Allosteric benzopyrone inhibitors of phosphoinositide 3-kinase (PI3K) for treatment of disease

Abstract

The present disclosure relates to compounds of formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein, as allosteric benzopyrone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases or disorders associated with PI3K modulation. The present disclosure also relates to methods of making and using a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 496,210 filed on April 14, 2023, U.S. Provisional Application No. 63 / 381,862 filed on November 1, 2022, U.S. Provisional Application No. 63 / 357,689 filed on July 1, 2022, and U.S. Provisional Application No. 63 / 336,658 filed on April 29, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to allosteric benzopyrone inhibitors of phosphoinositide 3-kinase (PI3K) that are useful for treating diseases or disorders associated with PI3K regulation. The present invention relates to compounds and compositions that inhibit PI3K, methods (or uses) for treating diseases or disorders associated with PI3K, such as CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer, and methods of using PI3K inhibitors in combination with one or more additional cancer therapies, or methods of using PI3K inhibitors in combination with one or more additional cancer therapies. Background Art

[0004] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling has been implicated in numerous other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, disorders associated with diabetic complications, and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

[0005] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylates 3'-OH groups on phosphatidylinositol or phosphoinositide. The PI3K family includes 15 kinases with different substrate specificities, expression patterns, and regulatory patterns (Katso et al., Annu Rev Cell Dev Biol. 2001; 17: 615-75). Class I PI3K (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt / PDK1 pathway, mTOR, Tec family kinases, and Rho family GTPases. Class II and Class III PI3Ks play a key role in intracellular transport by synthesizing PI(3)P and PI(3,4)P2.

[0006] PI3K isoforms are implicated in various human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations that cause upregulation of PI3K isoforms are thought to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations clustered within several hotspots in the helical and kinase domains. Due to the high rate of PI3K mutations, targeting this pathway could provide valuable therapeutic opportunities.

[0007] Genetic alterations in genes involved in PI3K signaling are thought to be involved in a range of cancers, including endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, miscellaneous neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Cancer. 2014). Engl J Med. 2018Nov 22;379(21):2052-2062).

[0008] The alpha (α) isoform of PI3K is implicated in, for example, various human cancers. Angiogenesis has been shown to selectively require the α isoform of PI3K to control endothelial cell migration (Graupera et al., Nature 2008; 453; 662-6). Mutations in the gene encoding PI3Kα or mutations that cause upregulation of PI3Kα are thought to occur in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the gene encoding PI3Kα are point mutations clustered within several hotspots in the helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high rate of PI3Kα mutations, targeting this pathway could provide valuable therapeutic opportunities. Although other PI3K isoforms such as PI3Kδ or PI3Kγ are primarily expressed in hematopoietic cells, PI3Kα is constitutively expressed together with PI3Kβ.

[0009] Mutated PI3Kα is implicated in brain metastases in HR+ / HER2- metastatic breast cancer. The development of brain-penetrant PI3Kα inhibitors could offer improved therapeutic benefits compared to current PI3Kα inhibitors (Fitzgerald et al., Association between PIK3CA mutation status and development of brain metastases in HR+ / HER2- metastatic breast cancer. Ann Oncol 30: v110, 2019 (suppl 5)).

[0010] Due to the central role of PI3Kα in regulating glucose homeostasis in the body, PI3K inhibition in patients often causes hyperglycemia and / or hyperinsulinemia (Busaidy NL et al., Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 2012; 30: 2919–28). High levels of circulating insulin may have mitogenic and / or anti-apoptotic effects on cancer cells, thereby counteracting the anti-proliferative effects of PI3K inhibitors (Blouin MJ et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013; 73: 4615).

[0011] In the case of cancers with mutant PI3Kα, one way to overcome the problem of compensatory insulin and / or glucose production following systemic PI3Kα inhibition is to develop inhibitors with enhanced selectivity for mutant PI3Kα relative to wild-type PI3Kα. This will create an enlarged drug quantification window to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that controls systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct; 6(10): 1090-1105), thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target (Ariella B. Hanker et al., Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 Apr; 9(4): 482–491).

[0012] Currently, PI3Kα inhibitors are nearly equally effective against wild-type and mutant PI3Kα. Because PI3Kα mutations are located far from the active site, mutation-selective inhibitors are elusive. Therefore, inhibitors targeting a second peripheral binding pocket near known mutations (e.g., H1047R) may provide a pathway for selective PI3Kα inhibition. Therefore, targeting the mutant peripheral binding pocket of PI3Kα provides a valuable therapeutic target for drug development.

[0013] Therefore, kinases, for example lipid kinases such as PI3K, are major targets for drug development.The present invention provides novel kinase inhibitors. Summary of the Invention

[0014] In one aspect, the present invention relates to compounds of formula (I):

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0018] R is -H or C1-C3 alkyl;

[0019] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, indole, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidazo[1,2-a]pyridine or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0020] R1 is a group of the formula:

[0021]

[0022]

[0023] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -C(O)-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 、-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -S(O)C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-C(O)-C1-C3 alkyl, -SO2N(R 11 )-CN、-SO2N(R 11 )(R 13 )-C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -C(O)NR 11 R 12 、-C(O)N(R 11 )-(CH2) n -R 13 、-C(O)-SR 12 、-C(O)-NHSO2R 16 、-C(O)CH=SOR 11 (R 11 ) or -C(O)CH2CN or a group of the formula:

[0024]

[0025] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0026] R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, 1,2,4-oxadiazolin-5-one, 1,4-oxazepane, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine or oxazepane; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-C(O)-R 11 、-N(R 11)-CN, -OH, C1-C3 alkoxy, -CN, halogen, morpholino, oxetane, C1-C6 haloalkyl or C1-C6 alkyl substituents, said C1-C6 alkyl optionally substituted with -OH, aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0027] R' is a group of the formula:

[0028]

[0029] R2 is a group of the formula:

[0030]

[0031] R2 is a group of the formula:

[0032]

[0033] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-C(O)NR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , -CD3, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, tetrahydropyran, oxetane, azetidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetane, C1-C3 alkoxy, -CH2CH(OH)CH(OH)R 11 ; or -C(O)NR 11 R 11Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O(CH2) n OR 11 、-C(O)C(CH3)2OH、-SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0034] R2 is an optionally substituted fused bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, indole, indazole, isoindazole, isoindolin-1-one, indolin-2-one, benzoxazole, benzotriazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine or 2,3-dihydro-[1,4]dioxino[2,3-b]pyri dine), imidazo[1,2-a]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[1,5-a]pyrimidine, or an optionally substituted bicyclic heteroaryl having 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2H、-CO2C1-C3 alkyl、-C(O)NR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -C(O)NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0035] R2 is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0036]

[0037] R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0038] R4, R5 and R6 are each independently -H, halogen, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0039] R7 is -CN, C1-C6 alkyl, -CH2OH or C1-C6 haloalkyl;

[0040] R8 is -H, -D or C1-C6 alkyl;

[0041] each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0042] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-SONR 11 R 11 、-CO2H、-CO2C1-C3 alkyl、-C(O)NR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 、-N(R 11 )C(O)R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula:

[0043]

[0044] wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -C(O)NR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN;

[0045] Each R11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl or C1-C3 haloalkyl;

[0046] Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 alkoxy, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula

[0047]

[0048] wherein the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole;

[0049] R 13 Yes-NR 11 R 11 、-OR 11 , -SO2C1-C3 alkyl or a ring selected from oxetane, tetrahydrofuran or oxadiazole, wherein the ring is optionally replaced by -NR 11 R 11 OR 11 replace;

[0050] R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl or 6-membered heteroaryl; wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl or 6-membered heteroaryl;

[0051] R 15 is optionally substituted aryl or optionally substituted 6-membered heteroaryl; wherein the optionally substituted aryl or the optionally substituted 6-membered heteroaryl are each optionally substituted by 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0052] R 16 is H, C1-C3 alkyl, -NH2, phenyl or pyridine, and

[0053] n is 0, 1, or 2.

[0054] In one aspect, the compounds of formula (I) may include asymmetric carbon atoms at the positions designated by asterisks (*). In one aspect, R7 is methyl and R8 is hydrogen, and the bond at the * position is represented by

[0055] In one aspect, the present invention relates to compounds of formula (I):

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein:

[0058] R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0059] R is -H or C1-C3 alkyl;

[0060] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0061] R1 is a group of the formula:

[0062]

[0063] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 、-SO2C1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR11 R 12 、-CON(R 11 )-(CH2) n -R 13 、-CO-SR 12 or a group of the formula:

[0064]

[0065] ; wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0066] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, C1-C6 haloalkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0067] R' is a group of the formula:

[0068]

[0069] R2 is a group of the formula:

[0070]

[0071] R2 is a group of the formula:

[0072]

[0073] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0074] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0075] R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0076]

[0077] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0078] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0079] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0080] R8 is -H or C1-C6 alkyl;

[0081] each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0082] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-SONR 11 R 11 、-CO2H、-CO2C1-C3 alkyl、-CONR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula:

[0083] wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN;

[0084] Each R 11 are independently -H or C1-C3 alkyl;

[0085] Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula

[0086]

[0087] wherein the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole;

[0088] R 13 Yes-NR 11 R 11 、-OR 11 , -SO2C1-C3 alkyl or a ring selected from oxetane, tetrahydrofuran or oxadiazole, wherein the ring is optionally replaced by -NR 11 R 11 OR 11 replace;

[0089] R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl or 6-membered heteroaryl; wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl or 6-membered heteroaryl;

[0090] R 15 is optionally substituted aryl or optionally substituted 6-membered heteroaryl; wherein the optionally substituted aryl or the optionally substituted 6-membered heteroaryl are each optionally substituted by 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0091] and

[0092] n is 0, 1, or 2.

[0093] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0094] In another aspect, the present invention provides a method of modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0095] In some aspects, the present invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0096] In some aspects, the present invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0097] In some aspects, the present invention provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0098] In some aspects, the present invention provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0099] In another aspect, the present invention provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0100] In another aspect, the present invention provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo).

[0101] In another aspect, the present invention provides a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof for selectively inhibiting mutant PI3Kα relative to wild-type PI3Kα.

[0102] In another aspect, the present invention provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0103] In another aspect, the present invention provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0104] In another aspect, the present invention provides use of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo).

[0105] In another aspect, the present invention provides use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0106] In another aspect, the present invention provides the use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0107] In another aspect, the present invention provides a method for preparing a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, the present invention provides a process for preparing a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, comprising one or more of the steps described herein.

[0109] In another aspect, the invention provides a compound obtainable or obtained by a method of preparing a compound as described herein.

[0110] In another aspect, the invention provides an intermediate as described herein, which is suitable for use in a method for preparing a compound as described herein (eg the intermediate is selected from the intermediates described in the Examples).

[0111] Other features and advantages of the invention will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0112] The present invention provides methods for treating, preventing, or ameliorating diseases or disorders in which PI3K plays a role (or uses in the treatment, prevention, or amelioration of diseases or disorders) by administering a therapeutically effective amount of a PI3K inhibitor of the present invention to a patient in need thereof. The methods (or uses) of the present invention can be used to treat various PI3K-dependent diseases and disorders.

[0113] In some embodiments, the disease or disorder is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer). In some embodiments, diseases or disorders associated with PI3K include, but are not limited to, CLOVES syndrome, PROS, endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, miscellaneous neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0114] The details of the present invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the present invention will be apparent from the description and claims. In the description and the appended claims, the singular also includes the plural, unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0115] definition

[0116] The articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0117] Unless stated otherwise, the term "and / or" means "and" or "or".

[0118] The terms "administer," "administering," and "administration" refer to administering a disclosed compound, a pharmaceutically acceptable salt of a disclosed compound, or a composition directly to a subject.

[0119] The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl.

[0120] The term "alkoxy" refers to a straight or branched saturated hydrocarbon containing 1 to 12 carbon atoms with a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0121] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0122] The term "alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl.

[0123] It is to be understood that, for example, the terms "alkenyl," "alkoxy," "alkyl," "alkynyl," "haloalkyl," "haloalkoxy," and "cycloalkyl" may be further defined by the number of carbon atoms they contain, e.g., the term "C1-C6 alkoxy" refers to an alkoxy group as defined above containing 1-6 carbon atoms.

[0124] The term "aromatic" refers to a planar ring having 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of connected p orbitals having delocalized electrons, and the system may include lone electron pairs.

[0125] Unless otherwise clearly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group with 1 to 3 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl. When containing two aromatic rings (bicyclic etc.), the aromatic rings of the aryl can be connected (such as biphenyl) or fused (such as naphthyl) at a single point. In addition, when containing two fused rings, the aryl defined herein can have one or more saturated or partially unsaturated rings fused with completely unsaturated aromatic rings. The exemplary ring systems of these aryls include but are not limited to phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl and tetrahydrobenzoannulyl.

[0126] The term "carrier" encompasses vehicles, excipients, and diluents, and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting an agent from one organ or body part to another in a subject.

[0127] The term "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond, ie, C≡N.

[0128] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, bicyclo[2.2.2]octyl, and bicyclo[2.2.2]octenyl.

[0129] Unless otherwise indicated, the term "disorder" refers to, and is used interchangeably with, the terms disease, condition, or illness.

[0130] The term "haloalkoxy" refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0131] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0132] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0133] Unless otherwise expressly defined, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 ring heteroatoms selected from N, O or S, and the remaining ring atoms are C. Polycyclic aromatic groups include two or more fused rings and may further include two or more spirofused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise expressly defined, "fused" means that two rings share two ring atoms. Unless otherwise expressly defined, "spirofused" means that two rings share one ring atom. Heteroaryl as defined herein also refers to a bicyclic heteroaromatic group wherein the heteroatoms are selected from N, O, S, P or B, preferably N, O or S. Heteroaryl as defined herein also refers to a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P or B, preferably N, O or S. Heteroaryl as defined herein also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P or B, preferably N, O or S.Examples of heteroaromatic groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,2 ... ,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinone, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[ 2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1 ,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and 3H-indolyl. Additionally, when containing two or more fused rings, a heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to saturated or partially unsaturated rings as described herein. In addition, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated spirofused rings. Any saturated or partially unsaturated rings described herein are optionally substituted with one or more oxy groups. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, chromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3 ,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0134] Unless expressly defined otherwise, the term "5-membered heteroaryl" refers to a monovalent monocyclic aromatic group of 5 ring atoms containing one or more ring heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 ring heteroatoms selected from N, O or S, with the remaining ring atoms being C. Exemplary 5-membered heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, triazolyl and tetrazolyl.

[0135] Unless expressly defined otherwise, the term "6-membered heteroaryl" refers to a monovalent monocyclic aromatic group of 6 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 ring heteroatoms selected from N, O or S, and the remaining ring atoms are C. Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.

[0136] The term "heterocyclyl", "heterocycle" or "heterocycloalkyl" refers to a monocyclic or polycyclic ring containing 3 to 24 atoms, preferably 3 to 10 atoms, including carbon and one or more heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 heteroatoms selected from N, O and S, and wherein the ring is not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Azepinyl, oxa Oxepinyl, diazepine tropanyl, oxazolidinone and homotropanyl.

[0137] The term "isomer" refers to a compound with the same molecular formula but different properties or order of the bonding of its atoms or the spatial arrangement of its atoms. Isomers with different spatial arrangements of their atoms are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S- ordering rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light, and are designated as right-handed or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0138] The terms "modulate," "modulation," and "modulating" refer to the inhibition and / or activation of the biological activity of a compound or substrate of PI3K.

[0139] The term "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human.

[0140] The term "therapeutically effective amount" when used in conjunction with a compound refers to the amount or dosage of a compound that provides the desired effect in the patient being diagnosed or treated when administered to the patient in a single dose or multiple doses. One skilled in the art can determine the effective amount by using known techniques and by observing the results obtained under similar circumstances. In determining the effective amount for a patient, the attending diagnostician considers many factors, including, but not limited to: the species of the patient; their size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; concomitant medications; and other relevant circumstances.

[0141] The term "treating" with respect to a subject includes inhibiting, slowing, stopping or reversing the progression or severity of an existing symptom or disorder.

[0142] Compounds of the present invention

[0143] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0144]

[0145] wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined for formula (I) in the Summary of the Invention.

[0146] In the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0147] R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or a group of the formula

[0148]

[0149] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0150] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl.

[0151] In the compound of formula (I), or a pharmaceutically acceptable salt thereof, R and R1, together with the nitrogen to which they are attached, form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents, each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0152] R is -H or C1-C3 alkyl; and

[0153] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidazo[1,2-a]pyridine or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 groups each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy substituents; or in some embodiments, R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0154] R1 is a group of the formula:

[0155]

[0156]

[0157] R1 is a group of the formula:

[0158]

[0159] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 、-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 、-SO2C1-C3 alkyl、-SOC1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN、-SO2N(R 11 )(R 13 )-C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 、-CO-SR 12 、-CO-NHSO2R 16 、-COCH=SOR 11 (R 11 ) or -COCH2CN or a group of the formula:

[0160]

[0161] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0162] R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13or a group of the formula

[0163]

[0164] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0165] R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, 1,2,4-oxadiazolin-5-one, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-C(O)-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, morpholine, oxetane, C1-C6 haloalkyl or C1-C6 alkyl substituents, wherein the C1-C6 alkyl is optionally substituted with aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0166] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0167] R' is a group of the formula:

[0168]

[0169] R2 is a group of the formula:

[0170]

[0171] R2 is a group of the formula:

[0172]

[0173] R2 is a group of the formula:

[0174]

[0175] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-C(O)NR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , -CD3, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, tetrahydropyran, oxetane, azetidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetane, C1-C3 alkoxy, -CH2CH(OH)CH(OH)R 11 or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O)(CH2) n OR 11 、C(O)C(CH3)2OH、-SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0176] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0177] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, indole, indazole, isoindazole, isoindolin-1-one, indolin-2-one, benzoxazole, benzotriazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazole wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2CH、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -C(O)NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11, -OH or -CN; or

[0178] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0179] R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0180]

[0181] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-SONR 11 R 11、 -CO2H, -CO2C1-C3 alkyl, -C(O)NR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 、-N(R 11 )COR 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine; or

[0182] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN;

[0183] Each R 11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl or C1-C3 haloalkyl;

[0184] R 12 is -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula

[0185]

[0186] wherein the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; and R 13 Yes-NR 11 R 11 、-OR 11 , oxetane or tetrahydrofuran.

[0187] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R' is hydrogen, halogen, C1-C3 alkyl, -CH(OH)-CH2OH, -CO-CH2OH or C3-C6 cycloalkyl.

[0188] In the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0189] R is -H or C1-C3 alkyl;

[0190] R1 is a group of the formula:

[0191]

[0192] R' is hydrogen, halogen, C1-C3 alkyl, -CH(OH)-CH2OH, -CO-CH2OH or C3-C6 cycloalkyl;

[0193] R2 is a group of the formula:

[0194]

[0195] R2 is a group of the formula:

[0196]

[0197] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0198] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0199] R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0200]

[0201] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CO2C1-C3 alkyl, -CONR 11 R 11 、-NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents.

[0202] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R8 is -H.

[0203] In a further aspect, the compound of formula (I) wherein R8 is -H has formula (II) or a pharmaceutically acceptable salt thereof:

[0204]

[0205] wherein R, R1, R2, R3, R4, R5, R6 and R7 are as defined for formula (I) in the Summary of the Invention.

[0206] In the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

[0207] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0208]

[0209] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R is -H.

[0210] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R4 is -H or halogen. R4 is preferably -H.

[0211] In a further aspect, the compound of formula (I) or (II) has formula (III) or a pharmaceutically acceptable salt thereof:

[0212]

[0213] wherein R1, R2, R3, R5, R6 and R7 are as defined above for formula (I) in the Summary of the Invention.

[0214] In still further compounds of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0215] In further embodiments of the compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane or isoxazole. Preferably, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl. More preferably, R3 is -H, -CN, methyl or trifluoromethyl. Most preferably, R3 is -H or methyl.

[0216] In yet further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Preferably, R5 is -H, halogen, methyl or trifluoromethyl.

[0217] In still further compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R6 is -H or halogen.

[0218] In further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl. Preferably, R7 is -CN, methyl or trifluoromethyl. More preferably, R7 is methyl.

[0219] In still further compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

[0220] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula

[0221]

[0222] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula

[0223]

[0224] In further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, each R9 is independently -H, halogen, C1-C3 alkyl or C3-C5 cycloalkyl, preferably each R9 is independently -H, halogen, methyl or cyclopropyl.

[0225] In still further compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0226] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or a group of the formula

[0227]

[0228] wherein Ring A is pyrrolidine optionally substituted with -CN.

[0229] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or a group of the formula

[0230]

[0231] wherein Ring A is pyrrolidine optionally substituted with -CN.

[0232] In yet further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is -SO2NR 11 R 11 、-SO2N(R 11)(R 13 )、-C(O)NR 11 R 12 、-C(O)N(R 11 )-(CH2) n -R 13 、-C(O)-NHSO2R 16 Or 1,2,4-oxadiazolin-5-one.

[0233] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -NR 11 R 11 、-OR 11 , -CN, C1-C6 haloalkyl or a substituent of C1-C6 alkyl optionally substituted by phenyl.

[0234] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -NR 11 R 11 、-OR 11 , -CN, C1-C6 haloalkyl or a substituent of C1-C6 alkyl optionally substituted by phenyl.

[0235] In still further compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R' is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -NR 11 R 11 、-OR 11 or substituted by a substituent of the C1-C6 alkyl group which is optionally substituted by an aryl group.

[0236] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is hydrogen, halogen, C1-C3 alkyl or C3-C6 cycloalkyl, preferably R' is hydrogen, halogen or methyl.

[0237] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R' is hydrogen, -Cl, -F-, -Br, methyl, difluoromethyl, trifluoromethyl, methoxy, -NO2, -CN or a group of the formula:

[0238]

[0239]

[0240] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula

[0241] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C3-C5 cycloalkyl, and R' is hydrogen, halogen, C1-C3 alkyl or C3-C6 cycloalkyl, preferably each R9 is independently -H, halogen, methyl or cyclopropyl and R' is hydrogen, halogen or C1-C3 alkyl.

[0242] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula

[0243] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C3-C5 cycloalkyl, and R' is hydrogen, halogen, C1-C3 alkyl or C3-C6 cycloalkyl, preferably each R9 is independently -H, halogen, methyl or cyclopropyl and R' is hydrogen, halogen or C1-C3 alkyl.

[0244] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula:

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R1 is a group of the formula

[0254]

[0255] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula

[0256]

[0257] ; Each R 10 R2 is independently -H, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -CO2C1-C3 alkyl; or R2 is optionally substituted pyrazole or optionally substituted indazole, each of which is optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -CO2C1-C3 alkyl. R2 is preferably a group of the formula

[0258] Among them, each R 10 R2 is independently -H, -CN or halogen; or R2 is optionally substituted pyrazole or optionally substituted indazole, each of which is optionally substituted with C1-C3 alkyl.

[0259] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0260]

[0261] ; Each R 10 are independently -H, -CN, C1-C6 haloalkyl, -NR 11 R 11 、-CH2-NR 11 R 11 , -CO2C1-C3 alkyl or -CH2-CO2C1-C3 alkyl; or R2 is optionally substituted indazole, which is optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0262] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula

[0263] Among them, each R 10 R2 is independently -H, -CN or C1-C3 haloalkyl; or R2 is optionally substituted indazole, which is optionally substituted with C1-C3 alkyl.

[0264] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0265]

[0266] where R 10 Selected from -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.

[0267] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0268]

[0269] where R 11 is selected from hydrogen, alkyl, cycloalkyl and haloalkyl.

[0270] In still further compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, R2 is optionally alkyl-substituted pyrazole or optionally alkyl-substituted triazole.

[0271] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0272]

[0273]

[0274]

[0275] In still further compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, R2 is a group of the formula

[0276]

[0277] In yet further compounds of formula (I), the compound is selected from:

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] or a pharmaceutically acceptable salt of any one of the above; wherein the bond at the * position is represented by

[0306] In yet further compounds of formula (I), the compound is selected from:

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] or a pharmaceutically acceptable salt of any of the foregoing;

[0316] The key at the * position is represented by In still further compounds of formula (I), the compound is selected from

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In yet further compounds of formula (I), the compound is selected from:

[0327]

[0328]

[0329] or a pharmaceutically acceptable salt of any one of the above; wherein the bond at the * position is represented by

[0330]

[0331] In still further compounds of formula (I), the compound is selected from

[0332]

[0333]

[0334]

[0335] or a pharmaceutically acceptable salt thereof. In a further compound of formula (I), the compound is selected from

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In further embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any of the compounds described herein or a pharmaceutically acceptable salt thereof. It will be appreciated that isotopic derivatives can be prepared using various industry-recognized techniques. For example, isotopic derivatives or pharmaceutically acceptable salts thereof can generally be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent to carry out the procedures disclosed in the Figures and / or Examples described herein. In the compounds of the present invention, any atom that is not specifically designated as a particular isotope is intended to represent a stable isotope of that atom.

[0362] In further embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is deuterated at one or more positions. Unless otherwise indicated, when an atom is specifically designated as "H" or "hydrogen", the atom is understood to have hydrogen at its natural abundance isotopic composition. Furthermore, unless otherwise indicated, when an atom is specifically designated as "D" or "deuterium", the atom is understood to have deuterium in an abundance significantly greater than the natural abundance of deuterium (which is 0.015%).

[0363] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R8 is -H, -D or C1-C6 alkyl. In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is selected from:

[0364]

[0365] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R2 is 1-(trideuterated methyl)pyrazol-4-yl. In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is:

[0366]

[0367] Pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. In addition, pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts or magnesium salts, ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Pharmaceutically acceptable salts and common methods for their preparation are well known in the art (see, e.g., P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Rev. ed. (Wiley-VCH, 2011); SM Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0368] Additional representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinol salt, hydrabamine, hydrobromide, hydrochloride, Hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / hydrogen phosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0369] The compounds of the present invention can be prepared in many ways known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of synthetic organic chemistry or variations thereof as recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0370] Further aspects

[0371] Following are further numbered aspects of the invention:

[0372] 1. Compounds of formula (I):

[0373]

[0374] or a pharmaceutically acceptable salt thereof, wherein:

[0375] R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0376] R is -H or C1-C3 alkyl;

[0377] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, indole, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidazo[1,2-A]pyridine or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0378] R1 is a group of the formula:

[0379]

[0380] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 、-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R15 、-SO2C1-C3 alkyl、-SOC1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN、-SO2N(R 11 )(R 13 )-C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 、-CO-SR 12 、-CO-NHSO2R 16 、-COCH=SOR 11 (R 11 ) or -COCH2CN or a group of the formula:

[0381]

[0382] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0383] R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, 1,2,4-oxadiazolin-5-one, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-C(O)-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, morpholine, oxetane, C1-C6 haloalkyl or C1-C6 alkyl substituents, wherein the C1-C6 alkyl is optionally substituted with aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0384] R' is a group of the formula:

[0385]

[0386] R2 is a group of the formula:

[0387]

[0388] R2 is a group of the formula:

[0389]

[0390] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-C(O)NR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , -CD3, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, tetrahydropyran, oxetane, azetidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetane, C1-C3 alkoxy, -CH2CH(OH)CH(OH)R 11 or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O)(CH2) n OR 11 、C(O)C(CH3)2OH、-SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0391] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, indole, indazole, isoindazole, isoindolin-1-one, indolin-2-one, benzoxazole, benzotriazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazole wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2CH、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -C(O)NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11, -OH or -CN; or

[0392] R2 is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0393]

[0394] R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0395] R4, R5 and R6 are each independently -H, halogen, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0396] R7 is -CN, C1-C6 alkyl, -CH2OH or C1-C6 haloalkyl;

[0397] R8 is -H, -D or C1-C6 alkyl;

[0398] each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0399] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-SONR 11 R 11 、-CO2H、-CO2C1-C3 alkyl、-C(O)NR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 、-N(R 11 )COR 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula:

[0400]

[0401] wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN;

[0402] Each R 11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl or C1-C3 haloalkyl;

[0403] Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 alkoxy, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula

[0404]

[0405] wherein the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole;

[0406] R13 Yes-NR 11 R 11 、-OR 11 , -SO2C1-C3 alkyl or a ring selected from oxetane, tetrahydrofuran or oxadiazole, wherein the ring is optionally replaced by -NR 11 R 11 OR 11 replace;

[0407] R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl or 6-membered heteroaryl; wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl or 6-membered heteroaryl;

[0408] R 15 is optionally substituted aryl or optionally substituted 6-membered heteroaryl; wherein the optionally substituted aryl or the optionally substituted 6-membered heteroaryl are each optionally substituted by 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0409] R 16 is H, C1-C3 alkyl, -NH2, phenyl or pyridine, and

[0410] n is 0, 1, or 2.

[0411] 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

[0412] R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0413] R is -H or C1-C3 alkyl;

[0414] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0415] R1 is a group of the formula:

[0416]

[0417] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 、-SO2C1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 、-CO-SR 12 or a group of the formula:

[0418]

[0419] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0420] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, C1-C6 haloalkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; or

[0421] R' is a group of the formula:

[0422]

[0423] R2 is a group of the formula:

[0424]

[0425] R2 is a group of the formula:

[0426]

[0427]

[0428] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0429] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0430] R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0431]

[0432] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0433] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0434] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0435] R8 is -H or C1-C6 alkyl;

[0436] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-SONR 11 R 11 、-CO2H、-CO2C1-C3 alkyl、-CONR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula:

[0437] wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN;

[0438] Each R 11 are independently -H or C1-C3 alkyl; and

[0439] Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula

[0440]

[0441] wherein the optionally substituted C1-C3 alkyl group is optionally substituted by -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl or indole.

[0442] 3. A compound as defined in aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or a group of the formula

[0443]

[0444] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0445] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl.

[0446] 4. A compound as defined in any one of aspects 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0447] R is -H or C1-C3 alkyl; and

[0448] R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or

[0449] R1 is a group of the formula:

[0450]

[0451] R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R11 )-(CH2) n -R 13 or a group of the formula

[0452]

[0453] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0454] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl.

[0455] 5. A compound as defined in aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen, C1-C3 alkyl, -CH(OH)-CH2OH, -CO-CH2OH or C3-C6 cycloalkyl.

[0456] 6. A compound as defined in aspect 1, 2 or 5, or a pharmaceutically acceptable salt thereof, wherein

[0457] R is -H or C1-C3 alkyl;

[0458] R1 is a group of the formula:

[0459]

[0460] R2 is a group of the formula:

[0461]

[0462] R2 is a group of the formula:

[0463]

[0464] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0465] R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or

[0466] R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula:

[0467]

[0468] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CO2C1-C3 alkyl, -CONR 11 R 11 、-NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents.

[0469] 7. A compound as defined in any one of aspects 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R8 is -H.

[0470] 8. A compound as defined in any one of aspects 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

[0471]

[0472] 9. A compound as defined in any one of aspects 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

[0473] 10. A compound as defined in aspect 9, or a pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring of the formula

[0474]

[0475] 11. A compound as defined in any one of aspects 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is -H.

[0476] 12. A compound as defined in any one of aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or halogen.

[0477] 13. A compound as defined in any one of aspects 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4 is -H.

[0478] 14. A compound as defined in any one of aspects 1-8 or 11-13, or a pharmaceutically acceptable salt thereof, having the formula

[0479]

[0480] 15. A compound as defined in any one of aspects 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl.

[0481] 16. A compound as defined in any one of aspects 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, methyl or trifluoromethyl.

[0482] 17. A compound as defined in any one of aspects 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3 is -H or methyl.

[0483] 18. A compound as defined in any one of aspects 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0484] 19. A compound as defined in any one of aspects 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, methyl or trifluoromethyl.

[0485] 20. A compound as defined in any one of aspects 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R6 is -H or halogen.

[0486] 21. A compound as defined in any one of aspects 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl.

[0487] 22. A compound as defined in any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, methyl or trifluoromethyl.

[0488] 23. A compound as defined in any one of aspects 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.

[0489] 24. A compound as defined in any one of aspects 1-8 or 11-23, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

[0490] 25. A compound as defined in any one of aspects 1-8 or 11-23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula

[0491]

[0492] 26. A compound as defined in any one of aspects 1-8 or 11-23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula

[0493]

[0494] 27. A compound as defined in any one of aspects 1-8, 11-23, 25 or 26, or a pharmaceutically acceptable salt thereof, wherein R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0495] 28. A compound as defined in any one of aspects 1-8, 11-23, 25 or 26, or a pharmaceutically acceptable salt thereof, wherein each R9 is independently -H, halogen, C1-C3 alkyl or C3-C5 cycloalkyl.

[0496] 29. A compound as defined in any one of aspects 1-4, 7-8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or a group of the formula

[0497]

[0498] wherein Ring A is pyrrolidine optionally substituted with -CN; or

[0499] R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected oxo, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or a substituent of C1-C6 alkyl optionally substituted by phenyl.

[0500] 30. A compound as defined in aspect 29, or a pharmaceutically acceptable salt thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 or

[0501]

[0502] wherein Ring A is pyrrolidine optionally substituted with -CN.

[0503] 31. A compound as defined in aspect 29, or a pharmaceutically acceptable salt thereof, wherein R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -NR 11 R 11 、-OR 11 , -CN, C1-C6 haloalkyl or a substituent of C1-C6 alkyl optionally substituted by phenyl.

[0504] 32. A compound as defined in any one of aspects 1-4, 7-8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R′ is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected radicals selected from oxo, -NR 11 R 11 、-OR 11 or substituted by a substituent of the C1-C6 alkyl group which is optionally substituted by an aryl group.

[0505] 33. A compound as defined in aspect 32, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen, C1-C3 alkyl or C3-C6 cycloalkyl.

[0506] 34. A compound as defined in aspect 32, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen or methyl.

[0507] 35. A compound as defined in any one of aspects 1-4, 7-8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, -Cl, -F-, -Br, methyl, difluoromethyl, trifluoromethyl, methoxy, -NO2, -CN or a group of the formula:

[0508]

[0509]

[0510] 36. A compound as defined in any one of aspects 1-8 or 11-23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519] 37. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0520]

[0521] 38. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0522]

[0523] 39. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0524]

[0525] 40. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0526]

[0527] R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11 、-NR 11 R 11 , -OH or -CN substituents.

[0528] 41. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0529]

[0530] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl or C2-C6 alkynyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl or heteroaryl is optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN substituents.

[0531] 42. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula

[0532]

[0533] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , C1-C6 alkyl, C2-C6 alkynyl optionally substituted by -OH, C3 cycloalkyl optionally substituted by -CN, or heteroaryl selected from pyrazole optionally substituted by 1 to 3 substituents each independently selected from C1-C3 alkyl.

[0534] 43. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-OH、-NR11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein The optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents.

[0535] 44. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of C1-C6 haloalkyl, C1-C6 alkyl, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, or an optionally substituted heteroaryl selected from pyridine or pyrimidine; wherein the optionally substituted phenyl, 1,3-benzodioxole, or heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 or -CN.

[0536] 45. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or a ring containing 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine an optionally substituted bicyclic heteroaryl having 8 to 10 ring atoms, 2, 3, 4 or 5 ring heteroatoms independently selected from N, O or S; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents.

[0537] 46. ​​A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 to 3 R 10Substituents are substituted, or R2 is a group of the formula:

[0538]

[0539] 47. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula:

[0540]

[0541] 48. A compound as defined in any one of aspects 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula:

[0542]

[0543]

[0544] 49. A compound as defined in aspect 1 or 2, selected from:

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565] or a pharmaceutically acceptable salt thereof.

[0566] 50. A compound as defined in aspect 1 or 2, selected from:

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] or a pharmaceutically acceptable salt thereof. 51. A compound as defined in aspect 1 or 2, selected from:

[0578]

[0579]

[0580]

[0581]

[0582] or a pharmaceutically acceptable salt thereof.

[0583] 52. A pharmaceutical composition comprising a compound as defined in any one of aspects 1 to 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0584] 53. A method for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.

[0585] 54. A method as defined in aspect 53, wherein the PI3K is PI3Kα.

[0586] 55. A method as defined in aspect 53 or aspect 54, wherein the PI3K associated with the disease or disorder has an H1047R mutation.

[0587] 56. A method as defined in any one of aspects 53 to 55, wherein the disease or disorder is cancer.

[0588] 57. A method as defined in aspect 56, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0589] 58. A method as defined in aspect 56, wherein the cancer is breast cancer.

[0590] 59. A method as defined in aspect 56, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

[0591] 60. A method as defined in any one of aspects 53 to 55, wherein the disorder is CLOVES syndrome or PROS.

[0592] 61. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.

[0593] 62. A method of treating a cancer or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52.

[0594] 63. A method as defined in aspect 62, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0595] 64. A method as defined in aspect 62, wherein the cancer is breast cancer.

[0596] 65. A method as defined in aspect 62, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

[0597] 66. A method as defined in aspect 62, wherein the disorder is CLOVES syndrome or PROS.

[0598] 67. A compound as defined in any one of aspects 1 to 51, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0599] 68. A compound as defined in any one of aspects 1 to 51, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with modulation of PI3K.

[0600] 69. A compound for use as defined in aspect 68, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder associated with modulation of PI3K is cancer.

[0601] 70. A compound for use as defined in aspect 69, or a pharmaceutically acceptable salt thereof, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0602] 71. A compound for use as defined in aspect 69, or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer.

[0603] 72. A compound for use as defined in aspect 69, or a pharmaceutically acceptable salt thereof, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

[0604] 73. A compound for use as defined in aspect 68, or a pharmaceutically acceptable salt thereof, wherein the disorder is CLOVES syndrome or PROS.

[0605] 74. Use of a compound as defined in any one of aspects 1 to 51, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder associated with modulation of PI3K.

[0606] 75. Use as defined in aspect 74, wherein the disease or disorder associated with modulation of PI3K is cancer.

[0607] 76. Use as defined in aspect 75, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

[0608] 77. Use as defined in aspect 75, wherein the cancer is breast cancer.

[0609] 78. The use as defined in aspect 75, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

[0610] 79. Use as defined in aspect 74, wherein the disorder is CLOVES syndrome or PROS.

[0611] Pharmaceutical composition

[0612] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0613] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0614] The compounds of formula (I), (II) or (III) can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of formula (I), (II) or (III) can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0615] The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous carrier. The aqueous carrier component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH regulators, and mixtures thereof.

[0616] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of the formulae disclosed herein, and a pharmaceutically acceptable diluent or carrier.

[0617] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0618] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0619] How to use

[0620] In some aspects, the disclosure provides a method of modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0621] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0622] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0623] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more therapeutic agents.

[0624] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and an effective amount of: a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof; a SERD, or a pharmaceutically acceptable salt thereof; an aromatase inhibitor, or a pharmaceutically acceptable salt thereof; a taxane, or a pharmaceutically acceptable salt thereof; an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an anti-androgen, or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor, or a pharmaceutically acceptable salt thereof; a MEK inhibitor, or a pharmaceutically acceptable salt thereof; an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof; a SERM, or a pharmaceutically acceptable salt thereof; or a PARP inhibitor, or a pharmaceutically acceptable salt thereof; or a combination thereof.

[0625] In some embodiments, the disease or disorder is associated with implicated PI3K activity. In some embodiments, the disease or disorder is one in which PI3K activity is implicated.

[0626] In some embodiments, the disease or disorder is cancer.

[0627] In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary site, cardiac (heart) tumor, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, craniopharyngioma, skin T-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma tumors, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic carcinoma, metastatic squamous neck cancer, midline tract cancer with nut gene changes, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative neoplasms, chronic myeloproliferative neoplasms, nasal cavity and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paraganglioma, sinus and nasal cavity cancer carcinoma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumors, plasmacytoma, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0628] In some embodiments, the cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumors, thyroid cancer, leukemia, or encapsulated glioma.

[0629] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0630] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is brain cancer.

[0631] In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, breast cancer is invasive ductal carcinoma. In some embodiments, breast cancer is triple-negative breast cancer. In some embodiments, breast cancer is medullary carcinoma. In some embodiments, breast cancer is tubular carcinoma. In some embodiments, breast cancer is mucinous carcinoma. In some embodiments, breast cancer is Paget's disease of the breast or nipple. In some embodiments, breast cancer is inflammatory breast cancer (IBC). In some embodiments, breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

[0632] In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma.

[0633] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is a choroid plexus carcinoma. In some embodiments, the brain cancer is a craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pinealoblastoma. In some embodiments, the brain cancer is a pituitary tumor.

[0634] In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome, PROS, breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0635] In some embodiments, the disease or disorder associated with PI3K is CLOVES syndrome.

[0636] In some embodiments, the disease or disorder associated with PI3K is PROS.

[0637] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0638] In some embodiments, the disease or disorder associated with PI3K is a breast tumor, a thyroid tumor, an ovarian tumor, a non-small cell lung cancer, an endometrioma, or a pancreatic tumor. In some embodiments, the disease or disorder associated with PI3K is a breast tumor. In some embodiments, the disease or disorder associated with PI3K is a thyroid tumor. In some embodiments, the disease or disorder associated with PI3K is an ovarian tumor. In some embodiments, the disease or disorder associated with PI3K is a non-small cell lung cancer. In some embodiments, the disease or disorder associated with PI3K is an endometrioma. In some embodiments, the disease or disorder associated with PI3K is a pancreatic tumor.

[0639] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0640] In some embodiments, the disease or disorder associated with PI3K is a leukemia, lymphoma, or sarcoma.

[0641] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma.

[0642] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma.

[0643] In some embodiments, the sarcoma is a soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.

[0644] In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissue, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant sarcoma, salamander tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft tissue sarcoma, soft tissue clear cell sarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, endometrial sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, not otherwise specified.

[0645] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0646] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0647] In some aspects, the present disclosure provides a method of treating or preventing breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0648] In some aspects, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0649] In some aspects, the present disclosure provides a method of treating or preventing prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0650] In some aspects, the present disclosure provides a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0651] In some aspects, the present disclosure provides a method of treating or preventing brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0652] In some aspects, the present disclosure provides a method of treating brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0653] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0654] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo).

[0655] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0656] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0657] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer.

[0658] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0659] In some aspects, the present disclosure provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing breast cancer.

[0660] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating breast cancer.

[0661] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing prostate cancer.

[0662] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer.

[0663] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing brain cancer.

[0664] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating brain cancer.

[0665] In some aspects, the disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating PI3K (eg, PI3Kα) activity (eg, in vitro or in vivo).

[0666] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0667] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0668] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0669] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0670] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing breast cancer in a subject in need thereof.

[0671] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof.

[0672] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing prostate cancer in a subject in need thereof.

[0673] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating prostate cancer in a subject in need thereof.

[0674] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing brain cancer in a subject in need thereof.

[0675] In some aspects, the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating brain cancer in a subject in need thereof.

[0676] The present disclosure provides compounds that act as modulators of PI3K activity.The present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0677] In some embodiments, PI3K modulation is inhibition of PI3K.

[0678] In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor.

[0679] The effectiveness of the compounds of the present disclosure can be determined by industry-recognized assays / disease models according to standard practices as described in the art and as found in the current general knowledge.

[0680] The present disclosure also provides a method of treating a disease or disorder involving PI3K activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0681] Route of administration

[0682] The compounds of formula (I), (II), or (III), or pharmaceutical compositions comprising these compounds, may be administered to the subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0683] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular.

[0684] Example

[0685] In the examples, exemplary compounds of formula (I), (II) and (III) were synthesized and tested. It will be appreciated that the compounds of formula (I), (II) and (III) can be converted into their corresponding pharmaceutically acceptable salts using conventional techniques in the art.

[0686] Unless otherwise stated, nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz and at 300.3 K as specified; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0687] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20AD&MS2020 instrument using a C-18 column, such as the Luna-C18 2.0 x 30 mm or the Xbridge Shield RPC18 2.1 x 50 mm. Injection volumes ranged from 0.7–8.0 μl, and flow rates were typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) with positive electrospray ionization. The MS range was 100–1000 Da. Solvents were gradients of water and acetonitrile, both containing a modifier (typically 0.01–0.04%), such as trifluoroacetic acid or ammonium carbonate.

[0688] abbreviation:

[0689] ACN acetonitrile

[0690] AcOH acetic acid

[0691] ADP adenosine diphosphate

[0692] ATP adenosine triphosphate

[0693] CDCl3 chloroform-d

[0694] CPhos 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl

[0695] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0696] DCM dichloromethane

[0697] DIEA N,N-Diisopropylethylamine

[0698] DIPEA N,N-Diisopropylethylamine

[0699] DMA N,N-dimethylacetamide

[0700] DMAP dimethylaminopyridine

[0701] DMEA Dimethylethylamine

[0702] DMF N,N-dimethylformamide

[0703] DMSO dimethyl sulfoxide

[0704] DMSO-d6 hexadeuterated dimethyl sulfoxide

[0705] EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide

[0706] eq equivalent

[0707] EtOAc

[0708] EtOH

[0709] h, hr hours

[0710] HCl Hydrogen chloride

[0711] 1 H NMR proton nuclear magnetic resonance spectroscopy

[0712] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0713] IPA Isopropyl alcohol

[0714] LC-MS liquid chromatography-mass spectrometry

[0715] mCPBA meta-chloroperbenzoic acid

[0716] MeOH methanol

[0717] MgSO4 magnesium sulfate

[0718] min

[0719] MS ES electrospray mass spectrometry

[0720] MTBE methyl tert-butyl ether

[0721] NaCl Sodium chloride

[0722] NaHCO3 sodium bicarbonate

[0723] NaHMDS Sodium bis(trimethylsilyl)amide

[0724] NaOH sodium hydroxide

[0725] Na2S2O3 sodium thiosulfate

[0726] Na2SO4 sodium sulfate

[0727] NH4Cl ammonium chloride

[0728] NH4HCO3 ammonium bicarbonate

[0729] NH4OH ammonium hydroxide

[0730] NMP N-Methyl-2-pyrrolidone

[0731] ppm parts per million

[0732] rt room temperature

[0733] SFC Supercritical Fluid Chromatography

[0734] TBAF Tetrabutylammonium fluoride

[0735] TFA trifluoroacetic acid

[0736] THF Tetrahydrofuran

[0737] Intermediate 1C: tert-Butyl 6-bromo-2,3-difluoro-benzoate

[0738]

[0739] A solution of 6-bromo-2,3-difluoro-benzoic acid (2.9 g, 12 mmol) in THF (24 mL) was treated dropwise with (Z)-N,N'-diisopropylaminoimidic acid tert-butyl ester (9.8 g, 49 mmol), and the resulting mixture was sealed and heated at 65 ° C for 18 hours. The reaction was cooled to room temperature and diluted with MTBE. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 30% EtOAc / hexane to obtain the title compound (3.3 g, 92%) as a colorless oil.

[0740] Intermediate 2C: tert-Butyl 4-(3-bromo-6-chloro-2-pyridyl)piperazine-1-carboxylate

[0741]

[0742] To a vial was loaded tert-butyl piperazine-1-carboxylate (0.43 g, 2.28 mmol), 3-bromo-6-chloro-2-fluoro-pyridine (0.20 g, 0.95 mmol), cesium carbonate (0.93 g, 2.85 mmol) and DMF (4 mL). The vial was sealed and stirred at room temperature overnight. The reaction was phase-split between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl solution, collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc / heptane to give the title compound (0.34 g, 94%) as a colorless oil. ES / MS m / z 322 (M- t Bu).

[0743] The following compounds in Table 1 were made in a similar manner as described for tert-butyl 4-(3-bromo-6-chloro-2-pyridinyl)piperazine-1-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0744] Table 1

[0745]

[0746]

[0747]

[0748] 1 DIPEA was used as a base.

[0749] Intermediate 17C: 2-Fluoro-N-methoxy-benzenesulfonamide

[0750]

[0751] Combine 2-fluorobenzenesulfonyl chloride (0.70 g, 3.60 mmol) and potassium carbonate (1.09 g, 7.91 mmol) in EtOH (5 mL) and water (5 mL) and stir at room temperature overnight. The reaction was diluted with water (20 mL) and the title compound (0.40 g, 54%) was removed by filtration. ES / MS m / z 206 (M+H).

[0752] Intermediate 18C: (1,5-dimethyl-6-oxo-3-pyridyl)boronic acid

[0753]

[0754] A solution of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (4 g, 16.06 mmol) in acetone (40 mL) and water (20 mL) was treated dropwise with concentrated aqueous HCl (20 mL, 36.5%) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 3 hours. The reaction was basified to pH 8 with NH4OH and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 eluting with 40% to 60% ACN / water (ACN in water) (containing 0.1% NH4OH) to give the title compound (2.0 g, 75%) as an off-white solid. ES / MS m / z 168 (M+H).

[0755] Intermediate 19C: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]cyclopropanecarbonitrile

[0756]

[0757] A solution of 1-(5-bromo-2-pyridyl)cyclopropanecarbonitrile (0.21 g, 0.94 mmol), bis(pinacolato)diboron (0.36 g, 1.41 mmol), and potassium acetate (0.28 g, 2.82 mmol) in anhydrous 1,4-dioxane (10 mL) was purged with argon for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69 mg, 0.09 mmol) was added and the reaction was purged with argon for an additional 3 minutes. The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% MeOH / DCM to give the title compound (0.35 g, 83%, 60% purity). ES / MS m / z 189 (M+H).

[0758] The following compounds in Table 2 were made in a similar manner as described for 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]cyclopropanecarbonitrile. Various methods were used to purify this compound, as would be apparent to one skilled in the art.

[0759] Table 2

[0760]

[0761] Intermediate 21C: Tributyl-(3,6-difluoro-2-pyridyl)stannane

[0762]

[0763] A solution of 2,5-difluoropyridine (2.0 g, 17.38 mmol) in THF (10 mL) was treated with a solution of lithium diisopropylamide (1 M in THF, 2.79 g, 26.07 mmol) at -78°C. The reaction was stirred at -78°C for 1 hour. Tributyltin chloride (5.94 g, 18.25 mmol) in 20 mL of THF was added dropwise at -78°C, and the reaction was stirred at -78°C for 1 hour. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3x). The combined extracts were dried over Na2SO4, filtered, and the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc / heptane to give the title compound (4.46 g, 64%). ES / MS m / z 406 (M+H).

[0764] Intermediate 22C: 3-Bromo-N-tert-butyl-pyridine-2-sulfonamide

[0765]

[0766] A solution of 3-bromopyridine-2-sulfonyl chloride (2.0 g, 7.80 mmol) in DCM was cooled to -20°C and treated dropwise with tert-butylamine. The reaction was stirred at -20°C for 30 minutes. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 50% EtOAc / petroleum ether to give the title compound (0.50 g, 22%) as a dark red solid. ES / MS m / z 293 / 295 (M+H).

[0767] Intermediate 23C: 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine

[0768]

[0769] A mixture of 5-chloro-1H-pyrazolo[4,3-b]pyridine (3.2 g, 20.84 mmol) and iodomethane (4.44 g, 31.26 mmol) in THF (30 mL) was treated portionwise with sodium hydride (1.0 g, 60% in oil, 25.0 mmol) at 0°C. The reaction was stirred at room temperature for 1 hour, quenched with water (30 mL), and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% EtOAc / petroleum ether to give the title compound (1.34 g, 38%) as a white solid. ES / MS m / z 168 (M+H).

[0770] Intermediate 24C: Trimethyl-(2-methylpyrazolo[4,3-b]pyridin-5-yl)stannane

[0771]

[0772] A solution of 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine (4.0 g, 23.87 mmol) in 1,4-dioxane (80 mL) was treated with hexamethylditin (11.73 g, 35.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.52 g, 4.77 mmol). The reaction was stirred at 100 ° C for 2 hours. The reaction was cooled to room temperature, quenched with saturated aqueous potassium fluoride solution, filtered and the solid was washed with EtOAc (3x100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6.0 g) as a black solid. ES / MS m / z 298 (M+H).

[0773] Intermediate 25C: Iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]zinc

[0774]

[0775] Lithium chloride (1.62 g, 38.17 mmol) was added to a dry flask equipped with a stir bar and a septum and heated at 170°C under high vacuum for 20 minutes. The vacuum was removed and nitrogen was introduced into the flask as it cooled. While cooling, zinc (2.50 g, 38.17 mmol) was added to the flask and dried at 170°C under high vacuum for 20 minutes, and backfilled with nitrogen as it cooled. When cooled to room temperature, THF (20 mL) and 1,2-dibromoethane (0.18 g, 38.17 mmol) were added via syringe, and the reaction was heated at 60°C until bubbling occurred. After cooling to room temperature, chlorotrimethylsilane (0.02 g, 0.19 mmol) and iodine (0.02 g, 0.1 mmol) in THF (1 mL) were added via syringe, and the reaction was heated at 60°C for 20 minutes, then cooled to room temperature. 1-Iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (5.0 g, 19.08 mmol) was added and the reaction was stirred overnight at 50° C. The reaction was allowed to stand at room temperature for 1 hour and the clear solution on top of the solid was carefully transferred via cannula to a dry flask for use without purification, assuming a concentration of ~0.45M.

[0776] The following compounds in Table 3 were made in a similar manner as described for iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]zinc.

[0777] Table 3

[0778]

[0779] Intermediate 28C: 1-(3-bromo-5-fluoro-2-hydroxy-phenyl)ethanone

[0780]

[0781] 1-(5-Fluoro-2-hydroxy-phenyl)ethanone (2.0 kg, 13 mol) was dissolved in DMF (20 L) and treated with N-bromosuccinimide (2.8 kg, 15.6 mol) to keep the temperature below 20 ° C. Stir at 0 to 10 ° C for 5 to 6 hours. Water (20 L) was slowly added to the reactor, stirred at room temperature for 2 hours, and the crude product was filtered out. This material was slurried in heptane (10 L) at 0 to 25 ° C for 2 hours and the title compound (2.5 kg, 83%) was removed as a yellow solid by filtration. 1 HNMR (400MHz, DMSO-d6) δppm 2.69 (3H, s), 7.90 (2H, m), 12.53 (1H, s).

[0782] Intermediate 1A: (2-bromo-4-methyl-phenyl) propionate

[0783]

[0784] A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propionyl chloride (5.44 g, 58.8 mmol) at 0 ° C and stirred at 25 ° C for 16 hours. The mixture was diluted with water (100 mL), the pH was adjusted to 5 with HCl (2 M), and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 x 150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product (13 g, crude) as an oil. 1 HNMR (400MHz, DMSO-d6) δppm 1.17 (t, J = 7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H).

[0785] Intermediate 29C: (2-bromo-4-fluoro-phenyl) propionate

[0786]

[0787] 2-Bromo-4-fluoro-phenol (3.0 kg, 15.7 mol) and EtOAc (15 L) were added to a 50 L reactor and stirred for 15 minutes. The reaction was slowly treated with triethylamine (1.9 kg, 18.8 mol). The reaction was cooled and propionyl chloride (1.6 kg, 17.3 mol) was added dropwise to maintain the temperature between 0 and 10 ° C. After the addition was complete, the reaction was stirred at room temperature for 15 hours. The reaction was carefully diluted with water (15 L) to maintain the reaction temperature below 30 ° C, and then stirred at room temperature for 30 minutes. The organic phase was separated, washed with water (10 L), collected, dried over MgSO 4 , filtered and concentrated under reduced pressure at 45 ° C to obtain the title compound (3.6 kg, 93%) as a yellow liquid. 1 H NMR (400MHz, DMSO-d6) δppm 1.15 (t, 3H), 2.65 (dd, 2H), 7.30 (m, 2H), 7.75 (m, 1H).

[0788] Intermediate 58A: 3-Bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide

[0789]

[0790] A 0°C solution of 3-bromo-6-chloro-pyridine-2-sulfonyl chloride (1.94 g, 6.68 mmol) in 40 mL of DCM was treated dropwise with 2-methylpropan-2-amine (3.90 g, 53.28 mmol) in 5 mL of DCM over 2 minutes. After the addition, the reaction was stirred at room temperature for 1 hour. The reaction was diluted with 50 mL of water and extracted with DCM (3 x 50 mL). The combined organics were washed with saturated aqueous sodium chloride solution (3 x 50 mL), collected, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% to 25% EtOAc / petroleum ether to give the title compound (1.2 g, 69%) as a white solid. MS ES+ m / z 327, 329 [M+H] + .

[0791] Intermediate 59A: 2-Benzylsulfanyl-3-bromo-6-chloro-pyridine

[0792]

[0793] A solution of phenylmethylmercaptan (0.97 g, 7.80 mmol) in THF (20 mL) was cooled to 0°C and treated with sodium hydride (0.31 g, 7.80 mmol). After stirring at 0°C, the reaction was treated with 3-bromo-6-chloro-2-fluoropyridine (1.5 g, 7.10 mmol). The reaction was allowed to stir at room temperature for 1.5 hours. The reaction was concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (2.10 g, 94%). MS ES+ m / z 314 [M+H] + .

[0794] Intermediate 60A: 8-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one

[0795]

[0796] 8-Bromo-3,4-dihydro-2H-isoquinolin-1-one (200 mg, 0.89 mmol) was dissolved in 5 mL of THF and cooled to 0 ° C. Upon cooling, the solution was treated with sodium hydride (38.9 mg, 60%, 0.97 mmol). After stirring at 0 ° C for 20 minutes, the reaction was treated with 4-methoxybenzyl chloride (152 mg, 0.97 mmol) and allowed to stir at room temperature for 2 hours. Another 152 mg of 4-methoxybenzyl chloride was added and stirred at 50 ° C for 23 hours. The reaction was phase-split between water and EtOAc. The organic layer was removed and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with saturated sodium chloride aqueous solution, and dry loaded onto celite. Purify by silica gel chromatography eluting with 0% to 40% EtOAc / heptane to give the title compound as a colorless oil (355 mg, >100%) containing some 4-methoxybenzyl chloride. MS ES+ m / z 347 [M+H] + .

[0797] Intermediate 61A: 8-bromo-2-(2-trimethylsilylethoxymethyl)isoquinolin-1-one

[0798]

[0799] 8-Bromo-2H-isoquinolin-1-one (0.34 g, 1.53 mmol) and DMF (5 mL) were loaded into a 20 mL vial, treated with sodium hydride (73.5 mg, 60%, 1.84 mmol), and stirred at room temperature for 10 minutes. The reaction was treated with 2-(trimethylsilyl)ethoxymethyl chloride (0.51 g, 3.06 mmol) and stirred at room temperature for 1 hour. The reaction was treated with another 0.51 g of 2-(trimethylsilyl)ethoxymethyl chloride, and the reaction was stirred at 50 ° C over the weekend. The reaction was phase-split between water and EtOAc. The organic layer was collected and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with saturated sodium chloride solution and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 40% EtOAc / heptane to obtain the title compound (231 mg, 432%) as an opaque oil. MS ES+m / z 354 / 356[M+H] + .

[0800] Intermediate 62A: (2-bromo-4-methyl-phenyl) acetate

[0801]

[0802] 2-bromo-4-methyl-phenol (300g, 1.6mol) and DCM (2.4L) mixture of pyridine (152g, 1.92mol) was treated with acetyl chloride at 0°C and stirred at 25°C for 16 hours. The mixture was diluted with water (1500mL), pH was adjusted to 5 with HCl (2M aqueous solution), and extracted with DCM (3X 500mL). The combined organic extracts were washed with saturated sodium chloride water (2x250mL), dried over NaSO, filtered, and concentrated to obtain the product (400g, rough) as an oil. 1 H NMR (400MHz, CDCl3) δppm 2.24 (s, 3H), 2.25 (s, 3H), 6.91 (d, J = 8.4Hz, 2H), 7.01-7.02 (m, 2H), 7.33 (s, 1H).

[0803] Intermediate 63A: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl) ketene

[0804]

[0805] A mixture of acetic acid (2-bromo-4-methyl-phenyl) ester (50g, 218mmol) and AlCl (102g, 764mmol) was degassed and purged three times with N and stirred at 140°C for 1 hour. After cooling to room temperature, the reaction was diluted with DCM (30mL) and added dropwise to 150mL of water at 0°C. The mixture was filtered and the aqueous phase was extracted with DCM (2x150mL). The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous NaSO, filtered and concentrated. The residue was triturated with petroleum ether (2x150mL) to obtain the product (30g, 52%) as a solid. 1 HNMR (400MHz, CDCl3) δppm2.30(s,3H),2.68(s,3H),7.73(s,1H),7.33(s,1H),12.64(s,1H).

[0806] Intermediate 2A: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one

[0807]

[0808] A mixture of (2-bromo-4-methyl-phenyl) propionate (12.5 g, 51.4 mmol) and AlCl (24.0 g, 180 mmol) was stirred at 140 ° C for 1 hour. When cooled to room temperature, the mixture was quenched dropwise with water (80 mL) and stirred for 30 minutes. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with saturated sodium chloride solution (2 x 200 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to obtain the product (9.82 g, 79%) as a solid. 1 H NMR (400MHz, DMSO-d6) δppm 1.10 (t, J = 7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).

[0809] Intermediate 30C: 1-(3-Bromo-5-fluoro-2-hydroxy-phenyl)propan-1-one

[0810]

[0811] (2-Bromo-4-fluoro-phenyl) propionate (3.5 kg, 14.2 mol) was heated to 75-85°C in a reactor and treated with AlCl3 (1.0 kg, 7.4 mol) in portions while the internal temperature was raised to 100-110°C. The reaction was heated to 100-120°C and treated with additional AlCl3 (1.1 kg, 8.2 mol). The reaction was stirred at 110-130°C for 18 hours. The reaction was cooled to room temperature and poured into a mixture of MTBE (20 L) and 1M aqueous HCl (20 L) at 0-10°C. The reaction was stirred at 0-15°C for 1 hour. The organic layer was separated and washed with water (2 x 10 L). The organic phase was dried over MgSO4 and concentrated under reduced pressure to provide the crude product. The crude material was slurried with n-heptane (7 L) at room temperature for 6 hours and then filtered to give the title compound (2.0 kg, 57%) as a brown solid after drying at 45 °C for 12 hours. 1 H NMR (400MHz, DMSO-d6) δppm 1.15 (t, 3H), 3.20 (m, 2H), 7.95 (m, 2H), 12.50 (s, 1H).

[0812] Intermediate 31C: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one

[0813]

[0814] Trifluoromethanesulfonic acid (237 g, 1.58 mol) was cooled to below -5 ° C and treated with (2-bromo-4-methyl-phenyl) propionate (80 g, 329 mmol) dropwise over 1 hour to maintain the temperature between -5 ° C and -20 ° C. After the addition was complete, the cooling bath was removed and the reaction was heated at 55-60 ° C for 1.5 hours. The mixture was cooled to 5-10 ° C, poured into ice water (5 V), stirred for 30 minutes, and the solid was removed by filtration. The filter cake was rinsed with water (2 V), slurried in water (5 V) for 30 minutes, and filtered to give the title compound (72.2 g, 90%) as an off-white solid after drying. ES / MS m / z 241 / 243 (MH).

[0815] Intermediate 64A: 1-[2-methoxy-5-(trifluoromethyl)phenyl]propan-1-one

[0816]

[0817] Trifluoromethanesulfonic acid (5.54kg, 36.90mol) was loaded into a 10L reactor and cooled to -10°C to -20°C. When cooled, propionyl chloride (2.05kg, 22.14mol) was slowly added and stirred for 0.5 hour. 1-methoxy-4-(trifluoromethyl)benzene (1.30kg, 7.38mol) was slowly added for 2 hours to maintain the temperature between -10°C to -20°C. The resulting solution was stirred for 20 hours. The solution was slowly added to ice-cold water (13L) to maintain the temperature between 0°C to 10°C and then stirred for 1 hour. The suspension was then filtered and the solid was rinsed with ice-cold water (7.5L). The filter cake was dissolved in MTBE (3.9L) and the aqueous phase was discarded. The organic phase was concentrated to obtain the title compound (1.65kg, 96%) as a pale solid. 1 HNMR(400MHz,CDCl3)δppm 1.13-1.25(3H,t,J=7.24Hz), 2.95-3.08(2H,q,J=7.23Hz), 3.97(3H,s), 7.06(1H,d,J=8.68Hz), 7.60-7.73(1H,m), 7.95(1H,d,J=2.16Hz).

[0818] Intermediate 65A: 1-[2-Hydroxy-5-(trifluoromethyl)phenyl]propan-1-one

[0819]

[0820] A mixture of NaOH (413.4 g, 10.34 mol) in DMF (8.25 L) was treated with 1-dodecanethiol (2.09 kg, 10.34 mol) at 25 ° C, and the mixture was stirred at 25 ° C for 1 hour. The reaction was treated with 1-[2-methoxy-5-(trifluoromethyl)phenyl]propan-1-one (1.60 kg, 6.89 mol), and the reaction was heated to 70 ° C and stirred at this temperature for 1.5 hours. The mixture was diluted with water (24 L) and extracted with MTBE (16 L). The pH of the aqueous phase was adjusted to 2-3 with aqueous HCl (2N) and extracted with MTBE (16 L). The organic phase was washed with 15% aqueous NaCl (8 L), collected and concentrated to give the title compound (1.24 kg, 82%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 1.25-1.32(3H,t,J=7.22Hz),3.02-3.17(2H,q,J=7.21Hz),3.97(3H,s),7.05-7 .13(1H,d,J=8.76Hz),7.65-7.74(1H,m),8.04(1H,d,J=1.28Hz),12.66(1H,s).

[0821] Intermediate 66A: 1-[3-Bromo-2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one

[0822]

[0823] A mixture of 1-[2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one (1.20 kg, 5.50 mol) in DMF (4.8 L) was treated with N-bromosuccinimide (1.08 kg, 6.05 mol) at 5° C. to 15° C., and the mixture was stirred at 20° C. to 30° C. for 5 hours. The reaction was diluted with water (14.4 L) and saturated aqueous Na2SO3 (3.6 L) and stirred at 25° C. for 1 hour. The mixture was filtered and the filter cake was slurried in water (6 L) at 20° C. to 25° C. for 0.5 hours, filtered, rinsed with water (3.6 L), and dried at 50° C. to provide the title compound (1.38 kg, 84%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δppm 1.08-1.14(3H,t,J=7.04Hz), 3.23-3.31(2H,q,J=7.05Hz), 3.97(3H,s), 8.21-8.35(2H,d,J=8.80Hz), 13.21(1H,s).

[0824] Intermediate 32C: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)propane-1,3-dione

[0825]

[0826] A suspension of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (300 g, 1.23 mol) in THF (600 mL) was cooled to -70-75°C and treated with lithium bis(trimethylsilyl)amide (5.4 L, 1 M in THF, 5.4 mol) over 14 hours, maintaining the internal temperature below -60°C. After the addition was complete, the mixture was stirred at -60 to -75°C for 30 minutes. The reaction was cooled to -70 to -75°C and treated with pyridine-3-carbonyl chloride hydrochloride (285.6 g, 1.60 mol) in portions, maintaining the internal temperature below -60°C. After the addition, the reaction was stirred at room temperature for 15 hours. The reaction was cooled to 0 to -10°C and quenched with AcOH / water (3 V / 3 V) until the pH reached 5-6. The reaction was concentrated under reduced pressure and the title compound (600 g, 100%) was removed by filtration, rinsed with water, and air-dried. ES / MS m / z 348 / 350 (M+H).

[0827] Intermediate 67A: 8-Bromo-4-hydroxy-6-methyl-benzopyran-2-thione

[0828]

[0829] A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (65 g, 284 mmol) in THF (800 mL) was treated with NaHMDS (851 mL, 1 M) at -50°C for 30 minutes, allowed to warm to between -5°C and 0°C, and stirred for 1 hour. The reaction was cooled to -20°C and treated dropwise with CS2 (64.8 g, 851 mmol) over 1 hour, allowed to warm to 25°C, and stirred for an additional 16 hours. The reaction was quenched with H2SO4 (800 mL, 15%) at -50°C for 1 hour, allowed to warm to room temperature, and extracted with EtOAc (2 x 1 L). The combined organic extracts were washed with saturated aqueous sodium chloride (1 L), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with EtOAc (0.5 L) to give the product as a solid (210 g crude, 64%, purity -76%).

[0830] Intermediate 33C: 8-Bromo-6-fluoro-4-hydroxy-3-methyl-benzopyran-2-thione

[0831]

[0832] Potassium tert-butoxide (3.2kg, 28.3mol) and THF (30L) are added to a 50L reactor and the mixture is stirred for 15 minutes to obtain a light yellow solution. 8-bromo-6-fluoro-4-hydroxy-3-methyl-benzopyran-2-thione (2.0kg, 8.1mol) is added to the reactor in batches so that the temperature remains between 0 and 15 ° C. Carbon disulfide (740g, 9.7mol) is added dropwise so that the temperature remains below 30 ° C. After the addition is complete, the reaction is stirred at 0 to 25 ° C for 12 hours. The reaction mixture is directly poured into 15% acetic acid aqueous solution (5L) and stirred at room temperature for 30 minutes. The mixture is filtered and the filter cake is washed with MTBE (2L). The filtrate is washed with water (2x5L) and a saturated NaCl aqueous solution (5L). Collect the organic phase, dry it through MgSO4, filter it and concentrate under reduced pressure to provide a crude product. This material was slurried in heptane (5 L), stirred for 6 hours, and filtered to afford the title compound as a yellow solid (2.8 kg, 120%) after drying at 45 °C for 12 hours. 1 H NMR (400MHz, DMSO-d6) δppm2.10(s,3H),7.65(m,1H),7.90(m,1H).

[0833] The following compounds in Table 4 were made in a similar manner as described for 8-bromo-6-fluoro-4-hydroxy-3-methyl-chromen-2-thione. Various methods were used to purify this compound, as would be apparent to one skilled in the art.

[0834] Table 4

[0835]

[0836] Intermediate 3A: (E)-1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one

[0837]

[0838] A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), AcOH (105.23 g, 1.75 mol) and piperidine (172.33 g, 2.02 mol) in EtOH (1600 mL) was stirred at 70°C for 16 hours. The resulting dark solution was poured into water (3 L), filtered, and the solid was dissolved in 6 L of DCM. The organic solution was dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a dark gum. MS ES+ m / z 331, 333 [M+H] + .

[0839] Intermediate 68A: 8-Bromo-2-ethylsulfanyl-6-methyl-chromen-4-one

[0840]

[0841] A mixture of 8-bromo-4-hydroxy-6-methyl-chromen-2-thione (20.0 g, 73.8 mmol), EtI (46 g, 295 mmol) and KCO (12.2 g, 88.5 mmol) in acetone (200 mL) was stirred at 60 ° C for 3 hours. When the reaction had cooled to room temperature, the mixture was diluted with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluting with 20% to 40% EtOAc / petroleum ether to obtain the product as a gum. 1 H NMR (400MHz, CDCl3) δppm 1.51 (t, J = 7.2 Hz, 3H), 2.45 (s, 3H), 3.22 (q, J = 7.2 Hz, 2H), 6.32 (s, 1H), 7.70 (s, 1H), 7.93 (s, 1H).

[0842] The following compounds in Table 5 were made in a similar manner as described for 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one. Various methods were used to purify this compound, as would be apparent to one skilled in the art.

[0843] Table 5

[0844]

[0845] Intermediate 36C: 8-Bromo-2-ethylsulfanyl-6-fluoro-benzopyran-4-one

[0846]

[0847] A crude THF solution (3.4 kg, 30 mol) from the synthesis of 8-bromo-6-fluoro-4-hydroxy-chromene-2-thione was treated with EtI (5.4 kg, 34.4 mol) at 20 to 25 ° C. The resulting solution was stirred at 60 to 65 ° C for 12 hours. The reaction was cooled to room temperature and the solid was removed by filtration. The filter cake was washed with MTBE (2 L). The combined filtrate was washed with water (2x6 L) and washed with a 10% NaCl aqueous solution. The organic phase was collected and concentrated under reduced pressure to provide a crude product. The crude solid was slurried with heptane (12 L) and stirred at room temperature for 3 hours. The title compound (2.0 kg, 77%) was taken out as a yellow solid. 1HNMR (400MHz, DMSO-d6) δppm 1.40 (t, 3H), 3.26 (dd, 2H), 6.47 (s, 1H), 7.69 (m, 1H), 8.15 (m, 1H).

[0848] Intermediate 69A: 8-Bromo-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one

[0849]

[0850] A mixture of 1-[3-bromo-2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one (1.26 kg, 4.24 mol) in THF (3.0 L) was slowly treated with lithium tert-butoxide (1.36 kg, 16.97 mol) and stirred for 0.5 hours. The reaction was then treated with carbon disulfide (355.2 g, 4.67 mol) in one go, and the mixture was stirred at 15 to 25 ° C for 16 hours. The reaction was added to a 15% H2SO4 aqueous solution (12.6 L) at 0 to 10 ° C. The organic layer was removed and the aqueous layer was extracted with 2-methyltetrahydrofuran (12.6 L). The organic layers were combined, washed with saturated sodium chloride aqueous solution (6.3 L), and concentrated to give a crude yellow solid. The solid was slurried with DCM (3.6 L) for 1 hour and filtered. The filter cake was dried at 40°C under vacuum to afford 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one as a yellow solid.

[0851] A 10 L reactor was charged with 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one (from above), cesium carbonate (586.6 g, 1.8 mol) and acetone (6.3 L). The reaction was slowly treated with EtI (421.1 g, 2.7 mol) at 15 to 25 ° C and then allowed to stir for 2 hours. The reaction was filtered and rinsed with acetone (3.78 L). The filtrate was concentrated to provide the title compound (650 g, 42%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 1.40-1.48(3H,t,J=7.30Hz), 1.93(3H,s), 3.33-3.40(2H,q,J=7.32Hz), 8.18(1H,d,J=1.52Hz), 8.45(1H,d,J=2.00Hz).

[0852] Intermediate 4A: 8-bromo-3,6-dimethyl-2-phenyl-benzopyran-4-one

[0853]

[0854] A mixture of (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) and I2 (21.76 g, 85.75 mmol) in DMSO (1200 mL) was stirred at 140°C for 2 hours to give a dark brown solution. After cooling to room temperature, the reaction was poured into 3 L of water, filtered, and the solid product was dissolved in DCM (4 L), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether / EtOAc (1:1, 1 L) to give the product as a light yellow solid (195 g, 69%). MS ES+ m / z 329, 331 [M+H] + .

[0855] Intermediate 37C: 8-Bromo-3,6-dimethyl-2-(3-pyridyl)chromen-4-one

[0856]

[0857] Crude 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)propane-1,3-dione (600 g, 1.23 mol) was suspended in HCl (0.15 V) and AcOH (3 V) and stirred at 90 to 100 ° C for 2 hours. The reaction was cooled to room temperature and basified with 5M NaOH aqueous solution to pH 8-9 to keep the temperature below 50 ° C. The resulting precipitate was collected by filtration and rinsed with water (2x2 V). The solid was slurried with MTBE (5 V), stirred at room temperature for 40 hours, and the title compound (368 g, 90%) was collected by filtration after drying at 50 ° C. ES / MS m / z ( 79 Br / 81 Br) 330 / 332 (M+H).

[0858] Intermediate 70A: 8-Acetyl-2-ethylsulfanyl-6-methyl-benzopyran-4-one

[0859]

[0860] A mixture of 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one (9.00 g, 30.0 mmol), tributyl(1-ethoxyvinyl)tin (13.3 g, 36.8 mmol), and Pd(PPh3)2Cl2 (2.11 g, 3.01 mmol) in 1,4-dioxane (90 mL) was stirred at 95°C for 16 hours. HCl (30 mL, 1 M) was added to the mixture and stirred at 50°C for 0.5 hours. Upon cooling to room temperature, the mixture was treated with saturated aqueous KF solution (100 mL) and stirred for 0.5 hours before being filtered. The filter cake was washed with EtOAc (3 x 40 mL). The filtrate was extracted with EtOAc (2 x 80 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluting with 0% to 60% EtOAc / petroleum ether to give the product (5.8 g, 60%) as a solid. MS ES+m / z 263[M+H] + .

[0861] Intermediate 5A: 8-acetyl-3,6-dimethyl-2-phenyl-benzopyran-4-one

[0862]

[0863] A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol) and tributyl(1-ethoxyvinyl)stannane (256.72 g, 710.84 mmol, 239.92 mL) in dioxane (1600 mL) was stirred at 95 ° C for 16 hours under N2 to obtain a dark brown solution. After cooling to room temperature, the reaction was treated with 1M HCl aqueous solution (100 mL) and stirred at 20 ° C for 30 minutes. The mixture was quenched with saturated KF aqueous solution (2000 mL), stirred for 30 minutes and filtered. The filter cake was washed with 10% MeOH / DCM (5x5000 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was triturated with petroleum ether / EtOAc (5 / 1, 1000 mL) to give the crude product, which was triturated with DCM / MeOH (10 / 1, 500 mL) to give the product as a light yellow solid (180 g, 96%, 92% purity). MS ES+ m / z 293 [M+H] + .

[0864] Intermediate 71A: 8-Acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)benzopyran-4-one

[0865]

[0866] A mixture of 8-bromo-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (980 g, 2.67 mol) in 1,4-dioxane (3.3 L) was treated with tributyl(1-ethoxyvinyl)stannane (1.06 kg, 2.94 mol). The reaction was evacuated and replaced with nitrogen three times before adding bis(triphenylphosphine)palladium(II) dichloride (74.93 g, 106.8 mmol) in one portion. The reaction was evacuated and replaced with nitrogen three times before heating to 85-95°C for 14 hours. The reaction was cooled to 50°C before adding aqueous HCl (4.9 L, 2 M) and stirring for 2 hours. The reaction was cooled to 20-25°C before extraction with EtOAc (14.7 L). The organic phase was quenched with saturated aqueous KF (4.9 L), stirred for 1 hour, and filtered. The organic phase was washed with saturated aqueous sodium chloride solution (4.9 L) and the organic phase was concentrated to 4.9 L under reduced pressure. IPA (9.8 L) was added two additional times and the mixture was concentrated to 4.9 L. IPA (4.9 L) was added to the mixture and heated to 70°C. The mixture was filtered, the filtrate was cooled to 0°C, stirred for 14 hours, filtered, and the solid was rinsed with IPA (1.96 L). The above crystallization process was repeated again and the combined solids were dried in vacuo at 40°C to provide the title compound (455.7 g, 52%) as an off-white solid. MS ES+ m / z 331 [M+H] + .

[0867] The following compounds in Table 6 were made in a manner similar to that described for 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0868] Table 6

[0869]

[0870] Intermediate 72A: 2-Ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-benzopyran-4-one

[0871]

[0872] A solution of 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (8.30 g, 31.6 mmol) in DCM (30 mL) and MeOH (30 mL) was treated portionwise with NaBH4 (1.32 g, 34.8 mmol) at 0°C and stirred at 15°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 4% MeOH / DCM to give the product as a solid (6.0 g, 60%). MS ES+ m / z 265 [M+H] + .

[0873] The following compounds in Table 7 were made in a similar manner as described for 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[0874] Table 7

[0875]

[0876] Intermediate 43C: 2-Ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-3-methyl-6-(trifluoromethyl)benzopyran-4-one

[0877]

[0878] A solution of 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (140 g, 0.42 mol) in DCM (1.4 L) was cooled to -5 ° C under a nitrogen atmosphere. Formic acid (58.5 g, 1.27 mol) was slowly added, followed by triethylamine (86.4 g, 0.85 mol) dropwise, maintaining the temperature below 10 ° C. Noyori catalyst (CAS: 74813-81-1, 2.7 g, 4.24 mmol) was added in one portion, and the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was washed with 1M aqueous HCl (2 x 500 mL), water (200 mL), and saturated aqueous NaCl (100 mL). The organic layers were collected, dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound (146 g, 100%, 99% purity) as a brown solid with an enantiomeric ratio of 93:7. ES / MS m / z 333 (M+H).

[0879] Intermediate 73A: 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-benzopyran-4-one

[0880]

[0881] A mixture of 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one (5.50 g, 20.8 mmol) in DCM (50 mL) was treated dropwise with PBr (16.9 g, 62.4 mmol) at 0°C and then stirred at 30°C for 4 hours. The reaction was quenched with water (20 mL) at 0°C and the pH was adjusted to 8 with saturated aqueous NaHCO. The mixture was extracted with DCM (2 x 80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous NaSO, filtered, and concentrated to give the product as an oil (4.7 g, 61%). MS ES+ m / z 329 [M+2+H]+.

[0882] The following compounds in Table 8 were made in a similar manner as described for 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0883] Table 8

[0884]

[0885] 11 HNMR (400MHz, CDCl3) δppm: 1.50~1.54(m,3H), 2.10(s,3H), 2.15~2.17(m,3H) ,3.27~3.42(m,2H),5.64~5.69(m,1H),7.50~7.53(m,1H),7.82~7.84(m,1H).

[0886] 21 HNMR(400MHz,CDCl3)δppm 1.48~1.51(m,3H),2.13~2.15(m,3H),3.12~3.27(m,2H),5.64~5.69(m,1H),6.32(s,1H),7.55~7.57(m,1H),7.79~7.81(m,1H).

[0887] Intermediate 74A: (NE,R)-N-[1-(2-Ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide

[0888]

[0889] A mixture of 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (9.49 g, 36.2 mmol) and (R)-2-methylpropane-2-sulfenamide (8.77 g, 72.4 mmol) in THF (100 mL) was treated with Ti(i-PrO)4 (41.1 g, 145 mmol) and stirred at 75°C for 16 hours. The reaction was treated with additional (R)-2-methylpropane-2-sulfenamide (6.58 g, 54.3 mmol) and Ti(i-PrO)4 (30.9 g, 109 mmol) and stirred at 75°C for 16 hours. The mixture was quenched with saturated aqueous sodium chloride solution (200 mL), stirred for 0.5 hours, and filtered. The filter cake was washed with EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the product as a solid (13 g, crude). MS ES+ m / z 366 [M+H] + .

[0890] Intermediate 6A: (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide

[0891]

[0892] To a mixture of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-sulfinamide (149.26 g, 1.23 mol) in THF (1500 mL) was added tetraisopropoxytitanium (700.01 g, 2.46 mol, 726.90 mL). The mixture was stirred at 80 ° C for 56 hours to obtain a dark brown solution. After cooling to room temperature, the reaction was quenched with saturated sodium chloride aqueous solution (2000 mL) and stirred for 30 minutes and filtered. The filter cake was washed with EtOAc (4000 mL). After separation of the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue. The residue was triturated with petroleum ether / EtOAc (1 / 1, 600 mL) to give the product as a white solid (186 g, 76%). MS ES+ m / z 396 [M+H] + .

[0893] The following compounds in Table 9 were made in a similar manner as described for (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide.

[0894] Table 9

[0895]

[0896] Intermediate 76A: (R)-N-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide

[0897]

[0898] A mixture of (NE,R)-N-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide (12.0 g, 32.8 mmol) in DCM (100 mL) and MeOH (100 mL) was treated with AcOH (15.8 g, 262 mmol) and NaBH3CN (6.19 g, 98.5 mmol) at -10°C and stirred at 25°C for 16 hours. The mixture was quenched with NH3·H2O (250 mL) and extracted with DCM (3 x 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a solid (11 g, isomer ratio: 3 / 2, crude). MS ES+ m / z 368 [M+H] + .

[0899] Intermediate 7A: (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide

[0900]

[0901] To a mixture of (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide (186 g, 470.27 mmol) and CeCl3·7H2O (87.61 g, 235.14 mmol, 22.35 mL) in MeOH (1600 mL) was added NaBH4 (26.69 g, 705.41 mmol) at 15°C. The mixture was stirred at 15°C for 1 hour to give a dark suspension. The reaction was quenched with saturated aqueous NH4Cl solution (1500 mL) at 15°C. The mixture was extracted with DCM (2 x 1500 mL), and the combined organic phases were washed with saturated aqueous sodium chloride solution (1500 mL). The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the product (180 g, 96%) as a yellow solid. MS ES+m / z 398[M+H] + .

[0902] Intermediate 47C: (R)-N-[(1R)-1-deuterated 1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide

[0903]

[0904] A solution of (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide (600 mg, 1.52 mmol) in tetradeuterated methanol (10 mL) was treated with cerium(III) chloride heptahydrate (283 mg, 0.76 mmol) and cooled to -78°C. The reaction was treated with sodium borodeuteride (127 mg, 3.03 mmol) in one portion. The reaction was stirred at -78°C. After 1 hour, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc (containing 25% EtOH) / heptane, followed by reverse phase chromatography on C18 eluting with 0% to 100% ACN / 10 mM aqueous NH4HCO3 (containing 5% MeOH) to give the title compound (530 mg, 88%). ES / MS m / z 399 (M+H).

[0905] Intermediate 77A: 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-6-methyl-benzopyran-4-one

[0906]

[0907] A mixture of (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (6.00 g, 16.3 mmol) in EtOAc (40 mL) was treated with HCl (82 mL, 4 M in EtOAc) and stirred at 25°C for 16 hours. The mixture was concentrated, diluted with water (100 mL), and washed with EtOAc (100 mL). The pH of the aqueous phase was adjusted to 8 with NH3·H2O (25%) and extracted with DCM (3 x 100 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (2.4 g, crude). MS ES+ m / z 264 [M+H] + .

[0908] Intermediate 48C: 8-[(1R)-1-amino-1-deutero-ethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[0909]

[0910] A solution of (R)-N-[(1R)-1-deutero-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide (530 mg, 1.33 mmol) in DCM (8 mL) was cooled to 0°C and treated with HCl (4N in 1,4-dioxane, 97 mg, 2.66 mmol). The reaction was allowed to stir overnight and gradually warmed to room temperature. The reaction was diluted with DCM and washed with saturated aqueous NaHCO₃. The aqueous layer was back-extracted with 25% IPA / chloroform. The organic layers were combined, dried over MgSO₄, filtered, and concentrated under reduced pressure to give the title compound, which was used without purification. ES / MS m / z 295 (M+H).

[0911] Intermediate 8A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[0912]

[0913] A mixture of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 g, 452.80 mmol) in MeOH (1500 mL) was treated with HCl / MeOH (4 M, 300 mL), and the mixture was stirred at 15°C for 1 hour to give a white suspension. The reaction was concentrated, and the residue was poured into water (1000 mL) and DCM (2000 mL), the pH was adjusted to 12 with NH3 / H2O (25%), and extracted with DCM (2 x 1000 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with DCM (200 mL) to give the product (122 g, 89%) as a white solid. MS ES+m / z 294[M+H] + .

[0914] Intermediate 9A: (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide

[0915]

[0916] A mixture of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (50 g, 0.18 mol) in 500 mL of toluene was treated with (R)-2-methylpropane-2-sulfenamide (32.7 g, 0.27 mol) and titanium ethoxide (82.1 g, 0.36 mol) in one portion. The reaction was heated at 80°C for 24 hours and then cooled to room temperature.

[0917] A toluene solution of (NE,R)-N-[1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide (0.18 mol) was cooled to between -10°C and 0°C and treated with sodium borohydride (20.4 g, 0.54 mmol) portionwise to maintain the internal temperature below 0°C. After stirring at -10°C and 0°C for 1 hour, the reaction was quenched with saturated aqueous NH4Cl. The resulting white slurry was filtered through celite, and the solids were washed with THF. The filtrate was washed with saturated aqueous sodium chloride, and the organic layer was concentrated onto silica gel. The material was purified by chromatography to give the product (26 g, 37% over 2 steps). MS ES+ m / z 382 [M+H] + .

[0918] The following compounds in Table 10 were made in a similar manner as described for (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide.

[0919] Table 10

[0920]

[0921] Intermediate 11A: 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-benzopyran-4-one

[0922]

[0923] A solution of (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide (20 g, 52.4 mmol) in THF (200 mL) was treated dropwise with 12 M aqueous HCl (2 eq) and stirred at room temperature. After 1 hour, the reaction was concentrated and the residue was dissolved in water and extracted with MTBE. The pH of the aqueous phase was adjusted to between 9 and 10 with 1 M aqueous NaOH and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and concentrated to give the product as a white solid (12.6 g, 87%). MS ES+ m / z 278 [M+H] + .

[0924] The following compounds in Table 11 were made in a similar manner as described for 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one.

[0925] Table 11

[0926]

[0927] Intermediate 13A: tert-Butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate

[0928]

[0929] A mixture of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (2.5 g, 9.0 mmol) and diisopropylethylamine (2.0 g, 16 mmol) in DCM (40 mL) was treated with di-tert-butyl dicarbonate (3.0 g, 14 mmol) and stirred at room temperature overnight. The reaction was concentrated and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the product (2.5 g, 73%). MS ES+ m / z 378 [M+H] + .

[0930] The following compounds in Table 12 were made in a similar manner as described for tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0931] Table 12

[0932]

[0933]

[0934] Intermediate 49C: tert-Butyl N-[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate

[0935]

[0936] Tert-butyl N-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate (5.00 g, 13.8 mmol) was dissolved in anhydrous THF (27.5 mL) and cooled to 0°C. While cooling, the reaction was treated dropwise with 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (41.3 mL, 41.3 mmol, 1 M in THF) over 15 minutes. The reaction was stirred at 0°C for 1 hour. A solution of iodine (6.98 g, 27.5 mmol) in THF (20 mL) was added dropwise, and the reaction was stirred for an additional 30 minutes. The reaction was concentrated under reduced pressure, and the residue was partitioned between water and DCM. The layers were separated, and the aqueous layer was re-extracted with DCM (2x). The organic layers were combined, washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound as a brown foam (8.33 g, 124%). ES / MS m / z 490 (M+H).

[0937] Intermediate 50C: tert-Butyl N-[(1R)-1-(2-ethylsulfanyl-6-methyl-3-oxazol-4-yl-4-oxo-chromen-8-yl)ethyl]carbamate

[0938]

[0939] Tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate (1.0 g, 2.04 mmol) and oxazol-4-ylboronic acid (0.46 g, 4.09 mmol) were transferred to a tube. 1,1'-bis(di-tert-butylphosphino)ferrocenedichlorid (0.33 g, 0.51 mmol) and cesium carbonate (2.0 g, 6.13 mmol) suspended in 9:11,4-dioxane / water (4.1 mL) were added. The reaction was bubbled with argon for 5 minutes and then stirred at 65 ° C for 2 hours. After cooling to room temperature, the reaction was filtered through celite and the solid was washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0% to 40% EtOAc / heptane to give the title compound (0.29 g, 33%). ES / MS m / z 431 (M+H).

[0940] Intermediate 80A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)benzopyran-4-one

[0941]

[0942] To a 20 mL vial was charged 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.30 g, 1.08 mmol), (2-methylindazol-5-yl)boronic acid (0.57 g, 3.24 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol), copper(I)thiophene-2-carboxylate (0.31 g, 1.62 mmol) and EtOH (15 mL). The reaction was degassed with argon, the vial was capped and stirred at 55 °C for 16 hours. The reaction mixture was loaded onto celite and purified by reverse phase C18 column chromatography eluting with 10% to 100% ACN / 5% MeOH in 10 mM NH4HCO3 to give the title compound (0.23 g, 60%). MS ES+ m / z 348 [M+H] + .

[0943] The following compounds in Table 13 were made in a similar manner as described for 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0944] Table 13

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955] 1 Stannane was used as the coupling partner.

[0956] Intermediate 86C: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]benzopyran-4-one

[0957]

[0958] A vial was charged with 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50 g, 1.80 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.35 g, 5.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol), 3-methylsalicylatecopper(I) (0.58 g, 2.70 mmol) and EtOH (8 mL). Nitrogen was bubbled through the reaction for 2 minutes, the vial was sealed, and the reaction was stirred at 60° C. for 16 hours. The reaction was re-treated with the same amount of 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, tetrakis(triphenylphosphine)palladium(0), and 3-methylsalicylate copper(I), and nitrogen was bubbled through the reaction for 5 minutes. The reaction was heated at 60°C for 16 hours. The reaction was cooled, filtered through celite, the solid washed with DCM / MeOH, and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 eluting with 10% to 65% ACN / 10mM NH4HCO3 aqueous solution to give the title compound (0.31 g, 51%). ES / MS m / z 340 (M+H).

[0959] The following compounds in Table 14 were made in a similar manner as described for 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[0960] Table 14

[0961]

[0962]

[0963] 1 Stannane was used as the coupling partner.

[0964] Intermediate 102A: tert-Butyl N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(2-pyridyl)chromen-8-yl]ethyl]carbamate

[0965]

[0966] Combine tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate (0.50 g, 1.32 mmol), copper(I)thiophene-2-carboxylate (0.63 g, 3.31 mmol), triphenylphosphine (0.28 g, 1.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol), and pyridin-2-ylboronic acid (0.37 g, 3.05 mmol) in 8 mL of EtOH and degassed with argon for 5 minutes. The reaction was stirred at 35° C. for 72 hours. An additional 300 mg of all reagents were added to the reaction, degassed, and stirred at 35° C. overnight. The reaction was filtered and purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (0.50 g, 96%). MS ES-m / z 395 [MH] - .

[0967] Intermediate 103A: 8-[(1R)-1-aminoethyl]-2-(2,6-difluorophenyl)-3,6-dimethyl-benzopyran-4-one

[0968]

[0969] Combine 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50 g, 1.80 mmol), zinc(II)2,6-difluorobenzen-1-idebromide (0.93 g, 3.61 mmol, 0.5 M), copper(I)thiophene-2-carboxylate (0.51 g, 2.70 mmol), and mesylate {[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.34 g, 0.54 mmol) in THF (5 mL) and degas for 10 minutes. The reaction was capped and allowed to stir at 130° C. overnight. The reaction was cooled to room temperature, diluted with 10 mL of DCM, filtered through celite and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / DCM and then 0% to 20% MeOH / DCM. The desired fraction was then repurified by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) / water (containing 0.1% formic acid). The product was then purified by reverse phase chromatography eluting with 10% to 100% ACN / 10 mM NH4HCO3 (containing 5% MeOH) to give the title compound (0.20 g, 34%). MS ES+ m / z 330 [M+H] + .

[0970] Intermediate 104A: tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate

[0971]

[0972] In a 500mL round-bottom flask, 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one (25.0g, 76.4mmol), tert-butyl 2-aminobenzoate (29.5g, 153mmol) and DIEA (14.8g, 20.0mL, 115mmol) were combined with DMF (150mL) and heated at 80°C. After cooling to room temperature, the reaction mixture was concentrated to 100mL, poured into 1.1L water, and extracted with EtOAc (2x350mL). The combined organic layer was washed with saturated sodium chloride aqueous solution (400mL). The combined aqueous layer was re-extracted with fresh EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain a thick oil. The residue was purified by silica gel chromatography using EtOAc / DCM (0% to 10%) to provide an off-white foam. Triturate with heptane / DCM and wash with heptane to give the product as a white solid (27.1 g, 81%). MS ES+ m / z 440 [M+H] + .

[0973] Intermediate 94C: tert-Butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate

[0974]

[0975] 8-(1-Bromoethyl)-2-ethylsulfanyl-6-fluoro-benzopyran-4-one (66.0 g, 200 mmol) was dissolved in CHCl₃ (660 mL) and treated with pyridine (17.34 g, 219 mmol) and tert-butyl 2-aminobenzoate (42.36 g, 219 mmol) at room temperature. The reaction was stirred at 80°C for 66 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was suspended in EtOAc (200 mL), sonicated and filtered. This procedure was repeated three times. The filtrate was concentrated under reduced pressure, and the residue was slurried in 300 mL of heptane for 30 minutes. The solid was removed by filtration, washed with heptane (3 x 150 mL) and dried to obtain the title compound (43 g, 49%). 1HNMR(400MHz,CDCl3)δppm 1.48~1.51(m,3H),1.65(s,9H),1.68~1.70(d,3H),3.11~3.17(m,2H),5.06~5.13(m,1H),6.23~6.26(d,1H),6.33(s,1 H), 6.59~6.63(m,1H),7.16~7.21(m,1H),7.41~7.44(m,1H),7.69~7.71(m,1H),7.91~7.93(m,1H),8.31~8.32(m,1H).

[0976] Intermediate 95C: 6-Chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid

[0977]

[0978] A solution of 8-[(1R)-1-bromoethyl]-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (223 g, 0.56 mol) and 3-amino-6-chloro-pyridine-2-carboxylic acid (146 g, 0.85 mol) in DMF (1.8 L) was stirred at 85 ° C for 3 days. The reaction was cooled to room temperature and slowly added to water (6.7 L). The resulting precipitate was collected by filtration, and the solid was slurried in water (3.3 L), filtered, and dried in an oven to give the title compound (232 g, 84%, 73% purity). ES / MS m / z 487 (M+H).

[0979] Intermediate 96C: 6-Chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid

[0980]

[0981] A solution of 8-(1-bromoethyl)-2-ethylsulfanyl-6-fluoro-3-methyl-chromen-4-one (100 g, 290 mmol) in DMF (800 mL) was treated with 3-amino-6-chloro-pyridine-2-carboxylic acid (50 g, 290 mmol). The reaction was stirred at 80 to 90 ° C for 58 hours. The reaction was concentrated under reduced pressure at 60 ° C, and the residue was slurried with MTBE (500 mL) and water (100 mL). After sonication for 30 minutes, the reaction was filtered and the solid was washed with MTBE (2 x 500 mL) to give the title compound (64 g, 51%) as a light yellow solid. 1HNMR(400MHz,CDCl3)δppm 1.47~1.51(m,3H),1.64~1.66(m,3H),1.98(s,3H)3.09~3.36(m,2H),5.15~5.21(m,1H),7.00~7.02 (d,1H),7.30~7.35(m,1H),7.49~7.51(m,1H),7.58~7.61(m,1H)8.29~8.31(m,1H),13.15(br,1H).

[0982] Intermediate 97C: tert-Butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate

[0983]

[0984] A solution of 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid (79 g, 181 mmol) in THF (800 mL) was cooled to 10 ° C and treated dropwise with 2-tert-butyl-1,3-diisopropyl-isourea (126.78 g, 633 mmol). The reaction was stirred at 20 ° C for 2 hours, filtered, and the solid was washed with THF (2 x 100 mL). The filtrate was concentrated under reduced pressure, and the residue was slurried in 200 mL of MTBE under ultrasonication for 30 minutes to obtain the title compound (76.3 g, 86%) after filtration, washing with MTBE (100 mL) and drying. 1 HNMR (400MHz, CDCl3) δppm1.47~1.51(m,3H),1.63~1.74(m,12H),2.12(s,3H),3.21~3.26(m,2H),5.01~5. 07(m,1H),6.59~6.61(d,1H),7.09~7.11(d,1H),7.30~7.33(m,1H),7.75~7.78(m,1H),8.32~8.33(d,1H).

[0985] The following compounds in Table 15 were made in a similar manner as described for tert-butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[0986] Table 15

[0987]

[0988] Intermediate 99C: 4-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-2-oxo-1H-pyridine-3-carboxylic acid methyl ester

[0989]

[0990] 8-[(1R)-1-Aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one (100 mg, 0.29 mmol), methyl 4-chloro-6-methyl-2-oxo-1H-pyridine-3-carboxylate (87 mg, 0.43 mmol), and triethylamine (58.3 mg, 0.58 mmol) were combined in MeOH (1 mL) and the reaction was stirred at 75° C. for 60 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound (148 mg, 100%). ES / MS m / z 513 (M+H).

[0991] The following compounds in Table 16 were made in a similar manner as described for 4-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-2-oxo-1H-pyridine-3-carboxylic acid methyl ester. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[0992] Table 16

[0993]

[0994] Intermediate 105A and Intermediate 106A: tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 1 and Isomer 2

[0995]

[0996] Tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (22.04 g, 50.14 mmol) was separated into its component isomers using a Chiralcel OJ column (8 x 34 cm; 20 microns) eluting with 100% MeOH containing 0.2% DMEA to give Isomer 1 (11.3 g wet) and Isomer 2 (12.9 g wet). MS ES+ m / z 440 [M+H] + .

[0997] Intermediate 101C and Intermediate 102C: tert-Butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate, Isomer 1 and Isomer 2

[0998]

[0999] Tert-butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate (76.3 g, 155 mmol) was separated into its component isomers using a ChiralPak IC column (250 x 50 mm, 10 mm) eluted with 45% i-PrOH (containing 0.1% NH4OH) in CO2 to afford crude isomer 1 (38.40 g) and crude isomer 2 (27 g). Isomer 1 was further purified by preparative HPLC using a Sharpsil-T C18 column (50 x 250 mm, 8 microns) eluted with 85% to 98% ACN / water (containing 0.05% TFA) to afford isomer 1 (28.60 g, 37%) as an off-white solid. ES / MS m / z 493 (M+H).

[1000] Intermediate 103C and Intermediate 104C: tert-Butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 1 and Isomer 2

[1001]

[1002] Chiral SFC [ChiralPak IG, 250x50mm, 10mm; MeOH in CO2] was used to separate tert-butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate (48.3g, 109mmol) into its component isomers to afford isomer 1 (22.4g, 46%) and isomer 2 (19.0g, 39%) as yellow solids. ES / MS m / z 466 (M+H).

[1003] Intermediate 105C and Intermediate 106C: tert-Butyl 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylate, Isomer 1 and Isomer 2

[1004]

[1005] Chiral SFC [WhelkO1-(R,R), 50x250mm, 10mm; 25% EtOH / CO2] was used to separate tert-butyl 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylate into its component isomers to give Isomer 1 (first eluting; 67.7g, 99%ee) and Isomer 2 (68.0g, 93.6%ee). ES / MS m / z 543 (M+H).

[1006] Intermediate 107A: tert-Butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate

[1007]

[1008] A vial was charged with 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.0 g, 3.61 mmol), tert-butyl 3-bromo-6-chloropicolinate (1.58 g, 5.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.27 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.42 g, 0.72 mmol), cesium carbonate (2.93 g, 9.01 mmol) and 12 mL of toluene. The suspension was purged with nitrogen for 10 minutes and the vial was sealed. The reaction was stirred at 130° C. overnight. The reaction was cooled to room temperature, filtered, and the solid was washed with DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / hexanes to give the title compound as a light brown solid (0.88 g, 50%). MS ES-m / z 433 [M+2H-tBu] + .

[1009] The following compounds in Table 17 were made in a similar manner as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1010] Table 17

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019] 1 1,4-Dioxane was used as the solvent.

[1020] 2 Use XantPhos Pd G4 instead of Pd2(dba)3 and Xantphos.

[1021] Intermediate 139C: N-tert-Butyl-6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide

[1022]

[1023] A solution of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (10 g, 36 mmol) in DMF (150 mL) was treated with cesium carbonate (23.49 g, 72 mmol), 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (15.36 g, 47.0 mmol), copper(I) iodide (1.37 g, 7 mmol), and N,N'-bis(furan-2-ylmethyl)oxamide (1.79 g, 7 mmol) at room temperature. The reaction was stirred at 100°C for 12 hours. The reaction was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 17% EtOAc / heptane to give the title compound (12.3 g, 65%) as an off-white solid. ES / MS m / z 524 (M+H).

[1024] Intermediate 140C: tert-Butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate

[1025]

[1026] A solution of tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (1.0 g, 2.05 mmol) in DCM (10 mL) was cooled to 0°C and treated with mCPBA (0.50 g, 77%, 2.25 mmol) portionwise. After the addition was complete, the reaction was stirred at 0°C for 1 hour. The reaction was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was removed and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (1.0 g, 97%) as a light brown solid. ES / MS m / z 503 (MH).

[1027] The following compounds in Table 18 were made in a similar manner as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1028] Table 18

[1029]

[1030] Intermediate 143C: tert-Butyl 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate

[1031]

[1032] A solution of tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.95 g, 1.87 mmol) and benzyl(triethyl)ammonium chloride (0.21 g, 0.94 mmol) in DCM (30 mL) was treated with HCl (0.78 mL, 37% aqueous solution, 9.37 mmol). The reaction was stirred at room temperature for 1 hour, treated with additional aqueous HCl (0.18 mL, 37% aqueous solution), and allowed to stir for 30 minutes. The reaction was quenched with saturated aqueous NaHCO₃ and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, collected, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc / heptane to give the title compound (0.42 g, 49%) as a white foam. ES / MS m / z 407(MH-t Bu).

[1033] The following compounds in Table 19 were made in a similar manner as described for tert-butyl 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1034] Table 19

[1035]

[1036] Intermediate 146C: tert-Butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxylate

[1037]

[1038] To a dry vial was charged tert-butyl 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (208 mg, 0.45 mmol), palladium(II) acetate (10.1 mg, 0.05 mmol) and 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl (CPhos, 39.2 mg, 0.09 mmol). The vial was evacuated and refilled with nitrogen three times. THF (2 mL) was added via syringe and the reaction was cooled to 0 ° C. Iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]zinc (220 mg, ~0.45 M in THF, 0.67 mmol) was added via syringe, the cooling bath was removed, and the mixture was stirred at room temperature overnight. The reaction was cooled to 0°C and reloaded with palladium(II) acetate (10.1 mg, 0.05 mmol), CPhos (39.2 mg, 0.09 mmol) and iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]zinc (220 mg, 0.67 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 8 hours. The reaction was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was removed and the aqueous layer was re-extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc / heptane to give the title compound (183.2 mg, 73%) as a brown foam. ES / MS m / z 561 (M+H).

[1039] The following compounds in Table 20 were made in a similar manner as described for tert-butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1040] Table 20

[1041]

[1042]

[1043] Intermediate 152C: 6-Chloro-3-[[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile

[1044]

[1045] A solution of 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (3.10 g, 7.75 mmol) in THF (50 mL) was purged with nitrogen and cooled to 0°C. The reaction was treated dropwise with a solution of 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (1 M, 23.26 mL, 23.26 mmol). The reaction was stirred for 1 hour while slowly warming to room temperature, then iodine (5.90 g, 23.26 mmol) was added and the reaction was stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl solution, concentrated under reduced pressure, and the residue was resuspended in 100 mL of DCM. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 100% EtOAc / heptane to give the title compound as a brown solid (3.20 g, 75%). ES / MS m / z 544 (M+H).

[1046] Intermediate 153C: tert-Butyl 6-chloro-3-[[(1R)-1-(3-chloro-2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate

[1047]

[1048] Tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (600 mg, 1.26 mmol), N-chlorosuccinimide (202 mg, 1.52 mmol), and benzoyl peroxide (30.6 mg, 0.13 mmol) were combined in ACN (10 mL) and stirred at 25° C. for 2 hours. The reaction was concentrated under reduced pressure and purified by silica gel chromatography eluting with 10% to 100% EtOAc / heptane to give the title compound (580 mg, 90%) as a white solid. ES / MS m / z 453 (M+H).

[1049] Intermediate 154C: 6-Chloro-3-[[(1R)-1-(2-ethylsulfanyl-3-isoxazol-4-yl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile

[1050]

[1051] Combine 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (4.0 g, 7.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.97 g, 15.2 mmol), cesium carbonate (7.44 g, 22.8 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium(II) dichloride (0.50 g, 0.76 mmol) in 1,4-dioxane (90 mL) and water (10 mL). Stir the reaction at 65°C for 1.5 hours. Cool the reaction to room temperature, filter through a pad of silica gel, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 80% EtOAc / hexanes to give the title compound as a white solid (3.1 g, 83%). ES / MS m / z 467 (M+H).

[1052] Intermediate-155C: 2-Ethylsulfanyl-8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridinyl]amino]ethyl]-3,6-dimethyl-benzopyran-4-one

[1053]

[1054] 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.37 g, 3.52 mmol), (2-fluorophenyl)boronic acid (0.49 g, 3.52 mmol), potassium carbonate (0.97 g, 7.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) were combined in 1,4-dioxane (12 mL) and water (3 mL). The reaction was bubbled with argon for 5 minutes and then stirred at 100 ° C for 16 hours. The reaction was purified by silica gel chromatography eluting with 0% to 60% EtOAc / heptane to give the title compound (1.10 g, 70%) as a yellow foam. ES / MS m / z 449 (M+H).

[1055] Intermediate 118A: 8-[(1R)-1-aminoethyl]-2-(2-fluorophenyl)-3,6-dimethyl-benzopyran-4-one

[1056]

[1057] A solution of tert-butyl N-[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]carbamate (0.68 g, 1.65 mmol) in 10 mL of DCM was treated with TFA (5 mL) and the reaction was stirred at 60 ° C for 2 hours. The reaction was concentrated and the residue was purified by reverse phase C18 column chromatography eluting with 0% to 100% ACN in 10 mM aqueous NH4HCO3 with 5% MeOH. The fractions containing the product were pooled, washed with saturated aqueous sodium chloride solution, and extracted with IPA / CHCl3 (1:3). The organics were collected, dried over MgSO4, filtered, and concentrated to give the title compound (0.26 g, 51%) as a yellow foam. MS ES+m / z 312[M+H] + .

[1058] The following compounds in Table 21 were made in a similar manner as described for 8-[(1R)-1-aminoethyl]-2-(2-fluorophenyl)-3,6-dimethyl-chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1059] Table 21

[1060]

[1061]

[1062]

[1063]

[1064] Intermediate 128A: 8-[(1R)-1-aminoethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one

[1065]

[1066] A solution of tert-butyl N-[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]carbamate (100 mg, 0.26 mmol) in 3 mL of DCM was treated with HCl (4 M in 1,4-dioxane, 190 mg, 5.22 mmol) and stirred at room temperature for 6 hours. The reaction was concentrated and the residue was purified by reverse phase chromatography eluting with 10% to 100% ACN (containing 5% MeOH) / 10 mM NH4HCO3 aqueous solution to provide the title compound (54 mg, 69%) as a white solid. MS ES+ m / z 284 [M+H] + .

[1067] The following compounds in Table 22 were made in a manner similar to that described for 8-[(1R)-1-aminoethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1068] Table 22

[1069]

[1070]

[1071] Intermediate 14A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid

[1072]

[1073] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30 g, 102.3 mmol), 2-iodobenzoic acid (25.36 g, 102.26 mmol), copper (13.00 g, 204.5 mmol) and potassium carbonate (21.20 g, 153.4 mmol) was suspended in DMF (300 mL) and stirred at 100 °C for 3 hours. A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30 g, 102.3 mmol), 2-iodobenzoic acid (25.36 g, 102.26 mmol), copper (13.00 g, 204.5 mmol) and potassium carbonate (21.20 g, 153.4 mmol) was suspended in DMF (300 mL) and stirred at 100° C. for 3 hours. The two reactions were combined, the pH was adjusted to ~3 with 2M aqueous HCl solution, diluted with DCM (1 L) and water (500 mL), filtered, and the layers separated. The organic layer was washed with saturated aqueous sodium chloride solution (3×1 L), dried over Na 2 SO 4 , and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc / petroleum ether). The resulting solid was triturated with EtOAc (300 mL) and collected by filtration. The resulting solid was suspended in boiling I (500 mL) and collected by filtration to give the product as a white solid (33 g; 39%). MS ES+ m / z 414 [M+H] + .

[1074] Intermediate 129A: N-tert-Butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridinyl)chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide

[1075]

[1076] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (0.60 g, 2.04 mmol) and 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (0.80 g, 2.45 mmol) in 6 mL of DMSO was treated with 4,7-dimethoxy-1,10-phenanthroline (97 mg, 0.41 mmol), cesium carbonate (1.33 g, 4.08 mmol) and copper (I) iodide (38 mg, 0.20 mmol) in portions at room temperature under nitrogen. The reaction was heated to 150 ° C for 30 minutes in a microwave. The reaction was cooled to room temperature, filtered, and the solid was washed with EtOAc (3x10 mL). The filtrate was diluted with water (50 mL) and extracted with EtOAc (3x30 mL). The combined organics were washed with saturated aqueous sodium chloride (3 x 30 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluting with 40% to 70% ACN / water (containing 0.1% formic acid) to give the title compound (0.18 g, 16%) as a yellow solid. MS ES+ m / z 541 [M+H] + .

[1077] The following compounds in Table 23 were made in a similar manner as described for N-tert-butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridinyl)chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1078] Table 23

[1079]

[1080]

[1081] Intermediate 183C: N-tert-Butyl-6-chloro-3-[[(1R)-1-[2-(1,5-dimethyl-6-oxo-3-pyridinyl)-6-methyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide

[1082]

[1083] A solution of 5-[8-[(1R)-1-aminoethyl]-6-methyl-4-oxo-chromen-2-yl]-1,3-dimethyl-pyridin-2-one (200 mg, 0.62 mmol) and 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (404 mg, 1.23 mmol) in DMF (6 mL) was treated portionwise with cesium carbonate (402 mg, 1.23 mmol) and copper (I) iodide (23.5 mg, 0.12 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at 120° C. overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography on C18 eluting with 20% to 50% ACN / water (containing 0.1% NH 4 OH) to give the title compound (88 mg, 25% as a white solid). ES / MS m / z 571 (M+H).

[1084] The following compounds in Table 24 were made in a similar manner as described for N-tert-butyl-6-chloro-3-[[(1R)-1-[2-(1,5-dimethyl-6-oxo-3-pyridinyl)-6-methyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1085] Table 24

[1086]

[1087]

[1088] Intermediate 189C: 6-Chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile

[1089]

[1090] A solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)chromen-4-one (0.57 g, 1.64 mmol) in DMF (10 mL) was treated with 6-chloro-3-fluoro-pyridine-2-carbonitrile (0.77 g, 4.91 mmol), potassium carbonate (2.26 g, 16.36 mmol) and DIPEA (0.63 g, 4.91 mmol) at room temperature. The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 99% EtOAc / petroleum ether to give the title compound as a brown solid (0.25 g, 32%). ES / MS m / z 485 (M+H).

[1091] The following compounds in Table 25 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[1092] Table 25

[1093]

[1094]

[1095] 1 DIPEA was not used in this reaction.

[1096] Intermediate 130A: tert-Butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate

[1097]

[1098] Tert-butyl 2-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]benzoate (1.00 g, 2.27 mmol; Intermediate 106, tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2), phenylboronic acid (0.56 g, 4.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.23 mmol), copper(I)thiophene-2-carboxylate (0.87 g, 4.55 mmol), zinc(II) acetate (0.84 g, 4.55 mmol) and tri(2-furyl)phosphine (0.26 g, 1.14 mmol) were combined in 1,4-dioxane (20 mL) and heated at 85 °C for 12 h. The crude product mixture was purified by silica gel chromatography eluting with 10% to 60% EtOAc / heptane, followed by reverse phase chromatography eluting with 0% to 100% ACN / water (containing 0.1% TFA) to provide the product (0.53 g, 48%). MS ES+ m / z 456 [M+H] + .

[1099] The following compounds in Table 26 were made in a similar manner as described for tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[1100] Table 26

[1101]

[1102] Intermediate 192C: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile

[1103]

[1104] A vial containing 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.31 g, 0.74 mmol), 1H-pyrazol-4-ylboronic acid (0.25 g, 2.23 mmol), tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.19 mmol), and 3-methylsalicylic acid copper(I) (0.24 g, 1.11 mmol) was suspended in EtOH (3 mL) and THF (3 mL). Nitrogen was bubbled through the reaction for 2 minutes, the vial was sealed, and the reaction was stirred at 60° C. for 4 hours. The reaction was charged with the same amount of 1H-pyrazol-4-ylboronic acid, tetrakis(triphenylphosphine)palladium(0), and 3-methylsalicylic acid copper(I). Nitrogen was bubbled through the reaction for 5 minutes, the vial was sealed, and the reaction was stirred at 60°C for 16 hours. The reaction was cooled, filtered through celite, and the solid was washed with DCM. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography on C18 eluting with 16% to 44% ACN / water (containing 0.1% formic acid) to give the title compound (60 mg, 19%). ES / MS m / z 420 (M+H).

[1105] The following compounds in Table 27 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1106] Table 27

[1107]

[1108]

[1109] 1 Stannane was used as the coupling partner.

[1110] Intermediate 15A: tert-Butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate

[1111]

[1112] Tris(dibenzylideneacetone)dipalladium(0) (1.17 g, 1.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.97 g, 3.41 mmol), (8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (5.00 g, 17.0 mmol), tert-butyl 3-bromopicolinate (5.28 g, 20.5 mmol) and Cs2CO3 (13.9 g, 42.6 mmol) were combined in toluene (80 mL). The reaction was heated to 115°C for 16 hours. The mixture was filtered through celite and the solids were rinsed with EtOAc and DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 80% EtOAc / heptane to give the title compound (7.1 g, 89%). MS ES+ m / z 471[M+H] + .

[1113] The following compounds in Table 28 were made in a similar manner as described for tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1114] Table 28

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135] 1 Use Xantphos Pd G4 instead of Pd2(dba)3 and Xantphos.

[1136] 2Use RuPhos Pd G4 instead of Pd2(dba)3 and Xantphos.

[1137] Intermediate 195A: tert-Butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate

[1138]

[1139]

[00145] Tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.30 g, 0.61 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (0.40 g, 1.53 mmol), tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.31 mmol), copper(I)thiophene-2-carboxylate (0.29 g, 1.53 mmol) and cesium carbonate (0.50 g, 1.53 mmol) were suspended in 6 mL of THF in a tube, degassed for 10 minutes, capped and stirred at 70 °C for 2 hours. The reaction was cooled to room temperature, diluted with 10 mL of DCM, filtered through celite and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% DCM / heptane to give the title compound (0.18 g, 53%). MS ES+ m / z 559 [M+H] + .

[1140] The following compounds in Table 29 were made in a similar manner as described for tert-butyl 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1141] Table 29

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148] 1 No cesium carbonate was used in this reaction.

[1149] 2 In this reaction no cesium carbonate was used and EtOH was used as solvent.

[1150] Intermediate 256C: 8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridinyl]amino]ethyl]-6-methyl-2-(3-pyridinyl)chromen-4-one

[1151]

[1152] 8-[(1R)-1-[(2-chloro-3-pyridinyl)amino]ethyl]-6-methyl-2-(3-pyridinyl)chromen-4-one (2.46 g, 6.28 mmol), (2-fluorophenyl)boronic acid (0.88 g, 6.28 mmol), potassium carbonate (1.74 g, 12.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.36 g, 0.31 mmol) were combined in 1,4-dioxane (20.9 mL) and water (5.46 mL), sparged with argon for 5 minutes, and stirred at 100° C. for 16 hours. The dried reaction was resuspended in DCM and purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound as a yellow foam (0.77 g, 27%). ES / MS m / z 452 (M+H).

[1153] Intermediate 257C: tert-Butyl 6-chloro-3-[[(1R)-1-[2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate

[1154]

[1155] Combine tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.50 g, 1.02 mmol), 2,6-difluorobenzene-1-carbanion zinc(II) bromide (0.79 g, 0.5 M, 3.07 mmol), mesylate {[4-N,N-dimethylamino)phenyl]di-tert-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.20 g, 0.31 mmol), and copper(I) thiophene-2-carboxylate (0.29 g, 1.53 mmol) in THF (3 mL) and degas for 5 minutes. The reaction was stirred at 75° C. for 6 hours. The reaction was filtered through celite, and the solid was washed with 20 mL of DCM. The filtrate was concentrated under reduced pressure to give the title compound (0.90 g, 160%), which was used without purification. ES / MS m / z 485 (MH- t Bu).

[1156] Intermediate 25A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid

[1157]

[1158] Tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (7.1 g, 15 mmol) was dissolved in DCM (1 mL) and TFA (1 mL). The reaction was sealed and heated at 50°C for 16 hours. Concentrated and purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN / NH4HCO3 aqueous solution (10 mM, plus 5% MeOH) to give the crude product. Recrystallization from MeOH (50 mL) and MTBE (50 mL) gave the title compound (3.4 g, 54%). MS ES+ m / z 415 [M+H] + .

[1159] The following compounds in Table 30 were made in a similar manner as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1160] Table 30

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172] Intermediate 235A: 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-6-fluoro-pyridine-2-carboxylic acid

[1173]

[1174] A solution of tert-butyl 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridinyl)chromen-8-yl]ethyl]amino]-6-fluoro-pyridine-2-carboxylate (0.23 g, 0.47 mmol) in DCM (5 mL) was treated with HCl (4 M in 1,4-dioxane) and allowed to stir at room temperature under nitrogen for 1 hour. The reaction was concentrated to give the title compound (0.21 g) which was used without purification. MS ES+ m / z 434 [M+H] + .

[1175] Intermediate 292C: 3-[[(1R)-1-[2-(5-tert-Butoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-pyridine-2-carboxylic acid

[1176]

[1177] A solution of 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid (100 mg, 0.20 mmol) in 1,4-dioxane (5 mL) was treated with DIPEA (262 mg, 2.02 mmol) and di-tert-butyldecarbonate (66.3 mg, 0.30 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, and then saturated aqueous NaCl. The organic layer was collected and concentrated under reduced pressure to give the title compound (180 mg, 90% purity, 130%), which was used without purification. ES / MS m / z 592 (MH).

[1178] Intermediate 293C: 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]benzaldehyde

[1179]

[1180] A vial was charged with 8-[(1R)-1-[2-(1,3-dioxolan-2-yl)anilino]ethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (479 mg, 1.08 mmol), 1,4-dioxane (10 mL), and water (3 mL). The reaction was treated with HCl (5 M in 1,4-dioxane, 1 g, 5 mmol) and stirred at room temperature for 2 hours. The reaction was diluted with DCM and neutralized with 1 M aqueous NaOH. After removing the organic layer, the aqueous layer was extracted three times with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 93%), which was used without purification. ES / MS m / z 399 (M+H).

[1181] The following compounds in Table 31 were made in a similar manner as described for 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridinyl)chromen-8-yl]ethyl]amino]benzaldehyde. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1182] Table 31

[1183]

[1184] Intermediate 236A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoic acid

[1185]

[1186] A solution of methyl 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoate (0.67 g, 1.51 mmol) in THF (9 mL) and water (3 mL) was treated with lithium hydroxide (0.11 g, 4.53 mmol) and allowed to stir at room temperature overnight. An additional 0.11 g of lithium hydroxide was added, and the reaction was stirred at 50°C for 6 hours. An additional 2 equivalents of lithium hydroxide were added, and the reaction was stirred at 60°C overnight. The reaction was cooled to room temperature, diluted with DCM, washed with saturated aqueous ammonium chloride, and extracted twice with IPA / CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to give the title compound (0.76 g, 93%, 80% purity) as a white solid. MS ES+ m / z 432 [M+H] + .

[1187] The following compounds in Table 32 were made in a similar manner as described for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoic acid. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1188] Table 32

[1189]

[1190] Intermediate 26A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide

[1191]

[1192] A solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.600 g, 1.45 mmol) in DCM (6 mL) was cooled to 0°C. Thionyl chloride (1.45 mL, 2.90 mmol) was added and the reaction was stirred at room temperature for 1 hour. Thionyl chloride (1.45 mL, 2.90 mmol) was added and the reaction was stirred at 60°C for 2 hours. The mixture was concentrated to dryness, DCM (6 mL) and triethylamine (0.61 mL, 4.34 mmol) were added, and the mixture was cooled to 0°C. N-BOC-hydrazine (0.48 g, 3.62 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, DCM (6 mL) and HCl (4 M in 1,4-dioxane, 1.81 mL, 7.24 mmol) were added, and the reaction was stirred at room temperature for 3 days. The product was concentrated and purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN / NH4HCO3 aqueous solution (10 mM, plus 5% MeOH). Fractions containing the product were diluted with saturated aqueous NaHCO3 and EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. Filtration from DCM / hexanes afforded the title compound (0.36 g, 58%). MS ES+ m / z 429 [M+H] + .

[1193] Intermediate 237A: 6-Chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide

[1194]

[1195] 6-Chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.40 g, 0.89 mmol), DIPEA (0.35 g, 2.67 mmol), 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphine-2,4,6-trioxide (1.69 g, 2.67 mmol) and hydrazine hydrate (0.21 g, 2.67 mmol) were combined in DMA (4 mL) and stirred at 25° C. for 12 hours. After 12 hours, the reaction was treated with the same amount of DIPEA, 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphine-2,4,6-trioxide and hydrazine hydrate and allowed to stir at room temperature. The reaction was purified by reverse phase chromatography eluting with 10% to 100% ACN / 0.1% aqueous formic acid to give the title compound (0.12 g, 29%). MS ES+ m / z 463 [M+H] + .

[1196] The following compounds in Table 33 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1197] Table 33

[1198]

[1199] Intermediate 238A: tert-Butyl N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate

[1200]

[1201] A solution of 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carboxylic acid (0.40 g, 0.83 mmol) in DMF (6 mL) was treated with HATU (0.95 g, 2.50 mmol) and DIPEA (0.54 g, 4.17 mmol). The mixture was stirred at room temperature for 5 minutes, treated with N-BOC hydrazine (0.33 g, 2.50 mmol), and stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with 10% aqueous LiCl. The organic layer was washed with saturated aqueous sodium chloride, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / EtOH (3:1) / heptane to give the title compound as a tan gel (0.50 g, 91%, 91% pure). MS ES+ m / z 597 [M+H] + .

[1202] The following compounds in Table 34 were made in a similar manner as described for tert-butyl N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1203] Table 34

[1204]

[1205]

[1206] 1 The material was used without purification.

[1207] Intermediate 244A: tert-Butyl N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonyl]sulfamoyl]carbamate

[1208]

[1209] A mixture of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.10 g, 0.24 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (92.5 mg, 0.36 mmol), tert-butyl sulfamoylcarbamate (94.7 mg, 0.48 mmol) and DMAP (2.95 mg, 0.02 mmol) was dissolved in DCM (2 mL) and stirred. After 5 minutes, triethylamine (73.2 mg, 0.72 mmol) was added to the reaction and allowed to stir at room temperature overnight. The reaction was concentrated and the residue was purified by reverse phase C18 flash chromatography eluting with ACN / water containing 0.1% formic acid. The fractions containing the product were combined, washed with saturated aqueous sodium chloride solution, extracted with IPA / CHCl3 (1:3), and the organics were collected, dried over MgSO4, filtered, and concentrated to give the title compound as a foam (0.12 g, 83%). MS ES+ m / z 591 [MH] - .

[1210] The following compounds in Table 35 were made in a similar manner as described for tert-butyl N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonyl]sulfamoyl]carbamate. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[1211] Table 35

[1212]

[1213] Intermediate 27A: 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid methyl ester

[1214]

[1215] Methyl 6-bromo-3-fluoropicolinate (0.25 g, 1.07 mmol) and 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.25 g, 0.89 mmol) were dissolved in DMSO (1 mL) and DIPEA (0.78 mL, 4.45 mmol) was added. The vial was sealed and the reaction was heated to 120°C for 24 hours. Concentrate with a small amount of celite and purify by reverse phase chromatography eluting with a gradient of 10 to 70% ACN / NH4HCO3 in water (10 mM, plus 5% MeOH) to give the title compound (0.18 g, 40%). MS ES+ m / z 491 [M+H] + .

[1216] The following compounds in Table 36 were made in a similar manner as described for 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid methyl ester.

[1217] Table 36

[1218]

[1219] 1 ACN was used as the solvent.

[1220] Intermediate 307C: 8-[(1R)-1-[2-[2-[dimethyl(oxo)-λ6-sulfanylidene]acetyl]anilino]ethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1221]

[1222] A vial containing trimethylsulfoxoniumiodide (291 mg, 1.32 mmol) was dried at 65 ° C for 2 hours and then treated with anhydrous THF (5 mL) while cooling. The reaction was treated with potassium tert-butoxide (148 mg, 1.32 mmol), the vial was sealed, and the reaction was stirred at 66 ° C for 2 hours. In a separate vial, 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (455 mg, 1.10 mmol) was suspended in toluene (5.5 mL), treated dropwise with thionyl chloride (131 mg, 1.10 mmol), and the reaction was stirred at 80 ° C for 15 minutes. The second vial was cooled to room temperature and concentrated under reduced pressure to obtain the acid chloride. Both vials were cooled in an ice bath, and the contents of the first vial were added to the acid chloride via a syringe. The reaction was removed from the cooling bath and allowed to warm to room temperature. The reaction was not complete, so a second batch of the first vial was used, but stirred at 66°C for only 15 minutes. The reaction was quenched with water and the mixture was concentrated under reduced pressure to remove the THF. The reaction was diluted with DCM, the layers separated, and the remaining aqueous layer was re-extracted with fresh DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / DCM and repurified by reverse phase chromatography on C18 eluting with 0% to 100% ACN / 10mM NH4HCO3 aqueous solution (containing 5% MeOH) to obtain the title compound. ES / MS m / z 488 (M+H).

[1223] Intermediate 308C: 8-[(1R)-1-[2-(2-chloroacetyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1224]

[1225] A vial was charged with 8-[(1R)-1-[2-[2-[dimethyl(oxo)-λ6-sulfanylidene]acetyl]anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one and 1,4-dioxane (6.2 mL), then treated with HCl / 1,4-dioxane (4M, 227 mg, 6.21 mmol). The reaction was heated at 90°C for 13 hours. The reaction was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography on C18 eluting with 0% to 100% ACN / 10 mM NH4HCO3 aqueous solution (containing 5% MeOH) and repurified by silica gel chromatography eluting with 0% to 100% EtOAc / DCM to give the title compound as a yellow powder (110.8 mg, 40%). ES / MS m / z 446 (M+H).

[1226] Intermediate 309C: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile

[1227]

[1228] A solution of 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxamide (97 mg, 0.19 mmol) in DCM (3 mL) was treated with triethylamine (0.29 g, 2.9 mmol) followed by trifluoroacetic anhydride (0.20 g, 0.96 mmol) at 0°C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (192 mg, 50% purity, 100%) as a yellow gel. ES / MS m / z 488 (M+H).

[1229] The following compounds in Table 37 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1230] Table 37

[1231]

[1232] Intermediate 29A: 8-(1-hydroxyethyl)-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1233]

[1234] 8-Acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (5.0 g, 17 mmol) was dissolved in MeOH (6 mL) and DCM (6 mL). Cooled to -10 ° C, NaBH4 (0.78 g, 21 mmol) was added and stirred for 30 minutes. Water (50 mL) was added and extracted with DCM (2 x 60 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH / DCM to give the title compound (4.2 g, 83%). MS ES+ m / z 295 [M+H] + .

[1235] Intermediate 30A: 8-(1-bromoethyl)-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1236]

[1237] Combine 8-(1-chloroethyl)-3,6-dimethyl-2-phenyl-chromen-4-one (2.0 g, 6.8 mmol) in DCM (25 mL). Cool to 0°C, add PBr (1.3 mL, 14 mmol) dropwise, and stir the reaction at room temperature for 2 hours. Saturated aqueous bicarbonate solution is slowly added, and the layers are separated. The organics are dried over anhydrous NaSO and concentrated to give the title compound (1.4 g, 58%). MS ES+ m / z 359 [M+H] + .

[1238] Intermediate 31A: 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1239]

[1240] A solution of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-cymene) [(R,R)-Ts-DPEN] (CAS 192139-92-7, 0.653 g, 1.03 mmol) in MeOH (50 mL) was stirred at 0-5°C. 1,8-diazabicyclo[5.4.0]undec-7-ene (15.3 mL, 103 mmol) was slowly added, maintaining the temperature below 25°C. Formic acid (3.87 mL, 103 mmol) was added portionwise, maintaining the temperature below 15°C. The reaction was stirred at 55°C for 3 hours and then cooled to room temperature. 4M aqueous HCl (50 mL) was slowly added. The resulting slurry was stirred overnight, filtered, and washed with water to give the title compound (9.9 g, 93%, 87% ee).

[1241] Intermediate 32A: 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1242]

[1243] A solution of 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (20 g, 68.0 mmol) in cyclopentyl methyl ether (200 mL) was stirred at room temperature. 2,4,6-trichloro[1,3,5]triazine (12.5 g, 68.0 mmol) was added, followed by DMF (7.9 mL, 102 mmol). The reaction was stirred at room temperature for 14 hours. The solution was diluted with 2M aqueous sodium hydroxide solution (100 mL) and the layers were separated. The organics were washed with water (100 mL) / saturated aqueous sodium bicarbonate solution (100 mL) and 5% aqueous lithium chloride solution (100 mL). The organics were concentrated and diluted with isopropanol (120 mL). The slurry was heated at 45 ° C for 2 hours and cooled to room temperature. Water (80 mL) was slowly added. Filtered to give the title compound (18.4 g, 87%, 94% ee). MS ES+m / z 313[M+H] + .

[1244] Intermediate 245A: 8-[(1R)-1-(2-iodoanilino)ethyl]-3,6-dimethyl-2-phenyl-benzopyran-4-one

[1245]

[1246] 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.60 g, 1.92 mmol), 2-iodoaniline (1.26 g, 5.75 mmol) and DIPEA (1.24 g, 9.59 mmol) were combined in IPA (6 mL) and stirred at 60 ° C overnight. The reaction was loaded with 1 g of 2-iodoaniline and 0.5 mL of DIPEA twice over 8 hours and then stirred overnight. The reaction was concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (0.70 g, 74%). MS ES+m / z 496[M+H] + .

[1247] Intermediate 246A: tert-Butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate

[1248]

[1249] A flask purged with dry argon was charged with tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate (1.40 g, 3.06 mmol) and THF (5 mL). The resulting solution was cooled to 0°C and treated dropwise with a solution of 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (3.49 g, 1 M, 12.30 mmol) over 30 minutes, then the reaction was stirred at 25°C for 7 hours. An additional 6 mL of the 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex solution was added, and the reaction was stirred at room temperature overnight. The reaction was cooled to 0°C and treated dropwise with a freshly prepared iodine solution (1.56 g, 1 M in THF, 6.15 mmol) over 30 minutes. The reaction was stirred at 0°C for 1 hour, then at room temperature for 12 hours. The reaction was cooled to -40 ° C and quenched with MeOH. The reaction was diluted with ammonium chloride / ammonia solution (50 mL, 2M in water) and extracted with DCM (3x300 mL). The combined organics were washed with Na2CO3 aqueous solution (50 mL), collected, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 10% EtOAc / heptane to give the title compound (1.64 g, 87%). MS ES+ m / z 582 [M + H] + .

[1250] The following compounds in Table 38 were made in a similar manner as described for tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1251] Table 38

[1252]

[1253]

[1254] Intermediate 317C: N-tert-Butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide

[1255]

[1256] A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (1.1 g, 2.09 mmol) in THF (10 mL) was cooled to -40 ° C under a nitrogen atmosphere and treated with 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (13 mL, 12.55 mmol, 1 M in THF). The reaction was stirred at -10 ° C for 2 hours. A solution of iodine in THF (4 mL, 4.18 mmol) was added dropwise at -40 ° C for 30 minutes and then stirred at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NH4Cl at 0 ° C. The reaction was extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EtOAc / petroleum ether to give the title compound as a yellow solid (0.30 g, 22%). ES / MS m / z 652 (M+H).

[1257] Intermediate 383C: 3-[[(1R)-1-[3-Bromo-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]-N-tert-butyl-6-chloro-pyridine-2-sulfonamide

[1258]

[1259] A mixture of N-tert-butyl-6-chloro-3-[[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide (400 mg, 0.75 mmol) and N-bromosuccinimide (134 mg, 0.75 mmol) in ACN was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography on C18 eluting with 65% to 70% ACN / water (containing 0.1% NH4OH) to give the title compound (250 mg, 54%) as a colorless solid. ES / MS m / z 608 / 610 (M+H).

[1260] Intermediate 384C: N-tert-Butyl-6-chloro-3-[[(1R)-1-(3-cyano-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide

[1261]

[1262] A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (180 mg, 0.28 mmol) in NMP (4 mL) was treated with copper (I) cyanide (124 mg, 1.38 mmol) at room temperature. The reaction was stirred at 120 ° C under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organics were washed with saturated aqueous NaCl solution (100 mL), collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 eluting with 80% to 95% ACN / water to give the title compound (73 mg, 48%) as a light yellow solid. ES / MS m / z 551 (M+H).

[1263] Intermediate 247A: tert-Butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-3-thiazol-5-yl-chromen-8-yl)ethyl]amino]benzoate

[1264]

[1265] A tube was charged with tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate (300 mg, 0.52 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (75.5 mg, 0.10 mmol), cuprous chloride (51 mg, 0.52 mmol), sodium carbonate (109 mg, 1.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (436 mg, 2.06 mmol) and toluene (15 mL). The reaction was heated at 80°C under a nitrogen atmosphere for 20 hours. The reaction was recharged and allowed to stir at 80°C overnight. The reaction was allowed to cool, filtered through celite, concentrated and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / heptane to give the title compound (208 mg, 75%). MS ES+ m / z 539 [M+H] + .

[1266] Intermediate 318C: N-tert-Butyl-6-chloro-3-[[(1R)-1-(3-isoxazol-4-yl-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide

[1267]

[1268] A solution of N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (80 mg, 0.12 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (48 mg, 0.25 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with potassium carbonate (34 mg, 0.25 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (16 mg, 0.03 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 33% EtOAc / petroleum ether to give the title compound as a light yellow solid (50 mg, 69%). ES / MS m / z 593 (M+H).

[1269] Intermediate 385C: N-tert-Butyl-6-chloro-3-[[(1R)-1-[3-isoxazol-4-yl-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide

[1270]

[1271] A mixture of 3-[[(1R)-1-[3-bromo-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]amino]-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (190 mg, 0.31 mmol), triethylamine (63.2 mg, 0.62 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (20.34 mg, 0.03 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (121.71 mg, 0.62 mmol) in THF (2 mL) and water (0.5 mL) was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was filtered and the solid was washed with THF (2 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography on C18 eluting with 75% to 85% ACN / water (containing 0.1% NH4OH) to give the title compound as a colorless solid (92 mg, 46%). ES / MS m / z 597 (M+H).

[1272] Intermediate 248A: 6-Chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid

[1273]

[1274] A solution of tert-butyl 6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.47 g, 0.96 mmol) in THF (3 mL) was treated with a solution of 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (0.68 mg, 1 M, 2.39 mmol) and allowed to stir at room temperature for 3 hours. The reaction was quenched with iodine (0.97 g, 3.83 mmol) dissolved in THF and allowed to stir for 1 hour. The reaction was diluted with 20 mL of EtOAc / water. The organic layer was collected, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) / water (containing 0.1% formic acid) to give the title product (0.20 g, 37%). MS ES+m / z 561[M+H] + .

[1275] Intermediate 33A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N'-hydroxy-pyridine-2-carboximidamide

[1276]

[1277] To a solution of 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.242 g, 0.612 mmol) in ethanol (5 mL) was added triethylamine (0.26 mL, 1.84 mmol) and hydroxylamine hydrochloride (0.085 g, 1.22 mmol). The reaction was heated at 80°C for 18 hours. Concentrate and purify by reverse phase chromatography eluting with a gradient of 0 to 100% ACN / H2O + 0.1% formic acid to give the title compound (0.26 g, 89%). MS ES+ m / z 429 [M+H] + .

[1278] The following compounds in Table 39 were made in a similar manner as described for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N'-hydroxy-pyridine-2-carboximidamide. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1279] Table 39

[1280]

[1281]

[1282]

[1283]

[1284]

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299] 1 NaHCO3 is used as the base in this reaction.

[1300] Intermediate 36A: N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide

[1301]

[1302] To a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.100 g, 0.242 mmol) in DMF (1 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.276 g, 0.726 mmol) , DIPEA (0.25 mL, 1.45 mmol) and 10-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (0.107 g, 0.726 mmol). The reaction was stirred at room temperature for 24 hours. Concentrated and purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound (0.171 g, 80% purity, 100%). MS ES+ m / z 543 [M+H] + .

[1303] The following compounds in Table 40 were made in a similar manner as described for N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide.

[1304] Table 40

[1305]

[1306] Intermediate 38A: 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile

[1307]

[1308] 2-[[(1R)-1-(2-Ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.100 g, 0.264 mmol), (2-fluorophenyl)boronic acid (0.111 g, 0.793 mmol), tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol) and copper(I)thiophene-2-carboxylate (0.076 g, 0.396 mmol) were combined in ethanol (15 mL). The reaction was degassed with argon and stirred at 50° C. for 16 hours. Concentrated and purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound (0.109 g, 100%). MS ES+ m / z 413 [M+H] + .

[1309] The following compounds in Table 41 were made in a similar manner as described for 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1310] Table 41

[1311]

[1312]

[1313]

[1314] Intermediate 47A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one

[1315]

[1316] To a solution of tert-butyl N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]carbamate (0.950 g, 2.41 mmol) in DCM (24 mL) was added HCl (4 M in 1,4-dioxane, 4 mL, 16 mmol). The reaction was stirred at room temperature for 2 hours. HCl (4 M in 1,4-dioxane, 1.2 mL, 4.8 mmol) was added and stirred at room temperature for 1 hour. The mixture was concentrated and diluted with saturated aqueous NaHCO₃ and IPA:CHCl₃ (1:3). The layers were separated. The organic extract was dried over MgSO₄, filtered, and concentrated. The residue was purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN / NH₄HCO₃ in water (10 mM, plus 5% MeOH). The clean fractions were washed with saturated aqueous sodium chloride solution and extracted with IPA:CHCl3 (1:3). The organic extract was dried over MgSO4, filtered, and concentrated to give the title compound (0.364 g, 51%). MS ES+ m / z 295 [M+H] + .

[1317] The following compounds in Table 42 were made in a similar manner as described for tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1318] Table 42

[1319]

[1320]

[1321] Intermediate 369C: 3-[3-[[(1R)-1-[2-[1-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridinyl]-4H-1,2,4-oxadiazol-5-one

[1322]

[1323] A solution of 3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-N'-hydroxy-pyridine-2-carboximidamide (134 mg, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with DBU (66.8 mg, 0.44 mmol) and 1,1'-carbonyldiimidazole (53.3 mg, 0.33 mmol). The reaction was stirred at 80°C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / EtOH (3:1) / heptane to give the title compound (98.4 mg, 70%) as a light tan foam. ES / MS m / z 637 (M+H).

[1324] The following compounds in Table 43 were made in a similar manner to that described for 3-[3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridinyl]-4H-1,2,4-oxadiazol-5-one. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1325] Table 43

[1326]

[1327] Intermediate 294A: 6-Chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid

[1328]

[1329] A solution of tert-butyl 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate (0.23 g, 0.44 mmol) in 2 mL of DCM was treated with TFA / DCM (1:1; 1 mL), and the reaction was stirred at 50°C for 2 hours. The reaction was concentrated, and the residue was purified by reverse phase C18 flash chromatography eluting with 0% to 100% ACN / 0.1% aqueous formic acid. The fractions containing product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA / CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered, and concentrated to give the title compound (68.8 mg, 34%) as a tan foam. MS ES+ m / z 467 [M+H]+ .

[1330] The following compounds in Table 44 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid.

[1331] Table 44

[1332]

[1333] Intermediate 296A: 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbohydrazide

[1334]

[1335] A solution of tert-butyl N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate (0.50 g, 0.84 mmol) in 10 mL of DCM was treated with HCl (4 M in 1,4-dioxane, 0.15 g, 1.05 mL, 4.19 mmol) and stirred at 50 ° C. After 3 hours, another 1.05 mL of HCl / dioxane was added and stirred at 60 ° C for 2 hours. The reaction was cooled to room temperature, concentrated, and the residue was placed in DCM and washed with saturated NaHCO3 aqueous solution. The aqueous layer was extracted twice with IPA / CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered and concentrated to a residue which was recrystallized from DCM / MTBE / hexanes to give the title compound as a light yellow powder (0.31 g, 73%). MS ES+ m / z 497 [M+H] + .

[1336] The following compounds in Table 45 were made in a similar manner as described for 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino]-6-methyl-pyridine-2-carbohydrazide. Various methods were used to purify these compounds, as would be apparent to one skilled in the art.

[1337] Table 45

[1338]

[1339]

[1340] Intermediate 303A: 6-Chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide

[1341]

[1342] 6-Chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.14 g, 0.25 mmol), methanesulfonamide (47.5 mg, 0.50 mmol), DCC (0.10 g, 0.50 mmol) and DMAP (0.12 g, 1.0 mmol) were combined in DCM (2 mL) and allowed to stir overnight at 25°C. The reaction was diluted with 1 mL of MeOH and directly purified by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) / water (containing 0.1% formic acid) to give the title compound (0.12 g, 75%). MS ES+ m / z 638 [M+H] + .

[1343] Intermediate 375C: 6-Chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide

[1344]

[1345] A solution of 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.50 g, 1.15 mmol) in DCM (1.2 mL) was cooled to 0°C and treated with methanesulfonamide (0.19 g, 1.96 mmol) and dichlorodipyrrolidinium hexafluorophosphate (0.58 g, 1.73 mmol), followed by the dropwise addition of DIPEA (0.75 g, 5.77 mmol). The reaction was stirred at 0°C for 5 minutes and then at room temperature over the weekend. The reaction was adsorbed onto silica gel and eluted with 0% to 10% MeOH / DCM to afford the title compound (0.34 g, 58%). ES / MS m / z 510 (M+H).

[1346] The following compounds in Table 46 were made in a similar manner as described for 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide. Various methods were used to purify the compounds, as would be apparent to one skilled in the art.

[1347] Table 46

[1348]

[1349] Intermediate 304A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzenesulfonamide

[1350]

[1351] A solution of N'-[2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]phenyl]sulfonyl-N,N-dimethyl-formamidine (0.45 g, 0.89 mmol) in 8 mL of EtOH was treated with concentrated HCl (0.16 g, 4.45 mmol), and the reaction was stirred at reflux for 2 hours. An additional 1 mL of concentrated HCl was added, and the reaction was stirred at 80°C for an additional 2 hours. The reaction was cooled to room temperature, diluted with DCM, and neutralized with saturated aqueous NaHCO3. The organic layer was removed, and the aqueous layer was extracted with IPA / CHCl3 (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography eluting with 0% to 100% ACN / water (containing 0.1% formic acid). The fractions containing the product were pooled and extracted with IPA / CHCl3 (1:3). The organics were combined, dried over MgSO4, filtered and concentrated to give the title compound as a white solid (0.12 g, 30%). MS ES+ m / z 449 [M+H] - .

[1352] Intermediate 53A: 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]benzopyran-4-one

[1353]

[1354] 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (1.12 g, 2.50 mmol), potassium acetate (0.736 g, 7.49 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.183 g, 0.250 mmol), and bis(pinacolato)diboron (0.761 g, 3.00 mmol) were combined in dimethoxyethane (12 mL). The reaction was degassed with argon for 1 minute and stirred at 95 °C for 16 hours. Filtered through celite, concentrated, and purified by silica gel chromatography eluting with EtOAc / heptane to give the title compound (1.1 g, 89%). MS ES+ m / z 496 [M+H] + .

[1355] The following compounds in Table 47 were made in a similar manner as described for 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one.

[1356] Table 47

[1357]

[1358] Intermediate 55A: 2-Ethylsulfanyl-3,6-dimethyl-8-[(1R)-1-[2-(2H-tetrazol-5-yl)anilino]ethyl]chromen-4-one

[1359]

[1360] Combine 2-[[(1R)-1-(2-Ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.500 g, 1.32 mmol), sodium azide (0.258 g, 3.96 mmol), and ammonium chloride (0.212 g, 3.96 mmol) in DMF (3 mL). The reaction was sealed and stirred at 140 °C for 3 hours. Purification by reverse phase chromatography gave the title compound (0.190 g, 34%). MS ES+ m / z 422 [M+H] + .

[1361] Intermediate 56A: 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2-trimethylsilylethynyl)anilino]ethyl]benzopyran-4-one

[1362]

[1363] To a solution of 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.35 g, 0.78 mmol) in DMF (4 mL) was added ethynyl-trimethyl-silane (0.46 g, 4.68 mmol) and triethylamine (0.65 mL, 4.68 mmol). The reaction was degassed with nitrogen and cuprous iodide (0.030 g, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) were added. The vial was sealed under nitrogen and heated in a microwave reactor at 100° C. for 18 hours. The mixture was diluted with 10% aqueous LiCl solution and extracted twice with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound (0.35 g, 70% purity, 67%). The crude material was used without further purification.

[1364] Intermediate 57A: 8-[(1R)-1-(2-ethynylanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one

[1365]

[1366] To a solution of 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2-trimethylsilylethynyl)anilino]ethyl]chromen-4-one (0.35 g, 70% purity, 0.52 mmol) in MeOH (4 mL) was added potassium carbonate (0.31 g, 2.25 mmol). The reaction was stirred at room temperature for 1 hour. Filtered, washed with DCM, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 60% EtOAc / hexanes to give the title compound (0.21 g, 90% purity, 90%). MS ES+ m / z 394 [M+H] + .

[1367] Intermediate 305A: 8-[(1R)-1-(2-dimethoxyphosphorylanilino)ethyl]-2-ethylsulfanyl-3,6-dimethyl-benzopyran-4-one

[1368]

[1369] 8-[(1R)-1-(2-Bromoanilino)ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.10 g, 0.23 mmol), cesium carbonate (82.2 mg, 0.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.1 mg, 0.01 mmol) were transferred to a microwave vial. The vial was evacuated and refilled with nitrogen three times before adding THF (0.5 mL) and dimethyl phosphonate (23.1 mg, 0.21 mmol). The vial was capped and the reaction was stirred at 120° C. for 10 minutes. The vial was recharged with dimethyl phosphonate (23.1 mg, 0.21 mmol) and the reaction was heated at 120° C. for an additional 10 minutes. The reaction was adsorbed onto celite and purified by reverse phase chromatography eluting with 0% to 80% ACN / 10 mM NH4HCO3 (containing 5% MeOH). MS ES+ m / z 462 [M+H] + .

[1370] Intermediate 306A: 8-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one

[1371]

[1372] A 20 mL pressure vial was charged with 8-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one (177 mg, 0.51 mmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (150 mg, 0.51 mmol), cesium carbonate (333 mg, 1.02 mmol), BINAP (95.5 mg, 0.15 mmol), palladium(II) acetate (11.5 mg, 0.05 mmol) and 1,4-dioxane (5 mL). The mixture was degassed with nitrogen for 5 minutes and then stirred at 90° C. for 17 hours. The reaction was passed through a syringe filter and purified by reverse phase chromatography eluting with 10% to 100% ACN / 10 mM aqueous NH4HCO3 to give the title compound (149 mg, 52%) as a yellow semi-solid. MS ES+m / z560[M+H] + .

[1373] The following compounds in Table 48 were made in a similar manner as described for 8-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridinyl)chromen-8-yl]ethyl]amino]-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one.

[1374] Table 48

[1375]

[1376] Intermediate 377C: tert-Butyl 2-[8-[(1R)-1-[[6-chloro-2-(methylsulfonylcarbamoyl)-3-pyridinyl]amino]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]indole-1-carboxylate

[1377]

[1378] A vial was charged with 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (170 mg, 0.33 mmol), (1-tert-butoxycarbonylindol-2-yl)boronic acid (131 mg, 0.50 mmol), 3-methylsalicylate copper(I) (107 mg, 0.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.07 mmol) and EtOH (5 mL). The reaction was degassed with argon, sealed, and stirred at 65° C. for 16 hours. After cooling, the reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 eluting with 10% to 100% ACN (containing 0.1% formic acid) / water (containing 0.1% formic acid) to give the title compound (15 mg, 7%). ES / MS m / z 665 (M+H).

[1379] Intermediate 1B: (2-bromo-4-methyl-phenyl) propionate

[1380]

[1381] A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propionyl chloride (5.44 g, 58.8 mmol) at 0 ° C and stirred at 25 ° C for 16 hours. The mixture was diluted with water (100 mL), the pH was adjusted to 5 with HCl (2 M), and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (2 x 150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the product (13 g, crude) as an oil. 1H NMR (DMSO-d6) δppm 1.17 (t, J=7.6Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H).

[1382] Intermediate 2B: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one

[1383]

[1384] A mixture of (2-bromo-4-methyl-phenyl) propionate (12.5 g, 51.4 mmol) and AlCl (24.0 g, 180 mmol) ...

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R is -H or C1-C3 alkyl; and R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, indole, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidazo[1,2-A]pyridine or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R1 is a group of the formula: R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -C(O)-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 、-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 、-SO2C1-C3 alkyl、-S(O)C1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-C(O)-C1-C3 alkyl, -SO2N(R 11 )-CN、-SO2N(R 11 )(R 13 )-C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-C(O)N(R 11 )-(CH2) n -R 13 、-C(O)-SR 12 、-C(O)-NHSO2R 16 、-C(O)CH=SOR 11 (R 11 ) or -C(O)CH2CN or a group of the formula: wherein Ring A is pyrrolidine optionally substituted with -CN; or R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, 1,2,4-oxadiazolin-5-one, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-C(O)-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, morpholine, oxetane, C1-C6 haloalkyl or C1-C6 alkyl substituents, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; or R' is a group of the formula: R2 is a group of the formula: R2 is a group of the formula: or R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-C(O)NR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, tetrahydropyran, oxetane, azetidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetane, C1-C3 alkoxy, -CH2CH(OH)CH(OH)R 11 or-CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O)(CH2) n OR 11 、C(O)C(CH3)2OH、-SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, indole, indazole, isoindazole, isoindolin-1-one, indolin-2-one, benzoxazole, benzotriazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazole wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; wherein the optionally substituted bicyclic heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2CH、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -C(O)NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula: and R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl; R4, R5 and R6 are each independently -H, halogen, -CN, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, -CH2OH or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; Each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 ,-SONR 11 R 11 、-CO2H、-CO2C1-C3alkyl、-C(O)NR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 、-N(R 11 )COR 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula: wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted with -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents; Each R 11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl or C1-C3 haloalkyl; Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 alkoxy, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula wherein the optionally substituted C1-C3 alkyl is optionally substituted by -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl or indole; R 13 Yes - NR 11 R 11 、-OR 11、 -SO2C1-C3 alkyl or a ring selected from oxetane, tetrahydrofuran or oxadiazole, wherein the ring is optionally replaced by -NR 11 R 11 OR 11 replace; R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl or 6-membered heteroaryl; wherein the optionally substituted C1-C3 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl; wherein the optionally substituted aryl or the optionally substituted 6-membered heteroaryl are each optionally substituted by 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl; R 16 is H, C1-C3 alkyl, -NH2, phenyl or pyridine, and n is 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R is -H or C1-C3 alkyl; R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R1 is a group of the formula: R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 、-SO2C1-C3 alkyl、-SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 、-CO-SR 12 or a group of the formula: wherein Ring A is pyrrolidine optionally substituted with -CN; or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, halogen, C1-C6 haloalkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; or R' is a group of the formula: R2 is a group of the formula: or R2 is a group of the formula: or R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected from N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each of the optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; Each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 ,-SONR 11 R 11 、-CO2H、-CO2C1-C3 alkyl、-CONR 11 R 12 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine, or a group of the formula: wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted with -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents; Each R 11 are independently -H or C1-C3 alkyl; Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl; -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 、-NR 11 R 11 、-OR 11 , -O-CH2-CH(OH)-CH2OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with methyl, or a group of the formula wherein the optionally substituted C1-C3 alkyl group is optionally substituted by -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl or indole.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is a group of the formula: and R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 Or a group of the formula wherein Ring A is pyrrolidine optionally substituted with -CN; or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R is -H or C1-C3 alkyl; and R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy; or R1 is a group of the formula: R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CO2C1-C3 alkyl, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 Or a group of the formula wherein Ring A is pyrrolidine optionally substituted with -CN; or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -OH, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; R2 is a group of the formula: or R2 is a group of the formula: or R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected from N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula: Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents; R 12 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, -O-CH2-CH(OH)-CH2OH, aryl, 5-membered heteroaryl or 6-membered heteroaryl; wherein the optionally substituted C1-C3 alkyl is optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl; and R 13 Yes - NR 11 R 11 、-OR 11 , oxetane or tetrahydrofuran.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula: and R' is hydrogen, halogen, C1-C3 alkyl, -CH(OH)-CH2OH, -CO-CH2OH or C3-C6 cycloalkyl.

6. The compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R is -H or C1-C3 alkyl; R1 is a group of the formula: R' is hydrogen, halogen, C1-C3 alkyl, -CH(OH)-CH2OH, -CO-CH2OH or C3-C6 cycloalkyl; R2 is a group of the formula: or R2 is a group of the formula: or R2 is an optionally substituted 5-membered ring heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole and thiadiazole; wherein the optionally substituted 5-membered ring heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S02R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-OH、-NR 11 R 11 、-NR 11 CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 substituted; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxin[2,3-b]pyridine or containing 1, 2, 3, 4 or 5 independently selected from N , O or S ring heteroatom having 8 to 10 ring atoms; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted by 1 to 3 substituents each independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by 1 to 3 R 10 Substituents are substituted, or R2 is a group of the formula: and Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CO2C1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole or pyridine; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy, -CO2C1-C3 alkyl, -CONR 11 R 11 、-NR 11 R 11 or phenyl; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle or heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN substituents.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R8 is -H.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which has the following formula:

9. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R and R together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone or quinazolinone; wherein the optionally substituted bicyclic ring is optionally substituted by 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R and R1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring of the formula 11. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is -H.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or halogen.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4 is -H.

14. A compound according to any one of claims 1 to 8 or 11 to 13 or a pharmaceutically acceptable salt thereof, which has the formula 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, methyl or trifluoromethyl.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3 is -H or methyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, methyl or trifluoromethyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R6 is -H or halogen.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, methyl or trifluoromethyl.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.

24. A compound according to any one of claims 1, 2, 4 or 11-23, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone or benzothiazolone; wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH or C1-C6 alkoxy.

25. A compound according to any one of claims 1 to 5, 7 or 11 to 23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula 26. A compound according to any one of claims 1 to 5, 7 or 11 to 23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula 27. The compound according to any one of claims 1-8, 11-23, 25 or 26, or a pharmaceutically acceptable salt thereof, wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

28. The compound according to any one of claims 1-8, 11-23, 25 or 26, or a pharmaceutically acceptable salt thereof, wherein each R9 is independently -H, halogen, C1-C3 alkyl or C3-C5 cycloalkyl.

29. A compound according to any one of claims 1-4, 7-8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 Or a group of the formula wherein Ring A is pyrrolidine optionally substituted with -CN; or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -NR 11 R 11 、-N(R 11 )-CO-R 11 、-N(R 11 )-CN、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl optionally substituted by phenyl.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 、-SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 、-CON(R 11 )-(CH2) n -R 13 Or a group of the formula wherein Ring A is pyrrolidine optionally substituted with -CN.

31. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine; each of which is optionally substituted by 1 to 3 independently selected from oxo, -NR 11 R 11 、-OR 11 , -CN, C1-C6 haloalkyl or C1-C6 alkyl optionally substituted by phenyl.

32. The compound according to any one of claims 1-4, 7-8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen, C1-C3 alkyl or C3-C6 cycloalkyl.

33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen or methyl.

34. A compound according to any one of claims 1, 2, 7, 8, 11-23 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, -Cl, -F, -Br, methyl, difluoromethyl, trifluoromethyl, methoxy, -NO2, -CN or a group of the formula:

35. A compound according to any one of claims 1 to 4, 7, 8 or 11 to 23, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the formula 36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula: Among them, each R 10 R2 is optionally substituted pyrazole or optionally substituted indazole, each of which is optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -CO2C1-C3 alkyl.

37. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula Among them, each R 10 R2 is independently -H, -CN or halogen; or R2 is optionally substituted pyrazole or optionally substituted indazole, each of which is optionally substituted with C1-C3 alkyl.

38. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula: Among them, each R 10 are independently -H, -CN, C1-C6 haloalkyl, -NR 11 R 11 、-CH2-NR 11 R 11 , -CO2C1-C3 alkyl or -CH2-CO2C1-C3 alkyl; or R2 is optionally substituted indazole, which is optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

39. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula Among them, each R 10 R2 is independently -H, -CN or C1-C3 haloalkyl; or R2 is optionally substituted indazole, which is optionally substituted with C1-C3 alkyl.

40. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the formula:

41. The compound according to claim 1 or 2, selected from: or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A method for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42.

44. The method of claim 43, wherein the PI3K is PI3Kα.

45. The method of claim 43 or claim 44, wherein the PI3K associated with the disease or disorder has a H1047R mutation.

46. ​​The method of any one of claims 43-45, wherein the disease or disorder is cancer.

47. The method of claim 46, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

48. The method of claim 46, wherein the cancer is breast cancer.

49. The method of claim 46, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

50. The method of any one of claims 43-45, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

51. A method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42 to a patient in need thereof.

52. A method of treating cancer or a disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42.

53. The method of claim 52, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

54. The method of claim 52, wherein the cancer is breast cancer.

55. The method of claim 52, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

56. The method of claim 52, wherein the disorder is CLOVES syndrome or PROS.

57. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, for use in therapy.

58. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with modulation of PI3K.

59. The compound for use according to claim 58, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder associated with modulation of PI3K is cancer.

60. The compound for use according to claim 59, or a pharmaceutically acceptable salt thereof, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

61. The compound for use according to claim 59, or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer.

62. The compound for use according to claim 59, or a pharmaceutically acceptable salt thereof, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

63. A compound for use according to claim 58, or a pharmaceutically acceptable salt thereof, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

64. Use of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder associated with modulation of PI3K.

65. The use according to claim 64, wherein the disease or disorder associated with modulation of PI3K is cancer.

66. The use according to claim 65, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

67. The use according to claim 65, wherein the cancer is breast cancer.

68. The use according to claim 65, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

69. The use according to claim 64, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

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