CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Application Ser. No. 62/574,583, filed October 19, 2017, the content of which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] Indolamine 2,3 -di oxygenase (IDO; also referred to as IDOl) plays a critical role in the regulation of natural-, or self-, tolerance and control of inflammation. See, e.g, Munn, et al. (1998) Science 281: 1191-1193 and Ravi shankar, et al. (2015) Proc Natl Acad Sci USA 112: 10774-10779. IDO is linked to cancer pathologies where high IDO expression correlates with poor prognosis. IDO, a heme-containing monomelic oxidoreductase is the rate-limiting enzyme in tryptophan catabolism, catalyzing the degradation of tryptophan (trp) to N-formyl- kynurenine. IDO is a 41kD monomer and has high homology on the amino acid level between species: for example, human IDOl has 62% homology with rat and 58% with mouse. A lesser studied homolog, indolamine 2,3-dioxygenase-2 (ID02) shares 43% homology with EDO, but might be less effective in converting trp to N-formyl kynurenine. See, e.g., Hunt, et al. (2009) Int J Biochem Cell Biol 41: 467-471, Lob, et al. (2009) Cancer Immunol Immunother 58: 153- 157, and Lob, et al. (2008) Blood 111: 2152-2154.

[0003] Overall IDO exerts an immune-inhibitory function. Specifically, IDO regulates immune responses by acting on both the dendritic cell (DC) as well as the T-cell axis. Expression of IDO in DCs can lead to immune suppression as well as allograft tolerance. See, e.g., Mellor, et al. (2003) J Immunol 111: 1652-1655, and Lan, et al. (2010) Transplantation 90: 1286-1293. T- cells do not express IDO, but both the depletion of tryptophan, as well as the accumulation of the bioactive tryptophan metabolite kynurenine, exert inhibitory effects on T-cells. Local depletion of tryptophan by IDO also activates the stress response kinase GCN2, which in T-cells leads to inhibition of T-cell proliferation and directing their development towards regulatory T- cells (T-reg). See, e.g., Munn, et al. (2005) Immunity 22: 633-642 and Fallanno, et al. (2006) J Immunol 176: 6752-6761. In addition, the metabolite kynurenine binds to the aryl hydrocarbon receptor (AhR) and can thus promote the differentiation of T-regs.

[0004] T-regs are a subpopulation of T-cells that modulate the immune system, maintain tolerance to self-antigens, and thus prevent autoimmune disease. T-regs exert a general immunosuppressive effect, and suppress or downregulate the induction and proliferation of effector T-cells. See, e.g., Mezrich, et al. (2010) J Immunol 185: 3190-3198. IDO expression acts as a prognostic marker in several cancer types, including melanoma ( See Speeckaert, et al. (2012) Eur Cancer 48: 2004-2011), serous ovarian cancer (Okamoto, et al. (2005) Clin Cancer Res 11: 6030-6039), high grade osteosarcoma (Urakawa , et al. (2009) Clin Exp

Metastasis 26: 1005-1012), endometrial cancer (Ino, et al. (2006) Br J Cancer 95: 1555-1561), acute monocytic leukemia (Yang, et al. (2007) J Exp Hematol 15: 478-82), acute lymphocytic leukemia {see Yang 2007), acute myeloid leukemia (Fuchs, et al. (2005) Cancer Lett 223:323- 9), T-cell leukemia/lymphoma (Parmentier, et al. (2003) Nat Med 9: 1269-74), breast cancer (Hu, et al. (2007) Clin Cancer Res 13:4016-25 and Parmentier 2003), gastric cancer {see Parmentier 2003), glioblastoma {see Parmentier 2003), head and neck cancers {see Parmentier 2003), non-small cell lung cancer (NSCLC) {see Parmentier 2003), small cell lung cancer {see Parmentier 2003), mesothelioma {see Parmentier 2003), pancreatic cancer {see Parmentier 2003), and colorectal cancer (Brandacher, et al. (2006) Clin Cancer Res 12: 1144-1 151), where higher IDO expression correlated with poor clinical outcome (Ferdinande, et al. (2012) Br J Cancer 106: 141-147). For example, IDO expression in sentinel lymph nodes in melanoma patients is inversely correlated with progression-free survival and patients with high IDO expression showed a higher frequency of T-regs in the sentinel lymph node. See Speeckaert 2012. As T-regs are involved in immune recognition of self-antigens, T-reg expression in cancer cells may suppress tumor immunity, thus impairing the body' s innate ability to detect and destroy cancer cells.

[0005] Indeed, immune cells can recognize and kill tumor cells and approaches to boost the immune system have shown very promising results in recent years. Yet, many challenges remain where tumors avoid immune recognition or actively develop tolerance through factors like IDO. Infiltration of effector T-cells into tumors generally correlate with an increased anti-tumor immune response and tumor regression. However, those very same CD8+ T cells that kill tumor cells can also upregulate IDO in tumor cells as well as in DCs. As a result, immune response against tumors is inhibited or lessened. For instance, IDO has been found upregulated in the tumor microenvironment as a consequence of the presence of CD8+ T cells. See Spranger, et al. (2013) Sci Transl Med 5: 200-116. IDO-positive DCs have been detected in tumor draining lymph nodes (Munn, et al. (2004) J Clin Invest 114: 280-290) and have been linked to the activation of resting T-reg. See Sharma, et al. (2007) J Clin Invest 111: 2570-2582.

Furthermore, IDO expression is upregulated in response to some types of therapy acting as a negative feedback to block the immune response. For example IDO has been found upregulated in some melanoma patients in response to immunotherapy targeting CTLA-4. When EDO knockout mice were treated with anti-CTLA-4 antibody, a strong synergy in the anti-tumor response between the mechanisms was noted. See Allison, et al. (2013) J Exp Med 210: 1389- 1402. With the increased expression of IDO in both the tumor and the DCs in the tumor draining lymph nodes, IDO appears to play a maj or role in regulating the anti -tumor immune response. By promoting the development and activation of T-regs and inhibiting T effector cell function IDO expression enhances tolerance to tumor antigens.

[0006] Pharmacological inhibition of IDO with 1 -methyl -tryptophan (1-MT) increases T-cell dependent tumor immune responses in mouse models and can enhance the immune response to cancer vaccines. See Hou, et al. (2007) Cancer Res 67: 792-801, Friberg, et al. (2002) Int J Cancer 101: 151-155, Uyttenhove, et al. (2003) Nat Med 9: 1269-1274, and Ou, et al. (2008) J Cancer Res Clin Oncol 134: 525-533; see also, PCT Publication Nos. WO2016/073774, WO2015173764, and WO2017048612. Thus, small molecule inhibitors of IDO will be very valuable as cancer treatments. In addition they can be used to strengthen the immune response in individuals with a weakened immune system, or to boost vaccine efficacy.

SUMMARY

[0007] This application provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, compositions comprising compounds of Formula (I), or pharmaceutically acceptable salts thereof and methods of making and using compounds of Formula (I), or pharmaceutically acceptable salts thereof. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used for treating certain diseases, disorders, and conditions, either as mono-therapies or as components of combination therapies. For example, with respect to the treatment of cancer, compounds for Formula (I), or pharmaceutically acceptable salts thereof, may be used alone, or in combination with other standard of care cancer therapies, including radiation, chemotherapy, cancer vaccines, and checkpoint inhibitors. IDO inhibitors such as compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be beneficial in individuals with weakened immune responses as in the case of HIV-1 infected individuals. Furthermore, IDO antagonists may be applied to boost existing or novel vaccines against infectious disease in individuals that typically lack a sufficient immune responses to vaccines, for example, the very young or the elderly.

[0008] Some embodiments provide a compound of Formula (I):

or a pharmaceutically acceptable, solvate, or solvate of the salt thereof.

[0009] In some embodiments, Ar ¹ is selected from the group consisting of: phenyl, naphthyl and pyridinyl.

[0010] In some embodiments, HAr is a 5- or 6-membered heteroaryl. [0011] In some embodiments, X is a bond or C(R ^a )(R ^b ).

[0012] In some embodiments, R ^la and R ^l are independently selected from the group consisting of: H, Ci _-4 alkyl, C3. cycloalkyl optionally substituted with one or two halogen atoms, and heterocyclyl. In some embodiments, R ^la and R ^l together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-R ^c , wherein said ring is optionally substituted with one or two groups independently selected from halogen, hydroxy and oxo; or wherein said ring is optionally spirofused to a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclyl.

[0013] In some embodiments, R ^c is selected from the group consisting of: H,

C(0)Ci. ₄ alkyl, and S0 ₂ -Ci _-4 alkyl.

[0014] In some embodiments, R ^2a and R ² are each independently selected from hydrogen and halogen.

[0015] In some embodiments, R ^3a and R ³ are independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n Ci- ₄ alkyl, C ₂ - ₄ alkenyl,

C3. ₆ cycloalkyl, and SF ₅ .

[0016] In some embodiments, R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, In some embodiments, R ^a and R ^b together represent =0.

[0017] In some embodiments, n is 0, 1 or 2.

[0018] In some embodiments, X is C(R ^a )(R ^b ). In some embodiments, R ^a and R ^b are

independently selected from hydrogen and halogen. In some embodiments, X is CH2 or CF2.

[0019] In some embodiments, Ar ¹ is phenyl. In some embodiments, Ar ¹ is pyridinyl.

[0020] In some embodiments, HAr is a 5-membered heteroaryl. In some embodiments, HAr is isoxazolyl. In some embodiments, HAr is a 6-membered heteroaryl. In some embodiments, HAr is pyridinyl. In some embodiment, HAr is pyrimidinyl.

[0021] In some embodiments, one of R ^la or R ^l is hydrogen, and the other is selected from Ci. ₄ alkyl and Cs^cycloalkyl. In some embodiments, one of R ^la or R ^l is hydrogen, and the other is Ci. ₄ alkyl.

[0022] In some embodiments, R ^3a and R ³ are independently selected from the group consisting of: hydrogen, halogen, CN, Ci.4alkyl, and Ci.4alkoxy. In some embodiments, one ofR ^3a and R ^3b is selected from the group consisting of: halogen, CN, Ci _-4 alkyl, and Ci. ₄ alkoxy.

[0023] In some embodiments, the compounds of Formula (I) is a compound having the Formula

(la):

or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof, wherein Y ¹ is N or CH.

[0024] In some embodiments the compound of Formula (I) is a compound having the formula (lb):

or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof.

[0025] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

4-(4-(3,3-difluoro-l-((2-methoxypyrimidin-5-yl)carbamoyl)cyc lobutyl)phenyl)-N- methylpicolinamide;

4-(4-(l -((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)phenyl)-N- methylpicolinamide;

N-ethyl-4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobut yl)phenyl)picolinamide;

N-cyclopropyl-4-(4-(l-((2-methoxypyrimidin-5-yl)- carbamoyl)cyclobutyl)phenyl)picolinamide;

4-(4-(l -((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)phenyl)-N-(m ethyl- d3)picolinamide;

4-(4-(l -((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)phenyl)-N-met hylpicolinamide;

N-methyl-4-(4-(l-((3-methylisoxazol-5-yl)carbamoyl)cyclob utyl)phenyl)picolinamide;

4-(4-(l -((5-bromopyridin-2-yl)carbamoyl)cyclobutyl)phenyl)-N-methyl picolinamide;

N-methyl-4-(4-(l-(pyridin-3-ylcarbamoyl)cyclobutyl)phenyl )picolinamide;

4-(4-(l -((5-fluoro-6-methoxypyridin-3-yl)carbamoyl)cyclobutyl)pheny l)-N- methylpicolinamide;

4-(4-(l -((2-ethylpyrimidin-5-yl)carbamoyl)cyclobutyl)phenyl)-N-meth ylpicolinamide; 4-(4-(l -((5-cyanopyrimidin-2-yl)carbamoyl)cyclobutyl)phenyl)-N-meth ylpicolinamide; N-methyl-4-(4-(l-(pyridin-2-ylcarbamoyl)cyclobutyl)phenyl)pi colinamide;

4-(4-(l -((5-chloropyridin-2-yl)carbamoyl)cyclobutyl)phenyl)-N-methy lpicolinamide; 6-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methy l-[3,4'-bipyridine]-2'- carboxamide; and

6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl -[3,4'-bipyridine]-2'- carboxamide;

or a pharmaceutically acceptable salt, solvate, or solvate of the salt of any of the foregoing.

[0026] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] Some embodiments provide a method for the treatment of cancer comprising

administering to a patient in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, said cancer is selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0029] In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0030] In some embodiments, said treatment further comprises an additional agent selected from an anti-PD-1 antibody and an anti-PD-Ll antibody.

[0031] [Some embodiments provide a method of inhibiting EDO, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, said cell is a cancer cell. In some embodiments, said cancer cell is from a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. [0033] Some embodiments provide a method for decreasing proliferation of regulatory T-cells, comprising administering to a patient in need thereof a compound of any of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the patient in need thereof has a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0035] Some embodiments provide a method of decreasing proliferation of regulatory T-cells, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, said cell is a cancer cell. In some embodiments, said cancer cell is from a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

DETAILED DESCRIPTION

[0036] Some embodiments provide compounds of Formula (I):

or a pharmaceutically acceptable, solvate, or solvate of the salt thereof.

[0037] In some embodiments, Arl is selected from the group consisting of: phenyl, naphthyl, and pyridinyl. In some embodiments, Arl is phenyl. In some embodiments, Arl is pyridinyl. In some embodiments, HAr is a 5 membered heteroaryl, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In some embodiments HAr is a 6 membered heteroaryl, for example, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine. In some embodiments, X is a bond or C(Ra)(Rb).

[0038] In some embodiments, Rla and Rib are independently selected from the group consisting of: hydrogen, Cl -4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, or t-butyl, C3-6cycloalkyl optionally substituted with one or two halogen atoms, for example, cyclopropyl, cyclobutyl, 2,2-difluorocyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, and heterocyclyl, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and pipendinyl. In some embodiments, Rd and Re together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-Rc, wherein said ring is optionally substituted with one or two groups independently selected from halogen, hydroxy and oxo, for example azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl; or wherein said ring is optionally spirofused to a 3 - to 6- membered cycloalkyl or a 4- to 6-membered heterocyclyl, for example 6-oxa-l- azaspiro[3.3]heptane or 2-oxa-6-azaspiro[3.3]heptane. In some embodiments, Rc is selected from the group consisting of: H, Cl -4alkyl, C(0)Cl-4alkyl, and S02-Cl-4alkyl. In some embodiments, one or both of Rla and Rib are C l-4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, one or both of Rla and Rib are C3-6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments, Rd and Re together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-Rc, wherein said ring is optionally substituted with oxo.

[0039] In some embodiments, R2a and R2b are each independently selected from hydrogen and halogen, for example, fluoro, chloro, or bromo. In some embodiments, one or both R2a and R2b are hydrogen.

[0040] In some embodiments, R3a and R3b are independently selected from the group consisting of: hydrogen, halogen, CN, S(0)nCl-4alkyl, Cl-4alkyl, Cl-4haloalkyl, C2-4alkenyl, Cl-4alkoxy, Cl-4haloalkoxy, C3-6cycloalkyl, and SF5, and R3a and R3b are not both hydrogen. In some embodiments, one of R3a and R3b is hydrogen and the other of R3a and R3b is independently selected from the group consisting of: hydrogen, halogen, CN, S(0)nC l- 4alkyl, Cl-4alkyl, C l-4haloalkyl, C2-4alkenyl, C l-4alkoxy, C l-4haloalkoxy, C3-6cycloalkyl, and SF5. In some embodiments, one or both of R3a and R3b are halogen, for example, fluoro, chloro, or bromo. In some embodiments, one or both of R3a and R3b are Cl-4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, one or both of R3a and R3b are Cl-4haloalkyl, for example, -CF3, -CF2H, - CH2CF3, -CF2Cl,or -CH(CF3)2. In some embodiments, one or both of R3a and R3b are Cl - 4alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t- butoxy. In some embodiments, one or both of R3a and R3b are Cl-4haloalkoxy, for example, - OCF3, -OCF2H, -OCH2CF3, -OCF2C1, or -OCH(CF3)2. In some embodiments, one or both of R3a and R3b are CN. In some embodiments, one or both of R3a and R3b are S(0)nCl-4alkyl, for example, methyl sulfane, ethylsulfane, n-propylsulfane, isopropylsulfane, n-butylsulfane, sec- butylsulfane, t-butyl sulfane, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n- butylsulfmyl, sec-butylsulfinyl, t-butyl sulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butyl sulfonyl, or t-butyl sulfonyl. In some embodiments, one or both of R3a and R3b are C3-6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments, one or both of R3a and R3b are SF5. In some embodiments, one or both of R3a and R3b are C2-4alkenyl, for example, vinyl, 1- or 2-propene, butene, isobutene, including E and Z isomers.

[0041] In some embodiments, X is C(Ra)(Rb). In some embodiments, X is a bond. In some embodiments, Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, hydroxy, Cl-4alkyl, and C l-4alkoxy. In some embodiments, Ra and Rb together represent =0. In some embodiments, Ra and Rb are each hydrogen. In some embodiments, Ra and Rb are each halogen, for example, fluoro, chloro, or bromo. In some embodiments, Ra and Rb are each Cl -4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, or t-butyl. In some embodiments, Ra and Rb are each Cl -4alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-butoxy. In some embodiments, Ra and Rb are each hydroxy. In some embodiments, one of Ra and Rb is hydrogen and the other of Ra and Rb is selected from the group consisting of hydrogen, halogen, hydroxy, Cl -4alkyl, and Cl-4alkoxy.

[0042] In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0. In some

embodiments, n is 1. In some embodiments, n is 2.

[0043] In some embodiments, Arl is phenyl. In some embodiments, Arl is pyridinyl.

[0044] In some embodiments, HAr is a 5-membered heteroaryl. In some embodiments, HAr is isoxazolyl. In some embodiments, HAr is a 6-membered heteroaryl. In some embodiments, HAr is pyridinyl. In some embodiments HAr is pyrimidinyl.

[0045] In some embodiments, the compound of Formula (I) has the structure of Formula (la):

or a pharmaceutically acceptable, solvate, or solvate of the salt thereof, wherein Y ¹ is N or CH.

[0046] In some embodiments, the compound of Formula (I) has the structure of Formula (lb):

(lb)

or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof.

[0047] In some embodiments, one of R3a and R3b is selected from the group consisting of: halogen, CN, Cl-4alkyl, and Cl-4alkoxy.

[0048] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

4-(4-(3,3-difluoro-l-((2-methoxypyrimidin-5-yl)carbamoyl)cyc lobutyl)phenyl)-N- methylpicolinamide;

4-(4-(l-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny l)-N-methylpicolinamide;

N-ethyl-4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclo butyl)phenyl)picolinamide;

N-cyclopropyl-4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cy clobutyl)phenyl)picolinamide;

4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)ph enyl)-N-(methyl-d3)picolinamide;

4-(4-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)phe nyl)-N-methylpicolinamide;

N-methyl-4-(4-(l-((3-methylisoxazol-5-yl)carbamoyl)cyclobuty l)phenyl)picolinamide;

4-(4-(l-((5-bromopyridin-2-yl)carbamoyl)cyclobutyl)phenyl)-N -methylpicolinamide;

N-methyl-4-(4-(l-(pyridin-3-ylcarbamoyl)cyclobutyl)phenyl)pi colinamide;

4-(4-(l-((5-fluoro-6-methoxypyridin-3-yl)carbamoyl)cyclobuty l)phenyl)-N-methylpicolinamide;

4-(4-(l-((2-ethylpyrimidin-5-yl)carbamoyl)cyclobutyl)phen yl)-N-methylpicolinamide;

4-(4-(l-((5-cyanopyrimidin-2-yl)carbamoyl)cyclobutyl)phenyl) -N-methylpicolinamide;

N-methyl-4-(4-(l-(pyridin-2-ylcarbamoyl)cyclobutyl)phenyl)pi colinamide;

4-(4-(l-((5-chloropyridin-2-yl)carbamoyl)cyclobutyl)phenyl)- N-methylpicolinamide;

6-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methy l-[3,4'-bipyridine]-2'- carboxamide; and

6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl -[3,4'-bipyridine]-2'- carboxamide; or a pharmaceutically acceptable, solvate, or solvate of the salt of any of the foregoing.

[0049] Some embodiments provide a compound of Formula (I) selected from:

or a pharmaceutically acceptable salt of any of the foregoing. In some embodiment of this paragraph, Ar ¹ is phenyl. In some embodiment of this paragraph, Ar ¹ is pyridinyl. In some embodiment of this paragraph, HAr is a 5 membered heteroaryl, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In some embodiments HAr is a 6 membered heteroaryl, for example, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3- triazine, 1,2,4-triazine, and 1,3,5-triazine. In some embodiments of this paragraph, R ^la and R ^lb are independently selected from the group consisting of: hydrogen, Ci _-4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl, C ₃ . ₆ cycloalkyl optionally substituted with one or two halogen atoms, for example, cyclopropyl, cyclobutyl, 2,2- difluorocyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, and heterocyclyl, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and piperidinyl. In some embodiments, R ^d and R ^e together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-R , wherein said ring is optionally substituted with one or two groups independently selected from halogen, hydroxy and oxo, for example azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl; or wherein said ring is optionally spirofused to a 3 - to 6-membered cycloalkyl or a 4- to 6- membered heterocyclyl, for example 6-oxa-l-azaspiro[3.3]heptane or 2-oxa-6- azaspiro[3.3]heptane. In some embodiments of this paragraph, R ^c is selected from the group consisting of: H, Ci.4alkyl, C(0)Ci.4alkyl, and In some embodiments of this paragraph, R ^2a and R ^2b are each independently selected from hydrogen and halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, R ^3a and R ^3b are independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n Ci-4alkyl, Ci. 4alkyl, C^haloalkyl, C2-4alkenyl, C^alkoxy, C^haloalkoxy, C ₃ _ ₆ cycloalkyl, and SF ₅ , and R ^3a and R ^b are not both hydrogen. In some embodiments of this paragraph, one of R ^3a and R ³ is hydrogen and the other of R ^3a and R ³ is independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n Ci. ₄ alkyl, Ci _-4 alkyl,

C ₃ . ₆ cycloalkyl, and SF ₅ . In some embodiments of this paragraph, one or both of R ^3a and R ^3b are halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, one or both of R ^3a and R are Ci _-4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are d _-4 haloalkyl, for example, -CF ₃ , -CF ₂ H, -CH ₂ CF ₃ , -CF ₂ Cl,or -CH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of ^3a and ^3b are Ci _-4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-butoxy. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are Ci _-4 haloalkoxy, for example, - OCF ₃ , -OCF ₂ H,

-OCH ₂ CF ₃ , -OCF ₂ CI, or -OCH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of R ^3a and R ^3b are CN. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are S(0) _n Ci- ₄ alkyl, for example, methylsulfane, ethylsulfane, n-propyl sulfane, isopropyl sulfane, n- butylsulfane, sec-butyl sulfane, t-butylsulfane, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butyl sulfinyl, sec-butylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, or t- butylsulfonyl. In some embodiments of this paragraph, one or both of R ^3a and ³ are

C ₃ .6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments of this paragraph, one or both of R ^a and R ³ are SF ₅ . In some embodiments of this paragraph, one or both of R ^a and R ³ are C _2-4 alkenyl, for example, vinyl, 1- or 2-propene, butene, isobutene, including E and Z isomers.

[0050] Some embodiments provide a compound of Formula (I) selected from:

a pharmaceutically acceptable salt of any of the foregoing. In some embodiment of this paragraph, Ar ¹ is phenyl. In some embodiment of this paragraph, Ar ¹ is pyridinyl. In some embodiments of this paragraph, R ^la and R ^lb are independently selected from the group consisting of: hydrogen, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, or t-butyl, C ₃ . ₆ cycloalkyl optionally substituted with one or two halogen atoms, for example, cyclopropyl, cyclobutyl, 2,2-difluorocyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, and heterocyclyl, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and piperidinyl. In some embodiments, R ^d and R ^e together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-R ^c , wherein said ring is optionally substituted with one or two groups independently selected from halogen, hydroxy and oxo, for example azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl; or wherein said ring is optionally spirofused to a 3 - to 6- membered cycloalkyl or a 4- to 6-membered heterocyclyl, for example 6-oxa-l- azaspiro[3.3]heptane or 2-oxa-6-azaspiro[3.3]heptane. In some embodiments, R ^c is selected from the group consisting of: H, Ci- ₄ alkyl, C(0)Ci. ₄ alkyl, and SC>2-Ci. ₄ alkyl. In some embodiments, one or both of R ^la and R ^l are for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, one or both of R ^la and R ^lb are C ₃ . ₆ cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments, R ^d and R ^e together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ring optionally containing one additional heteroatom selected from O, S and N-R ^c , wherein said ring is optionally substituted with oxo. In some embodiments of this paragraph, R ^2a and R ² are each independently selected from hydrogen and halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, R ^3a and R ^3b are independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n Ci _-4 alkyl, Ci _-4 alkyl, Ci _-4 haloalkyl, C ₂ - ₄ alkenyl, C . ₄ alkoxy, Ci _-4 haloalkoxy, C3. ₆ cycloalkyl, and SF ₅ , and R ^3a and R ³ are not both hydrogen. In some embodiments of this paragraph, one of R ^3a and R ^3b is hydrogen and the other of R ^3a and R ³ is independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n Ci. ₄ alkyl, Ci. ₄ alkyl, Ci. ₄ haloalkyl, C2- ₄ alkenyl, Ci. ₄ alkoxy, Ci. ₄ haloalkoxy, C3. ₆ cycloalkyl, and SF ₅ . In some embodiments of this paragraph, one or both of R ^3a and R ^b are halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are Ci. ₄ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are Ci _-4 haloalkyl, for example, -CF ₃ , -CF ₂ H, -CH ₂ CF ₃ , -CF ₂ Cl,or -CH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of R ^3a and R ³ are for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-butoxy. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are Ci. ₄ haloalkoxy, for example, -OCF ₃ , -OCF ₂ H, -OCH ₂ CF ₃ , -OCF ₂ Cl, or -OCH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of R ^a and R are CN. In some embodiments of this paragraph, one or both ofR ^3a and R ^3b are S(0) _n Ci- ₄ alkyl, for example, methylsulfane, ethylsulfane, n-propylsulfane, isopropylsulfane, n-butylsulfane, sec-butyl sulfane, t-butylsulfane, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec- butylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, or t-butylsulfonyl. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are C _3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are SF ₅ . In some embodiments of this paragraph, one or both of R ^a and R ³ are C2- ₄ alkenyl, for example, vinyl, 1- or 2-propene, butene, isobutene, including E and Z isomers. In some embodiments of this paragraph, X is C(R ^a )(R ). In some embodiments of this paragraph, X is C(R ^a )(R ^b ); and R ^a and R ^b are independently selected from hydrogen and halogen. In some embodiments of this paragraph, R ^a and R ^b are both hydrogen. In some embodiments of this paragraph, R ^a and R ^b are both halogen, for example, bromo, chloro, or fluoro. In some embodiments of this paragraph, one of R ^a and R ^b is hydrogen and the other of R ^a and R is halogen, for example, bromo, chloro, or fluoro. In some embodiments of this paragraph, X is CH ₂ or CF ₂ . In some embodiments of this paragraph, X is a bond.

[0051] Some embodiments provide a compound of Formula (I) selected from:

- 17-

or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of this paragraph, R ^a and R are independently selected from hydrogen and halogen, for example, bromo, chloro, and fluoro. In some embodiments of this paragraph, R ^a and R ^b are both hydrogen. In some embodiments of this paragraph, R ^a and R ^b are both halogen, for example, bromo, chloro, or fluoro. In some embodiments of this paragraph, one of R ^a and R ^b is hydrogen and the other of R ^a and R ^b is halogen, for example, bromo, chloro, or fluoro. In some embodiments of this paragraph, HAr is a 5 membered heteroaryl, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In some embodiments HAr is a 6 membered heteroaryl, for example, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3- triazine, 1,2,4-triazine, and 1,3,5-triazine. In some embodiments of this paragraph, HAr is pyridinyl. In some embodiments of this paragraph, HAr is pyrimidinyl. In some embodiments of this paragraph, R ^3a and R ^3b are independently selected from the group consisting of:

hydrogen, halogen, CN, S(0) _n Ci_4alkyl, C2-4alkenyl, Ci^alkoxy, Ci. ₄ haloalkoxy, C3. ₆ cycloalkyl, and SF ₅ , and R ^a and R are not both hydrogen. In some embodiments of this paragraph, one of R ^3a and R ^3b is hydrogen and the other of R ^3a and R ³ is independently selected from the group consisting of: hydrogen, halogen, CN, S(0) _n C _1-4 alkyl, Ci. ₄ alkyl, Ci. ₄ haloalkyl, C _2-4 alkenyl, Ci. ₄ alkoxy, Ci. ₄ haloalkoxy, C ₃ . ₆ cycloalkyl, and SF ₅ . In some embodiments of this paragraph, one or both of R ^3a and R ^3b are halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are Ci. ₄ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments of this paragraph, one or both of R ^3a and R ³ are Ci _-4 haloalkyl, for example, -CF ₃ , -CF ₂ H, -CH ₂ CF ₃ , -CF ₂ Cl,or -CH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of R ^3a and R ³ are Ci _-4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-butoxy. In some embodiments of this paragraph, one or both of ^3a and R ^3b are Ci. ₄ haloalkoxy, for example, -OCF ₃ , -OCF ₂ H, -OCH ₂ CF ₃ , -OCF ₂ Cl, or -OCH(CF ₃ ) ₂ . In some embodiments of this paragraph, one or both of R ^3a and R ³ are CN. In some embodiments of this paragraph, one or both ofR ^3a and R ^3b are S(0) _n Ci _-4 alkyl, for example, methylsulfane, ethylsulfane, n-propylsulfane, isopropylsulfane, n-butyl sulfane, sec-butyl sulfane, t-butyl sulfane, methylsulfinyl, ethylsulfinyl, n-propyl sulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec- butylsulfinyl, t-butylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butyl sulfonyl, sec-butylsulfonyl, or t-butylsulfonyl. In some embodiments of this paragraph, one or both of R ^3a and R ^3b are C _3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments of this paragraph, one or both of R ^3a and R ³ are SF5. In some embodiments of this paragraph, one or both of R ^a and R ³ are C _2-4 alkenyl, for example, vinyl, 1- or 2-propene, butene, isobutene, including E and Z isomers.

[0052] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Some embodiments provide a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Some embodiments provide a pharmaceutical composition comprising a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0053] Some embodiments provide a method for the treatment of cancer comprising

administering to a patient in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for the treatment of cancer comprising administering to a patient in need thereof a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for the treatment of cancer comprising administering to a patient in need thereof a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, said cancer is selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0055] In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0056] In some embodiments, said treatment further comprises an additional agent selected from an anti-PD-1 antibody and an anti-PD-Ll antibody.

[0057] Some embodiments provide a method of inhibiting IDO, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of inhibiting IDO, comprising contacting a cell with a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of inhibiting IDO, comprising contacting a cell with a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, IDO activity is inhibited by about 1% to about 20%, about 25% to about 50%, about 60% to about 90%, about 95% to about 99%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about70% to about 80%, about 80% to about 90%, about 90% to about 99%, or any value in between.

[0059] In some embodiments, said cell is a cancer cell. In some embodiments, said cancer cell is from a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. [0060] Some embodiments provide a method for decreasing proliferation of regulatory T-cells, comprising administering to a patient in need thereof a compound of any of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for decreasing proliferation of regulatory T-cells, comprising administering to a patient in need thereof a compound of any of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for decreasing proliferation of regulatory T-cells, comprising administering to a patient in need thereof a compound of any of Formula (lb), or a pharmaceutically acceptable salt thereof, or a

pharmaceutical composition comprising a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the proliferation of regulatory T-cells is decreased by about 1% to about 50%, about 2% to about 45%, about 3% to about 40%, about 4% to about 35%, about 5% to about 30%, about 6% to about 25% about 7% to about 20%, about 8% to about 15%, about 1% to about 10%, about 35% to about 50, about 10% to about 25%, or any value in between.

[0062] In some embodiments, the patient in need thereof has a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0063] Some embodiments provide a method of decreasing proliferation of regulatory T-cells, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of decreasing proliferation of regulatory T- cells, comprising contacting a cell with a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of decreasing proliferation of regulatory T-cells, comprising contacting a cell with a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, said cell is a cancer cell. In some embodiments, said cancer cell is from a cancer selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

[0065] Some embodiments provide pharmaceutical compositions comprising a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt of any of the foregoing, for example, a compound of Formula (I), a compound of Formula (la), a compound of Formula (lb), or a combination thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

[0066] Some embodiments provide methods for the treatment of cancer comprising

administering to a patient in need thereof a compound of any of the preceding embodiments or a pharmaceutical composition of any of the preceding embodiments, for example, a compound of Formula (I), a compound of Formula (la), a compound of Formula (lb) or a combination thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable carrier. Some embodiments a method of treating cancer comprising administering a therapeutically effective amount of a compound of any of the preceding embodiments or a pharmaceutical composition of any of the preceding embodiments, for example, a compound of Formula (I), a compound of Formula (la), a compound of Formula (lb), or a combination thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable carrier.

[0067] In some embodiments the cancer is selected from the group consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments the cancer is a metastatic or secondary cancer.

[0068] In some embodiments, the cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments the cancer is a metastatic or secondary cancer.

[0069] In some embodiments the cancer is glioblastoma. In some embodiments the cancer is bone cancer. In some embodiments the cancer is head and neck cancer. In some embodiments the cancer is melanoma. In some embodiments the cancer is basal cell carcinoma. In some embodiments the cancer is squamous cell carcinoma. In some embodiments the cancer is adenocarcinoma. In some embodiments the cancer is oral cancer. In some embodiments the cancer is esophageal cancer. In some embodiments the cancer is gastric cancer. In some embodiments the cancer is intestinal cancer. In some embodiments the cancer is colon cancer. In some embodiments the cancer is bladder cancer. In some embodiments the cancer is hepatocellular carcinoma. In some embodiments the cancer is renal cell carcinoma. In some embodiments the cancer is pancreatic cancer. In some embodiments the cancer is ovarian cancer. In some embodiments the cancer is cervical cancer. In some embodiments the cancer is lung cancer. In some embodiments the cancer is breast cancer. In some embodiments the cancer is prostate cancer. In some embodiments the cancer is a metastatic or secondary cancer.

[0070] In some embodiments the treatment further comprises an additional agent selected from an anti-PD-1 antibody and an anti-PD-Ll antibody, including, but not limited to atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

[0071] Any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.

Definitions

[0072] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0073] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and/or pharmacology are employed to characterize compounds and salts thereof. The use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0074] The term "patient" includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. In some embodiments, the patient is a human.

[0075] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0076] The term "alkyl" refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. In some

embodiments, an alkyl is a C1-C6 alkyl, which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0077] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having the indicated number of ring carbon atoms. Multicyclic cycloalkyl may be fused, bridged or spiro ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl. In some embodiments, cycloalkyl is a monocyclic C3-C8 cycloalkyl.

[0078] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluorom ethyl).

[0079] As referred to herein, the term "alkoxy" refers to a group of formula -O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term "thioalkoxy" refers to a group of formula -S-(alkyl). The terms "haloalkoxy" and "thiohaloalkoxy" refer to -O-(haloalkyl) and - S-(haloalkyl), respectively.

[0080] In any of the aforementioned groups, one or more hydrogen atoms in the alkyl portion of the group may be replaced with deuterium, for example, a deutero methoxy group (-OCD3) or a deutero methyl group (-CD3). [0081] The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Non-limiting examples of "aralkyl" include benzyl, 2- phenyl ethyl, and 3 -phenylpropyl groups.

[0082] The term "alkenyl" refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Alkenyl groups can include, e.g., vinyl, allyl, 1 -butenyl, and 2-hexenyl. In some embodiments, an alkenyl is a C2-C6 alkenyl.

[0083] The term "cycloalkenyl" refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be optionally substituted e.g., by one or more substituents. Cycloalkenyl moieties can include, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.

[0084] The term "alkynyl" refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups can include, e.g., ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In some embodiments, an alkynyl is a C2-C6 alkynyl.

[0085] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein except where noted, represents a stable 4-, 5-, 6- or 7-membered monocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 1 1-, or 12-membered bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide or sulfone, and wherein the nitrogen atom may optionally be quaternized. A heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged, or spiro bicyclic heterocyclic ring system(s). In some embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, a heterocyclyl group is bicyclic, and in which case, the second ring may be an aromatic or a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from the group consisting of N, O and S, or the second ring may be a benzene ring, or a "cycloalkyl", or a "cycloalkenyl", as defined herein. Examples of such heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3 -oxazolidine, 1,3 -thiazolidine, tetrahydrothiopyran, tetrahydrotnazine, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro- oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-l,4-diazepine, perhydro-1,4- oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6- azaspiro[3.3]heptane, dihydrobenzofuran, diydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof.

[0086] The term "aryl" as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring (i.e., 6 to 10 total ring atoms) wherein at least one ring is aromatic. For example, a C6-C 10 aryl group such as phenyl, naphthyl,

tetrahydronaphthyl, indanyl, or lH-indenyl.

[0087] The term "heteroaryl", as used herein except where noted, represents a stable 5-, 6- or 7- membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the case of a "heteroaryl" which is a bicyclic group, the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, bicyclic

"heteroaryl" includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic "heteroaryl", or a

"heterocyclyl", a "cycloalkyl", or a "cycloalkenyl", as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrol opyri dines, imidazopyri dines such as imidazo[l,2-a]pyridine, pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof.

[0088] The term "treating", "treat", or "treatment" refers generally to controlling, alleviating, ameliorating, slowing the progress of or eliminating a named condition once the condition has been established. In addition to its customary meaning, the term "preventing", "prevent", or "prevention" also refers to delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, or the recurrence of symptoms of a condition.

[0089] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

[0090] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11 :942-944 (1972)).

Compound Forms and Salts

[0091] The compounds of this disclosure may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of the present disclosure may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (e.g., enantiomers, diastereomers).

[0092] It will also be appreciated that when two or more asymmetric centers are present in the compounds of the disclosure, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the disclosure.

[0093] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this disclosure are encompassed within the scope of this disclosure. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by various methods. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.

[0094] The compounds of the present disclosure include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. In addition, where a term used in the present disclosure encompasses a group that may tautomerize, all tautomeric forms are expressly included thereunder. For example, hydroxy substituted heteroaryl groups include, but are not limited to, 2-hydroxypyridine as well as 2-pyridone, 1-hydroxyisoquinoline as well as 1 -oxo- 1,2-dihyroisoquinoline, 2-hydroxypyrimidine as well as 2-pyrimidone, 2-hydroxyquinoline as well as 2-quinolinone, 5-hydroxy-l,2,4-oxadiazole as well as l,2,4-oxadiazole-5(4H)one, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure.

[0095] The compounds of the present disclosure include the compounds themselves, as well as their salts, solvate, and solvate of the salt, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as

tetramethylammonium ion.

[0096] As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of

pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. When the compound of the present disclosure is basic, pharmaceutically acceptable salts include non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedi sulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic, pantothenic, oxalic, isethionic, and the like.

[0097] When the compound of the present disclosure is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.

[0098] Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19; and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.

[0099] Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure, which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in greater detail in "Solvents and Solvent Effects in Organic Chemistry"; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety.

[00100] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 18F, 36C1, 82Br, 1231, 1241, 1251, 1291 and 13 11. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Due to comparatively easy preparability and detectability, especially compounds labeled with 3H, 14C and/or 18F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Such modifications of the compounds according to the present disclosure may therefore in some cases also constitute a preferred embodiment of the present disclosure. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. Isotopic variants of the compounds according to the present disclosure can be prepared by processes various methods, including, for example, by the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.

Pharmaceutical Compositions

[00101] The term "pharmaceutical composition" as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier.

[00102] The term "pharmaceutically acceptable carrier" refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or salt of the solvate thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[00103] In some embodiments, the compounds of the present application are administered at about 1 mg to 1,000 mg, about 2 mg to 900 mg, about 3 mg to 800 mg, about 4 mg to 700 mg, about 5 mg to 600 mg, about 10 mg to 500 mg, about 50 mg to 400 mg, about 100 mg to 300 mg, about 150 mg to 250 mg, or any value in between. In some embodiments, the total daily dosage may be divided and administered in portions during the day, for example, once per day, twice per day, three times per day or four times per day. In some embodiments, the total dosage may be administered once per week, twice per week, three times per week, four times per week, five times per week or six times per week.

[00104] In some embodiments, the pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [00105] In some embodiments, the pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.

Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. The compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Such formulations may provide more effective distribution.

[00106] In some embodiments, the pharmaceutical compositions that are injectable

formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00107] In some embodiments, solid dosage forms of the instant pharmaceutical compositions for oral administration. In some embodiments, the oral dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00108] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[00109] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions, which can be used include polymeric substances and waxes.

[00110] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[00111] Some embodiments provide liquid dosage forms of the instant pharmaceutical compositions for oral administration. In some embodiments, the liquid dosages include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[00112] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00113] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[00114] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at RT but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00115] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.

Uses

[00116] Some embodiments provide methods of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof. In some embodiments the cancers include, but are not limited to: glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer, oral cancer, or esophageal cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is

adenocarcinoma. In some embodiments, the cancer is gastric cancer, intestinal cancer, colon cancer, or bladder cancer. In some embodiments, the cancer is hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer or cervical cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formulae (la) or (lb) or a pharmaceutically acceptable salt of any of the foregoing.

[00117] Some embodiments provide methods preventing the onset of and/or recurrence of cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.

[00118] Some embodiments provide methods of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof. In some embodiments the cancers include, but are not limited to: glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer, oral cancer, or esophageal cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is gastric cancer, intestinal cancer, colon cancer, or bladder cancer. In some embodiments, the cancer is hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer or cervical cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formulae (la) or (lb) or a pharmaceutically acceptable salt of any of the foregoing.

[00119] Some embodiments provide methods preventing the onset of and/or recurrence of cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.

[00120] Some embodiments provide a compound of Formula (I), or pharmaceutically acceptable salts thereof, for use in treating cancer. In some embodiments the cancers include, but are not limited to: glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer, oral cancer, or esophageal cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is gastric cancer, intestinal cancer, colon cancer, or bladder cancer. In some embodiments, the cancer is hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer or cervical cancer. In some embodiments, the cancer is breast cancer.

[00121] Some embodiments provide a compound of Formula (I), or pharmaceutically acceptable salts thereof, for use in preventing the onset of and/or recurrence of cancer.

[00122] Some embodiments provide a compound of Formula (I), or pharmaceutically acceptable salts thereof, for the preparation of a medicament for treating cancer. In some embodiments the cancers include, but are not limited to: glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer, oral cancer, or esophageal cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is gastric cancer, intestinal cancer, colon cancer, or bladder cancer. In some embodiments, the cancer is hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer or cervical cancer. In some embodiments, the cancer is breast cancer.

[00123] Some embodiments provide a compound of Formula (I), or pharmaceutically acceptable salts thereof, for the preparation of a medicament for use in preventing the onset of and/or recurrence of cancer.

[00124] Some embodiments provide a method for inhibiting the activity of IDO, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from a compound of Formula (la), a compound of Formula (lb), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is a cell selected from glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, or prostate cancer. Administration

[00125] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, or any value in between (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg, or any value in between) every 4 to 120 hours, or any value in between. The

interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by, for example, Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[00126] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, and the judgment of the treating physician.

[00127] In some embodiments, dosage forms include from about 0.001 milligrams to about 2,000 milligrams, or any value in between (including, from about 0.001 milligrams to about 1,000 milligrams, from about 0.001 milligrams to about 500 milligrams, from about 0.01 milligrams to about 250 milligrams, from about 0.01 milligrams to about 100 milligrams, from about 0.05 milligrams to about 50 milligrams, and from about 0.1 milligrams to about 25 milligrams, or any value in between) of a compound of Formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

[00128] Appropriate dosage levels may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used.

[00129] Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve a desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. In certain cases, dosages may deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit may be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.

[00130] In some embodiments, the compounds of the present disclosure may be coadministered with one or more additional agents used in the treatment of cancer. In some embodiments, the additional agents include, but are not limited to: alkylating agents such as cyclophosphamide, chlorambucil, meclorethamine, ifosfamide, or melphalan; antimetabolites such as methotrexate, cytarabine, gemcitabine, fludarabine, 6-mercaptopurine, azathioprene, or 5-fluorouracil; antimitotic agents such as vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, or docetaxel; platinum derivatives such as cisplatin, carboplatin or oxaliplatin;

hormone therapeutics such as tamoxifen; aromatase inhibitors such as bicalutamide, anastrozole, exemestane or letrozole; signaling inhibitors such as imatinib (tyrosine kinase inhibitor;

Gleevac), gefitinib (EGFR inhibitor; Iressa) or erlotinib (receptor TKI, which acts on EGFR; Tarceva); monoclonal antibodies such as trastuzumab, pertuzumab, inotuzumab, or ozogamicins thereof, as well as other antibody-drug conjugates such as ado-trastuzumab emtansine;

anti angiogenic agents such as bevacizumab, sorafenib (tyrosine protein kinase), pazopanib or sunitinib (receptor tyrosine kinase inhibitor); tivozanib, axitinib, and cediranib; -tinibs (tyrosine kinase inhibitors) such as lapatinib; biologic response modifiers such as interferon-alpha;

topoisomerase inhibitors such as camptothecins (including irinotecan and topotecan), amsacrine, etoposide, etoposide phosphate, or teniposide; anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, sabarubicin, aclarubicin, carubicin and valrubicin; other cytotoxic agents such as actinomycin, bleomycin, plicamycin or mitomycin; mTOR inhibitors such as rapamycin, temsirolimus and everolimus; and antibody therapy such as CTLA4 antibody therapy, PDL1 antibody therapy, and PD 1 antibody therapy.

[00131] The terms "CTLA4 antibody" and "anti-CTLA4" refer to an antibody or antibodies directed towards cytotoxic t-lymphocyte antigen 4 (CTLA4). Exemplary antibodies include, but are not limited to, antibodies that are CTLA4 antagonists or the CTLA4 antibodies as set forth in U. S. Patent Nos. 8,685,394 and 8,709,417. Some embodiments of the antibody include ipilimumab (YERVOY®, Bristol-Myers Squibb) and CP-675,206 (tremelimumab, Pfizer). In a particular embodiment, the antibody is ipilimumab.

[00132] "PDL1 antibody" or "anti-PDLl" refers to an antibody directed towards programmed death ligand 1 (PDL1). Exemplary antibodies include, but are not limited to, the antibodies set forth in U. S. Patent Nos. 8,217, 149, 8,383,796, 8,552, 154 and 8,617,546. Some embodiments of the antibody include avelumab (Merck KGA Pfizer), durvalumab (AstraZeneca) and

atezolizumab (TECENTRIQ®, Roche). In a particular embodiment, the antibody is

atezolizumab.

[00133] The terms "PD1 antibody" and "anti-PDl" refers to an antibody directed towards programmed death protein 1 (PD1). Exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546 and 8,709,417. Particular embodiments of the antibody include BGB-A317, nivolumab (OPDIVO®, Bristol-Myers Squibb), labrolizumab (Merck), and pembrolizumab (KEYTRUDA®, Merck).

[00134] In some embodiments, the antibody, e.g., anti-CTLA4, anti-PDLl or anti-PDl, will be mixed, prior to administration, with a non-toxic, pharmaceutically acceptable carrier substance (e.g., normal saline or phosphate-buffered saline), and may be administered using any medically appropriate procedure, for example, including but not limited to, intravenous or intra-arterial administration, and injection into the cerebrospinal fluid. In certain cases, intraperitoneal intradermal, intracavity, intrathecal or direct administration to a tumor or to an artery supplying the tumor may be advantageous.

[00135] The terms "antibody" and "antibodies" as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein. The antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that retain specific binding to the protein or epitope, for example, CTLA4, PDL1 or PD1, bound by the antibody used in the present disclosure are included within the scope of the term "antibody." The antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies and antibody fragments may be obtained or prepared using various methods.

[00136] In some embodiments, the additional agents may be administered separately from the compounds of the present disclosure as part of a multiple dose regimen (e.g., sequentially, or on different overlapping schedules with the administration of one or more compounds of Formula (I), or pharmaceutically acceptable salts thereof). In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition. In some embodiments, these agents can be given as a separate dose that is administered at about the same time as one or more compounds of Formula (I), or

pharmaceutically acceptable salts thereof, are administered (e.g., simultaneously with the administration of one or more compounds of Formula (I), or pharmaceutically acceptable salts thereof, (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof)). In some embodiments, at least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same cancer. In some embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration. [00137] When the compositions of the present disclosure include a combination of a compound of the formulae described herein and one or more additional agents, both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

Cell based IDOl inhibition assay

[00138] Compounds were screened for their ability to inhibit IDOl by measuring the change in production of L-kynurenine. HeLa cells were maintained in DMEM, high glucose (Sigma D5671) with 10% FCS, 1% Pen/Strep, 4mM L-Glutamine, 1% non-essential amino acids and ImM sodium pyruvate at 37oC and 5% C02.

[00139] For the assay, HeLa cells were harvested and plated in growth media except that FCS was replaced with 10% human serum (Valley Biomedical # HS 101HI). Cells were plated at 2xl04/well in flat-bottom 96-well plates (Corning #3595, Low evaporation lids). The next day tryptophan (250μΜ, Sigma-Aldrich #T0254) and IFN-γ (lOng/ml, Peprotech #300-02) were added, followed by addition of compounds. A serial dilution of compounds was first performed in 100% DMSO, followed by a second dilution step in culture media. The final concentration of DMSO in each well was 0.1% and 0.1% DMSO was used as vehicle control. Cells were incubated for additional 48h at 37°C and 5% C02.

[00140] To measure L-Kynurenine in the cell cultures, plates were centrifuged at 1000 rpm for 5 min and 130μ1 of the cell culture supernatant was collected and transferred to a 96-well polypropylene conical bottom plate (Nunc#249944). After addition of 20μ1 26% trichloroacetic acid, the plate was sealed and incubated at 50°C for 30 min. The plate was centrifuged at 3400 rpm for 10 min and 60μ1 of the supernatant was transferred to a polystyrene flat bottom 96-well plate (Corning#3596). Kynurenine was detected by adding 60μ1 of 1% diethyl amino 2- methoxy benzaldehyde in glacial acetic acid and absorbance was read at 460nm using the Molecular Devices FlexStation 3 microplate reader. IC5 ₀ values were obtained using CBIS software.

Human whole blood IDOl inhibition assay

[00141] Blood was obtained by venipuncture from healthy volunteers and collected in heparinized vials. 170 μL of whole blood was plated into a 96-well flat bottom plate. A serial dilution of compounds was first performed in 100% DMSO, followed by a second dilution step in culture media. The final concentration of DMSO in each well was 0.1% and 0.1% DMSO was used as vehicle control. Compounds were added to the blood 15 minutes prior to the addition of LPS (100ng/mL 011 1 :B4 Sigma-Aldrich L3012), Tryptophan (250μΜ, Sigma-Aldrich #T0254) and IFN-γ (lOng/ml, Peprotech #300-02). The blood was incubated for 24h at 37oC and 5% C02. The next day the plasma was collected and Kynurenine was detected by Kynurenine ELISA (ImmuSmol #BA E220) and absorbance was measured using the Molecular Devices FlexStation 3 microplate reader. IC50 values were obtained using CBIS software.

[00142] Results in the cell based IDOl inhibition assay are provided for selected compounds. An IC50 value of "A" is less than or equal to 1 nM, "B" is greater than 1 nM but less than or equal to 2 nM, "C" is greater than 2 nM but less than or equal to 5 nM, and "D" is greater than 10 nM.

Ex IC ₅₀ (nM)

1 B

2 A

3 C

4 D

5 B

6 A

7 B

8 A

9 B

10 C

1 1 A

12 B

13 B

14 A

15 C

16 C

Abbreviations

[00143] The following abbreviations may be referred to in the Examples and schemes in the disclosure:

hr(s) Hour(s)

l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyri dinium 3-oxide

HATU

hexafluorophosphate

Hex Hexanes

HOBt 1 -Hydroxybenzotriazole

HBTU N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate

KHMDS Potassium hexamethyldisilazide

LC-MS Liquid chromatography/mass spectrometry (Shimazu, Model#: LCMS-2020)

M Molar

Me-THF 2-methyltetrahydrofuran

min Minute(s)

N Normal

NMP N-methyl-2-pyrrolidone

O N Overnight

++PBS Phosphate buffered saline with added calcium(II) and magnesium(II)

Pd(dppf)Cl ₂ [1, 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

RT Room temperature

TFA Trifluoracetic acid

THF Tetrahydrofuran

V volume

Alkyl abbreviations include: Me (methyl), Et (ethyl), Pr (propyl), iPr (isopropyl), Bu (butyl), sBu (sec-butyl), tBu (tertiary butyl).

General Synthetic Schemes

[00144] Compounds of Formula (I) of the present disclosure may be prepared using various methods such as those illustrated in the general reaction schemes below, and in the Examples section. In the schemes, LG is an appropriate leaving group (e.g., CI, Br, I, triflate, and the like), and R is hydrogen or an alkyl group such as methyl or ethyl. Scheme 1 shows the preparation of intermediate 3 from an acid/ester 1 and amine 2 using amide coupling methods. For example the acid is coupled with an appropriate amine using amide coupling techniques (for example, HATU, EDCI, DCC, HOBt HBTU, and the like, with an organic base such as triethylamine or diisopropyl ethyl amine), or the ester is coupled with an appropriate amine using amide coupling techniques (e.g., iPrMgBr in THF). The acid/ester 1, in turn, are either commercially available or can be prepared from a substituted aryl acetonitrile or a substituted aryl acetic acid ester by reacting with a substituted or unsubstituted dihalo alkane using an appropriate base (e.g., NaH, KOtBu, KHMDS, and the like) in a polar aprotic solvent (e.g., DMF, DMSO, THF, and the like). The cycloalkylarylcarbonitrile is hydrolyzed to the corresponding acid using aqueous KOH in an appropriate polar protic solvent (e.g., MeOH, ethanol, ethylene glycol, and the like). Scheme 1

[00145] Compounds of Formula (I) can be prepared from Intermediate1 or Intermediate 3 as shown in Scheme 2. Treatment of 1 with bis(pinacolato)diboron in the presence of palladium catalyst and a base to provide the boronate ia, followed by coupling with bromide 5, and amide formation with 2 using methods as described in Scheme 1, provides compounds of Formula (I). Alternatively, converting 3 to the corresponding boronate 3a using bis(pinacolato)diboron, followed by coupling with a bromide 5 provides compounds of Formula (I).

Scheme 2

EXAMPLES

Intermediate 1. l -(4-Bromophenyl)-3,3-difluorocvclobutanecarboxylic acid

[00146] Step 1. To a stirring mixture of 2-(4-bromophenyl)acetonitrile (4.00 g, 20.40 mmol) in DMF (100 mL) at 0 °C was added NaH (0.898 g, 22.44 mmol, 60% dispersion in mineral oil). After stirring for 15 min, l,3-dibromo-2,2-dimethoxypropane (5.34 g, 20.40 mmol) was added and the reaction was heated to 60 °C for 12 h. The solution was quenched with H20 and diluted with EtOAc and brine. The organic phase was washed with H20 (3X) and concentrated. The crude material was purified on silica gel eluting with 0% to 40% EtOAc in hexanes to afford 1 - (4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile.

[00147] Step 2. To a stirring mixture of l-(4-bromophenyl)-3,3- dimethoxycyclobutanecarbonitrile (4.00 g, 13.50 mmol) in EtOH (40 mL) and H20 (20 mL) was added 2.5 M aq. NaOH (27.00 mL, 67.52 mmol). The mixture was stirred at reflux for 16 h and partitioned between EtOAc and aq. 1M HCl. The organics were washed with H20 (3X) and concentrated. The crude material containing l-(4-bromophenyl)-3,3- dimethoxycyclobutanecarboxylic acid was coevaporated with heptanes and used in the next step.

[00148] Step 3. To a stirring solution of l-(4-bromophenyl)-3,3-dimethoxycyclo

butanecarboxylic acid (4.10 g, 13.01 mmol), K2C03 (5.39, 39.03 mmol) in DMF (100 mL) at 0 °C was added iodomethane (0.81 mL, 13.01 mmol). The ice-bath was removed and the mixture was stirred for 16h at rt then partitioned between EtOAc and 1 : 1 H20/brine. The organics were washed sequentially with water (IX), aq. 1M citric acid, H20 (2X), concentrated in vacuo, and coevaporated twice with EtOAc. The crude material was sufficiently pure and afforded methyl l-(4-bromophenyl)-3,3-dimethoxycyclobutanecarboxylate.

[00149] Step 4. To a stirring mixture of methyl l-(4-bromophenyl)-3,3-dimethoxy- cyclobutanecarboxylate (4.20 g, 12.76 mmol) in dioxane (100 mL) was added aq. 6M HC1 (12.76 mL, 76.55 mmol). The reaction was stirred at 50 °C for 16 h, cooled to rt, and partitioned between EtOAc and aq. 1M citric acid. The organics were washed with H20 (3X), concentrated in vacuo and coevaporated once with EtOAc. The residue was purified on silica gel eluting with 0% to 50% EtOAc in hexanes to afford methyl l-(4-bromophenyl)-3- oxocyclobutanecarboxylate.

[00150] Step 5. Methyl l-(4-bromophenyl)-3-oxocyclobutanecarboxylate (3.00 g, 10.59 mmol) in DCM (75 mL) was stirred at -20 °C and DAST (2.80 mL, 21.18 mmol) was added. The reaction was stirred slowly to RT over 16 h and the solvents were removed. The residue was partitioned between EtOAc and saturated aq. NaHC03. The organic phase was washed once more with saturated aq. NaHC03, H20, and concentrated in vacuo. The crude material was purified on silica gel eluting with 0% to 40% EtOAc in hexanes to afford methyl l-(4- bromophenyl)-3 , 3 -difluorocy cl obutanecarb oxyl ate .

[00151] To methyl l -(4-bromophenyl)-3, 3 -difluorocy clobutanecarboxylate (1 85g, 6.1 mmol) in THF (50 mL) was added LiOH (1M, 12 mL). The solution was stirred O N, diluted with EtOAc and 1M citric acid and the organic layer was washed with water. The organic layer was dried (MgS04), filtered and evaporated to yield a white solid.

Example 1. 4-(4-(3,3-difluoro-l-((2-methoxypyrimidin-5-yl)carbamoyl)cvc lobutyl)phenyl)-N- methylpicolinamide

[00152] Step 1. l-(4-Bromophenyl)-3,3-difluorocyclobutanecarboxylic acid (0.50 g, 1.72 mmol,), HATU (0.79 g, 2.06 mmol) and DMF (20 mL) were combined in an RBF and stirred at rt for 5 min followed by the addition of 2-methoxypyrimidin-5-amine (0.22 g, 1.72 mmol) and DIEA (0.90 mL, 5.16 mmol). The mixture was stirred at RT for 16 h and diluted with EtOAc and aq. 0.5 M HC1. The organics were washed once more with 0.5 M HC1, H20 (2X), concentrated in vacuo and coevaporated once with EtOAc. The crude solid containing l-(4- bromophenyl)-3,3-difluoro-N-(2-methoxypyrimidin-5-yl)cyclobu tanecarboxamide was carried on to the next step.

[00153] Step 2. l-(4-Bromophenyl)-3,3-difluoro-N-(2-methoxypyrimidin-5- yl)cyclobutanecarboxamide (0.33 g, 0.82 mmol), bis(pinacolato)diborane (0.31 g, 1.23 mmol), KOAc (0.20 g, 2.05 mmol) were combined with dioxane (10 mL), and the solution was purged with N2 for 5 minutes. Pd(dppf)C12 (0.03 g, 0.04 mmol) was added and the mixture was stirred at 90 °C for 16 hrs. The cooled solution was filtered through a pad of celite and the crude 3,3- difluoro-N-(2-methoxypyrimidin-5-yl)-l -(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutanecarboxamide, was carried on to the next step.

[00154] Step 3. To a solution of 3,3-difluoro-N-(2-methoxypyrimidin-5-yl)-l -(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarbox amide (0.36 g, 0.82 mmol) in dioxane (10 mL) and saturated aq. NaHC03 (5 mL) was added 4-bromo-N-methylpicolinamide (0.26 mg, 1.23 mmol). The mixture was sparged with N2 for 5 min before

tetrakis(triphenylphosphine) palladium(O) (0.05 g, 0.04 mmol) was added. The reaction was heated at 90 °C for 16 h under a nitrogen atmosphere and partitioned between EtOAc and brine. The organic phase was extracted with water (2X), concentrated in vacuo and coevaporated once with EtOAc. The crude material was purified on silica gel eluting with a solvent gradient of 20% to 100% EtOAc in hexanes to afford 4-(4-(3,3-difluoro-l-((2-methoxypyrimidin-5- yl)carbamoyl)cyclobutyl)phenyl)-N-methylpicolinamide. LC-MS: 454 (M+H) ⁺ .

Example 2. 4-(4-(l-((2-Methoxypyrimidin-5-vncarbamoyl)cvclobutyl)phenyl )-N- methylpicolinamide

[00155] Step 1. l-(4-Bromophenyl)-N-(2-methoxypyrimidin-5-yl)cyclobutane-l- carboxamide: Into a 200 mL round bottom flask equipped with a magnetic stir bar and under N2 was added 2-methoxypyrimidin-5-amine (1.23 g, 9.80 mmol) and l-(4-bromophenyl)cyclo- butanecarboxylic acid (2 g, 7.84 mmol). The solids were dissolved in EtOAc (20 mL) and treated with pyridine (1.24 g, 15.68 mmol, 1.27 mL) followed by propylphosphonic anhydride (7.48 g, 1 1.76 mmol, 6.99 mL, 50% purity) in EtOAc. The yellow-orange solution was stirred at 24 °C for 5 hr, the reaction was worked up by adding HC1 ( 1M, 20 mL). The EtOAc layer was concentrated and purified by column chromatography eluting with 10% to 100 %

EtOAc/hexanes gradient over 10 min. The desired fractions were combined, concentrated and further dried under high vacuum O/N, yielding a white solid (2 g). LCMS (ESI+) m/z = 362,364 (M+l, M+3).

[00156] Step 2. N-(2-Methoxypyrimidin-5-yl)-l -(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)cyclobutane-l -carboxamide: Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 was added 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.68 g, 6.63 mmol), l-(4-bromophenyl)-N-(2- methoxypyrimidin-5-yl)cyclobutanecarboxamide (2 g, 5.52 mmol), Pd(dppf)C12, complex with DCM (228.24 mg, 276.07 μηιοΐ) and potassium acetate (1.63 g, 16.56 mmol). The flask was evacuated under vacuum and refilled with N2. DMF (50 mL) was added, and the mixture was degassed for 10 minutes with N2 and then heated to 100 °C O/N. The black reaction mixture was cooled to RT, diluted with Et20 (50 mL) and poured into a 250 mL separatory funnel containing water (150 mL) and extracted with Et20 (3 x 50 mL). The combined organic layers were washed with brine (75 mL), dried over MgS04, filtered and concentrated under reduced pressure. The material was purified on silica gel eluting with 100:0 to 60:40 Hexanes:EtOAc as a gradient over 25 minutes. The desired fractions were combined, concentrated

and further dried under high vacuum O/N to provide a yellow solid (1 g) LCMS (ESI+) m/z = 410 (M+l).

[00157] Step 3. 4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny l)picolinic acid: Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under N2 was added methyl 4-bromopyridine-2-carboxylate (791 mg, 3.66 mmol), N-(2-methoxypyrimidin-5- yl)-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl ]cyclobutanecarboxamide (1 g, 2.44 mmol), tetrakis[triphenylphosphine] palladium (282mg, 244.33 μπιοΐ), sodium carbonate (517mg, 4.89 mmol), 1,4-dioxane (15 mL) and water (3 mL). The vial was sealed and the suspension degassed with N2 for 10 minutes and the mixture was heated to 100 °C O/N. The reaction mixture was cooled to RT and diluted with water (30 mL) and acidified to pH = 5 with 1M citric acid solution (approx 30 mL). The mixture was poured into a Cl-phase separatory cartridge and extracted with CH2C12 (3 x 30 mL), and the combined organic layers were concentrated under reduced pressure. The off-white solid was used directly without further purification.

[00158] Step 4. 4-(4-(l-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny l)-N-methyl- picolinamide: Into a 20 mL vial was added 4-(4-(l-((2-methoxypyrimidin-5-yl)carbamoyl)- cyclobutyl)phenyl)picolinic acid (80 mg), methyl amine (HC1 salt, 14 mg), HATU (112 mg) and DMF (2 mL), followed by N,N-diisopropylethylamine (77 mg). The solution was stirred for 30 minutes, then water (1 mL) was added. The solution was loaded on a reverse phase column (50 g) eluting with 100:0 to 0: 100 water (0.1% formic acid):MeCN (0.1% formic acid) as a gradient over 25 minutes to provide the product. LCMS (ESI+) m/z = 418 (M+1).

[00159] The following compounds were prepared using a similar procedure as described in Example 2.

Example 6. 4-(4-(l-((5-chloropyrimidin-2-yl)carbamovncvclobutyl)phenyl) -N- methylpicolinamide

[00160] Step 1. Methyl l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutane-l -carboxylate: Into a 40 ml vial equipped with a magnetic stir bar and under N2 were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-2-yl)-l,3,2- dioxaborolane (2.26 g, 8.92 mmol), methyl l-(4-bromophenyl)cyclobutanecarboxylate (2 g, 7.43 mmol), Pd(dppf)C12, complex with DCM (307.18 mg, 371.56 μιτιοΐ) and potassium acetate (2.19 g, 22.29 mmol). The vial was evacuated under vacuum and refilled with N2. DMF (15 mL) was added, and the mixture was degassed for 10 minutes with N2 and then heated to 100 °C O/N. The black reaction mixture was cooled to RT, and purified by column chromatography through silica gel eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient over 25 minutes. The desired fractions were combined, concentrated and further dried under high vacuum O/N to provide a yellow solid (1.6 g) LCMS (ESI+) m/z = 317 (M+l).

[00161] Step 2. Methyl l-(4-(2-(methylcarbamoyl)pyridin-4-yl)phenyl)cyclobutane-l- carboxylate: Into a 20 mL microwave vial equipped with a magnetic stir bar and under N2 were added 4-bromo-N-methyl-pyridine-2-carboxamide (204mg, 948.77 μιτιοΐ), methyl l-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclobutanecarbox ylate (300 mg, 948.77 μπιοΐ), tetrakis(triphenylphosphine)palladium(0) (109mg, 94.88 μπιοΐ), potassium carbonate (393 mg, 2.85 mmol), MeOH (3 mL) and DMF (6 mL). The vial was sealed and the suspension degassed with nitrogen for 10 minutes and the mixture was heated to 150 °C for 10 minutes. The mixture was purified by column chromatography through silica gel eluting with 100:0 to 0: 100 hexanes:EtOAc as a gradient over 25 minutes. The desired fractions were combined, concentrated and further dried under high vacuum O/N to provide a yellow solid (250 mg). LCMS (ESI+) m/z = 325 (M+l).

[00162] Step 3. 4-(4-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)phenyl )-N- methylpicolinamide: In a 20 ml vial were added 5-chloropyrimidin-2-amine (93 mg, 721.39 μηιοΐ) and THF (5 niL), and the mixture was cooled to 00C. A solution of i-BuMgBr (2 M, 360 μΕ) in ether was added dropwise. After 10 minutes at 23 OC, a solution of methyl l-[4-[2- (methylcarbamoyl)-4-pyridinyl]phenyl]cyclobutanecarboxylate (39 mg, 120.23 μηιοΐ) in THF (3 mL) was added, and the mixture stirred at 50 0C for 16 hours. The reaction was quenched by adding water (8 mL) and 2 mL of brine. The top organic layer was purified by column chromatography through silica gel eluting with 100:0 to 0: 100 hexanes:EtOAc (10% MeOH) as a gradient over 25 minutes. The desired fractions were combined, concentrated

and further dried under high vacuum O/N to provide a yellow solid (250 mg). LCMS (ESI+) m/z = 422 (M+1)

[00163] The following compounds were prepared using a similar procedure as described in Example 6.

Example 15. 6-(l-((2-methoxypyrimidin-5-yl carbamoyl)cyclobutyn-N-metliyl-[3,4'- bipyridine ^" |-2'-carboxamide

[00164] Step 1 : l-(5-bromopyridin-2-yl)cyclobutanecarbonitrile: n-Butyllithium solution (4.8 mL of a 2.5 M solution in hexanes, 12.0 mmol) was added slowly to a stirred, 0°C solution of diisopropyl amine (1.68 mL, 12.0 mmol) in THF (25 mL). Stirring was continued at 0°C for 10 min, then the mixture was cooled further to -78°C, at which time cyclobutane carbonitrile (0.80 mL, 8.56 mmol) was added neat, via syringe. Stirring was continued at -78°C for 30 min, after which time a solution of 2,5-dibromopyridine (2.12 g, 8.94 mmol) in THF (6 mL) was added via syringe. The cooling bath was then removed, and the reaction was left to stir at RT O N. The mixture was then diluted with water (100 mL) and EtOAc (200 mL) and transferred to a separatory funnel where layers were separated. The aqueous layer was drained, and the organic layer was washed with an additional portion of water (50 mL). The combined aqueous layers were back-extracted with EtOAc (50 mL), and the organic layers were then combined, dried over MgS04, filtered and concentrated to dryness. The crude residue was purified by silica gel column chromatography, eluting with 0% to 30% EtOAc in hexanes to afford, following removal of volatiles, l -(5-bromopyridin-2-yl)cyclobutanecarbonitrile (1.05 g) as waxy crystalline solid. LC-MS : 237, 239 (M+H)+.

[00165] Step 2: l-(5-bromopyridin-2-yl)cyclobutanecarboxylic acid: To a vial containing l-(5- bromopyridin-2-yl)cyclobutanecarbonitrile (1.0 g, 4.2 mmol) and a stirbar were added H20 (4 mL), concentrated H2S04, (4 mL) and acetic acid (4 mL). The mixture was warmed to 1 15°, stirred for 90 min, then cooled to RT and diluted with water (50 mL) and EtOAc (100 mL), and then treated with 1M aqueous NaOH (75 mL). The biphasic mixture was then transferred to a separatory funnel where layers were separated. The aqueous layer was drained and discarded, and the organic layer was washed with water (50 mL), dried over MgS04, filtered and concentrated to dryness to afford l -(5-bromopyridin-2-yl)cyclobutanecarboxylic acid (0.94 g) as a white solid. LC-MS: 256, 258 (M+H)+.

[00166] Step 3 : l-(5-bromopyridin-2-yl)-N-(2-methoxypyrimidin-5- yl)cyclobutanecarboxamide: To a stirred, RT solution of l-(5-bromopyridin-2- yl)cyclobutanecarboxylic acid (0.255 g, 1.0 mmol), 2-methoxypyrimidin-5-amine (0.150 g, 1.2 mmol) and diisopropyl ethylamine (0.52 mL, 3.0 mmol) in DMF (6 mL) was added HATU (0.418 g, 1.1 mmol) in one portion. The mixture was stirred at RT for 2 h, then diluted with brine (20 mL), water (20 mL), and 1 : 1 EtOAc:hexanes (100 mL) and transferred to a separatory funnel where layers were separated. The aqueous layer was drained, and the organic layer was washed with additional portions of water (3X20 mL) and brine (50 mL). The combined aqueous layers were back-extracted with EtOAc (50 mL). The organic portions were combined, dried over MgS04, filtered and concentrated to dryness. The crude residue was purified by silica gel column chromatography, eluting with 0% to 100% EtOAc in hexanes to afford, following removal of volatiles, l -(5-bromopyridin-2-yl)-N-(2-methoxypyrimidin-5- yl)cyclobutanecarboxamide (0.28 g) as a tan solid. LC-MS: 363, 365 (M+H)+.

[00167] Step 4: 6-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methy l-[3,4'- bipyridine]-2'-carboxamide: l-(5-Bromopyridin-2-yl)-N-(2-methoxypyrimidin-5- yl)cyclobutanecarboxamide (0.28 g, 0.77 mmol), bis(pinacolato)diboron (0.236 g, 0.93 mmol), and potassium acetate (0.226 g, 2.31 mmol) were combined in dioxane (10 mL) and the mixture was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM (0.03 lg, 0.038 mmol) was then added, and the mixture was warmed to 100°C, stirred for 2 hrs, then cooled to RT and diluted with EtOAc (20 mL). The mixture was filtered through celite and concentrated to dryness. The residue was redissolved in dioxane (6 mL) and 4-bromo-N-methylpyridine-2- carboxamide (0.200 g, 0.93 mmol) was added, followed by saturated aqueous sodium bicarbonate (2 mL). The mixture was again bubbled with nitrogen for 5 min, after which time Pd(dppf)C12 complex with DCM (0.03 lg, 0.038 mmol) was added. The mixture was warmed to 75°C, stirred for 2 hrs, then cooled to RT and diluted with EtOAc (50 mL) and water (20 mL). The aqueous layer was separated and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness. The crude residue was purified by silica gel column chromatography, eluting with 0% to 20% EtOAc in hexanes to afford 6-(l-((2- methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'-b ipyridine]-2'-carboxamide (0.063 g) as a tan solid. LC-MS: 419 (M+H) ⁺ .

Example 16. 6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cvclobutyl)-N-methyl -r3.4'-bipyridinel- 2'-carboxamide

[00168] Step 1 : methyl l -(5-bromopyridin-2-yl)cyclobutanecarboxylate:

(Trimethylsilyl)diazom ethane (4.42 mmol, 2.21 mL of a 2.0M solution in hexanes) was added slowly over 2 min to a stirred, RT, nitrogen flushed solution of l-(5-bromopyridin-2- yl)cyclobutanecarboxylic acid (0.94 g, 3.69 mmol) in EtOAc (30 mL) and MeOH (3 mL).

Bubbles were observed during addition, but subsided after approximately 3 min. The reaction was left to stir at RT for a total of 20 min, after which time the mixture was concentrated via rotary evaporation, redissolved in EtOAc (100 mL), transferred to a separatory funnel and partitioned with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was drained and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness. The crude residue was purified using automated silica gel column chromatography, eluting with 0% to 20% EtOAc in hexanes to afford methyl l-(5-bromopyridin-2- yl)cyclobutanecarboxylate (0.79 g) as a tan solid. LC-MS: 270, 272 (M+H)+.

[00169] Step 2: l-(5-bromopyridin-2-yl)-N-(5-chloropyrimidin-2-yl)cyclobutan ecarboxamide: Isopropylmagnesium bromide solution (2.57 mL of a 2.9M solution in 2-methyl-THF, 7.46 mmol) was added to a 0°C solution of 5-chloropyrimidin-2-amine (0.92 g, 7.1 mmol) in THF (20 mL). The mixture was warmed slowly to RT and left to stir for 20 min, after which time it was added via syringe to a stirred, 0°C solution of methyl l-(5-bromopyridin-2- yl)cyclobutanecarboxylate (0.96 g, 3.55 mmol) in THF (10 mL). The reaction was warmed to RT, stirred for 30 min, and then quenched with 1M aqueous HC1 (20 mL). The crude mixture was diluted with EtOAc (150 mL) and saturated aqueous sodium bicarbonate (100 mL) then transferred to a separatory funnel where layers were separated. The aqueous layer was drained, and the organic layer was washed water (50 mL), then dried over MgS04, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 100% EtOAc in hexanes to afford, following removal of volatiles, l-(5-bromopyridin-2-yl)- N-(5-chloropyrimidin-2-yl)cyclobutanecarboxamide (0.91 g) as tan solid. LC-MS: 369

(M+H)+.

[00170] Step 3 : 6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl -[3,4'- bipyridine]-2'-carboxamide: l-(5-Bromopyridin-2-yl)-N-(5-chloropyrimidin-2- yl)cyclobutanecarboxamide (0.55 g, 1.5 mmol), bis(pinacolato)diboron (0.495 g, 1.95 mmol), and potassium acetate (0.441 g, 4.5 mmol) were combined in dioxane (20 mL) and the mixture was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM (0.060g, 0.074 mmol) was then added, and the mixture was warmed to 100°C, stirred for 2 hrs, then cooled to RT and 4-bromo-N-methylpyridine-2-carboxamide (0.39 g, 1.8 mmol) was added, followed by saturated aqueous sodium bicarbonate (4 mL). The mixture was again bubbled with nitrogen for 5 min, after which time additional Pd(dppf)C12 complex with DCM (0.030 g, 0.037 mmol) was added. The mixture was warmed to 85°C, stirred O/N, then cooled to RT and diluted with EtOAc (100 mL) and water (30 mL). The aqueous layer was separated and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness. The crude residue was purified by reversed-phase column chromatography, eluting with 5% to 100% ACN (modified with 0.5% formic acid) in water (modified with 0.5% formic acid). Product- containing fractions were then combined in a separatory funnel and partitioned with EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was drained and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness to afford 6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl -[3,4'-bipyridine]-2'- carboxamide (0.49 g) as a tan solid. LC-MS: 423 (M+H)+.

[00171] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.