Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3k) for treatment of disease

Abstract

To provide compounds as allosteric chromenone inhibitors of phosphoinositide 3 kinase (PI3K) useful in treatment of diseases or disorders associated with PI3K modulation.SOLUTION: The disclosure relates to compounds of Formula (I) or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

Technical field

[0001] Cross-reference of related applications This application is based on U.S. Provisional Application No. 63 / 336,658 filed on April 29, 2022, U.S. Provisional Application No. 63 / 357,689 filed on July 1, 2022, and U.S. Provisional Application No. 63 / 381,862 filed on November 1, 2022. , and No. 63 / 496,210, filed April 14, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful for the treatment of diseases or disorders associated with PI3K regulation. The present invention provides compounds and compositions that inhibit PI3K, diseases or disorders associated with PI3K, such as CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal cord syndrome). , PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. PI3K inhibitors in combination with one or more additional cancer therapies. [Background technology]

[0003] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is associated with allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders associated with diabetic complications, and acute coronary It is implicated in many other disease states, including inflammatory complications of the cardiovascular system, such as the syndrome.

[0004] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositide. The PI3K family is comprised of 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., Annu Rev Cell Dev Biol. 2001;17:615-75). Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G protein-coupled receptors to produce PIP3, which in turn is activated by downstream effectors such as Akt / PDK1, Engages effectors present in the mTOR, Tec family kinase, and Rho family GTPase pathways. Class II and III PI3K are PI(3)P and PI(3,4)P 2 plays an important role in intracellular movement through synthesis of

[0005] PI3K isoforms, for example, have been implicated in a variety of human cancers and disorders. Mutations in the genes encoding PI3K isoforms or mutations that result in upregulation of PI3K isoforms are thought to occur in many human cancers. Mutations in the genes encoding PI3K isoforms are point mutations clustered within several hotspots in the helical and kinase domains. Because of the high rate of PI3K mutations, targeting this pathway may provide valuable therapeutic opportunities.

[0006] Genetic changes in PI3K signaling are associated with endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, and bladder urothelium. glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor, squamous cell carcinoma of the head and neck, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, and fibrolamellar cancer. Hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal cell carcinoma, It is thought to be involved in a variety of cancers, including clear cell renal cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, mixed neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma. (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer.N Engl J Med.2018 Nov 22;379(21):2052-2062).

[0007] The alpha (α) isoform of PI3K, for example, has been implicated in various human cancers. It has been shown that angiogenesis selectively requires the alpha isoform of PI3K under the control of endothelial cell migration. (Graupera et al, Nature 2008;453;662-6). Mutations in the gene encoding PI3Kα or mutations that result in upregulation of PI3Kα are associated with lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and It is thought to occur in many human cancers, including 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. Because of the high rate of PI3Kα mutations, targeting this pathway may provide valuable therapeutic opportunities. PI3Kα, along with PI3Kβ, is constitutively expressed while other PI3K isoforms such as PI3Kδ or PI3Kγ are expressed primarily in hematopoietic cells.

[0008] Mutated PI3Kα is involved in brain metastasis in HR+ / HER2- metastatic breast cancer. The development of brain-penetrant PI3Kα inhibitors may provide improved therapeutic efficacy over 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)).

[0009] Because PI3Kα plays a central role in the control of organismal glucose homeostasis, inhibition of PI3K in patients often leads to 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 blood insulin levels may have mitogenic and / or anti-apoptotic effects on cancer cells and may therefore override the anti-proliferative effects of PI3K inhibitors (Blouin M-J, et al, Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antitineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013;73:4615).

[0010] In the context of cancers with mutant PI3Kα, one way to overcome the problem of compensatory production of insulin and / or glucose by systemic PI3Kα inhibition is to increase selectivity for mutant PI3Kα over wild-type PI3Kα. The objective is to develop inhibitors that have the following properties. This increases the opportunity for drug administration to selectively inhibit pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues, which 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), therefore limiting toxicity. , allowing for higher doses to be administered 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).

[0011] Currently, PI3Kα inhibitors have approximately the same potency as wild-type and mutant PI3Kα. Mutation-selective inhibitors have been elusive because the location of PI3Kα mutations is far from the active site. Therefore, inhibitors that target a second peripheral binding pocket near known mutations (eg, H1047R) may provide a route to selective PI3Kα inhibition. Therefore, targeting the mutated peripheral binding pocket of PI3Kα provides a valuable therapeutic target for drug development.

[0012] Kinases, such as lipid kinases such as PI3K, are therefore prime targets for drug development. The present invention provides new kinase inhibitors. [Summary of the invention]

[0013] In one aspect, the invention provides compounds of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in which: R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R is -H or C 1 -C 3 is alkyl, R 1 are isobenzofuranone, benzofuranone, indole, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidaza[1,2-a]pyridine, or a benzothiazolone, wherein the optionally substituted bicyclic ring is selected from oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is the group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -OH, -CH(OH)-CH 2 OH, -CH(OH)C 1 -C 3 Haloalkyl, -C(O)-CH 2 OH,C 3 -C 6 Cycloalkyl, -NO 2 ,-NR 11 R 11 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 R 15 ,-SO 2 C 1 -C 3 Alkyl, -S(O)C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-C(O)-C 1 -C 3 Alkyl, -SO 2 N(R 11 )-CN,-SO 2 N(R 11 )(R 13 ) -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 12 , -C(O)N(R 11 )-(CH 2 ) n -R 13 , -C(O)-SR 12 , -C(O)-NHSO 2 R 16 , -C(O)CH=SOR 11 (R 11 ), or -C(O)CH 2 CN, or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is 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 oxo, -OH, -NR 11 R 11 , -N(R 11 )-C(O)-R 11 , -N(R 11 )-CN, -OH, C 1 -C 3 Alkoxy, -CN, halogen, morpholino, oxetane, C 1 -C 6 C optionally substituted with haloalkyl, or -OH, aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl, or R' is a group of the following formula, [ka] R 2 is a group of the following formula, [ka] or R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 ,-CD 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, tetrahydropyran, oxetane, azetidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzo selected from dioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole optionally substituted with 1 to 3 substituents each independently selected from optionally substituted heteroaryl; 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CH 2 CH(OH)CH(OH)R 11 ; or -C(O)NR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C3 Haloalkoxy, -C(O(CH 2 ) n OR 11 , -C(O)C(CH 3 ) 2 OH, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 are 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, 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]pyridine, From 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 8 to 10 optionally substituted fused bicyclic rings of choice, or containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S is an optionally substituted bicyclic heteroaryl on the ring atoms of which the optionally substituted bicyclic ring is a halogen and a C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -C(O)NR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 But 1~3 R 10 or R 2 is the group of the following formula, [ka] or R 3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 C.O. 2 H), -C(O)-C 1 -C 3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 3 -C 5 an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S; , or an optionally substituted heteroaryl of 5 or 6 ring atoms, including 1, 2, or 3 ring heteroatoms independently selected from S; or heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 each optionally substituted with 1 to 3 substituents each independently selected from haloalkyl; R 4 ,R 5 , and R 6 Each of is independently -H, halogen, -CN, C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 7 ,-CN,C 1 -C 6 Alkyl, -CH 2 OH or C 1 -C 6 is haloalkyl, R 8 is -H, -D, or C 1 -C 6 is alkyl, Each R 9 but independently -H, halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 3 -C 5 cycloalkyl, Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-SONR 11 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 alkyl, - C(O)NR 11 R 12 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -N(R 11 )C(O)R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or of the formula is the basis of [ka] optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy or -C(O)NR 11 R 11 and each optionally replaced C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, Each R 11 but independently -H,C 1 -C 3 Alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 3 is haloalkyl, Each R 12 is, independently, -H, optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 haloalkyl, -SO 2 NR 11 R 11 ,-NR 11 R 11 ,-OR 11 , -O-CH 2 -CH(OH)-CH 2 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, methyl, or a group of the formula [ka] optionally substituted C 1 -C 3 Alkyl is -OH, C 3 -C 6 optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But -NR 11 R 11 ,-OR 11 ,-SO 2 C 1 -C 3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is -NR 11 R 11 or -OR 11 is optionally replaced with R 14 , -H, optionally substituted C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, optionally substituted 1 -C 3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, and the optionally substituted aryl or the optionally substituted 6-membered heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 optionally substituted with 1 to 3 substituents each independently selected from haloalkyl; R 16 But, H, C 1 -C 3 Alkyl, -NH 2 , phenyl, or pyridine, It relates to a compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0014] In one embodiment, the compound of formula (I) may contain an asymmetric carbon atom at the position designated by an asterisk (*). [ka] In one aspect, R 7 is methyl and R 8 is hydrogen, and the bond at the * position is [ka] It is expressed as

[0015] In one aspect, the invention provides compounds of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in which: R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R is -H or C 1 -C 3 is alkyl, R 1 is optionally substituted with selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone is a bicyclic ring, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is the group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -OH, -CH(OH)-CH 2 OH, -CO-CH 2 OH,C 3 -C 6 cycloalkyl, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 R 15 ,-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -SO 2 N(R 11 )-CN, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 ,-CO-SR 12 , or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, selected from pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl; R' is a group of the following formula, [ka] R 2 is a group of the following formula, [ka] or R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CONR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 But 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2 is the group of the following formula, [ka] R 3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 C.O. 2 H), -CO-C 1 -C 3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S; , or an optionally substituted heteroaryl of 5 or 6 ring atoms, including 1, 2, or 3 ring heteroatoms independently selected from S; or heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 each optionally substituted with 1 to 3 substituents independently selected from haloalkyl; R 4 ,R 5 , and R 6 each independently -H, halogen, C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 7 ,-CN,C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 8 But -H or C 1 -C 6 is alkyl, Each R 9 but independently -H, halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 3 -C 5 cycloalkyl, Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-SONR 11 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 alkyl, - CONR 11 R 12 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or of the formula is the basis of [ka] optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 and each optionally replaced C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, Each R 11 but independently -H or C 1 -C 3 is alkyl, Each R 12 is, independently, -H, optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 haloalkyl, -SO 2 NR 11 R 11 ,-NR 11 R 11 ,-OR 11 , -O-CH 2 -CH(OH)-CH 2 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, methyl, or a group of the formula: [ka] optionally substituted C 1 -C 3 Alkyl is -OH, C 3 -C 6 optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But -NR 11 R 11 ,-OR 11 ,-SO 2 C 1 -C 3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is -NR 11 R 11 or -OR 11 is optionally replaced with R 14 , -H, optionally substituted C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, optionally substituted 1 -C 3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, and the optionally substituted aryl or the optionally substituted 6-membered heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 optionally substituted with 1 to 3 substituents each independently selected from haloalkyl; It relates to a compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0016] In another aspect, the invention comprises a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition is provided.

[0017] In another aspect, the invention provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo) comprising administering a therapeutically effective amount of formula (I), (II), or (III) to a cell. ), or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I); Provided is a method comprising administering to a subject a compound of (II) or (III), or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I); Provided is a method comprising administering to a subject a pharmaceutical composition of the compound (II) or (III), or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the invention provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II) ), or (III), or a pharmaceutically acceptable salt thereof, is provided.

[0021] In some embodiments, the invention provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II) ), or (III), or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, is provided.

[0022] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0023] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutical composition thereof, for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo). Provides legally acceptable salts.

[0024] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable compound thereof, for use in selectively inhibiting mutant PI3Kα over wild-type PI3Kα. Provide salt.

[0025] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease or disorder disclosed herein. Provide acceptable salt.

[0026] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable compound thereof, for use in the treatment of a disease or disorder disclosed herein. provide salt that is

[0027] In another aspect, the invention provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), or Uses of pharmaceutically acceptable salts thereof are provided.

[0028] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. Provides for the use of legally acceptable salts.

[0029] In another aspect, the invention provides a compound of formula (I), (II), or (III), or a pharmaceutical compound thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein. Provide for the use of acceptable salts.

[0030] In another aspect, the invention provides a method of preparing a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the invention provides for preparing a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, comprising one or more steps described herein. provide a method to do so.

[0032] In another aspect, the invention provides compounds obtainable or obtained by the methods for preparing the compounds described herein.

[0033] In another aspect, the invention provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (e.g., the intermediates are (selected from the intermediates described in ).

[0034] Other features and advantages of the invention will be apparent from the following detailed description and from the claims. [Form for carrying out the invention]

[0035] The present invention provides a method for treating, preventing, or ameliorating a disease or disorder in which PI3K acts (or a use in treating, preventing, or ameliorating a disease or disorder), which provides a therapeutically effective amount of PI3K to a patient in need thereof. A method is provided by administering a PI3K inhibitor of the invention. The methods (or uses) of the invention can be used to treat a variety of PI3K-dependent diseases and disorders.

[0036] 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 CLOVES syndrome, PROS, endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma , colorectal adenocarcinoma, bladder urothelial cancer, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue Histosarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical cancer , non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated nerve Including, but not limited to, glioma.

[0037] Details of the 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 this disclosure, exemplary methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In this specification and the appended claims, the singular forms include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0038] definition The articles "a" and "an" refer to one or more (ie, at least one) of the grammatical objects of the article. As an example, "an element" means one element or more than one element.

[0039] The term "and / or" means either "and" or "or" unless specified otherwise.

[0040] The terms "administering," "administering," or "administering" refer to either direct administration of a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition to a subject. point to something.

[0041] 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 may be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

[0042] The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms with a terminal "O" in the chain, ie, -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0043] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. C 1 -C 6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0044] 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, iso-butynyl, pentynyl, or hexynyl.

[0045] For example, the terms "alkenyl," "alkoxy," "alkyl," "alkynyl," "haloalkyl," "haloalkoxy," and "cycloalkyl" can be further defined by the number of carbons they contain; For example, “C 1 -C 6 The term "alkoxy" refers to an alkoxy group as defined above containing 1 to 6 carbon atoms.

[0046] The term "aromatic" means a planar ring having 4n+2 electrons in the conjugated system. As used herein, "conjugated system" refers to a bonded p-orbital system with delocalized electrons, which may include lone pairs of electrons.

[0047] The term "aryl", unless specifically defined otherwise, refers to a cyclic aromatic hydrocarbon group having from 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Point. When containing two aromatic rings (such as a bicyclic ring), the aromatic rings of the aryl group may be bonded at one point (eg, biphenyl) or fused (eg, naphthyl). Additionally, when containing two fused rings, an aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems for these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzaannulenyl.

[0048] The term "carrier" includes carriers, excipients, and diluents that are involved in the delivery or transport of a drug from one organ or body part to another. or a material, composition, or vehicle such as a solid filler, diluent, excipient, solvent, or encapsulating material.

[0049] The term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, ie, C≡N.

[0050] The term "cycloalkyl" means a monocyclic or polycyclic saturated carbocycle containing from 3 to 18 carbon atoms, preferably from 3 to 10 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norbolenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl. Not limited.

[0051] The term "disorder" means, and is used interchangeably with, the term disease, condition, or disease, unless otherwise indicated.

[0052] 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.

[0053] 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.

[0054] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0055] The term "heteroaryl", unless expressly defined otherwise, means one or more ring heteroatoms selected from N, O, S, P, or B, preferably selected from N, O, or S. A monovalent monocyclic of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing 1, 2, 3, or 4 ring heteroatoms, with the remaining ring atoms being C or means a polycyclic aromatic radical. Polycyclic aromatic radicals include two or more fused rings, and may further include two or more spirofused rings, such as bicyclic, tricyclic, tetracyclic, and the like. Unless explicitly defined otherwise, "fused" means two rings that share two ring atoms. Unless specifically defined otherwise, "spirofused" means two rings that share one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, or B, preferably N, O, or S. do. Heteroaryl as defined herein also refers to tricyclic heteroaromatics containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. It also means a family group. Heteroaryl as defined herein also refers to a tetracyclic heteroaromatic containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. It also means a family group. Examples of heteroaromatic groups include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, 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-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, 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, benzoxazoli 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][ Examples include, but are not limited to, 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 three or more fused rings, saturated or partially unsaturated rings may be fused with further saturated or partially unsaturated rings as described herein. Additionally, when containing three or more fused rings, a heteroaryl group as defined herein may have one or more spirofused saturated or partially unsaturated rings. Any saturated or partially unsaturated rings described herein are optionally substituted with one or more oxo. Exemplary ring systems for these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H- Isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H -pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 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]indole-1(2H) -onyl, benzo[c][1,2]oxaborole-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.

[0056] The term "5-membered heteroaryl", unless expressly defined otherwise, means one or more ring heteroatoms selected from N, O, S, P, or B, preferably selected from N, O, or S. means a monovalent monocyclic aromatic radical of 5 ring atoms, including 1, 2, 3, or 4 ring heteroatoms where the remaining ring atoms are C. Exemplary 5-membered heteroaryl groups include, but are not limited to, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazole, triazolyl, and tetrazolyl.

[0057] The term "6-membered heteroaryl", unless expressly defined otherwise, means one or more ring heteroatoms selected from N, O, S, P, or B, preferably selected from N, O, or S. means a monovalent monocyclic aromatic radical of 6 ring atoms containing 1, 2, 3, or 4 ring heteroatoms in which the remaining ring atoms are C. Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0058] The term "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a compound containing carbon, 3 to 24 atoms, preferably 3 to 10 atoms, and N, O, S, P, or B. means a monocyclic or polycyclic ring containing one or more heteroatoms selected from, preferably 1, 2, 3 or 4 heteroatoms selected from N, O, and S, where the ring is aromatic isn't it. Examples of heterocyclyl rings include oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl Examples include, but are not limited to, S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanil, oxazolidinonyl, and homotropanyl.

[0059] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." If a compound has an asymmetric center, for example if the compound is attached to four different groups, enantiomeric pairing is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center, described by the Cahn-Prelog R and S order rules, or by the manner in which the molecule rotates the plane of polarized light, dextrorotatory or levorotatory. (i.e., as the (+)- or (-)-isomer, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing the enantiomers in equal proportions is called a "racemic mixture."

[0060] The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K.

[0061] The term "patient" or "subject" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or It is a rhesus monkey. Preferably the mammal is a human.

[0062] The term "therapeutically effective amount" when used in reference to a compound refers to the amount or dose of the compound that, upon administration to the patient in single or multiple doses, produces the desired effect in the patient being diagnosed or treated. Point. Effective amounts can be determined by one of skill in the art using known techniques and by observing results obtained under similar circumstances. Numerous factors are considered by the attending diagnostician when determining an effective dose for a patient; these factors include the patient's race; the patient's size, age, and overall health; the specific disease or disorder; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; administration regimen; concomitant drug use; and other relevant circumstances.

[0063] The term "treating" with respect to a subject includes inhibiting, slowing, halting, or reversing the progression or severity of an existing condition or disorder. Compounds of the invention

[0064] In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: [ka] In the formula, R, R 1 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 ,R 7 , and R 8 provides a compound, or a pharmaceutically acceptable salt thereof, as defined in the Summary of the Invention for Formula (I).

[0065] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or the following group, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine selected from, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 Optionally substituted with 1 to 3 substituents independently selected from alkyl.

[0066] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted Bicyclic rings include oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R is -H or C 1 -C 3 is alkyl, R 1 is isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidaza[1,2-a]pyridine, or benzothiazolone an optionally substituted bicyclic ring selected from oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or in some embodiments, R 1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone, where the optionally substituted bicyclic ring is , oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is a group of the following formula, or [ka] or R 1 is a group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C3 Alkoxy, C 1 -C 3 Haloalkoxy, -OH, -CH(OH)-CH 2 OH, -CH(OH)C 1 -C 3 haloalkyl, -CO-CH 2 OH,C 3 -C 6 cycloalkyl, -NO 2 ,-NR 11 R 11 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 R 15 ,-SO 2 C 1 -C 3 Alkyl, -SOC 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -SO 2 N(R 11 )-CN,-SO 2 N(R 11 )(R 13 ) -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 ,-CO-SR 12 , -CO-NHSO 2 R 16 ,-COCH=SOR 11 (R 11 ), or -COCH 2 CN, or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or the following group, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is 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 oxo, -OH, -NR 11 R 11 , -N(R 11 )-C(O)-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, morpholine, oxetane, C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl, or R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine selected from, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl, or R’ is a group of the following formula, [ka] R 2 is a group of the following formula, or [ka] or R 2 is a group of the following formula, or [ka] or R 2 is a group of the following formula, or [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 ,-CD 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, tetrahydropyran, oxetane, azetidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzo selected from dioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole optionally substituted with 1 to 3 substituents each independently selected from optionally substituted heteroaryl; 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CH 2 CH(OH)CH(OH)R 11 , or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -C(O)(CH 2 ) n OR 11 ,C(O)C(CH 3 ) 2 OH, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; Optionally substituted 5-membered heteroaryl includes -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle, or heteroaryl means halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 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]pyridine, From 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 8 to 10 optionally substituted bicyclic rings containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S. a bicyclic heteroaryl optionally substituted on the ring atoms, wherein the optionally substituted bicyclic ring is a halogen and a C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 CH, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -C(O)NR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CONR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2 is a group of the following formula, [ka] Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-SONR 11 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 12 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -N(R 11 )COR 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted is a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine; or Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy or -CONR 11 R 11 and each optionally replaced C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, Each R 11 are independently -H,C 1 -C 3 Alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 3 is haloalkyl, R 12 -H, optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 haloalkyl, -SO 2 NR 11 R 11 ,-NR 11 R 11 ,-OR 11 , -O-CH 2 -CH(OH)-CH 2 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, methyl, or a group of the formula: [ka] C substituted with said option 1 -C 3 Alkyl is -OH, C 3 -C 6 optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; 13 -NR 11 R 11 ,-OR 11 , oxetane, or tetrahydrofuran.

[0067] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R' is hydrogen, halogen, C 1 -C 3 Alkyl, -CH(OH)-CH 2 OH, -CO-CH 2 OH or C 3 -C 6 It is cycloalkyl.

[0068] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C 1 -C 3 is alkyl, R 1 is a group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, -CH(OH)-CH 2 OH, -CO-CH 2 OH or C 3 -C 6 cycloalkyl, R 2 is a group of the following formula, or [ka] or R 2 is a group of the following formula, or [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; Optionally substituted 5-membered heteroaryl includes -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle, or heteroaryl means halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CONR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2 is a group of the following formula, [ka] as well as Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine; C replaced with 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 , or phenyl, each optionally substituted with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each is optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN.

[0069] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 8 is -H.

[0070] In a further aspect, R 8 is -H, the compound of formula (I) has formula (II) or a pharmaceutically acceptable salt thereof; [ka] In the formula, R, R 1 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 , and R 7 is as defined in the summary of the invention for formula (I).

[0071] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted Bicyclic rings include oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 Optionally substituted with 1 to 3 substituents each independently selected from alkoxy.

[0072] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 1 is the basis of the following formula. [ka]

[0073] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R is -H.

[0074] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R 4 is -H or halogen. Preferably, R 4 is -H.

[0075] In a further embodiment, the compound of formula (I) or (II) has formula (III) or a pharmaceutically acceptable salt thereof; [ka] In the formula, R 1 ,R 2 ,R 3 ,R 5 ,R 6 , and R 7 is as defined in the summary of the invention for formula (I) above.

[0076] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 C.O. 2 H), -C(O)-C 1 -C 3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 3 -C 5 an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S; , or an optionally substituted heteroaryl of 5 or 6 ring atoms, including 1, 2, or 3 ring heteroatoms independently selected from S; or heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 Each is optionally substituted with 1 to 3 substituents independently selected from haloalkyl.

[0077] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 3 -H, halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxetane, or isoxazole. Preferably, R 3 -H, -CN,C 1 -C 3 alkyl or C 1 -C 3 It is haloalkyl. More preferably, R 3 is -H, -CN, methyl, or trifluoromethyl. Most preferably, R 3 is -H or methyl.

[0078] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 5 -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 It is haloalkyl. Preferably, R 5 is -H, halogen, methyl, or trifluoromethyl.

[0079] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 6 is -H or halogen.

[0080] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 7 -CN,C 1 -C 3 alkyl or C 1 -C 3 It is haloalkyl. Preferably, R 7 is -CN, methyl, or trifluoromethyl. More preferably, R 7 is methyl.

[0081] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone, and the optionally substituted bicyclic ring is oxo, - CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 Optionally substituted with 1 to 3 substituents each independently selected from alkoxy.

[0082] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula. [ka]

[0083] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula. [ka]

[0084] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, each R 9 are independently -H, halogen, C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl, preferably each R 9 are independently -H, halogen, methyl, or cyclopropyl.

[0085] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, each R 9 are independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 It is alkoxy.

[0086] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN.

[0087] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN.

[0088] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )(R 13 ), -C(O)NR 11 R 12 , -C(O)N(R 11 )-(CH 2 ) n -R 13 , -C(O)-NHSO 2 R 16 , or 1,2,4-oxadiazolin-5-one.

[0089] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, selected from thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -NR 11 R 11 ,-OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl or phenyl 1 -C 6 Optionally substituted with 1 to 3 substituents independently selected from alkyl.

[0090] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, selected from isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -NR 11 R 11 ,-OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl or phenyl 1 -C 6 Optionally substituted with 1 to 3 substituents independently selected from alkyl.

[0091] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt 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 oxo, -NR 11 R 11 ,-OR 11 , or C optionally substituted with aryl 1 -C 6 Optionally substituted with 1 to 3 substituents independently selected from alkyl.

[0092] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is hydrogen, halogen, C 1 -C 3 alkyl or C 3 -C 6 Cycloalkyl, preferably R' is hydrogen, halogen, or methyl.

[0093] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R' is hydrogen, -Cl, -F-, -Br, methyl, difluoromethyl , trifluoromethyl, methoxy, -NO 2 , -CN, or a group of the following formula. [ka] [ka]

[0094] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula, [ka] In the formula, each R 9 are independently -H, halogen, C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl, R’ is hydrogen, halogen, C 1 -C 3 alkyl or C 3 -C 6cycloalkyl, preferably each R 9 are independently -H, halogen, methyl, or cyclopropyl, and R' is hydrogen, halogen, or C 1 -C 3 It is an alkyl.

[0095] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula. [ka] In the formula, each R 9 are independently -H, halogen, C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl, R’ is hydrogen, halogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, preferably each R 9 are independently -H, halogen, methyl, or cyclopropyl, and R' is hydrogen, halogen, or C 1 -C 3 It is an alkyl.

[0096] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0097] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula. [ka]

[0098] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula, [ka] Each R 10 are independently -H, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -CO 2 C 1 -C 3 is alkyl or R 2 is an optionally substituted pyrazole or an optionally substituted indazole, each of which represents -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or -CO 2 C 1 -C 3 Optionally substituted with 1 to 3 substituents each independently selected from alkyl. Preferably, R 2 is a group of the following formula, [ka] In the formula, each R 10 is independently -H, -CN, or halogen, or R 2 is an optionally substituted pyrazole or an optionally substituted indazole, each of which is C 1 -C 3 Optionally substituted with alkyl.

[0099] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula, [ka] In the formula, each R 10 are independently -H, -CN, C 1 -C 6 haloalkyl, -NR 11 R 11 ,-CH 2 -NR 11 R 11 ,-CO 2 C 1 -C 3 Alkyl or -CH 2 -CO 2 C 1 -C 3 is alkyl or R 2 -CN, halogen, C 1 -C 6 alkyl or C 1 -C 6 An optionally substituted indazole optionally substituted with 1 to 3 substituents each independently selected from haloalkyl.

[0100] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula, [ka] In the formula, each R 10 is independently -H, -CN, or C 1 -C 3 is haloalkyl or R 2 is C 1 -C 3 An optionally substituted indazole optionally substituted with alkyl.

[0101] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula, [ka] In the formula, R 10 -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 selected from haloalkoxy.

[0102] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula, [ka] In the formula, R 11 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl.

[0103] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a pyrazole optionally substituted with alkyl or a triazole optionally substituted with alkyl.

[0104] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula. [ka] [ka]

[0105] In still further compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula. [ka]

[0106] In still further compounds of formula (I), the compounds are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing, in which the bond at the * position is as depicted; [ka] It is.

[0107] In still further compounds of formula (I), the compounds are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; In the formula, the bond at position * is as shown, or [ka] It is.

[0108] In still further compounds of formula (I), the compounds are [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0109] In still further compounds of formula (I), the compounds are [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing, in which the bond at the * position is as depicted; [ka] It is.

[0110] In still further compounds of formula (I), the compounds are [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0111] In still further compounds of formula (I), the compounds are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0112] In a further embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof. It is salt. It is understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives are generally disclosed in the Schemes and / or Examples described herein or their pharmaceutically acceptable salts by substituting isotopic labeling reagents for non-isotopic labeling reagents. It can be prepared by performing the following procedure. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent a stable isotope of that atom.

[0113] In a further embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is deuterated at one or more positions. Unless otherwise stated, when an atom is specifically designated as "H" or "hydrogen", that atom is understood to have hydrogen in its naturally occurring isotopic composition. Also, unless otherwise noted, when an atom is specifically designated as "D" or "deuterium", that atom has an abundance substantially greater than the natural abundance of deuterium, which is 0.015%. It is understood to have deuterium.

[0114] In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 8 is -H, -D, or C 1 -C 6 It is an alkyl. In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is selected from: [ka]

[0115] In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 is 1-(trideuteriomethyl)pyrazol-4-yl. In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound is: [ka]

[0116] Pharmaceutically acceptable salts of the compounds of the invention include, for example, acid addition salts of the compounds of the invention that are sufficiently basic, such as inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. It is an acid addition salt with an acid such as trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. In addition, pharmaceutically acceptable salts of the compounds of the invention that are sufficiently acidic include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, or a salt with an organic base that provides a pharmaceutically acceptable cation, such as a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine. Pharmaceutically acceptable salts and general methodologies for their preparation are well known in the art (e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2 nd Revised Edition (Wiley-VCH, 2011), S.M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0117] Additional representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), Benzene sulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate , clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptanate, gluconate, glutamate, glycolylarsa diphosphate, hexafluorophosphate, hexylresorucinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium , malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy -2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluene Sulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, tannates, tartrates, theocurates, tosylates, triethiodides, and valerates. Can be mentioned.

[0118] The compounds of the invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the invention can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0119] Further aspects The following are further numbered embodiments of the invention. 1. A compound of the following formula (I), [ka] or a pharmaceutically acceptable salt thereof, in which: R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R is -H or C 1 -C 3 is alkyl, R 1 is isobenzofuranone, benzofuranone, indole, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidaza[1,2-a]pyridine, or a benzothiazolone, wherein the optionally substituted bicyclic ring is selected from oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is the group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -OH, -CH(OH)-CH 2 OH, -CH(OH)C 1 -C 3 haloalkyl, -CO-CH 2 OH,C 3 -C 6 cycloalkyl, -NO 2 ,-NR 11 R 11 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 R 15 ,-SO 2 C 1 -C 3 Alkyl, -SOC 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -SO 2 N(R 11 )-CN,-SO 2 N(R 11 )(R 13 ) -C(=N-OH)-NH 2 , -CN, -CO 2 C 1-C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 ,-CO-SR 12 , -CO-NHSO 2 R 16 ,-COCH=SOR 11 (R 11 ), or -COCH 2 CN, or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is 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 oxo, -OH, -NR 11 R 11 , -N(R 11 )-C(O)-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, morpholine, oxetane, C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl, or R' is a group of the following formula, [ka] R 2 is a group of the following formula, [ka] or R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 ,-CD 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, tetrahydropyran, oxetane, azetidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzo selected from dioxole, optionally substituted 2,3-dihydro-1,4-benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole optionally substituted with 1 to 3 substituents each independently selected from optionally substituted heteroaryl; 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CH 2 CH(OH)CH(OH)R 11 , or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -C(O)(CH 2 ) n OR 11 ,C(O)C(CH 3 ) 2 OH, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 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]138iridin-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]pyridine , 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 an optionally substituted bicyclic ring selected from or 8 to 10 containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S; is an optionally substituted bicyclic heteroaryl on the ring atoms of which the optionally substituted bicyclic ring is a halogen and a C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 CH, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -C(O)NR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 But 1~3 R 10 or R 2 is a group of the following formula, [ka] or R 3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 C.O. 2 H), -CO-C 1 -C 3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 3 -C 5 an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S; , or an optionally substituted heteroaryl of 5 or 6 ring atoms, including 1, 2, or 3 ring heteroatoms independently selected from S; or heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 each optionally substituted with 1 to 3 substituents independently selected from haloalkyl; R 4 ,R 5 , and R 6 Each of is independently -H, halogen, -CN, C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 7 ,-CN,C 1 -C 6 Alkyl, -CH 2 OH or C 1 -C 6 is haloalkyl, R 8 is -H, -D, or C 1 -C 6 is alkyl, Each R 9 but independently -H, halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 3 -C 5 cycloalkyl, Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-SONR 11 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 Alkyl, -C(O)NR 11 R 12 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -N(R 11 )COR 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or of the formula is the basis of [ka] optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 and each optionally replaced C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, Each R 11 but independently -H,C 1 -C 3 Alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 3 is haloalkyl, Each R 12 is, independently, -H, optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 haloalkyl, -SO 2 NR 11 R 11 ,-NR 11 R 11 ,-OR 11 , -O-CH 2 -CH(OH)-CH 2 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, methyl, or a group of the formula: [ka] optionally substituted C 1 -C 3 Alkyl is -OH, C 3 -C 6 optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But -NR 11 R 11 ,-OR 11 ,-SO 2 C 1 -C 3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is -NR 11 R 11 or -OR 11 is optionally replaced with R 14 , -H, optionally substituted C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, optionally substituted 1 -C 3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, and the optionally substituted aryl or the optionally substituted 6-membered heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 optionally substituted with 1 to 3 substituents each independently selected from haloalkyl; R 16 But, H, C 1 -C 3 Alkyl, -NH 2 , phenyl, or pyridine, A compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. 2.R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R is -H or C 1 -C 3 is alkyl, R 1 is optionally substituted with selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone is a bicyclic ring, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is the group of the following formula, [ka] R’ is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -OH, -CH(OH)-CH 2 OH, -CO-CH 2 OH,C 3 -C 6 cycloalkyl, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 R 15 ,-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -SO 2 N(R 11 )-CN, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 ,-CO-SR 12 , or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, selected from pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 optionally substituted with 1 to 3 substituents independently selected from alkyl; R' is a group of the following formula, [ka] R 2 is a group of the following formula, [ka] or R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CONR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 But 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2 is the group of the following formula, [ka] R 3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 C.O. 2 H), -CO-C 1 -C 3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 3 -C 5 an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S; , or an optionally substituted heteroaryl of 5 or 6 ring atoms, including 1, 2, or 3 ring heteroatoms independently selected from S; or heteroaryl is halogen, C 1 -C 3 alkyl or C 1 -C 3 each optionally substituted with 1 to 3 substituents independently selected from haloalkyl; R 4 ,R 5 , and R 6 Each of is independently -H, halogen, C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 7 ,-CN,C 1 -C 6 alkyl or C 1 -C 6 is haloalkyl, R 8 But -H or C 1 -C 6 is alkyl, Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-SONR 11 R 11 ,-CO 2 H, -CO 2 C 1 -C 3 alkyl, - CONR 11 R 12 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or of the formula is the basis of [ka] optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 and each optionally replaced C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, Each R 11 but independently -H or C 1 -C 3 is alkyl, Each R 12 is, independently, -H, optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, -SO 2C 1 -C 3 Alkyl, -SO 2 C 1 -C 3 haloalkyl, -SO 2 NR 11 R 11 ,-NR 11 R 11 ,-OR 11 , -O-CH 2 -CH(OH)-CH 2 5-membered heteroaryl, 6-membered heteroaryl optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, methyl, or a group of the formula [ka] optionally substituted C 1 -C 3 Alkyl is -OH, C 3 -C 6 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole. 3.R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or the following group, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine selected from, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 A compound as defined in embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents independently selected from alkyl. 4.R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy; R is -H or C 1 -C 3 is alkyl, R 1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone, and the optionally substituted bicyclic ring is oxo, - CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 optionally substituted with 1 to 3 substituents each independently selected from alkoxy, or R 1 is the group of the following formula, [ka] R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or the following group, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine selected from, each of which is oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl, or aryl, 5-membered heteroaryl, or 6-membered heteroaryl 1 -C 6 A compound as defined in any of embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, which is optionally substituted with 1 to 3 substituents independently selected from alkyl. 5.R’ is hydrogen, halogen, C 1 -C 3 Alkyl, -CH(OH)-CH 2 OH, -CO-CH 2 OH or C 3 -C 6 A compound as defined in embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, which is cycloalkyl. 6.R is -H or C 1 -C 3 is alkyl, R 1 is the group of the following formula, [ka] R 2 is a group of the following formula, [ka] or R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CONR 11 R 11 , or each optionally substituted with phenyl, optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or R 2 But 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2 is the group of the following formula, [ka] Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 -CO 2 R 11 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine; C replaced with 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 , or phenyl, each optionally substituted with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 , -OH, or -CN, each optionally substituted with 1 to 3 substituents independently selected from , -OH, or -CN, or a pharmaceutically acceptable compound thereof. salt. 7.R 8 is -H, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 6. 8. A compound as defined in any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, having the following formula: [ka] 9.R and R 1 together with the nitrogen to which they are attached form an optionally substituted bicyclic ring selected from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, optionally substituted The bicyclic ring is oxo, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 9. A compound as defined in any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents each independently selected from alkoxy. 10.R and R 1 A compound as defined in embodiment 9 or a pharmaceutically acceptable salt thereof, wherein, together with the nitrogen to which they are attached, form an optionally substituted bicyclic ring of the formula: [ka] 11. The compound defined in any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is -H. 12.R 4 is -H or a halogen, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 11. 13.R 4 is -H, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 12. 14. A compound as defined in any one of embodiments 1 to 8 or 11 to 13, or a pharmaceutically acceptable salt thereof, having the following formula. [ka] 15.R 3 , -H, -CN,C 1 -C 3 alkyl or C 1 -C 3 15. A compound as defined in any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, which is haloalkyl. 16.R 3 is -H, -CN, methyl, or trifluoromethyl, or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1 to 15. 17.R 3 is -H or methyl, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 16. 18.R 5 -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 17. A compound as defined in any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, which is haloalkyl. 19.R 5 is -H, halogen, methyl, or trifluoromethyl, or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1 to 18. 20.R 6 is -H or a halogen, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 19. 21.R 7 ,-CN,C 1 -C 3 alkyl or C 1 -C 3 21. A compound as defined in any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, which is haloalkyl. 22.R 7 is -CN, methyl, or trifluoromethyl, or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1 to 21. 23.R 7 is methyl, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 22. 24.R 1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone, and the optionally substituted bicyclic ring is oxo, - CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, -OH, or C 1 -C 6 A compound as defined in any one of embodiments 1 to 8 or 11 to 23, or a pharmaceutically acceptable compound thereof, optionally substituted with 1 to 3 substituents each independently selected from alkoxy salt. 25.R 1 is a group of the following formula, the compound defined in any one of embodiments 1 to 8 or 11 to 23, or a pharmaceutically acceptable salt thereof. [ka] 26.R 1 is a group of the following formula, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or 11 to 23. [ka] 27.R 9 but independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 A compound as defined in any one of embodiments 1 to 8, 11 to 23, 25, or 26, or a pharmaceutically acceptable salt thereof, which is alkoxy. 28.Each R 9 but independently -H, halogen, C 1 -C 3 alkyl or C 3 -C 5 A compound as defined in any one of embodiments 1 to 8, 11 to 23, 25, or 26, or a pharmaceutically acceptable salt thereof, which is cycloalkyl. 29.R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or a group of the following formula, [ka] where ring A is pyrrolidine optionally substituted with -CN, or R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine selected from, each of which is oxo, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl or phenyl 1 -C 6 A compound as defined in any one of embodiments 1 to 4, 7 to 8, 11 to 23, or 25 to 28, optionally substituted with 1 to 3 substituents independently selected from alkyl or a pharmaceutically acceptable salt thereof. 30.R’ is C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, -NO 2 , -N(R 11 )-CO 2 C 1 -C 3 Alkyl, -N(R 11 )-SO 2 C 1 -C 3 Alkyl, -SO 2 NR 11 R 11 ,-SO 2 N(R 11 )-CO-C 1 -C 3 Alkyl, -C(=N-OH)-NH 2 , -CN, -CO 2 C 1 -C 3 Alkyl, -CONR 11 R 12 ,-CON(R 11 )-(CH 2 ) n -R 13 , or less, [ka] A compound as defined in embodiment 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrrolidine optionally substituted with -CN. 31.R' is oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazines, each of which is selected from oxo, -NR 11 R 11 ,-OR 11 ,-CN,C 1 -C 6 C optionally substituted with haloalkyl or phenyl 1 -C 6 A compound as defined in embodiment 29, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents independently selected from alkyl. 32.R' is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine; Each is oxo, -NR 11 R 11 ,-OR 11 , or C optionally substituted with aryl 1 -C 6 A compound as defined in any one of embodiments 1 to 4, 7 to 8, 11 to 23, or 25 to 28, optionally substituted with 1 to 3 substituents independently selected from alkyl or a pharmaceutically acceptable salt thereof. 33.R’ is hydrogen, halogen, C 1 -C 3 alkyl or C 3 -C 6 A compound as defined in embodiment 32, or a pharmaceutically acceptable salt thereof, which is cycloalkyl. 34. A compound as defined in embodiment 32, or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, halogen, or methyl. 35.R’ is hydrogen, -Cl, -F, -Br, methyl, difluoromethyl, trifluoromethyl, methoxy, -NO 2 , -CN, or a group of the following formula, the compound defined in any one of embodiments 1 to 4, 7 to 8, 11 to 23, or 25 to 28, or a pharmaceutically acceptable salt thereof. [ka] [ka] 36.R 1 is a group of the following formula, the compound defined in any one of embodiments 1 to 8 or 11 to 23, or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 37.R 2 is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] 38.R 2 is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] 39.R 2 is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] 40.R 2 is a group of the following formula, [ka] or R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole; The optionally substituted 5-membered heteroaryl is -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 A compound as defined in any one of embodiments 1 to 36, or a pharmaceutical compound thereof, each optionally substituted with 1 to 3 substituents each independently selected from , -OH, or -CN. Acceptable salt. 41.R 2 is the group of the following formula, [ka] Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, -SO 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 cycloalkyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, and an optionally substituted C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl is -CN, -OH, or C 1 -C 3 optionally substituted with alkoxy and optionally substituted C 3 -C 5 cycloalkyl or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -NR11 R 11 A compound as defined in any one of embodiments 1 to 36, or a pharmaceutically acceptable compound thereof, optionally substituted with 1 to 3 substituents each independently selected from , -OH, or -CN. salt. 42.R 2 is the group of the following formula, [ka] Each R 10 are independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, -SO 2 R 11 ,C 1 -C 6 alkyl, C optionally substituted with -OH 2 -C 6 alkynyl, C optionally substituted with -CN 3 cycloalkyl, or C 1 -C 3 A compound as defined in any one of embodiments 1 to 36 or its pharmaceutical composition is a heteroaryl selected from pyrazole optionally substituted with 1 to 3 substituents each independently selected from alkyl Salt allowed in. 43.R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole; 5-membered heteroaryl substituted with -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CONR 11 R 11 , -OH, -NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, or C 1 -C 3 each optionally substituted with alkoxy and optionally substituted C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 A compound as defined in any one of embodiments 1 to 36, or a pharmaceutical compound thereof, each optionally substituted with 1 to 3 substituents each independently selected from , -OH, or -CN. Acceptable salt. 44.R 2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole; 5-membered heteroaryl substituted with C 1 -C 6 haloalkyl, C 1 -C 6 1 each independently selected from alkyl, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, or optionally substituted heteroaryl selected from pyridine or pyrimidine. Optionally substituted with ~3 substituents, the optionally substituted phenyl, 1,3-benzodioxole, or heteroaryl is halogen, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 , or a pharmaceutically acceptable compound thereof, each optionally substituted with 1 to 3 substituents independently selected from , or -CN. salt. 45.R 2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, Optionally selected from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine optionally from 8 to 10 ring atoms containing substituted bicyclic rings or 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S a substituted bicyclic heteroaryl, wherein the optionally substituted bicyclic ring is halogen and C 1 -C 6 an optionally substituted bicyclic heteroaryl optionally substituted with 1 to 3 substituents each independently selected from alkyl, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 ,-CO 2 C 1 -C 3 Alkyl, -CONR 11 R 11 ,-NR 11 R 11 ,-NR 11 C.O. 2 R 11 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 5 an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted a substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted hetero selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole aryl optionally substituted with 1 to 3 substituents each independently selected, optionally substituted C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 Alkynyl is -CN, -OH, oxetanyl, C 1 -C 3 Alkoxy, or -CONR 11 R 11 each optionally replaced with and optionally replaced with C 3 -C 5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is halogen, C 1 -C 3 Alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 haloalkoxy, -SO 2 R 11 ,-NR 11 R 11 A compound as defined in any one of embodiments 1 to 36, or a pharmaceutical compound thereof, each optionally substituted with 1 to 3 substituents each independently selected from , -OH, or -CN. Acceptable salt. 46.R 2 But 1~3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R 2is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] 47.R 2 is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] 48.R 2 is a group of the following formula, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 36. [ka] [ka] 49. A compound as defined in embodiment 1 or 2, selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 50. A compound as defined in embodiment 1 or 2, selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 51. A compound as defined in embodiment 1 or 2, selected from: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 52. A pharmaceutical composition comprising the compound defined in any one of embodiments 1 to 51 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 53. A method of 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 embodiments 1 to 51. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 52. 54. The method as defined in embodiment 53, wherein PI3K is PI3Kα. 55. A method as defined in embodiment 53 or embodiment 54, wherein the PI3K associated with the disease or disorder has the H1047R mutation. 56. The method as defined in any one of embodiments 53 to 55, wherein the disease or disorder is cancer. 57.The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. , the method defined in aspect 56. 58. The method as defined in embodiment 56, wherein the cancer is breast cancer. 59. The method as defined in embodiment 56, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. 60. The method as defined in any one of embodiments 53 to 55, wherein the disorder is CLOVES syndrome or PROS. 61. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of the compound defined in any one of embodiments 1 to 51 or a pharmaceutically acceptable amount thereof. 53. A method comprising administering a salt, or a pharmaceutical composition as defined in embodiment 52. 62. A method of treating a cancer or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount as defined in any one of embodiments 1 to 51. 53. A method comprising administering a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in embodiment 52. 63.The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. , the method defined in aspect 62. 64. The method defined in embodiment 62, wherein the cancer is breast cancer. 65. The method as defined in embodiment 62, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. 66. A method as defined in embodiment 62, wherein the disorder is CLOVES syndrome or PROS. 67. A compound as defined in any one of embodiments 1 to 51 or a pharmaceutically acceptable salt thereof for use in therapy. 68. A compound as defined in any one of embodiments 1 to 51 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder associated with the modulation of PI3K. 69. A compound or a pharmaceutically acceptable salt thereof for use as defined in embodiment 68, wherein the disease or disorder associated with modulation of PI3K is cancer. 70.The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. , or a pharmaceutically acceptable salt thereof for use as defined in embodiment 69. 71. A compound or a pharmaceutically acceptable salt thereof for use as defined in embodiment 69, wherein the cancer is breast cancer. 72. A compound for use as defined in embodiment 69 or its pharmaceutical composition, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. Salt allowed in. 73. A compound or a pharmaceutically acceptable salt thereof for use as defined in embodiment 68, wherein the disorder is CLOVES syndrome or PROS. 74. Use of a compound as defined in any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the modulation of PI3K. 75. Use as defined in embodiment 74, wherein the disease or disorder associated with the regulation of PI3K is cancer. 76.The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. , use of definitions in aspect 75. 77. Use of the definition in aspect 75, where the cancer is breast cancer. 78. Use as defined in embodiment 75, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. 79. Use of the definitions in embodiment 74, wherein the disorder is CLOVES syndrome or PROS.

[0120] pharmaceutical composition In some embodiments, the present disclosure provides pharmaceutical compositions that include a compound of formula (I), (II), or (III) as an active ingredient. In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or A pharmaceutical composition comprising an excipient.

[0121] As used herein, the term "composition" includes products containing specified ingredients in specified amounts, and includes any products that result directly or indirectly from the combination of specified ingredients in specified amounts. It is also intended to encompass products.

[0122] Compounds of formula (I), (II), or (III) can be prepared in tablets, capsules (each of which includes sustained or sustained release formulations), pills, powders, granules, elixirs, tinctures, etc. They can be formulated for oral administration in the form of tablets, suspensions, syrups, emulsions, and the like. Compounds of formula (I), (II), or (III) may be administered intravenously (bolus or infusion), intraperitoneally, topically, subcutaneously, intramuscularly, intravenously (bolus or infusion), subcutaneously, intramuscularly, etc., all using forms well known to those skilled in the pharmaceutical arts. Or they can be formulated for transdermal (eg, patch) administration.

[0123] Formulations of the present disclosure may be in the form of an aqueous solution, including an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, thickening / suspending agents, buffering agents, and pH adjusting agents, and mixtures thereof. Contains selected items.

[0124] According to a further aspect of the disclosure, comprising a compound of any one of the formulas disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. Pharmaceutical compositions are provided.

[0125] The compositions of the present disclosure are 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), topical for use (e.g., as a cream, ointment, gel, or aqueous or oily solution or suspension), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder), or parenterally. It may be in a form suitable for administration (eg, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0126] 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, sweetening, flavoring, and / or preservative agents.

[0127] how to use In some embodiments, the present disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo) in which a cell is treated with a therapeutically effective amount of formula (I), (II), or ( A method is provided, comprising contacting the compound of III), or a pharmaceutically acceptable salt thereof.

[0128] 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: a therapeutically effective amount of formula (I); Provided are methods comprising administering to a subject a compound of (II) or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0129] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II); ), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, is provided.

[0130] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II); ), or (III), or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents, to a subject.

[0131] In some aspects, the present disclosure provides methods of treating a disease or disorder disclosed herein in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of Formula (I). ), (II), or (III), or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, SERD or a pharmaceutically acceptable salt thereof. aromatase inhibitor or its pharmaceutically acceptable salt, taxane or its pharmaceutically acceptable salt, mTOR inhibitor or its pharmaceutically acceptable salt, tyrosine kinase inhibitor or its pharmaceutically acceptable salt Acceptable salts, platinum agents, anthracyclines or their pharmaceutically acceptable salts, immune checkpoint inhibitors or their pharmaceutically acceptable salts, anti-androgens or their pharmaceutically acceptable salts, anti-HER2 Monoclonal antibodies, anti-HER2 antibody drug conjugates, KRAS inhibitors or pharmaceutically acceptable salts thereof, MEK inhibitors or pharmaceutically acceptable salts thereof, ERK inhibitors or pharmaceutically acceptable salts thereof, topoisomerase including administration in combination with an 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. .

[0132] In some embodiments, the disease or disorder is associated with PI3K activity. In some embodiments, the disease or disorder is one that involves PI3K activity.

[0133] In some embodiments, the disease or disorder is cancer.

[0134] In some embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical cancer, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocyte cancer. tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary origin, heart (cardiac) 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, cutaneous T-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonoma, medulloblastoma, endometrial cancer, Ependymomas, esophageal cancers, sensory neuroblastomas, Ewing sarcomas, extracranial germ cell tumors, extragonadal germ cell tumors, fallopian tube cancers, gallbladder cancers, gastric cancers, gastrointestinal carcinoid tumors, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, Kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, Midline cancer with nut gene alterations, mouth cancer, multiple endocrine tumor syndrome, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative tumor, chronic bone marrow Proliferative tumors, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral 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, paranasal sinus and nasal cavity cancer, Thyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell tumor, 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 cancer, thyroid cancer, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter. , urethral cancer, uterine sarcoma, vaginal cancer, vascular tumor, vulvar cancer, and Wilms' tumor.

[0135] 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. Cancer, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma type cancer, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal cell carcinoma , clear cell renal cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0136] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0137] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is brain cancer.

[0138] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary cancer. In some embodiments, the breast cancer is a tubular cancer. In some embodiments, the breast cancer is mucinous cancer. In some embodiments, the breast cancer is Paget's disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). In some embodiments, the breast cancer is a hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer.

[0139] In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is small cell cancer. 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.

[0140] In some embodiments, the brain cancer is 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 choroid plexus cancer. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is ependymoma. In some embodiments, the brain cancer is glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor.

[0141] In some embodiments, diseases or disorders associated with PI3K include CLOVES syndrome, PROS, breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, These include, but are not limited to, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0142] In some embodiments, the disease or disorder associated with PI3K is CLOVES syndrome.

[0143] In some embodiments, the disease or disorder associated with PI3K is PROS.

[0144] 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.

[0145] In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm, thyroid neoplasm, ovarian neoplasm, non-small cell lung cancer, endometrial neoplasm, or pancreatic neoplasm. In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm. In some embodiments, the disease or disorder associated with PI3K is a thyroid neoplasm. In some embodiments, the disease or disorder associated with PI3K is an ovarian neoplasm. In some embodiments, the disease or disorder associated with PI3K is non-small cell lung cancer. In some embodiments, the disease or disorder associated with PI3K is endometrial neoplasm. In some embodiments, the disease or disorder associated with PI3K is a pancreatic neoplasm.

[0146] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, stomach cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. It's cancer.

[0147] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.

[0148] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0149] 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.

[0150] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.

[0151] In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is, unless otherwise specified, liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, malignant myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissue, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, soft tissue Angiosarcoma, extraosseous osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stroma Sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft tissue sarcoma, clear cell sarcoma of soft tissue, extraosseous myxoid chondrosarcoma, extraosseous Ewing's sarcoma , desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma.

[0152] In some embodiments, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II), or (III); or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure to a subject.

[0153] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising: 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, to a subject.

[0154] In some embodiments, the present disclosure provides a method of treating or preventing breast cancer in a subject in need thereof, comprising a therapeutically effective amount of formula (I), (II), or (III). A method is provided comprising administering to a subject a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0155] In some embodiments, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising: 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, is provided.

[0156] In some embodiments, the present disclosure provides a method of treating or preventing prostate cancer in a subject in need thereof, comprising a therapeutically effective amount of formula (I), (II), or (III). ), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, to a subject.

[0157] In some embodiments, the present disclosure provides a method of treating prostate cancer in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II), or (III); A method is provided comprising administering to a subject a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0158] In some embodiments, the present disclosure provides a method of treating or preventing brain cancer in a subject in need thereof, comprising a therapeutically effective amount of formula (I), (II), or (III). ), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, to a subject.

[0159] In some embodiments, the present disclosure provides a method of treating brain cancer in a subject in need thereof, comprising: a therapeutically effective amount of formula (I), (II), or (III); A method is provided comprising administering to a subject a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0160] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0161] In some embodiments, the disclosure provides compounds of formula (I), (II), or (III), or compounds thereof, for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo). Pharmaceutically acceptable salts are provided.

[0162] In some embodiments, the present disclosure provides compounds of formula (I), (II), or (III), or pharmaceutical formulations thereof, for use in the treatment or prevention of diseases or disorders disclosed herein. Provide acceptable salt.

[0163] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable compound thereof, for use in treating a disease or disorder disclosed herein. Provide the salt to be used.

[0164] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer. .

[0165] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0166] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of breast cancer.

[0167] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer.

[0168] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of prostate cancer. do.

[0169] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer.

[0170] In some embodiments, 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. do.

[0171] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating brain cancer.

[0172] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or the like, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. Provides for the use of pharmaceutically acceptable salts.

[0174] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein. Provide for the use of acceptable salts.

[0175] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof. , or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for treating cancer in a subject in need thereof; Uses of pharmaceutically acceptable salts thereof are provided.

[0177] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for treating or preventing breast cancer in a subject in need thereof; or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III), or a compound thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof. Provides for the use of pharmaceutically acceptable salts.

[0179] In some embodiments, the present disclosure provides a method of formula (I), (II), or (III) in the manufacture of a medicament for treating or preventing prostate cancer in a subject in need thereof. Uses of the compound, or a pharmaceutically acceptable salt thereof, are provided.

[0180] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for treating prostate cancer in a subject in need thereof; or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the present disclosure provides a method of formula (I), (II), or (III) in the manufacture of a medicament for treating or preventing brain cancer in a subject in need thereof. Uses of the compound, or a pharmaceutically acceptable salt thereof, are provided.

[0182] In some embodiments, the present disclosure provides a compound of formula (I), (II), or (III) in the manufacture of a medicament for treating brain cancer in a subject in need thereof; or a pharmaceutically acceptable salt thereof.

[0183] The present disclosure provides compounds that function as modulators of PI3K activity. Accordingly, the present disclosure provides a method of modulating PI3K activity in vitro or in vivo comprising contacting a cell with a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof. , provides a method.

[0184] In some embodiments, PI3K modulation is inhibition of PI3K.

[0185] In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutation inhibitor.

[0186] The efficacy of the compounds of the present disclosure is determined by industry-recognized assays / disease models in accordance with standard practices elucidating the same as those described in the art and found in current general knowledge. be able to.

[0187] The present disclosure provides a method of treating a disease or disorder in which PI3K activity is involved in a patient in need of treatment for the disease or disorder, comprising administering to the patient a therapeutically effective amount of a compound or a compound as defined herein. Also provided are methods comprising administering the pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0188] Route of administration Compounds of formula (I), (II), or (III), or pharmaceutical compositions containing these compounds, whether systemic / peripheral or local (i.e., at the desired site of action), It may be administered to a subject by any convenient route of administration.

[0189] Routes of administration include oral (e.g., by ingestion), buccal, sublingual, transdermal (including, e.g., via patches, bandages, etc.), transmucosal (including, e.g., via patches, bandages, etc.), and intranasal. (e.g. by nasal spray), eye (e.g. by eye drops), lung (e.g. via aerosol, e.g. through the mouth or nose, e.g. by inhalation or insufflation therapy), rectum (e.g. by suppository). or by enema), intravaginally (e.g., by pessary), parenterally, e.g., subcutaneously, intradermally, intramuscularly, intravenously, intraarterially, intracardially, intrathecally, intrathecally, intracapsularly, subcapsularly, By injection, including, but not limited to, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, intrathecal, and intrasternal, by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly. .

Example

[0190] In the Examples, exemplary compounds of Formulas (I), (II), and (III) are synthesized and tested. It is understood that compounds of formulas (I), (II), and (III) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using ordinary techniques in the art. Ru.

[0191] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as specified, or 300.3 K unless otherwise specified, and chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0192] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as Luna-C18 2.0x30mm or Xbridge Shield RPC18 2.1x50mm. The injection volume was 0.7-8.0 μl and the flow rate was typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD), and positive ion electrospray ionization. The MS range was 100-1000Da. The solvent was a gradient of water and acetonitrile, both containing a modifier such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0193] Abbreviation: ACN Acetonitrile AcOH Acetic acid ADP adenosine diphosphate ATP adenosine triphosphate CDCl 3 chloroform-d CPhos 2-dicyclohexylphosphino-2’,6’-bis(N,N-dimethylamino)biphenyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP dimethylaminopyridine DMEA dimethylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d 6 Hexadeuterodimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide eq equivalent EtOAc ethyl acetate EtOH ethanol h, hr time HCl hydrogen chloride 1 H NMR proton nuclear magnetic resonance spectroscopy HATU O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-hexafluorophosphate tetramethyluronium IPA Isopropanol LC-MS Liquid Chromatography-Mass Spectrometry mCPBA meta-chloroperbenzoic acid MeOH methanol MgSO 4 magnesium sulfate min minutes MS ES mass spectrometry electrospray MTBE Methyl tert-butyl ether NaCl sodium chloride NaHCO 3 sodium bicarbonate NaHMDS Sodium bis(trimethylsilyl)amide NaOH Sodium hydroxide Na 2 S 2 O 3 sodium thiosulfate Na 2 S.O. 4 sodium sulfate N.H. 4 Cl ammonium chloride N.H. 4 HCO 3 ammonium bicarbonate N.H. 4 OH ammonium hydroxide NMP N-methyl-2-pyrrolidone ppm 1 part per million rt room temperature SFC supercritical fluid chromatography TBAF Tetrabutylammonium iodide TFA trifluoroacetic acid THF Tetrahydrofuran

[0194] Intermediate 1C: tert-butyl 6-bromo-2,3-difluoro-benzoate [ka] A solution of 6-bromo-2,3-difluoro-benzoic acid (2.9 g, 12 mmol) in THF (24 mL) was added dropwise with tert-butyl (Z)-N,N'-diisopropylcarbamate (9.8 g, 49 mmol). 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 in hexane to give the title compound (3.3g, 92%) as a colorless oil.

[0195] Intermediate 2C: tert-butyl 4-(3-bromo-6-chloro-2-pyridyl)piperazine-1-carboxylate [ka] A vial was prepared with tert-butyl piperazine-1-carboxylate (0.43 g, 2.28 mmol), 3-bromo-6-chloro-2-fluoro-pyridine (0.20 g, 0.95 mmol), and cesium carbonate (0.93 g, 2.85 mmol). , and DMF (4 mL). The vial was sealed and stirred overnight at room temperature. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, collected, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc in heptane to give the title compound (0.34g, 94%) as a colorless oil. ES / MS m / z 322(M- t Bu).

[0196] The following compounds in Table 1 were made in a similar manner to that described for tert-butyl 4-(3-bromo-6-chloro-2-pyridyl)piperazine-1-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 1-1] [Table 1-2] [Table 1-3]

[0197] Intermediate 17C: 2-Fluoro-N-methoxy-benzenesulfonamide [ka] 2-Fluorobenzenesulfonyl chloride (0.70 g, 3.60 mmol) and potassium carbonate (1.09 g, 7.91 mmol) were combined in EtOH (5 mL) and water (5 mL) and allowed to stir at room temperature overnight. The reaction was diluted with water (20 mL) and the title compound was removed by filtration (0.40 g, 54%). ES / MS m / z 206(M+H).

[0198] Intermediate 18C: (1,5-dimethyl-6-oxo-3-pyridyl)boronic acid [ka] 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (4 g) in acetone (40 mL) and water (20 mL) , 16.06 mmol) was treated dropwise with concentrated aqueous HCl (20 mL, 36.5%) under nitrogen atmosphere at room temperature. The reaction was stirred for 3 hours at room temperature. The reactant is NH 4 The mixture was basified to pH 8 with OH and concentrated under reduced pressure. The residue was dissolved in water (0.1% NH 4 Purification by reverse phase chromatography on C18 eluting with 40% to 60% ACN in (containing OH) afforded the title compound (2.0 g, 75%) as an off-white solid. ES / MS m / z 168(M+H).

[0199] Intermediate 19C: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]cyclopropanecarbonitrile [ka] 1-(5-bromo-2-pyridyl)cyclopropanecarbonitrile (0.21 g, 0.94 mmol), bis(pinacolato)diborane (0.36 g, 1.41 mmol), and potassium acetate in dry 1,4-dioxane (10 mL). A solution of (0.28 g, 2.82 mmol) was purged with argon for 10 min. [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 diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% MeOH in DCM to give the title compound (0.35g, 83%, 60% purity). ES / MS m / z 189(M+H).

[0200] The following compounds in Table 2 are written in the form described for 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]cyclopropanecarbonitrile. It was made in a similar manner. This compound was purified using various methods that would be apparent to those skilled in the art. [Table 2]

[0201] Intermediate 21C: Tributyl-(3,6-difluoro-2-pyridyl)stannane [ka] A solution of 2,5-difluoropyridine (2.0 g, 17.38 mmol) in THF (10 mL) at −78° C. was treated with lithium diisopropylamide solution (1M in THF, 2.79 g, 26.07 mmol). 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 to the reaction at -78°C, and then the reaction was stirred at -78°C for 1 hour. The reactant is NH 4 Quenched with aqueous Cl solution and extracted with EtOAc (3x). The combined extracts were 2 S.O. 4 dried, filtered and the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc in heptane to give the title compound (4.46g, 64%). ES / MS m / z 406(M+H).

[0202] Intermediate 22C: 3-bromo-N-tert-butyl-pyridine-2-sulfonamide [ka] 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 in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc in petroleum ether to give the title compound (0.50 g, 22%) as a dark red solid. ES / MS m / z 293 / 295(M+H).

[0203] Intermediate 23C: 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine [ka] 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) at 0 °C was mixed with sodium hydride (1.0 g , 60% in oil, 25.0 mmol) in portions. The reaction was stirred at room temperature for 1 h, quenched with water (30 mL), and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 30 mL) and diluted with Na 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% EtOAc in petroleum ether to give the title compound (1.34g, 38%) as a white solid. ES / MS m / z 168(M+H).

[0204] Intermediate 24C: Trimethyl-(2-methylpyrazolo[4,3-b]pyridin-5-yl)stannane [ka] 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 mixed with hexamethyldistin (11.73 g, 35.8 mmol) and tetrakis Treated with (triphenylphosphine)palladium(0) (5.52g, 4.77mmol). The reaction was stirred at 100°C for 2 hours. The reaction was cooled to room temperature, quenched with saturated aqueous potassium fluoride, filtered, and the solids were washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (6.0 g) as a black solid. ES / MS m / z 298(M+H).

[0205] Intermediate 25C: iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]zinc [ka] An oven-dried flask equipped with a stir bar and septum was charged with lithium chloride (1.62 g, 38.17 mmol) and heated at 170° C. for 20 minutes under high vacuum. The vacuum was removed and nitrogen gas was introduced into the flask while cooling. Once cooled, zinc (2.50 g, 38.17 mmol) was added to the flask, dried under high vacuum at 170° C. for 20 minutes, backfilled with nitrogen, and cooled simultaneously. Once 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 to boiling at 60°C. Once cooled 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 after heating the reaction at 60 °C for 20 min. , 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 at 50° C. overnight. The reaction was allowed to stand at room temperature for 1 hour, and the clear solution above the solid was carefully transferred via cannula to a dry flask. This was intended to be used without purification, assuming a concentration of approximately 0.45M.

[0206] The following compounds in Table 3 were made in a similar manner to that described for iodo-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]zinc. [Table 3]

[0207] Intermediate 28C: 1-(3-bromo-5-fluoro-2-hydroxy-phenyl)ethanone [ka] 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) while keeping the temperature below 20 °C. did. Stirred at 0-10°C for 5-6 hours. Water (20 L) was slowly added to the reactor, stirred at room temperature for 2 hours, and the crude product was filtered off. This material was slurried in heptane (10 L) at 0-25° C. for 2 hours and the title compound (2.5 kg, 83%) as a yellow solid was removed by filtration. 1 H NMR(400MHz,DMSO-d6)δ ppm 2.69(3H,s),7.90(2H,m),12.53(1H,s).

[0208] Intermediate 1A: (2-bromo-4-methyl-phenyl)propanoate [ka] 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 propanoyl chloride (5.44 g, 58.8 mmol) at 0 °C. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (100 mL), the pH was adjusted to 5 with HCl (2M) and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 x 150 mL) and anhydrous Na 2 S.O. 4 , filtered and concentrated to give an oily product (13 g, crude). 1 H NMR(400MHz,DMSO-d6)δ ppm 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).

[0209] Intermediate 29C: (2-bromo-4-fluoro-phenyl)propanoate [ka] 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 solution was slowly treated with triethylamine (1.9 kg, 18.8 mol). The reaction was cooled and propionic acid chloride (1.6 kg, 17.3 mol) was added dropwise while maintaining the temperature between 0 and 10°C. Once the addition was complete, the reaction was stirred at room temperature for 15 hours. The reaction was carefully diluted with water (15 L) keeping the temperature of the reaction below 30° C. and then stirred at room temperature for 30 minutes. The organic phase was separated, washed with water (10L), collected and treated with MgSO 4 , filtered and concentrated under reduced pressure at 45° C. to give the title compound (3.6 kg, 93%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.15(t,3H),2.65(dd,2H),7.30(m,2H),7.75(m,1H).

[0210] Intermediate 58A: 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide [ka] 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 mixed with a solution of 2-methylpropan-2-amine (3.90 g, 53.28 mmol) was added dropwise over 2 minutes. After addition, the reaction was allowed to stir 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 (3 x 50 mL), collected, and 2 S.O. 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% to 25% EtOAc in petroleum ether to give the title compound (1.2 g, 69%) as a white solid. MS ES+m / z 327,329[M+H] + .

[0211] Intermediate 59A: 2-Benzylsulfanyl-3-bromo-6-chloro-pyridine [ka] A solution of phenylmethanethiol (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 (1.5g, 7.10mmol). 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 in heptane to give the title compound (2.10g, 94%). MS ES+m / z 314[M+H] + .

[0212] Intermediate 60A: 8-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydroisoquinolin-1-one [ka] 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. Once cooled, 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. Furthermore, 152 mg of 4-methoxybenzyl chloride was added, and the mixture was stirred at 50°C for 23 hours. The reaction was partitioned 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 aqueous sodium chloride solution, and dry packed onto Celite. Purification by silica gel chromatography eluting with 0% to 40% EtOAc in heptane gave the title compound (355 mg, >100%) as a colorless oil containing some 4-methoxybenzyl chloride. MS ES+m / z 347[M+H] + .

[0213] Intermediate 61A: 8-bromo-2-(2-trimethylsilylethoxymethyl)isoquinolin-1-one [ka] A 20 mL vial was charged with 8-bromo-2H-isoquinolin-1-one (0.34 g, 1.53 mmol) and DMF (5 mL) and treated with sodium hydride (73.5 mg, 60%, 1.84 mmol) at room temperature. Stir 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 further treated with 0.51 g of 2-(trimethylsilyl)ethoxymethyl chloride and the reaction was stirred at 50° C. over the weekend. The reaction was partitioned 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 aqueous sodium chloride solution, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 40% EtOAc in heptane to give the title compound (231 mg, 432%) as a opaque oil. MS ES+m / z 354 / 356[M+H] + .

[0214] Intermediate 62A: (2-bromo-4-methyl-phenyl)acetate [ka] A mixture of 2-bromo-4-methyl-phenol (300g, 1.6mol) and pyridine (152g, 1.92mol) in DCM (2.4L) at 0°C was treated with acetyl chloride and stirred at 25°C for 16 hours. The mixture was diluted with water (1500 mL), the pH was adjusted to 5 with HCl (2M aqueous solution) and extracted with DCM (3 x 500 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 x 250 mL) and 2 S.O. 4 , filtered and concentrated to give an oily product (400 g, crude). 1 H NMR(400MHz, CDCl 3 )δ ppm 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).

[0215] Intermediate 63A: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethenone [ka] (2-Bromo-4-methyl-phenyl)acetate (50g, 218mmol) and AlCl 3 (102g, 764mmol) was degassed and N 2 The mixture was purged three times with water and stirred at 140°C for 1 hour. After cooling to room temperature, the reaction was diluted with DCM (30 mL) and added dropwise to 150 mL of water at 0°C. The mixture was filtered and the aqueous phase was extracted with DCM (2 x 150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution and anhydrous Na 2 S.O. 4 dried, filtered and concentrated. The residue was triturated with petroleum ether (2 x 150 mL) to give the product as a solid (30 g, 52%). 1 H NMR(400MHz, CDCl 3 )δ ppm 2.30(s,3H),2.68(s,3H),7.73(s,1H),7.33(s,1H),12.64(s,1 H).

[0216] Intermediate 2A: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one [ka] (2-Bromo-4-methyl-phenyl)propanoate (12.5g, 51.4mmol) and AlCl 3 (24.0g, 180mmol) was stirred at 140°C for 1 hour. Once 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 aqueous sodium chloride (2 x 200 mL) and anhydrous Na 2 S.O. 4 and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). 1 H NMR(400MHz,DMSO-d6)δ ppm 1.10(t,J=7.2Hz,3H),2.28(s,3H),3.15(q,J=7.2Hz,2H),7.66-7.73(m,1H) ,7.77-7.83(m,1H),12.66(s,1H).

[0217] Intermediate 30C: 1-(3-bromo-5-fluoro-2-hydroxy-phenyl)propan-1-one [ka] (2-Bromo-4-fluoro-phenyl)propanoate (3.5 kg, 14.2 mol) in the reactor was heated to 75-85°C and mixed with AlCl in several portions. 3 (1.0 kg, 7.4 mol) during which the internal temperature was raised to 100-110 °C. Heat the reaction to 100-120 °C and add more AlCl 3 (1.1.kg, 8.2mol). 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 (20L) and 1M aqueous HCl (20L) at 0-10°C. The reaction was stirred at 0-15°C for 1 hour. The organic layer was separated and washed with water (2x10L). MgSO organic phase 4 and concentrated under reduced pressure to obtain the crude product. The crude material was slurried with n-heptane (7 L) at room temperature for 6 hours, then filtered and dried at 45° C. for 12 hours to give the title compound (2.0 kg, 57%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.15(t,3H),3.20(m,2H),7.95(m,2H),12.50(s,1H).

[0218] Intermediate 31C: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one [ka] Trifluoromethanesulfonic acid (237 g, 1.58 mol) was cooled to below -5°C and treated with (2-bromo-4-methyl-phenyl)propanoate (80 g, 329 mmol) while maintaining the temperature between -5°C and -20°C. The dropwise treatment was carried out over 1 hour. Once 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 (5V), stirred for 30 minutes and the solids were removed by filtration. The cake was rinsed with water (2V), slurried in water (5V) for 30 minutes, filtered and dried to give the title compound (72.2g, 90%) as an off-white solid. ES / MS m / z 241 / 243(M-H).

[0219] Intermediate 64A: 1-[2-methoxy-5-(trifluoromethyl)phenyl]propan-1-one [ka] A 10 L reactor was charged with trifluoromethanesulfonic acid (5.54 kg, 36.90 mol) and cooled to -10°C to -20°C. Once cooled, propionic acid chloride (2.05 kg, 22.14 mol) was slowly added and stirred for 0.5 hour. 1-Methoxy-4-(trifluoromethyl)benzene (1.30 kg, 7.38 mol) was slowly added for 2 hours while keeping the temperature between -10°C and -20°C. The resulting solution was stirred for 20 hours. The solution was slowly added to ice-cold water (13 L) while keeping the temperature between 0°C and 10°C, and then stirred for 1 hour. The suspension was then filtered and the solids were rinsed with ice-cold water (7.5L). The cake was dissolved in MTBE (3.9L) and the aqueous phase was discarded. The organic phase was concentrated to give the title compound (1.65 kg, 96%) as an off-white solid. 1 H NMR(400MHz, CDCl 3 )δ ppm 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=2.16 Hz).

[0220] Intermediate 65A: 1-[2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one [ka] A mixture of NaOH (413.4g, 10.34mol) in DMF (8.25L) was treated with 1-dodecanethiol (2.09kg, 10.34mol) 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 that temperature for 1.5 h. did. The mixture was diluted with water (24L) and extracted with MTBE (16L). The pH of the aqueous phase was adjusted to 2-3 with an aqueous HCl solution (2N) and extracted with MTBE (16L). 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, CDCl 3 )δ ppm 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).

[0221] Intermediate 66A: 1-[3-bromo-2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one [ka] A mixture of 1-[2-hydroxy-5-(trifluoromethyl)phenyl]propan-1-one (1.20 kg, 5.50 mol) in DMF (4.8 L) was mixed with N-bromosuccinimide (1.08 kg, 6.05 mol). The mixture was stirred at 20°C to 30°C for 5 hours. The reactants were mixed with water (14.4L) and saturated Na 2 S.O. 3 It was diluted with aqueous solution (3.6L) and stirred at 25°C for 1 hour. The mixture was filtered and the cake was slurried in water (6 L) at 20°C to 25°C for 0.5 h, filtered, rinsed with water (3.6 L) and dried at 50°C to give the title compound (1.38 kg) as an off-white solid. , 84%). 1 H NMR(400MHz,DMSO-d6)δ ppm 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).

[0222] Intermediate 32C: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)propane-1,3-dione [ka] 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 internally Treated with lithium bis(trimethylsilyl)amide (5.4 L, 1M in THF, 5.4 mol) over 14 hours while maintaining the temperature below -60°C. After the addition was completed, the mixture was stirred at -60 to -75°C for 30 minutes. The reaction was cooled to -70--75°C and treated in portions with pyridine-3-carbonyl chloride hydrochloride (285.6g, 1.60mol) while maintaining the internal temperature below -60°C. After addition, the reaction was stirred at room temperature for 15 hours. The reaction was cooled to 0~-10°C and quenched with AcOH / water (3V / 3V) until pH reached 5~6. The reaction was concentrated in vacuo and the title compound (600g, 100%) was removed by filtration, rinsed with water, and air dried. ES / MS m / z 348 / 350(M+H).

[0223] Intermediate 67A: 8-bromo-4-hydroxy-6-methyl-chromene-2-thione [ka] 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, 1M) at -50 °C for 30 min. , warmed to -5°C to 0°C, and stirred for 1 hour. Cool the reaction to -20 °C and add CS 2 (64.8g, 851mmol) dropwise over 1 hour, warmed to 25°C and stirred for a further 16 hours. H reaction 2 S.O. 4 (800 mL, 15%) at −50° C. for 1 h, allowed to warm to room temperature, and extracted with EtOAc (2×1 L). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1 L) and diluted with anhydrous Na 2 S.O. 4 dried, filtered and concentrated. The residue was triturated with EtOAc (0.5 L) to give a solid product (crude 210 g, 64%, 76% pure).

[0224] Intermediate 33C: 8-bromo-6-fluoro-4-hydroxy-3-methyl-chromene-2-thione [ka] Potassium tert-butoxide (3.2 kg, 28.3 mol) and THF (30 L) were added to a 50 L reactor and the mixture was stirred for 15 minutes to give a pale yellow solution. 8-Bromo-6-fluoro-4-hydroxy-3-methyl-chromene-2-thione (2.0 kg, 8.1 mol) was added to the reactor in several portions keeping the temperature between 0 and 15 °C. Carbon disulfide (740g, 9.7mol) was added dropwise keeping the temperature below 30°C. Once the addition was complete, the reaction was stirred at 0-25°C for 12 hours. The reaction mixture was poured directly into 15% aqueous acetic acid (5 L) and stirred at room temperature for 30 minutes. The mixture was filtered and the filter cake was washed with MTBE (2L). The filtrate was washed with water (2 x 5L) and saturated aqueous NaCl (5L). Collect the organic phase and add MgSO 4 The crude product was obtained by drying, filtering, and concentrating in vacuo. This material was slurried in heptane (5L), stirred for 6 hours, filtered and dried at 45° C. for 12 hours to give the title compound (2.8 kg, 120%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 2.10(s,3H),7.65(m,1H),7.90(m,1H).

[0225] The following compounds in Table 4 were made in a similar manner to that described for 8-bromo-6-fluoro-4-hydroxy-3-methyl-chromene-2-thione. This compound was purified using various methods that would be apparent to those skilled in the art. [Table 4]

[0226] Intermediate 3A: (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one [ka] 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), and AcOH (105.23 g) in EtOH (1600 mL). , 1.75 mol) and piperidine (172.33 g, 2.02 mol) was stirred at 70°C for 16 hours. The resulting dark solution was poured into water (3L), filtered and the solid was dissolved in 6L of DCM. Organic solution with anhydrous Na 2 S.O. 4 Dried, filtered and concentrated to give a dark gummy product. MS ES+m / z 331,333[M+H] + .

[0227] Intermediate 68A: 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] 8-bromo-4-hydroxy-6-methyl-chromene-2-thione (20.0 g, 73.8 mmol) in acetone (200 mL), EtI (46 g, 295 mmol), and K 2 C.O. 3 (12.2g, 88.5mmol) was stirred at 60°C for 3 hours. Once the reaction was 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 in petroleum ether to give a gummy product. 1 H NMR(400MHz, CDCl 3 )δ ppm 1.51(t,J=7.2Hz,3H),2.45(s,3H),3.22(q,J=7.2Hz,2H),6.32(s,1H),7.70(s,1H),7.93( s,1H).

[0228] The following compounds in Table 5 were made in a similar manner to that described for 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one. This compound was purified using various methods that would be apparent to those skilled in the art. [Table 5]

[0229] Intermediate 36C: 8-bromo-2-ethylsulfanyl-6-fluoro-chromen-4-one [ka] The crude THF solution from the synthesis of 8-bromo-6-fluoro-4-hydroxy-chromene-2-thione (3.4 kg, 30 mol) was treated with EtI (5.4 kg, 34.4 mol) at 20-25 °C. The resulting solution was stirred at 60-65°C for 12 hours. The reaction was cooled to room temperature and the solids were removed by filtration. The cake was washed with MTBE (2L). The filtrates were combined and washed with water (2 x 6L) and 10% aqueous NaCl. The organic phase was collected and concentrated under reduced pressure to obtain the 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%) as a yellow solid was taken out. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.40(t,3H),3.26(dd,2H),6.47(s,1H),7.69(m,1H),8.15(m,1H).

[0230] Intermediate 69A: 8-bromo-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one [ka] 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 added to lithium tert-butoxide (1.36 kg). , 16.97 mol) and stirred for 0.5 h. The reaction was then treated with carbon disulfide (355.2g, 4.67mol) in one portion and the mixture was stirred at 15°C to 25°C for 16 hours. 15%H to reactants 2 S.O. 4 An aqueous solution (12.6 L) was added at 0°C to 10°C. The organic layer was removed and the aqueous layer was extracted with 2-methyltetrahydrofuran (12.6L). The organic layers were combined, washed with saturated aqueous sodium chloride (6.3 L), and concentrated to give a yellow solid crude material. The solid was slurried with DCM (3.6L) for 1 hour and filtered. The cake was dried under vacuum at 40°C to obtain 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one as a yellow solid.

[0231] A 10L reactor was charged with 8-bromo-3-methyl-2-sulfanyl-6-(trifluoromethyl)chromen-4-one (from above), cesium carbonate (586.6g, 1.8mol), and acetone (6.3L). ) was charged. The reaction mixture was slowly treated with EtI (421.1 g, 2.7 mol) at 15°C to 25°C, and then stirred for 2 hours. The reaction was filtered and rinsed with acetone (3.78L). The filtrate was concentrated to give the title compound (650 g, 42%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 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).

[0232] Intermediate 4A: 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one [ka] (E)-1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) in DMSO (1200 mL) ) and I 2 (21.76g, 85.75mmol) was stirred at 140°C for 2 hours to obtain a dark brown solution. Cool to room temperature, pour the reaction into 3 L of water, filter, dissolve the solid product in DCM (4 L) and add anhydrous Na 2 S.O. 4 , 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 pale yellow solid (195 g, 69%). MS ES+m / z 329,331[M+H] + .

[0233] Intermediate 37C: 8-bromo-3,6-dimethyl-2-(3-pyridyl)chromen-4-one [ka] Crude 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)propane-1,3-dione (600 g, 1.23 mol) was dissolved in HCl (0.15 V). and AcOH (3V), and stirred at 90 to 100°C for 2 hours. The reaction was cooled to room temperature and basified to pH 8-9 with 5M aqueous NaOH while keeping the temperature below 50°C. The resulting precipitate was collected by filtration and rinsed with water (2x2V). After slurrying the solid with MTBE (5V), stirring at room temperature for 40 hours and drying at 50°C, the title compound was collected by filtration (368g, 90%). ES / MS m / z( 79 Br / 81 Br)330 / 332(M+H).

[0234] Intermediate 70A: 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] 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) in 1,4-dioxane (90 mL) ) and Pd(PPh 3 ) 2 Cl 2 (2.11g, 3.01mmol) was stirred at 95°C for 16 hours. HCl (30 mL, 1M) was added to the mixture and stirred at 50 °C for 0.5 h. Once cooled to room temperature, the mixture was treated with saturated aqueous KF (100 mL), stirred for 0.5 h, and then 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 in petroleum ether to give the product as a solid (5.8 g, 60%). MS ES+m / z 263[M+H] + .

[0235] Intermediate 5A: 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol) in dioxane (1600 mL) and bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol) ) and tributyl(1-ethoxyvinyl)stannane (256.72g, 710.84mmol, 239.92mL) was 2After stirring at 95° C. for 16 hours, a dark brown solution was obtained. After cooling to room temperature, the reaction was treated with 1M aqueous HCl (100 mL) and stirred at 20° C. for 30 min. The mixture was quenched with saturated aqueous KF (2000 mL), stirred for 30 minutes, and filtered. The filter cake was washed with 10% MeOH in DCM (5 x 5000 mL). The combined extracts were diluted with anhydrous Na 2 S.O. 4 , filtered and concentrated to give 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 yield a pale yellow solid. (180 g, 96%, purity 92%) was obtained. MS ES+m / z 293[M+H] + .

[0236] Intermediate 71A: 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one [ka] 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 mixed with tributyl (1- ethoxyvinyl)stannane (1.06 kg, 2.94 mol). After emptying the reaction and replacing the air with nitrogen three times, bis(triphenylphosphine)palladium(II) dichloride (74.93 g, 106.8 mmol) was added in one portion. After emptying the reaction and replacing the air with nitrogen three times, the reaction was heated to 85°C to 95°C for 14 hours. After the reaction was cooled to 50° C., aqueous HCl (4.9 L, 2M) was added and the reaction was stirred for 2 hours. After cooling the reaction to 20°C to 25°C, it was extracted with EtOAc (14.7L). The organic phase was quenched with saturated aqueous KF (4.9L), stirred for 1 hour and filtered. The organic phase was washed with a saturated aqueous sodium chloride solution (4.9 L), and the organic phase was concentrated under reduced pressure to 4.9 L. IPA (9.8L) was added and the mixture was concentrated two more times to 4.9L. IPA (4.9L) 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 solids were rinsed with IPA (1.96 L). The above crystallization process was repeated once more and the combined solids were dried in vacuo at 40° C. to give the title compound (455.7 g, 52%) as an off-white solid. MS ES+m / z 331[M+H] + .

[0237] The following compounds in Table 6 were made in a similar manner to that described for 8-acetyl-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 6]

[0238] Intermediate 72A: 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one [ka] 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (8.30 g, 31.6 mmol) in DCM (30 mL) and MeOH (30 mL) was dissolved in NaBH 4 (1.32g, 34.8mmol) in portions at 0°C and stirred at 15°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with DCM (2x100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (80 mL) and diluted with anhydrous Na 2 S.O. 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 4% MeOH in DCM to give the product as a solid (6.0 g, 60%). MS ES+m / z 265[M+H] + .

[0239] The following compounds in Table 7 were made in a similar manner to that described for 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 7]

[0240] Intermediate 43C: 2-ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-3-methyl-6-(trifluoromethyl)chromen-4-one [ka] 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 nitrogen atmosphere. did. Formic acid (58.5g, 1.27mol) was added slowly followed by triethylamine (86.4g, 0.85mol) dropwise while maintaining the temperature below 10°C. Noyori catalyst (CAS:74813-81-1, 2.7g, 4.24mmol) 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). Collect the organic layer and MgSO 4 , filtered and concentrated in vacuo to give the title compound (146 g, 100%, 99% purity) as a brown solid in an enantiomeric ratio of 93:7. ES / MS m / z 333(M+H).

[0241] Intermediate 73A: 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] A mixture of 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one (5.50 g, 20.8 mmol) in DCM (50 mL) was mixed with PBr 3 (16.9 g, 62.4 mmol) was added dropwise at 0°C, and then stirred at 30°C for 4 hours. Quench the reaction with water (20 mL) at 0 °C and adjust the pH to saturated NaHCO 3 Adjusted to 8 with an aqueous solution. The mixture was extracted with DCM (2 x 80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution and anhydrous Na 2 S.O. 4 , filtered and concentrated to give the product as an oil (4.7g, 61%). MS ES+m / z 329[M+2+H] + .

[0242] The following compounds in Table 8 were made in a similar manner to that described for 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 8]

[0243] Intermediate 74A: (NE,R)-N-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-fulfinamide [ka] 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (9.49 g, 36.2 mmol) and (R)-2-methylpropane-2-fulfinamide (8.77 g, 72.4mmol) of Ti(i-PrO) 4 (41.1g, 145mmol) and stirred at 75°C for 16 hours. The reactants were further combined with (R)-2-methylpropane-2-fulfinamide (6.58 g, 54.3 mmol) and Ti(i-PrO) 4 (30.9g, 109mmol) and stirred for a further 16 hours at 75°C. The mixture was quenched with saturated aqueous sodium chloride (200 mL), stirred for 0.5 h, 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 (2 x 200 mL) and anhydrous Na 2 S.O. 4 Dried, filtered and concentrated to give a solid product (13 g, crude). MS ES+m / z 366[M+H] + .

[0244] Intermediate 6A: (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-fulfinamide [ka] 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-fulfinamide (149.26 g, Tetraisopropoxytitanium (700.01 g, 2.46 mol, 726.90 mL) was added to the mixture with 1.23 mol). 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 aqueous sodium chloride (2000 mL), stirred for 30 minutes, and filtered. The filter cake was washed with EtOAc (4000 mL). After separating the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were diluted with anhydrous Na 2 S.O. 4 , filtered and concentrated to give 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] + .

[0245] The following compounds in Table 9 were converted into (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2 -Made in a similar manner to that described for flufinamide. [Table 9]

[0246] Intermediate 76A: (R)-N-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2-fulfin Amide [ka] (NE,R)-N-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane in DCM (100 mL) and MeOH (100 mL) A mixture of -2-flufinamide (12.0 g, 32.8 mmol) was mixed with AcOH (15.8 g, 262 mmol) and NaBH 3 Treated with CN (6.19g, 98.5mmol) at -10°C and stirred at 25°C for 16 hours. NH mixture 3 ·H 2 Quenched with O (250 mL) and extracted with DCM (3 x 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (300 mL) and diluted with anhydrous Na 2 S.O. 4 After drying, filtering and concentrating, a solid product (11 g, isomer ratio: 3 / 2, crude) was obtained. MS ES+m / z 368[M+H] + .

[0247] Intermediate 7A: (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-fur finamide [ka] (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-fur in MeOH (1600 mL) Finamide (186g, 470.27mmol) and CeCl 3 . 7H 2 NaBH 4 (26.69g, 705.41mmol) was added at 15°C. The mixture was stirred at 15° C. for 1 hour to obtain a dark suspension. Saturate the reactants with aqueous NH 4 Quenched with Cl (1500 mL) at 15°C. Extract with DCM (2 x 1500 mL), wash the combined organic phases with saturated aqueous sodium chloride solution (1500 mL), and remove the organic phase with anhydrous NaCl. 2 S.O. 4 , filtered and concentrated to give the product as a yellow solid (180 g, 96%). MS ES+m / z 398[M+H] + .

[0248] Intermediate 47C: (R)-N-[(1R)-1-deuterio-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane -2-sulfinamide [ka] (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane- in tetradeuteromethanol (10 mL) A solution of 2-sulfinamide (600 mg, 1.52 mmol) 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 allowed to stir at -78°C. After 1 h, the reaction was concentrated in vacuo and the residue was chromatographed on silica gel eluting with 0% to 100% EtOAc in heptane (containing 25% EtOH) followed by 10 mM NH 4 HCO 3 Purification by reverse phase chromatography on C18 eluting with 0% to 100% ACN in aqueous solution (containing 5% MeOH) gave the title compound (530 mg, 88%). ES / MS m / z 399(M+H).

[0249] Intermediate 77A: 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane- in EtOAc (40 mL) A mixture of 2-flufinamide (6.00 g, 16.3 mmol) was treated with HCl (82 mL, 4M in EtOAc) and stirred at 25° C. for 16 h. The mixture was concentrated, diluted with water (100 mL) and washed with EtOAc (100 mL). The pH of the aqueous phase is NH 3 ·H 2 Adjusted to 8 with O (25%) and extracted with DCM (3 x 100 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL) and diluted with anhydrous Na 2 S.O. 4 , filtered and concentrated to give an oily product (2.4 g, crude). MS ES+m / z 264[M+H] + .

[0250] Intermediate 48C: 8-[(1R)-1-amino-1-deuterio-ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] (R)-N-[(1R)-1-deuterio-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl in DCM (8 mL) A solution of -propane-2-sulfinamide (530 mg, 1.33 mmol) 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. Dilute the reaction with DCM and saturated NaHCO 3 Washed with aqueous solution. The aqueous layer was back extracted with 25% IPA in chloroform. Combine the organic layers and add MgSO 4 Dry, filter, and concentrate in vacuo to give the title compound, which was used without purification. ES / MS m / z 295(M+H).

[0251] Intermediate 8A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2 in MeOH (1500 mL) A mixture of -flufinamide (180 g, 452.80 mmol) was treated with HCl / MeOH (4 M, 300 mL) and the mixture was stirred at 15° C. for 1 h to give a white suspension. The reaction was concentrated, the residue was poured into water (1000 mL) and DCM (2000 mL), and the pH was adjusted to H 2 NH in O 3 (25%) and extracted with DCM (2 x 1000 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (1000 mL) and diluted with anhydrous Na 2 S.O. 4 , filtered and concentrated to give a residue. The residue was triturated with DCM (200 mL) to give the product as a white solid (122 g, 89%). MS ES+m / z 294[M+H] + .

[0252] Intermediate 9A: (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane-2- flufinamide [ka] A mixture of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (50 g, 0.18 mol) in 500 mL of toluene was mixed with (R)-2-methylpropane-2-fulfinamide ( 32.7 g, 0.27 mol) and titanium ethoxide (82.1 g, 0.36 mol) at once. The reaction was heated at 80° C. for 24 hours, then cooled to room temperature.

[0253] (NE,R)-N-[1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethylidene]-2-methyl-propane-2-fulfinamide (0.18mol ) was cooled to -10°C to 0°C and treated portionwise with sodium borohydride (20.4g, 0.54mmol) while keeping the internal temperature below 0°C. After stirring for 1 h at -10 °C and 0 °C, the reaction was dissolved in saturated aqueous NH 4 Quenched with Cl. The resulting white slurry was filtered through diatomaceous earth and the solids were washed with THF. The filtrate was washed with saturated aqueous sodium chloride solution 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] + .

[0254] The following compounds in Table 10 were converted into (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl- Made in a similar manner to that described for propane-2-flufinamide. [Table 10]

[0255] Intermediate 11A: 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one [ka] (R)-N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]-2-methyl-propane- in THF (200 mL) A solution of 2-flufinamide (20 g, 52.4 mmol) 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 9-10 with 1M NaOH and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO 4 , filtered and concentrated to give the product as a white solid (12.6 g, 87%). MS ES+m / z 278[M+H] + .

[0256] The following compounds in Table 11 were made in a similar manner to that described for 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one. [Table 11]

[0257] Intermediate 13A: tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate [ka] 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 bicarbonate (3.0 g, 14 mmol) and stirred overnight at room temperature. The reaction was concentrated and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the product (2.5g, 73%). MS ES+m / z 378[M+H] + .

[0258] The following compounds in Table 12 are described in the format for tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate. It was made in a similar manner. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 12]

[0259] Intermediate 49C: tert-butyl N-[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate [ka] Tert-butyl N-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]carbamate (5.00 g, 13.8 mmol) was dried in THF (27.5 mL). and cooled to 0°C. Once cooled, the reaction was treated dropwise with 2,2,6,6-tetramethylpiperidinyl zinc chloride lithium chloride complex (41.3 mL, 41.3 mmol, 1M 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). Combine the organic layers and add saturated Na 2 S 2 O 3 Wash with aqueous solution and Na 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (8.33g, 124%) as a brown foam. ES / MS m / z 490(M+H).

[0260] Intermediate 50C: tert-butyl N-[(1R)-1-(2-ethylsulfanyl-6-methyl-3-oxazol-4-yl-4-oxo-chromen-8-yl)ethyl]carbamate [ka] 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 oxazole- 4-ylboronic acid (0.46g, 4.09mmol) was transferred to a test tube. 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.33 g, 0.51 mmol) and cesium carbonate (2.0 g, 6.13 mmol) were dissolved in 9:1 1,4-dioxane / water (4.1 mL). ). The reaction was sparged with argon gas for 5 minutes and then stirred at 65° C. for 2 hours. After cooling to room temperature, the reaction was filtered through diatomaceous earth and the solids were washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0% to 40% EtOAc in heptane to give the title compound (0.29g, 33%). ES / MS m / z 431(M+H).

[0261] Intermediate 80A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one [ka] A 20 mL vial was prepared with 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 (15mL). The reaction was degassed with argon, the vial was capped, and stirred at 55° C. for 16 hours. The reaction mixture was packed onto Celite and diluted with 10 mM NH containing 5% MeOH. 4 HCO 3 Purification by reverse phase C18 flash chromatography eluting with 10% to 100% ACN in aqueous solution gave the title compound (0.23g, 60%). MS ES+m / z 348[M+H] + .

[0262] The following compounds in Table 13 were prepared in the same manner as described for 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one. It was made in the style of Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9]

[0263] Intermediate 86C: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]chromen-4-one [ka] A vial was prepared 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 (1.35g, 5.41mmol), tetrakis(triphenylphosphine)palladium(0) (0.52g, 0.45 mmol), copper(I) 3-methylsalicylate (0.58 g, 2.70 mmol), and EtOH (8 mL). Nitrogen was bubbled through the mixture for 2 minutes, the vial was sealed, and the reaction was stirred at 60° C. for 16 hours. The reactants were mixed with the same amount of 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, tetrakis(triphenylphosphine) ) Palladium(0), and copper(I) 3-methylsalicylate again and nitrogen was bubbled through the reaction for 5 minutes. The reaction was heated at 60°C for 16 hours. The reaction was cooled and filtered through diatomaceous earth, the solids were washed with DCM / MeOH, and the filtrate was concentrated under reduced pressure. Residue, 10mM NH 4 HCO 3 Purification by reverse phase chromatography on C18 eluting with 10% to 65% ACN in aqueous solution gave the title compound (0.31 g, 51%). ES / MS m / z 340(M+H).

[0264] 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]chromen-4-one It was made in a similar manner to that described. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 14-1] [Table 14-2]

[0265] Intermediate 102A: tert-butyl N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(2-pyridyl)chromen-8-yl]ethyl]carbamate [ka] tert-Butyl N-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]carbamate (0.50g, 1.32mmol), thiophene-2- Copper(I) 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-ylboron The acid (0.37g, 3.05mmol) was combined in 8mL of EtOH and degassed with argon for 5 minutes. The reaction was allowed to stir at 35°C for 72 hours. The reaction was recharged with 300 mg of total reagents, degassed, and allowed to stir at 35° C. overnight. The reaction was filtered and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.50g, 96%). MS ES-m / z 395[M-H] - .

[0266] Intermediate 103A: 8-[(1R)-1-aminoethyl]-2-(2,6-difluorophenyl)-3,6-dimethyl-chromen-4-one [ka] 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.50g, 1.80mmol), 2,6-difluorobenzene-1-idezinc bromide (II) (0.93g, 3.61mmol, 0.5M), copper(I) thiophene-2-carboxylate (0.51g, 2.70mmol), and methanesulfonate {[4-(N,N-dimethylamino)phenyl] Di-t-butylphosphino)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.34 g, 0.54 mmol) was combined in THF (5 mL) and degassed for 10 min. did. 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 in DCM, then 0% to 20% MeOH in DCM. The desired fractions were then purified again by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) in water (containing 0.1% formic acid). The product was then mixed with 10mM NH 4 HCO 3 Purification by reverse phase chromatography eluting with 10% to 100% ACN in (containing 5% MeOH) gave the title compound (0.20 g, 34%). MS ES+m / z 330[M+H] + .

[0267] Intermediate 104A: tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate [ka] 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) , 20.0 mL, 115 mmol) were combined with DMF (150 mL) in a 500 mL round bottom flask and heated at 80 °C. After cooling to room temperature, the reaction was partially concentrated to 100 mL, poured into 1.1 L of water, and extracted with EtOAc (2 x 350 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (400 mL). The combined aqueous layers were re-extracted with fresh EtOAc. Combine the organic layers and add anhydrous Na 2 S.O. 4 Dry, filter, and concentrate to give a thick oil. The residue was purified by silica gel chromatography using EtOAc (0% to 10%) in DCM to give an off-white foam. Trituration with heptane / DCM and washing with heptane gave the product as a white solid (27.1 g, 81%). MS ES+m / z 440[M+H] + .

[0268] Intermediate 94C: tert-butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate [ka] 8-(1-bromoethyl)-2-ethylsulfanyl-6-fluoro-chromen-4-one (66.0 g, 200 mmol) in CHCl 3 (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 mixture was allowed to cool 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 give the title compound (43 g, 49%). 1 HNMR(400MHz, CDCl 3 )δ ppm 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,1H),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).

[0269] Intermediate 95C: 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid [ka] 8-[(1R)-1-bromoethyl]-2-ethylsulfanyl-3-methyl-6-(trifluoromethyl)chromen-4-one (223g, 0.56mol) and 3-amino in DMF (1.8L) A solution of -6-chloro-pyridine-2-carboxylic acid (146g, 0.85mol) was stirred at 85°C for 3 days. The reaction was cooled to room temperature and slowly added to water (6.7L). The resulting precipitate was collected by filtration and the solid was slurried in water (3.3L), filtered and dried in an oven to give the title compound (232g, 84%, 73% purity). ES / MS m / z 487(M+H).

[0270] Intermediate 96C: 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid [ka] A solution of 8-(1-bromoethyl)-2-ethylsulfanyl-6-fluoro-3-methyl-chromen-4-one (100 g, 290 mmol) in DMF (800 mL) Treated with 2-carboxylic acid (50g, 290mmol). The reaction mixture was stirred at 80-90°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 30 minutes of sonication, 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 pale yellow solid. 1 HNMR(400MHz, CDCl 3 )δ ppm 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).

[0271] Intermediate 97C: tert-butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate [ka] 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid (79 g) in THF (800 mL) , 181 mmol) 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 solids were washed with THF (2×100 mL). The filtrate was concentrated under reduced pressure and the residue was slurried in 200 mL of MTBE with sonication for 30 min to give the title compound (76.3 g, 86%) after filtration, washed with MTBE (100 mL), Dry. 1 HNMR(400MHz, CDCl 3 )δ ppm 1.47~1.51(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).

[0272] 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid Made in a similar manner to that described for tert-butyl. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 15]

[0273] 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-carboxylate [ka] 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylindazol-5-yl)chromen-4-one (100 mg, 0.29 mmol), 4-chloro-6-methyl 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).

[0274] The following compounds in Table 16 were converted into 4-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl] Made in a similar manner to that described for methyl amino]-6-methyl-2-oxo-1H-pyridine-3-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 16]

[0275] 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 [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (22.04 g, 50.14 mmol) in 100% with 0.2% DMEA The isomeric components were separated using a Chiralcel OJ column (8 x 34 cm, 20 microns) eluted with MeOH to give isomer 1 (11.3 g wet) and isomer 2 (12.9 g wet). MS ES+m / z 440[M+H] + .

[0276] Intermediate 101C and Intermediate 102C: 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylic acid tert-butyl, isomer 1 and isomer 2 [ka] tert-Butyl 6-chloro-3-[1-(2-ethylsulfanyl-6-fluoro-3-methyl-4-oxo-chromen-8-yl)ethylamino]pyridine-2-carboxylate (76.3g, 155mmol ), CO 2 45% i-PrOH (0.1% NH 4 The component isomers were separated using a ChiralPak IC column (250 x 50 mm, 10 mm) eluted with OH) to give crude isomer 1 (38.40 g) and crude isomer 2 (27 g). Isomer 1 was repurified by preparative HPLC using a Sharpsil-T C18 column (50 x 250 mm, 8 microns) eluting with 85% to 98% ACN in water (containing 0.05% TFA) to give an off-white color. Solid isomer 1 (28.60 g, 37%) was obtained. ES / MS m / z 493(M+H).

[0277] 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 [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-fluoro-4-oxo-chromen-8-yl)ethylamino]benzoate (48.3 g, 109 mmol) was purified by chiral SFC [ChiralPak IG, 250 × 50 mm , 10mm; CO 2 The component isomers were separated using [MeOH] to give isomer 1 (22.4 g, 46%) and isomer 2 (19.0 g, 39%) as yellow solids. ES / MS m / z 466(M+H).

[0278] Intermediate 105C and Intermediate 106C: 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2 -tert-butyl carboxylate, isomer 1 and isomer 2 [ka] tert-butyl 6-chloro-3-[1-[2-ethylsulfanyl-3-methyl-4-oxo-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylate, Chiral SFC [WhelkO1-(R,R), 50×250mm, 10mm;CO 2 The component isomers were separated using 25% EtOH] to give isomer 1 (first elution; 67.7 g, 99% ee) and isomer 2 (68.0 g, 93.6% ee). ES / MS m / z 543(M+H).

[0279] Intermediate 107A: 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid tert-butyl [ka] A vial containing 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.0 g, 3.61 mmol), 3-bromo-6-chloropicolinic acid tert. -butyl (1.58g, 5.41mmol), tris(dibenzylideneacetone)dipalladium(0) (0.25g, 0.27mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.42g, 0.72 mmol), cesium carbonate (2.93 g, 9.01 mmol), and 12 mL of toluene. The suspension was purged with nitrogen gas 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 solids were washed with DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in hexanes to give the title compound (0.88 g, 50%) as a tan solid. MS ES- m / z 433[M+2H-tBu] + .

[0280] The following compounds in Table 17 were converted into 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine- Made in a similar manner to that described for tert-butyl 2-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8]

[0281] 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 [ka] A solution of 8-[(1R)-1-aminoethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (10 g, 36 mmol) in DMF (150 mL) was mixed 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′- Treated with bis(furan-2-ylmethyl)oxalamide (1.79g, 7mmol) at room temperature. The reaction was stirred at 100°C for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 17% EtOAc in heptane to give the title compound (12.3 g, 65%) as an off-white solid. ES / MS m / z 524(M+H).

[0282] Intermediate 140C: 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid tert-butyl [ka] 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2- in DCM (10 mL). A solution of tert-butyl carboxylate (1.0 g, 2.05 mmol) was cooled to 0° C. and treated in portions with mCPBA (0.50 g, 77%, 2.25 mmol). Once the addition was complete, the reaction was stirred at 0° C. for 1 hour. Dilute the reaction with DCM and saturated NaHCO 3 Washed with aqueous solution. The organic layer was removed and the aqueous layer was extracted with DCM. Combined organic layers with MgSO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to give the title compound (1.0 g, 97%) as a tan solid. ES / MS m / z 503(M-H).

[0283] The following compounds in Table 18 were converted into 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine- Made in a similar manner to that described for tert-butyl 2-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 18]

[0284] Intermediate 143C: 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid tert -butyl [ka] 6-chloro-3-[[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2- in DCM (30 mL). A solution of tert-butyl carboxylate (0.95 g, 1.87 mmol) and benzyl(triethyl)ammonium chloride (0.21 g, 0.94 mmol) 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) and allowed to stir for 30 minutes. Saturate the reactants with NaHCO 3 Quenched with aqueous solution and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, collected, and MgSO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc in heptane to give the title compound (0.42g, 49%) as a white foam. ES / MS m / z 407(MH- t Bu).

[0285] The following compounds from Table 19 were converted into 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2 -Made in a similar manner to that described for tert-butyl-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 19]

[0286] Intermediate 146C: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] tert-butyl chromen-8-yl]ethyl]amino]pyridine-2-carboxylate [ka] Add the dried vial to 6-chloro-3-[[(1R)-1-(2-chloro-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid. tert-Butyl (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 emptied and backfilled 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]pentanyl]zinc (220 mg, approximately 0.45 M in THF, 0.67 mmol) was added via syringe, the cooling bath was removed, and the temperature was kept at room temperature overnight. It was stirred with The reaction was cooled to 0 °C and treated 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 ]pentanyl]zinc (220 mg, 0.67 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 8 hours. Dilute the reaction with EtOAc and saturated NH 4 Washed with Cl aqueous solution. The organic layer was removed and the aqueous layer was re-extracted with EtOAc. Combine the organic layers and add Na 2 S.O. 4dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc in heptane to give the title compound (183.2 mg, 73%) as a brown foam. ES / MS m / z 561(M+H).

[0287] The following compounds in Table 20 were converted to 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1. It was made in a similar manner to that described for tert-butyl 1]pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 20]

[0288] Intermediate 152C: 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2- carbonitrile [ka] 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile in THF (50 mL) A solution of (3.10 g, 7.75 mmol) was purged with nitrogen gas and cooled to 0 °C. The reaction was treated dropwise with 2,2,6,6-tetramethylpiperidinyl zinc chloride lithium chloride complex solution (1M, 23.26 mL, 23.26 mmol). After stirring the reaction for 1 hour while slowly warming to room temperature, iodine (5.90 g, 23.26 mmol) was added and the reaction was stirred for an additional 30 minutes. Saturate the reactants with NH 4 Quenched with aqueous Cl, 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 in heptane to give the title compound (3.20 g, 75%) as a brown solid. ES / MS m / z 544(M+H).

[0289] Intermediate 153C: 6-chloro-3-[[(1R)-1-(3-chloro-2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2- tert-butyl carboxylate [ka] 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 in vacuo and purified by silica gel chromatography eluting with 10% to 100% EtOAc in heptane to give the title compound (580 mg, 90%) as a white solid. ES / MS m / z 453(M+H).

[0290] 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 [ka] 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) were combined in 1,4-dioxane (90 mL) and water (10 mL). . The reaction was stirred at 65°C for 1.5 hours. The reaction was cooled to room temperature, filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10% to 80% EtOAc in hexanes to give the title compound (3.1 g, 83%) as a white solid. ES / MS m / z 467(M+H).

[0291] Intermediate-155C: 2-ethylsulfanyl-8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-3,6-dimethyl-chromen-4-one [ka] 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (1.37g, 3.52mmol), (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) in 1,4-dioxane ( 12 mL) and water (3 mL). The reaction was sparged 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 in heptane to give the title compound (1.10 g, 70%) as a yellow foam. ES / MS m / z 449(M+H).

[0292] Intermediate 118A: 8-[(1R)-1-aminoethyl]-2-(2-fluorophenyl)-3,6-dimethyl-chromen-4-one [ka] tert-Butyl N-[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]carbamate (0.68 g , 1.65 mmol) 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 dissolved in 10mM NH containing 5% MeOH. 4 HCO 3 Purified by reverse phase C18 flash chromatography eluting with 0% to 100% ACN in aqueous solution. The product-containing fractions were pooled, washed with saturated aqueous sodium chloride solution, and washed with IPA / CHCl. 3 (1:3). Collect organic matter and MgSO 4 , filtered and concentrated to give the title compound (0.26 g, 51%) as a yellow foam. MS ES+m / z 312[M+H] + .

[0293] The following compounds from Table 21 were prepared in a manner similar to that described for 8-[(1R)-1-aminoethyl]-2-(2-fluorophenyl)-3,6-dimethyl-chromen-4-one. Created. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4]

[0294] Intermediate 128A: 8-[(1R)-1-aminoethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one [ka] tert-butyl N-[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethyl]carbamate ( A solution of 100 mg, 0.26 mmol) was treated with HCl (4M 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 dissolved in 10mM NH 4 HCO 3 Purification by reverse phase chromatography eluting with 10% to 100% ACN (containing 5% MeOH) in aqueous solution gave the title compound (54 mg, 69%) as a white solid. MS ES+m / z 284[M+H] + .

[0295] The following compounds in Table 22 were prepared in a manner similar to that described for 8-[(1R)-1-aminoethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one. It was made with Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 22]

[0296] Intermediate 14A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid [ka] 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30g, 102.3mmol), 2-iodobenzoic acid (25.36g, 102.26mmol), A mixture of 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. 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30g, 102.3mmol), 2-iodobenzoic acid (25.36g, 102.26mmol), A mixture of 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 and the pH was adjusted to ~3 with 2M aqueous HCl, DCM (1 L) and water (500 mL), filtered and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride solution (3 x 1 L), and Na 2 S.O. 4 and concentrated. The residue was purified by silica gel chromatography (5 to 50% EtOAc in 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] + .

[0297] Intermediate 129A: N-tert-butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl] Amino]pyridine-2-sulfonamide [ka] 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (0.60 g, 2.04 mmol) and 3-bromo-N- in 6 mL of DMSO. A mixture of tert-butyl-6-chloro-pyridine-2-sulfonamide (0.80 g, 2.45 mmol), 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) were treated in portions at room temperature under nitrogen. The reaction was heated to 150°C in a microwave for 30 minutes. The reaction was cooled to room temperature, filtered and the solids were washed with EtOAc (3 x 10 mL). The filtrate was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with saturated aqueous sodium chloride (3 x 30 mL), collected, and 2 S.O. 4 dried, filtered and concentrated. The residue was purified by reverse phase chromatography, eluting with 40% to 70% ACN in 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] + .

[0298] The following compounds in Table 23 were converted to N-tert-butyl-6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromene-8- Made in a similar manner to that described for yl]ethyl]amino]pyridine-2-sulfonamide. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 23]

[0299] Intermediate 183C: N-tert-butyl-6-chloro-3-[[(1R)-1-[2-(1,5-dimethyl-6-oxo-3-pyridyl)-6-methyl-4-oxo -chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide [ka] 5-[8-[(1R)-1-aminoethyl]-6-methyl-4-oxo-chromen-2-yl]-1,3-dimethyl-pyridin-2-one (200 mg) in DMF (6 mL) , 0.62 mmol) and 3-bromo-N-tert-butyl-6-chloro-pyridine-2-sulfonamide (404 mg, 1.23 mmol) was mixed with cesium carbonate (402 mg, 1.23 mmol) and copper(I) iodide. (23.5 mg, 0.12 mmol) in portions at room temperature under nitrogen atmosphere. The reaction was stirred at 120°C overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in water (0.1% NH 4 Purification by reverse phase chromatography on C18 eluting with 20% to 50% ACN in (containing OH) gave the title compound (88 mg, 25%) as a white solid. ES / MS m / z 571 ( M+H).

[0300] The following compounds in Table 24 were converted to N-tert-butyl-6-chloro-3-[[(1R)-1-[2-(1,5-dimethyl-6-oxo-3-pyridyl)-6-methyl -4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-sulfonamide was made in a similar manner as described for. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 24-1] [Table 24-2]

[0301] Intermediate 189C: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)-4-oxo-chromene -8-yl]ethyl]amino]pyridine-2-carbonitrile [ka] 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(2-methylpyrazolo[4,3-b]pyridin-5-yl)chromen-4-one ( A solution of 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 and 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 99% EtOAc in petroleum ether to give the title compound (0.25 g, 32%) as a brown solid. ES / MS m / z 485(M+H).

[0302] The following compounds in Table 25 were converted into 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 was made in a similar manner as described for. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 25]

[0303] Intermediate 130A: tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate [ka] 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) (0.21g, 0.23mmol), copper(I) thiophene-2-carboxylate (0.87g, 4.55mmol), zinc(II) acetate (0.84g, 4.55mmol), 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 hours. The crude product mixture was purified by silica gel chromatography, eluting with 10% to 60% EtOAc in heptane, followed by reverse phase chromatography, eluting with 0% to 100% ACN in water (containing 0.1% TFA). Purification gave the product (0.53g, 48%). MS ES+m / z 456[M+H] + .

[0304] The following compounds in Table 26 are written in the format for tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. It was made in a similar manner. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 26]

[0305] 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 [ka] 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), copper(I) 3-methylsalicylate (0.24 g, A vial containing 1.11 mmol) was suspended in EtOH (3 mL) and THF (3 mL). Nitrogen was bubbled through the mixture for 2 minutes, the vial was sealed, and the reaction was stirred at 60° C. for 4 hours. The reaction was recharged with equal amounts of 1H-pyrazol-4-ylboronic acid, tetrakis(triphenylphosphine)palladium(0), and copper(I) 3-methylsalicylate. Nitrogen was bubbled through the mixture for 5 minutes, the vial was sealed, and the reaction was stirred at 60° C. for 16 hours. The reaction was cooled, filtered through diatomaceous earth, and the solids were washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by reverse phase chromatography on C18 eluting with 16% to 44% ACN in water (containing 0.1% formic acid) to give the title compound (60 mg, 19%). Obtained. ES / MS m / z 420(M+H).

[0306] The following compounds in Table 27 were converted to 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl] Made in a similar manner to that described for ethyl]amino]pyridine-2-carbonitrile. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 27-1] [Table 27-2]

[0307] Intermediate 15A: tert-butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate [ka] Tris(dibenzylideneacetone)dipalladium(0) (1.17g, 1.28mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.97g, 3.41mmol), (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 Cs 2 C.O. 3 (13.9g, 42.6mmol) were combined in toluene (80mL). The reaction was heated to 115°C for 16 hours. The mixture was filtered through diatomaceous earth 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 in heptane to give the title compound (7.1 g, 89%). MS ES+m / z 471[M+H] + .

[0308] The following compounds in Table 28 were converted to 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid tert -Made in a similar manner to that described for butyl. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5] [Table 28-6] [Table 28-7] [Table 28-8] [Table 28-9] [Table 28-10] [Table 28-11] [Table 28-12] [Table 28-13] [Table 28-14] [Table 28-15] [Table 28-16] [Table 28-17] [Table 28-18] [Table 28-19] [Table 28-20] [Table 28-21]

[0309] Intermediate 195A: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- tert-butyl chromen-8-yl]ethyl]amino]pyridine-2-carboxylate [ka] tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate ( 0.30g, 0.61mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (0.40g, 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) was suspended in 6 mL of THF in a test tube, which was 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 in heptane to give the title compound (0.18g, 53%). MS ES+m / z 559[M+H] + .

[0310] The following compounds in Table 29 were converted to 6-chloro-3-[[(1R)-1-[3,6-dimethyl-2-(2-methylimidazo[1,2-a]pyridin-6-yl)- Made in a similar manner to that described for tert-butyl 4-oxo-chromen-8-yl]ethyl]amino]pyridine-2-carboxylate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5] [Table 29-6]

[0311] Intermediate 256C: 8-[(1R)-1-[[2-(2-fluorophenyl)-3-pyridyl]amino]ethyl]-6-methyl-2-(3-pyridyl)chromen-4-one [ka] Combined 8-[(1R)-1-[(2-chloro-3-pyridyl)amino]ethyl]-6-methyl-2-(3-pyridyl)chromen-4-one (2.46g, 6.28mmol), ( 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) 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 dry reaction was resuspended in DCM and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.77g, 27%) as a yellow foam. ES / MS m / z 452(M+H).

[0312] Intermediate 257C: 6-chloro-3-[[(1R)-1-[2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino] tert-butyl pyridine-2-carboxylate [ka] tert-butyl 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate ( 0.50g, 1.02mmol), zinc(II) bromide 2,6-difluorobenzene-1-ide (0.79g, 0.5M, 3.07mmol), methanesulfonate {[4-N,N-dimethylamino)phenyl] di-t-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) were combined with THF (3 mL) and degassed for 5 minutes. The reaction was stirred at 75°C for 6 hours. The reaction was filtered through diatomaceous earth and the solids were 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).

[0313] Intermediate 25A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid [ka] tert-Butyl 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (7.1g, 15mmol) was dissolved in DCM (1 mL) and TFA (1 mL). It was sealed and the reaction was heated at 50° C. for 16 hours. Concentrate, NH 4 HCO 3 Purification by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in aqueous solution (10 mM, containing 5% MeOH) gave 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] + .

[0314] The following compounds in Table 30 were prepared for 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid. It was made in a similar manner to that described. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 30-5] [Table 30-6] [Table 30-7] [Table 30-8] [Table 30-9] [Table 30-10] [Table 30-11]

[0315] Intermediate 235A: 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-6-fluoro-pyridine-2 -carboxylic acid [ka] 3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]-6-fluoro-pyridine in DCM (5 mL) A solution of tert-butyl-2-carboxylate (0.23 g, 0.47 mmol) was treated with HCl (4M in 1,4-dioxane) and allowed to stir under nitrogen at room temperature 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] + .

[0316] 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 [ka] 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(4,5,6,7-tetrahydropyrazolo[ A solution of 1,5-a]pyrazin-3-yl)chromen-8-yl]ethyl]amino]pyridine-2-carboxylic acid (100 mg, 0.20 mmol) was mixed with DIPEA (262 mg, 2.02 mmol) and di-tert- Treated with butyl decarbonate (66.3 mg, 0.30 mmol). The reaction was stirred at room temperature for 3 hours. Convert the reactants to saturated NaHCO 3 Aqueous solution, saturated NH 4 Washed with aqueous Cl solution and then saturated aqueous NaCl solution. The organic layer was collected and concentrated under reduced pressure to give the title compound (180 mg, purity 90%, 130%), which was used without purification. ES / MS m / z 592(M-H).

[0317] Intermediate 293C: 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]benzaldehyde [ka] The vial was replaced 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 (5M in 1,4-dioxane, 1 g, 5 mmol) and then stirred at room temperature for 2 hours. The reaction was diluted with DCM and neutralized with 1M aqueous NaOH. After removing the organic layer, the aqueous layer was extracted with DCM three times. Combine the organic layers and add Na 2 S.O. 4 Dry, filter and concentrate under reduced pressure to give the title compound (400 mg, 93%), which was used without purification. ES / MS m / z 399(M+H).

[0318] The following compounds in Table 31 were described for 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]amino]benzaldehyde. It was made in the same style as the above. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 31]

[0319] Intermediate 236A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro-benzoic acid [ka] 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluoro in THF (9 mL) and water (3 mL). A solution of methyl-benzoate (0.67 g, 1.51 mmol) 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. Two more equivalents of lithium hydroxide were added and the reaction was stirred at 60° C. overnight. The reaction was allowed to cool to room temperature, diluted with DCM, washed with saturated aqueous ammonium chloride, and purified with IPA / CHCl. 3 Extracted twice with (1:3). Combine organics and MgSO 4 , 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] + .

[0320] The following compounds in Table 32 were prepared for 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-6-fluorobenzoic acid. It was made in a similar manner to that described. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 32]

[0321] Intermediate 26A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide [ka] 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.600 g) in DCM (6 mL) , 1.45 mmol) 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 stirred at 60°C for 2 hours. Concentrated to dryness, added DCM (6 mL) and triethylamine (0.61 mL, 4.34 mmol) and cooled to 0°C. N-BOC-hydrazine (0.48g, 3.62mmol) was added and the reaction was stirred at room temperature for 1 hour. Concentrated to dryness, added DCM (6 mL) and HCl (4M in 1,4-dioxane, 1.81 mL, 7.24 mmol) and stirred at room temperature for 3 days. Concentrate, NH 4 HCO 3 It was purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in aqueous solution (10 mM, containing 5% MeOH). Fractions containing the product were purified with saturated NaHCO 3 Diluted with aqueous solution and EtOAc. organic matter Na 2 S.O. 4 dried, filtered and concentrated. Filtration from DCM / hexane gave the title compound (0.36g, 58%). MS ES+m / z 429[M+H] + .

[0322] Intermediate 237A: 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbohydrazide [ka] 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.40g, 0.89 mmol), DIPEA (0.35g, 2.67mmol), 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide (1.69g, 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 mixed with equal amounts of DIPEA, 2,4,6-tripropyl-1,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide, and hydrazine water. and allowed to stir at room temperature. The reaction was purified by reverse phase chromatography eluting with 10% to 100% ACN in 0.1% aqueous formic acid to give the title compound (0.12g, 29%). MS ES+m / z 463[M+H] + .

[0323] 6-chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2 -Made in a similar manner to that described for carbohydrazide. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 33]

[0324] Intermediate 238A: N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl] tert-butyl]-6-methyl-pyridine-2-carbonyl]amino]carbamate [ka] 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl]amino] in DMF (6 mL) A solution of -6-methyl-pyridine-2-carboxylic acid (0.40 g, 0.83 mmol) 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 solution, collected, and 2 S.O. 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / EtOH (3:1) in heptane to give the title compound (0.50 g, 91%, 91% purity) as a tan gel. Obtained. MS ES+m / z 597[M+H] + .

[0325] The following compounds in Table 34 were converted into It was made in a similar manner to that described for tert-butyl]ethyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 34-1] [Table 34-2]

[0326] Intermediate 244A: N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonyl]sulfamoyl ]tert-butyl carbamate [ka] 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 -Mixture of 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 allowed to stir. After 5 minutes, triethylamine (73.2 mg, 0.72 mmol) was added to the reaction and allowed to stir overnight at room temperature. The reaction was concentrated and the residue was purified by reverse phase C18 flash chromatography eluting with ACN in water containing 0.1% formic acid. The product-containing fractions were combined, washed with saturated aqueous sodium chloride solution, and purified with IPA / CHCl. 3 Collect organic matter by extraction with (1:3) MgSO 4 Dried, filtered and concentrated to give the title compound (0.12g, 83%) as a foam. MS ES+m / z 591[M-H] - .

[0327] The following compounds in Table 35 were converted into N-[[3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2 It was made in a similar manner to that described for tert-butyl -carbonyl]sulfamoyl]carbamate. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 35]

[0328] Intermediate 27A: 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid methyl [ka] 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) was dissolved in DMSO (1 mL) and DIPEA (0.78 mL, 4.45 mmol) was added. The vial was sealed and the reaction heated to 120°C for 24 hours. Concentrate with a small amount of diatomaceous earth and NH 4 HCO 3 Purification by reverse phase chromatography eluting with a gradient of 10 to 70% ACN in aqueous solution (10 mM, containing 5% MeOH) gave the title compound (0.18 g, 40%). MS ES+m / z 491[M+H] + .

[0329] The following compounds from Table 36 were prepared from 6-bromo-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine- Made in a similar manner to that described for methyl 2-carboxylate. [Table 36]

[0330] Intermediate 307C:8-[(1R)-1-[2-[2-[dimethyl(oxo)-lambda6-sulfanylidene]acetyl]anilino]ethyl]-3,6-dimethyl-2-phenyl-chromene-4 -on [ka] The vial containing trimethylsulfoxonium iodide (291 mg, 1.32 mmol) was dried at 65° C. for 2 hours and then treated with dry THF (5 mL) once cooled. 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 added to toluene. (5.5 mL) and treated dropwise with thionyl chloride (131 mg, 1.10 mmol) and the reaction was stirred at 80 °C for 15 min. The second vial was allowed to cool to room temperature, concentrated in vacuo, and the acid chloride I got something. Both vials were cooled in an ice bath and the contents of the first vial were added to the acid chloride via syringe. The reaction was removed from the cooling bath and allowed to warm to room temperature. The second batch of the first vial was processed except that the reaction was incomplete so it was only stirred for 15 minutes at 66°C. The reaction was quenched with water and the mixture was concentrated in vacuo to remove THF. The reaction was diluted with DCM, the layers were separated and the remaining aqueous layer was re-extracted with fresh DCM. Combined organic layers with MgSO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM, 10mM NH 4 HCO 3 Repurification by reverse phase chromatography on C18 eluting with 0% to 100% ACN in aqueous solution (containing 5% MeOH) gave the title compound. ES / MS m / z 488(M+H).

[0331] Intermediate 308C: 8-[(1R)-1-[2-(2-chloroacetyl)anilino]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] Add the vial to 8-[(1R)-1-[2-[2-[dimethyl(oxo)-lambda-6-sulfanylidene]acetyl]anilino]ethyl]-3,6-dimethyl-2-phenyl-chromene-4- 1,4-dioxane (6.2 mL) and then treated with HCl in 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 diluted with 10 mM NH 4 HCO 3 Purified by reverse phase chromatography on C18 eluting with 0% to 100% ACN in aqueous solution (containing 5% MeOH) and repurified by silica gel chromatography eluting with 0% to 100% EtOAc in DCM. The title compound (110.8 mg, 40%) was obtained as a yellow powder. ES / MS m / z 446(M+H).

[0332] Intermediate 309C: 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] Chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile [ka] 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1] in DCM (3 mL) A solution of pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carboxamide (97 mg, 0.19 mmol) was treated with triethylamine (0.29 g, 2.9 mmol) followed by trifluoroacetic anhydride (0.20 g, 0.96 mmol). Processed at 0°C. The reaction was warmed to room temperature and stirred for 2 hours. Dilute the reaction with EtOAc and saturated NaHCO 3 Washed with aqueous solution. Collect the organic layer and Na 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (192 mg, 50% pure, 100%) as a yellow gel. ES / MS m / z 488(M+H).

[0333] The following compounds from Table 37 were converted to 6-chloro-3-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[3-(trifluoromethyl)-1-bicyclo[1.1. Made in a similar manner to that described for 1]pentanyl]chromen-8-yl]ethyl]amino]pyridine-2-carbonitrile. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 37]

[0334] Intermediate 29A: 8-(1-hydroxyethyl)-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 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). Cool to -10 °C and NaBH 4 (0.78g, 21mmol) 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 diluted with anhydrous Na 2 S.O. 4 , concentrated and purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound (4.2g, 83%). MS ES+m / z 295[M+H] + .

[0335] Intermediate 30A: 8-(1-bromoethyl)-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 8-(1-chloroethyl)-3,6-dimethyl-2-phenyl-chromen-4-one (2.0 g, 6.8 mmol) was combined in DCM (25 mL). Cool to 0 °C and PBr 3 (1.3 mL, 14 mmol) was added dropwise and the reaction was stirred for 2 hours at room temperature. After slowly adding saturated aqueous bicarbonate solution, the layers were separated. Organic matter anhydrous Na 2 S.O. 4 and concentrated to give the title compound (1.4g, 58%). MS ES+m / z 359[M+H] + .

[0336] Intermediate 31A: 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN]( A solution of CAS 192139-92-7, 0.653 g, 1.03 mmol) was stirred at 0-5°C. 1,8-Diazabicyclo[5.4.0]undes-7-ene (15.3 mL, 103 mmol) was added slowly keeping the temperature below 25°C. Formic acid (3.87 mL, 103 mmol) was added in portions while maintaining the temperature below 15°C. The reaction was stirred at 55° C. for 3 hours, then cooled to room temperature. 4M HCl aqueous solution (50 mL) was added slowly. The resulting slurry was stirred overnight, filtered, and washed with water to yield the title compound (9.9 g, 93%, 87% ee).

[0337] Intermediate 32A: 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 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. Diluted with 2M aqueous sodium hydroxide (100 mL) and separated the layers. The organics were washed with water (100 mL) / saturated aqueous sodium bicarbonate (100 mL) and 5% aqueous lithium chloride (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 added slowly. Filtration gave the title compound (18.4g, 87%, 94% ee). MS ES+m / z 313[M+H] + .

[0338] Intermediate 245A: 8-[(1R)-1-(2-iodoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 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 (1.24g, 9.59mmol) were combined in IPA (6mL) and stirred at 60°C overnight. The reaction was recharged twice over 8 hours with 1 g of 2-iodoaniline and 0.5 mL of DIPEA, then stirred overnight. The reaction was concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.70g, 74%). MS ES+m / z 496[M+H] + .

[0339] Intermediate 246A: tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate [ka] A flask flushed 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 obtained solution was cooled to 0°C and treated dropwise with 2,2,6,6-tetramethylpiperidinichloride zinc chloride lithium chloride complex solution (3.49 g, 1 M, 12.30 mmol) over 30 minutes, and then the reaction was carried out. The mixture was allowed to stir at 25° C. for 7 hours. An additional 6 mL of 2,2,6,6-tetramethylpiperidinichloride zinc chloride lithium chloride complex solution was added and the reaction was stirred overnight at room temperature. The reaction was cooled to 0 °C and treated dropwise with a freshly prepared solution of iodine (1.56 g, 1M in THF, 6.15 mmol) over 30 min, and the reaction was incubated at 0 °C for 1 h and then at room temperature for 12 h. Stir for 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 (3 x 300 mL). The combined organic matter is Na 2 C.O. 3 Wash with aqueous solution (50 mL), collect and Na 2 S.O. 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 10% EtOAc in heptane to give the title compound (1.64g, 87%). MS ES+m / z 582[M+H] + .

[0340] The following compounds in Table 38 were prepared using tert-butyl 2-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoate. It was made in a similar manner to that described. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 38]

[0341] 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 [ka] N-tert-butyl-6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine in THF (10 mL) A solution of -2-sulfonamide (1.1 g, 2.09 mmol) was cooled to -40 °C under a nitrogen atmosphere, and a solution of 2,2,6,6-tetramethylpiperidyl chloride magnesium lithium chloride complex (13 mL, 12.55 mmol, 1M in THF). The reaction was stirred at -10°C for 2 hours. A THF solution of iodine (4 mL, 4.18 mmol) was added dropwise over 30 minutes at -40°C, followed by stirring at room temperature for 2 hours. Saturate the reactants with NH 4 Quenched with Cl aqueous solution at 0°C. The reaction was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), collected, and 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EtOAc in petroleum ether to give the title compound (0.30 g, 22%) as a yellow solid. ES / MS m / z 652(M+H).

[0342] 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 [ka] N-tert-butyl-6-chloro-3-[[(1R)-1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl in ACN A mixture of ]ethyl]amino]pyridine-2-sulfonamide (400 mg, 0.75 mmol) and N-bromosuccinimide (134 mg, 0.75 mmol) was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was dissolved in water (0.1% NH 4 Purification by reverse phase chromatography on C18 eluting with 65% to 70% ACN in (containing OH) gave the title compound (250 mg, 54%) as a colorless solid. ES / MS m / z 608 / 610(M+H).

[0343] 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 [ka] N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl in NMP (4 mL) A solution of ]amino]pyridine-2-sulfonamide (180 mg, 0.28 mmol) was treated with copper(I) cyanide (124 mg, 1.38 mmol) at room temperature. The reaction was stirred at 120° C. under nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), collected, and 2 S.O. 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 eluting with 80% to 95% ACN in water to give the title compound (73 mg, 48%) as a pale yellow solid. ES / MS m / z 551(M+H).

[0344] Intermediate 247A: tert-butyl 2-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-3-thiazol-5-yl-chromen-8-yl)ethyl]amino]benzoate [ka] Add 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 Charged with -(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. for 20 hours under nitrogen atmosphere. 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 in heptane to give the title compound (208 mg, 75%). Ta. MS ES+m / z 539[M+H] + .

[0345] Intermediate 318C: N-tert-butyl-6-chloro-3-[[(1R)-1-(3-isoxazol-4-yl-6-methyl-4-oxo-2-phenyl-chromene-8- yl)ethyl]amino]pyridine-2-sulfonamide [ka] N-tert-butyl-6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2) in 1,4-dioxane (2 mL) and water (0.2 mL). -phenyl-chromen-8-yl)ethyl]amino]pyridine-2-sulfonamide (80 mg, 0.12 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- A solution of isoxazole (48 mg, 0.25 mmol) was treated with potassium carbonate (34 mg, 0.25 mmol) and 1,1'-bis(di-t-butylphosphino)ferrocenepalladium dichloride (16 mg, 0.03 mmol) under nitrogen atmosphere. Processed at lower room temperature. The reaction was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 33% EtOAc in petroleum ether to give the title compound (50 mg, 69%) as a pale yellow solid. Ta. ES / MS m / z 593(M+H).

[0346] 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 [ka] 3-[[(1R)-1-[3-bromo-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromene- in THF (2 mL) and water (0.5 mL). 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- t-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) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was filtered and the solids were washed with THF (2 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in water (0.1% NH 4 Purification by reverse phase chromatography on C18 eluting with 75% to 85% ACN in (containing OH) gave the title compound (92 mg, 46%) as a colorless solid. ES / MS m / z 597(M+H).

[0347] Intermediate 248A: 6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carvone acid [ka] tert-butyl 6-chloro-3-[[(1R)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylate (0.47g, A solution of 0.96 mmol) in THF (3 mL) was treated with 2,2,6,6-tetramethylpiperidinichloride zinc lithium chloride complex solution (0.68 mg, 1M, 2.39 mmol) and allowed to stir at room temperature for 3 hours. . The reaction was quenched with iodine (0.97g, 3.83mmol) dissolved in THF and the reaction was allowed to stir for 1 hour. The reaction was diluted with 20 mL of EtOAc / water. Collect the organic layer and MgSO 4 dried, filtered and concentrated. The residue was purified by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to give the title product (0.20 g, 37%). Obtained. MS ES+m / z 561[M+H] + .

[0348] Intermediate 33A: 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N’-hydroxy-pyridine-2-carboxamidine [ka] 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carbonitrile (0.242 g) in ethanol (5 mL) , 0.612 mmol), triethylamine (0.26 mL, 1.84 mmol) and hydroxylamine hydrochloride (0.085 g, 1.22 mmol) were added. The reaction was heated at 80°C for 18 hours. Concentrate, H 2 Purification by reverse phase chromatography eluting with a gradient of 0 to 100% ACN in O+0.1% formic acid gave the title compound (0.26 g, 89%). MS ES+m / z 429[M+H] + .

[0349] The following compounds from Table 39 were converted into 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]-N'-hydroxy-pyridine. Made in a similar manner to that described for -2-carboxamidine. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 39-1] [Table 39-2] [Table 39-3] [Table 39-4] [Table 39-5] [Table 39-6] [Table 39-7] [Table 39-8] [Table 39-9] [Table 39-10] [Table 39-11] [Table 39-12] [Table 39-13] [Table 39-14] [Table 39-15] [Table 39-16] [Table 39-17] [Table 39-18]

[0350] 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 [ka] 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) (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 I-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (0.107 g, 0.726 mmol) were added. The reaction was stirred at room temperature for 24 h. Stir. Concentrate and purify by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexane to give the title compound (0.171 g, 80% purity, 100%). MS ES+m / z 543[M+H] + .

[0351] The following compounds in Table 40 were converted into Made in a similar manner to that described for dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzamide. [Table 40]

[0352] Intermediate 38A: 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile [ka] 2-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.100 g, 0.264 mmol), (2-fluoro phenyl)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) in ethanol. (15 mL). The reaction was degassed with argon and stirred at 50°C for 16 hours. Concentration and purification by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexane gave the title compound (0.109g, 100%). MS ES+m / z 413[M+H] + .

[0353] The following compounds from Table 41 were converted into 2-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzonitrile. It was made in a similar manner to that described. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 41-1] [Table 41-2] [Table 41-3]

[0354] Intermediate 47A: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one [ka] tert-butyl N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethyl]carbamate (0.950 g, To a solution of 2.41 mmol) was added HCl (4M in 1,4-dioxane, 4 mL, 16 mmol). The reaction was stirred at room temperature for 2 hours. HCl (4M in 1,4-dioxane, 1.2 mL, 4.8 mmol) was added and stirred at room temperature for 1 h. Concentrated and saturated NaHCO 3 Aqueous solution and IPA:CHCl 3 (1:3). The layers were separated. MgSO organic extract 4 dried, filtered and concentrated. Residue, NH 4 HCO 3 It was purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in aqueous solution (10 mM, containing 5% MeOH). The clean fractions were washed with saturated aqueous sodium chloride and IPA:CHCl 3 (1:3). MgSO organic extract 4 dried, filtered and concentrated to give the title compound (0.364g, 51%). MS ES+m / z 295[M+H] + .

[0355] The following compounds in Table 42 were converted to 3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid tert -Made in a similar manner to that described for butyl. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 42]

[0356] 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-pyridyl]-4H-1,2,4-oxadiazol-5-one [ka] 3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3,6 in 1,4-dioxane (4 mL) -Dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-N'-hydroxy-pyridine-2-carboxamidine (134 mg, 0.22 mmol) was added to a solution of 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 the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc / EtOH in heptane (3:1) to give the title compound (98.4 mg, 70%) as a tan foam. ES / MS m / z 637(M+H).

[0357] The following compounds in Table 43 can be expressed as 3-[3-[[(1R)-1-[2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]-3, Similar format to that described for 6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-6-chloro-2-pyridyl]-4H-1,2,4-oxadiazol-5-one It was made in a style. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 43]

[0358] Intermediate 294A: 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine- 2-carboxylic acid [ka] 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]pyridine in 2 mL of DCM. A solution of tert-butyl-2-carboxylate (0.23 g, 0.44 mmol) 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 in 0.1% aqueous formic acid. The product-containing fractions were combined, washed with saturated aqueous sodium chloride solution, and purified with IPA / CHCl. 3 (1:3). Combine organics and MgSO 4 Dried, filtered and concentrated to give the title compound (68.8 mg, 34%) as a tan foam. MS ES+m / z 467[M+H] + .

[0359] The following compounds in Table 44 were converted to 6-chloro-3-[[(1R)-1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl] It was made in a similar manner to that described for amino]pyridine-2-carboxylic acid. [Table 44]

[0360] 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 [ka] N-[[3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl in 10 mL of DCM A solution of tert-butyl]amino]-6-methyl-pyridine-2-carbonyl]amino]carbamate (0.50 g, 0.84 mmol) in HCl (4M in 1,4-dioxane, 0.15 g, 1.05 mL, 4.19 mmol) ) and stirred at 50°C. After 3 hours, an additional 1.05 mL of HCl in dioxane was added and stirred at 60° C. for 2 hours. The reaction was allowed to cool to room temperature, concentrated, and the residue was taken up in DCM and saturated NaHCO 3 Washed with aqueous solution. IPA / CHCl aqueous layer 3 Extracted twice with (1:3). Combine organics and MgSO 4 , filtered and concentrated to a residue which was recrystallized from DCM / MTBE / hexane to give the title compound (0.31 g, 73%) as a pale yellow powder. MS ES+m / z 497[M+H] + .

[0361] The following compounds in Table 45 were converted into 3-[[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethyl] [amino]-6-methyl-pyridine-2-carbohydrazide was made in a similar manner to that described for. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 45-1] [Table 45-2]

[0362] 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 [ka] 6-chloro-3-[[(1R)-1-(3-iodo-6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]pyridine-2-carboxylic acid (0.14g) , 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 cooled at 25°C. The mixture was stirred overnight. The reaction was diluted with 1 mL of MeOH and purified directly by reverse phase chromatography eluting with 10% to 100% ACN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to yield the title compound (0.12 g, 75%). MS ES+m / z 638[M+H] + .

[0363] Intermediate 375C: 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N-methylsulfonyl- Pyridine-2-carboxamide [ka] 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]pyridine-2 in DCM (1.2 mL) A solution of -carboxylic acid (0.50 g, 1.15 mmol) was cooled to 0°C and treated with methanesulfonamide (0.19 g, 1.96 mmol) and chlorodipyrrolidinecarbenium hexafluorophosphate (0.58 g, 1.73 mmol). , followed by 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 in DCM to give the title compound (0.34g, 58%). ES / MS m / z 510(M+H).

[0364] The following compounds in Table 46 were converted to 6-chloro-3-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]-N -Methylsulfonyl-pyridine-2-carboxamide was made in a similar manner as described for. Compounds were purified using various methods that would be apparent to those skilled in the art. [Table 46]

[0365] Intermediate 304A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzenesulfonamide [ka] N'-[2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]phenyl]sulfonyl-N, in 8 mL of EtOH. A solution of N-dimethyl-formamidine (0.45 g, 0.89 mmol) was treated with concentrated HCl (0.16 g, 4.45 mmol) and the reaction was stirred at reflux for 2 hours. Another 1 mL of concentrated HCl was added and the reaction was stirred at 80° C. for an additional 2 hours. The reaction was allowed to cool to room temperature, diluted with DCM, and saturated NaHCO 3 Neutralized with aqueous solution. Remove organic layer and aqueous layer with IPA / CHCl 3 (1:3). Combined extracts with MgSO 4 dried, filtered and concentrated. The residue was purified by reverse phase chromatography eluting with 0% to 100% ACN in water (containing 0.1% formic acid). Pool fractions containing product and IPA / CHCl 3 (1:3). Combine organics and MgSO 4 , filtered and concentrated to give the title compound (0.12g, 30%) as a white solid. MS ES+m / z 449[M+H] + .

[0366] Intermediate 53A: 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 [ka] 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (1.12 g, 2.50 mmol) and potassium acetate (0.736 g, 7.49 mmol) , 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (0.183g, 0.250mmol), and bis(pinacolato)diboron (0.761g, 3.00mmol) in dimethoxyethane (12mL). ). The reaction was degassed with argon for 1 min and stirred at 95°C for 16 h. Filtered through diatomaceous earth, concentrated and purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound (1.1 g, 89%). MS ES+m / z 496[M+H] + .

[0367] The following compounds in Table 47 were converted to 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Made in a similar manner to that described for 2-yl)anilino]ethyl]chromen-4-one. [Table 47]

[0368] Intermediate 55A: 2-ethylsulfanyl-3,6-dimethyl-8-[(1R)-1-[2-(2H-tetrazol-5-yl)anilino]ethyl]chromen-4-one [ka] 2-[[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethyl]amino]benzonitrile (0.500 g, 1.32 mmol) and sodium azide (0.258g, 3.96mmol) and ammonium chloride (0.212g, 3.96mmol) were combined in DMF (3mL). The reaction was sealed and stirred at 140° C. for 3 hours. Purification by reverse phase chromatography gave the title compound (0.190g, 34%). MS ES+m / z 422[M+H] + .

[0369] Intermediate 56A: 3,6-dimethyl-2-phenyl-8-[(1R)-1-[2-(2-trimethylsilylethynyl)anilino]ethyl]chromen-4-one [ka] 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 with ethynyl -Trimethyl-silane (0.46g, 4.68mmol) and triethylamine (0.65mL, 4.68mmol) were added. 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 at 100° C. for 18 hours in a microwave reactor. The mixture was diluted with 10% aqueous LiCl and extracted twice with EtOAc. Organic extract Na 2 S.O. 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexane to give the title compound (0.35 g,...

Claims

1. The compound of the following formula, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R and R １ However, together with the nitrogen to which they are bonded, they form a bicyclic ring which is optionally substituted from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R is -H or C １ -C ３ is alkyl, R １ However, the bicyclic ring is optionally substituted with isobenzofuranone, benzofuranone, indole, isoindolinone, indolone, quinazolinone, 3,4-dihydro-2H-isoquinoline-1-one, 2H-isoquinoline-1-one, imidaza[1,2-a]pyridine, or benzothiazolon, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R １ However, this is the basis of the following equation, 【Chemistry 2】 R' is halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -OH, -CH(OH)-CH ２ OH, -CH(OH)C １ -C ３ Haloalkyl, -C(O)-CH ２ OH, C ３ -C ６ Cycloalkyl, -NO ２ , -NR １１ R １１ , -N(R １１ )-CO ２ C １ -C ３ Alkyl, -N(R) １１ ) - SO ２ C １ -C ３ Alkyl, -N(R) １１ ) - SO ２ R １５ , -SO ２ C １ -C ３ Alkyl, -S(O)C １ -C ３ Alkyl, -SO ２ NR １１ R １１ , -SO ２ N(R) １１ )-C(O)-C １ -C ３ Alkyl, -SO ２ N(R) １１ )-CN,-SO ２ N(R) １１ ) (Caution １３ ) -C(=N-OH)-NH ２ , -CN, -CONR １１ R １２ , -C(O)N(R １１ )-(CH ２ ) ｎ -R １３ , -C(O)-SR １２ , -C(O)-NHSO ２ R １６ , -C(O)CH=SOR １１ (R １１ ), or -C(O)CH ２ CN, or the base of the following formula, 【Transformation 3】 In the formula, ring A is a 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 oxo, -OH, -NR １１ R １１ , -N(R １１ )-C(O)-R １１ , -N(R １１ ) -CN, -OR １１ -CN, halogen, morpholine, oxetane, C １ -C ６ C is optionally substituted with a haloalkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl. １ -C ６ It is optionally substituted with 1 to 3 substituents independently selected from the alkyl group, or R' is the basis of the following equation, 【Chemistry 4】 R ２ However, is it the basis of the following equation? 【Transformation 5】 or R ２ However, is it the basis of the following equation? 【Transformation 6】 or R ２ is optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is -CN, halogen, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, -SO ２ R １１ 、-CO ２ C １ -C ３ alkyl, -C(O)NR １１ R １１ 、-OH, -NR １１ R １１ 、-NR １１ CO ２ R １１ 、optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C ３ -C ５ cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, tetrahydropyran, oxetane, azetidine, or morpholine, an optionally substituted heterocyclic ring, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, each independently selected from 1 to 3 substituents of an optionally substituted heteroaryl, and the optionally substituted C １ -C ６ alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, -CH ２ CH(OH)CH(OH)R １１ , or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C is replaced by the aforementioned arbitrary selection. ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -C(O)(CH) ２ ) ｎ OR １１ , C(O)C(CH ３ ) ２ OH, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, 1,3-benzodioxol, 2,3-dihydro-1,4-benzodioxin, indole, indazole, isoindazole, isoindorin-1-one, indorin-2-one, benzoxazole, benzotriazole, benzo[d]oxazole-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-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 A bicyclic ring optionally substituted from dr-[1,4]dioxyno[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, or pyrazolo[1,5-a]pyrimidine, or a bicyclic heteroaryl ring optionally substituted with 8 to 10 ring atoms including 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is a halogen and C １ -C ６ The alkyl group is optionally substituted with one to three substituents independently selected from each alkyl group, and the optionally substituted bicyclic heteroaryl group is -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ CH, -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ , -NR １１ R １１ , -NR １１ CO ２ R １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with a cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine; an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin; or an optionally substituted heteroaryl, each optionally substituted with a cycloalkyl, pyrrolidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; and the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, -C(O)NR １１ R １１ C, which is optionally substituted with phenyl, and the C that is optionally substituted with phenyl ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, 1 to 3 R １０ Cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, or cyclohexyl, each optionally substituted with a substituent, or R ２ However, this is the basis of the following equation, 【Transformation 7】 and R ３ However, -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C １ -C ３ Alkyl), -N(C １ -C ３ Alkyl) ２ ,-N(H)(CH ２ CH ２ CO ２ H), -CO-C １ -C ３ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxylalkyl, C ３ -C ５ A heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is a halogen, C １ -C ３ Alkyl, or C １ -C ３ Each haloalkyl group is independently substituted with one to three substituents, each of which can be arbitrarily selected. R ４ , R ５ , and R ６ Each of these independently represents -H, halogen, -CN, and C. １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ７ However, -CN, C １ -C ６ Alkyl, -CH ２ OH, or C １ -C ６ It is a haloalkyl, R ８ However, -H or C １ -C ６ It is alkyl, Each R ９ However, independently, -H, halogen, -CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C ５ It is a cycloalkyl, Each R １０ However, independently, -H, -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ ,-SONR １１ R １１ , -CO ２ H, -CO ２ C １ -C ３ Alkyl, -C(O)NR １１ R １２ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , -N(R １１ ) COR １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted from cycloalkyl, pyrrolidine, pyrrolidinone, 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, or a group of the following formula: 【Transformation 8】 The C that was replaced by the aforementioned optional selection １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C which is replaced by the aforementioned arbitrary selection ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN. Each R １１ However, independently, -H, C １ -C ３ Alkyl, C ３ -C ７ Cycloalkyl, or C １ -C ３ It is a haloalkyl, Each R １２ However, independently, -H, and C, which are substituted by choice. １ -C ３ Alkyl, C ３ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, -SO ２ C １ -C ３ Alkyl, -SO ２ C １ -C ３ Haloalkyl, -SO ２ NR １１ R １１ , -NR １１ R １１ , -OR １１ , -O-CH ２ -CH(OH)-CH ２ A 5-membered heteroaryl, 6-membered heteroaryl, or group of the following formula, optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, or methyl. 【Chemistry 9】 The C that was replaced by the aforementioned optional selection １ -C ３ Alkyl groups are -OH, C ３ -C ６ It is optionally substituted with cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole. R １３ However, -NR １１ R １１ , -OR １１ , -SO ２ C １ -C ３ A ring selected from alkyl, oxetane, tetrahydrofuran, or oxadiazole, wherein the ring is -NR １１ R １１ OR １１ It is replaced by an optional selection, R １４ However, C is replaced by -H, which is of arbitrary choice. １ -C ３ Alkyl, -SO ２ C １ -C ３ C is an alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, and is substituted in any of the above options. １ -C ３ The alkyl group is optionally substituted with an aryl group, a five-membered heteroaryl group, or a six-membered heteroaryl group. R １５ However, the aryl or six-membered heteroaryl is optionally substituted, and the optionally substituted aryl or six-membered heteroaryl is a halogen, C １ -C ３ Alkyl, or C １ -C ３ Each haloalkyl group is optionally substituted with one to three substituents that are independently selected from the group. R １６ However, H, C １ -C ３ Alkyl, -NH ２ , phenyl, or pyridine, A compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

2. R and R １ However, together with the nitrogen to which they are bonded, they form a bicyclic ring which is optionally substituted from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R is -H or C １ -C ３ It is alkyl, R １ However, the bicyclic ring is optionally substituted with isobenzofuranone, benzofuranone, isoindlinone, indlinone, quinazolinone, 3,4-dihydro-2H-isoquinoline-1-one, 2H-isoquinoline-1-one, or benzothiazolon, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R １ However, this is the basis of the following equation, 【Chemistry 10】 R' is halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -OH, -CH(OH)-CH ２ OH, -CO-CH ２ OH, C ３ -C ６ Cycloalkyl, -NO ２ , -N(R １１ )-CO ２ C １ -C ３ Alkyl, -N(R) １１ ) - SO ２ C １ -C ３ Alkyl, -N(R) １１ ) - SO ２ R １５ , -SO ２ C １ -C ３ Alkyl, -SO ２ NR １１ R １１ , -SO ２ N(R) １１ )-CO-C １ -C ３ Alkyl, -SO ２ N(R) １１ )-CN, -C(=N-OH)-NH ２ , -CN, -CONR １１ R １２ , -CON(R １１ )-(CH ２ ) ｎ -R １３ , -CO-SR １２ , or the basis of the following formula, 【Chemistry 11】 In the formula, ring A is a 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 oxo, -OH, -NR １１ R １１ , -N(R １１ )-CO-R １１ , -N(R １１ ) -CN, -OR １１ -CN, halogen, C １ -C ６ C is optionally substituted with a haloalkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl. １ -C ６ It is optionally substituted with 1 to 3 substituents independently selected from the alkyl group. R' is the basis of the following equation, 【Chemistry 12】 R ２ However, is it the basis of the following equation? 【Chemistry 13】 or R ２ However, is it the basis of the following equation? 【Chemistry 14】 or R ２ However, the five-membered ring heteroaryl is optionally substituted from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted five-membered ring heteroaryl is -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ -OH, -NR １１ R １１ , -NR １１ CO ２ R １１ , C replaced by arbitrary selection １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with a cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine; an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin; or an optionally substituted heteroaryl, each optionally substituted with a cycloalkyl, pyrrolidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; and the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C is replaced by the aforementioned arbitrary selection. ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, the compound is a bicyclic ring substituted with an optional bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindorin-1-one, indorin-2-one, benzo[d]oxazole-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, or 2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine, or a bicyclic heteroaryl compound substituted with an optional bicyclic ring containing 8 to 10 ring atoms including 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optional bicyclic ring is a halogen and C １ -C ６ The alkyl group is optionally substituted with one to three substituents independently selected from each alkyl group, and the optionally substituted bicyclic heteroaryl group is -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ , -NR １１ R １１ , -NR １１ CO ２ R １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with a cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine; an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin; or an optionally substituted heteroaryl, each optionally substituted with a cycloalkyl, pyrrolidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; and the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, -CONR １１ R １１ C, which is optionally substituted with phenyl, and the C that is optionally substituted with phenyl ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, 1 to 3 R １０ Cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R ２ However, this is the basis of the following equation, 【Chemistry 15】 R ３ However, -H, halogen, -CN, -N(H)(C １ -C ３ Alkyl), -N(C １ -C ３ Alkyl) ２ ,-N(H)(CH ２ CH ２ CO ２ H), -CO-C １ -C ３ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxylalkyl, C ３ -C ５ A heterocycle substituted with 3 to 5 ring atoms of any choice, including 1, 2, or 3 ring heteroatoms independently selected from cycloalkyl, N, O, or S, or a heteroaryl substituted with 5 or 6 ring atoms of any choice, including 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is a halogen, C １ -C ３ Alkyl, or C １ -C ３ Each haloalkyl group is independently substituted with one to three substituents, each of which can be arbitrarily selected. R ４ , R ５ , and R ６ Each of these independently represents -H, halogen, and C. １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ７ However, -CN, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ８ However, -H or C １ -C ６ It is alkyl, Each R ９ However, independently, -H, halogen, -CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C ５ It is a cycloalkyl, Each R １０ However, independently, -H, -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ ,-SONR １１ R １１ , -CO ２ H, -CO ２ C １ -C ３ Alkyl, -CONR １１ R １２ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted from cycloalkyl, pyrrolidine, pyrrolidinone, 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, or a group of the following formula: 【Chemistry 16】 The C that was replaced by the aforementioned optional selection １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C which is replaced by the aforementioned arbitrary selection ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN. Each R １１ However, independently, -H or C １ -C ３ It is alkyl, Each R １２ However, independently, -H, and C, which are substituted by choice. １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl; -SO ２ C １ -C ３ Alkyl, -SO ２ C １ -C ３ Haloalkyl, -SO ２ NR １１ R １１ , -NR １１ R １１ , -OR １１ , -O-CH ２ -CH(OH)-CH ２ A 5-membered heteroaryl, 6-membered heteroaryl, or group of the following formula, optionally substituted with OH, -CN, oxetane, tetrahydrofuran, aryl, or methyl. 【Chemistry 17】 The C that was replaced by the aforementioned optional selection １ -C ３ Alkyl groups are -OH, C ３ -C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with a cycloalkyl, oxetane, tetrahydrofuran, aryl, five-membered heteroaryl, six-membered heteroaryl, or indole.

3. R and R １ However, together with the nitrogen to which they are bonded, they form a bicyclic ring which is optionally substituted from dihydrobenzimidazolone, dihydroindazolone, indolinone, or quinazolinone, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R is -H or C １ -C ３ It is alkyl, R １ However, the bicyclic ring is optionally substituted with isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolon, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, or C １ -C ６ They are optionally substituted with one to three substituents that are independently selected from each alkoxy, or R １ However, this is the basis of the following equation, [Chemistry 18] R' is C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, -NO ２ , -N(R １１ )-CO ２ C １ -C ３ Alkyl, -N(R) １１ ) - SO ２ C １ -C ３ Alkyl, -SO ２ NR １１ R １１ , -SO ２ N(R) １１ )-CO-C １ -C ３ Alkyl, -C(=N-OH)-NH ２ , -CN, -CONR １１ R １２ , -CON(R １１ )-(CH ２ ) ｎ -R １３ , or the following base, 【Chemistry 19】 In the formula, ring A is a 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 oxo, -OH, -NR １１ R １１ , -N(R １１ )-CO-R １１ , -N(R １１ ) -CN, -OR １１ ,-CN,C １ -C ６ C is optionally substituted with a haloalkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl. １ -C ６ It is optionally substituted with 1 to 3 substituents independently selected from the alkyl group. R ２ However, is it the basis of the following equation? 【Chemistry 20】 or R ２ However, is it the basis of the following equation? 【Chemistry 21】 or R ２ However, the five-membered ring heteroaryl is optionally substituted from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted five-membered ring heteroaryl is -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ -OH, -NR １１ R １１ , -NR １１ CO ２ R １１ , C replaced by arbitrary selection １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with a cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine; an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin; or an optionally substituted heteroaryl, each optionally substituted with a cycloalkyl, pyrrolidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; and the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C is replaced by the aforementioned arbitrary selection. ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, the compound is a bicyclic ring substituted with an optional bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, isoindorin-1-one, indorin-2-one, benzo[d]oxazole-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, or 2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine, or a bicyclic heteroaryl compound substituted with an optional bicyclic ring containing 8 to 10 ring atoms including 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optional bicyclic ring is a halogen and C １ -C ６ The alkyl group is optionally substituted with one to three substituents independently selected from each alkyl group, and the optionally substituted bicyclic heteroaryl group is -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ , -NR １１ R １１ , -NR １１ CO ２ R １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with a cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine; an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin; or an optionally substituted heteroaryl, each optionally substituted with a cycloalkyl, pyrrolidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; and the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, -CONR １１ R １１ C, which is optionally substituted with phenyl, and the C that is optionally substituted with phenyl ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN, or R ２ However, 1 to 3 R １０ Cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with a substituent, or R ２ However, this is the basis of the following equation, 【Chemistry 22】 Each R １０ However, independently, -H, -CN, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -CO ２ C １ -C ３ Alkyl, -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , -OH, C substituted by any choice １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C substituted by choice ２ -C ６ Alkinyl, optionally replaced with C ３ -C ５ A heterocycle optionally substituted with cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted with phenyl, optionally substituted with 1,3-benzodioxole, optionally substituted with 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is -CN, -OH, oxetanyl, C １ -C ３ Alkoxy, or -CONR １１ R １１ Each is replaced by an arbitrary selection, and C which is replaced by the aforementioned arbitrary selection ３ -C ５ Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocyclic, or heteroaryl compounds are halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, -SO ２ R １１ , -NR １１ R １１ Each of the substituents is optionally substituted with one to three substituents independently selected from -OH or -CN. R １２ However, C is replaced by -H, which is of arbitrary choice. １ -C ３ Alkyl, -SO ２ C １ -C ３ Alkyl, -O-CH ２ -CH(OH)-CH ２ OH, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, and C substituted as optionally described above. １ -C ３ The alkyl group is optionally substituted with an aryl group, a five-membered heteroaryl group, or a six-membered heteroaryl group. R １３ is -NR １１ R １１ , -OR １１ , oxetane, or tetrahydrofuran, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ８ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the following formula. 【Chemistry 23】

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

7. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H or a halogen.

8. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H.

9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the following formula. 【Chemistry 24】

10. R ３ is -H, -CN, C １ -C ３ alkyl, or C １ -C ３ haloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H, -CN, methyl, or trifluoromethyl.

12. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H or methyl.

13. R ５ However, -H, halogen, C １ -C ３ Alkyl, or C １ -C ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

14. R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H, halogen, methyl, or trifluoromethyl.

15. R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -H or a halogen.

16. A compound according to claim 1, selected from the following: 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 【Chemistry 25-6】 【Chemistry 25-7】 【Chemistry 25-8】 【Chemistry 25-9】 【Chemistry 25-10】 【Chemistry 25-11】 【Chemistry 25-12】 【Chemistry 25-13】 [Chemistry 25-14] 【Chemistry 25-15】 [Chemistry 25-16] 【Chemistry 25-17】 [Chemistry 25-18] 【Chemistry 25-19】 【Chemistry 25-20】 【Chemistry 25-21】 [Chemistry 25-22] [Chemistry 25-23] [Chemistry 25-24] 【Chemistry 25-25】 [Chemistry 25-26] [Chemistry 25-27] [Chemistry 25-28] [Chemistry 25-29] [Chemistry 25-30] [Chemistry 25-31] [Chemistry 25-32] [Chemistry 25-33] [Chemistry 25-34] [Chemistry 25-35] [Chemistry 25-36] [Chemistry 25-37] [Chemistry 25-38] [Chemistry 25-39] [Chemistry 25-40] [Chemistry 25-41] [Chemistry 25-42] [Chemistry 25-43] [Chemistry 25-44] [Chemistry 25-45] [Chemistry 25-46] [Chemistry 25-47] [Chemistry 25-48] [Chemistry 25-49] [Chemistry 25-50] [Chemistry 25-51] [Chemistry 25-52] [Chemistry 25-53] [Chemistry 25-54] [Chemistry 25-55] [Chemistry 25-56] [Chemistry 25-57] [Chemistry 25-58] [Chemistry 25-59] [Chemistry 25-60] [Chemistry 25-61] [Chemistry 25-62] [Chemistry 25-63] [Chemistry 25-64] [Chemistry 25-65] [Chemistry 25-66] [Chemistry 25-67] [Chemistry 25-68] [Chemistry 25-69] [Chemistry 25-70] [Chemistry 25-71] [Chemistry 25-72] [Chemistry 25-73] [Chemistry 25-74] [Chemistry 25-75] [Chemistry 25-76] 【Chemistry 25-77】 [Chemistry 25-78] or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmacopoeia for treating diseases or disorders associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable composition according to claim 17.

19. A pharmacokinetic agent for inhibiting phosphoinositide 3-kinase (PI3K), comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable composition according to claim 17.

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