Condensed pyrazine derivatives as A2A / A2B inhibitors

Abstract

To provide a compound or pharmaceutically acceptable salt thereof that modulates the activity of adenosine receptor such as subtype A2A receptor or an A2B receptor, and is used for the treatment of diseases associated with adenosine receptor activity, including, for example, cancer, inflammatory disease, cardiovascular disease, and neurodegenerative disease.SOLUTION: For example, the following pyrazolo[1,5-a]pyrazine compounds are shown. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-ethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide, 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-propyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention provides condensed pyrazine derivatives that regulate the activity of adenosine receptors such as subtype A2A and A2B and are useful for the treatment of diseases associated with the activity of adenosine receptors, including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.

Background Art

[0002] Adenosine is an extracellular signaling molecule that can regulate the immune response through many immune cell types. Adenosine was first recognized as a physiological regulator of coronary vascular tone by Drury and Szent-Gyorgyu (Sachdeva, S. and Gupta, M. Saudi Pharmaceutical Journal, 2013, 21, 245-253), but it was not until 1970 that Sattin and Rall showed that adenosine regulates cell function by occupying specific receptors on the cell surface (Sattin, A., and Rall, T. W., 1970. Mol. Pharmacol. 6, 13-23; Hasko´, G., at al., 2007, Pharmacol. Ther. 113, 264-275).

[0003] Adenosine plays an important role in various other physiological functions. Adenosine is involved in nucleic acid synthesis and forms ATP, an essential component of the cell energy system, when bound to a triphosphate group. Adenosine can be generated by the enzymatic degradation of extracellular ATP or released from damaged nerve cells and glial cells through the disrupted plasma membrane (Tautenhahn, M. et al. Neuropharmacology, 2012, 62, 1756 - 1766). Adenosine produces various pharmacological effects in both the peripheral and central nervous systems through its action on specific receptors located on the cell membrane (Matsumoto, T. et al. Pharmacol. Res., 2012, 65, 81 - 90). Alternative pathways for generating extracellular adenosine have been described. Such pathways include the production of adenosine from nicotinamide dinucleotide (NAD), an alternative to ATP, through the coordinated action of CD38, CD203a, and CD73. CD73-independent production of adenosine can also occur by other phosphates such as alkaline phosphatase or prostate-specific phosphatase.

[0004] There are four known subtypes of adenosine receptors in humans, including the A1 receptor, A2A receptor, A2B receptor, and A3 receptor. A1 and A2A are high-affinity receptors, while A2B and A3 are low-affinity receptors. Adenosine and its agonists can act through one or more of such receptors and can regulate the activity of adenylate cyclase, an enzyme involved in the increase of cyclic AMP (cAMP). Depending on the receptor, the stimulatory and inhibitory effects on this enzyme are different. When the intracellular concentration of cAMP increases, the activity of immune cells and inflammatory cells can be suppressed (Livingston, M. et al., Inflamm. Res., 2004, 53, 171 - 178).

[0005] The A2A adenosine receptor can transmit signals in the peripheral system and the CNS. Agonists are being explored as anti-inflammatory drugs, and antagonists are being investigated for neurodegenerative diseases (Carlsson, J. et al., J. Med. Chem., 2010, 53, 3748 - 3755). In most cell types, the A2A subtype inhibits intracellular calcium levels, while A2B enhances it. The A2A receptor is generally regarded as inhibiting the inflammatory response from immune cells (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994 - 4006).

[0006] The A2B receptor is highly expressed in the gastrointestinal tract, bladder, lung, and mast cells (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842 - 857). The A2B receptor is structurally closely related to the A2A receptor and can activate adenylate cyclase, but is functionally different. This subtype is assumed to utilize signal transduction systems other than adenylate cyclase (Livingston, M. et al., Inflamm. Res., 2004, 53, 171 - 178). Among all adenosine receptors, the A2B adenosine receptor is a low - affinity receptor, thought to be silent under physiological conditions and activated as a result of increased extracellular adenosine levels (Ryzhov, S. et al. Neoplasia, 2008, 10, 987 - 995). When the A2B adenosine receptor is activated, it can stimulate adenylate cyclase and phospholipase C by activating Gs protein and Gq protein, respectively. Binding to mitogen - activated protein kinase has also been described (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994 - 4006).

[0007] In the immune system, the involvement of adenosine signaling can be an important regulatory mechanism for protecting tissues from excessive immune responses. Adenosine negatively regulates immune responses through many immune cell types, including T cells, natural killer cells, macrophages, dendritic cells, mast cells, and myeloid-derived suppressor cells (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16).

[0008] In tumors, this pathway is hijacked by the tumor microenvironment, interfering with the antitumor ability of the immune system and promoting cancer progression. In the tumor microenvironment, adenosine is mainly produced from extracellular ATP by CD39 and CD73. By expressing CD39 and CD73, multiple cell types can produce adenosine. This applies to tumor cells, T effector cells, T regulatory cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), endothelial cells, cancer-associated fibroblasts (CAF), and mesenchymal stromal / stem cells (MSC). Hypoxia, inflammation, and other immunosuppressive signaling in the tumor microenvironment can induce the expression of CD39, CD73, and subsequent adenosine production. As a result, adenosine levels in solid tumors are abnormally high compared to normal physiological conditions.

[0009] A2A is mainly expressed in lymphoid-derived cells, including T effector cells, T regulatory cells, and natural killer cells. Blocking the A2A receptor can block downstream immunosuppressive signals and temporarily inactivate T cells. The A2B receptor is mainly expressed in monocyte-derived cells, including dendritic cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and mesenchymal stromal / stem cells (MSC). Blocking the A2B receptor in preclinical models can inhibit tumor growth, prevent metastasis, and increase the presentation of tumor antigens.

[0010] Regarding the safety profile of ADORA2A / ADORA2B (A2A / A2B) blockade, all A2A receptor and A2B receptor knockout mice do not show growth abnormalities and are viable and fertile (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16). A2A KO mice showed an increase in the levels of inflammatory cytokines only when exposed to LPS, and there was no evidence of inflammation at baseline (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). A2B KO mice showed normal platelet, red blood cell, and white blood cell counts, but there was an increase in inflammation (TNF-alpha, IL-6) at baseline in naive A2B KO mice (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). After LPS treatment, overproduction of TNF-alpha and IL-6 was detected. A2B KO mice also showed increased inflammation and an increase in vascular adhesion molecules that mediate leukocyte adhesion / rolling, enhanced mast cell activation, increased sensitivity to IgE-mediated anaphylaxis, and increased vascular permeability and neutrophil infiltration under hypoxia (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857).

[0011] In summary, there is a need to develop new adenosine receptor selective ligands for subtypes such as A2A and A2B to treat diseases such as cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. This application addresses such needs and others.

Summary of the Invention

[0012] The present invention relates, inter alia, to a compound of formula (I):

Chemical formula

[0013] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0014] The present invention further provides a method for inhibiting the activity of an adenosine receptor, the method comprising contacting the receptor with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] The present invention further provides a method for treating a disease or disorder associated with abnormal expression of an adenosine receptor, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0017] The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in any of the methods described herein.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] Compound This application particularly provides a compound of formula (I):

Chemical formula

[0019] In some embodiments, any "alkyl", "alkenyl", "alkynyl", "aryl", "cycloalkyl", "heterocycloalkyl", or "heteroaryl" substituent, or "-C 1-6 Alkyl-", "alkylene", "alkenylene", and "alkynylene" linking groups, one, two, three, four, five, six, seven, or eight hydrogen atoms attached to the carbon atoms are each optionally replaced with deuterium atoms.

[0020] In some embodiments, the compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof is of formula (II):

Chemical formula

[0021] In some embodiments of formulas (I) and (II), R 1 Is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 Selected from haloalkyl, and the C 1 Of R 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 Haloalkyl are each optionally, one, two, three, or four independently selected R 1AIt is substituted with a substituent.

[0022] In some embodiments of formulas (I) and (II), R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl selected from.

[0023] In some embodiments of formulas (I) and (II), R 1 is H or C 1-3 alkyl.

[0024] In some embodiments of formulas (I) and (II), R 1 is H.

[0025] In some embodiments of formulas (I) and (II), R 3 is H, D, halo, OH, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-5 cycloalkyl, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, C 1-3Alkylcarbonyloxy, aminocarbonyloxy, C 1-3 Alkylaminocarbonyloxy, di(C 1-3 Alkyl)aminocarbonyloxy, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino, and di(C 1-3 Alkyl)aminocarbonylamino, is selected from.

[0026] In some embodiments of formulas (I) and (II), R 3 is H, D, halo, OH, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, is selected from.

[0027] In some embodiments of formulas (I) and (II), R 3 is CN or H.

[0028] In some embodiments of formulas (I) and (II), R 3 is H.

[0029] In some embodiments of formulas (I) and (II), R 2 is H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a2 , SR a2 , C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 Aryl-C 1-6Selected from alkyl, R 2 of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl-C 1-6 alkyl- are each optionally substituted with one, two, three, or four independently selected R 2A substituents.

[0030] In some embodiments of formulas (I) and (II), R 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and R 2 of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 2A substituents.

[0031] In some embodiments of formulas (I) and (II), each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 , C(O)R b21 , NR c21C(O)OR a21 , N.R. c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 are independently selected from

[0032] In some embodiments of Formula (I) and (II), each R 2A D, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, OR a21 , S.R. a21 , N.H.O.R. a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , O.C.(O)R b21 , O-C(O)NR c21 R d21 , N.R. c21 R d21 , N.R. c21 C(O)R b21 , N.R. c21 C(O)OR a21 , N.R. c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 are independently selected from

[0033] In some embodiments of formula (I) and (II), R a21 , R b21 , R c21 , and R d21 are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 independently selected from alkyl-, R a21 , R b21 , R c21 , and R d21 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with one or two independently selected R 2B substituents.

[0034] In some embodiments of formulas (I) and (II), R a21 , R b21 , R c21 , and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl.

[0035] In some embodiments of formulas (I) and (II), R 2 is C 6-10 aryl, C3-10 Selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, R 2 of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents, each R 2A is selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 and S(O)2R b21 and is independently selected from.

[0036] In some embodiments of Formulas (I) and (II), R 2 is selected from C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, R 2 of C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R2A is substituted with a substituent.

[0037] In some embodiments of formulas (I) and (II), each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 SR a21 NHOR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)OR a21 NR c21 C(O)NR c21 R d21 and S(O)R b21 is independently selected from.

[0038] In some embodiments of formulas (I) and (II), R a21 R b21 R c21 and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl.

[0039] In some embodiments of formulas (I) and (II), R 2 is C3-6 Selected from cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, R 2 of C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 2A substituents; Each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 、SR a21 、NHOR a21 、C(O)R b21 、C(O)NR c21 R d21 、C(O)OR a21 、OC(O)R b21 、OC(O)NR c21 R d21 、NR c21 R d21 、NR c21 C(O)R b21 、NR c21 C(O)OR a21 、NR c21 C(O)NR c21 R d21 、and S(O)R b21 independently selected from; R a21 、R b21 、R c21 、and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl.

[0040] In some embodiments of formulas (I) and (II), R 2 is selected from cyclopropyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionally substituted with one or two independently selected R 2A substituents.

[0041] In some embodiments of formulas (I) and (II), each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 independently selected from.

[0042] In some embodiments of formulas (I) and (II), R a21 , R b21 , R c21 , and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0043] In some embodiments of formulas (I) and (II), R 2is selected from cyclopropyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionally substituted with one or two independently selected R 2A substituents; each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a21 SR a21 NHOR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)OR a21 NR c21 C(O)NR c21 R d21 and S(O)R b21 independently selected from; R a21 R b21 R c21 and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0044] In some embodiments of formulas (I) and (II), R 2 is selected from phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the phenyl of R 2 C 3-7Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 2A substituents; each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 and is independently selected from R 2A the above phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 2B substituents; R a21 , R b21 , R c21 and R d21 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; each R 2B is halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4Alkyl, C 1-4 Haloalkyl, amino, C 1-3 Alkylamino, and di(C 1-3 alkyl)amino, independently selected therefrom.

[0045] In some embodiments of formulas (I) and (II), R 2 is selected from C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, and the C 2 of R 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 2A substituents; Each R 2A is selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and C(O)NR c21 R d21 and the above C 2A alkyl of R 1-4 is optionally substituted with one, two, or three independently selected R 2B substituents; R a21 , R b21 , R c21 and R d21 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 2B is independently selected from halo and OH.

[0046] In some embodiments of formulas (I) and (II), R 2 is selected from cyclopropyl, oxazolyl, triazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionally substituted with one or two independently selected R 2A substituents; Each R 2A is selected from halo, C 1-6 alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, NO2, OR a21 , S.R. a21 , N.H.O.R. a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , O.C.(O)R b21 , O-C(O)NR c21 R d21 , N.R. c21 R d21 , N.R. c21 C(O)R b21 , N.R. c21 C(O)OR a21 , N.R. c21 C(O)NR c21 R d21 , and S(O)R b21 are independently selected from R 2A C above 1-6 Alkyl is optionally selected from 1, 2, or 3 independently selected R 2B is substituted with a substituent; R a21 , R b21 , R c21 , and R d21 are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 independently selected from alkynyl; Each R 2B is independently selected from halo and OH.

[0047] In some embodiments of formula (I) and (II), R 2is selected from 1-(trifluoromethyl)cyclopropan-1-yl, 1-ethyl-1H-pyrazol-5-yl, 1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, pyridin-4-yl, 4-(1-hydroxyethyl)-2-methyloxazol-5-yl, 2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl, 1-ethyl-1H-1,2,3-triazol-5-yl, and 1-methyl-1H-1,2,3-triazol-5-yl.

[0048] In some embodiments of formulas (I) and (II), R 2 is selected from 1-(trifluoromethyl)cyclopropan-1-yl, 1-ethyl-1H-pyrazol-5-yl, 1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, pyridin-4-yl, 4-(1-hydroxyethyl)-2-methyloxazol-5-yl, 2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl, 1-ethyl-1H-1,2,3-triazol-5-yl, and 1-methyl-1H-1,2,3-triazol-5-yl.

[0049] In some embodiments of formulas (I) and (II), R 2 is selected from 1-(trifluoromethyl)cyclopropan-1-yl, 1-ethyl-1H-pyrazol-5-yl, 1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, and pyridin-4-yl.

[0050] In some embodiments of formulas (I) and (II), R 4 is H, D, halo, C 1-6 alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 selected from, R 4 of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- are each optionally, one, two, three, or four independently selected R 4AIt is substituted with a substituent.

[0051] In some embodiments of formulas (I) and (II), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 , C(O)R b41 , NR c41 , C(O)OR a41 , NR c41 , C(O)NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from, and the C 4A alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 3-10 substituents. 4B It is substituted with a substituent.

[0052] In some embodiments of formulas (I) and (II), each R 4B is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 is independently selected from alkyl-.

[0053] In some embodiments of Formulas (I) and (II), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 , C(O)NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from.

[0054] In some embodiments of Formulas (I) and (II), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 selected from, R 4 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally, independently selected from 1, 2, 3, or 4 R 4A substituents; each R4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from

[0055] In some embodiments of Formulas (I) and (II), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , and NR c4 C(O)NR c4 R d4 is selected from, and R4 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl-C 1-6 alkyl-, and (5- to 6-membered heteroaryl)-C 1-6 alkyl- is each optionally, independently selected from one or two R 4A substituents.

[0056] In some embodiments of formulas (I) and (II), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, and OR a41 is independently selected from.

[0057] In some embodiments of formulas (I) and (II), R a4 , R b4 , R c4 , and R d4 are each, independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0058] In some embodiments of formulas (I) and (II), each R a41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0059] In some embodiments, any R c4 and R d4are attached to the same N atom and, together with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group is optionally substituted with one, two, three, or four independently selected R 4A substituents.

[0060] In some embodiments, any R c4 and R d4 are attached to the same N atom and, together with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group is optionally substituted with one or two independently selected R 4A substituents.

[0061] In some embodiments of formulas (I) and (II), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 and NR c4 C(O)NR c4 R d4 is selected from, and the C 4 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl-C 2-6 alkyl-, and (5- to 6-membered heteroaryl)-C 1-6 alkyl- are each optionally substituted with one or two independently selected R 1-6 substituents; 4A ; each R 4Ais D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, and OR a41 is independently selected from; R a4 , R b4 , R c4 and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R a41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0062] In some embodiments of formula (I) and (II), R 4 is selected from C 1-6 alkyl, phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 and NR c4 C(O)OR a4 wherein the C 4 alkyl, phenyl-C 1-6 alkyl- and (5- to 6-membered heteroaryl)-C 1-6 alkyl- are each optionally substituted with one or two independently selected R 1-6 substituents. 4A

[0063] In some embodiments of formula (I) and (II), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C​2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, and OR a41 is independently selected from

[0064] In some embodiments of Formulas (I) and (II), R a4 , R c4 , and R d4 are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, or alternatively, any R c4 and R d4 are attached to the same N atom and, together with the N atom to which they are attached, form a 4- to 6-membered heterocycloalkyl group.

[0065] In some embodiments of Formulas (I) and (II), each R a41 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0066] In some embodiments of Formulas (I) and (II), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-6 alkyl-, CN, NO2, OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 selected from, R 4 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally, independently selected from 1, 2, 3, or 4 R 4A substituents; R a4 , R b4 , R c4 , and R d4 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, independently selected, R a4 , R b4 , R c4 , and Rd4 said C above 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R 4A substituents; each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, NO2, OR a41 SR a41 NHOR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 S(O)R b41 and S(O)2R b41 is independently selected from R 4A said C of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R 4B substituents; R a41 R b41 R c41 and R d41 is each H, C 1-6 alkyl, and C 1-6Independently selected from haloalkyl, R a41 , R b41 , R c41 , and R d41 's said C 1-6 alkyl is optionally substituted with one, two, or three independently selected R 4B substituents; Each R 4B is independently selected from halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

[0067] In some embodiments of formulas (I) and (II), R 4 is selected from phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, C(O)R b4 , C(O)NR c4 R d4 , and NR c4 R d4 ; R 4 's phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- are each optionally substituted with one or two independently selected R 4A substituents; R a4 , R b4 , R c4 , and R d4 are each independently selected from H, C 1-6 alkyl, phenyl, and 4- to 7-membered heterocycloalkyl, and R a4 , R b4 , Rc4 and R d4 the above C of 1-6 Alkyl, phenyl, and 4- to 7-membered heterocycloalkyl are optionally substituted with one, two, or three independently selected R 4A substituents; each R 4A is independently selected from halo, 4- to 7-membered heterocycloalkyl, and OH, and the above 4- to 7-membered heterocycloalkyl of R 4A is optionally substituted with one or two independently selected R 4B substituents; each R 4B is independently selected from halo, OH, and C 1-4 alkyl.

[0068] In some embodiments of formulas (I) and (II), R 4 is selected from phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 and NR c4 C(O)OR a4 and R 4 the C of 1-6 alkyl, phenyl-C 1-6 alkyl-, and (5- to 6-membered heteroaryl)-C 1-6 alkyl- are each optionally substituted with one or two independently selected R 4A substituents; each R 4A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, and OR a41 ; R a4 R c4 and R d4 are each, H, C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 is independently selected from alkynyl, or alternatively, any R c4 and R d4 are attached to the same N atom and together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group; Each R a41 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 is independently selected from alkynyl.

[0069] In some embodiments of formulas (I) and (II), R 4 is C(O)NHC 1-6 alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)N(C 1-6 alkyl)2, NHC(O)OC 1-6 alkyl, (azetidinyl)-C 1-6 alkyl, (pyridyl)-C 1-6 alkyl, (phenyl)-C 1-6 alkyl, (fluorophenyl)-C 1-6 alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), and pyridyl.

[0070] In some embodiments of formulas (I) and (II), R 4 is C(O)NHC 1-6 alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)N(C 1-6 alkyl)2, NHC(O)OC 1-6 alkyl, (azetidinyl)-C 1-6 alkyl, (pyridyl)-C 1-6 alkyl, (phenyl)-C 1-6 alkyl, (fluorophenyl)-C 1-6 alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), pyridyl, and (pyrrolo[3,2-b]pyridinyl-C1-6 selected from alkyl, each C 1-6 the alkyl and azetidinyl groups are optionally substituted with one or two OH groups, and each pyridyl is optionally substituted with a methylpiperazinyl group.

[0071] In some embodiments of formulas (I) and (II), R 4 is C(O)NHC 1-6 alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)N(C 1-6 alkyl)2, NHC(O)OC 1-6 alkyl, (azetidinyl)-C 1-6 alkyl, (pyridyl)-C 1-6 alkyl, (phenyl)-C 1-6 alkyl, (fluorophenyl)-C 1-6 alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), and pyridyl, each C 1-6 the alkyl and azetidinyl groups are optionally substituted with one or two OH groups, and each pyridyl is optionally substituted with a methylpiperazinyl group.

[0072] In some embodiments of formulas (I) and (II), R 4 is selected from C(O)NHCH2CH3, C(O)N(CH3)(CH2CH3), C(O)N(CH2CH3)2, NHC(O)OCH2CH3, C(O)-azetidinyl, C(O)-hydroxyazetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, CH2-azetidinyl, CH2-pyridyl, CH2-fluorophenyl, CH(OH)-fluorophenyl, NH-phenyl, 3,6-dihydro-2H-pyranyl, (methylpiperazinyl)pyridinyl, and (1H-pyrrolo[3,2-b]pyridin-3-yl)methyl.

[0073] In some embodiments of formulas (I) and (II), R 4It is selected from C(O)NHCH2CH3, C(O)N(CH3)(CH2CH3), C(O)N(CH2CH3)2, NHC(O)OCH2CH3, C(O)-azetidinyl, C(O)-hydroxyazetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, CH2-azetidinyl, CH2-pyridyl, CH2-fluorophenyl, CH(OH)-fluorophenyl, NH-phenyl, 3,6-dihydro-2H-pyranyl, and (methylpiperazinyl)pyridinyl.

[0074] In some embodiments of formulas (I) and (II), R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , S(O)R b2 and S(O)2R b2 is selected from.

[0075] In some embodiments of formulas (I) and (II), R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0076] In some embodiments of formula (I) and (II), R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , S(O)R b2 and S(O)2R b2 selected from; R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0077] In some embodiments of formula (I) and (II), R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, and CN.

[0078] In some embodiments of formula (I) and (II), R 2 is selected from H, difluoroethyl, bromo, and CN.

[0079] In some embodiments of formula (I) and (II), R 4 is C6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl-, C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 selected from, R 4 of C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally, 1, 2, 3, or 4 independently selected R 4A substituted with substituents.

[0080] In some embodiments of formulas (I) and (II), R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0081] In some embodiments of formulas (I) and (II), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 , NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from

[0082] In some embodiments of formulas (I) and (II), R 4 is 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 , NR a4 , NR c4 , NR c4 R d4 , S(O)R b4and S(O)2R b4 selected from 4 C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with one, two, three, or four independently selected R 4A substituents; R a4 R b4 R c4 and R d4 are each independently selected from H and C 1-6 alkyl; each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 SR a41 NHOR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 S(O)R b41 and S(O)2R b41 independently selected from.

[0083] In some embodiments of formulas (I) and (II), R 4 is phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 , and NR c4 C(O)OR a4 selected from, each C 1-6 alkyl is optionally substituted with one or two OH groups; phenyl-C 1-6 alkyl- is optionally substituted with one or two independently selected halo groups.

[0084] In some embodiments of formulas (I) and (II), R a4 , R b4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0085] In some embodiments of formulas (I) and (II), each R 4 is phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, and C(O)NR c4 R d4 selected from, phenyl-C 4 alkyl- and (5- to 6-membered heteroaryl)-C 1-6 alkyl- of R 1-6 are each optionally substituted with one or two substituents independently selected from OH and halo; R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0086] In some embodiments of formulas (I) and (II), R 4 is phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 Rd4 、 NR c4 C(O)OR a4 selected from, each C 1-6 alkyl is optionally substituted with one or two OH groups; phenyl-C 1-6 alkyl- is optionally substituted with one or two independently selected halo groups; R a4 、 R c4 、 and R d4 are each independently selected from H and C 1-6 alkyl.

[0087] In some embodiments of formulas (I) and (II), R 4 is selected from C(O)NHCH2CH3, -CH2-pyridyl, CH2-fluorophenyl, and CH(OH)-fluorophenyl.

[0088] In some embodiments of formula (II), R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, OR a2 、 SR a2 、 NHOR a2 、 C(O)R b2 、 C(O)NR c2 R d2 、 C(O)NR c2 (OR a2 )、 C(O)OR a2 、 OC(O)R b2 、 OC(O)NR c2 R d2, NR c2 R d2 , NR c2 NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NOH)R b2 , C(=NCN)R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 C(=NOH)NR c2 R d2 , NR c2 C(=NCN)NR c2 R d2 , NR c2 C(=NR e2 )R b2 , NR c2 S(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)(=NR e2 )R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , S(O)2NR c2 R d2 , OS(O)(=NR e2 )R b2 , OS(O)2R b2 , SF5, P(O)R f2 R g2 , OP(O)(OR h2 )(OR i2)、P(O)(OR h2 )(OR i2 )、and BR j2 R k2 selected from, R 2 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 2A substituents; R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 Rd4 , NR c4 R d4 , NR c4 NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(=NR e4 )R b4 , C(=NOH)R b4 , C(=NCN)R b4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 C(=NOH)NR c4 R d4 , NR c4 C(=NCN)NR c4 R d4 , NR c4 C(=NR e4 )R b4 , NR c4 S(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)(=NR e4 )R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , S(O)2NR c4 R d4 , OS(O)(=NR e4 )R b4 , OS(O)2R b4 , SF5, P(O)R f4 R g4 , OP(O)(OR h4 )(ORi4 ), P(O)(OR h4 )(OR i4 ), and BR j4 R k4 , selected from 4 C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 4A substituents.

[0089] In some embodiments of formulas (I) and (II), Cy 1 is aryl optionally substituted with 1, 2, 3, or 4 independently selected R 7 substituents. 6-10

[0090] In some embodiments of formulas (I) and (II), Cy 1 is phenyl optionally substituted with 1 or 2 independently selected R 7 substituents.

[0091] In some embodiments of formulas (I) and (II), each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0092] In some embodiments of formulas (I) and (II), Cy 1 ​is phenyl optionally substituted with one or two independently selected R 7 substituents, each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0093] In some embodiments of Formulas (I) and (II), Cy 1 is phenyl substituted with one or two independently selected R 7 substituents, each R 7 is independently selected from halo and CN.

[0094] In some embodiments of Formulas (I) and (II), Cy 1 is unsubstituted phenyl.

[0095] In some embodiments of Formulas (I) and (II), Cy 1 is cyanophenyl.

[0096] In some embodiments of Formulas (I) and (II), Cy 1 is 3-cyanophenyl.

[0097] In some embodiments of Formulas (I) and (II), Cy 1 is 3-cyanophenyl or 3-cyano-2-fluorophenyl.

[0098] In some embodiments of Formulas (I) and (II), Cy 1 is phenyl substituted with C(O)NR c7 R d7 wherein R c7 and R d7 are each independently selected from H and C 1-6 alkyl.

[0099] In some embodiments of formulas (I) and (II), Cy 1 is phenyl substituted with C(O)NH2.

[0100] In some embodiments of formulas (I) and (II), Cy 1 is 3-formylphenyl.

[0101] In some embodiments of formulas (I) and (II), R 1 is H; Cy 1 is aryl optionally substituted with one, two, three, or four independently selected R 7 substituents; 6-10 and R 2 is selected from aryl, cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and the aryl, cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl of R 6-10 are each optionally substituted with one, two, three, or four independently selected R 3-10 substituents. 2 of 6-10 R 3-10 is selected from aryl, cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and the aryl, cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl of R 2A are each optionally substituted with one, two, three, or four independently selected R

[0102] In some embodiments of formulas (I) and (II), R 1 is H; Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents; R 2 is selected from aryl, cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and the aryl, cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl of R 6-10 are each optionally substituted with one, two, three, or four independently selected R 3-10 substituents. 2 of 6-10 R 3-10Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

[0103] In some embodiments of the compounds of formulas (I) and (II), R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; R 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C 2 of R 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents; R 4 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)ORa4 、 OC(O)R b4 、 OC(O)NR c4 R d4 、 NR c4 R d4 、 NR c4 C(O)R b4 、 NR c4 C(O)OR a4 、 NR c4 C(O)NR c4 R d4 、 S(O)R b4 、 and S(O)2R b4 selected from, R 4 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally, independently selected, 1, 2, 3, or 4 R 4A substituted with substituents; each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 、 SR a21 、 NHOR a21 、 C(O)R b21 、 C(O)NR c21 R d21 、 C(O)OR a21 、 OC(O)R b21 、 OC(O)NR c21 R d21 、 NRc21 R d21 、 NR c21 C(O)R b21 、 NR c21 C(O)OR a21 、 NR c21 C(O)NR c21 R d21 、 S(O)R b21 、 and S(O)2R b21 is independently selected from R c21 and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; each R 4A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 、 SR a41 、 NHOR a41 、 C(O)R b41 、 C(O)NR c41 R d41 、 C(O)OR a41 、 OC(O)R b41 、 OC(O)NR c41 R d41 、 NR c41 R d41 、 NR c41 C(O)R b41 、 NR c41 C(O)OR a41 、 NR c41 C(O)NR c41 R d41 、 S(O)R b41 、 and S(O)2R b41 is independently selected from; Cy1 is C aryl optionally substituted with one, two, three, or four independently selected R 7 substituents; 6-10 and R , R a4 , R b4 , and R c4 are each independently selected from H, C 4 alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, and C 2-6 alkynyl, or 2-6 any R and R c4 are attached to the same N atom and together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group; d4 and R , R a41 , R b41 , and R c41 are each independently selected from H, C d41 alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, and C 2-6 alkynyl; 2-6 each R is independently selected from halo, C 7 alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, C 2-6 alkynyl, CN, and NO2. 2-6 In some embodiments of the compounds of formulas (I) and (II),

[0104] R is selected from H, C 1 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, and C 2-6 haloalkyl; 1-6 and R is selected from H, D, halo, C 2 alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a2 , SR 2-6 , and NRa2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , S(O)R b2 , and S(O)2R b2 is selected from; R 4 is, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 is selected from, R 4 of C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-6 Alkyl- is each optionally substituted with one, two, three, or four independently selected R 4A substituents; Each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , S(O)R b41 and S(O)2R b41 and is independently selected from; Cy 1 is an optionally substituted C 7 aryl with one, two, three, or four independently selected R 6-10 substituents; R a4 , R b4 , R c4 and R 4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, or alternatively, any R c4 and R d4are attached to the same N atom and, together with the N atom to which they are attached, form a 4- to 6-membered hetero cycloalkyl group; R a41 、R b41 、R c41 、and R d41 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; Each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0105] In some embodiments of the compounds of formulas (I) and (II), R 1 is H; R 2 is selected from C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered hetero cycloalkyl, and the C 2 of R 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered hetero cycloalkyl are each optionally substituted with one or two independently selected R 2A substituents; R 4 is selected from C 1-6 alkyl, phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 、and NR c4 C(O)OR a4 , and the C 4 of R 1-6 alkyl, phenyl-C 1-6 alkyl-, and (5- to 6-membered heteroaryl)-C 1-6 alkyl- are each optionally substituted with one or two independently selected R 4A substituents; Each R 2A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 and is independently selected from R a21 , R b21 , R c21 , and R d21 each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; Each R 4A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, and OR a41 and is independently selected from; Cy 1 is one or two independently selected R 7phenyl optionally substituted with a substituent; R a4 、R c4 、and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, or alternatively, any R c4 and R d4 are attached to the same N atom and together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group; each R a41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0106] In some embodiments of the compounds of formulas (I) and (II), R 1 is H; R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, and CN; R 4 is selected from phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 、NR c4 C(O)OR a4 wherein each C 1-6 alkyl is optionally substituted with one or two OH groups; phenyl-C 1-6 alkyl- is optionally substituted with one or two independently selected halo groups; Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents; R a4 , R c4 , and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, or alternatively, any R c4 and R d4 are attached to the same N atom and together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group; each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0107] In some embodiments of the compounds of formulas (I) and (II), R 1 is H; R 2 is selected from cyclopropyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionally substituted with one or two independently selected R 2A substituents; R 4 is C(O)NHC 1-6 alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)N(C 1-6 alkyl)2, NHC(O)OC 1-6 alkyl, (azetidinyl)-C 1-6 alkyl, (pyridyl)-C 1-6 alkyl, (phenyl)-C 1-6 alkyl, (fluorophenyl)-C 1-6Selected from alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), and pyridyl, each C 1-6 The alkyl and azetidinyl groups are optionally substituted with one or two OH groups, and each pyridyl is optionally substituted with a methylpiperazinyl group; Each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 independently selected from; Cy 1 is cyanophenyl; R a21 , R b21 , R c21 , and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0108] In some embodiments of the compounds of formulas (I) and (II), R 1 is H; R 2 is selected from H, difluoroethyl, bromo, and CN; R 4is phenyl-C 1-6 alkyl-, (5- or 6-membered heteroaryl)-C 1-6 alkyl-, C(O)NR c4 R d4 , NR c4 C(O)OR a4 selected from, each C 1-6 alkyl is optionally substituted with one or two OH groups; phenyl-C 1-6 alkyl- is optionally substituted with one or two independently selected halo groups; Cy 1 is cyanophenyl; R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0109] In some embodiments of formulas (I) and (II), the compound is of formula (IIa):

Chemical formula

[0110] In some embodiments of formula (IIa), R 3 is H or CN; Cy 1 is phenyl substituted with one or two independently selected R 7 substituents; each R 7 is independently selected from halo and CN; R 2 is selected from phenyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the phenyl of R 2 , C 3-7Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 2A substituents; Each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 and is independently selected from R 2A The above phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 2B substituents; R a21 , R b21 , R c21 and R d21 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 2B is halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4Alkyl, C 1-4 Haloalkyl, amino, C 1-3 Alkylamino, and di(C 1-3 alkyl)amino are independently selected; R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, OR a4 SR a4 NHOR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 S(O)R b4 and S(O)2R b4 are selected from, R 4 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C3-10 Cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with one, two, three, or four independently selected R 4A substituents; R a4 、R b4 、R c4 、and R d4 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, independently selected, and R a4 、R b4 、R c4 、and R d4 of the above C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 4A substituents; each R 4A is, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, NO2, OR a41 、SR a41 、NHOR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 、NR c41 R d41 、NR c41 C(O)R b41 、NR c41 C(O)ORa41 , NR c41 C(O)NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from, R 4A of the above C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 4B substituents; R a41 , R b41 , R c41 , and R d41 are each, H, C 1-6 alkyl, and C 1-6 haloalkyl are independently selected from, R a41 , R b41 , R c41 , and R d41 of the above C 1-6 alkyl is optionally substituted with one, two, or three independently selected R 4B substituents; Each R 4B is selected from halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino are independently selected.

[0111] In some embodiments of formula (IIa), R 3 is H or CN; Cy 1 is 3-cyanophenyl or 3-cyano-2-fluorophenyl; R 2 is selected from C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, R2 of C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 2A substituents; Each R 2A is selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and C(O)NR c21 R d21 independently, and the C 2A alkyl of R 1-4 is optionally substituted with one, two, or three independently selected R 2B substituents; R a21 , R b21 , R c21 and R d21 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 2B is independently selected from halo and OH. R 4 is selected from phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, C(O)R b4 C(O)NR c4 R d4 and NR c4 R d4 and R 4 phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl- are each optionally substituted with one or two independently selected R 4A substituents; R a4 , R b4 Rc4 and R d4 is each independently selected from H, C 1-6 alkyl, phenyl, and 4- to 7-membered heterocycloalkyl, and R a4 , R b4 , R c4 , and R d4 of the above C 1-6 alkyl, phenyl, and 4- to 7-membered heterocycloalkyl are optionally substituted with one, two, or three independently selected R 4A substituents; each R 4A is independently selected from halo, 4- to 7-membered heterocycloalkyl, and OH, and the above 4- to 7-membered heterocycloalkyl of R 4A is optionally substituted with one or two independently selected R 4B substituents; each R 4B is independently selected from halo, OH, and C 1-4 alkyl.

[0112] In some embodiments of formula (IIa), R 3 is H or CN; Cy 1 is phenyl substituted with one or two independently selected R 7 substituents; each R 7 is independently selected from halo and CN; R 2 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, and CN; R 4 is selected from phenyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, and C(O)NR c4 R d4 and R 4 of the phenyl-C 1-6 alkyl- and (5- to 6-membered heteroaryl)-C 1-6Alkyl- is each optionally substituted with one or two substituents independently selected from OH and halo; R a4 、R c4 、and R d4 are each independently selected from H and C 1-6 alkyl.

[0113] In some embodiments of formulas (I) and (II), the compound is of formula (IIb):

Chemical formula

[0114] In some embodiments of formulas (I) and (II), the compound is of formula (IIc):

Chemical formula

[0115] In some embodiments, the compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof is of formula (III):

Chemical formula

[0116] In some embodiments of formulas (I) and (III), R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, and C 1-6 selected from haloalkyl, and R 1 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl are each optionally substituted with one, two, three, or four independently selected R 1A substituents.

[0117] In some embodiments of formulas (I) and (III), R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 selected from haloalkyl.

[0118] In some embodiments of formulas (I) and (III), R 1 is H or C 1-6 alkyl.

[0119] In some embodiments of formulas (I) and (III), R 1 is H.

[0120] In some embodiments of formulas (I) and (III), R 2 is H, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and R 2 of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 2A substituents.

[0121] In some embodiments of formulas (I) and (III), R 2 is C 6-10 aryl, C 3-10Selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, R 2 of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 2A substituents.

[0122] In some embodiments of Formulas (I) and (III), each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 , NR c21 R d21 , S(O)R b21 , and S(O)2R b21 independently selected from.

[0123] In some embodiments of Formulas (I) and (III), R 2 is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl selected from, R 2 of C 6-10Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 2A substituents; Each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 and is independently selected from R 2A The above C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 2B substituents; R a21 , R 241 , R c21 , and R d21 are each H, C1-6 Alkyl, and C 1-6 independently selected from haloalkyl, R a21 , R 241 , R c21 , and R d21 The above C 1-6 alkyl is optionally substituted with one, two, or three independently selected R 2A substituents; Each R 2B is selected independently from D, halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

[0124] In some embodiments of formulas (I) and (III), R 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C 2 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl of R 3-10 are each optionally substituted with one, two, three, or four independently selected R 2A substituents; Each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)Rb21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 , and S(O)2R b21 is independently selected from

[0125] In some embodiments of Formulas (I) and (III), R 2 is selected from 5- to 10-membered heteroaryl and 4- to 7-membered heterocycloalkyl, and the 5- to 10-membered heteroaryl and 4- to 7-membered heterocycloalkyl of R 2 are each optionally substituted with one, two, or three independently selected R 2A substituents; Each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OH, and the above C 2A alkyl of R 1-6 is optionally substituted with one, two, or three independently selected R 2B substituents; Each R 2B is independently selected from D, halo, and OH.

[0126] In some embodiments of Formulas (I) and (III), R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl of R 2 are each optionally substituted with one or two independently selected R 2A substituents.

[0127] In some embodiments of Formulas (I) and (III), each R 2A is D, halo, C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 is independently selected from

[0128] In some embodiments of Formulas (I) and (III), R a21 , R b21 , R c21 , and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0129] In some embodiments of Formulas (I) and (III), R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl of R 2 are each optionally substituted with one or two independently selected R 2A substituents; each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a21, SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 is independently selected from; R a21 , R b21 , R c21 , and R d21 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0130] In some embodiments of formulas (I) and (III), R 2 is a 5- to 6-membered heteroaryl optionally substituted with one, two, or three independently selected R 2A substituents.

[0131] In some embodiments of formulas (I) and (III), R 2 is a 5- to 6-membered heteroaryl.

[0132] In some embodiments of formulas (I) and (III), R 2 is a 5- to 6-membered heterocycloalkyl.

[0133] In some embodiments of formulas (I) and (III), R 2is selected from 6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl, 4-ethyloxazol-5-yl, 3-methylpyridin-4-yl, 4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl, 2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl, 1-ethyl-1H-pyrazol-5-yl, 6-hydroxypyridin-3-yl, 2,6-dimethylpyridin-4-yl, 3-methyl-1H-pyrazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, oxazol-5-yl, imidazo[1,2-a]pyridin-6-yl, 3-fluoropyridin-4-yl, and 1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl.

[0134] In some embodiments of formulas (I) and (III), R 2 is selected from 6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl, 4-ethyloxazol-5-yl, and 3-methylpyridin-4-yl.

[0135] In some embodiments of formulas (I) and (III), R 2 is pyridinonyl.

[0136] In some embodiments of formulas (I) and (III), R 2 is 6-oxo-1,6-dihydropyridin-3-yl.

[0137] In some embodiments of formulas (I) and (III), R 2 is pyrimidin-4-yl.

[0138] In some embodiments of formulas (I) and (III), R 2 is selected from the group consisting of 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-4-yl, and 2,6-dimethylpyridin-4-yl.

[0139] In some embodiments of formulas (I) and (III), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, and R is selected from 4 the C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with one or two independently selected R 4A substituents.

[0140] In some embodiments of formulas (I) and (III), each R 4A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , S(O)R b41 , and S(O)2R b41 is independently selected from 4A C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with one, two, three, or four independently selected R 4B substituents.

[0141] In some embodiments of Formulas (I) and (III), R 4 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6is selected from alkynyl.

[0142] In some embodiments of formulas (I) and (III), R 4 is H.

[0143] In some embodiments of formulas (I) and (III), R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 is selected from alkynyl.

[0144] In some embodiments of formulas (I) and (III), R 2 is H.

[0145] In some embodiments of formulas (I) and (III), R 2 is 6-oxo-1,6-dihydropyridin-3-yl or imidazo[1,2-a]pyridin-6-yl; R 4 is H.

[0146] In some embodiments of formulas (I) and (III), R 2 is H; R 4 is -NHC(O)OC 1-6 alkyl.

[0147] In some embodiments of formulas (I) and (III), R 4 is C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)Rb4 and S(O)2R b4 is selected from

[0148] In some embodiments of formulas (I) and (III), R a4 , R b4 , R c4 , and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0149] In some embodiments of formulas (I) and (III), R 4 is selected from C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 ; R a4 , R b4 , R c4 , and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0150] In some embodiments of formulas (I) and (III), R 4 is selected from C(O)NR c4 R d4 and NR c4 C(O)OR a4 ;

[0151] In some embodiments of formulas (I) and (III), R 4 is NR c4 C(O)OR a4 .

[0152] In some embodiments of formulas (I) and (III), R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0153] In some embodiments of formulas (I) and (III), R 4 is selected from C(O)NR c4 R d4 and NR c4 C(O)OR a4 ; R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl.

[0154] In some embodiments of formulas (I) and (III), R 4 is -NHC(O)OC 1-6 alkyl.

[0155] In some embodiments of formulas (I) and (III), R 4 is -NHC(O)OCH2CH3.

[0156] In some embodiments of formulas (I) and (III), R 4 is C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, OR a4 , C(O)R b4 , C(O)NRc4 R d4 、 C(O)OR a4 、 NR c4 R d4 、 S(O)2NR c4 R d4 、 and S(O)2R b4 selected from, where R 4 's C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with one, two, or three independently selected R 4A substituents; R a4 、 R b4 、 R c4 、 and R d4 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are independently selected from, and R a4 、 R b4 、 R c4 、 and R d4 's C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-6 Alkyl- is each optionally substituted with one, two, or three independently selected R 4A substituents; Each R 4A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , NR c41 R d41 , S(O)2NR c41 R d41 , and S(O)2R b41 and is independently selected from R 4A wherein the C 1-6 alkyl, 5C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally substituted with one, two, or three independently selected R 4B substituents; R a41 , R b41 , R c41 , and R d41 are each H, C 1-6 alkyl, C 1-6Haloalkyl, phenyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, independently selected, R a41 , R b41 , R c41 , and R d41 's C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 4B Substituents; Each R 4B Is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, phenyl-C 1-3 Alkyl-, (C 3-6 Cycloalkyl)-C 1-3 Alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 Alkyl-, (5- to 6-membered heteroaryl)-C 1-3 Alkyl-, CN, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , NR c42 R d42 , S(O)2NR c42 R d42 , and S(O)2R b42 Independently selected from, R 4B 's C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, phenyl-C 1-3 Alkyl-, (C 3-6 Cycloalkyl)-C 1-3 Alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 Alkyl-, (5- to 6-membered heteroaryl)-C 1-3 Alkyl- are each optionally substituted with one, two, or three independently selected R 4Csubstituted with a substituent; R a42 、R b42 、R c42 、and R d42 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the C a42 、R b42 、R c42 、and R d42 alkyl, phenyl, C 1-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 3-6 substituents; Each R 4C is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a43 、C(O)R b43 、C(O)NR c43 R d43 、C(O)OR a43 、NR c43 R d43 、S(O)2NR c43 R d43 、and S(O)2R b43 ,and the C 4C alkyl of R 1-6 is optionally substituted with one or two independently selected R 4D substituents; R a43 、R b43 、R c43 、and R d43 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, and the C a43 alkyl of R b43 、R c43 、R d43 、and R 1-6 is optionally substituted with one or two independently selected R 4D substituents; substituted with a substituent, or alternatively, any R c43 and R d43 are attached to the same N atom and, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group, and the 4-, 5-, or 6-membered heterocycloalkyl group is optionally substituted with one, two, three, or four independently selected R 4D substituents; each R 4D is independently selected from C 1-3 alkyl and OH.

[0157] In some embodiments of formulas (I) and (III), R 4 is selected from phenyl-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, OR a4 , C(O)R b4 and S(O)2R b4 wherein the phenyl-C 4 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, and (5- to 10-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one, two, or three independently selected R 1-3 substituents; 4A R R a4 R b4 R c4 and R d4 are each independently selected from phenyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 alkyl-, and the phenyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C a4 R b4 R c4 and R d4 are each optionally substituted with one, two, or three independently selected R 1-3 substituents; 4A 4A Each R 4A is halo, C 1-6 alkyl, C 1-6 haloalkyl, 5- to 6-membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl-, OR a41 , S(O)2R b41 , and NR c41 R d41 is independently selected from, and R 4A 's C 1-6 alkyl, 5- to 6-membered heteroaryl, and (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl- are each optionally substituted with one, two, or three independently selected R 4B substituents; R a41 , R b41 , R c41 , and R d41 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and R a41 , R b41 , R c41 , and R d41 's C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 4B substituents; Each R 4B is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, CN, OR a42 , C(O)R b42 , C(O)OR a42 , and NR c42 R d42 is independently selected from, and R 4B 's C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3Alkyl- is each optionally substituted with one, two, or three independently selected R 4C substituents; R a42 R b42 R c42 and R d42 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycloalkyl, and the C a42 R b42 R c42 and R d42 alkyl, C 1-6 cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one, two, or three independently selected R 3-6 substituents; Each R 4C is independently selected from C 1-6 alkyl, CN, C(O)NR c43 R d43 C(O)OR a43 NR c43 R d43 and S(O)2R b43 and the C 4C alkyl of R 1-6 is optionally substituted with one or two independently selected R 4D substituents; R a43 R b43 R c43 and R d43 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, and the C a43 alkyl of R b43 R c43 R d43 and R 1-6 alkyl are each optionally substituted with one or two independently selected R 4D substituents or, c43 alternatively, any R d43 and R 4D ​are attached to the same N atom and, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group, and the 4-, 5-, or 6-membered heterocycloalkyl group is optionally substituted with one, two, three, or four independently selected R 4D substituents; each R 4D is independently selected from C 1-3 alkyl and OH.

[0158] In some embodiments of Formulas (I) and (III), R 4 is selected from C 6-10 aryl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, OR a4 , C(O)R b4 , and S(O)2R b4 , and the C 4 of R 6-10 aryl-C 1-6 alkyl- and (5- to 10-membered heteroaryl)-C 1-6 alkyl- are each optionally substituted with one, two, three, or four independently selected R 4A substituents; each R 4A is selected independently from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, OR a41 , SR a41 , and NR c41 R d41 , and the C 4A of R 1-6 alkyl, C 6-10 aryl, C3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally substituted with one, two, three, or four independently selected R 4B substituents.

[0159] In some embodiments of Formulas (I) and (III), R 4 is selected from C 6-10 Aryl-C 1-3 Alkyl-, (5- to 10-membered heteroaryl)-C 1-3 Alkyl-, OR a4 , C(O)R b4 , and S(O)2R b4 ; R 4 of C 6-10 Aryl-C 1-6 Alkyl- and (5- to 10-membered heteroaryl)-C 1-3 Alkyl- is each optionally substituted with one, two, three, or four independently selected R 4A substituents; each R 4A is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl-, C 3-10 Cycloalkyl-C 1-3 Alkyl-, (5- to 10-membered heteroaryl)-C 1-3 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-3 Alkyl-, CN, OR a41 , SR a41 , and NR c41 R d41Selected independently from, R 4A of C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl-, C 3-10 cycloalkyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl- are each optionally substituted with one, two, or three independently selected R 4B substituents; each R 4B is halo, C 1-6 alkyl, C 1-6 haloalkyl, OR a42 , COOR a42 and NR c42 R d42 selected independently from; R a4 and R b4 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, and azetidinyl, phenyl is optionally substituted with one or two groups selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R a41 R c41 and R d41 are each, H and C 1-6 alkyl; R a42 R c42 and R d42 are each, H and C 1-6 alkyl.

[0160] In some embodiments of formulas (I) and (III), R 4 is, C 6-10 aryl-C 1-3Alkyl- and (5- to 10-membered heteroaryl)-C 1-3 selected from alkyl-, where R 4 of C 6-10 aryl-C 1-3 Alkyl- and (5- to 10-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one, two, three, or four independently selected R 4A substituents; each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OR a41 ; each R a41 is independently selected from H and C 1-3 alkyl.

[0161] In some embodiments of formulas (I) and (III), R 4 is C6 aryl-C 1-3 alkyl- optionally substituted with one, two, or three substituents independently selected from OH and halo.

[0162] In some embodiments of formulas (I) and (III), R 4is pyridin-2-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 7H-pyrrolo[2,3-b]pyridin-7-yl, 2-fluorophenoxy, hydroxy(pyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl, (imidazo[1,2-a]pyridin-8-yl)methyl, (pyrazolo[1,5-a]pyridin-7-yl)methyl, (2H-indazol-2-yl)methyl, (1H-indazol-1-yl)methyl, (2,6-difluorophenyl)(hydroxy)methyl, (2,5-difluorophenyl)(hydroxy)methyl, (2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl, (2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, phenylsulfonyl, azetidine-1-carbonyl, benzodioxazol-4-ylmethyl, 2-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzyl, 2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl, 2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)benzyl, 2-fluoro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl, 2-fluoro-6-((3-oxopiperazin-1-yl)methyl)benzyl, 2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl, 2-fluoro-6-(((2-methyl-2H-1,2,3-triazol-4-yl)amino)methyl)benzyl, 2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl, amino(2,6-difluorophenyl)methyl, (2,6-difluorophenyl)(methylamino)methyl, (2,6-difluorophenyl)((2-hydroxyethyl)amino)methyl, amino(2-fluorophenyl)methyl, amino(2,Selected from (6-difluorophenyl)methyl, (3-(oxazol-5-yl)pyridin-2-yl)methyl, 2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)benzyl, (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl, 2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl, (2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl, 2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl, (2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl, 2-fluoro-6-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzyl, (2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl, 2-fluoro-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)benzyl, 2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl, 2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl, 2-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-6-fluorobenzyl, 2-fluoro-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)benzyl, (3-methylpyridin-2-yl)methoxy, (3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl, (3-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl, (3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl, 2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl, and (6-methoxypyridin-2-yl)methyl.,

[0163] In some embodiments of Formulas (I) and (III), R 4is selected from pyridin-2-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 7H-pyrrolo[2,3-b]pyridin-7-yl, 2-fluorophenoxy, hydroxy(pyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl, imidazo[1,2-a]pyridin-8-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, (2H-indazol-2-yl)methyl, 1H-indazol-1-yl)methyl, (2,6-difluorophenyl)(hydroxy)methyl, (2,5-difluorophenyl)(hydroxy)methyl, (2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl, (2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, phenylsulfonyl, and azetidine-1-carbonyl.

[0164] In some embodiments of formulas (I) and (III), Cy 1 is C 7 aryl optionally substituted with one, two, three, or four independently selected R 6-10 substituents.

[0165] In some embodiments of formulas (I) and (III), Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents.

[0166] In some embodiments of formulas (I) and (III), each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0167] In some embodiments of formulas (I) and (III), Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents, and each R7 is selected independently from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NO2.

[0168] In some embodiments of formulas (I) and (III), Cy 1 is phenyl substituted with one or two independently selected R 7 substituents, each R 7 is selected independently from halo and CN.

[0169] In some embodiments of formulas (I) and (III), Cy 1 is phenyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl, halo, and CN.

[0170] In some embodiments of formulas (I) and (III), Cy 1 is phenyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl and CN.

[0171] In some embodiments of formulas (I) and (III), Cy 1 is unsubstituted phenyl.

[0172] In some embodiments of formulas (I) and (III), Cy 1 is cyanophenyl or cyanofluorophenyl.

[0173] In some embodiments of formulas (I) and (III), Cy 1 is cyanophenyl.

[0174] In some embodiments of formulas (I) and (III), Cy 1 is 3-cyanophenyl or 3-cyano-2-fluorophenyl.

[0175] In some embodiments of formulas (I) and (III), R 1 is H; Cy 1 is phenyl optionally substituted with one, two, three, or four independently selected R 7 substituents; 6-10 is aryl; R 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and the C 2 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 3-10 substituents. 2A

[0176] In some embodiments of formulas (I) and (III), R 1 is H; Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents; R 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C 2 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 3-10 substituents. 2A

[0177] In some embodiments of formulas (I) and (III), R 1 is H or C 1-6 alkyl;​​ R 2 is a 5- to 6-membered heteroaryl optionally substituted with one, two, or three independently selected R 2A substituents; R 4 is selected from C 6-10 aryl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, OR a4 , C(O)R b4 , and S(O)2R b4 wherein the C 4 aryl-C 6-10 alkyl- and (5- to 10-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one, two, three, or four independently selected R 1-3 substituents; Each R 4A is independently selected from halo, C 4A alkyl, C 1-6 haloalkyl, C 1-6 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3-10 aryl-C 6-10 alkyl-, C 1-3 cycloalkyl-C 3-10 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl-, CN, OR 1-3 , SR a41 , and NR a41 R c41 wherein the C d41 alkyl, C 4A aryl, C 1-6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 3-10 alkyl-, C 6-10 cycloalkyl-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 3-10 alkyl- are each independently selected from the group consisting of halo, C 1-3 alkyl, C 1-3Alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-3 Each alkyl- is optionally substituted with one, two, or three independently selected R 4B substituents; Each R 4B is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, OR a42 , COOR a42 and NR c42 R d42 ; Cy 1 is phenyl optionally substituted with one, two, or three independently selected R 7 substituents; R a4 and R b4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, and azetidinyl, where phenyl is optionally substituted with one or two groups selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; R a41 , R c41 , and R d41 are each independently selected from H and C 1-6 alkyl; R a42 , R c42 , and R d42 are each independently selected from H and C 1-6 alkyl; Each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and CN.

[0178] In some embodiments of formulas (I) and (III), R 1 is H or C 1-6 alkyl; R 2 is one, two, or three independently selected R2A a 5- or 6-membered heteroaryl optionally substituted with substituents; R 4 is selected from C 6-10 aryl-C 1-3 alkyl- and (5- to 10-membered heteroaryl)-C 1-3 alkyl-, and the C of R 4 aryl-C 6-10 alkyl- and (5- to 10-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one, two, three, or four independently selected R 1-3 substituents; 4A Each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OR a41 ; Cy 1 is phenyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl and CN; Each R a41 is independently selected from H and C 1-3 alkyl.

[0179] In some embodiments of formulas (I) and (III), R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R 4 is C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NRc4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)OR a4 , N.R. c4 C(O)NR c4 R d4 , S(O)R b4 , and S(O)2R b4 Selected from; Cy 1 is one, two, three, or four independently selected R 7 C optionally substituted with a substituent 6-10 is aryl; R a4 , R b4 , R c4 , and R d4 are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 independently selected from alkynyl; Each R 7 Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Independently selected from alkynyl, CN, and NO2.

[0180] In some embodiments of formula (I) and (III), R 1 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; R 2 is C 6-10 Aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R 2 C 6-10 Aryl, C 3-10Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 2A substituents; R 4 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R 2A is selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , S(O)R b21 and S(O)2R b21 independently selected from; Cy 1 is optionally substituted with one, two, three, or four independently selected R 7 substituents and is C 6-10 aryl; R a21 , R b21 , R c21 and R d21 are each independently selected from H, C 1-6 alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, and C 2-6 is independently selected from alkynyl; Each R 7 is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 is independently selected from alkynyl, CN, and NO2.

[0181] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 is selected from alkynyl; R 4 is C(O)NR c4 R d4 and NR c4 is selected from C(O)OR a4 ; Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents; R a4 , R c4 , and R d4 are each independently selected from H and C 1-6 alkyl; Each R 7 is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 is independently selected from alkynyl, CN, and NO2.

[0182] In some embodiments of formulas (I) and (III), R 1 is H; R 2is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and R 2 the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl of R 2A are each optionally substituted with one or two independently selected R R 4 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R 2A is selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 C(O)R b21 , NR c21 C(O)OR a21 , NR c21 C(O)NR c21 R d21 , and S(O)R b21 independently; Cy 1 is phenyl optionally substituted with one or two independently selected R 7 substituents; R a21 , R b21 , R c21 , and R d21 are each independently selected from H and C 1-6 alkyl; each R 7 is selected from halo, C 1-6 alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, and NO2 are independently selected.

[0183] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is H; R 4 is NR c4 C(O)OR a4 and; Cy 1 is cyanophenyl; R a4 and R c4 are each independently selected from H and C 1-6 alkyl.

[0184] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl; R 4 is H; Cy 1 is cyanophenyl.

[0185] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two C 1-3 alkyl groups; R 4 is phenyl-C 1-3 alkyl- or pyridyl-C 1-3 alkyl-, and phenyl-C 1-3 alkyl- and pyridyl-C 1-3Alkyl- is each optionally substituted with one, two, or three substituents independently selected from OH and halo; Cy 1 is cyanophenyl.

[0186] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl; R 4 is phenyl-C optionally substituted with one, two, or three substituents independently selected from OH and halo 1-3 alkyl-; Cy 1 is cyanophenyl.

[0187] In some embodiments of formulas (I) and (III), R 1 is H; R 2 is pyrimidin-4-yl; R 4 is phenyl-C optionally substituted with one, two, or three substituents independently selected from OH and halo 1-3 alkyl-; Cy 1 is cyanophenyl.

[0188] In some embodiments of formulas (I) and (III), the compound is of formula (IIIa):

Chemical formula

[0189] In some embodiments of formula (IIIa), Cy 1 is phenyl substituted with one or two independently selected R 7 substituents; each R 7 is independently selected from halo and CN; R 2 is H, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C 2 aryl, C 6-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected R 3-10 substituents; 2A each R 2A is D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 a21 , C(O)OR b21 , OC(O)R c21 , OC(O)NR d21 R c21 , NR d21 R c21 , NR b21 C(O)R c21 , NR a21 C(O)OR c21 , NR c21 C(O)NR d21 R b21 , S(O)R b21 , and S(O)2R 2A and is independently selected from R 1-6 wherein said C 1-6 ​​Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by one, two, or three independently selected R 2B is substituted with a substituent; R a21 , R 241 , R c21 , and R d21 are H and C, respectively. 1-6 Alkyl, and C 1-6 haloalkyl; R a21 , R 241 , R c21 , and R d21 C above 1-6 Alkyl is optionally selected from 1, 2, or 3 independently selected R 2A is substituted with a substituent; Each R 2B D, halo, OH, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0190] R 4 is C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , S(O)NR c4 R d4, and S(O)2R b4 selected from, R 4 of C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with one, two, or three independently selected R 4A substituents; R a4 , R b4 , R c4 , and R d4 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are independently selected from, R a4 , R b4 , R c4 , and R d4 of C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with one, two, or three independently selected R 4A substituents; each R4A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , NR c41 R d41 , S(O)2NR c41 R d41 , and S(O)2R b41 is independently selected from, R 4A of C 1-6 alkyl, 5C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with one, two, or three independently selected R 4B substituents; R a41 , R b41 , R c41 , and R d41 are each, H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are independently selected from, R a41 , Rb41 , R c41 , and R d41 's C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 4B substituents; Each R 4B is halo, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, phenyl-C 1-3 alkyl-, (C 3-6 cycloalkyl)-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl-, CN, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , NR c42 R d42 , S(O)2NR c42 R d42 , and S(O)2R b42 is independently selected from, and R 4B 's C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, phenyl-C 1-3 alkyl-, (C 3-6 cycloalkyl)-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, (5- to 6-membered heteroaryl)-C 1-3 alkyl- is each optionally substituted with one, two, or three independently selected R 4C substituents; R a42 , R b42 , R c42 , and R d42are each, H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, independently selected, R a42 , R b42 , R c42 , and R d42 of C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 4C substituents; each R 4C is, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)OR a43 , NR c43 R d43 , S(O)2NR c43 R d43 , and S(O)2R b43 is independently selected from, R 4C of C 1-6 alkyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one or two independently selected R 4D substituents; R a43 , R b43 , R c43 , and R d43 are each, H, C 1-6 alkyl, and C 1-6 haloalkyl, independently selected, R a43 , R b43 , R c43 , and R d43 of C 1-6 alkyl are each optionally substituted with one or two independently selected R 4D substituents, or alternatively, any Rc43 and R d43 are attached to the same N atom and, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group, and the 4-, 5-, or 6-membered heterocycloalkyl group is optionally substituted with one, two, three, or four independently selected R 4D substituents; Each R 4D is independently selected from C 1-3 alkyl and OH.

[0191] In some embodiments of formula (IIIa), Cy 1 is 3-cyanophenyl or 3-cyano-2-fluorophenyl; R 2 is selected from H, 5- to 10-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the 5- to 10-membered heteroaryl and 4- to 7-membered heterocycloalkyl of R 2 are each optionally substituted with one, two, or three independently selected R 2A substituents; Each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OH, and the above C 2A alkyl of R 1-6 is optionally substituted with one, two, or three independently selected R 2B substituents; Each R 2B is independently selected from D, halo, and OH; R 4 is selected from phenyl-C 1-3 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 alkyl-, (5- to 10-membered heteroaryl)-C 1-3 alkyl-, OR a4 , C(O)R b4 , and S(O)2R b4 and the phenyl-C 4 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-3 of R1-3 Alkyl- and (5- to 10-membered heteroaryl)-C 1-3 Each alkyl- is optionally substituted with one, two, or three independently selected R 4A substituents; R a4 R b4 R c4 and R d4 are each independently selected from phenyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 alkyl-; each R a4 R b4 R c4 and R d4 of phenyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 alkyl- is optionally substituted with one, two, or three independently selected R 4A substituents; Each R 4A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, 5- to 6-membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl-, OR a41 S(O)2R b41 and NR c41 R d41 ; each R 4A of C 1-6 alkyl, 5- to 6-membered heteroaryl, and (4- to 10-membered heterocycloalkyl)-C 1-3 alkyl- is optionally substituted with one, two, or three independently selected R 4B substituents; R a41 R b41 R c41 and R d41 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl; each R a41 R b41 R c41 and R d41 of C 1-6Each of the alkyl and 5- to 6-membered heteroaryl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent; Each R 4B Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, (5-6 membered heteroaryl)-C 1-3 Alkyl-, CN, OR a42 , C(O)R b42 , C(O)OR a42 , and N.R. c42 R d42 are independently selected from R 4B C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 Each alkyl- is optionally selected from 1, 2, or 3 independently selected R 4C is substituted with a substituent; R a42 , R b42 , R c42 , and R d42 are H and C, respectively. 1-6 Alkyl, C 3-6 R is independently selected from cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycloalkyl; a42 , R b42 , R c42 , and R d42 C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycloalkyl are each optionally represented by one, two, or three independently selected R 4C is substituted with a substituent; Each R 4C is C 1-6 Alkyl, CN, C(O)NR c43 R d43 , C(O)OR a43 , N.R. c43 R d43 , and S(O)2Rb43 selected independently from, R 4C of C 1-6 alkyl, 4- to 7-membered heterocycloalkyl, and (5- to 6-membered heteroaryl)-C 1-3 alkyl- are each optionally substituted with one or two independently selected R 4D substituents; R a43 、R b43 、R c43 、and R d43 are each, H, C 1-6 alkyl, and C 1-6 haloalkyl, selected independently from, R a43 、R b43 、R c43 、and R d43 of C 1-6 alkyl are each optionally substituted with one or two independently selected R 4D substituents, or alternatively, any R c43 and R d43 are attached to the same N atom and together with the N atom to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl group, and the 4-, 5-, or 6-membered heterocycloalkyl group is optionally substituted with one, two, three, or four independently selected R 4D substituents; each R 4D is selected from C 1-3 alkyl and OH.

[0192] In some embodiments of formula (IIIa), R 2 is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two C 1-3 alkyl groups; R 4 is phenyl-C 1-3 alkyl- or pyridyl-C 1-3 alkyl-, and phenyl-C 1-3 alkyl- and pyridyl-C1-3 Alkyl- is each optionally substituted with one, two, or three substituents independently selected from OH and halo; Cy 1 is 3-cyanophenyl.

[0193] In some embodiments of formulas (I) and (III), the compound is of formula (IIIb):

Chemical formula

[0194] In some embodiments of formulas (I) and (III), the compound is of formula (IIIc):

Chemical formula

[0195] In some embodiments, the compound is the (S)-enantiomer of one of the foregoing compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the (R)-enantiomer of one of the foregoing compounds, or a pharmaceutically acceptable salt thereof.

[0196] Furthermore, it is understood that the specific features of the invention described in connection with individual embodiments for purposes of clarity can also be provided as a single embodiment by combination. Conversely, the various features of the invention described in connection with a single embodiment for purposes of brevity can be provided individually or in any suitable sub-combination.

[0197] Throughout various portions of this specification, divalent linking substituents are described. Specifically, each divalent linking substituent is intended to include linking substituents in both forward and reverse configurations. For example, -NR(CR’R’’) n - includes both -NR(CR’R’’) n and -(CR’R’’) n NR-. When a structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

[0198] The term "n-membered" (where n is an integer) typically refers to the number of ring-forming atoms in a moiety, and in this case the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0199] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected and substitution can occur at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms. Substitution at a given atom should be understood to be limited by valence.

[0200] As used herein, the phrase "each 'variable' is independently selected" means substantially the same thing as "the 'variable' is selected for each occurrence".

[0201] Throughout the definitions, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C 1-3 , C 1-4 , C 1-6 and so on.

[0202] As used herein, the term "C" when used alone or in combination with other terms n-m "alkyl" refers to a saturated hydrocarbon group that can be straight-chain or branched and has n to m carbon atoms. Examples of alkyl moieties include chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc., but are not limited thereto. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0203] As used herein, "C" n-m "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and n to m carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0204] As used herein, "C" n-m "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0205] As used herein, the term "C" when used alone or in combination with other terms n-mThe term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group in the formula has from n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0206] As used herein, the term "amino" refers to a group of the formula -NH2.

[0207] As used herein, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m aryl" refers to an aryl group having from n to m ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, the aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl.

[0208] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0209] As used herein, "C n-m haloalkoxy" refers to a group of the formula -O-haloalkyl having from n to m carbon atoms. Examples of haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0210] As used herein, the term "C n-m haloalkyl", whether used alone or in combination with other terms, refers to an alkyl group having from 1 halogen atom to 2s + 1 halogen atoms, where the halogen atoms may be the same or different, "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbons. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0211] As used herein, the term "thio" refers to a group of the formula -SH.

[0212] As used herein, the term "carbonyl" refers to a group of the formula -C(O)NH2.

[0213] As used herein, the term "carbonyl", whether used alone or in combination with other terms, refers to a -C(O)- group.

[0214] As used herein, the term "C n-m alkylamino", whether used alone or in combination with other terms, refers to a group of the formula -NH(alkyl), where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0215] As used herein, the term "C n-m alkoxycarbonyl", whether used alone or in combination with other terms, refers to a group of the formula -C(O)O-alkyl, where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0216] As used herein, "C n-m alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, wherein the alkyl group in the formula has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0217] As used herein, "C n-m alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, wherein the alkyl group in the formula has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0218] As used herein, "C n-m alkylsulfonylamino" refers to a group of the formula -NHS(O)2-alkyl, wherein the alkyl group in the formula has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0219] As used herein, the term "aminosulfonyl" refers to a group of the formula -S(O)2NH2.

[0220] As used herein, "C n-m alkylaminosulfonyl" refers to a group of the formula -S(O)2NH(alkyl), wherein the alkyl group in the formula has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0221] As used herein, "di(C n-m alkyl)aminosulfonyl" refers to a group of the formula -S(O)2N(alkyl)2, wherein each alkyl group in the formula independently has from n to m carbon atoms. In some embodiments, each alkyl group independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0222] As used herein, the term "aminosulfonylamino" refers to a group of the formula -NHS(O)2NH2.

[0223] As used herein, the term "C n-m alkylaminosulfonylamino" refers to a group of the formula -NHS(O)2NH(alkyl), wherein the alkyl group in the formula refers to a group having n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0224] As used herein, the term "di(C n-m alkyl)aminosulfonylamino" refers to a group of the formula -NHS(O)2N(alkyl)2, wherein each alkyl group in the formula independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0225] As used herein, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group of the formula -NHC(O)NH2.

[0226] As used herein, the term "C n-m alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), wherein the alkyl group in the formula refers to a group having n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0227] As used herein, the term "di(C n-m alkyl)aminocarbonylamino" refers to a group of the formula -NHC(O)N(alkyl)2, wherein each alkyl group in the formula independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0228] As used herein, the term "C n-mThe term "alkylcarbamyl" refers to a group of the formula -C(O)-NH(alkyl), where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0229] As used herein, "C" n-m The term "alkylthio" refers to a group of the formula -S-alkyl, where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0230] As used herein, "C" n-m The term "alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0231] As used herein, "C" n-m The term "alkylsulfonyl" refers to a group of the formula -S(O)2-alkyl, where the alkyl group in the formula has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0232] As used herein, "cyano-C" 1-n The term "alkyl" refers to a group of the formula -(C 1-n alkylene)-CN, where the alkyl group in the formula has 1 to n carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms, for example -(C 1-3 alkylene)-CN.

[0233] As used herein, "HO-C" 1-n The term "alkyl" refers to a group of the formula -(C 1-nA group of (alkylene)-OH, wherein the alkyl group in the formula refers to a group having 1 to n carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms, for example, -(C 1-3 alkylene)-OH.

[0234] As used herein, "C 1-n alkoxy-C 1-n alkyl" refers to a group of the formula -(C 1-n alkylene)-O(C 1-n alkyl), wherein the alkyl group in the formula refers to a group having 1 to n carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms, for example, -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0235] As used herein, the term "carboxy" refers to a group of the formula -C(O)OH.

[0236] As used herein, the term "di(C n-m -alkyl)amino" refers to a group of the formula -N(alkyl)2, wherein the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0237] As used herein, the term "di(C n-m -alkyl)carbamyl" refers to a group of the formula -C(O)N(alkyl)2, wherein the two alkyl groups in the formula each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0238] As used herein, "C n-m alkylcarbonyloxy" refers to a group of the formula -OC(O)-alkyl, wherein the alkyl group in the formula has n to m carbon atoms.

[0239] As used herein, "aminocarbonyloxy" is a group of the formula -OC(O)-NH2.

[0240] As used herein, "C n-m alkylaminocarbonyloxy" is a group of the formula -OC(O)-NH-alkyl, wherein the alkyl group in the formula has n to m carbon atoms.

[0241] As used herein, "di(C n-m alkyl)aminocarbonyloxy" is a group of the formula -OC(O)-N(alkyl)2, wherein each alkyl group in the formula independently has n to m carbon atoms.

[0242] As used herein, "C n-m alkoxycarbonylamino" is a group of the formula -NHC(O)O(C n-m alkyl), wherein the alkyl group in the formula has n to m carbon atoms.

[0243] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon containing a cyclic alkyl group and a cyclic alkenyl group. The cycloalkyl group can include monocyclic or polycyclic (e.g., having two fused rings) groups, spiro rings, and bridged rings (e.g., bridged bicycloalkyl groups). The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted with oxo or sulfide (e.g., C(O) or C(S)). Also, the definition of cycloalkyl includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond), such as benzo derivatives or thienyl derivatives of cyclopentane, cyclohexane, etc. A cycloalkyl group containing a fused aromatic ring can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. The cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C 3-10 ). In some embodiments, cycloalkyl is monocyclic or bicyclic C 3-10It is cycloalkyl. In some embodiments, the cycloalkyl is C 3-7 It is a monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 4-7 It is a monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 4-10 of spirocyclic or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0244] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any N that forms a ring in the heteroaryl moiety can be an N-oxide. In some embodiments, heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 3 to 10, 4 to 10, 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, 1 to 2, or 1 ring-forming heteroatom. When the heteroaryl group contains a plurality of heteroatom ring members, the heteroatoms may be the same or different.Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, etc.

[0245] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocyclic ring having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are substituted with a heteroatom selected from N, O, S, and B, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted with one or more oxo or sulfide groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). When the ring-forming carbon atom or ring-forming heteroatom of the heterocycloalkyl group is optionally substituted with one or more oxo or sulfide groups, the O or S of the above group is added to the number of ring-forming atoms specified herein (e.g., 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, the ring-forming carbon atom is substituted with an oxo group, and the 6-membered heterocycloalkyl group is further substituted with a methyl group). The heterocycloalkyl group includes monocyclic and polycyclic (e.g., having 2 fused rings) systems. The heterocycloalkyl includes monocyclic and polycyclic 3- to 10-membered, 4- to 10-membered, 5- to 10-membered, 4- to 7-membered, 5- to 7-membered, or 5- to 6-membered heterocycloalkyl groups. The heterocycloalkyl group may also include spiro rings and bridged rings (e.g., a 5- to 10-membered bridged biheterocycloalkyl ring in which one or more of the ring-forming carbon atoms are substituted with a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0246] Also, the definition of heterocycloalkyl includes moieties having one or more aromatic rings fused to the non-aromatic heterocyclic ring (i.e., having a common bond), such as benzo derivatives or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including the ring-forming atoms of the fused aromatic ring.

[0247] In some embodiments, the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocycloalkyl has 1 or 2 heteroatoms independently selected from N, O, S, and B and is a monocyclic 4- to 6-membered heterocycloalkyl having one or more oxidized ring members. In some embodiments, the heterocycloalkyl has 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and is a monocyclic or bicyclic 5- to 10-membered heterocycloalkyl having one or more oxidized ring members. In some embodiments, the heterocycloalkyl has 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and is a monocyclic or bicyclic 5- to 10-membered heterocycloalkyl having one or more oxidized ring members. In some embodiments, the heterocycloalkyl has 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and is a monocyclic 5- to 6-membered heterocycloalkyl having one or more oxidized ring members.

[0248] Examples of heterocycloalkyl groups include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline, benzazepine, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azadamantanyl, diazadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like. For example, examples of heterocycloalkyl groups include the following groups (with and without N-methyl substitution): [Chemical formula] .

[0249] As used herein, "C o-p cycloalkyl-C n-m alkyl-" refers to a group of the formula cycloalkyl-alkylene- in which the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0250] As used herein, "C o-p aryl-C n-m alkyl-" refers to a group of the formula aryl-alkylene- in which the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0251] As used herein, "heteroaryl-C n-m alkyl-" refers to a group of the formula heteroaryl-alkylene- in which the alkylene linking group has n to m carbon atoms.

[0252] As used herein, "heterocycloalkyl-C n-m alkyl-" refers to a group of the formula heterocycloalkyl-alkylene- in which the alkylene linking group has n to m carbon atoms.

[0253] As used herein, "alkyl linking group" is a divalent straight-chain or branched alkyl linking group ("alkylene group"). For example, "C o-p cycloalkyl-C n-m alkyl-", "C o-p aryl-C n-m alkyl-", "phenyl-C n-m alkyl-", "heteroaryl-C n-m alkyl-", and "heterocycloalkyl-C n-m alkyl-" contain an alkyl linking group. Examples of an "alkyl linking group" or "alkylene group" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0254] In certain instances, the definition or embodiment refers to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise specified, these rings can be attached to any ring member provided that the valence of the atoms is not exceeded. For example, the azetidine ring can be attached at any position of the ring, and thus the pyridin-3-yl ring is attached at the 3-position.

[0255] As used herein, the term "oxo" refers to an oxygen atom as a divalent substituent (i.e., =O), which forms a carbonyl group (e.g., C=O or C(O)) when attached to carbon, or forms a nitroso group, a sulfinyl group, or a sulfonyl group when attached to a heteroatom such as nitrogen or sulfur.

[0256] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent, e.g., R 7 or R 2A is independently selected from the corresponding list for each occurrence.

[0257] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the present disclosure containing an asymmetrically substituted carbon atom may be isolated in the form of an optically active form or a racemic form. Methods for preparing an optically active form from an optically inactive starting material are known in the art and include, for example, resolution of a racemic mixture or stereoselective synthesis. Many geometric isomers such as olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Although the cis and trans geometric isomers of the compounds of the present disclosure are described, these may be isolated as a mixture of isomers or as a separated isomeric form. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The formulas provided herein (e.g., formula (I), (II), etc.) include the stereoisomers of the compounds.

[0258] The resolution of a racemic mixture of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using an acidic chiral resolving agent that is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method include, for example, optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0259] The resolution of a racemic mixture can also be carried out by elution through a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). One of ordinary skill in the art can determine a suitable elution solvent composition.

[0260] The compounds provided herein also include tautomers. Tautomers are formed by the exchange of a single bond with an adjacent double bond accompanied by the movement of a proton. Tautomers include prototropic tautomers, which are isomers in protonated states having the same empirical formula and the same total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imido acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomers may be in an equilibrium state or may be stereochemically fixed in one form by appropriate substitution.

[0261] All compounds and their pharmaceutically acceptable salts may be present together with other substances such as water and solvents (e.g., hydrates and solvates), or may be isolated.

[0262] In some embodiments, the preparation of the compounds may involve the addition of an acid or a base, for example, which affects the catalysis of the desired reaction or the formation of a salt form such as an acid addition salt.

[0263] In some embodiments, the compounds or salts thereof provided herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partially separated materials can include, for example, concentrated compositions of the compounds provided herein. Substantially separated materials can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds or salts thereof provided herein. Methods for isolating the compounds and their salts are routine in the art.

[0264] As used herein, the term "compound" means all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. Compounds herein that are identified by name or structure as a particular tautomer are intended to include other tautomers unless otherwise specified.

[0265] The phrase "pharmaceutically acceptable" as used herein means that such compounds, substances, compositions, and / or dosage forms are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0266] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by converting an existing acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid or free base form with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two, and generally, solvents such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. A list of suitable salts is described in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0267] Synthesis As will be appreciated by those skilled in the art, the compounds provided herein can be prepared using known organic synthetic techniques, including their salts and stereoisomers, and can be synthesized according to any of a number of possible synthetic routes.

[0268] The compounds of Formulas 1-14 and 1-15 can be prepared via the synthetic route outlined in Scheme 1. Alkylation of the commercially available starting material 1-1 with the carbonyl adduct 1-2 (Hal is a halide such as F, Cl, Br, or I) followed by a condensation reaction at elevated temperature using a suitable reagent such as ammonium acetate yields the bicyclic compound 1-3. Next, reacting compound 1-3 with a reagent such as phosphoryl chloride (POCl3) affords the intermediate 1-4. Aromatic nucleophilic substitution (S N Ar) reaction of the intermediate 1-4 with the amine adduct 1-5 (PG is a suitable protecting group such as 2,4-dimethoxybenzyl) followed by reduction of the ester functional group with a suitable reducing agent (e.g., DIBAL-H) gives the alcohol 1-6. Halogenation of 1-6 with a suitable reagent such as phosphorus tribromide (PBr3) yields the intermediate 1-7. Next, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), compound 1-7 is cross-coupled with the adduct of Formula 1-8 to obtain a cross-coupling product, followed by removal of the protecting group to generate the intermediate 1-9. Wherein, M is boric acid, boric acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. In some embodiments, Cy 4 is R 4 or R 4 -R 4a and can be. Halogenation of 1-9 with a suitable reagent such as N-bromosuccinimide (NBS) gives two isomers 1-10 and 1-11. Next, using reaction conditions similar to those described for the preparation of 1-9 from 1-7, reacting the two isomers 1-10 and 1-11 with either of the adducts 1-12 or 1-13 allows the preparation of the final products 1-14 and 1-15. Scheme 1.

Chemical formula

[0269] The compound of Formula 2-7 can be prepared via the synthetic route outlined in Scheme 2. Alkylation of a commercially available starting material 2-1 (Hal is a halide such as F, Cl, Br, or I) with a carbonyl adduct 1-2, followed by condensation at high temperature using a suitable reagent such as ammonium acetate, yields a bicyclic compound 2-2. Next, when compound 2-2 is reacted with a suitable reagent such as phosphoryl chloride (POCl3), an intermediate 2-3 can be obtained. An aromatic nucleophilic substitution (S N Ar) reaction of intermediate 2-3 with an amine adduct 1-5 (PG is a suitable protecting group such as 2,4-dimethoxybenzyl), followed by removal of the protecting group, gives compound 2-4. Halogenation of 2-4 with a suitable reagent such as N-bromosuccinimide (NBS) gives compound 2-5. Next, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), intermediate 2-5 is cross-coupled with an adduct of Formula 1-12 to give compound 2-6. Wherein, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. Next, a second cross-coupling reaction with compound 1-8 is carried out on intermediate 2-6 using the same procedure as described for the preparation of 2-6 from 2-5 to give product 2-7. Scheme 2.

Chemical formula

[0270] The compound of Formula 3-6 can be prepared via the synthetic route outlined in Scheme 3. An aromatic nucleophilic substitution (S NIntermediate 3-1 is obtained by reaction (Ar) followed by removal of the protecting group. Halogenation of 3-1 with a suitable reagent such as N-bromosuccinimide (NBS) and subsequent reduction of the ester functional group with a suitable reducing agent (e.g., DIBAL-H) yields alcohol 3-2. Next, intermediate 3-2 is oxidized with a suitable oxidizing agent (e.g., Dess-Martin periodinane) to afford aldehyde 3-3. Then, secondary alcohol 3-5 is obtained by an addition reaction of 3-3 and 3-4 (M 1 is a metal group such as MgBr or Li). The final product 3-6 can be prepared by a cross-coupling reaction of intermediate 3-5 and the adduct of formula 1-12 under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). In the formula, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. Scheme 3.

Chemical Structure

[0271] The compound of Formula 4-5 can be prepared via the synthetic route outlined in Scheme 4. By a halogenation reaction of an appropriate reagent such as N-bromosuccinimide (NBS) with Compound 3-1 (prepared using the procedure of Scheme 3), Compound 4-1 (Hal is a halide such as F, Cl, Br, or I) is obtained. Next, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), Compound 4-1 is cross-coupled with the adduct of Formula 1-12 to generate Intermediate 4-2. Wherein, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. By hydrolysis of 4-2 with a suitable reagent such as sodium hydroxide, Carboxylic Acid 4-3 is obtained. Next, under standard amide coupling conditions such as using HATU as a coupling reagent and DIPEA as a base, Compound 4-3 is reacted with Amine 4-4 to generate Product 4-5. Scheme 4.

Chemical Structure

[0272] The compound of Formula 5-7 can be prepared via the synthetic route outlined in Scheme 5. Aromatic nucleophilic substitution of a commercially available starting material 5-1 (Hal is a halide such as F, Cl, Br, or I) with Amine 1-5 (PG is a suitable protecting group such as 2,4-dimethoxybenzyl) (S NCompound 5-2 is obtained by reaction (Ar). Next, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), compound 5-2 can be cross-coupled with an adduct of formula 5-3 to produce intermediate 5-4. In the formula, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. The protecting group of 5-4 can be removed to obtain compound 5-5. Halogenation of 5-5 with a suitable reagent such as N-bromosuccinimide (NBS) gives intermediate 5-6. Next, compound 5-6 can be cross-coupled with an adduct of formula 1-12 using the same procedure as described for the preparation of 5-4 from 5-2 to obtain product 5-7. Scheme 5.

Chemical Structure

[0273] The compound of formula 6-9 can be prepared via a synthetic route outlined in Scheme 6. A commercially available starting material 6-1 (Hal is a halide such as F, Cl, Br, or I) can be reacted with a suitable reagent such as t-butyl O-mesitylenecarbamate (Journal of Heterocyclic Chemistry, 1975, 12, 107) to form a pyridinium salt 6-2. Next, intermediate 6-2 can be condensed with an adduct of formula 6-3 to form compound 6-4. Aromatic nucleophilic substitution of 6-4 with amine 1-5 (PG is a suitable protecting group such as 2,4-dimethoxybenzyl) (S NCompound 6-5 is obtained by reaction (Ar). Compound 6-6 can be prepared by a cross-coupling reaction of intermediate 6-5 with an adduct of formula 5-3 under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). Wherein, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. The protecting group of 6-6 is removed to obtain compound 6-7, and a halogenation reaction can be carried out on this using a suitable reagent such as N-bromosuccinimide (NBS) to form compound 6-8. The final product 6-9 can be synthesized by coupling 6-8 with an adduct of formula 1-12 using the same procedure as described for the preparation of compound 6-6 from 6-5. Scheme 6.

Chemical Structure

[0274] The compound of formula 7-9 can be prepared via a synthetic route outlined in Scheme 7. Alkylation of a commercially available starting material 7-1 (Hal is a halide such as F, Cl, Br, or I) with a carbonyl adduct 1-2, followed by a condensation reaction at high temperature using a suitable reagent such as ammonium acetate, yields a bicyclic compound 7-2. Next, when compound 7-2 is reacted with a reagent such as phosphoryl chloride (POCl3), intermediate 7-3 can be obtained. Aromatic nucleophilic substitution (S of intermediate 7-3 with an amine adduct 7-4 (PG is a suitable protecting group such as 4-methoxybenzyl) NIntermediate 7-5 is obtained by reaction (Ar). Next, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), compound 7-5 can be cross-coupled with the adduct of formula 7-6 to produce compound 7-7. In the formula, M is boric acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. A halogenation reaction is carried out on the intermediate obtained by removing the protecting group of 7-7 with a suitable reagent such as N-bromosuccinimide (NBS) to obtain adduct 7-8. Next, the final product 7-9 can be synthesized by coupling 7-8 with the adduct of formula 1-12 using the same procedure as described for the preparation of compound 7-7 from 7-5. Scheme 7

Chemical Structure

[0275] The compounds of Formulas 8-7, 8-10, and 8-11 can be prepared via the synthetic routes outlined in Scheme 8. First, under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), compound 7-5 (which can be prepared as described in Scheme 7) can be cross-coupled with a reagent of Formula 8-1 to produce compound 8-2. Wherein, M is a boronic acid, a boronic acid ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. Next, an appropriate reagent such as 1-bromopyrrolidine-2,5-dione can be used to carry out a halogenation reaction of 8-2 to obtain intermediate 8-3. Next, another cross-coupling reaction of 8-3 with reagent 1-12 can be carried out under the same conditions as described for the conversion from 7-5 to 8-2 to obtain compound 8-4. The vinyl group of 8-4 is cleaved under suitable conditions such as using osmium(VIII) oxide and sodium periodate, and the resulting aldehyde 8-5 is reacted with 3-4 (M 1 is a metal group such as MgCl or Li) in a 1,2-addition reaction to produce alcohol 8-6. Next, the protecting group (PG) of 8-6 can be removed to produce the desired product 8-7.

[0276] On the other hand, when a reduction reaction is carried out on aldehyde 8-5 using an appropriate reagent such as NaBH4, alcohol 8-8 can be obtained. Next, when a halogenation reaction is carried out on 8-8 using a reagent such as PBr3, intermediate 8-9 is obtained. The cross-coupling reaction of 8-9 with 1-8 (using the conditions described for the synthesis of 8-2 from 7-5) followed by the removal of the protecting group (PG) produces product 8-10. Alternatively, after reacting 8-9 with amine 4-4 in a nucleophilic substitution (S N 2) reaction, the product 8-11 can be obtained by removing the protecting group (PG). The reaction sequence described in this scheme can be rearranged and adjusted accordingly to suit the synthesis of each required analog. Scheme 8

Chem.

[0277] The compound of formula 9-9 can be prepared using the synthetic route outlined in Scheme 9. Aromatic nucleophilic substitution (S N Ar) with an amine 7-4 (PG is a suitable protecting group such as 4-methoxybenzyl) on a commercially available starting material 9-1 (Hal is a halide such as F, Cl, Br, or I) gives compound 9-2. Intermediate 9-2 can be reacted with a suitable reagent such as O-(mesitylsulfonyl)hydroxylamine (Journal of Heterocyclic Chemistry, 1975, 12, 107) to form the pyrazinium salt 9-3. Next, intermediate 9-3 can be condensed with an intermediate of formula 9-4 to form compound 9-5. Using a cross-coupling reaction of intermediate 9-5 with an intermediate of formula 5-3 under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), compound 9-6 can be prepared. Wherein, M is a boronic acid, a boronic ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]. Halogenation of compound 9-6 using a suitable reagent such as N-bromosuccinimide (NBS) forms compound 9-7. Compound 9-8 can be synthesized by coupling 9-7 with an intermediate of formula 1-12 using a procedure similar to that described for the preparation of compound 9-6 from 9-5. Removal of the protecting group of intermediate 9-8 forms the final product 9-9. Different analogs can be prepared by rearranging and / or omitting the specific synthetic steps described herein. Scheme 9.

Chem.

[0278] Method of Use The compounds of the present disclosure can modulate the activity of adenosine receptors such as subtype A2A receptor and A2B receptor. Accordingly, the compounds, salts, or any one or more of the compositions described herein can be used in a method of inhibiting adenosine receptors (e.g., A2A receptor and / or A2B receptor) by contacting the receptor with any one or more of the compounds, salts, or stereoisomers described herein. In some embodiments, the compounds or salts described herein can be used in a method of inhibiting the activity of adenosine receptors in an individual / patient in need of inhibition by administering the compounds or salts in an effective amount. In some embodiments, modulation is inhibition. In some embodiments, the contact is in vivo. In some embodiments, the contact is ex vivo or in vitro.

[0279] The compounds or salts described herein can be selective. "Selective" means that the compound binds to the adenosine receptor with high affinity or inhibits the adenosine receptor with high potency as compared to at least one other receptor such as a kinase. The compounds of the present disclosure can be dual antagonists (i.e., inhibitors) of adenosine receptors, such as A2A and A2B adenosine receptors.

[0280] Another aspect of the present disclosure relates to a method of treating an adenosine receptor-related disease or disorder in an individual (e.g., a patient), the method comprising administering to an individual in need of such treatment one or more compounds of the present disclosure or a pharmaceutical composition thereof in a therapeutically effective amount or therapeutically effective dose. Adenosine receptor-related diseases or disorders can include any disease, disorder, or condition directly or indirectly related to the expression or activity of adenosine receptors, including overexpression of adenosine receptors and / or abnormal activity levels.

[0281] The compounds of the present disclosure are useful for the treatment of diseases associated with the activity of adenosine receptors, including, for example, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, immunomodulatory deficiencies, central nervous system diseases, and diabetes.

[0282] Inhibitors developed based on the notable role of adenosine (e.g., A2A, A2B) receptors in multiple immunosuppressive mechanisms can enhance the immune system and suppress tumor progression. Adenosine receptor inhibitors can be used alone or in combination with other therapies to treat bladder cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC), lung metastases), melanoma (e.g., metastatic melanoma), breast cancer, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, uterine cancer, head and neck cancer, and renal cell carcinoma (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). https: / / globenewswire.com / news-release / 2017 / 04 / 04 / 954192 / 0 / en / Corvus-Pharmaceuticals-Announces-Interim-Results-from-Ongoing-Phase-1-1b-Study-Demonstrating-Safety-and-Clinical-Activity-of-Lead-Checkpoint-Inhibitor-CPI-444-in-Patients-with-Adva.html; Cekic C. et al., J Immunol, 2012, 188:198-205; Iannone, R. et al., Am. J. Cancer Res. 2014, 4:172-181 (studies have shown that blockade of both A2A and CD73 enhances the antitumor activity of anti-CTLA-4 mAb therapy in a B16F10 mouse melanoma model); Iannone, R. et al., Neoplasia, 2013, 15:1400-1410, and Beavis PA., et al., Proc Natl Acad Sci. USA, 2013, 110:14711-14716 (studies have shown that blockade of A2A and CD73 reduced metastases in a 4T1 breast tumor model with high CD73 expression). See also. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the colorectal cancer is colorectal cancer (CRC).

[0283] In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, squamous cell carcinoma of the head and neck, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is an Askin tumor, botryoid sarcoma, chondrosarcoma, Ewing sarcoma, malignant angioendothelioma, malignant Schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, fibromatosis, epitheloid sarcoma, extraskeletal chondroma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), pericytic tumor, angiosarcoma, Kaposi sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0284] In some embodiments, the disease or disorder is mesothelium Swollen is. In some embodiments, the disease or disorder is a mesothelioma 。

[0285] Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immune cells that originate from the myeloid lineage (the cell lineages derived from hematopoietic stem cells). MDSCs expand significantly as a result of changes in hematopoiesis in pathological conditions such as chronic infections and cancer. MDSCs are distinguished from other myeloid cell types in that they have a strong immunosuppressive effect rather than immunostimulatory properties. Similar to other myeloid cells, MDSCs interact with other immune cell types such as T cells, dendritic cells, macrophages, and natural killer cells to regulate their functions. In some embodiments, compounds described herein and the like can be used in methods related to cancer tissues (e.g., tumors) with high MDSC infiltration, including solid tumors with high macrophage and / or MDSC infiltration.

[0286] In some embodiments, the compounds of the present disclosure can be used for the treatment of pulmonary inflammation, including bleomycin-induced pulmonary fibrosis and injuries associated with adenosine deaminase deficiency (Baraldi, et al., Chem. Rev., 2008, 108, 238-263).

[0287] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for inflammatory diseases such as allergic reactions (e.g., A2B adenosine receptor-dependent allergic reactions) and other adenosine receptor-dependent immune reactions. Other inflammatory diseases that can be treated by the compounds of the present disclosure include respiratory disorders, sepsis, reperfusion injury, and thrombosis.

[0288] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for cardiovascular diseases such as coronary artery disease (myocardial infarction, angina pectoris, heart failure), cerebrovascular disease (stroke, transient ischemic attack), peripheral artery disease, and atherosclerosis and aortic aneurysm. Atherosclerosis is the root cause of various cardiovascular diseases. Atherosclerosis begins as fatty streaks in youth, progresses to plaques in adulthood, and ultimately causes thrombotic events leading to vascular occlusion, resulting in clinically significant morbidity and mortality. Antagonists against the A2B adenosine receptor and the A2A adenosine receptor may be beneficial for the prevention of atherosclerotic plaque formation (Eisenstein, A. et al., J. Cell Physiol., 2015, 230(12), 2891-2897).

[0289] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for disorders of motor activity; deficiencies caused by degeneration of the striatonigral dopamine system; and Parkinson's disease; and some of the symptoms that induce depression (Collins, L.E. et al. Pharmacol. Biochem. Behav., 2012, 100, 498-505.).

[0290] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for diabetes and related disorders, such as insulin resistance. Diabetes stimulates the production of adenosine, the expression of the A2B adenosine receptor (A2BR) that stimulates the production of IL-6 and CRP, insulin resistance, and the A 2B R gene single nucleotide polymorphism (ADORA2B SNP) affects the association with inflammatory markers. Increased A2BR signaling in diabetes may partially increase insulin resistance due to elevated inflammatory mediators. Selective A2BR blockers may be useful for the treatment of insulin resistance (Figler, R.A. et al. Diabetes, 2011, 60(2), 669-679).

[0291] The compounds provided herein, such as the compounds of formula (I) or any of its embodiments, are considered to have good pharmacological profiles and promising biopharmaceutical properties, such as toxicity profiles, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that the determination of appropriate biopharmaceutical properties is within the scope of the knowledge of those skilled in the art. For example, the determination of cytotoxicity in cells or the inhibition of specific targets or channels to determine potential toxicity.

[0292] The terms "individual" or "patient", used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0293] The phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that induces a biological or pharmaceutical response in a tissue, system, animal, individual, or human being sought by a researcher, veterinarian, physician, or other clinician.

[0294] As used herein, the terms "treat" or "treatment" refer to one or more of (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual in whom a lesion or symptom of the disease, condition, or disorder has occurred or is occurring (i.e., preventing further manifestation of the lesion and / or symptom); and (2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual in whom a lesion or symptom of the disease, condition, or disorder has occurred or is occurring (i.e., reversing the lesion and / or symptom), e.g., reducing the severity of the disease.

[0295] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases referenced herein, e.g., preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder, but in whom a lesion or symptom of the disease has not yet occurred or is not yet occurring.

[0296] Combination therapy I. Immune checkpoint therapy In some embodiments, the A2A and A2B dual inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer described herein. In some embodiments, they can be used in combination with one or more immune checkpoint inhibitors described herein for the treatment of melanoma. The compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of the present disclosure shown herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0297] In some embodiments, the A2A and A2B dual inhibitors provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, OX40, GITR, and CD137 (also known as 4-1BB).

[0298] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0299] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab or utomilumab).

[0300] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0301] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, for example, an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0302] In some embodiments, the inhibitor is INCB086550.

[0303] In some embodiments, the inhibitor is MCLA-145.

[0304] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0305] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0306] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0307] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, for example, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0308] In some embodiments, the inhibitor of the immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0309] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, for example, an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0310] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, a tumor-specific antigen (e.g., CD70), or a TGFβ receptor.

[0311] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0312] As shown throughout, additional compounds, inhibitors, agents, etc. can be formulated with the compounds of the invention into a single dosage form or a sustained-release dosage form, or can be co-administered or sequentially administered as separate dosage forms.

[0313] II. Cancer Treatment The growth and survival of cancer cells can be affected by multiple signaling pathways. Thus, combining inhibitors of different enzymes / proteins / receptors that exhibit different selectivities for targets that regulate activity is useful for treating such pathologies. By targeting multiple signaling pathways (or multiple biological molecules involved in a given signaling pathway), the potential for drug resistance that develops in the cell population can be reduced and / or the toxicity of the treatment can be alleviated.

[0314] The compounds of the present disclosure can be used in combination with inhibitors of one or more other enzymes / proteins / receptors or one or more therapies for the treatment of diseases such as cancer. Examples of diseases and indications treatable by combination therapy are those described herein.

[0315] The compounds of the present disclosure can be used in combination with one or more additional pharmaceuticals such as, for example, chemotherapeutic agents, immuno-oncology drugs, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, and FAK kinase inhibitors. The one or more additional pharmaceuticals can be administered to a patient simultaneously or sequentially.

[0316] For example, the compounds disclosed herein can be used in combination with one or more inhibitors of the following kinases for the treatment of cancer and other diseases or disorders described herein: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. For the treatment of cancer and other diseases and disorders described herein, non-limiting examples of inhibitors that can be used in combination with the compounds of the present disclosure include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (such as epacadostat, NLG919, or BMS-986205), LSD1 inhibitors (such as INCB59872 and INCB60003), TDO inhibitors, PI3K delta inhibitors (such as INCB50797 and INCB50465), Pim inhibitors, CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), histone deacetylase inhibitors (HDAC) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra terminal family member inhibitors (such as bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643), and adenosine receptor antagonists, or combinations thereof.

[0317] Examples of antibodies used in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (trade name Avastin, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (anti-CD20), and antibodies against c-MET.

[0318] One or more of the following agents can be used in combination with the compounds of the present disclosure, and the following is a non-limiting list: cytostatic agents, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlorambucil, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate ester, oxaliplatin, leucovorin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17.Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, tamoxifen, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, abaxin, HERCEPTIN (trademark) (trastuzumab), BEXXAR (trademark) (tositumomab), VELCADE (trademark) (bortezomib), ZEVALIN (trademark) (ibritumomab tiuxetan), TRISENOX (trademark) (arsenic trioxide), XELODA (trademark) (capecitabine), vinorelbine, porfimer, ERBITUX (trademark) (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolin, rituxan, sunitinib, dasatinib, tiazofurin, Sml1, fludarabine, pentostatin, triapine, zidovudine, trimidox, amidox, 3-AP, and MDL-101,731.

[0319] The compounds of the present disclosure can further be used in combination with other cancer treatment methods, such as chemotherapy, radiotherapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, adoptive T cell transfer, Toll receptor agonists, STING agonists, oncolytic virus therapy, and immunomodulatory small molecules including thalidomide or JAK1 / 2 inhibitors. The compounds can be administered in combination with one or more anti-cancer agents such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib tosylate hydrate, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nolatrexed,Any one of olaparib, oxaliplatin, paclitaxel, pamidronic acid, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, lestaurtinib, lucaparib, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib, and zoledronic acid.

[0320] As additional examples of chemotherapeutic agents, proteasome inhibitors (e.g., bortezomib), thalidomide, lenalidomide, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, etc. are included.

[0321] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts thereof. Examples of other suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. Application No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0322] Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Examples of other suitable Flt-3 inhibitors include the compounds disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120 and pharmaceutically acceptable salts thereof.

[0323] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Examples of other suitable RAF inhibitors include the compounds disclosed in WO00 / 09495 and WO05 / 028444 and pharmaceutically acceptable salts thereof.

[0324] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharmaceutically acceptable salts thereof. Examples of other suitable FAK inhibitors include the compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402 and pharmaceutically acceptable salts thereof.

[0325] In some embodiments, the compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

[0326] In some embodiments, in the treatment of cancer, the compounds of the present disclosure can be used in combination with chemotherapeutic agents and can improve the treatment response without worsening the toxic effects of the chemotherapeutic agents as compared to the response to the chemotherapeutic agents alone. In some embodiments, the compounds of the present disclosure can be used in combination with the chemotherapeutic agents shown herein. For example, additional pharmaceuticals used in the treatment of multiple myeloma can include, but are not limited to, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). The desired result of the combination of the PI3K inhibitor of the present disclosure and the additional agent is an additive or synergistic effect.

[0327] In some embodiments, the compounds of the present disclosure can be used in combination with an inhibitor of JAK or PI3Kδ.

[0328] The agent can be formulated with the compound of the present invention into a single dosage form or a sustained release dosage form, or each agent can be administered simultaneously or sequentially as an individual dosage form.

[0329] The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infectious diseases. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections.

[0330] In some embodiments, an adrenal corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure. In that case, dexamethasone is administered intermittently rather than continuously.

[0331] A compound of formula (I) or any of the formulas described herein, listed in any of the claims, a compound described herein, or a salt thereof, can be combined with another immunogenic agent such as cancer cells, a purified tumor antigen (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with a gene encoding an immunostimulatory cytokine. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens such as gp100, MAGE antigens, Trp-2, MART1, and / or peptides of tyrosinase, or transfected tumor cells that express the cytokine GM-CSF.

[0332] For cancer treatment, a compound of formula (I) or any of the formulas described herein, listed in any of the claims, a compound described herein, or a salt thereof can be used in combination with a vaccination protocol. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). In some embodiments, a tumor-specific antigen such as a heat shock protein isolated from the tumor tissue itself can be used in combination with a compound of the present disclosure. In some embodiments, combining a compound of formula (I) or any of the formulas described herein, listed in any of the claims, a compound described herein, or a salt thereof with dendritic cell immunotherapy can activate a strong anti-tumor response.

[0333] A bispecific macrocyclic peptide that targets Fe alpha receptor or Fe gamma receptor-expressing effector cells to tumor cells can be used in combination with the compounds of the present disclosure. The compounds of the present disclosure can also be combined with a macrocyclic peptide that activates host immune responsiveness.

[0334] In some further embodiments, a combination of a compound of the present disclosure and another therapeutic agent can be administered to a patient before, during, and / or after bone marrow transplantation or stem cell transplantation. For the treatment of various tumors of hematopoietic origin, the compounds of the present disclosure can be used in combination with bone marrow transplantation.

[0335] A compound of formula (I) or any of the formulas described herein, listed in any of the claims, described herein, or a salt thereof can be used in combination with a vaccine to stimulate an immune response against pathogens, toxins, and autoantigens. Examples of pathogens for which this treatment approach may be particularly useful include pathogens for which there is currently no effective vaccine or for which conventional vaccines are not fully effective. Such pathogens include, but are not limited to, HIV, hepatitis (type A, B, C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

[0336] Viruses that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus.

[0337] Pathogens that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Chlamydia, Rickettsia bacteria, Mycobacteria, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Gonococcus, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum, Anthrax, Plague, Leptospira, and Lyme disease bacteria.

[0338] Pathogenic fungi that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum. Pathogenic parasites that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0339] Methods for safely and effectively administering such most chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians’ Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is hereby incorporated by reference as if fully set forth herein.

[0340] Pharmaceutical formulations and dosage forms When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. Such compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and depending on the area to be treated. Administration can be local (including transdermal, epithelial, intraocular, and transmucosal including nasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including with a nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, by means of a continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be required or may be desirable.

[0341] The present disclosure also includes pharmaceutical compositions containing, as an active ingredient, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for local administration. In the manufacture of the compositions of the present disclosure, the active ingredient is usually admixed with, diluted by, or enclosed within a carrier such as in the form of capsules, sachets, paper, or other containers. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0342] When preparing the formulation, before compounding with other ingredients, the active compound can be ground to an appropriate particle size. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, by grinding, for example, adjusting the particle size to about 40 mesh, a substantially uniform dispersion in the formulation can be obtained.

[0343] The compounds of the present disclosure can be ground using known grinding procedures such as wet grinding to obtain a particle size suitable for tablet formulations and other dosage forms. Micronized (nanoparticle-like) preparations of the compounds of the present disclosure can be prepared by methods known in the art (see, for example, International Application No. WO2002 / 000196).

[0344] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated to provide rapid release, sustained release, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0345] The composition can be formulated in unit dosage forms containing from about 5 to about 1,000 mg (1 g), more typically from about 100 to about 500 mg of the active ingredient per dosage. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect under suitable pharmaceutical excipients.

[0346] In some embodiments, the compositions of the present disclosure contain from about 5 to about 50 mg of the active ingredient. Those skilled in the art will understand that this includes compositions containing from about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.

[0347] In some embodiments, the compositions of the present disclosure contain from about 50 to about 500 mg of the active ingredient. Those skilled in the art will understand that this includes compositions containing from about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.

[0348] In some embodiments, the compositions of the present disclosure contain from about 500 to about 1000 mg of the active ingredient. Those skilled in the art will understand that this includes compositions containing from about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.

[0349] In the methods and uses of the present disclosure, similar dosages can be used for the compounds described herein.

[0350] The active compound can be effective over a wide range of dosages, but is generally administered in a pharmaceutically effective amount. However, the amount of the compound actually administered will usually be determined by the physician according to relevant circumstances including the condition of the patient to be treated, the selected route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0351] When preparing solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preliminary preparation composition containing a uniform mixture of the compounds of the present disclosure. When such a preliminary preparation composition is referred to as uniform, generally the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily redispersed into equal unit dosage forms such as tablets, pills, and capsules. This solid preliminary preparation is further redispersed into unit dosage forms of the above types containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0352] By coating or otherwise compounding the tablets or pills of the present disclosure, a dosage form with the advantage of sustained action can be obtained. For example, a tablet or pill may include an internal administration component and an external administration component, and the external administration component may be in the form of a coating that covers the internal administration component. By separating the two components with an enteric layer that is difficult to disintegrate in the stomach, it becomes possible to send the internal component to the duodenum in a complete state or to delay the release. Various materials can be used for such an enteric layer or enteric coating, and examples of such materials include a number of polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0353] Liquid forms in which the compounds and compositions of the present disclosure can be incorporated when administered orally or by injection include aqueous solutions, properly flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0354] Examples of compositions for inhalation or aspiration include solutions and suspensions of pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic effects. The composition can be nebulized using an inert gas. The nebulized solution can be inhaled directly from the nebulizer device or the nebulizer device can be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. A solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0355] Topical formulations can contain one or more conventional carriers. In some embodiments, an ointment can contain water and one or more hydrophobic carriers (e.g., selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc.). The carrier composition of a cream can be an aqueous component combined with glycerol and one or more other components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. A gel can be formulated using isopropyl alcohol and water in appropriate combination with other components, such as glycerol, hydroxyethyl cellulose, etc. In some embodiments, the topical formulation contains at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of the compound of the present disclosure. The topical formulation can preferably be packaged, for example, in a 100 g tube and optionally accompanied by instructions regarding the treatment of a selected indication, such as psoriasis or other skin conditions.

[0356] The amount of the compound or composition to be administered to a patient will vary depending on factors such as the administered substance, the purpose of administration such as prophylaxis or treatment, the condition of the patient, and the method of administration. In the case of therapeutic use, a composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective amount will be determined by the judgment of the attending clinician according to factors such as the pathophysiology of the disease being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0357] The composition to be administered to a patient can be in the form of the above pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or may be sterile filtered. An aqueous solution may be packaged for use as is or may be lyophilized, and this lyophilized preparation is mixed with a sterile aqueous carrier prior to administration. The pH of the compound preparation is generally from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that certain of the foregoing excipients, carriers, or stabilizers may result in the formation of a pharmaceutical salt.

[0358] The therapeutic dosage of the compounds of the present disclosure can be varied, for example, according to the particular use for which treatment is being carried out, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present disclosure in a pharmaceutical composition can be varied according to several factors including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present disclosure can be provided in the form of an aqueous physiological buffer solution containing from about 0.1 to about 10 w / v% of the compound for parenteral administration. Certain general dosage ranges are from about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dosage is often determined according to variables such as the progressive nature and stage of the disease or disorder, the overall health of a particular patient, the relative biological effectiveness of the selected compound, the formulation of excipients, and its route of administration. The effective amount can be estimated from a dose-response curve derived from in vitro or animal model test systems.

[0359] The compositions of the present disclosure can further include one or more additional pharmaceuticals such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are listed herein.

[0360] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds (such as radiolabels, fluorescent labels, etc.) of the present disclosure that are useful for localizing and quantifying A2A receptors and / or A2B receptors in tissue samples, including humans, in both in vitro and in vivo assays, as well as for identifying A2A antagonists and / or A2B antagonists by binding inhibition of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure can also be useful for creating differences in ADME (absorption, distribution, metabolism, and excretion). Accordingly, the present disclosure includes adenosine receptor (e.g., A2A and / or A2B) assays containing such labeled compounds or substituted compounds.

[0361] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotope" compound or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include, 2 H (also denoted as D for deuterium), 3 H (also denoted as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br,123 I. 124 I. 125 I, and 131 I are included, but not limited thereto. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., one or more hydrogen atoms of the C 1-6 alkyl group can be optionally replaced with deuterium atoms such as -CD3 instead of -CH3). In some embodiments, any of the disclosed formulas, e.g., the alkyl group of formula (I), can be perdeuterated.

[0362] One or more constituent atoms of the compounds presented herein can be replaced with isotopes of atoms in natural or non-natural abundances. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein can be replaced with deuterium (e.g., one or more hydrogen atoms of the C 1-6 alkyl group can be replaced with deuterium atoms such as -CD3 instead of -CH3). In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound can be replaced with deuterium atoms.

[0363] In some embodiments, any of the "alkyl", "alkenyl", "alkynyl", "aryl", "phenyl", "cycloalkyl", "heterocycloalkyl", or "heteroaryl" substituents, or the "-C 1-6 alkyl-", "alkylene", "alkenylene", and "alkynylene" linking groups described herein, the 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms attached to the carbon atoms are each optionally replaced with deuterium atoms.

[0364] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various tests such as NMR spectroscopy, metabolic experiments, and / or assays.

[0365] Substitution with heavier isotopes such as deuterium can, depending on the situation, be favorable because it can lead to certain therapeutic advantages obtained by increased metabolic stability, such as an increased in vivo half-life or a reduction in the required dose (see, for example, A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites can result in one or more therapeutic advantages.

[0366] The radionuclide incorporated into the radiolabeled compound of the present invention will be determined according to the specific use of the radiolabeled compound. For example, in in vitro labeling assays and competitive assays of adenosine receptors, 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 S incorporating compounds may be useful. For radioimaging applications, 11 C, 18 F,125 I、 123 I、 124 I、 131 I、 75 Br、 76 Br, or 77 Br may be useful.

[0367] "Radioactive label" or "labeled compound" is understood to be a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C, 125 I, 35 S, and 82 selected from the group consisting of Br.

[0368] The present disclosure may further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods applicable to the disclosed compounds.

[0369] The labeled compounds of the present disclosure can be used in screening assays for identifying and / or evaluating compounds. For example, a newly synthesized or identified compound (i.e., a test compound) can be labeled and its label tracked to monitor concentration changes upon contact with an adenosine receptor, thereby evaluating the ability of the test compound to bind to the adenosine receptor. For example, the ability of a test compound (labeled) to reduce the binding of another compound known to bind to the adenosine receptor (i.e., a standard compound) can be evaluated. Thus, the ability of a test compound to compete with a standard compound for binding to the adenosine receptor is directly correlated with the binding affinity of the test compound. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. In that case, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, thereby confirming the relative binding affinity of the test compound.

[0370] Kit The present disclosure also includes a pharmaceutical kit useful, for example, for the treatment or prevention of adenosine receptor-related diseases or disorders (such as cancer, inflammatory diseases, cardiovascular diseases, or neurodegenerative diseases, etc.), which includes one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such a kit may further include, if desired, one or more of various conventional pharmaceutical kit components, such as a container containing one or more pharmaceutically acceptable carriers, additional containers, etc., which would be apparent to those skilled in the art. Instructions in the form of either an accompanying document or a label indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit.

[0371] The present invention will be further described in detail by specific examples. The following examples are described for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily understand that essentially the same results can be obtained by changing or modifying various non-critical parameters. According to at least one assay described herein, the compounds of each example have been found to inhibit the activity of adenosine receptors (such as A2A and / or A2B).

Example

[0372] The preparative LC-MS purification of some of the prepared compounds was carried out on a Waters mass-directed fractionation system. The basic instrument settings, protocols, and control software suitable for the operation of this system are described in detail in the literature (see, for example, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874 - 883 (2004)). The separated compounds were usually subjected to purity analysis by liquid chromatography-mass spectrometry (LCMS) for analysis under the following conditions: instrument; Agilent 1100 series, LC / MSD, column: Waters Sunfire™ C 18 5 μm, 2.1×50 mm, buffer: mobile phase A: 0.025% aqueous TFA solution, and mobile phase B: acetonitrile; gradient of B 2% - 80%, flow rate 2.0 mL / min for 3 minutes.

[0373] Some of the prepared compounds were also separated on a preparative scale by reverse-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) equipped with an MS detector as shown in each example. Typical column conditions for preparative reverse-phase high-performance liquid chromatography (RP-HPLC) are as follows:

[0374] Purification at pH = 2: Waters Sunfire™ C 185 μm, 30 × 100 mm column, or Waters XBridge™ C 18 5 μm, 30 × 100 mm column, eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution and mobile phase B: acetonitrile; flow rate was 60 mL / min, separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature (see, for example, “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)).

[0375] Purification at pH = 10: Waters XBridge™ C 18 5 μm, 30 × 100 mm column, eluted with mobile phase A: 0.1% NH4OH aqueous solution and mobile phase B: acetonitrile; flow rate was 60 mL / min, separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature (see, for example, “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)).

[0376] Example 1. 4 - Amino - 6 - (3 - cyanophenyl) - N - ethyl - 7 - (1 - ethyl - 1H - pyrazol - 5 - yl)pyrazolo[1,5 - a]pyrazine - 2 - carboxamide

Chemical formula

Chemical formula

[0377] Step 2: Ethyl 6-(3-cyanophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate

Chemical formula

[0378] Step 3: Ethyl 4-chloro-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate

Chemical formula

[0379] Step 4. Ethyl 6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylate

Chemical Structure

[0380] Step 5: 6-(3-Cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylic acid

Chemical Structure

[0381] Step 6. 4-Amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide

Chemical formula

[0382] Step 7. 4-Amino-7-bromo-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide [Chemical] To a solution of 4-amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide (747 mg, 2.439 mmol) in DCM (5 mL) and DMF (1.250 mL) was added N-bromosuccinimide (NBS, 421 mg, 2.365 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The precipitate was collected and washed with ethyl acetate to give the desired product as a white solid (0.75 g, 80%). LC-MS C 16 H 14 BrN6O (M+H) + Calculated for: m / z = 385.0, 387.0; Found 385.0, 387.0.

[0383] Step 8. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-ethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide A mixture of 4-amino-7-bromo-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide (14 mg, 0.036 mmol), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.69 mg, 0.044 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol), and tripotassium phosphate hydrate (18.41 mg, 0.080 mmol) in 1,4-dioxane (0.6 mL) / water (0.200 mL) was stirred at 80 °C for 1 hour. The residue was dissolved in methanol and 1N HCl and purified by preparative LCMS (pH 2, acetonitrile / water + TFA) to give the desired product as the TFA salt. LC-MS C 21 H 21 N8O (M+H) +Calculated value for: m / z = 401.2; Measured value 401.2. 1 H NMR (600 MHz, DMSO) δ 8.07 (t, J = 6.0 Hz, 1H), 7.80 - 7.73 (m, 3H), 7.73 - 7.70 (m, 1H), 7.56 - 7.46 (m, 4H), 6.32 (d, J = 1.8 Hz, 1H), 3.87 (m, 1H), 3.75 (m, 1H), 3.27 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).

[0384] Example 2. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-propyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Chemical Structure

[0385] Example 3. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Chemical Structure

[0386] Example 4. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Chem.

[0387] Example 5. 4-Amino-6-(3-cyanophenyl)-7-(1,1-difluoroethyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide [Chemical formula] 4-Amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide (Example 1, Step 6; 20.0 mg, 0.065 mmol), sodium 1,1-difluoroethane-1-sulfinate (59.6 mg, 0.392 mmol), diethyl carbonate (2.0 mL), water (1.3 mL), and tert-butyl hydroperoxide (0.090 mL, 0.653 mmol) were added to a vial. The resulting mixture was heated at 90 °C for 3 hours. The reaction mixture was purified by preparative LCMS (pH = 2, acetonitrile / water + TFA) to obtain the desired product as the TFA salt (5.6 mg, 23%). LC-MS C 18 H 17 F2N6O (M+H) + Calculated for: m / z = 371.1; Found 371.1.

[0388] Example 6. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrazine-2-carboxamide [Chemical formula] Using a procedure similar to that described in Example 5, the title compound was prepared using sodium 1-(trifluoromethyl)cyclopropane-1-sulfinate instead of sodium 1,1-difluoroethane-1-sulfinate. The reaction mixture was purified by preparative LCMS (pH = 2, acetonitrile / water + TFA) to obtain the desired product as the TFA salt. LC-MS C 20 H 18 F3N6O (M+H) + Calculated for: m / z = 415.1; Found 415.1.

[0389] Example 7. 3-(4-Amino-2-(azetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile [Chemical formula] Step 1. Ethyl 4-amino-7-bromo-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate

Chem.

[0390] Step 2. Ethyl 4-amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

Chem.

[0391] Step 3. 4-Amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid

Chemical Structure

[0392] Step 4.3 - (4-Amino-2-(azetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile To a solution of 4-amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (8.0 mg, 0.022 mmol) and HATU (8.51 mg, 0.022 mmol) in N,N-dimethylformamide (1.0 mL) were added azetidine (3.02 μl, 0.045 mmol) and DIEA (7.82 μl, 0.045 mmol). After stirring at room temperature for 2 hours, the reaction mixture was purified by preparative HPLC (pH = 2, acetonitrile / water + TFA) to give the desired product as the TFA salt (2.5 mg, 28%). LC-MS C 21 H 17 N8O (M+H) + Calculated for: m / z = 397.1; Found 397.1. 1 H NMR (500 MHz, DMSO) δ 9.11 (m, 1H), 8.94 (d, J = 5.2 Hz, 1H), 7.96 - 7.90 (m, 2H), 7.79 - 7.73 (m, 3H), 7.55 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 4.29 (t, J = 7.7 Hz, 2H), 4.03 (t, J = 7.7 Hz, 2H), 2.24 (m, 2H).

[0393] Example 8. 3-(4-Amino-7-(pyrimidin-4-yl)-2-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chem.

[0394] Example 9. 3-(4-Amino-2-(piperidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0395] Example 10. 4-Amino-6-(3-cyanophenyl)-N,N-diethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Chemical formula

[0396] Example 11. 4-Amino-6-(3-cyanophenyl)-N-ethyl-N-methyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Chemical formula

[0397] Example 12. 3-(4-Amino-2-(3-hydroxyazetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0398] Example 13. 3-(4-Amino-2-(azetidin-1-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chem.

Chem.

[0399] Step 2. 3-(4-Amino-2-(hydroxymethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chem.

[0400] Step 3. 3-(4-Amino-2-formyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical Structure

[0401] Step 4.3 - (4-Amino-2-(azetidin-1-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile To a mixture of 3-(4-amino-2-formyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (10 mg, 0.029 mmol) and azetidine (3.35 mg, 0.059 mmol) in DCM (1 mL) was added sodium triacetoxyborohydride (12.4 mg, 0.059 mmol). After stirring at room temperature for 2.5 h, the solvent was removed in vacuo. The resulting residue was dissolved in methanol and 1N HCl (1N) and purified by preparative LCMS (pH = 2, acetonitrile / water + TFA) to give the desired product as the TFA salt. LC-MS C 21 H 19 N8(M + H) + Calculated for: m / z = 383.2; found 383.2.

[0402] Example 14. Ethyl (8-amino-6-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate

Chemical formula

Chemical formula

[0403] Step 2. O-(Mesitylsulfonyl)hydroxylamine

Chemical formula

[0404] Step 3. 1,2-Diamino-3,5-dibromopyrazin-1-ium 2,4,6-trimethylbenzenesulfonate

Chemical formula

[0405] Step 4. Ethyl (6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate [Chem.] A suspension of 1,2-diamino-3,5-dibromopyrazin-1-ium 2,4,6-trimethylbenzenesulfonate (190 mg, 0.406 mmol) in DCM (1.0 mL) and N,N-dimethylformamide (1 mL) was added with O-ethylcarbonisothiocyanidate (52.7 μl, 0.446 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to obtain the desired product (10 mg, 8%). LC-MS C8H8Br2N5O2(M+H) + Calculated for: m / z = 365.9; Found 365.8.

[0406] Step 5. Ethyl (6-bromo-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate [Chem.] To a mixture of ethyl (6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate (10 mg, 0.027 mmol) and (2,4-dimethoxyphenyl)methanamine (4.58 mg, 0.027 mmol) in DCM (1 mL) was added DIEA (9.57 μl, 0.055 mmol). After stirring at 40 °C for 2.5 hours, the solvent was removed in vacuo. The residue was purified by flash chromatography to obtain the desired product (6.0 mg, 49%). LC-MS C 17 H 20 BrN6O4(M+H) + Calculated for: m / z = 451.1, 453.1; Found 451.1, 453.1.

[0407] Step 6. Ethyl (6-(3-cyanophenyl)-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate [Chemical formula] A mixture of ethyl (6-bromo-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate (6.0 mg, 0.013 mmol), (3-cyanophenyl)boronic acid (1.954 mg, 0.013 mmol), dicyclohexyl(2´,4´,6´-triisopropylbiphenyl-2-yl)phosphine-(2´-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.046 mg, 1.330 μmol), and tripotassium phosphate hydrate (6.74 mg, 0.029 mmol) in 1,4-dioxane (0.6 mL) / water (0.200 mL) was stirred at 70 °C for 1 hour. The resulting residue was dissolved in methanol and 1 N HCl and purified by preparative LCMS (pH 2) to give the desired product as a white solid (4.2 mg, 66%). LC-MS C 24 H 24 N7O4(M+H) + Calculated for: m / z = 474.2; Found 474.2.

[0408] Step 7. Ethyl (8-amino-6-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate A mixture of ethyl (6-(3-cyanophenyl)-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate (6.3 mg, 0.013 mmol) and trifluoroacetic acid (0.3 mL) was stirred at 90 °C for 30 minutes. The volatiles were removed and the resulting residue was diluted with methanol and purified by preparative LCMS (pH = 2, acetonitrile / water + TFA) to give the desired product as the TFA salt (0.3 mg, 7%). LC-MS C 15 H 14 N7O2(M+H) + Calculated for: m / z = 324.1; Found 324.1.

[0409] Example 15. 3-(8-Amino-5-(6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chem.

Chem.

[0410] Step 2. 3-(8-((2,4-Dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chem.

[0411] Step 3. 3-(8-Amino-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0412] Step 4. 3-(8-Amino-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0413] Step 5. 3-(8-Amino-5-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0414] Step 6.3-(8-Amino-5-(6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile A mixture of 3-(8-amino-5-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile (10 mg, 0.029 mmol), potassium iodide (14.50 mg, 0.087 mmol), and acetic acid (1.0 mL) was heated at 90 °C for 1 h. The mixture was diluted with methanol and purified by preparative LCMS (pH = 2, acetonitrile / water + TFA) to give the desired product as the TFA salt (3.5 mg, 37%). LC-MS C 17 H 12 N7O (M+H) + Calculated for: m / z = 330.1; Found 330.1.

[0415] Example 16. 3-(4-Amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

Chemical formula

[0416] Step 2: 3-(2-(Bromomethyl)-4-(2,4-dimethoxybenzylamino)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0417] Step 3: 3-(4-(2,4-Dimethoxybenzylamino)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0418] Step 4. 3-(4-Amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile 3-(4-(2,4-Dimethoxybenzylamino)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (428 mg, 0.9 mmol) and TFA (1 mL) were placed in a reaction vial. The mixture was heated at 70 °C for 20 minutes. The mixture was diluted with water and quenched with saturated NaHCO3. The mixture was extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to obtain the desired product as a pale yellow solid (260 mg, 89%). LC-MS C 19 H 15 N6 (M+H) +Calculated value for: m / z = 327.1; measured value 327.2.

[0419] Example 17. 3-(4-Amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

Chemical formula

[0420] Step 2. 3-(4-Amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile A mixture of 3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (15 mg, 0.037 mmol), CuI (1.4 mg, 0.007 mmol), CsF (11 mg, 0.074 mmol), tetrakis(triphenylphosphine)palladium(0) (4.2 mg, 0.004 mmol), and 4-(tributylstannyl)pyrimidine (16.4 mg, 0.044 mmol) in 1,4-dioxane was heated at 140 °C for 1 h in a microwave reactor. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in methanol. A few drops of TFA were added, and purification by preparative LCMS (pH 2, acetonitrile / water + TFA) gave the desired product as the TFA salt. LC-MS C 23 H 17 N8(M+H) + Calculated for: m / z = 405.2 Found 405.2.

[0421] Example 18. 3-(4-Amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chemical formula

[0422] Example 19. 4-(4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyr...

Claims

1. Compound of formula (IIa): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: R ３ is H or CN; Cy １ is 3-cyanophenyl or 3-cyano-2-fluorophenyl; R ２ is C ３－６ selected from cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, and the R ２ said C ３－６ cycloalkyl, said 5- to 6-membered heteroaryl, and said 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two independently selected R ２Ａ substituents; Each R ２Ａ is selected independently from halo, C １－４ alkyl, C １－４ haloalkyl, and C(O)NR ｃ２１ R ｄ２１ and the C ２Ａ alkyl of R １－４ is optionally substituted with one, two, or three independently selected R ２Ｂ substituents; R ｃ２１ and R ｄ２１ are each independently selected from H, C １－６ alkyl, and C １－６ haloalkyl; Each R ２Ｂ is independently selected from halo and OH; R ４ is phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－３ Alkyl-, (5- to 10-membered heteroaryl)-C １－３ Alkyl-, (4- to 7-membered heterocycloalkyl)-C １－３ Alkyl-, C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , and N.R. ｃ４ R ｄ４ is selected from R ４ the phenyl, the 5- to 6-membered heteroaryl, the 4- to 7-membered heterocycloalkyl, the phenyl-C １－３ alkyl-, the (5- to 10-membered heteroaryl)-C １－３ alkyl-, and the (4- to 7-membered heterocycloalkyl)-C １－３ Each alkyl- is optionally selected from one or two independently selected R ４Ａ is substituted with a substituent; R ｂ４ 、 R ｃ４ 、 and R ｄ４ are each independently selected from H, C １－６ alkyl, phenyl, and 4- to 7-membered heterocycloalkyl, and the R ｂ４ 、 R ｃ４ 、 and R ｄ４ said C １－６ alkyl, said phenyl, and said 4- to 7-membered heterocycloalkyl are optionally substituted with one, two, or three independently selected R ４Ａ substituents; Alternatively, any R ｃ４ and R ｄ４ are bonded to the same N atom and, together with said N atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group optionally substituted with one or two independently selected R ４Ａ substituents; Each R ４Ａ is independently selected from halo, 4- to 7-membered heterocycloalkyl, and OH, and the 4- to 7-membered heterocycloalkyl of R ４Ａ is optionally substituted with one or two independently selected R ４Ｂ substituents; and Each R ４Ｂ is independently selected from halo, OH, and C １－４ alkyl Said compound or a pharmaceutically acceptable salt thereof.

2. Any alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent, or a -C １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one, two, three, four, five, six, seven, or eight hydrogen atoms bonded to the carbon atoms of the alkyl-, alkylene, alkenylene, and alkynylene linking groups are each optionally substituted with deuterium atoms.

3. R ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is H.

4. R ２ is selected from cyclopropyl, oxazolyl, triazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionally substituted with one or two independently selected R ２Ａ substituents; Each R ２Ａ is selected independently from halo, C １－４ alkyl, C １－４ haloalkyl, and C(O)NR ｃ２１ R ｄ２１ and the said C ２Ａ alkyl of R １－４ is optionally substituted with one, two, or three independently selected R ２Ｂ substituents; R ｃ２１ and R ｄ２１ each is independently selected from H, C １－６ alkyl, and C １－６ haloalkyl; and Each R ２Ｂ is independently selected from halo and OH, A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R ２ is 1-(trifluoromethyl)cycloprop-1-yl, 1-ethyl-1H-pyrazol-5-yl, 1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, pyridin-4-yl, 4-(1-hydroxyethyl)-2-methyloxazol-5-yl, (2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl, 1-ethyl-1H-1,2,3-triazol-5-yl, and 1-methyl-1H-1,2,3-triazol-5-yl, the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. R ４ is C(O)NHC １－６ alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)N(C １－６ alkyl) ２ , (azetidinyl)-C １－６ alkyl, (pyridyl)-C １－６ alkyl, (phenyl)-C １－６ alkyl, (fluorophenyl)-C １－６ alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), pyridyl, and (pyrrolo[3,2-b]pyridinyl)-C １－６ selected from alkyl, Each C １－６ The alkyl and azetidinyl groups are optionally substituted with one or two OH groups, and each pyridyl is optionally substituted with a methylpiperazinyl group. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R ４ is C(O)NHCH ２ CH ３ 、C(O)N(CH ３ )(CH ２ CH ３ ), C(O)N(CH ２ CH ３ ), ２ C(O)-azetidinyl, C(O)-hydroxyazetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl, CH ２ -azetidinyl, CH ２ -pyridyl, CH ２ -fluorophenyl, CH(OH)-fluorophenyl, NH-phenyl, 3,6-dihydro-2H-pyranyl, (methylpiperazinyl)pyridinyl, and (1H-pyrrolo[3,2-b]pyridin-3-yl)methyl, a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. R ４ is phenyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and C(O)NR ｃ４ R ｄ４ selected from; said phenyl-C ４ alkyl- and said (5- to 6-membered heteroaryl)-C １－６ alkyl- are each optionally substituted with one or two substituents independently selected from OH and halo; and １－６ ​ R ｃ４ and R ｄ４ are each independently selected from H and C １－６ alkyl A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

9. R ４ is selected from -C(O)NHCH ２ CH ３ -, -CH ２ -pyridyl, CH ２ -fluorophenyl, and CH(OH)-fluorophenyl, a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

10. R ２ is a 6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl, 4-ethyloxazol-5-yl, 3-methylpyridin-4-yl, 4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl, 2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl, 1-ethyl-1H-pyrazol-5-yl, 2,6-dimethylpyridin-4-yl, 3-methyl-1H-pyrazol-4-yl, oxazol-5-yl, and 3-fluoropyridin-4-yl, and is the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

11. R ４ is pyridin-2-ylmethyl, hydroxy(pyridin-2-yl)methyl, (imidazo[1,2-a]pyridin-8-yl)methyl, (pyrazolo[1,5-a]pyridin-7-yl)methyl, (2H-indazol-2-yl)methyl, (1H-indazol-1-yl)methyl, (2,6-difluorophenyl)(hydroxy)methyl, (2,5-difluorophenyl)(hydroxy)methyl, (2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl, (2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, azetidine-1-carbonyl, and benzodioxazol-4-ylmethyl, and the compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

12. R ２ is selected from 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocycloalkyl are each optionally substituted with one or two C １－３ alkyl groups; and R ４ is phenyl-C １－３ alkyl- or pyridyl-C １－３ alkyl-, and the phenyl-C １－３ alkyl- and the pyridyl-C １－３ alkyl- are each optionally substituted with one, two, or three substituents independently selected from OH and halo, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-ethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-propyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 3-(4-Amino-2-(azetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(pyrimidin-4-yl)-2-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(piperidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 4-Amino-6-(3-cyanophenyl)-N,N-diethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 4-Amino-6-(3-cyanophenyl)-N-ethyl-N-methyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide; 3-(4-Amino-2-(3-hydroxyazetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(azetidin-1-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxamide; 3-(4-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(phenylamino)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(4-(1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(1-ethyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 3-(4-Amino-7-(1-methyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; and 3-(2-((1H-Pyrrolo[3,2-b]pyridin-3-yl)methyl)-4-amino-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile, and their pharmaceutically acceptable salts A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from

14. 4-Amino-6-(3-cyanophenyl)-7-(1,1-difluoroethyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide; 3-(4-Amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile; 4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazine-7-carbonitrile; 4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazine-3-carbonitrile; and 3-(4-Amino-7-bromo-2-((2-fluorophenyl)(hydroxy)methyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile A compound selected from, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

16. A medicament for treating a disease or disorder, comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is bladder cancer, lung cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, or head and neck cancer. The medicament.

17. The medicament according to claim 16, wherein the disease or disorder is head and neck cancer.

18. The medicament according to claim 17, wherein the head and neck cancer is head and neck squamous cell carcinoma.

19. The medicament according to claim 16, wherein the disease or disorder is lung cancer.

20. The medicament according to claim 19, wherein the lung cancer is non-small cell lung cancer (NSCLC).

21. The medicament according to claim 16, wherein the disease or disorder is ovarian cancer.

22. The medicament according to claim 16, wherein the disease or disorder is prostate cancer.

23. The medicament according to claim 22, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

24. The medicament according to claim 16, wherein the disease or disorder is breast cancer.

25. The medicament according to claim 16, wherein the disease or disorder is bladder cancer.

26. The medicament according to claim 16, wherein the disease or disorder is colorectal cancer.

27. The medicament according to claim 16, wherein the disease or disorder is pancreatic cancer.

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