhibitors of a composition provided herein include the or combination thereof. In some embodiments, the antimi compounds of Table 1 and the salts and solvates of the crobial agent comprises an antiviral agent. In some embodi compounds of Table 1. ments, the antiviral agent comprises imiquimod, efavirenz, 0.178 Provided herein, in various aspects, are composi or a salt, Solvate or combination thereof. In some embodi tions comprising an antimicrobial agent. In some embodi ments, the antimicrobial agent comprises chlorquinaldol, or ments, the compositions further comprise and/or are admin a salt or solvate thereof. istered with one or more of the following additional active 0179 Provided herein, in various aspects, are composi agents: an additional antimicrobial agent, adrenergic agent, tions comprising an adrenergic agent. In some embodiments, serotonergic agent, NSAID, Sulfonamide, phosphodiesterase the compositions further comprise and/or are administered inhibitor, proton pump inhibitor, acetocholinesterase inhibi with one or more of the following additional active agents: tor, adrogenic agent, coumarin, anti-inflammatory drug, antimicrobial agent, additional adrenergic agent, serotoner antipsychotic agent, dopamenergic agent, GABA modulator, gic agent, NSAID, Sulfonamide, phosphodiesterase inhibi laxative, muscle relaxant, sigmaergic agent, vasodilator, tor, proton pump inhibitor, acetocholinesterase inhibitor, Vitamin, antioxidant, any active agent comprising a com adrogenic agent, coumarin, anti-inflammatory drug, antip pound from Table 1, a salt or Solvate of any active agent sychotic agent, dopamenergic agent, GABA modulator, comprising a compound from Table 1, or combination laxative, muscle relaxant, sigmaergic agent, vasodilator, thereof. In exemplary embodiments, the antimicrobial agent Vitamin, antioxidant, any active agent comprising a com is a TDO/IDO inhibitor. In some cases, one of the one or pound from Table 1, a salt or Solvate of any active agent more additional active agents is a TDO/IDO inhibitor. In comprising a compound from Table 1, or combination Some embodiments, the composition further comprises and/ thereof. In exemplary embodiments, the adrenergic agent is or is administered with 1, 2, 3, 4, 5, or more CTLA-4 a TDO/IDO inhibitor. In some cases, one of the one or more inhibitors. In some embodiments, the composition further additional active agents is a TDO/IDO inhibitor. In some comprises and/or is administered with 1, 2, 3, 4, 5, or more embodiments, the composition further comprises and/or is PD-1 inhibitors. In some embodiments, the composition administered with 1, 2, 3, 4, 5, or more CTLA-4 inhibitors. further comprises and/or is administered with 1, 2, 3, 4, 5, In some embodiments, the composition further comprises or more IDO inhibitors. In some embodiments, the compo and/or is administered with 1, 2, 3, 4, 5, or more PD-1 sition further comprises and/or is administered with 1, 2, 3, inhibitors. In some embodiments, the composition further 4, 5, or more TDO inhibitors. In some embodiments, the comprises and/or is administered with 1, 2, 3, 4, 5, or more composition further comprises and/or is administered with IDO inhibitors. In some embodiments, the composition one or more CTLA-4 inhibitors, PD-1 inhibitors, IDO further comprises and/or is administered with 1, 2, 3, 4, 5, inhibitors, TDO inhibitors, or a combination thereof. In or more TDO inhibitors. In some embodiments, the com Some cases, the composition is useful for the treatment of position further comprises and/or is administered with one cancer. In some cases, the composition further comprises or more CTLA-4 inhibitors, PD-1 inhibitors, IDO inhibitors, and/or is administered with an anti-cancer agent. In some TDO inhibitors, or a combination thereof. In some cases, the cases, the composition is useful for the treatment of an composition is useful for the treatment of cancer. In some infectious disease. In some embodiments, the antimicrobial cases, the composition further comprises and/or is admin agent comprises an antibacterial agent. In some embodi istered with an anti-cancer agent. In some cases, the com ments, the antibacterial agent comprises cloxiquine, bet position is useful for the treatment of an infectious disease. amipronum, chloroXine, nalidixic acid, paZufloxacin, propi In some embodiments, the adrenergic agent comprises octo US 2016/0361298 A1 Dec. 15, 2016 34 pamine, ephedrine, epinephrine, levonordefrin, norfene further comprises and/or is administered with 1, 2, 3, 4, 5, frine, methoxamine, mirtazapine, norpseudoephedrine, or more TDO inhibitors. In some embodiments, the com pseudophedrine, norepinephrine, adrenochrome, position further comprises and/or is administered with one amezinium, clobenzorex, mirtazapine, or a salt, Solvate or or more CTLA-4 inhibitors, PD-1 inhibitors, IDO inhibitors, combination thereof. TDO inhibitors, or a combination thereof. In some cases, the 0180 Provided herein, in various aspects, are composi composition is useful for the treatment of cancer. In some tions comprising a serotonergic agent. In some embodi cases, the composition further comprises and/or is admin ments, the compositions further comprise and/or are admin istered with an anti-cancer agent. In some cases, the com istered with one or more of the following additional active position is useful for the treatment of an infectious disease. agents: antimicrobial agent, adrenergic agent, additional In some embodiments, the Sulfonamide is a diuretic. In some serotonergic agent, NSAID, Sulfonamide, phosphodiesterase embodiments, the Sulfonamide comprises furosemide, chlo inhibitor, proton pump inhibitor, acetocholinesterase inhibi rthalidone, indapamide, cyclopenthiazide, alilusem, benzthi tor, adrogenic agent, coumarin, anti-inflammatory drug, azide, polythiazide, or a salt, Solvate or combination thereof. antipsychotic agent, dopamenergic agent, GABA modulator, 0182 Provided herein, in various aspects, are composi laxative, muscle relaxant, sigmaergic agent, vasodilator, tions comprising a NSAID. In some embodiments, the Vitamin, antioxidant, any active agent comprising a com compositions further comprise and/or are administered with pound from Table 1, a salt or Solvate of any active agent one or more of the following additional active agents: comprising a compound from Table 1, or combination antimicrobial agent, adrenergic agent, serotonergic agent, thereof. In exemplary embodiments, the serotonergic agent additional NSAID, sulfonamide, phosphodiesterase inhibi is a TDO/IDO inhibitor. In some cases, one of the one or tor, proton pump inhibitor, acetocholinesterase inhibitor, more additional active agents is a TDO/IDO inhibitor. In adrogenic agent, coumarin, anti-inflammatory drug, antip Some embodiments, the composition further comprises and/ sychotic agent, dopamenergic agent, GABA modulator, or is administered with 1, 2, 3, 4, 5, or more CTLA-4 laxative, muscle relaxant, sigmaergic agent, vasodilator, inhibitors. In some embodiments, the composition further Vitamin, antioxidant, any active agent comprising a com comprises and/or is administered with 1, 2, 3, 4, 5, or more pound from Table 1, a salt or Solvate of any active agent PD-1 inhibitors. In some embodiments, the composition comprising a compound from Table 1, or combination further comprises and/or is administered with 1, 2, 3, 4, 5, thereof. In exemplary embodiments, the NSAID is a TDO/ or more IDO inhibitors. In some embodiments, the compo IDO inhibitor. In some cases, one of the one or more sition further comprises and/or is administered with 1, 2, 3, additional active agents is a TDO/IDO inhibitor. In some 4, 5, or more TDO inhibitors. In some embodiments, the embodiments, the composition further comprises and/or is composition further comprises and/or is administered with administered with 1, 2, 3, 4, 5, or more CTLA-4 inhibitors. one or more CTLA-4 inhibitors, PD-1 inhibitors, IDO In some embodiments, the composition further comprises inhibitors, TDO inhibitors, or a combination thereof. In and/or is administered with 1, 2, 3, 4, 5, or more PD-1 Some cases, the composition is useful for the treatment of inhibitors. In some embodiments, the composition further cancer. In some cases, the composition further comprises comprises and/or is administered with 1, 2, 3, 4, 5, or more and/or is administered with an anti-cancer agent. In some IDO inhibitors. In some embodiments, the composition cases, the composition is useful for the treatment of an further comprises and/or is administered with 1, 2, 3, 4, 5, infectious disease. In some embodiments, the serotonergic or more TDO inhibitors. In some embodiments, the com agent comprises 1-tryptophan, froVatriptan Succinate, position further comprises and/or is administered with one ramosetron, mazindol, ondansetron, itasetron, indisetron, or more CTLA-4 inhibitors, PD-1 inhibitors, IDO inhibitors, naratriptan, or a salt, Solvate or combination thereof. TDO inhibitors, or a combination thereof. In some cases, the 0181 Provided herein, in various aspects, are composi composition is useful for the treatment of cancer. In some tions comprising a Sulfonamide. In some embodiments, the cases, the composition further comprises and/or is admin compositions further comprise and/or are administered with istered with an anti-cancer agent. In some cases, the com one or more of the following additional active agents: position is useful for the treatment of an infectious disease. antimicrobial agent, adrenergic agent, serotonergic agent, In some embodiments, the NSAID comprises glucosamine, NSAID, additional sulfonamide, phosphodiesterase inhibi nabumetone, fenoprofen, loxoprofen, diflunisal, ketoprofen, tor, proton pump inhibitor, acetocholinesterase inhibitor, dexketoprofen, fenbufen, nepafenac, tolmetin, pelubiprofen, adrogenic agent, coumarin, anti-inflammatory drug, antip tiaprofenic acid, Suprofen, metiazinic acid, carprofen, cli sychotic agent, dopamenergic agent, GABA modulator, danac, etodolac, Zaltoprofen, nifenaZone, rofecoxib, pro laxative, muscle relaxant, sigmaergic agent, vasodilator, tizinic acid, methyl salicylate, piroxicam, meloxicam, Vitamin, antioxidant, any active agent comprising a com diacerein, lornoxicam, glafenine, or a salt, Solvate, or com pound from Table 1, a salt or Solvate of any active agent bination thereof. comprising a compound from Table 1, or combination 0183 Provided herein, in various aspects, are composi thereof. In exemplary embodiments, the Sulfonamide is a tions comprising a phosphodiesterase inhibitor. In some TDO/IDO inhibitor. In some cases, one of the one or more embodiments, the compositions further comprise and/or are additional active agents is a TDO/IDO inhibitor. In some administered with one or more of the following additional embodiments, the composition further comprises and/or is active agents: antimicrobial agent, adrenergic agent, sero administered with 1, 2, 3, 4, 5, or more CTLA-4 inhibitors. tonergic agent, NSAID, Sulfonamide, additional phosphodi In some embodiments, the composition further comprises esterase inhibitor, proton pump inhibitor, acetocholinest and/or is administered with 1, 2, 3, 4, 5, or more PD-1 erase inhibitor, adrogenic agent, coumarin, anti inhibitors. In some embodiments, the composition further inflammatory drug, antipsychotic agent, dopamenergic comprises and/or is administered with 1, 2, 3, 4, 5, or more agent, GABA modulator, laxative, muscle relaxant, sigmaer IDO inhibitors. In some embodiments, the composition gic agent, vasodilator, vitamin, antioxidant, any active agent US 2016/0361298 A1 Dec. 15, 2016 comprising a compound from Table 1, a salt or Solvate of agent, dopamenergic agent, GABA modulator, laxative, any active agent comprising a compound from Table 1, or muscle relaxant, sigmaergic agent, vasodilator, Vitamin, combination thereof. In exemplary embodiments, the phos antioxidant, or a combination thereof. In some embodi phodiesterase inhibitor is a TDO/IDO inhibitor. In some ments, the compositions further comprise and/or are admin cases, one of the one or more additional active agents is a istered with one or more of the following additional active TDO/IDO inhibitor. In some embodiments, the composition agents: antimicrobial agent, adrenergic agent, serotonergic further comprises and/or is administered with 1, 2, 3, 4, 5, agent, NSAID, sulfonamide, phosphodiesterase inhibitor, or more CTLA-4 inhibitors. In some embodiments, the proton pump inhibitor, any active agent comprising a com composition further comprises and/or is administered with pound from Table 1, a salt or Solvate of any active agent 1, 2, 3, 4, 5, or more PD-1 inhibitors. In some embodiments, the composition further comprises and/or is administered comprising a compound from Table 1, or combination with 1, 2, 3, 4, 5, or more IDO inhibitors. In some embodi thereof. In exemplary embodiments, the acetocholinesterase ments, the composition further comprises and/or is admin inhibitor, adrogenic agent, coumarin, anti-inflammatory istered with 1, 2, 3, 4, 5, or more TDO inhibitors. In some drug, antipsychotic agent, dopamenergic agent, GABA embodiments, the composition further comprises and/or is modulator, laxative, muscle relaxant, sigmaergic agent, administered with one or more CTLA-4 inhibitors, PD-1 vasodilator, vitamin, and/or antioxidant is a TDO/IDO inhibitors, IDO inhibitors, TDO inhibitors, or a combination inhibitor. In some cases, one of the one or more additional thereof. In some cases, the composition is useful for the active agents is a TDO/IDO inhibitor. In some embodiments, treatment of cancer. In some cases, the composition further the composition further comprises and/or is administered comprises and/or is administered with an anti-cancer agent. with 1, 2, 3, 4, 5, or more CTLA-4 inhibitors. In some In some cases, the composition is useful for the treatment of embodiments, the composition further comprises and/or is an infectious disease. In some embodiments, the phosphodi administered with 1, 2, 3, 4, 5, or more PD-1 inhibitors. In esterase inhibitor comprises theophylline, ibudilast, anagrel Some embodiments, the composition further comprises and/ ide, doxofylline, rolipram, cilomilast, Vinpocetine, or a salt, or is administered with 1, 2, 3, 4, 5, or more IDO inhibitors. solvate or combination thereof. In some embodiments, the composition further comprises 0184 Provided herein, in various aspects, are composi and/or is administered with 1, 2, 3, 4, 5, or more TDO tions comprising a proton pump inhibitor. In some embodi inhibitors. In some embodiments, the composition further ments, the compositions further comprise and/or are admin comprises and/or is administered with one or more CTLA-4 istered with one or more of the following additional active inhibitors, PD-1 inhibitors, IDO inhibitors, TDO inhibitors, agents: antimicrobial agent, adrenergic agent, serotonergic or a combination thereof. In some cases, the composition is agent, NSAID, sulfonamide, phosphodiesterase inhibitor, useful for the treatment of cancer. In some cases, the additional proton pump inhibitor, acetocholinesterase inhibi composition further comprises and/or is administered with tor, adrogenic agent, coumarin, anti-inflammatory drug, an anti-cancer agent. In some cases, the composition is antipsychotic agent, dopamenergic agent, GABA modulator, useful for the treatment of an infectious disease. In some laxative, muscle relaxant, sigmaergic agent, vasodilator, embodiments, the acetocholinesterase inhibitor comprises Vitamin, antioxidant, any active agent comprising a com edrophonium, tacrine, or a salt, Solvate or combination pound from Table 1, a salt or Solvate of any active agent thereof. In some embodiments, the adrogenic agent com comprising a compound from Table 1, or combination prises trenbolone acetate, abiraterone acetate, or a salt, thereof. In exemplary embodiments, the proton pump inhibi solvate or combination thereof. In some embodiments, the tor is a TDO/IDO inhibitor. In some cases, one of the one or coumarin comprises coumarin, cantabiline, methoXSalen, more additional active agents is a TDO/IDO inhibitor. In phenprocoumon, or a salt, Solvate or combination thereof. In Some embodiments, the composition further comprises and/ Some embodiments, the anti-inflammatory drug comprises or is administered with 1, 2, 3, 4, 5, or more CTLA-4 mesalazine, felbinac ethyl ester, perisoxalum, or a salt, inhibitors. In some embodiments, the composition further solvate or combination thereof. In some embodiments, the comprises and/or is administered with 1, 2, 3, 4, 5, or more antipsychotic agent comprises blonanserin, acetophenazine, PD-1 inhibitors. In some embodiments, the composition carfenazine, pimozide, or a salt, Solvate or combination further comprises and/or is administered with 1, 2, 3, 4, 5, thereof. In some embodiments, the dopamenergic agent or more IDO inhibitors. In some embodiments, the compo comprises Zelandopam, droperidol, benperidol, domperi sition further comprises and/or is administered with 1, 2, 3, done, or a salt, Solvate or combination thereof. In some 4, 5, or more TDO inhibitors. In some embodiments, the embodiments, the GABA modulator comprises Zaleplon, composition further comprises and/or is administered with cyclothiazide, or a salt, Solvate or combination thereof. In one or more CTLA-4 inhibitors, PD-1 inhibitors, IDO Some embodiments, the laxative comprises 1,8-dihydroxy inhibitors, TDO inhibitors, or a combination thereof. In anthraquinone, emodin, or a salt, Solvate or combination Some cases, the composition is useful for the treatment of thereof. In some embodiments, the muscle relaxant com cancer. In some cases, the composition further comprises prises chlorZoxaZone, methocarbamol, chlorphenesin car and/or is administered with an anti-cancer agent. In some bamate, tolperisone, or a salt, Solvate or combination cases, the composition is useful for the treatment of an thereof. In some embodiments, the sigmaergic agent com infectious disease. In some embodiments, the proton pump prises berberine, noscapine, or a salt, Solvate or combination inhibitor comprises esomeprazole, omeprazole, tenatopra thereof. In some embodiments, the vasodilator comprises Zole, rabeprazole, lanSoprazole, pantoprazole, or a salt, trapidil, cyclandelate, diaZOxide, or a salt, Solvate or com solvate or combination thereof. bination thereof. In some embodiments, the vitamin com 0185. Provided herein, in various aspects, are composi prises pyridoxine, menadione, caldibasic phosphate, benzyl tions comprising an acetocholinesterase inhibitor, adrogenic nicotinate, cycotiamine, d-panthenol, or a salt, Solvate or agent, coumarin, anti-inflammatory drug, antipsychotic combination thereof. In some embodiments, the antioxidant US 2016/0361298 A1 Dec. 15, 2016 36 comprises edaravone, alphalipoic acid, lipoic acid, Santo ments, an additional active agent is an IDO inhibitor. In quin, melatonin, or a salt, Solvate or combination thereof. Some embodiments, an additional active agent is a TDO 0186 Provided herein, in various aspects, are composi inhibitor. In some embodiments, an additional active agent tions comprising a compound, or a salt or Solvate thereof, of is a CTLA-4 inhibitor. In some cases, the methods further Table 1. In some embodiments, the compositions further comprise the administration of one or more anti-cancer comprise and/or are administered with one or more of the therapies, wherein the one or more anti-cancer therapies is following additional active agents: antimicrobial agent, administered with or separately from the one or more adrenergic agent, serotonergic agent, NSAID, Sulfonamide, TDO/IDO inhibitors. In some cases, the composition com phosphodiesterase inhibitor, proton pump inhibitor, aceto prising the one or more TDO/IDO inhibitors further com cholinesterase inhibitor, adrogenic agent, coumarin, anti prises one or more anti-cancer agents. In some cases, an inflammatory drug, antipsychotic agent, dopamenergic anti-cancer agent is a PD-1 inhibitor, IDO inhibitor, CTLA-4 agent, GABA modulator, laxative, muscle relaxant, sigmaer inhibitor, TDO inhibitor, or any combination thereof. In gic agent, vasodilator, vitamin, antioxidant, any additional some embodiments, a TDO/IDO inhibitor useful in the active agent comprising a compound from Table 1, or a salt, compositions and methods described herein comprises a Solvate or combination thereof. In exemplary embodiments, compound of Table 1, or a salt or solvate thereof. Additional the compound of Table 1 is a TDO/IDO inhibitor. In some non-limiting examples of TDO/IDO inhibitors useful in the cases, one of the one or more additional active agents is a compositions and methods described herein include indoxi TDO/IDO inhibitor. In some embodiments, the composition mod, F001287, NLG919 (D-1MT), INCB024360, or a salt, further comprises and/or is administered with 1, 2, 3, 4, 5, solvate or combination thereof. Non-limiting examples of or more TDO inhibitors. In some embodiments, the com PD-1 inhibitors useful in the compositions and methods position further comprises and/or is administered with 1, 2, described herein include BMS-93.6559, MEDI4736, 3, 4, 5, or more PD-1 inhibitors. In some embodiments, the MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem composition further comprises and/or is administered with brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave 1, 2, 3, 4, 5, or more IDO inhibitors. In some embodiments, lumab, compounds of Table 2, and salts and Solvates thereof. the composition further comprises and/or is administered Non-limiting examples of IDO inhibitors useful in the with 1, 2, 3, 4, 5, or more CTLA-4 inhibitors. In some compositions and methods described herein include indoxi embodiments, the composition further comprises and/or is mod, F001287, NLG919, INCB024360, and salts and sol administered with one or more CTLA-4 inhibitors, PD-1 vates thereof. Non-limiting examples of CTLA-4 inhibitors inhibitors, IDO inhibitors, TDO inhibitors or a combination useful in the compositions and methods described herein thereof. In some cases, the composition is useful for the include ipilimumab, tremelimumab, antibody clone 9H10, treatment of cancer. In some cases, the composition further antibody clone BNI3, Del 60, M9-14 del 55, compounds of comprises and/or is administered with an anti-cancer agent. Table 3, and salts and solvates thereof. In some cases, the composition is useful for the treatment of 0188 A composition described herein is useful for the an infectious disease. treatment of diseases and conditions in Subjects and patients that include humans and non-human mammals (e.g., mice, Methods of Treatment rats, pigs, cats, dogs, horses). Additional Subjects include, 0187 Provided herein, in various embodiments, are without limitation, livestock Such as cattle, sheep, goats, methods of treating a disease or condition comprising the Swine; poultry Such as chickens, ducks, geese, turkeys; and administration of a composition comprising one or more domesticated animals such as dogs and cats. In addition, TDO/IDO inhibitors. Non-limiting examples of TDO/IDO subjects include, without limitation, subjects suitable for inhibitors for treating a disease or condition are provided in diagnostic or research applications. Additional Subjects Table 1 and include salts and solvates of the compounds in include, without limitation, rodents such as mice, rats and Table 1. In some instances, a composition comprising two or hamsters; rabbits; primates and Swine Such as inbred pigs. more TDO/IDO inhibitors is useful for treating a disease or The terms do not denote a particular age. Thus, both adult condition. In some instances, a composition comprising 3, 4, and children are intended to be covered. 5 or more TDO/IDO inhibitors is useful for treating a disease 0189 In many instances, a treatment is an act upon a or condition. In some cases, the disease is cancer. In some disease or condition with a composition to reduce or ame embodiments, the TDO/IDO inhibitors provided herein are liorate the pharmacologic and/or physiologic effects of the useful in immunotherapy, stem cell therapy, and/or CAR disease or condition and/or its symptoms. In some examples, T-cell therapy. As used herein, use of a TDO/IDO inhibitor the disease is cancer. In some embodiments, treatment for the treatment of cancer as described herein extends to includes reducing the risk of occurrence of a disease in a immunotherapies, stem cell therapies, and CART-cell thera subject determined to be predisposed to the disease but not pies, without limitation. Accordingly, any TDO/IDO inhibi yet diagnosed as infected with the disease. In this instance, tor described herein is useful for immunotherapies, stem cell a treatment may be considered a way of inhibiting said therapies, and/or CART-cell therapies. In some cases, the disease. In some embodiments, treatment includes impeding disease is an infectious disease. In some instances, the the development of a disease. In other or additional embodi methods further comprise the administration of one or more ments, treatment includes relieving a disease by causing active agents, where the one or more active agents are regression of the disease and/or relief from one or more administered with the one or more TDO/IDO inhibitors disease symptoms. Treatment, in many implementations, together or separately from the one or more TDO/IDO includes the delivery of an agent to provide a pharmacologic inhibitors. In some instances, the composition comprising effect, even in the absence of a disease or condition. In the one or more TDO/IDO inhibitors further comprises one various embodiments, treatment comprises administration or more additional active agents. In some embodiments, an of a composition comprising at least one active agent. In additional active agent is a PD-1 inhibitor. In some embodi exemplary embodiments, a TDO/IDO inhibitor is an active US 2016/0361298 A1 Dec. 15, 2016 37 agent of a composition described herein. In some embodi -continued ments, a PD-1 inhibitor is an active agent of a composition OH described herein. In some embodiments, an IDO inhibitor is an active agent of a composition described herein. In some NH2, embodiments, a CTLA-4 inhibitor is an active agent of a (R) composition described herein. In some embodiments, a TDO inhibitor is an active agent of a composition described HO herein. In some embodiments, an anti-cancer agent is an active agent of a composition described herein. OH 0190. In one aspect, provided herein is a method of (norepinephrine) treating cancer comprising administering to a patient in need OH thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or Solvate thereof: N

HO Formula (I) OH OH R4 (epinephrine) -N (R)-

4 - N R2 3 O

(0191 wherein (0192 R and Rare each independently selected from hydrogen or C-C alkyl; (levonordefrin) (0193 each Rare independently selected from hydro gen, halogen, —OH, C-C alkyl, or C-C alkoxy; O (0194 R is hydrogen, halogen, or C-C alkyl; and HO (0195 n is 1, 2, 3, or 4. (0196) In some embodiments, R' and Rare each hydro gen. In some embodiments, R' is hydrogen and R is methyl. HN In some embodiments, R is hydrogen. In some embodi O ments, R is methyl. In some embodiments, n is 1 and R is hydrogen. In some embodiments, n is 1 and R is OH. In (methoxamine) some embodiments, n is 2 and Rare each —OH. In some embodiments, n is 2 and R are each —OMe. In some 0.197 In some embodiments, a method of treating a embodiments, the compound of Formula (I) or a pharma disease comprises administering to a patient in need thereof ceutically acceptable salt or Solvate comprises: an effective amount of a compound of Formula (I), or a salt or Solvate thereof, and one or more additional active agents.

Additional active agents include, without limitation, PD-1 OH inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi tors, and combinations thereof. In some cases, an additional active agent is an anti-cancer agent. In some embodiments, the compound of Formula (I) is a TDO/IDO inhibitor, i.e. the compound of Formula (I) is a TDO inhibitor, IDO inhibitor, oran inhibitor of both TDO and IDO. In some embodiments, (norpseudoephedrine) (octopamine) the compound of Formula (I) is not a TDO inhibitor. In some OH embodiments, a compound of Formula (I) is not an IDO HO NH2, n. 1 inhibitor. In some embodiments, a compound of Formula (I) N is not an inhibitor of both TDO and IDO. In some embodi ments, the disease is cancer. 0.198. In another aspect, provided herein is a method of (norfenefrine) treating cancer comprising administering to a patient in need OH thereof an effective amount of a compound of Formula (II), (2-(dimethylamino)-1- or a pharmaceutically acceptable salt or Solvate thereof: phenylethanol) OH Formula (II)

OH CH3, CH3, (ephedrine) (pseudophedrine) US 2016/0361298 A1 Dec. 15, 2016

(0199 wherein -continued 0200 Ring A is optionally substituted aryl or option ally substituted heteroaryl. 0201 In some embodiments, Ring A is optionally sub stituted heteroaryl. In some embodiments, Ring A is option ally Substituted aryl. In some embodiments, the compound of Formula (II) is of Formula (IIa):

Formula (IIa) (pelubiprofen) O O N OH OH, R0 S 2 O

0202 wherein (tiaprofenic acid) 0203 R' is X R'': O 0204 X is —O , —CH2—, —(C=O)—, or S —CH=; and 0205) R' is optionally substituted aryl, optionally sub \ / O stituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. OH, 0206. In some embodiments, R' is phenyl. In some embodiments, X is —O— or —(C=O)—. In some embodi (suprofen) ments, the compound of Formula (II) or a pharmaceutically C O acceptable salt or Solvate comprises:

N H (carprofen)

c (fenoprofen)isO,

(Zaltoprofen)

0207. In some embodiments, a method of treating a (loxoprofen) disease comprises administering to a patient in need thereof O H an effective amount of a compound of Formula (II), or a salt or Solvate thereof, and one or more additional active agents. Additional active agents include, without limitation, PD-1 HO inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi tors, and combinations thereof. In some cases, an additional active agent is an anti-cancer agent. In some embodiments, the compound of Formula (I) is a TDO/IDO inhibitor, i.e. the compound of Formula (II) is a TDO inhibitor, IDO inhibitor, O oran inhibitor of both TDO and IDO. In some embodiments, (ketoprofen) the compound of Formula (II) is not a TDO inhibitor. In O Some embodiments, a compound of Formula (II) is not an IDO inhibitor. In some embodiments, a compound of For O OH ( ). mula (II) is not an inhibitor of both TDO and IDO. In some embodiments, the disease is cancer. H ( ) 0208. In another aspect, provided herein is a method of treating cancer comprising administering to a patient in need (dexketoprofen) thereof an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt or Solvate thereof: US 2016/0361298 A1 Dec. 15, 2016 39

-continued Formula (III) OCH3 B Y O 's--- n N H3CO 21 N N \ s r-f y--/ X- N / 2 N I N N \, H (tenatoprazole) H 0209 wherein N O 0210 Ring B is an optionally substituted heteroaryl; / N (0211 Y is —CH or N. ; and R' is hydrogen, / o halogen, C-C alkyl, C-C alkoxy, or C-C, N \ / haloalkoxy. 0212. In some embodiments, Ring B is optionally sub stituted pyridyl. In some embodiments, the compound of Formula (III) is of Formula (IIIa): \ O- OT (rabeprazole) Formula (IIIa) N O (R), S N Ny W \ Y O y H 1 n N R2- N S O F. 2 N I F F (lansoprazole) 0213 wherein 0214) each R is independently hydrogen, C-C, alkyl, C-C haloalkyl, C-C alkoxy, alkoxy 0217. In some embodiments, a method of treating a C-Calkoxy, or C-C haloalkoxy; and disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (III), or a salt 0215 p is 1, 2, 3, or 4. or Solvate thereof, and one or more additional active agents. 0216. In some embodiments, p is 2. In some embodi Additional active agents include, without limitation, PD-1 ments, p is 3. In some embodiments, each R" is indepen inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi dently hydrogen, methyl, methoxy, 2.2.2-trifluoroethoxy, or tors, and combinations thereof. In some cases, an additional 2-methoxypropoxy. In some embodiments, Y is —CH-. In active agent is an anti-cancer agent. In some embodiments, some embodiments, R” is hydrogen, methoxy, or difluo the compound of Formula (III) is a TDO/IDO inhibitor, i.e. romethoxy. In some embodiments, the compound of For the compound of Formula (III) is a TDO inhibitor, IDO mula (III) or a pharmaceutically acceptable salt or Solvate inhibitor, or an inhibitor of both TDO and IDO. In some comprises: embodiments, the compound of Formula (III) is not a TDO inhibitor. In some embodiments, a compound of Formula (III) is not an IDO inhibitor. In some embodiments, a compound of Formula (III) is not an inhibitor of both TDO F O " / O O and IDO. In some embodiments, the disease is cancer. 0218. In another aspect, provided herein is a method of treating cancer comprising administering to a patient in need O)-( )-\ / thereof an effective amount of a compound of Formula (IV), N or a pharmaceutically acceptable salt or Solvate thereof: (pantroprazole) O

I Formula (IV) S Y Yo-au O

(omeprazole) US 2016/0361298 A1 Dec. 15, 2016 40

0219 wherein thereof an effective amount of a compound of Formula (V), (0220) R' is an optionally substituted aryl or an option or a pharmaceutically acceptable salt or Solvate thereof: ally substituted heteroaryl; 0221 Ring C is an optionally substituted aryl or an optionally substituted heteroaryl. Formula (V) R2 0222. In some embodiments, Ring C is optionally sub stituted phenyl or optionally substituted thiophenyl. In some Y (R'), embodiments, Ring C in phenyl. In some embodiments, Ring C in optionally substituted thiophenyl. In some R11Ns embodiments, R is optionally substituted heteroaryl. In / \, some embodiments, R is pyridyl or methyl substituted thiazolyl. In some embodiments, the compound of Formula (IV) or a pharmaceutically acceptable salt or Solvate com 0225 wherein prises: 0226 F is a single bond or a double bond; 0227) R' is hydrogen or C-C alkyl when it is a single bond; or 0228) R' is absent when it is a double bond; 0229) R' is C-C alkyl, optionally substituted aryl, Cl O OH optionally substituted aralkyl, optionally substituted H s heteroaryl, optionally Substituted heteroaralkyl, option ally substituted cycloalkyl, optionally substituted 1ns cycloalkylalkyl, or -(CH2) S-R': / \, 0230 each R" is independently hydrogen, halogen, (piroxicam) C-C alkyl, C-C alkoxy, or —S(=O)NH2, 0231) R' is C-C alkyl, C-C haloalkyl, or option ally substituted aralkyl; and O OH 0232 q is 1, 2, 3, or 4. 0233. In some embodiments, the compound of Formula (V) is of Formula (Va): so1ns /\, Formula (Va) 4 (meloxicam) R2 C Cl O OH r DOC / R'?./\, / { NH. N r). C. -N-N/MV 0234. In some embodiments, it is a single bond and R' O O is hydrogen. In some embodiments, r is a single bond and (lornoxicam) R' is methyl. In some embodiments, r is a double bond and R' is absent. In some embodiments, R is optionally substituted aralkyl, optionally substituted cycloalkyl, or 0223) In some embodiments, a method of treating a optionally substituted cycloalkylalkyl. In some embodi disease comprises administering to a patient in need thereof ments, R is benzyl, cyclopentylmethyl, or bicyclo[2.2.1 an effective amount of a compound of Formula (IV), or a salt hept-2-ene. In some embodiments, R is —(CH)—S or Solvate thereof, and one or more additional active agents. R". In some embodiments, R is C-C haloalkyl, or Additional active agents include, without limitation, PD-1 optionally substituted aralkyl. In some embodiments, R is inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi benzyl or 2.2.2-trifluoroethyl. In some embodiments, the tors, and combinations thereof. In some cases, an additional compound of Formula (V) or a pharmaceutically acceptable active agent is an anti-cancer agent. In some embodiments, salt or Solvate comprises: the compound of Formula (IV) is a TDO/IDO inhibitor, i.e. the compound of Formula (IV) is a TDO inhibitor, IDO inhibitor, or an inhibitor of both TDO and IDO. In some embodiments, the compound of Formula (IV) is not a TDO inhibitor. In some embodiments, a compound of Formula (IV) is not an IDO inhibitor. In some embodiments, a compound of Formula (IV) is not an inhibitor of both TDO and IDO. In some embodiments, the disease is cancer. 0224. In another aspect, provided herein is a method of (cyclopenthiazide) treating cancer comprising administering to a patient in need US 2016/0361298 A1 Dec. 15, 2016 41

-continued thereof an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt or Solvate thereof: C O Formula (VI) S-NH2, R51 H S O y O HN-SjSo N O O (benzylhydrochlorothiazide) OH O

C 0237 wherein 0238) R' is optionally substituted aryl, optionally sub O stituted heteroaryl, or -CHR'R'': HN { 0239) R' is C-C alkyl; and /\, / NH, 0240 R is optionally substituted aryl, optionally sub (cyclothiazide) stituted heteroaryl, or optionally substituted aryloxy. H N C (0241. In some embodiments, R is optionally substituted isoxazolyl. In some embodiments, the compound of For S ~ mula (VI) is of Formula (VIa): Ns S -NH2,

/ \, / \, Formula (VIa) (benzthiazide) N R55 H / N F N C O le H San S ~ N R56 S F F 1ns -NH2. O O / \, / \, N (polythiazide) O H OH HC N C O

OOCNs C. 0242 wherein / \, 0243 R is C-C alkyl; and (diazoxide) 0244 R is optionally substituted aryl. 0245. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is methyl. In some 0235. In some embodiments, a method of treating a embodiments, R is CHR'R''. In some embodiments, disease comprises administering to a patient in need thereof R’ is phenyl and R is –C(=O)CR. In some embodi an effective amount of a compound of Formula (V), or a salt ments, the compound of Formula (VI) or a pharmaceutically or Solvate thereof, and one or more additional active agents. acceptable salt or Solvate comprises: Additional active agents include, without limitation, PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi tors, and combinations thereof. In some cases, an additional active agent is an anti-cancer agent. In some embodiments, the compound of Formula (V) is a TDO/IDO inhibitor, i.e. the compound of Formula (V) is a TDO inhibitor, IDO inhibitor, or an inhibitor of both TDO and IDO. In some embodiments, the compound of Formula (V) is not a TDO O), inhibitor. In some embodiments, a compound of Formula (V) is not an IDO inhibitor. In some embodiments, a compound of Formula (V) is not an inhibitor of both TDO and IDO. In some embodiments, the disease is cancer. 0236. In another aspect, provided herein is a method of (propicillin) treating cancer comprising administering to a patient in need US 2016/0361298 A1 Dec. 15, 2016 42

-continued Formula (VII) R62 R61 R63 N / N O OH le R64

O O O 0248 wherein 0249) R' is C-C alkyl or cycloalkyl: (0250) R' is halogen, C-C alkyl, or C-C alkoxy; or (oxacillin) 0251) R' and R taken together with the atoms to which they are attached form an optionally substituted C heterocycloalkyl: 0252 R is optionally substituted cycloalkyl or N optionally substituted heterocycloalkyl; and / N O (0253) R' is halogen, C-C alkyl, or C-C alkoxy. le 0254. In some embodiments, the compound of Formula (VII) or a pharmaceutically acceptable salt or Solvate com prises: O

O

(cloxacillin)

(paZufloxacin) O O C F

OH, or

(dicloxacillin)

0246. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (VI), or a salt (besifloxacin) or Solvate thereof, and one or more additional active agents. Additional active agents include, without limitation, PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi OCH | tors, and combinations thereof. In some cases, an additional N active agent is an anti-cancer agent. In some embodiments, the compound of Formula (VI) is a TDO/IDO inhibitor, i.e. OH. the compound of Formula (VI) is a TDO inhibitor, IDO F inhibitor, or an inhibitor of both TDO and IDO. In some embodiments, the compound of Formula (VI) is not a TDO O O inhibitor. In some embodiments, a compound of Formula (moxifloxacin) (VI) is not an IDO inhibitor. In some embodiments, a compound of Formula (VI) is not an inhibitor of both TDO 0255. In some embodiments, a method of treating a and IDO. In some embodiments, the disease is cancer. disease comprises administering to a patient in need thereof 0247. In another aspect, provided herein is a method of an effective amount of a compound of Formula (VII), or a treating cancer comprising administering to a patient in need salt or solvate thereof, and one or more additional active thereof an effective amount of a compound of Formula agents. Additional active agents include, without limitation, (VII), or a pharmaceutically acceptable salt or solvate PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO thereof: inhibitors, and combinations thereof. In some cases, an US 2016/0361298 A1 Dec. 15, 2016

additional active agent is an anti-cancer agent. In some 0262) R' is hydrogen or optionally substituted C-C, embodiments, the compound of Formula (VII) is a TDO/ alkyl: IDO inhibitor, i.e. the compound of Formula (VII) is a TDO inhibitor, IDO inhibitor, or an inhibitor of both TDO and 0263) R' is —(C-C alkylene) (optionally substituted IDO. In some embodiments, the compound of Formula (VII) aryl), —(C-C alkylene) (optionally substituted het is not a TDO inhibitor. In some embodiments, a compound eroaryl), —(C-C alkylene)-O-(optionally substituted of Formula (VII) is not an IDO inhibitor. In some embodi aryl), or—O—(C-C alkylene) (optionally substituted ments, a compound of Formula (VII) is not an inhibitor of aryl), provided that when R is —O (C-C alkylene) both TDO and IDO. In some embodiments, the disease is (optionally substituted aryl), then X is N. CaCC. 0264. In some embodiments, the compound of Formula 0256 In another aspect, provided herein is a method of treating cancer comprising administering to a patient in need (VIII), or a pharmaceutically acceptable salt or solvate thereof an effective amount of a compound of Formula thereof is of Formula (VIIIa) or a pharmaceutically accept (VIII), or a pharmaceutically acceptable salt or solvate able salt or solvate thereof: thereof:

Formula (VIIIa) R72-X Formula (VIII) y NYN C-H S.

C

0257 wherein (0258 each it are independently a single bond or a 0265 wherein double bond provided that they are not both double 0266 X is O or S; and bonds; 0259 Ring A is optionally substituted aryl, or option 0267 R’ is —(C-C alkylene) (optionally substituted ally substituted heteroaryl; aryl) or —(C-C alkylene) (optionally substituted het 0260 X is O or S, when eroaryl). 0268. In some embodiments, the compound of Formula (VIII) or a pharmaceutically acceptable salt or solvate Wy comprises:

C is CyW N Wy O Cl,

O 0261 X is N, when

C (econazole) ''. N & s is C

S

Wy C Cl, (sulconazole) US 2016/0361298 A1 Dec. 15, 2016 44

-continued -continued N s Cl C C

O

C C Cl, (isoconazole) (tioconazole) C

C O C C C Cl, or

(butoconazole)

C (miconazole) cro (fenticonazole)

0269. In some embodiments, a method of treating a C Cl, disease comprises administering to a patient in need thereof (omoconazole) an effective amount of a compound of Formula (VIII), or a salt or solvate thereof, and one or more additional active agents. Additional active agents include, without limitation, PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO K inhibitors, and combinations thereof. In some cases, an additional active agent is an anti-cancer agent. In some embodiments, the compound of Formula (VIII) is a TDO/ C / IDO inhibitor, i.e. the compound of Formula (VIII) is a TDO O-N inhibitor, IDO inhibitor, or an inhibitor of both TDO and IDO. In some embodiments, the compound of Formula C C (VIII) is not a TDO inhibitor. In some embodiments, a (Oxiconazole) compound of Formula (VIII) is not an IDO inhibitor. In Some embodiments, a compound of Formula (VIII) is not an inhibitor of both TDO and IDO. In some embodiments, the disease is cancer. 0270. In one aspect, provided herein is a method of Cl, treating cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt or Solvate thereof: Formula (DX)

C (sertaconazole) US 2016/0361298 A1 Dec. 15, 2016

0271 wherein -continued (0272 R is hydrogen, or optionally substituted C-C, alkyl: (0273 R is hydrogen, or optionally substituted C-C, alkyl: (0274 R is optionally substituted aryl or optionally substituted heteroaryl; (0275 R is hydrogen, or optionally substituted C-C, alkyl: 0276 or (0277 the oxygen from the –OH and R are taken together to form an epoxide; and (0278 R is optionally substituted aryl, optionally sub stituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. 0279. In some embodiments, R and Rare both hydro gen. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is phenyl substituted with one or more halogen. In some embodiments, R is phenyl substituted with one or more fluoro. In some embodi

ments, R is phenyl substituted with two fluoro. In some embodiments, R is hydrogen. In some embodiments, the oxygen from the –OH and R are taken together to form an epoxide. In some embodiments, R is methyl. In some embodiments, R is optionally substituted aryl. In some embodiments, R is optionally substituted heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted thiazole, EN, optionally substituted pyridine, optionally substituted pyrimidine, or optionally Substituted triazole. In some embodiments, R is optionally substituted heterocy cloalkyl. (isaVuconazole) 0280. In some embodiments, the compound of Formula N (IX) or a pharmaceutically acceptable salt or Solvate com prises: ( ) N-N NE / S OH 2 o le F ( ) N C N N-N CH3 n OH N F F, or

O CH3 (ravuconazole)

(albaconazole)

(Voriconazole)

In some embodiments, a method of treating a disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (IX), or a salt or Solvate thereof, and one or more additional active agents. (efinaconazole) Additional active agents include, without limitation, PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi US 2016/0361298 A1 Dec. 15, 2016 46 tors, and combinations thereof. In some cases, an additional of Formula (II), a compound of Formula (I), a compound of active agent is an anti-cancer agent. In some embodiments, Formula (IV), a compound of Formula (V), a compound of the compound of Formula (IX) is a TDO/IDO inhibitor, i.e. Formula (VI), a compound of Formula (VII). Formula the compound of Formula (IX) is a TDO inhibitor, IDO (VIII). Formula (IX) or salts, solvates, or any combinations inhibitor, or an inhibitor of both TDO and IDO. In some thereof. In some cases, the method further comprises admin embodiments, the compound of Formula (IX) is not a TDO istering to the patient one or more additional active agents inhibitor. In some embodiments, a compound of Formula comprising one or more PD-1 inhibitors, IDO inhibitors, (IX) is not an IDO inhibitor. In some embodiments, a CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or compound of Formula (IX) is not an inhibitor of both TDO combinations thereof. In some embodiments, the disease is and IDO. In some embodiments, the disease is cancer. CaCC. 0281. In some embodiments, a method of treating a 0286. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a salt an effective amount of a compound of Formula (III), or a salt or Solvate thereof, and an effective amount of a compound or Solvate thereof, and an effective amount of an active agent of Formula (II), a compound of Formula (III), a compound comprising a compound of Table 1, or a salt or Solvate of a of Formula (IV), a compound of Formula (V), a compound compound of Table 1. In some cases, the method further of Formula (VI), a compound of Formula (VII). Formula comprises administering to the patient one or more addi (VIII). Formula (IX) or salts, solvates, or any combinations tional active agents comprising one or more PD-1 inhibitors, thereof. In some cases, the method further comprises admin IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti istering to the patient one or more additional active agents cancer agents, or combinations thereof. In some embodi comprising one or more PD-1 inhibitors, IDO inhibitors, ments, the disease is cancer. CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or 0287. In some embodiments, a method of treating a combinations thereof. In some embodiments, the disease is disease comprises administering to a patient in need thereof CaCC. an effective amount of a compound of Formula (IV), or a salt 0282. In some embodiments, a method of treating a or Solvate thereof, and an effective amount of a compound disease comprises administering to a patient in need thereof of Formula (II), a compound of Formula (III), a compound an effective amount of a compound of Formula (I), or a salt of Formula (I), a compound of Formula (V), a compound of or Solvate thereof, and an effective amount of an active agent Formula (VI), a compound of Formula (VII). Formula comprising a compound of Table 1, or a salt or solvate of a (VIII), Formula (IX) or salts, solvates, or any combinations compound of Table 1. In some cases, the method further thereof. In some cases, the method further comprises admin comprises administering to the patient one or more addi istering to the patient one or more additional active agents tional active agents comprising one or more PD-1 inhibitors, comprising one or more PD-1 inhibitors, IDO inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or cancer agents, or combinations thereof. In some embodi combinations thereof. In some embodiments, the disease is ments, the disease is cancer. CaCC. 0283. In some embodiments, a method of treating a 0288. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (II), or a salt an effective amount of a compound of Formula (IV), or a salt or Solvate thereof, and an effective amount of a compound or Solvate thereof, and an effective amount of an active agent of Formula (I), a compound of Formula (III), a compound of comprising a compound of Table 1, or a salt or Solvate of a Formula (IV), a compound of Formula (V), a compound of compound of Table 1. In some cases, the method further Formula (VI), a compound of Formula (VII). Formula comprises administering to the patient one or more addi (VIII). Formula (IX) or salts, solvates, or any combinations tional active agents comprising one or more PD-1 inhibitors, thereof. In some cases, the method further comprises admin IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti istering to the patient one or more additional active agents cancer agents, or combinations thereof. In some embodi comprising one or more PD-1 inhibitors, IDO inhibitors, ments, the disease is cancer. CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or 0289. In some embodiments, a method of treating a combinations thereof. In some embodiments, the disease is disease comprises administering to a patient in need thereof CaCC. an effective amount of a compound of Formula (V), or a salt 0284. In some embodiments, a method of treating a or Solvate thereof, and an effective amount of a compound disease comprises administering to a patient in need thereof of Formula (II), a compound of Formula (III), a compound an effective amount of a compound of Formula (II), or a salt of Formula (IV), a compound of Formula (I), a compound of or Solvate thereof, and an effective amount of an active agent Formula (VI), a compound of Formula (VII). Formula comprising a compound of Table 1, or a salt or Solvate of a (VIII). Formula (IX) or salts, solvates, or any combinations compound of Table 1. In some cases, the method further thereof. In some cases, the method further comprises admin comprises administering to the patient one or more addi istering to the patient one or more additional active agents tional active agents comprising one or more PD-1 inhibitors, comprising one or more PD-1 inhibitors, IDO inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or cancer agents, or combinations thereof. In some embodi combinations thereof. In some embodiments, the disease is ments, the disease is cancer. CaCC. 0285. In some embodiments, a method of treating a 0290. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (III), or a salt an effective amount of a compound of Formula (V), or a salt or Solvate thereof, and an effective amount of a compound or Solvate thereof, and an effective amount of an active agent US 2016/0361298 A1 Dec. 15, 2016 47 comprising a compound of Table 1, or a salt or Solvate of a Formula (VII). Formula (IX) or salts, solvates, or any compound of Table 1. In some cases, the method further combinations thereof. In some cases, the method further comprises administering to the patient one or more addi comprises administering to the patient one or more addi tional active agents comprising one or more PD-1 inhibitors, tional active agents comprising one or more PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti cancer agents, or combinations thereof. In some embodi cancer agents, or combinations thereof. In some embodi ments, the disease is cancer. ments, the disease is cancer. 0291. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof 0296. In some embodiments, a method of treating a an effective amount of a compound of Formula (VI), or a salt disease comprises administering to a patient in need thereof or Solvate thereof, and an effective amount of a compound an effective amount of a compound of Formula (IX), or a salt of Formula (II), a compound of Formula (III), a compound or Solvate thereof, and an effective amount of a compound of Formula (IV), a compound of Formula (V), a compound of Formula (II), a compound of Formula (III), a compound of Formula (I), a compound of Formula (VII), Formula of Formula (IV), a compound of Formula (V), a compound (VIII). Formula (IX) or salts, solvates, or any combinations of Formula (VI), a compound of Formula (I), Formula thereof. In some cases, the method further comprises admin (VIII). Formula (VII) or salts, solvates, or any combinations istering to the patient one or more additional active agents thereof. In some cases, the method further comprises admin comprising one or more PD-1 inhibitors, IDO inhibitors, istering to the patient one or more additional active agents CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or comprising one or more PD-1 inhibitors, IDO inhibitors, combinations thereof. In some embodiments, the disease is CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or CaCC. combinations thereof. In some embodiments, the disease is 0292. In some embodiments, a method of treating a CaCC. disease comprises administering to a patient in need thereof 0297. In some embodiments, a method of treating a an effective amount of a compound of Formula (VI), or a salt disease comprises administering to a patient in need thereof or Solvate thereof, and an effective amount of an active agent an effective amount of a compound of Formula (VIII), or a comprising a compound of Table 1, or a salt or Solvate of a salt or solvate thereof, and an effective amount of an active compound of Table 1. In some cases, the method further agent comprising a compound of Table 1, or a salt or Solvate comprises administering to the patient one or more addi of a compound of Table 1. In some cases, the method further tional active agents comprising one or more PD-1 inhibitors, comprises administering to the patient one or more addi IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti tional active agents comprising one or more PD-1 inhibitors, cancer agents, or combinations thereof. In some embodi IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti ments, the disease is cancer. cancer agents, or combinations thereof. In some embodi 0293. In some embodiments, a method of treating a ments, the disease is cancer. disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (VII), or a 0298. In some embodiments, a method of treating a salt or Solvate thereof, and an effective amount of a com disease comprises administering to a patient in need thereof pound of Formula (II), a compound of Formula (III), a an effective amount of a compound of Formula (IX), or a salt compound of Formula (IV), a compound of Formula (V), a or Solvate thereof, and an effective amount of an active agent compound of Formula (VI), a compound of Formula (I), comprising a compound of Table 1, or a salt or Solvate of a Formula (VIII). Formula (IX) or salts, solvates, or any compound of Table 1. In some cases, the method further combinations thereof. In some cases, the method further comprises administering to the patient one or more addi comprises administering to the patient one or more addi tional active agents comprising one or more PD-1 inhibitors, tional active agents comprising one or more PD-1 inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti cancer agents, or combinations thereof. In some embodi cancer agents, or combinations thereof. In some embodi ments, the disease is cancer. ments, the disease is cancer. 0299. In another aspect, provided herein is a method of 0294. In some embodiments, a method of treating a treating cancer comprising administering to a patient in need disease comprises administering to a patient in need thereof thereof an effective amount of a compound or a pharma an effective amount of a compound of Formula (VII), or a ceutically acceptable salt or Solvate thereof comprising: salt or solvate thereof, and an effective amount of an active agent comprising a compound of Table 1, or a salt or Solvate of a compound of Table 1. In some cases, the method further comprises administering to the patient one or more addi tional active agents comprising one or more PD-1 inhibitors, OHr) N IDO inhibitors, CTLA-4 inhibitors, TDO inhibitors, anti cancer agents, or combinations thereof. In some embodi ments, the disease is cancer. 0295. In some embodiments, a method of treating a disease comprises administering to a patient in need thereof an effective amount of a compound of Formula (VIII), or a salt or Solvate thereof, and an effective amount of a com pound of Formula (II), a compound of Formula (III), a S compound of Formula (IV), a compound of Formula (V), a (acetophenazine) compound of Formula (VI), a compound of Formula (I), US 2016/0361298 A1 Dec. 15, 2016

-continued -continued S O O OH, HN O s Y O -( ls N O NH N NH2 O (euresol) (allantoin) O'Na', N ~ O Nu (sodium phenylbutyrate)

OH, (carfenazine) O H Y- N ((R)-3-(methoxymethyl)-2,3- N dihydro-1H O N pyrrolo2,3-bipyridine) N s V / HO OH HO N-1 s o s F HO \ / (droperidol) (edrophonium) (pyridoxine) O O C l

N CCX-CO?O F, (chlorZoxazone) O NX=o (menadione) N H N2N o O OH, (benperidol) N O N O N e N NH, s (edaravone) (cantabiline) 2 N 2 C N H N (allopurinol) OH ON 21 (indium in-111 s s oxyquinoline) N H OH N N N HO OH N cloxiquine) O O, OH, O (coumarin) (lutine) (methoxycinnamate) HO O

2. O\ {OH, HO s

O O OH (phenoxyacetic acid) (mesalazine) (glucose) (theophylline) US 2016/0361298 A1 Dec 15, 2016 49

-continued -continued OH OH 1N1N O HC N CH

HOHO O N NN1 N NH2 O N ( alse OH, Y-H, N 1\ct, (glucosamine) (adrenochrome) (trapidil)

OH

F O O

'no.'' '', OC)S (alphalipoic acid)

OH OH, s O (fludeoxyglucose) (dibenzothiophene) O O OH,

HO--> N S e S H (lipoic acid)

(betamipronum) 21 O N s N O O O 1. N ONa", \ O O2R e O HO O (benzyl nicotinate) (sodium ferulic) (caldibasic phos) O y H. s OH HC N in N 2- C N

O N N 2

CH 3 NH 2 C (caffeine) N (acrisorcinum) (chloroxime) n

2 s O s

NH2 (benzyl peroxide) (tacrine) HN —V / / N M / O O-S-O , N-N | \ O O O,

1.O (methoxsalen) (amezinium) O o

| OH, HN O HN NH2 (1-tryptophan) (Santoquin) US 2016/0361298 A1 Dec. 15, 2016 50

-continued -continued O HQ -( -O HN

a. OH, HG OH ((n-acetylmannosamine), (I)-isomer

O 1. HO\ (nalidixic acid) % s /

H oc)O N s (hyrdocotarnine) s | Y (GUAIAC) N O OH O OH (melatonin) ON N Ny / CH3, s -N N s (dithranol) Yor 2 O HO CH3 (hydroxyethyltheophylline) (eptazocine) C \ O O o s

C NN 2 s S/3-kN-( \ / OH (chlorquinaldol) (4-methoxy-2-(5-methoxy-3-methyl O 1 h-pyrazol-1-yl)- N s 6-methyl-pyrimidine) /NN F N le NH2, O (nabumetone) F O 21 NN (rufinamide) S S. O

O

(ibudilast) OH O OH NS N (1,8-dihydroxyanthraquinone) O N NH, O

HO

(acitazanolast) (benzyl cinnamate) US 2016/0361298 A1 Dec. 15, 2016 51

-continued -continued

(tolperisone) (felbinac ethyl ester) O O NH2 S --- N OH, 1y O H 21 N (erdosteine) \s, O OH OH, (imiquimod) OH Null- NH2, F F O (diflunisal) O / \ (methocarbamol)

O O

O -O s s O O (benzoxiquine) NS- S s^ S Nuk

(2-(4-morpholino)thiobenzothiazole) O O s/ YOH, 'it

O (menadione bisulfite sodium) O

(froVatriptan Succinate) HO { HN O O Y (fenbufen) O O NH2 O Cl, NH2, HO H O (chlorphenesin carbamate) (nepafenac) US 2016/0361298 A1 Dec. 15, 2016

-continued -continued NH2 O ) N O N-1 s O -, s N N + 2 N HN2 NH 1. / O N

O HO (doxofylline)

O (ethacridine lactate) O

HO N

O (tolmetin) (mirtazapine)

O OOO OH,

OH O OH (petoxil) (emodin) S

NN-N H NDO s

N C X- O, O OH (metiazinic acid) C O (anagrelide) N N

C OH (perisoxalum)

H N s

(clobenzorex) O

O 1- NH

(hexylcaine) N X-sV S HN s

(n-cyclohexyl-2-benzothiazylsulfenamide) (rolipram) US 2016/0361298 A1 Dec. 15, 2016

-continued -continued Cl, O ( ) O s HO

OH N (cyclandelate) N C HO N (mazindol) O,

(clidanac ) \ O O. OH N N1 OH, (etodolac)

O N N 21 (Venlafaxine) CH3 s OH (naftifine) O N O HO O O OH, s H O O N (phenprocoumon)

N.S O C s (lobenzarit) H

O1 OH 4 - N11 NN (esonarimod) \=/ O 5. \ N \ (ondansetron)

N O (ramosetron) 1n SN O S O wN S, H HO w HN-4, 'H. HN 2 N HO HO na O (insc-4911) (leucogen)

US 2016/0361298 A1 Dec. 15, 2016

-continued -continued

OH N O

(protizinic acid) ((R)-(5-(3-aminophenyl)-1H-pyrrolo2,3-bipyridin-3-yl) (5-methyl-4,5-dihydroisoxazol-3-yl)methanone) 1- N

N

2 C N (chloroquine) N

O O

(efavirenz) O O HO ). HO OH, III N s (glabridin)

(nateglinide) N

N C O -'sO,

O (epsiprantel) O O | O NN O, O OH, C (choline fenofibrate) N C OH s (niclosamide)

H3C n N NH2,

HC

HC CH3 (cyclic adenosine monophosphate) (butenafine) US 2016/0361298 A1 Dec. 15, 2016 56

-continued -continued -S O

(o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n- methylthio-2-pyridinecarbamate) rN 2 C N (hydroxychloroquine) C

OH HN / \, HN s

O (chlorthalidone) O OH,

O Rw O N (mitomycin) (cilomilast) O -\ O,

N N O 2 CH O NCH, (berberine)

CH3, M N

O O VW (repirinast) H3CN 1. S N N C N N1 s1 NH22 (naratriptan) M \, O O O

(indapamide) US 2016/0361298 A1 Dec. 15, 2016 57

-continued -continued O O uls, O -N CCC. 2O, O OH (diacerein) F

N N r (domperidone) N- N-1 s F (blonanserin) O NH, orro. Y OH O O

F (pimozide) O N N (glafenine) N / S, f s -le O C O NH N \e (thiabendazole) V NH2 (Zonisamide)

NNN \ OH, (alilusem) r O (bendazac)

O 2 N,

dihydroxy-5-methoxytetrahydro-2H-pyran-2- yloxy)-4),5-dihydroxy-6- methoxytetrahydro-2H-pyran-2-carboxylic acid) (alosetron) US 2016/0361298 A1 Dec. 15, 2016 58

-continued -continued O C C O-7O -(-)-O( )-( O,

N V Clus)H (dolasetron) ly (ketoconazole) F C C W

e (luliconazole) O S C C Nu N (timiperone) Co-C Nd N ty (itraconazole)

(liarozole) N (posaconazole) Cy C Oro 2 S CC(bifonazole) (propiconazole) so CC lySn N (clotrimazole) (terconazole) US 2016/0361298 A1 Dec. 15, 2016 59

-continued 3), and TDO inhibitors (e.g., Table 1). In some cases, an additional active agent is an anti-cancer agent. HN , or Combinations HN 0302) In various aspects, provided herein are composi S tions comprising one or more TDO/IDO inhibitors (e.g., inhibitors of TDO, IDO, or both TDO and IDO) and one or ) 2 more additional active agents useful for the treatment of a disease or condition. Further provided are compositions comprising one or more TDO/IDO inhibitors that are admin istered with compositions comprising one or more active agents for the treatment of a disease or condition. In some c O embodiments, one or more of the additional active agents are (abafungin) PD-1 inhibitors. In some embodiments, one or more of the additional active agents are IDO inhibitors. In some embodi C ments, one or more of the additional active agents are CTLA-4 inhibitors. In some embodiments, one or more of the additional active agents are TDO inhibitors. In some embodiments, one or more of the additional active agents are C S CN anti-cancer agents. In some embodiments, at least one S N TDO/IDO inhibitor is a small molecule. In some embodi ments, at least one TDO/IDO inhibitor is a peptide. In some ( ). cases, at least one TDO/IDO inhibitor is not an immuno N globulin or immunoglobulin derived protein. Non-limiting (lanoconazole) examples of TDO/IDO inhibitors include the compounds of Table 1. Formula (I), Formula (II), Formula (III). Formula 0300. In some embodiments, the method further com (IV). Formula (V), Formula (VI). Formula (VII). Formula prises administering to the patient in need thereof an effec (VIII). Formula (IX), and the salts and solvates thereof. tive amount of a compound of Formula (I), a compound of TDO inhibitors include, without limitation, indoximod, Formula (II), a compound of Formula (III), a compound of F001287, NLG919, INCB024360, and any TDO inhibitor Formula (IV), a compound of Formula (V), a compound of described elsewhere herein, such as in Table 1, and salts and Formula (VI), a compound of Formula (VII), a compound of solvates thereof. Non-limiting examples of PD-1 inhibitors Formula (VIII), a compound of Formula (IX), or salts, include BMS-936559, MEDI4736, MPDL3280A, Solvates, or any combinations thereof. In some cases, the MSB0010718C, AMP-224, nivolumab, pembrolizumab, method further comprises administering to the patient one or pidilizumab, BMS-98.6016, MDX1105-01, avelumab, any more additional active agents comprising one or more PD-1 PD-1 inhibitor of Table 2, and salts and solvates thereof. inhibitors, IDO inhibitors, CTLA-4 inhibitors, TDO inhibi Non-limiting examples of IDO inhibitors include indoxi tors, anti-cancer agents, or combinations thereof. In some mod, F001287, NLG919, INCB024360, any IDO inhibitors embodiments, the disease is cancer. In some embodiments, described elsewhere herein, such as in Table 1, and salts and the method further comprises administering to the patient in solvates thereof. Non-limiting examples of CTLA-4 inhibi need thereof an effective amount of an active agent com tors include ipilimumab, tremelimumab, antibody clone prising a compound of Table 1, or a salt or Solvate of a 9H10, antibody clone BNI3, Del 60, M9-14 del 55, any compound of Table 1. CTLA-4 inhibitor of Table 3, and salts and solvates thereof. 0301 In some embodiments, a method of treating a 0303. In some instances, the disease is cancer and the disease or condition comprises the administration of an treatment inhibits tumor cell Survival. In some instances, the active agent comprising econazole, Sulconazole, isocon disease is cancer and the treatment promotes tumor cell azole, miconazole, Sertaconazole, tioconazole, fenticon death. In some instances, the disease is cancer and the azole, liarozole, cloconazole, itraconazole, niclosamide, treatment prevents tumor cell growth. In some instances, the deferasiroX, eltrombopag, or a pharmaceutically acceptable disease is cancer and the treatment attenuates tumor cell salt, Solvate or combination thereof. In some instances, the growth. In some instances, the disease is cancer and the disease is cancer. In some instances, the disease is an treatment prevents tumor cell invasion. In some instances, infectious disease. In some embodiments, the active agent is the disease is cancer and the treatment attenuates tumor cell a TDO/IDO inhibitor, i.e. the active agent is a TDO inhibitor, invasion. In some instances, the disease is cancer and the IDO inhibitor, or an inhibitor of both TDO and IDO. In some treatment prevents tumor metastasis. In some instances, the embodiments, the active agent is not a TDO inhibitor. In disease is cancer and the treatment attenuates tumor metas Some embodiments, an active agent is not an IDO inhibitor. tasis. In some instances, the disease is an infectious disease, In some embodiments, an active agent is not an inhibitor of Such as a disease caused by a bacteria, virus or parasite. both TDO and IDO. In some instances, the composition 0304. In some embodiments, a composition comprising further comprises one or more additional active agents. In one or more TDO/IDO inhibitors and one or more additional Some instances, the composition is administered with one or active agents are administered to a patient with one or more more additional active agents. Additional active agents additional therapies. Additional therapies include, but are include, without limitation, PD-1 inhibitors (e.g., Table 2), not limited to, chemotherapy and known cancer treatment IDO inhibitors (e.g., Table 1), CTLA-4 inhibitors (e.g., Table methods. US 2016/0361298 A1 Dec. 15, 2016 60

0305. In various aspects, provided herein are composi Some embodiments, the antibacterial agent comprises clox tions comprising 2, 3, 4 or more TDO/IDO inhibitors. In iquine, betamipronum, chloroxine, nalidixic acid, paZu some embodiments, at least one TDO/IDO inhibitor com floxacin, propicillin, besifloxacin, oxacillin Sodium, moxi prises a compound of Formula (I), or a salt or Solvate floxacin, cloxacillin, dicloxacillin, or a salt, Solvate or thereof. In some embodiments, at least one TDO/IDO combination thereof. In some embodiments, the antimicro inhibitor comprises a compound of Formula (II), or a salt or bial agent comprises an antifungal agent. In some embodi solvate thereof. In some embodiments, at least one TDO/ ments, the antifungal agent comprises tioconazole, liarozole, IDO inhibitor comprises a compound of Formula (III), or a Sertaconazole, econazole, Sulconazole, miconazole, isocon salt or Solvate thereof. In some embodiments, at least one azole, itraconazole, fenticonazole, cloconazole, acrisorci TDO/IDO inhibitor comprises a compound of Formula (IV), num, climbazole, croconazole, diphenylimidazole, exal or a salt or Solvate thereof. In some embodiments, at least amide, lanoconazole, oxiconazole, bifonazole, luliconazole, one TDO/IDO inhibitor comprises a compound of Formula thiabendazole, butoconazole, clotrimazole, ketoconazole, (V), or a salt or solvate thereof. In some embodiments, at luliconazole, albaconazole, efinaconazole, epoxiconazole, least one TDO/IDO inhibitor comprises a compound of fluconazole, isavuconazole, posaconazole, propiconazole, Formula (VI), or a salt or solvate thereof. In some embodi ravuconazole, terconazole, Voriconazole, abafungin, omo ments, at least one TDO/IDO inhibitor comprises a com conazole, phenoxyacetic acid, naftifine, tolindate, tolnaftate, pound of Formula (VII), or a salt or solvate thereof. In some butenafine, o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n- embodiments, at least one TDO/IDO inhibitor comprises a methylthio-2-pyridinecarbamate, or a salt, Solvate or com compound from Table 1, or a salt or Solvate of a compound bination thereof. In some embodiments, the antimicrobial from Table 1. In some embodiments, the composition further agent comprises an antiparasitic agent. In some embodi comprises one or more PD-1 inhibitors, IDO inhibitors, ments, the antiparasitic agent comprises praziquantel, chlo CTLA-4 inhibitors, TDO inhibitors, anti-cancer agents, or roquine, epsiprantel, niclosamide, hydroxychloroquin, or a any combination thereof. salt, Solvate or combination thereof. In some embodiments, 0306 Combinations with PD-1 Inhibitors the antimicrobial agent comprises an antiseptic. In some 0307. In some embodiments, a composition comprises embodiments, the antiseptic comprises iodochlorohydroxy one or more TDO/IDO inhibitors and one or more PD-1 quinoline, euresol, acrisorcinum, benzyl peroxide, benzoyl inhibitors. In other embodiments, a composition comprising peroxide, benzoxiduine, ethacridine lactate, or a salt, Solvate one or more TDO/IDO inhibitors is configured for admin or combination thereof. In some embodiments, the antimi istered with a composition comprising one or more PD-1 crobial agent comprises an antiviral agent. In some embodi inhibitors. In some cases, a composition comprises 2, 3, 4, ments, the antiviral agent comprises imiquimod, efavirenz, 5, or more TDO/IDO inhibitors. In some cases, a composi or a salt, Solvate or combination thereof. In some embodi tion comprises 2, 3, 4, 5, or more PD-1 inhibitors. In some ments, the antimicrobial agent comprises chlorquinaldol, or embodiments, a composition comprising one or more PD-1 a salt or solvate thereof. In some embodiments, a PD-1 inhibitors and one or more TDO/IDO inhibitors further inhibitor comprises an antimicrobial agent, Sulfonamide, comprises one or more IDO inhibitors, TDO and/or CTLA-4 NSAID, ACE inhibitor, beta adrenergic agonist, beta antago inhibitors. In some embodiments, a composition comprising nist, alpha adrenergic agonist, vitamin, benzamide, or a one or more TDO/IDO inhibitors and one or more PD-1 combination thereof. In some embodiments, a PD-1 inhibi inhibitors is administered with one or more IDO inhibitors, tor comprises a compound of Table 2, or a salt, Solvate, or TDO and/or CTLA-4 inhibitors. In some embodiments, a combination thereof. In some embodiments, a TDO/IDO TDO/IDO inhibitor comprises a compound of Formula (I), inhibitor comprises a compound of Table 1. Formula (I), Formula (II), Formula (III), Formula (IV). Formula (V), Formula (II), Formula (III), Formula (IV). Formula (V), Formula (VI), Formula (VII). Formula (VIII), Formula (IX), Formula (VI), Formula (VII). Formula (VIII), Formula (IX), Table 1, indoximod, F001287, NLG919, INCB024360, or a indoximod, F001287, NLG919, INCB024360, any TDO/ salt, Solvate, or combination thereof. In some cases, a PD-1 IDO inhibitor described elsewhere herein, or a salt, solvate, inhibitor comprises BMS-936559, MEDI4736, or combination thereof. In some embodiments, an IDO MPDL3280A, MSB0010718C, AMP-224, nivolumab, pem inhibitor comprises indoximod, F001287, NLG919, brolizumab, pidilizumab, BMS-98.6016, MDX1105-01, ave INCB024360, any IDO inhibitors described elsewhere lumab, compound of Table 2, or a salt, Solvate, or combi herein, or a salt, Solvate or combination thereof. In some nation thereof. embodiments, a CTLA-4 inhibitor comprises ipilimumab, 0308. In some embodiments, provided herein are com tremelimumab, antibody clone 9H10, antibody clone BNI3, positions comprising an antimicrobial agent, a PD-1 inhibi Del 60, M9-14 del 55, a compound of Table 3, or a salt, tor, and optionally one or more additional active agents. In solvate or combination thereof. Some embodiments, provided herein are compositions com 0309. In some embodiments, provided herein are com prising an antimicrobial agent administered with a PD-1 positions comprising one or more compounds of Table 1, or inhibitor and optionally one or more additional active salts or solvates thereof: a PD-1 inhibitor, and optionally one agents. In some embodiments, the antimicrobial agent is a or more additional active agents. In some embodiments, TDO/IDO inhibitor. In various embodiments, the composi provided herein are compositions comprising one or more tions are useful for the treatment of a disease or condition. compounds of Table 1, or salts or solvates thereof, admin In some cases, the disease is cancer. In some cases, the istered with a PD-1 inhibitor and optionally one or more disease is an infectious disease. In some embodiments, an additional active agents. In some embodiments, the com additional active agent comprises an anti-cancer agent, pound of Table 1, or salt or solvate thereof, is a TDO/IDO CTLA-4 inhibitor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor. In various embodiments, the compositions are inhibitor, or combinations thereof. In some embodiments, useful for the treatment of a disease or condition. In some the antimicrobial agent comprises an antibacterial agent. In cases, the disease is cancer. In some cases, the disease is an US 2016/0361298 A1 Dec. 15, 2016

infectious disease. In some embodiments, an additional 0311 Combinations with IDO Inhibitors active agent comprises an anti-cancer agent, CTLA-4 inhibi 0312. In some embodiments, a composition comprises tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com one or more TDO/IDO inhibitors (e.g., inhibitor of TDO, binations thereof. In some embodiments, a PD-1 inhibitor IDO, or both TDO and IDO) and one or more IDO inhibi comprises an antimicrobial agent, Sulfonamide, NSAID, tors. In other embodiments, a composition comprising one ACE inhibitor, beta adrenergic agonist, beta antagonist, or more TDO/IDO inhibitors is configured for administered alpha adrenergic agonist, Vitamin, benzamide, or a combi with a composition comprising one or more IDO inhibitors. nation thereof. In some embodiments, a PD-1 inhibitor In some instances, for compositions comprising TDO/IDO comprises a compound of Table 2, or a salt, Solvate, or inhibitors that further comprise and/or are administered with combination thereof. In some embodiments, a TDO/IDO one or more IDO inhibitors, the compositions and/or admin inhibitor comprises a compound of Table 1. Formula (I), istered combinations of inhibitors inhibit TDO, IDO, or both Formula (II), Formula (III), Formula (IV). Formula (V), TDO and IDO to a greater extent that a TDO/IDO inhibitor Formula (VI), Formula (VII). Formula (VIII), Formula (IX), or IDO inhibitor alone. Inhibition activity of compositions indoximod, F001287, NLG919, INCB024360, any TDO/ and combinations include in vitro and in vivo assays known IDO inhibitor described elsewhere herein, or a salt, solvate, to one of skill in the art. In some instances, an IDO inhibitor or combination thereof. In some embodiments, an IDO is a TDO inhibitor. In some cases, a composition comprises inhibitor comprises indoximod, F001287, NLG919, 2, 3, 4, 5, or more TDO/IDO inhibitors. In some cases, a INCB024360, any IDO inhibitors described elsewhere composition comprises 2, 3, 4, 5, or more IDO inhibitors. In herein, or a salt, Solvate or combination thereof. In some Some embodiments, a composition comprising one or more embodiments, a CTLA-4 inhibitor comprises ipilimumab, IDO inhibitors and one or more TDO/IDO inhibitors further tremelimumab, antibody clone 9H10, antibody clone BNI3, comprises one or more PD-1 inhibitors, TDO and/or Del 60, M9-14 del 55, a compound of Table 3, or a salt, CTLA-4 inhibitors. In some embodiments, a composition solvate or combination thereof. comprising one or more TDO/IDO inhibitors and one or 0310. In some embodiments, provided herein are com more IDO inhibitors is administered with one or more PD-1 positions comprising a compound of Formula (I), Formula inhibitors, TDO and/or CTLA-4 inhibitors. In some embodi (II), Formula (III). Formula (IV). Formula (V), Formula ments, a TDO/IDO inhibitor comprises a compound of (VI). Formula (VII), Formula (VIII), Formula (IX), or a salt Formula (I). Formula (II), Formula (III). Formula (IV), or solvate thereof, a PD-1 inhibitor, and optionally one or Formula (V), Formula (VI), Formula (VII). Formula (VIII), more additional active agents. In some embodiments, pro Formula (IX), Table 1, indoximod, F001287, NLG919, vided herein are compositions comprising a compound of INCB024360, or a salt, solvate, or combination thereof. In Formula (I). Formula (II), Formula (III), Formula (IV), Some cases, an IDO inhibitor comprises indoximod, Formula (V), Formula (VI), Formula (VII). Formula (VIII), F001287, NLG919, INCB024360, or a salt, solvate, or Formula (IX), or a salt or solvate thereof, administered with combination thereof. In some cases, an IDO inhibitor com a PD-1 inhibitor and optionally one or more additional prises a compound of Table 1, or a salt, Solvate, or combi active agents. In some embodiments, the compound of nation thereof. In some cases, any of the aforementioned Formula (I). Formula (II), Formula (III), Formula (IV), IDO inhibitor compounds are also inhibitors of TDO. Formula (V), Formula (VI), Formula (VII). Formula (VIII), 0313. In some embodiments, provided herein are com Formula (IX), or salt or solvate thereof, is a TDO/IDO positions comprising an antimicrobial agent, an IDO inhibi inhibitor. In various embodiments, the compositions are tor, and optionally one or more additional active agents. In useful for the treatment of a disease or condition. In some Some embodiments, provided herein are compositions com cases, the disease is cancer. In some cases, the disease is an prising an antimicrobial agent administered with an IDO infectious disease. In some embodiments, an additional inhibitor and optionally one or more additional active active agent comprises an anti-cancer agent, CTLA-4 inhibi agents. In some embodiments, the antimicrobial agent is a tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com TDO/IDO inhibitor. In various embodiments, the composi binations thereof. In some embodiments, a PD-1 inhibitor tions are useful for the treatment of a disease or condition. comprises an antimicrobial agent, Sulfonamide, NSAID, In some cases, the disease is cancer. In some cases, the ACE inhibitor, beta adrenergic agonist, beta antagonist, disease is an infectious disease. In some embodiments, an alpha adrenergic agonist, Vitamin, benzamide, or a combi additional active agent comprises an anti-cancer agent, nation thereof. In some embodiments, a PD-1 inhibitor CTLA-4 inhibitor, PD-1 inhibitor, IDO inhibitor, TDO comprises a compound of Table 2, or a salt, Solvate, or inhibitor, or combinations thereof. In some embodiments, combination thereof. In some embodiments, a TDO/IDO the antimicrobial agent comprises an antibacterial agent. In inhibitor comprises a compound of Table 1. Formula (I), Some embodiments, the antibacterial agent comprises clox Formula (II), Formula (III), Formula (IV). Formula (V), iquine, betamipronum, chloroxine, nalidixic acid, paZu Formula (VI), Formula (VII). Formula (VIII), Formula (IX), floxacin, propicillin, besifloxacin, oxacillin Sodium, moxi indoximod, F001287, NLG919, INCB024360, any TDO/ floxacin, cloxacillin, dicloxacillin, or a salt, Solvate or IDO inhibitor described elsewhere herein, or a salt, solvate, combination thereof. In some embodiments, the antimicro or combination thereof. In some embodiments, an IDO bial agent comprises an antifungal agent. In some embodi inhibitor comprises indoximod, F001287, NLG919, ments, the antifungal agent comprises tioconazole, liarozole, INCB024360, any IDO inhibitors described elsewhere Sertaconazole, econazole, Sulconazole, miconazole, isocon herein, or a salt, Solvate or combination thereof. In some azole, itraconazole, fenticonazole, cloconazole, acrisorci embodiments, a CTLA-4 inhibitor comprises ipilimumab, num, climbazole, croconazole, diphenylimidazole, exal tremelimumab, antibody clone 9H10, antibody clone BNI3, amide, lanoconazole, oxiconazole, bifonazole, luliconazole, Del 60, M9-14 del 55, a compound of Table 3, or a salt, thiabendazole, butoconazole, clotrimazole, ketoconazole, solvate or combination thereof. luliconazole, albaconazole, efinaconazole, epoxiconazole, US 2016/0361298 A1 Dec. 15, 2016 62 fluconazole, isavuconazole, posaconazole, propiconazole, UV light absorber, or combination thereof. In some embodi raVuconazole, terconazole, Voriconazole, abafungin, omo ments, an IDO inhibitor comprises a compound of Table 1, conazole, phenoxyacetic acid, naftifine, tolindate, tolnaftate, or a salt, Solvate or combination thereof. In some embodi butenafine, o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n- ments, a TDO/IDO inhibitor comprises a compound of Table methylthio-2-pyridinecarbamate, or a salt, Solvate or com 1. Formula (I). Formula (II), Formula (III). Formula (IV), bination thereof. In some embodiments, the antimicrobial Formula (V), Formula (VI), Formula (VII). Formula (VIII), agent comprises an antiparasitic agent. In some embodi Formula (IX), indoximod, F001287, NLG919, ments, the antiparasitic agent comprises praziquantel, chlo INCB024360, any TDO/IDO inhibitor described elsewhere roquine, epsiprantel, niclosamide, hydroxychloroquin, or a herein, or a salt, Solvate, or combination thereof. In some salt, Solvate or combination thereof. In some embodiments, the antimicrobial agent comprises an antiseptic. In some embodiments, a PD-1 inhibitor comprises BMS-936559, embodiments, the antiseptic comprises iodochlorohydroxy MEDI4736, MPDL3280A, MSB0010718C, AMP-224, quinoline, euresol, acrisorcinum, benzyl peroxide, benzoyl nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, peroxide, benzoxiduine, ethacridine lactate, or a salt, Solvate MDX 1105-01, avelumab, a compound of Table 2, or a salt, or combination thereof. In some embodiments, the antimi Solvate or combination thereof. In some embodiments, a crobial agent comprises an antiviral agent. In some embodi CTLA-4 inhibitor comprises ipilimumab, tremelimumab, ments, the antiviral agent comprises imiquimod, efavirenz, antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 or a salt, Solvate or combination thereof. In some embodi del 55, a compound of Table 3, or a salt, solvate or ments, the antimicrobial agent comprises chlorquinaldol, or combination thereof. a salt or solvate thereof. In some embodiments, an IDO 0315. In some embodiments, provided herein are com inhibitor comprises an antimicrobial agent (e.g., antibacte positions comprising a compound of Formula (I), Formula rial, antifungal, antiviral), antiprotozoal agent, taenicide, insecticide, sulfonamide (e.g., diuretic), NSAID, beta adren (II), Formula (III). Formula (IV). Formula (V), Formula ergic agonist, beta adrenergic antagonist, alpha adrenergic (VI). Formula (VII), Formula (VIII), Formula (IX), or a salt or solvate thereof, an IDO inhibitor, and optionally one or agonist, sympathomimetic drug, antihistamine, GABA more additional active agents. In some embodiments, pro modulator, UV light absorber, or combination thereof. In vided herein are compositions comprising a compound of Some embodiments, an IDO inhibitor comprises a com Formula (I). Formula (II), Formula (III). Formula (IV), pound of Table 1, or a salt, solvate or combination thereof. Formula (V), Formula (VI), Formula (VII). Formula (VIII), In some embodiments, a TDO/IDO inhibitor comprises a Formula (IX), or a salt or solvate thereof, administered with compound of Table 1. Formula (I), Formula (II), Formula an IDO inhibitor and optionally one or more additional (III). Formula (IV). Formula (V). Formula (VI). Formula active agents. In some embodiments, the compound of (VII), Formula (VIII), Formula (IX), indoximod, F001287, Formula (I). Formula (II), Formula (III). Formula (IV), NLG919, INCB024360, any TDO/IDO inhibitor described Formula (V), Formula (VI), Formula (VII). Formula (VIII), elsewhere herein, or a salt, solvate, or combination thereof. Formula (IX), or salt or solvate thereof, is a TDO/IDO In some embodiments, a PD-1 inhibitor comprises BMS inhibitor. In various embodiments, the compositions are 936559, MEDI4736, MPDL3280A, MSB0010718C, AMP useful for the treatment of a disease or condition. In some 224, nivolumab, pembrolizumab, pidilizumab, BMS cases, the disease is cancer. In some cases, the disease is an 98.6016, MDX1105-01, avelumab, a compound of Table 2, infectious disease. In some embodiments, an additional or a salt, Solvate or combination thereof. In some embodi active agent comprises an anti-cancer agent, CTLA-4 inhibi ments, a CTLA-4 inhibitor comprises ipilimumab, tremeli tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com mumab, antibody clone 9H10, antibody clone BNI3, Del 60, binations thereof. In some embodiments, an IDO inhibitor M9-14 del 55, a compound of Table 2, or a salt, solvate or comprises an antimicrobial agent (e.g., antibacterial, anti combination thereof. fungal, antiviral), antiprotozoal agent, taenicide, insecticide, 0314. In some embodiments, provided herein are com Sulfonamide (e.g., diuretic), NSAID, beta adrenergic ago positions comprising one or more compounds of Table 1, or nist, beta adrenergic antagonist, alpha adrenergic agonist, salts or solvates thereof; an IDO inhibitor, and optionally sympathomimetic drug, antihistamine, GABA modulator, one or more additional active agents. In some embodiments, UV light absorber, or combination thereof. In some embodi provided herein are compositions comprising one or more ments, an IDO inhibitor comprises a compound of Table 1, compounds of Table 1, or salts or solvates thereof, admin or a salt, Solvate or combination thereof. In some embodi istered with an IDO inhibitor and optionally one or more ments, a TDO/IDO inhibitor comprises a compound of Table additional active agents. In some embodiments, the com 1. Formula (I). Formula (II), Formula (III). Formula (IV), pound of Table 1, or salt or solvate thereof, is a TDO/IDO Formula (V), Formula (VI), Formula (VII). Formula (VIII), inhibitor. In various embodiments, the compositions are Formula (IX), indoximod, F001287, NLG919, useful for the treatment of a disease or condition. In some INCB024360, any TDO/IDO inhibitor described elsewhere cases, the disease is cancer. In some cases, the disease is an herein, or a salt, Solvate, or combination thereof. In some infectious disease. In some embodiments, an additional embodiments, a PD-1 inhibitor comprises BMS-936559, active agent comprises an anti-cancer agent, CTLA-4 inhibi MEDI4736, MPDL3280A, MSB0010718C, AMP-224, tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, binations thereof. In some embodiments, an IDO inhibitor MDX 1105-01, avelumab, a compound of Table 2, or a salt, comprises an antimicrobial agent (e.g., antibacterial, anti Solvate or combination thereof. In some embodiments, a fungal, antiviral), antiprotozoal agent, taenicide, insecticide, CTLA-4 inhibitor comprises ipilimumab, tremelimumab, Sulfonamide (e.g., diuretic), NSAID, beta adrenergic ago antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 nist, beta adrenergic antagonist, alpha adrenergic agonist, del 55, a compound of Table 3, or a salt, solvate or sympathomimetic drug, antihistamine, GABA modulator, combination thereof. US 2016/0361298 A1 Dec. 15, 2016

0316 Combinations with CTLA-4 Inhibitors embodiments, the antiseptic comprises iodochlorohydroxy 0317. In some embodiments, a composition comprises quinoline, euresol, acrisorcinum, benzyl peroxide, benzoyl one or more TDO/IDO inhibitors and one or more CTLA-4 peroxide, benzoxiduine, ethacridine lactate, or a salt, Solvate inhibitors. In other embodiments, a composition comprising or combination thereof. In some embodiments, the antimi one or more TDO/IDO inhibitors is configured for admin crobial agent comprises an antiviral agent. In some embodi istered with a composition comprising one or more CTLA-4 inhibitors. In some cases, a composition comprises 2, 3, 4, ments, the antiviral agent comprises imiquimod, efavirenz, 5, or more TDO/IDO inhibitors. In some cases, a composi or a salt, Solvate or combination thereof. In some embodi tion comprises 2, 3, 4, 5, or more CTLA-4 inhibitors. In ments, the antimicrobial agent comprises chlorquinaldol, or Some embodiments, a composition comprising one or more a salt or solvate thereof. In some embodiments, a CTLA-4 CTLA-4 inhibitors and one or more TDO/IDO inhibitors inhibitor comprises an antibacterial agent, an antifungal further comprises one or more IDO inhibitors, TDO and/or agent, a Sulfonamide, a NSAID, an antihistamine, a hor PD-1 inhibitors. In some embodiments, a composition com mone, a serotonergic compound, a topoisomerase inhibitor, prising one or more TDO/IDO inhibitors and one or more an alpha adrenergic antagonist, a phosphodiesterase inhibi CTLA-4 inhibitors is administered with one or more IDO tor, a benzamide, a diazepine, or a combination thereof. In inhibitors, TDO and/or PD-1 inhibitors. In some embodi Some embodiments, a CTLA-4 inhibitor comprises a com ments, a TDO/IDO inhibitor comprises a compound of pound of Table 3, or a salt, solvate, or combination thereof. Formula (I). Formula (II), Formula (III), Formula (IV), In some embodiments, a TDO/IDO inhibitor comprises a Formula (V), Formula (VI), Formula (VII). Formula (VIII), compound of Table 1. Formula (I), Formula (II), Formula Formula (IX), Table 1, indoximod, F001287, NLG919, (III). Formula (IV). Formula (V). Formula (VI). Formula INCB024360, or a salt, solvate, or combination thereof. In (VII), Formula (VIII), Formula (IX), indoximod, F001287, Some cases, a CTLA-4 inhibitor comprises ipilimumab, NLG919, INCB024360, any TDO/IDO inhibitor described tremelimumab, antibody clone 9H10, antibody clone BNI3, elsewhere herein, or a salt, solvate, or combination thereof. Del 60, M9-14 del 55, or a combination thereof. In some In some embodiments, an IDO inhibitor comprises indoxi cases, a CTLA-4 inhibitor comprises a compound of Table mod, F001287, NLG919, INCB024360, a compound of 3, or a salt, solvate or combination thereof. Table 1, or a salt, solvate or combination thereof. In some 0318. In some embodiments, provided herein are com embodiments, a PD-1 inhibitor comprises BMS-936559, positions comprising an antimicrobial agent, a CTLA-4 MEDI4736, MPDL3280A, MSB0010718C, AMP-224, inhibitor, and optionally one or more additional active nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, agents. In some embodiments, provided herein are compo MDX1105-01, avelumab, a compound of Table 1, or a salt, sitions comprising an antimicrobial agent administered with solvate or combination thereof. a CTLA-4 inhibitor and optionally one or more additional 0319. In some embodiments, provided herein are com active agents. In some embodiments, the antimicrobial agent positions comprising one or more compounds of Table 1, or is a TDO/IDO inhibitor. In various embodiments, the com salts or solvates thereof; a CTLA-4 inhibitor, and optionally positions are useful for the treatment of a disease or condi one or more additional active agents. In some embodiments, tion. In some cases, the disease is cancer. In some cases, the provided herein are compositions comprising one or more disease is an infectious disease. In some embodiments, an compounds of Table 1, or salts or solvates thereof, admin additional active agent comprises an anti-cancer agent, istered with a CTLA-4 inhibitor and optionally one or more CTLA-4 inhibitor, PD-1 inhibitor, IDO inhibitor, TDO additional active agents. In some embodiments, the com inhibitor, or combinations thereof. In some embodiments, pound of Table 1, or salt or solvate thereof, is a TDO/IDO the antimicrobial agent comprises an antibacterial agent. In inhibitor. In various embodiments, the compositions are Some embodiments, the antibacterial agent comprises cloX useful for the treatment of a disease or condition. In some iquine, betamipronum, chloroxine, nalidixic acid, paZu cases, the disease is cancer. In some cases, the disease is an floxacin, propicillin, besifloxacin, oxacillin Sodium, moxi infectious disease. In some embodiments, an additional floxacin, cloxacillin, dicloxacillin, or a salt, Solvate or active agent comprises an anti-cancer agent, CTLA-4 inhibi combination thereof. In some embodiments, the antimicro tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com bial agent comprises an antifungal agent. In some embodi binations thereof. In some embodiments, a CTLA-4 inhibi ments, the antifungal agent comprises tioconazole, liarozole, tor comprises an antibacterial agent, an antifungal agent, a Sertaconazole, econazole, Sulconazole, miconazole, isocon Sulfonamide, a NSAID, an antihistamine, a hormone, a azole, itraconazole, fenticonazole, cloconazole, acrisorci serotonergic compound, a topoisomerase inhibitor, an alpha num, climbazole, croconazole, diphenylimidazole, exal adrenergic antagonist, a phosphodiesterase inhibitor, a ben amide, lanoconazole, oxiconazole, bifonazole, luliconazole, Zamide, a diazepine, or a combination thereof. In some thiabendazole, butoconazole, clotrimazole, ketoconazole, embodiments, a CTLA-4 inhibitor comprises ipilimumab, luliconazole, albaconazole, efinaconazole, epoxiconazole, tremelimumab, antibody clone 9H10, antibody clone BNI3, fluconazole, isavuconazole, posaconazole, propiconazole, Del 60, M9-14 del 55, a compound of Table 3, or a salt, raVuconazole, terconazole, Voriconazole, abafungin, omo Solvate, or combination thereof. In some embodiments, a conazole, phenoxyacetic acid, naftifine, tolindate, tolnaftate, TDO/IDO inhibitor comprises a compound of Table 1, butenafine, o-(5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-n- Formula (I). Formula (II), Formula (III). Formula (IV), methylthio-2-pyridinecarbamate, or a salt, Solvate or com Formula (V), Formula (VI), Formula (VII). Formula (VIII), bination thereof. In some embodiments, the antimicrobial Formula (IX), indoximod, F001287, NLG919, agent comprises an antiparasitic agent. In some embodi INCB024360, any TDO/IDO inhibitor described elsewhere ments, the antiparasitic agent comprises praziquantel, chlo herein, or a salt, Solvate, or combination thereof. In some roquine, epsiprantel, niclosamide, hydroxychloroquin, or a embodiments, an IDO inhibitor comprises indoximod, salt, Solvate or combination thereof. In some embodiments, F001287, NLG919, INCB024360, a compound of Table 1, the antimicrobial agent comprises an antiseptic. In some or a salt, Solvate or combination thereof. In some embodi US 2016/0361298 A1 Dec. 15, 2016 64 ments, a PD-1 inhibitor comprises BMS-936559, agent is a TDO inhibitor. In some cases, the additional active MEDI4736, MPDL3280A, MSB0010718C, AMP-224, agent is an anti-cancer agent. In some cases, the patient has nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, a disease or condition Such as cancer and/or an infectious MDX 1105-01, avelumab, a compound of Table 2, or a salt, disease. solvate or combination thereof. 0322 Further provided herein are pharmaceutical com 0320 In some embodiments, provided herein are com binations that result from the mixing or combining of more positions comprising a compound of Formula (I), Formula than one active agents or ingredients. A pharmaceutical (II), Formula (III). Formula (IV). Formula (V), Formula combination includes both fixed and non-fixed combinations (VI). Formula (VII), Formula (VIII), Formula (IX), or a salt of the active agents. In some cases, the active agents are or solvate thereof, a CTLA-4 inhibitor, and optionally one or provided in a fixed combination, where the active agents of more additional active agents. In some embodiments, pro the fixed combination are administered to a patient simul vided herein are compositions comprising a compound of taneously in the form of a single entity or dosage. In some Formula (I). Formula (II), Formula (III), Formula (IV), cases, the active agents are provided in a non-fixed combi Formula (V), Formula (VI), Formula (VII). Formula (VIII), nation, wherein the active agents of the non-fixed combina Formula (IX), or a salt or solvate thereof, administered with tion are administered to a patient as separate entities either a CTLA-4 inhibitor and optionally one or more additional simultaneously, concurrently or sequentially with no specific active agents. In some embodiments, the compound of intervening time limits, and wherein such administration Formula (I). Formula (II), Formula (III), Formula (IV), provides effective levels of the two compounds in the body Formula (V), Formula (VI), Formula (VII). Formula (VIII), of the patient. The latter also applies to cocktail therapy, for Formula (IX), or salt or solvate thereof, is a TDO/IDO example, the administration of three or more active agents. inhibitor. In various embodiments, the compositions are 0323. As used herein, a TDO/IDO inhibitor includes its useful for the treatment of a disease or condition. In some pharmaceutically acceptable salts and/or Solvates. Similarly, cases, the disease is cancer. In some cases, the disease is an reference to an active agent includes its pharmaceutically infectious disease. In some embodiments, an additional acceptable salts and/or solvates. Further, reference to a active agent comprises an anti-cancer agent, CTLA-4 inhibi composition comprising a TDO/IDO inhibitor is inclusive of tor, PD-1 inhibitor, IDO inhibitor, TDO inhibitor, or com a composition comprising a pharmaceutically acceptable binations thereof. In some embodiments, a CTLA-4 inhibi salt and/or solvate of the TDO/IDO inhibitor. In some tor comprises an antibacterial agent, an antifungal agent, a embodiments, one or more compounds of Table 1, and salts Sulfonamide, a NSAID, an antihistamine, a hormone, a serotonergic compound, a topoisomerase inhibitor, an alpha and solvates thereof, are TDO/IDO inhibitors. adrenergic antagonist, a phosphodiesterase inhibitor, a ben 0324. A pharmaceutical composition or composition, in Zamide, a diazepine, or a combination thereof. In some various embodiments, comprises an active agent as embodiments, a CTLA-4 inhibitor comprises ipilimumab, described herein. Non-limiting examples of active agents tremelimumab, antibody clone 9H10, antibody clone BNI3, include anti-cancer agents, PD-1 inhibitors, IDO inhibitors, Del 60, M9-14 del 55, compound of Table 3, or a salt, CTLA-4 inhibitors, TDO/IDO inhibitors, TDO inhibitors, Solvate, or combination thereof. In some embodiments, a and combinations thereof. In many embodiments, a compo TDO/IDO inhibitor comprises a compound of Table 1, sition is suitable for administration to a Subject, Such as a Formula (I). Formula (II), Formula (III), Formula (IV), human. In some embodiments, the composition is sterile and Formula (V), Formula (VI), Formula (VII). Formula (VIII), preferably free of contaminants that are capable of eliciting Formula (IX), indoximod, F001287, NLG919, an undesirable response within a Subject. In some embodi INCB024360, any TDO/IDO inhibitor described elsewhere ments, the composition is of pharmaceutical grade. Pharma herein, or a salt, Solvate, or combination thereof. In some ceutical compositions are designed for administration to a embodiments, an IDO inhibitor comprises indoximod, patient in need thereof via a number of non-limiting routes F001287, NLG919, INCB024360, a compound of Table 1, including, without limitation, oral, intravenous, buccal, rec or a salt, Solvate or combination thereof. In some embodi tal, parenteral, intraperitoneal, intradermal, intracheal, intra ments, a PD-1 inhibitor comprises BMS-936559, muscular, Subcutaneous, gastric or duodenal feeding tube, MEDI4736, MPDL3280A, MSB0010718C, AMP-224, and inhalational. The terms administer, administering, nivolumab, pembrolizumab, pidilizumab, BMS-98.6016, administration, and the like, as used herein, refer to the MDX 1105-01, avelumab, a compound of Table 2, or a salt, methods that may be used to enable delivery of compounds solvate or combination thereof. or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, inhalational, transdermal, transmucosal, Sublingual, buccal, Pharmaceutical Compositions intraduodenal routes, parenteral injection (including intra 0321. In some embodiments, disclosed herein are com venous, Subcutaneous, intraperitoneal, intramuscular, intra positions comprising one or more TDO/IDO inhibitors (e.g., vascular, intraarterial, intracardial, intradermal, intraduode inhibitors of TDO, IDO, or both TDO and IDO), wherein the nal, intramedullary, intraosseous, intrathecal, intravitreal, compositions are formulated for administration to a patient epidural or infusion), topical (including epicutaneous, der in need thereof. In some embodiments, disclosed herein are mal, enema, eye drops, ear drops, intranasal, vaginal) and compositions comprising one or more TDO/IDO inhibitors rectal administration. In some embodiments, the compounds and one or more additional active agents, wherein the and compositions described herein are administered orally. compositions are formulated for administration to a patient The terms co-administration or the like, as used herein, in need thereof. In some cases, an additional active agent is encompass administration of the selected therapeutic agents a PD-1 inhibitor. In some cases, an additional active agent is to a single patient, and include treatment regimens in which an IDO inhibitor. In some cases, an additional active agent the agents are administered by the same or different route of is an CTLA-4 inhibitor. In some cases, an additional active administration, at the same or different time. In some US 2016/0361298 A1 Dec. 15, 2016

embodiments, the compositions described herein are admin dichlorodifluoromethane, trichlorofluoromethane, dichloro istered either alone or in combination with pharmaceutically tetrafluoroethane, carbon dioxide or other suitable gas. In acceptable carriers, excipients or diluents in a pharmaceu Some cases, pharmaceutical compositions are formulated as tical composition. a dry powder for administered with the aid of an inhalator or 0325 In some embodiments, pharmaceutical composi insufflator. tions suitable for oral administration are presented as dis 0332. In various aspects, one or more active agents of crete units such as capsules, cachets or tablets each contain compositions described herein (e.g., PD-1 inhibitors, IDO ing a predetermined amount of an active agent (e.g., TDO/ inhibitors, CTLA-4 inhibitors, TDO/IDO inhibitors, TDO IDO inhibitor); as a powder or granules; as a solution or a inhibitors, anti-cancer agents, and combinations thereof) are Suspension in an aqueous liquid or a non-aqueous liquid; or in the form of pharmaceutically acceptable salts. In addi as an oil-in-water liquid emulsion or a water-in-oil liquid tional embodiments, one or more active agents exist in emulsion. In some embodiments, the active agent is pre unsolvated or Solvated forms with pharmaceutically accept sented as a bolus, electuary or paste. able solvents such as water, ethanol, and the like. Reference 0326 In some embodiments, pharmaceutical composi to a PD-1 inhibitor herein includes both pharmaceutically tions are formulated for parenteral administration by injec acceptable salts and solvates of the PD-1 inhibitor. Refer tion, e.g., by bolus injection or continuous infusion. Formu ence to an IDO inhibitor herein includes both pharmaceu lations for injection may be presented in unit dosage form, tically acceptable salts and solvates of the IDO inhibitor. e.g., in ampoules or in multi-dose containers, optionally with Reference to a CTLA-4 inhibitor herein includes both phar an added preservative. The compositions may take Such maceutically acceptable salts and solvates of the CTLA-4 forms as Suspensions, Solutions or emulsions in oily or inhibitor. Reference to a TDO/IDO inhibitor herein includes aqueous vehicles, and may contain formulatory agents such both pharmaceutically acceptable salts and solvates of the as Suspending, stabilizing and/or dispersing agents. In some TDO/IDO inhibitor. Reference to a TDO inhibitor herein embodiments, the compositions are formulated in unit-dose includes both pharmaceutically acceptable salts and Solvates or multi-dose containers, for example sealed ampoules and of the TDO inhibitor. In some embodiments, pharmaceuti vials, and may be stored in powder form or in a freeze-dried cally acceptable refers a material. Such as a carrier or diluent, (lyophilized) condition requiring only the addition of the which does not abrogate the biological activity or properties sterile liquid carrier, for example, Saline or sterile pyrogen of the agent, and is relatively nontoxic, i.e., the material is free water, immediately prior to use. Pharmaceutical com administered to a subject without causing undesirable bio positions for parenteral administration include aqueous and logical effects or interacting in a deleterious manner with non-aqueous (oily) Sterile injection solutions of the active any of the agents of the composition in which it is contained. agents which may contain antioxidants, buffers, bacte 0333. In some embodiments, a pharmaceutically accept riostats and solutes which render the formulation isotonic able salt refers to a form of a therapeutically active agent that with the blood of the intended recipient; and aqueous and consists of a cationic form of the therapeutically active agent non-aqueous sterile Suspensions which may include Sus in combination with a suitable anion, or in alternative pending agents and thickening agents. embodiments, an anionic form of the therapeutically active 0327. In some embodiments, pharmaceutical composi agent in combination with a suitable cation. In some tions are formulated as a depot preparation, for example, for embodiments, pharmaceutically acceptable salts are administration by implantation (e.g., Subcutaneously or obtained by reacting an active agent (e.g., TDO/IDO inhibi intramuscularly) or by intramuscular injection. In some tor) with an acid. In some embodiments, the active agent is cases, the compositions are formulated with Suitable poly basic and is reacted with an organic acid or an inorganic meric or hydrophobic materials or ion exchange resins, or as acid. In some embodiments, an active agent is prepared as a sparingly soluble derivatives, for example, as a sparingly chloride salt, Sulfate salt, bromide salt, mesylate salt, soluble salt. maleate salt, citrate salt or phosphate salt. In some embodi 0328. In some embodiments, pharmaceutical composi ments, an active agent is prepared as a hydrochloride salt. In tions are formed into tablets, lozenges, pastilles or gels for Some embodiments, pharmaceutically acceptable salts are buccal or Sublingual administration. obtained by reacting an active agent with a base. In some 0329. In some embodiments, pharmaceutical composi embodiments, the active agent is acidic and is reacted with tions are formulated in rectal compositions such as Supposi a base. In some embodiments, the active agent is prepared as tories or retention enemas, e.g., containing conventional a sodium salt, calcium salt, potassium salt, magnesium salt, Suppository bases such as cocoa butter, polyethylene glycol, meglumine salt, N-methylglucamine salt or ammonium salt. or other glycerides. In some embodiments, the compounds provided herein are 0330. In some embodiments, pharmaceutical composi prepared as a sodium salt. tions are administered topically such that the compound 0334. In some embodiments, compositions described does not significantly enter the blood stream. Pharmaceuti herein comprise one or more active agents that are prepared cal compositions Suitable for topical administration include as prodrugs. A prodrug refers to an agent that is converted liquid or semi-liquid preparations suitable for penetration into the parent drug in vivo. In certain embodiments, upon through the skin Such as gels, liniments, lotions, creams, in vivo administration, a prodrug is chemically converted to ointments or pastes, and drops suitable for administration to the biologically, pharmaceutically or therapeutically active the eye, ear or nose. form of the compound. In certain embodiments, a prodrug is 0331. In some embodiments, pharmaceutical composi enzymatically metabolized by one or more steps or pro tions are formulated for administration by inhalation using cesses to the biologically, pharmaceutically or therapeuti an insufflator, nebulizer pressurized packs or other conve cally active form of the compound. In some aspects, pro nient means of delivering an aerosol spray. Pressurized vided are compositions comprising a prodrug formulation of packs include those comprising a Suitable propellant Such as a CTLA-4 inhibitor described herein. In some aspects, US 2016/0361298 A1 Dec. 15, 2016 66 provided are compositions comprising a prodrug formula symptoms, or causes of a disease, or any other desired tion of an IDO inhibitor described herein. In some aspects, alteration of a biological system. For example, an effective provided are compositions comprising a prodrug formula amount for therapeutic uses is the amount of the composi tion of a PD-1 inhibitor described herein. In some aspects, tion comprising a compound as disclosed herein required to provided are compositions comprising a prodrug formula provide a clinically significant decrease in disease symp tion of a TDO/IDO inhibitor described herein. In some toms. An appropriate effective amount in any individual case aspects, provided are compositions comprising a prodrug is optionally determined using techniques, such as a dose formulation of a TDO inhibitor described herein. In addi escalation study. tional embodiments, provided are compositions comprising 0336 A unit dosage form, in many instances, refers to a prodrug formulation of a TDO/IDO inhibitor described physically discrete units Suitable as unitary dosages for herein and at least one additional active agent, for example, Subjects, wherein each unit comprises a predetermined a PD-1 inhibitor, IDO inhibitor, TDO inhibitor, and/or quantity of a composition comprising an active agent Such as CTLA-4 inhibitor. In additional embodiments, provided are an anti-cancer agent, as described herein. In many embodi compositions comprising a prodrug formulation of a TDO/ ments, a composition further comprises a pharmaceutically IDO inhibitor described herein and a prodrug formulation of acceptable diluent, carrier or vehicle. The specifications for an active agent, for example, a PD-1 inhibitor, IDO inhibitor, unit dosage forms depend on the particular composition TDO inhibitor, and/or CTLA-4 inhibitor. In additional employed, the route and frequency of administration, the embodiments, provided are compositions comprising a effect to be achieved and the pharmacodynamics associated TDO/IDO inhibitor described herein and a prodrug formu with the composition in the host. lation of an active agent, for example, a PD-1 inhibitor, IDO inhibitor, TDO inhibitor, and/or CTLA-4 inhibitor. In addi tional or further embodiments, the PD-1 inhibitor, IDO Pharmaceutical Formulations inhibitor, TDO/IDO inhibitor, TDO inhibitor, and/or CTLA-4 inhibitor is metabolized upon administration to a 0337 Provided herein are compositions comprising one Subject to produce a metabolite that is then used to produce or more active agents, for example, a TDO/IDO inhibitor, a desired effect, including a desired therapeutic effect. In formulated with one or more pharmaceutically acceptable Some embodiments, a metabolite of an active agent is a excipients, diluents, carriers and/or adjuvants. In addition, derivative of that compound that is formed when the com compositions of the disclosure include active agents formu pound is metabolized. The term active metabolite refers to a lated with one or more pharmaceutically acceptable auxil biologically active derivative of a compound that is formed iary substances. Auxiliary substances, such as pH adjusting when the compound is metabolized. In some cases, a pro and buffering agents, tonicity adjusting agents, stabilizers, drug is easier to administer than the parent drug, for wetting agents and the like are readily available to the example, the prodrug is bioavailable by oral administration public. Suitable excipient vehicles for a composition whereas the parent is not. In some cases, the prodrug has include, for example, water, saline, dextrose, glycerol, etha improved solubility in pharmaceutical compositions over nol and combinations thereof. In addition, the vehicle may the parent drug. In a non-limiting example, a prodrug of an comprise auxiliary Substances such as wetting or emulsify active agent described herein is administered as an ester ing agents or pH buffering agents. prodrug to facilitate transmittal across a cell membrane 0338. In some embodiments, a composition described where water solubility is detrimental to mobility, where the herein is administered to a patient using any means capable prodrug is metabolically hydrolyzed to the carboxylic acid, to result in a desired effect. In some cases, the patient has the active entity, once inside the cell where water-solubility cancer and the desired effect is tumor cell death. In some is beneficial. As a further non-liming example, a prodrug is cases, the patient has cancer and the desired effect is the a short peptide bonded to an acid group, where the peptide prevention of tumor cell growth. In some cases, the patient is metabolized to reveal the active moiety. In some embodi has cancer and the desired effect is the prevention of tumor ments, a prodrug is designed to alter the metabolic stability cell invasion. In some cases, the patient has cancer and the and/or the transport characteristics of an active agent, to desired effect is the inhibition of tumor cell invasion. In mask side effects and/or toxicity, to improve the flavor of an Some cases, the patient has cancer and the desired effect is agent, and/or to alter other characteristics or properties of the the prevention of tumor cell metastasis. In some cases, the active. In some embodiments, some of the herein-described patient has cancer and the desired effect is the inhibition of compounds are prodrugs for other derivatives or active tumor cell metastasis. compounds. In some embodiments, some of the herein 0339. In many embodiments, the active agent is formu described compounds are formulated as prodrugs. lated into a pharmaceutical composition by combination 0335 A therapeutically effective amount of an agent or with appropriate, pharmaceutically acceptable carriers or composition is generally the amount of an agent or compo diluents, into Solid, semi-solid, liquid or gaseous forms, such sition that is required to relieve to some extent one or more as tablets, capsules, powders, granules, ointments, Solutions, symptoms of a disease being treated (e.g., cancer) and/or the Suppositories, injections, inhalants and aerosols. For oral amount that will prevent, to Some extent, one or more preparations, the active agent may be used alone or in symptoms of a disease that the host being treated has or is combination with appropriate additives to make tablets, at risk of developing. The terms effective amount or thera powders, granules or capsules, for example, with conven peutically effective amount, as used herein, refer to a Suf tional additives, such as lactose, mannitol, corn starch, or ficient amount of an agent or a compound being adminis potato starch; with binders such as crystalline cellulose, tered, which will relieve to some extent one or more of the cellulose derivatives, acacia, corn starch or gelatins; with symptoms of the disease or condition being treated. The disintegrators, such as corn starch, potato starch, or sodium result includes reduction and/or alleviation of the signs, carboxymethylcellulose; with lubricants, such as talc or US 2016/0361298 A1 Dec. 15, 2016 67 magnesium Stearate; and/or if desired, with diluents, buff 0346. In some embodiments, an active agent of a com ering agents, moistening agents, preservatives and/or flavor position herein is formulated for delivery by a continuous or ing agents. controlled delivery system. Examples include the use of 0340 Compositions described herein, in various imple continuous or controlled delivery devices in combination mentations, comprise a Sustained-release or controlled with catheters, injection devices and the like. In other or release matrix. In addition, embodiments of the composi additional embodiments, the composition is delivered using tions may be used in conjunction with other treatments that a pump, including mechanical and electromechanical infu use Sustained-release formulations. A Sustained-release sion pumps. In general, pumps provide consistent and/or matrix, in many instances, is a matrix made of materials, controlled release of the composition over time. In some usually polymers, which are degradable by enzymatic or embodiments, the active agent is in a liquid formulation in acid-based hydrolysis or by dissolution. Once inserted into a drug-impermeable reservoir, and is delivered in a continu the body, the matrix may be acted upon by enzymes and ous or controlled manner to a patient. In some embodiments, body fluids. Examples of Sustained-release matrix materials a drug delivery system is at least partially implantable. An include, without limitation, liposomes, polylactides (poly implantable device can be implanted at any suitable implan lactic acid), polyglycolide (polymer of glycolic acid), poly tation site using methods and devices well known in the art lactide co-glylide (copolymers of lactic acid and glycolic Implantation sites include, but are not limited to, a Subder acid), polyanhydrides, poly(ortho)esters, polypeptides, mal. Subcutaneous, intramuscular or other Suitable site hyaluronic acid, collagen, chondroitin Sulfate, carboxylic within a Subject's body. Subcutaneous implantation sites are acids, fatty acids, phospholipids, polysaccharides, nucleic used in Some embodiments for convenience in implantation acids, polyamino acids, amino acids (e.g., phenylalanine, and removal of the drug delivery device. In some embodi tyrosine, isoleucine), polynucleotides, polyvinyl propylene, ments, the active agent is delivered in a controlled release polyvinylpyrrolidone and silicone. Illustrative biodegrad system. In exemplary embodiments, the active agent is able matrices include a polylactide matrix, a polyglycolide administered using intravenous infusion, implantable matrix and a polylactide co-glycolide (co-polymers of lactic osmotic pump, transdermal patch or liposomes. acid and glycolic acid) matrix. 0347 In other embodiments, an active agent of a com 0341 In some embodiments, an active agent of a com position described herein is formulated into absorptive mate position herein is formulated into a preparation for injection rials, such as Sutures, bandages and gauze; or coated onto the by dissolving, Suspending or emulsifying the agent in an Surface of Solid phase materials, such as Surgical staples, aqueous or non-aqueous solvent, such as Vegetable or other Zippers and catheters to deliver the agent. similar oils, synthetic aliphatic acid glycerides, esters of high aliphatic acids, or propylene glycol, and if desired, with Methods of Dosing and Treatment Regimens conventional additives such as solubilizers, isotonic agents, 0348. The compositions comprising one or more active Suspending agents, emulsifying agents, stabilizers and pre agents described herein may be administered to a patient in servatives. one or more doses. In some embodiments, a composition 0342. In some embodiments, an active agent of a com comprises two or more active agents. In some embodiments, position herein is utilized in an aerosol formulation to be a composition comprising one or more active agents is administered via inhalation. As examples, the agent is for administered with one or more addition compositions, each mulated into a pressurized acceptable propellant such as comprising one or more additional active agents. In some dichlorodifluoromethane, propane and nitrogen. instances, a patient is administered one dose of one active 0343. In some embodiments, an active agent of a com agent and another dose of another active agent. In some position herein is made into a Suppository by mixing with a embodiments, an active agent is a TDO/IDO inhibitor. In base. Such as an emulsifying base or water-soluble base. In some embodiments, an active agent is a PD-1 inhibitor. In Some instances, an active agent is administered rectally via Some embodiments, an active agent is an IDO inhibitor. In a Suppository. The Suppository may include vehicles Such as Some embodiments, an active agent is a CTLA-4 inhibitor. cocoa butter, carbowaxes and polyethylene glycols, which In some embodiments, an active agent is a TDO inhibitor. In melt at body temperature, yet are solidified at room tem Some cases, the patient has cancer. perature. 0349. In various embodiments, the compositions contain 0344. In some embodiments, an active agent of a com ing the one or more active agents described herein are position is formulation in an injectable composition. Typi administered for prophylactic and/or therapeutic treatments. cally, injectable compositions are prepared as liquid solu In some therapeutic applications, the compositions are tions or Suspensions. In some instances, a Solid form is administered to a patient already Suffering from a disease or provided which is suitable for solubilization or suspension in condition, in an amount Sufficient to cure or at least partially a liquid vehicle prior to injection. In other embodiments, an arrest at least one of the symptoms of the disease or active agent is emulsified or the active agent is encapsulated condition. Amounts effective for this use depend on the in a liposome vehicle. severity and course of the disease or condition, previous 0345. In some embodiments, unit dosage forms for oral therapy, the patient’s health status, weight, and response to or rectal administration, Such as syrups, elixirs and Suspen the drugs, and the judgment of the treating physician. sions are provided wherein each dosage unit (e.g., teaspoon Therapeutically effective amounts are optionally determined ful, tablespoonful, table, Suppository) comprises a predeter by methods including, but not limited to, a dose escalation mined amount of the composition comprising one or more and/or dose ranging clinical trial. In some embodiments, the active agents. In some embodiments, unit dosage forms for disease is cancer. In some embodiments, the disease is an injection or intravenous administration comprises the active infectious disease. agent in a composition as a solution in Sterile water, normal 0350. In prophylactic applications, compositions contain saline or other pharmaceutically acceptable carrier. ing the one or more active agents described herein are US 2016/0361298 A1 Dec. 15, 2016

administered to a patient Susceptible to or otherwise at risk embodiments, an active agent is a TDO/IDO inhibitor. In of a particular disease, disorder or condition. Such an some embodiments, an active agent is a TDO inhibitor. amount is defined to be a prophylactically effective amount 0356. In some embodiments, an active agent is adminis or dose. In this use, the precise amounts also depend on the tered in about a 50 mg dosage. In some embodiments, an patient’s state of health, weight, and the like. When used in active agent is administered in about a 100 mg dosage. In patients, effective amounts for this use will depend on the Some embodiments, an active agent is administered in about severity and course of the disease, disorder or condition, a 200 mg dosage. In some embodiments, an active agent is previous therapy, the patient’s health status and response to administered in about a 300 mg dosage. In some embodi the drugs, and the judgment of the treating physician. In one ments, an active agent is administered in about a 400 mg aspect, prophylactic treatments include administering to a dosage. In some embodiments, an active agent is adminis patient who previously experienced at least one symptom of tered in about a 500 mg dosage. In some embodiments, an the disease being treated and is currently in remission, a active agent is administered in about a 600 mg dosage. In pharmaceutical composition comprising an active agent, or Some embodiments, an active agent is administered in about a pharmaceutically acceptable salt of the active agent, in a 700 mg dosage. In some embodiments, an active agent is order to prevent a return of the symptoms of the disease or administered in about a 800 mg dosage. In some embodi condition. In some embodiments, the disease is cancer. In ments, an active agent is administered in about a 900 mg Some embodiments, the disease is an infectious disease. dosage. In some embodiments, an active agent is adminis 0351. In certain embodiments wherein the patient’s con tered in about a 1000 mg dosage. In some embodiments, an dition does not improve, upon the doctor's discretion the active agent is administered in about a 1,500 mg dosage. In administration of composition comprising the one or more some embodiments, an active agent is a PD-1 inhibitor. In active agents is administered chronically, that is, for an Some embodiments, an active agent is an IDO inhibitor. In extended period of time, including throughout the duration Some embodiments, an active agent is a CTLA-4 inhibitor. of the patient’s life in order to ameliorate or otherwise In some embodiments, an active agent is a TDO/IDO control or limit the symptoms of the patient’s disease or inhibitor. In some embodiments, an active agent is a TDO condition. inhibitor. 0352. In certain embodiments wherein a patient’s status 0357. A composition as described herein, in various does improve, the dose of active agent(s) being administered embodiments, comprises two or more active agents. In some is temporarily reduced or temporarily Suspended for a cer embodiments, one active agent comprises one or more tain length of time (i.e., a drug holiday). In some embodi CTLA-4 inhibitors. In some embodiments, one active agent ments, the length of the drug holiday is between 2 days and comprises one or more PD-1 inhibitors. In some embodi 1 year, including by way of example only, 2 days, 3 days, 4 ments, one active agent comprises one or more IDO inhibi days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 tors. In some embodiments, one active agent comprises one days, 28 days, or more than 28 days. The dose reduction or more TDO/IDO inhibitors. In some embodiments, one during a drug holiday is, for example, by 10%-100%, active agent comprises one or more TDO inhibitors. In some including only 10%, 15%, 20%, 25%, 30%, 35%, 40%, embodiments, a composition comprises two or more TDO/ 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, IDO inhibitors. In some embodiments, a composition com 95%, and 100%. prises at least one TDO/IDO inhibitor and at least one PD-1 0353. Once improvement of the patient’s conditions has inhibitor. In some embodiments, a composition comprises at occurred, a maintenance dose is administered if necessary. least one TDO/IDO inhibitor and at least one IDO inhibitor. Subsequently, in specific embodiments, the dosage or the In some embodiments, a composition comprises at least one frequency of administration, or both, is reduced, as a func TDO/IDO inhibitor and at least one CTLA-4 inhibitor. In tion of the symptoms, to a level at which the improved Some embodiments, a composition comprises at least one disease, disorder or condition is retained. In certain embodi TDO/IDO inhibitor and at least one TDO inhibitor. In some ments, however, the patient requires intermittent treatment cases, a PD-1 inhibitor is administered in about a 1 mg to on a long-term basis upon any recurrence of symptoms. about 2,000 mg dose. In some cases, an IDO inhibitor is 0354. In some embodiments, the dose of an active agent administered in about a 1 mg to about 2,000 mg dose. In administered to a patient varies depending on factors such as Some cases, a CTLA-4 inhibitor is administered in about a time point during therapy, identity of active agent or com 1 mg to about 2,000 mg dose. In some cases, a TDO/IDO bination of active agents, identity of disease, disease con inhibitor is administered in about a 1 mg to about 2,000 mg dition/severity, identity of patient (e.g., age, weight, sex), dose. In some cases, a TDO inhibitor is administered in and route of administration. about a 1 mg to about 2,000 mg dose. In many implemen 0355. In some embodiments, an active agent is adminis tations of the disclosure, the amount of active agent per dose tered an amount from about 25 mg to about 100 mg per dose. is determined on a per body weight basis. For example, in an In some embodiments, an active agent is administered an embodiment, the active agent is administered in an amount amount from about 100 mg to about 200 mg per dose. In of about 0.5 mg/kg body weight to about 100 mg/kg body Some embodiments, an active agent is administered an weight. In some cases, a PD-1 inhibitor is administered in a amount from about 200 mg to about 400 mg per dose. In dose of about 0.5 mg/kg to about 100 mg/kg. In some cases, Some embodiments, an active agent is administered an an IDO inhibitor is administered in a dose of about 0.5 amount from about 400 mg to about 500 mg. In some mg/kg to about 100 mg/kg. In some cases, a CTLA-4 embodiments, an active agent is administered an amount inhibitor is administered in a dose of about 0.5 mg/kg to from about 500 mg to about 1,500 mg. In some embodi about 100 mg/kg. In some cases, a TDO/IDO inhibitor is ments, an active agent is a PD-1 inhibitor. In some embodi administered in a dose of about 0.5 mg/kg to about 100 ments, an active agent is an IDO inhibitor. In some embodi mg/kg. In some cases, a TDO inhibitor is administered in a ments, an active agent is a CTLA-4 inhibitor. In some dose of about 0.5 mg/kg to about 100 mg/kg. Those of skill US 2016/0361298 A1 Dec. 15, 2016 69 will readily appreciate that dose levels often vary as a positions and methods described herein include ipilimumab function of the specific active agent administered, the sever (also known as MDX-010, BMS-734016), tremelimumab, ity of the symptoms of an infected patient and the Suscep antibody clone 9H10, antibody clone BNI3, Del 60, M9-14 tibility of the subject to side effects. Preferred dosage forms del 55, a compound of Table 3, any CTLA-4 inhibitors of a given compound are readily determinable by those of described elsewhere herein, and salts and solvates thereof. skill in the art. In some embodiments, the daily dosage or the Non-limiting examples of PD-1 inhibitors useful in the amount of active agent in the dosage form are lower or compositions and methods described herein include BMS higher than the ranges indicated herein, based on a number 936559, MEDI4736, MPDL3280A, MSB0010718C, AMP of variables in regard to an individual treatment regime. In 224, nivolumab, pembrolizumab, pidilizumab, BMS various embodiments, the daily and unit dosages are altered 98.6016, MDX1105-01, avelumab, a compound of Table 2, depending on a number of variables including, but not any PD-1 inhibitors described elsewhere herein, and salts limited to, the activity of the inhibitor used, the disease or and solvates thereof. Non-limiting examples of IDO inhibi condition to be treated, the mode of administration, the tors useful in the compositions and methods described requirements of the individual subject, the severity of the herein include indoximod, F001287, NLG919, disease or condition being treated, and/or the judgment of INCB024360, a compound of Table 1, any IDO inhibitors the practitioner. described elsewhere herein, and salts and solvates thereof. 0358. In various embodiments, the dose of an active agent in a composition described herein is administered 0361. In some embodiments, cancer refers to an abnor multiple times. The frequency of administration, in some mal growth of cells that proliferate in an uncontrolled way instances, is dependent on the method of use, for example, and, in Some cases, metastasize. Types of cancer include, but for treatment of cancer or infectious disease. In some are not limited to, solid tumors (such as those of the bladder, embodiments, an active agent is administered once per bowel, brain, breast, endometrium, heart, kidney, lung, liver, month, twice per month, three times per month, every other uterus, lymphatic tissue (lymphoma), ovary, pancreas or week, once per week, twice per week, three times per week, other endocrine organ (thyroid), prostate, skin (melanoma or four times per week, five times per week, six times per week, basal cell cancer)) and hematological tumors (such as the every other day, daily, twice a day, three times a day, four leukemias and lymphomas) at any stage of the disease with times a day, five times a day, six times a day or more. In or without metastases. Some embodiments, an active agent is administered continu 0362. In some embodiments, the cancer is a solid tumor. ously. In some embodiments, the cancer is bladder cancer, colon 0359 The duration of administration of the active agent cancer, brain cancer, breast cancer, endometrial cancer, heart (period of time over which the agent is administered), in cancer, kidney cancer, lung cancer, liver cancer, uterine many instances, varies depending on a number of factors. cancer, blood and lymphatic cancer, ovarian cancer, pancre Examples of Such factors include, without limitation, patient atic cancer, prostate cancer, thyroid cancer, or skin cancer. In response, severity of symptoms, and disease type (e.g., Some embodiments, the cancer is a sarcoma, carcinoma, or cancer type). In an example, an active agent is administered lymphoma. In some instances, the cancer is metastatic over a period of time of about one day to about one week, melanoma. In some instances, the cancer is non-small cell about one week to about two weeks, about two weeks to lung cancer. In some instances, the cancer is renal-cell about four weeks, about one month to about two months, cancer. In some instances, the cancer is prostate cancer. In about two months to about four months, about four months Some instances, the cancer is colorectal cancer. In some to about six months, about six months to about eight months, instances, the cancer is pancreatic cancer. In some instances, about eight months to about 1 year, about 1 year to about 2 the cancer is cervical cancer. In some instances, the cancer years or more. is gastric cancer. In some instances, the cancer is ovarian cancer. In some instances, the cancer is breast cancer. Treatment of Cancer 0363. In some embodiments, the cancer is colon cancer. 0360. In some embodiments, disclosed herein are com In some embodiments, the cancer is pancreatic cancer. In positions comprising one or more TDO/IDO inhibitors for Some embodiments, the cancer is cutaneous T-cell lym the treatment of a disease Such as cancer. In some embodi phoma. In some embodiments, the cancer is a glioma. In ments, disclosed herein are compositions comprising one or Some embodiments, the cancer is head and neck cancer. In more TDO/IDO inhibitors and one or more additional active Some embodiments, the cancer is hepatocarcinoma, leuke agents for the treatment of a disease Such as cancer. In some mia, glioblastoma, colorectal carcinoma, gallbladder, mas embodiments, disclosed herein are compositions comprising tocytoma, acute myeloid leukemia, adrenocortical carci one or more TDO/IDO inhibitors that are administered with noma, bladder urothelial carcinoma, brain tumor, brain one or more additional compositions comprising one or lower grade glioma, breast carcinoma, breast invasive car more additional active agents. In some cases, an additional cinoma, cervical carcinoma, cholangiocarcinoma, cutaneous active agent is a PD-1 inhibitor. In some cases, an additional melanoma, diffuse large B-cell lymphoma, endometrial car active agent is an IDO inhibitor. In some cases, an additional cinoma, glioblastoma multiform, H&N squamous cell car active agent is a CTLA-4 inhibitor. In some cases, an cinoma, hepatocellular carcinoma, kidney chromophobe additional active agent is a TDO inhibitor. In some cases, an carcinoma, lung carcinoma, lung adenocarcinoma, lung additional active agent is an anti-cancer agent. Non-limiting squamous cell carcinoma, mesothelioma, ovarian serous examples of TDO/IDO inhibitors include the compounds of cystadenocarcinoma, pancreatic adenocarcinoma, pheochro Table 1. Formula (I), Formula (II), Formula (III). Formula mocytoma and paraganglioma, prostate adenocarcinoma, (IV). Formula (V), Formula (VI). Formula (VII), Formula prostate carcinoma, rectum adenocarcinoma, rectum carci (VIII). Formula (IX), and salts and solvates thereof. Non noma, renal cell carcinoma, renal papillary cell carcinoma, limiting examples of CTLA-4 inhibitors useful in the com sarcoma, testicular germ cell tumors, thymoma, thyroid US 2016/0361298 A1 Dec. 15, 2016 70 carcinoma, uterine carcinosarcoma, melanoma, uveal mela cer, thyroid cancer, pancreatic cancer, esophageal cancer, noma, or a combination thereof. Hodgkin’s lymphoma, leukemia-related disorders, mycosis 0364. Additional non-limiting examples of cancers fungoides, myelodysplastic syndrome, pancreatic cancer, include acute lymphoblastic leukemia, acute myeloid leu T-cell lymphoma, glioma, head and neck cancer, hepatocar kemia, adrenocortical carcinoma, anal cancer, appendix can cinoma, leukemia, glioblastoma, colorectal carcinoma, gall cer, astrocytomas, atypical teratoid/rhabdoid tumor, basal bladder, mastocytoma, acute myeloid leukemia, adrenocor cell carcinoma, bile duct cancer, bladder cancer, bone cancer tical carcinoma, bladder urothelial carcinoma, brain tumor, (osteosarcoma and malignant fibrous histiocytoma), brain brain lower grade glioma, breast carcinoma, breast invasive stem glioma, brain tumors, brain and spinal cord tumors, carcinoma, cervical carcinoma, cholangiocarcinoma, cuta breast cancer, bronchial tumors, Burkitt lymphoma, cervical neous melanoma, diffuse large B-cell lymphoma, endome cancer, chronic lymphocytic leukemia, chronic myelog trial carcinoma, glioblastoma multiform, H&N Squamous enous leukemia, colon cancer, colorectal cancer, craniophar cell carcinoma, hepatocellular carcinoma, kidney chromo yngioma, cutaneous T-Cell lymphoma, desmoid tumors, phobe carcinoma, lung carcinoma, lung adenocarcinoma, embryonal tumors, endometrial cancer, ependymoblastoma, lung Squamous cell carcinoma, mesothelioma, ovarian ependymoma, esophageal cancer, ewing sarcoma family of serous cystadenocarcinoma, pancreatic adenocarcinoma, tumors, eye cancer, retinoblastoma, gallbladder cancer, gas pheochromocytoma and paraganglioma, prostate adenocar tric (stomach) cancer, gastrointestinal carcinoid tumor, gas cinoma, prostate carcinoma, rectum adenocarcinoma, rec trointestinal stromal tumor (GIST), gastrointestinal stromal tum carcinoma, renal cell carcinoma, renal papillary cell cell tumor, germ cell tumor, glioma, hairy cell leukemia, carcinoma, sarcoma, testicular germ cell tumors, thymoma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin thyroid carcinoma, uterine carcinosarcoma, melanoma, lymphoma, hypopharyngeal cancer, intraocular melanoma, uveal melanoma, or a combination thereof. islet cell tumors (endocrine pancreas), Kaposi sarcoma, 0366. In some embodiments, a composition disclosed kidney cancer, Langerhans cell histiocytosis, laryngeal can herein, or a pharmaceutically acceptable salt thereof, is used cer, leukemia, Acute lymphoblastic leukemia, acute myeloid in the treatment of non-Small cell lung cancer, pancreatic leukemia, chronic lymphocytic leukemia, chronic myelog cancer, breast cancer, ovarian cancer, colorectal cancer, or enous leukemia, hairy cell leukemia, liver cancer, non-Small head and neck cancer. cell lung cancer, Small cell lung cancer, Burkitt lymphoma, 0367. In some embodiments, a composition disclosed cutaneous T-cell lymphoma, Hodgkin lymphoma, non herein, or a pharmaceutically acceptable salt thereof, is used Hodgkin lymphoma, lymphoma, Waldenstrom macroglobu in the treatment of a carcinoma, a tumor, a neoplasm, a linemia, medulloblastoma, medulloepithelioma, melanoma, lymphoma, a melanoma, a glioma, a sarcoma, or a blastoma. mesothelioma, mouth cancer, chronic myelogenous leuke mia, myeloid leukemia, multiple myeloma, nasopharyngeal 0368. In some embodiments, the carcinoma comprises cancer, neuroblastoma, non-Hodgkin lymphoma, non-Small adenocarcinoma, adenoid cystic carcinoma, adenosquamous cell lung cancer, oral cancer, oropharyngeal cancer, osteo carcinoma, adrenocortical carcinoma, well differentiated sarcoma, malignant fibrous histiocytoma of bone, ovarian carcinoma, Squamous cell carcinoma, Serous carcinoma, cancer, ovarian epithelial cancer, ovarian germ cell tumor, Small cell carcinoma, invasive squamous cell carcinoma, ovarian low malignant potential tumor, pancreatic cancer, large cell carcinoma, islet cell carcinoma, oat cell carci papillomatosis, parathyroid cancer, penile cancer, pharyn noma, squamous carcinoma, undifferentiated carcinoma, geal cancer, pineal parenchymal tumors of intermediate Verrucous carcinoma, renal cell carcinoma, papillary serous differentiation, pineoblastoma and Supratentorial primitive adenocarcinoma, merkel cell carcinoma, hepatocellular car neuroectodermal tumors, pituitary tumor, plasma cell neo cinoma, soft tissue carcinomas, bronchial gland carcinomas, plasm/multiple myeloma, pleuropulmonary blastoma, pri capillary carcinoma, bartholin gland carcinoma, basal cell mary central nervous system lymphoma, prostate cancer, carcinoma, carcinosarcoma, papilloma/carcinoma, clear cell rectal cancer, renal cell (kidney) cancer, retinoblastoma, carcinoma, endometrioid adenocarcinoma, mesothelial, rhabdomyosarcoma, Salivary gland cancer, sarcoma, Sezary metastatic carcinoma, mucoepidermoid carcinoma, cholan syndrome, skin cancer, Small cell lung cancer, Small intes giocarcinoma, actinic keratoses, cystadenoma, and hepatic tine cancer, soft tissue sarcoma, squamous cell carcinoma, adenomatosis. stomach (gastric) cancer, Supratentorial primitive neuroec 0369. In some embodiments, the tumor comprises astro todermal tumors, T-cell lymphoma, testicular cancer, throat cytic tumors, malignant mesothelial tumors, ovarian germ cancer, thymoma and thymic carcinoma, thyroid cancer, cell tumor, Supratentorial primitive neuroectodermal tumors, urethral cancer, uterine cancer, uterine sarcoma, vaginal Wilm's tumor, pituitary tumors, extragonadal germ cell cancer, Vulvar cancer, Waldenstrom macroglobulinemia, and tumor, gastrinoma, germ cell tumors, gestational trophoblas Wilms tumor. tic tumor, brain tumors, pineal and Supratentorial primitive 0365. In some embodiments, a composition disclosed neuroectodermal tumors, pituitary tumor, somatostatin-se herein, or a pharmaceutically acceptable salt thereof, is used creting tumor, endodermal sinus tumor, carcinoids, central in the treatment of oral cancer, prostate cancer, rectal cancer, cerebral astrocytoma, glucagonoma, hepatic adenoma, insu non-Small cell lung cancer, lip and oral cavity cancer, liver linoma, medulloepithelioma, plasmacytoma, Vipoma, and cancer, lung cancer, anal cancer, kidney cancer, Vulvar pheochromocytoma. cancer, breast cancer, oropharyngeal cancer, nasal cavity and 0370. In some embodiments, the neoplasm comprises paranasal sinus cancer, nasopharyngeal cancer, urethra can intraepithelial neoplasia, multiple myeloma/plasma cell neo cer, Small intestine cancer, bile duct cancer, bladder cancer, plasm, plasma cell neoplasm, interepithelial squamous cell ovarian cancer, laryngeal cancer, hypopharyngeal cancer, neoplasia, endometrial hyperplasia, focal nodular hyperpla gallbladder cancer, colon cancer, colorectal cancer, head and sia, hemangioendothelioma, lymphangioleio myomatosis neck cancer, parathyroid cancer, penile cancer, vaginal can and malignant thymoma. US 2016/0361298 A1 Dec. 15, 2016

0371. In some embodiments, the lymphoma comprises kin I1 (including recombinant interleukin II, or rlL2), nervous system lymphoma, AIDS-related lymphoma, cuta interferon alfa-2a: interferon alfa-2b; interferon alfa-n1; neous T-cell lymphoma, non-Hodgkin’s lymphoma, mantle interferon alfa-n3; interferon beta-1a; interferon gamma-1 cell lymphoma, follicular lymphoma and Waldenstrom's b; iproplatin; irinotecan hydrochloride; ixabepilone; lan macroglobulinemia. reotide acetate; lapatinib; lenalidomide; letrozole; leuprolide 0372. In some embodiments, the melanoma comprises acetate; leucovorin calcium; leuprolide acetate; levamisole; acral lentiginous melanoma, Superficial spreading mela liposomal cytarabine; lometrexol Sodium, lomustine; losox noma, uveal melanoma, lentigo maligna melanomas, mela antrone hydrochloride; masoprocol; maytansine; mechlore noma, intraocular melanoma, adenocarcinoma nodular thamine hydrochloride; megestrol acetate; melengestrol melanoma, and hemangioma. acetate; melphalan; menogaril; mercaptopurine; methotrex 0373) In some embodiments, the sarcoma comprises ate; methotrexate sodium; methoXSalen; metoprine; meture adenomas, adenosarcoma, chondosarcoma, endometrial depa; mitindomide; mitocarcin, mitocromin, mitogillin; stromal sarcoma, Ewings sarcoma, Kaposi's sarcoma, leio mitomalcin, mitomycin C; mitosper, mitotane; mitoxantrone myosarcoma, rhabdomyosarcoma, sarcoma, uterine sar hydrochloride; mycophenolic acid; nandrolone phenpropi coma, osteosarcoma, and pseudosarcoma. onate; nelarabine; nilotinib. nocodaZoie; nofetumomab; 0374. In some embodiments, the glioma comprises nogalamycin; ofatumumab, oprelvekin, ormaplatin: Oxali glioma, brain stem glioma, and hypothalamic and visual platin:OXisuran; paclitaxel; palifermin; palonosetron hydro pathway glioma. chloride; pamidronate; pegfilgrastim; pemetrexed disodium; 0375. In some embodiments, the blastoma comprises pulmonary blastoma, pleuropulmonary blastoma, retino pentostatin: panitumumab; paZopanib hydrochloride; pem blastoma, neuroblastoma, medulloblastoma, glioblastoma, etrexed disodium; plerixafor, pralatrexate; pegaspargase; and hemangiblastomas. peliomycin; pentamustine; peplomycin Sulfate; perfoSf 0376. In various aspects of the subject matter provided amide; pipobroman; piposulfan, piroxantrone hydrochlo herein, a composition comprising a TDO/IDO inhibitor and ride; plicamycin; plomestane; pomalidomide, porfimer optionally one or more active agents, such as an IDO, PD-1 Sodium; porfiromycin; prednimustine; procarbazine hydro and/or CTLA-4 inhibitor, further comprises or is adminis chloride; puromycin; puromycin hydrochloride; pyrazofu tered in combination with an anti-cancer agent and/or anti rin, quinacrine; raloxifene hydrochloride; rasburicase; Cancer treatment. recombinant HPV bivalent vaccine; recombinant HPV qua 0377. In some embodiments, anti-cancer agents include drivalent vaccine; riboprine; rogletimide; rituximab, one or more of the following abiraterone; abarelix; abraxane, romidepsin; romiploStim; Safingol; Safingol hydrochloride; adriamycin; actinomycin; acivicin; aclarubicin; acodazole Sargramostim: Semustine; simtraZene; sipuleucel-T: hydrochloride; acronine; adoZelesin; aldesleukin; alemtu Sorafenib: sparfosate sodium; sparsomycin; spirogermanium Zumab; allopurinol; allitretinoin, altretamine; ametantrone hydrochloride; spiromustine; Spiroplatin; Streptonigrin: acetate; aminoglutethimide; aminolevulinic acid; ami streptozocin, Sulofenur, Sunitinib malate; talisomycin; fostine; amsacrine; anastroZole; anthramycin, aprepitant; tamoxifen citrate; tecogalan Sodium, tegafur, teloxantrone arsenic trioxide; asparaginase; asperlin; azacitidine; azetepa; hydrochloride; temozolomide; temoporfin, temsirolimus; aZotomycin; batimastat; bendamustine hydrochloride; ben teniposide; teroxirone; testolactone; thalidomide; thia Zodepa; bevacizumab; beXarotene; bicalutamide; bisantrene miprine; thioguanine; thiotepa; tiazofurin; tirapazamine; hydrochloride; bisnafide dimesylate; bizelesin: bleomycin; topotecan hydrochloride; toremifene; tositumomab and I' bleomycin sulfate; bortezomib; brequinar sodium; bropirim Iodine to situmomab, trastuzumab; trestolone acetate; ine; buSulfan; cactinomycin; calusterone; caracemide; car tretinoin; triciribine phosphate; trimetrexate; trimetrexate betimer, carboplatin: carmustine; carubicin hydrochloride; glucuronate; triptorelin; tubulozole hydrochloride: uracil carzelesin; capecitabine; cedefingol, cetuximab, chlorambu mustard; uredepa; valrubicin; vapreotide; verteporfin, Vin cil; cirolemycin; cisplatin: cladribine; clofarabine; crisinatol blastine; vinblastine sulfate; Vincristine sulfate; Vindesine; mesylate; cyclophosphamide; cytarabine; dacarbazine; vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; dasatinib, daunorubicin hydrochloride; dactinomycin; dar Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine sulfate; bepoetin alfa: decitabine; degarelix; denileukin diftitox: Vinzolidine Sulfate; Vorinostat; Vorozole; Zeniplatin: Zinos dexormaplatin; dexraZoxane hydrochloride; deZaguanine; tatin: Zoledronic acid; and Zorubicin hydrochloride. deZaguanine mesylate; diaziquone; docetaxel, doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; 0378. In some embodiments, a composition described dromostanolone propionate; duaZomycin, edatrexate; eflo herein is used in combination with an anti-emetic agent to rnithine hydrochloride; elsamitrucin; enloplatin; enpromate; treat nausea or emesis, which results from the use of the epipropidine; epirubicin hydrochloride: epoetin alfa, erbu composition, anti-cancer agent(s) and/or radiation therapy. lozole; erlotinib hydrochloride; esorubicin hydrochloride: 0379. In some embodiments, a composition described estramustine; estramustine phosphate Sodium; etanidazole; herein comprises or is administered with a NSAID. NSAIDs etoposide; etoposide phosphate: etoprine; everolimus; include, but are not limited to: aspirin, salicylic acid, gentisic exemestane: fadrozole hydrochloride; fazarabine; fenretin acid, choline magnesium salicylate, choline salicylate, cho ide; filgrastim; floxuridine; fludarabine phosphate; fluorou line magnesium salicylate, choline Salicylate, magnesium racil; flurocitabine; fosquidone; fostriecin Sodium; fulves salicylate, Sodium salicylate, diflunisal, carprofen, fenopro trant, gefitinib, gemcitabine; gemcitabine hydrochloride; fen, fenoprofen calcium, flurobiprofen, ibuprofen, ketopro gemcitabine-cisplatin; gemtuzumab ozogamicin; goserelin fen, nabutone, ketolorac, ketorolac tromethamine, naproxen, acetate; histrelin acetate; hydroxyurea; idarubicin hydro oxaprozin, diclofenac, etodolac, indomethacin, Sulindac, tol chloride; ifosfamide; iimofosine; ibritumomab tiuxetan; ida metin, meclofenamate, meclofenamate Sodium, mefenamic rubicin; ifosfamide; imatinib mesylate; imiquimod; interleu acid, piroxicam, meloxicam, and COX-2 specific inhibitors US 2016/0361298 A1 Dec. 15, 2016 72

(such as, but not limited to, celecoxib, rofecoxib, Valde and/or inhibition of CTLA-4; or in which PD-1, IDO, TDO, coxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE and/or CTLA-4 is a mediator or contributor to the symptoms 522, L-745,337 and NS398). O CalS. 0380. In some embodiments, a composition described 0387. The container(s) optionally have a sterile access herein is used in combination with radiation therapy. Radia port (for example the container is an intravenous Solution tion therapy is optionally used to treat localized solid bag or a vial having a stopper pierceable by a hypodermic tumors, such as cancers of the skin, tongue, larynx, brain, injection needle). Such kits optionally comprise a compo breast, prostate, colon, liver, uterus and/or cervix. It is also sition with an identifying description or label or instructions optionally used to treat leukemia and lymphoma (cancers of relating to its use in the methods described herein. the blood-forming cells and lymphatic system, respectively). 0388 A kit will typically include one or more additional containers, each with one or more of various materials (such Kits as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of 0381 Provided herein, in one aspect, are kits which a compound described herein. Non-limiting examples of include one or more reagents or devices for the performance such materials include, but not limited to, buffers, diluents, of the methods disclosed herein. In some embodiments, the filters, needles, Syringes, carrier, package, container, vial kit comprises a composition as described herein. In some and/or tube labels listing contents and/or instructions for embodiments, the kit comprises one, two or more active use, and package inserts with instructions for use. A set of agents. In some embodiments, the active agents are formu instructions will also typically be included. lated together. In other embodiments, the active agents are 0389. In some embodiments, a label is on or associated formulated separately. In some embodiments, the kit com with the container. A label can be on a container when prises a means to administrate a composition comprising one letters, numbers or other characters forming the label are or more active agents as described herein. In some embodi attached, molded or etched into the container itself a label ments, one or more of the compositions of a kit comprises can be associated with a container when it is present within one or more compounds of Table 1, Table 2, Table 3, a receptacle or carrier that also holds the container, e.g., as Formula (I). Formula (II), Formula (III), Formula (IV), a package insert. A label can be used to indicate that the Formula (V), Formula (VI), Formula (VII). Formula (VIII), contents are to be used for a specific therapeutic application. Formula (IX), or salts, solvates, or combinations thereof. The label can also indicate directions for use of the contents, 0382. In some embodiments, the kit comprises suitable such as in the methods described herein. instructions in order to perform the methods of the kit. The 0390. In certain embodiments, a pharmaceutical compo instructions may provide information of performing any of sition comprising a TDO/IDO inhibitor described herein and the methods disclosed herein, whether or not the methods optional additional active agent is presented in a pack or may be performed using only the reagents provided in the dispenser device which can contain one or more unit dosage kit. The kit and instructions may require additional reagents forms. The pack can for example contain metal or plastic or systems. foil. Such as ablister pack. The pack or dispenser device can 0383. In some embodiments, many reagents may be be accompanied by instructions for administration. The pack provided in a kit of the invention, only some of which should or dispenser can also be accompanied with a notice associ be used together in a particular reaction or procedure. ated with the container in form prescribed by a governmen 0384. In some embodiments, a kit provided herein tal agency regulating the manufacture, use, or sale of phar includes a carrier means being compartmentalized to receive maceuticals, which notice is reflective of approval by the in close confinement one or more containers such as vials, agency of the form of the drug for human or veterinary tubes, and the like, each of the containers comprising one of administration. Such notice, for example, can be the labeling the separate elements to be used in a method provided approved by the U.S. Food and Drug Administration for herein. prescription drugs, or the approved product insert. Compo 0385 For use in the therapeutic applications described sitions containing a compound provided herein formulated herein, kits and articles of manufacture are also described in a compatible pharmaceutical carrier can also be prepared, herein. In some embodiments, such kits include a carrier, placed in an appropriate container, and labeled for treatment package, or container that is compartmentalized to receive of an indicated condition. one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate EXAMPLES elements to be used in a method described herein. Suitable 0391 The following examples are set forth to illustrate containers include, for example, bottles, vials, Syringes, and more clearly the principle and practice of embodiments test tubes. The containers can be formed from a variety of disclosed herein to those skilled in the art and are not to be materials such as glass or plastic. construed as limiting the scope of any claimed embodi 0386 The articles of manufacture provided herein con tain packaging materials. Examples of pharmaceutical pack mentS. aging materials include, but are not limited to, blister packs, Example 1 bottles, tubes, inhalers, pumps, bags, vials, containers, Syringes, bottles, and any packaging material Suitable for a selected formulation and intended mode of administration Computational Assessment of IDO/TDO Inhibitors and treatment. A wide array of formulations of the com 0392 Potential IDO/TDO inhibitors were assessed using pounds and compositions provided herein are contemplated a computational ligand-based screen. The potential IDO/ as are a variety of treatments for any disorder that benefit by TDO inhibitors were compared for structural similarity to a inhibition of PD-1, inhibition of IDO, inhibition of TDO, database of known IDO and TDO inhibitors. Conforma US 2016/0361298 A1 Dec. 15, 2016 73 tional flexibility of the potential inhibitors was first evalu TABLE 4-continued ated, and representative conformers for each compound were generated. Subsequently, each conformer of each com Inhibition of TDO and IDO with TDO/IDO test compounds. pound was evaluated for structural and chemical similarity to each of the known inhibitors. After scoring, the potential TDO Inhibition Assay IDO Inhibition Assay IDO/TDO inhibitors in the top 1% of all potential IDO/TDO inhibitors screened were compiled into Table 1. Dose Dose Screening Resp. Screening Resp. Example 2 (Activity, %) (IC50, (Activity, %) (IC50, In Vitro Assay for TDO/IDO Inhibition 0393. Inhibition of IDO by TDO/IDO test inhibitors was Common Name 10 IM 1 M nM) 10 IM 1 M nM) assessed in vitro. A Substrate mixture was prepared by Sertaconazole 15 74 4070 37 63 82SO mixing equal volumes of 80 mMascorbic acid diluted in Econazole 2O 8O 5350 28 71 4910 0.405 M Tris, pH 8.0 and a mixture of 800 uL L-tryptophan, Sulconazole 17 72 3510 11 36 740 9,000 units/mL catalase and 40 uM methyene blue. Recom Miconazole 16 74 3700 27 67 4690 binant TDO or IDO was diluted to 16 ng/ul, and 50 ul Isoconazole 17 58 412O 53 76 1461 O loaded into wells of a 96-well plate. The reaction was started Itraconazole 82 93 4.6960 56 72 1742O by the addition of 50 uI substrate mixture. The plate was Nicosamide 62 82 75 84 read in kinetic mode at 321 nm for 5 minutes. The rate of Deferasirox 69 107 85 90 increase of absorbance measured in the absence of a TDO/ Fenticonazole -34 89 2731 56 85 IDO inhibitor is taken as the maximum rate of enzymatic Cloconazole 5 532 76 activity. Active TDO/IDO inhibitors decrease the rate of Eltrombopag 5 1047 83 increased absorbance over time, indicating a reduced rate of conversion of tryptophan to N-formyl-kynurenine in a dose dependent manner. Table 4 shows the inhibition of TDO and Example 3 IDO with various TDO/IDO test compounds.

TABLE 4 In Vitro Assay for Cancer Cell Cytotoxicity Inhibition of TDO and IDO with TDOIDO test compounds. 0394 TDO/IDO test compounds were incubated with TDO Inhibition Assay IDO Inhibition Assay various cancer cell lines to determine the effect of the test compounds on cancer cell death. The CelTiter-Glo Lumi Dose Dose Screening Resp. Screening Resp. nescent Cell Viability Assay was used to determine cell Activity, 90 (IC50, Activity. 90 (IC50, cytotoxicity by determining the number of viable cells in culture based on quantitation of ATP, which signals the Common Name 10 IM 1 M nM) 10 IM 1 M nM) presence of metabolically active cells. INCBO24360 and Tioconazole 28 83 416O 47 76 9330 Cisplatin were used as control anti-cancer agents. The ICso Liarozole 43 89 9330 88 99 63390 values corresponding to each test compound and cell line are shown in Table 5. TABLE 5 Cancer cell cytotoxicity with TDO/IDO test compounds. IC50 (LIM Cell line Tioconazole Sulconazole Coconazole Fenticonzole Isoconazole Sertaconazole INCB024360 Cisplatin HT78 12.14 9.37 1943 9.16 15.69 17.69 72.55 4...SO (human CTCL cell line) U87MG 26.14 13.56 26.67 1564 63.92 13.89 NA 8.95 (human glioblastoma) SCC4 28.20 109.39 46.23 78.78 83.83 NA NA 18.95 (human Squamous cell carcinoma) HT29 (human 18.15 8.74 10.68 13.93 14.82 11.91 53.70 23.16 colorectal adenocarcinoma) CT26 14.04 NA 8.06 7.60 14.78 10.94 69.92 4.11 (murine colon) Pano2 22.15 9.35 9.61 16.07 12.61 16.10 53.52 6.40 (murine pancreatic) US 2016/0361298 A1 Dec. 15, 2016 74

TABLE 5-continued Cancer cell cytotoxicity with TDO/IDO test compounds. IC50 (LIM Cell line Tioconazole Sulconazole Coconazole Fenticonzole Isoconazole Sertaconazole INCB024360 Cisplatin GL261 26.99 61.77 20.30 15.25 15.56 30.12 48.87 9.09 (murine glioma)

Example 4 markers CD69+ and CD71+, and (3) CD8 cell survival and activation, by looking at the expression of activation mark In Vitro Assay for IDO Inhibition Via Cell Based ers CD69+ and CD71+. Enzymatic Assay 0397 CT26 Cell Death 0395. Inhibition of IDO by a TDO/IDO inhibitor 0398 CT26 cell line was maintained in culture as per described herein is assessed in vitro by a cell based assay. standard cell culture procedures. Single cell Suspension of HeLa cells are routinely maintained in minimum essential splenocytes were Balb/c (H2d) mice were prepared; RBCs media with supplements. HeLa cells are seeded in a 96-well were lysed using distilled water and 10xPBS and resus plate at a density of 5x10 and grown overnight. On the pended in complete RPMI medium supplemented with fetal following day, human IFNy at 50 ng/mL final concentration bovine serum, Supplements and 2-mercaptoethanol. CT26 and serial dilutions of TDO/IDO inhibitor in a total volume cells were harvested using Trypsin/EDTA, first treated with of 200 uL culture medium per well are added to the cells. 50 mg/ml Mitomycin C for 20 min at 37°C., washed 3 times The plates are incubated for 48 hours and then 140 uL of in complete medium and then stained with 1 mg/ml of CFSE supernatant per well is transferred to a new 96-well plate. To for one hour at 37° C. TDO/IDO test compounds (tiocon hydrolyze N-formyl-kynurenine produced by IDO to azole, niclosamide, eltrombopag, deferasirox, Sulconazole, kynurenine, 10 uI of 6.1 NTCA is mixed into each well with cloconazole, miconazole) were added to final concentrations incubation at 50° C. for 30 min The reaction mixture is of 0, 0.1, 1.0, 10.0, 25.0 and 50.0 mM in triplicates in 96 centrifuged to remove sediments. Supernatant from each well round-bottom plates. 1-methyl tryptophan (1MT) was well are transferred to a clean 96-well plate and mixed with used as a control compound. Effector and target cells were equal volumes of 2% (w/v) p-dimethylaminobenzaldehyde seeded at a 50:1 E:T ratio. Plates were incubated for 96 hat in acetic acid. Absorbance from kynurenine is measured at 37° C. 1 ml of PI (400 mg/ml) was added to each of the wells 480 nm. L-Kynurenine is used as a standard and is prepared and transferred to FACS tubes. Samples were analyzed by in a series of concentrations (240, 120, 60, 30, 15, 7.5, FACS on BDFACScan. The frequencies of non-viable target 3.75, 1.87 uM) in HeLa cell culture media and analyzed in cells (CFSE+PI+) and viable target cells (CFSE+PI-) cells the same procedure. The percent inhibition at individual were measured and cell killing reported as the frequency of concentrations is determined The data is processed using viable target cells as percentage of total target cell, as shown nonlinear regression to generate IC50 values. The rate of in FIG. 1, panel A and panel B. increase of absorbance measured in the absence of a TDO/ 0399 Effector Cell Activation IDO inhibitor is taken as the maximum rate of enzymatic activity. Active inhibitors decrease the rate of increased 04.00 CT26 cell line was maintained in culture as per absorbance over time in a dose-dependent manner, indicat standard cell culture procedures. Single cell Suspension of ing a reduced rate of conversion of tryptophan to N-formyl splenocytes were Balb/c (H2d) mice were prepared; RBCs kynurenine. were lysed using distilled water and 10xPBS and resus pended in complete RPMI medium supplemented with fetal bovine serum, Supplements and 2-mercaptoethanol. CT26 Example 5 cells were harvested using Trypsin/EDTA, treated with 50 mg/ml Mitomycin C for 20 min at 37° C., washed 3 times Murine Colon Cancer In Vitro Assay in complete medium and added to effector cells. TDO/IDO test compounds (tioconazole, niclosamide, eltrombopag, 0396 TDO/IDO inhibitor test compounds were tested in deferasirox, Sulconazole, cloconazole, miconazole) were co-culture experiments in which CT26 murine colon cancer added to final concentrations of 0, 0.1, 1.0, 10.0, 25.0 and cells and murine immune cells were seeded together. The 50.0 mM in triplicates in 96 well round-bottom plates. experimental conditions were selected to reflect the tumor 1-methyl tryptophan was used as a control compound. microenvironment, in which cancer cells and immune cells Effector and target cells were seeded at a 50:1 E:T ratio. exist in dynamic interaction. Because immune cell Suppres Plates were incubated for 96 hrs at 37° C. Cells were sion by cancer cells can act through the TDO/IDO pathway, harvested into FACS tubes, stained with markers (CD71, the experiment was designed to determine if TDO/IDO test CD69, CD4, CD8) and analyzed by FACS on BDFACScan compounds could reverse the immune Suppression, encour using CellOuest Analysis Software. Data are represented as age cancer cell killing, either directly or indirectly, and % of Live cells (based on FSC/SCC gating) for effector cell activate immune cells. The following compound effects (CD4, CD8) distribution. Live CD4/CD8 cells were ana were assessed: (1) cancer cell killing, (2) CD4 cell survival lyzed for activation marker (CD69, CD expression), as and activation, by looking at the expression of activation shown in panels A and B of FIGS. 2-7. US 2016/0361298 A1 Dec. 15, 2016 75

Example 6 thereof, is dissolved in sterile water. Optionally, a sterile saline, a taste masking excipient, and/or a buffer is added to Mouse Tumor Model to Evaluate In Vivo Activity the composition. of IDO Inhibitors 0408. To prepare a composition comprising an IDO inhibitor and a TDO/IDO inhibitor suitable for administra 04.01. In vivo activity of TDO/IDO inhibitors described tion by injection or oral administration, 1 mg to 5,000 mg of herein is assessed via a mouse tumor model. an IDO inhibitor, or a pharmaceutically acceptable salt or 0402. Eight week old female C57BL/6 mice are inocu solvate thereof, and 1 mg to 5,000 mg of a TDO/IDO lated subcutaneously with 1x10 B16-GMCSF tumor cells. inhibitor, or a pharmaceutically acceptable salt or Solvate Tumor sizes are measured twice weekly in two dimensions thereof, is dissolved in sterile water. Optionally, a sterile using a caliper, and the Volume presented in mm using the saline, a taste masking excipient, and/or a buffer is added to formula: V=0.5(AxB2), where A and B are the long and the composition. short diameters of the tumor, respectively. Tumor bearing 04.09 To prepare a composition comprising an TDO animals are sorted into groups with mean tumor Volumes of inhibitor and a TDO/IDO inhibitor suitable for administra 110-125 mm. Each day of the study, TDO/IDO inhibitors tion by injection or oral administration, 1 mg to 5,000 mg of are reconstituted in 5% DMA, 47.5% propylene glycol. a TDO inhibitor, or a pharmaceutically acceptable salt or Body weights are monitored throughout the study as a gross solvate thereof, and 1 mg to 5,000 mg of a TDO/IDO measure of toxicity and morbidity. Tumor growth control, inhibitor, or a pharmaceutically acceptable salt or Solvate expressed in %, is calculated using the formula: 1-(treated thereof, is dissolved in sterile water. Optionally, a sterile (day X)-treated (day Y))/(vehicle (day X)-vehicle (day Y). saline, a taste masking excipient, and/or a buffer is added to where X is the day of last or interim measurement and Y is the composition. the day when dosing commenced. 0403. The average size of tumors in mice untreated with Example 8 TDO/IDO inhibitors is a positive control. Active IDO inhibi tors lead to a decrease in tumor size as compared to the Pharmaceutical Oral Dosage positive control. 0410. A tablet is prepared by mixing 1 mg to 5 g of a Example 7 TDO/IDO inhibitor, or a pharmaceutically acceptable salt or solvate thereof, with starch or other suitable powder blend. Pharmaceutical Liquid Compositions The mixture is incorporated into an oral dosage unit suitable for oral administration. The TDO/IDO inhibitors formulated 04.04 To prepare a TDO/IDO inhibitor composition suit in tablet compositions using the methods of this example are able for administration by injection or oral administration, 1 listed in Table 1. mg to 5,000 mg of a TDO/IDO inhibitor, or a pharmaceu 0411 A tablet is prepared by mixing 1 mg to 5g of a first tically acceptable salt or solvate thereof, is dissolved in TDO/IDO inhibitor, or a pharmaceutically acceptable salt or sterile water. Optionally, a sterile Saline, a taste masking solvate thereof, and 1 mg to 5 g of a second TDO/IDO excipient, and/or a buffer is added to the composition. The inhibitor, or a pharmaceutically acceptable salt or Solvate TDO/IDO inhibitors formulated in liquid compositions thereof, with starch or other suitable powder blend. The using the methods of this example are listed in Table 1. mixture is incorporated into an oral dosage unit Suitable for 04.05 To prepare a composition comprising two TDO/ oral administration. The TDO/IDO inhibitors formulated in IDO inhibitors for administration by injection or oral admin tablet compositions using the methods of this example are istration, 1 mg to 5,000 mg of a first a TDO/IDO inhibitor, listed in Table 1. or a pharmaceutically acceptable salt or Solvate thereof, and 0412. A tablet is prepared by mixing 1 mg to 5 g of a 1 mg to 5,000 mg of a second a TDO/IDO inhibitor, or a PD-1 inhibitor, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt or Solvate thereof, is dis solvate thereof, and 1 mg to 5g of a TDO/IDO inhibitor, or solved in sterile water. Optionally, a sterile saline, a taste a pharmaceutically acceptable salt or solvate thereof, with masking excipient, and/or a buffer is added to the compo starch or other suitable powder blend. The mixture is incor sition. The TDO/IDO inhibitors formulated in liquid com porated into an oral dosage unit Suitable for oral adminis positions using the methods of this example are listed in tration. Table 1. 0413 A tablet is prepared by mixing 1 mg to 5 g of a 0406 To prepare a composition comprising a PD-1 TDO/IDO inhibitor, or a pharmaceutically acceptable salt or inhibitor and a TDO/IDO inhibitor suitable for administra solvate thereof, and 1 mg to 5g of a CTLA-4 inhibitor, or tion by injection or oral administration, 1 mg to 5,000 mg of a pharmaceutically acceptable salt or solvate thereof, with a PD-1 inhibitor, or a pharmaceutically acceptable salt or starch or other suitable powder blend. The mixture is incor solvate thereof, and 1 mg to 5,000 mg of a TDO/IDO porated into an oral dosage unit Suitable for oral adminis inhibitor, or a pharmaceutically acceptable salt or Solvate tration. thereof, is dissolved in sterile water. Optionally, a sterile 0414. A tablet is prepared by mixing 1 mg to 5 g of an saline, a taste masking excipient, and/or a buffer is added to IDO inhibitor, or a pharmaceutically acceptable salt or the composition. solvate thereof, and 1 mg to 5g of a TDO/IDO inhibitor, or 04.07 To prepare a composition comprising a TDO/IDO a pharmaceutically acceptable salt or solvate thereof, with inhibitor and a CTLA-4 inhibitor suitable for administration starch or other suitable powder blend. The mixture is incor by injection or oral administration, 1 mg to 5,000 mg of a porated into an oral dosage unit Suitable for oral adminis TDO/IDO inhibitor, or a pharmaceutically acceptable salt or tration. solvate thereof, and 1 mg to 5,000 mg of a CTLA-4 0415. A tablet is prepared by mixing 1 mg to 5 g of a inhibitor, or a pharmaceutically acceptable salt or Solvate TDO inhibitor, or a pharmaceutically acceptable salt or US 2016/0361298 A1 Dec. 15, 2016 76 solvate thereof, and 1 mg to 5g of a TDO/IDO inhibitor, or 0424 Intervention a pharmaceutically acceptable salt or solvate thereof, with 0425 Arm 1: Chemotherapy and placebo starch or other suitable powder blend. The mixture is incor 0426 Arm 2: Chemotherapy and a TDO/IDO inhibitor (5 porated into an oral dosage unit Suitable for oral adminis to 500 mg) tration. 0427 Detailed Description: Patients are given a TDO/ IDO inhibitor in combination with chemotherapy. Prior to Example 9 each dosing cycle, a physical exam, blood work and assess ment of any side effects are performed. Chemotherapy includes docetaxel, paclitaxel, cisplatin, carboplatin, Vinore Clinical Study of TDO/IDO Inhibitor for Subjects 1bine, capecitabine, liposomal doxorubicin, gemcitabine, with Relapsed or Refractory Solid Tumors mitoxantrone, ixabepilone, nab-paclitaxel and eribulin. 0416 Purpose: The purposes of this study are to assess TDO/IDO inhibitors are selected from econazole, sulcon the efficacy of a TDO/IDO inhibitor as a single agent or in azole, isoconazole, miconazole, Sertaconazole, tioconazole, combination, in the treatment of patients with breast cancer, fenticonazole, liarozole, cloconazole, itraconazole, niclos lung cancer, melanoma, pancreatic cancer, Solid tumor, amide, deferasiroX, and eltrombopag. collect information on any side effects a TDO/IDO inhibitor 0428 Eligibility and Inclusion Criteria: Male and female may cause as single agent or in combination, and evaluate subjects that are 18 to 80 years old that have been histo the pharmacokinetic properties of the compound as single pathologically or clinically diagnosed with metastatic breast agent or in combination. cancer, metastatic disease evaluable on imaging; measure 0417 Intervention: Patients are administered 5 mg to 500 able disease having at least one lesion that can be accurately mg of a TDO/IDO inhibitor as a single agent or in combi measured; and Eastern Cooperative Oncology Group per nation in escalating doses. TDO/IDO inhibitors are selected formance statussl. from econazole, Sulconazole, isoconazole, miconazole, sert 0429 Exclusion Criteria: Patients with a psychiatric dis aconazole, tioconazole, fenticonazole, liaroZole, clocon order that might cause difficulty in obtaining informed azole, itraconazole, niclosamide, deferasiroX, and eltrom consent or in conducting the trial; pregnant or nursing: bopag. fertile patients must use effective contraception during study treatment; no other non-malignant systemic disease that 0418 Detailed Description: Patients are given a TDO/ would preclude drug administration or prolonged follow-up; IDO inhibitor as a single agent or in a combination. Prior to patients who have had chemotherapy for the treatment of each dosing cycle, a physical exam, blood work and assess metastatic breast cancer; patients currently receiving other ment of any side effects are performed. A combination investigational agents; and patients with active autoimmune includes a TDO/IDO inhibitor combined with PD-1 inhibitor disease or condition requiring concurrent use of immuno pidilizumab, IDO inhibitor indoximod, or CTLA-4 inhibitor Suppressants. ipilimumab. 0430 Primary Outcome Measures: Progression free sur 0419 Eligibility and Inclusion Criteria: Male and female vival; frequency and grade of adverse events of a TDO/IDO subjects that are 18 to 80 years old that have been histo inhibitor and chemotherapy versus chemotherapy with pla pathologically or clinically diagnosed with recurrent or cebo, refractory solid tumor malignancy. 0431 Secondary Outcome Measures: Safety and toler 0420 Exclusion Criteria: Patients with a psychiatric dis ability by adverse event assessment; objective response rate order that might cause difficulty in obtaining informed as measured by RECIST 1.1 of a TDO/IDO inhibitor and consent or in conducting the trial; pregnant or nursing: chemotherapy versus chemotherapy with placebo. fertile patients must use effective contraception during study treatment; no other non-malignant systemic disease that Example 11 would preclude drug administration or prolonged follow-up. Clinical Study of a TDO/IDO Inhibitor in 0421 Primary Outcome Measures: Determine the safety Combination with Ipilimumab for Subjects with and efficacy of administration of a single agent or combi Metastatic Melanoma nation; establish toxicities; and define any dose limiting 0432 Purpose: The purposes of this study are to assess toxicities. the efficacy of a TDO/IDO inhibitor in combination with 0422 Secondary Outcome Measures: Safety and toler ipilimumab in the treatment of patients with metastatic ability by adverse event assessment; duration of overall melanoma as compared to ipilimumab alone, collect infor Survival, tumor biomarkers. mation on any side effects a TDO/IDO inhibitor may cause in combination, and evaluate the pharmacokinetic properties Example 10 of the compound in combination. 0433 Intervention Clinical Study of a TDO/IDO Inhibitor in 0434 Arm 1: Ipilimumab is administered intravenously Combination with Chemotherapy for Subjects with at 3 mg/kg once per 21 day cycle; 4 cycles. Metastatic Breast Cancer 0435 Arm 2: Ipilimumab is administered intravenously at 3 mg/kg once per 21 day cycle: 5-500 mg of a TDO/IDO 0423 Purpose: The purposes of this study are to assess inhibitor is administered daily on each day of the cycles; 4 the efficacy of a TDO/IDO inhibitor in combination with cycles; the dose is escalated depending on patient response. chemotherapy in the treatment of patients with breast cancer 0436 Detailed Description: Patients are given a TDO/ as compared to standard care therapy (chemotherapy alone), IDO inhibitor in combination with ipilimumab at recom collect information on any side effects a TDO/IDO inhibitor mended approved dose for treatment of metastatic mela may cause in combination, and evaluate the pharmacoki noma. Patients are evaluated clinically and radiographically netic properties of the compound in combination. throughout treatment for tumor evaluation. TDO/IDO US 2016/0361298 A1 Dec. 15, 2016 77 inhibitors are selected from econazole, Sulconazole, isocon 12. The method of claim 1, provided that the cancer azole, miconazole, Sertaconazole, tioconazole, fenticon comprises colon cancer, pancreatic cancer, cutaneous T-cell azole, liarozole, cloconazole, itraconazole, niclosamide, lymphoma, glioma, head and neck cancer, hepatocarcinoma, deferasiroX, and eltrombopag. leukemia, glioblastoma, colorectal cancer, gallbladder, mas 0437. Eligibility and Inclusion Criteria: Male and female tocytoma, acute myeloid leukemia, adrenocortical cancer, subjects that are 18 years and older that have been diagnosed bladder urothelial cancer, brain tumor, brain lower grade with metastatic melanoma; measureable disease having at glioma, breast cancer, breast invasive cancer, cervical can least one lesion that can be accurately measured; and Eastern cer, cholangiocarcinoma, cutaneous melanoma, diffuse large Cooperative Oncology Group performance statuss2. B-cell lymphoma, endometrial cancer, glioblastoma multi 0438 Exclusion Criteria: Patients with a psychiatric dis form, H&N squamous cell carcinoma, hepatocellular carci order that might cause difficulty in obtaining informed noma, kidney chromophobe carcinoma, lung cancer, lung consent or in conducting the trial; pregnant or nursing: adenocarcinoma, lung squamous cell carcinoma, mesothe fertile patients must use effective contraception during study lioma, ovarian serous cystadenocarcinoma, pancreatic treatment; no other non-malignant systemic disease that adenocarcinoma, pheochromocytoma and paraganglioma, would preclude drug administration or prolonged follow-up; prostate adenocarcinoma, prostate cancer, rectum adenocar patients currently receiving other investigational agents; cinoma, rectum cancer, renal cell cancer, renal papillary cell patients with previous therapy with CTLA-4 inhibitors: cancer, sarcoma, testicular germ cell tumors, thymoma, patients with previous therapy with IDO inhibitors; patients thyroid cancer, uterine carcinosarcoma, melanoma, uveal with previous therapy with TDO inhibitors; and patients melanoma, or a combination thereof. with active autoimmune disease or condition requiring con 13. The method of claim 1, provided that the effective current use of immunosuppressants. amount is from about 5 mg to about 5,000 mg. 0439 Primary Outcome Measures: Median progression 14. The method of claim 1, provided that the individual is free survival (PFS); overall incidence of adverse events as a administered an additional active agent comprising a PD-1/ measure of safety and tolerability. PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, 0440 Secondary Outcome Measures: Overall survival; CTLA-4 inhibitor, or a combination thereof; or provided that number of participants with adverse events. the individual is administered an additional active agent as What is claimed is: part of an immunotherapy, CART-cell therapy, stem cell 1. A method of treating cancer comprising administering therapy, or a combination thereof. to an individual in need thereof an effective amount of 15. A method of inhibiting tryptophan 2,3-dioxygenase econazole, Sulconazole, isoconazole, miconazole, Sertacon (TDO), indoleamine 2,3-dioxygenase (IDO), or both TDO azole, tioconazole, fenticonazole, liarozole, cloconazole, and IDO in an individual in need thereof, the method itraconazole, niclosamide, deferasiroX, eltrombopag, or a comprising administering to the individual an effective pharmaceutically acceptable salt, Solvate, or combination amount of an antifungal agent, thrombopoietin (TPO) thereof. receptor agonist, or a combination thereof. 2. The method of claim 1, provided that econazole or a 16. The method of claim 15, provided that the antifungal pharmaceutically acceptable salt or Solvate of econazole is agent comprises tioconazole, liarozole, Sertaconazole, econ administered to the individual. azole, Sulconazole, miconazole, isoconazole, itraconazole, 3. The method of claim 1, provided that sulconazole or a fenticonazole, cloconazole; or a pharmaceutically accept pharmaceutically acceptable salt or Solvate of Sulconazole is able salt, solvate or combination thereof. administered to the individual. 17. The method of claim 15, provided that the TPO 4. The method of claim 1, provided that isoconazole or a receptor agonist comprises eltrombopag or a pharmaceuti pharmaceutically acceptable salt or Solvate of isoconazole is cally acceptable salt or Solvate of eltrombopag. administered to the individual. 18. The method of claim 15, provided that the individual 5. The method of claim 1, provided that miconazole or a has colon cancer, pancreatic cancer, cutaneous T-cell lym pharmaceutically acceptable salt or Solvate of miconazole is phoma, glioma, head and neck cancer, hepatocarcinoma, administered to the individual. leukemia, glioblastoma, colorectal cancer, gallbladder, mas 6. The method of claim 1, provided that sertaconazole or tocytoma, acute myeloid leukemia, adrenocortical cancer, a pharmaceutically acceptable salt or Solvate of Sertacon bladder urothelial cancer, brain tumor, brain lower grade azole is administered to the individual. glioma, breast cancer, breast invasive cancer, cervical can 7. The method of claim 1, provided that tioconazole or a cer, cholangiocarcinoma, cutaneous melanoma, diffuse large pharmaceutically acceptable salt or Solvate oftioconazole is B-cell lymphoma, endometrial cancer, glioblastoma multi administered to the individual. form, H&N squamous cell carcinoma, hepatocellular carci 8. The method of claim 1, provided that fenticonazole or noma, kidney chromophobe carcinoma, lung cancer, lung a pharmaceutically acceptable Salt or Solvate of fenticon adenocarcinoma, lung squamous cell carcinoma, mesothe azole is administered to the individual. lioma, ovarian serous cystadenocarcinoma, pancreatic 9. The method of claim 1, provided that liarozole or a adenocarcinoma, pheochromocytoma and paraganglioma, pharmaceutically acceptable salt or Solvate of liaroZole is prostate adenocarcinoma, prostate cancer, rectum adenocar administered to the individual. cinoma, rectum cancer, renal cell cancer, renal papillary cell 10. The method of claim 1, provided that cloconazole or cancer, sarcoma, testicular germ cell tumors, thymoma, a pharmaceutically acceptable salt or Solvate of cloconazole thyroid cancer, uterine carcinosarcoma, melanoma, uveal is administered to the individual. melanoma, or a combination thereof. 11. The method of claim 1, provided that eltrombopag or 19. A composition comprising: (a) an antifungal agent, a pharmaceutically acceptable salt or Solvate of eltrombopag thrombopoietin (TPO) receptor agonist, or a combination is administered to the individual. thereof, and (b) an anti-cancer agent. US 2016/0361298 A1 Dec. 15, 2016 78

20. The composition of claim 19, provided that the anti-cancer agent comprises a PD-1/PD-L pathway inhibitor, IDO inhibitor, TDO inhibitor, CTLA-4 inhibitor, an immu notherapy agent, a stem cell therapy agent, a CART-cell agent, or a combination thereof. k k k k k