MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 1. (canceled)2. A method for attenuating or ameliorating one or more symptoms of a cancerous tumor in a mammal in need thereof , the method comprising:(a) determining if the cancerous tumor exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and(b) if the cancerous tumor is determined to exhibit one or more of overexpression, activation, amplification, and mutation of a Trk kinase, administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R, 15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1 (24),7, 9,11,18(25), 19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '23,27, '(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0.0.0]heptacosa-1 (26),7,9,11,20(27),21,24-heptaen-19-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9,15,15- ...

Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors

Compounds of Formula I: and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

KRAS G12C INHIBITORS

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor. 2. A pharmaceutical composition claim 1 , comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.3. A method for inhibiting KRas G12C activity in a cell claim 1 , comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of according to any one of or .4. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound according to any one of or .5. The method of claim 4 , wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.6. The method of claim 5 , wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.7. The method of claim 4 , wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma claim 4 , fibrosarcoma claim 4 , rhabdomyosarcoma claim 4 , liposarcoma) claim 4 , myxoma claim 4 , rhabdomyoma claim 4 , fibroma claim 4 , lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell claim 4 , undifferentiated small cell claim 4 , undifferentiated large cell claim 4 , adenocarcinoma) claim 4 , alveolar (bronchiolar) carcinoma claim 4 , bronchial adenoma claim 4 , sarcoma claim 4 , lymphoma claim 4 , chondromatous hamartoma claim 4 , mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma claim 4 , adenocarcinoma claim 4 , leiomyosarcoma claim 4 , lymphoma) claim 4 , stomach (carcinoma claim 4 , lymphoma claim 4 , leiomyosarcoma) claim 4 , pancreas (ductal adenocarcinoma claim 4 , insulinoma claim 4 , glucagonoma claim 4 , gastrinoma claim 4 , carcinoid tumors claim 4 , vipoma) ...

PYRROLIDINYL UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS

Compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R, R, R, R, R, R, X, Ring B, and Ring C are as defined herein, and wherein Ring B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome. 2. A compound according to claim 1 , wherein X is O.34-. (canceled)5. A compound according to claim 1 , wherein Ris (1-3C alkoxy)(1-6C)alkyl.6. A compound according to claim 1 , wherein Ring B is Ar.710-. (canceled)11. A compound according to claim 1 , wherein Ring C is formula C-1 or C-2.12. (canceled)13. A compound according to claim 1 , wherein Ring C is formula C-3 claim 1 , C-4 claim 1 , C-5 claim 1 , C-6 or C-13.1415-. (canceled)16. A compound according to claim 1 , wherein Ring C is formula C-7.17. (canceled)18. A compound according to claim 1 , wherein Ring C is formula C-8 or C-9.1925-. (canceled)26. A compound according to claim 1 , wherein Ring C is formula C-10 claim 1 , C-11 or C-12.27. (canceled)28. A compound according to claim 1 , wherein Ris H.29. A compound according to claim 1 , wherein R claim 1 , R claim 1 , Rand Rare H.32. A compound of claim 1 , selected from a compound of Examples 1-56 or a pharmaceutically acceptable salt thereof.33. A pharmaceutical composition claim 1 , which comprises a compound of Formula I as defined in or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable diluent or carrier.34. A method for treating a disease or disorder selected from pain claim 1 , cancer claim 1 , inflammation/inflammatory diseases claim 1 , neurodegenerative diseases claim 1 , certain infectious ...

PYRROLIDINYL UREA, PYRROLIDINYL THIOUREA AND PYRROLIDINYL GUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS

Compounds of Formula I: 137-. (canceled)39. The method of claim 38 , where Aris phenyl optionally substituted with one or m ore halogens.40. The method of claim 39 , where hetAris a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N claim 39 , S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl. The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to pyrrolidinyl urea and pyrrolidinyl thiourea compounds which exhibit TrkA kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.The current treatment regimens for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addictions. Non-steroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., 2001, 11, 272-280).Inhibitors of the Trk/ ...

KRAS G12C INHIBITORS

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor. 3. The method of claim 2 , wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.4. The method of claim 2 , wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.5. The method of claim 2 , wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma claim 2 , fibrosarcoma claim 2 , rhabdomyosarcoma claim 2 , liposarcoma) claim 2 , myxoma claim 2 , rhabdomyoma claim 2 , fibroma claim 2 , lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell claim 2 , undifferentiated small cell claim 2 , undifferentiated large cell claim 2 , adenocarcinoma) claim 2 , alveolar (bronchiolar) carcinoma claim 2 , bronchial adenoma claim 2 , sarcoma claim 2 , lymphoma claim 2 , chondromatous hamartoma claim 2 , mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma claim 2 , adenocarcinoma claim 2 , leiomyosarcoma claim 2 , lymphoma) claim 2 , stomach (carcinoma claim 2 , lymphoma claim 2 , leiomyosarcoma) claim 2 , pancreas (ductal adenocarcinoma claim 2 , insulinoma claim 2 , glucagonoma claim 2 , gastrinoma claim 2 , carcinoid tumors claim 2 , vipoma) claim 2 , small bowel (adenocarcinoma claim 2 , lymphoma claim 2 , carcinoid tumors claim 2 , Kaposi's sarcoma claim 2 , leiomyoma claim 2 , hemangioma claim 2 , lipoma claim 2 , neurofibroma claim 2 , fibroma) claim 2 , large bowel (adenocarcinoma claim 2 , tubular adenoma claim 2 , villous adenoma claim 2 , hamartoma claim 2 , leiomyoma); Genitourinary tract: kidney (adenocarcinoma claim 2 , Wilm's tumor (nephroblastoma) claim 2 , lymphoma claim 2 , leukemia) claim 2 , bladder and urethra (squamous cell carcinoma claim 2 , ...

PYRROLIDINYL UREA, PYRROLIDINYL THIOUREA AND PYRROLIDINYL GUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R, R, R, R, R, R, X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 2. A compound according to claim 1 , wherein Ris (1-3C alkoxy)(1-6C)alkyl claim 1 , (trifluoromethoxy)(1-6C)alkyl claim 1 , (1-3C sulfanyl)(1-6C)alkyl claim 1 , mono fluoro(1-6C)alkyl claim 1 , difluoro(1-6C)alkyl claim 1 , trifluoro(1-6C)alkyl claim 1 , tetrafluoro(2-6C)alkyl claim 1 , pentafluro(2-6C)alkyl claim 1 , cyano(1-6C)alkyl claim 1 , aminocarbonyl(1-6C)alkyl claim 1 , hydroxy(1-6C)alkyl claim 1 , dihydroxy(2-6C)alkyl claim 1 , (1-6C)alkyl claim 1 , or (1-3Calkylamino)(1-3C)alkyl.3. A compound according to claim 2 , wherein Ris selected from (1-3C alkoxy)(1-6C)alkyl claim 2 , difluoro(1-6C)alkyl claim 2 , and trifluoro(1-6C)alkyl.4. A compound according to claim 3 , wherein Ris (1-3C alkoxy)(1-6C)alkyl.5. A compound according to claim 1 , wherein B is Aror hetAr.6. A compound according to claim 1 , wherein B is Ar.7. A compound according to claim 6 , wherein Aris phenyl optionally substituted with one or more halogens.8. A compound according to claim 1 , wherein B is hetAr.9. A compound according to claim 8 , wherein hetAris pyridyl optionally substituted with 1-2 groups independently selected from (1-6C)alkyl or halogen.10. A compound according to claim 1 , wherein Ris H.11. A compound according to claim 1 , wherein R claim 1 , R claim 1 , Rand Rare H.12. A compound according to claim 1 , wherein Y is a bond.13. A compound according to claim 1 , wherein:{'sup': '1', 'Ris selected from (1-3C alkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, and trifluoro(1-6C)alkyl;'}Y is a ...

Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors

Compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Ring B, and Ring C are as defined herein, and wherein Ring B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

MACROCYCLIC COMPOUNDS AS ROS1 KINASE INHIBITORS

Methods for inhibiting a ROS1 kinase with compounds of Formula I: 1. A method for treating a ROS1-associated cancer in a subject in need thereof , wherein the cancer has a fusion selected from the group consisting of: TPD52L1-ROS1 , CCDC30-ROS1 , FYN-ROS1 , MKX-ROS1 , and LIMA1-ROS1 , the method comprising administering a compound selected from the group consisting of:(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7, 9,11,18(25), 19,22-heptaen-17-one;(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.02,6.07,12.023,27]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23- ...

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and salts thereof in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: 1. (canceled)2. A compound selected from the group consisting of:5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)—N-(2-(1H-imidazol-4-yl)ethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-(methylsulfonamido)propan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((cis)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;N-(1-cyclopropylethyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;5-((R)-2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and 'or a pharmaceutically acceptable salt thereof.', '(R)—N-(cyclopropylmethyl)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,'}3. The compound of claim 2 , wherein the compound is5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.4. The compound of claim 2 , wherein the compound is(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.5. The compound of claim 2 , ...

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 1. (canceled)2. A pharmaceutical composition comprising a compound selected from the group consisting of:{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one'}{'sup': 2,6', '7,12', '22,26, '(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7, 9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '23,27, '(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0.0.0]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)- ...

Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

N-Substituted-N-Sulfonylaminocyclopropane Compounds and Pharmaceutical Use Thereof

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a N-substituted-N-sulfonylaminocyclopropane compound of formula (1) wherein R1 is —W-A1-W1-A2, W is —(CH2)m—X—(CH2)n—, wherein W1 is —(CH2)m1—X1—(CH2)n1—, m, m1, n and n1 are the same or different and each is 0 to 6, X and X1 are the same or different and each is a single bond, etc., A1 is an optionally substituted C3-14 hydrocarbon ring group, etc. and A2 is a substituted C3-14 hydrocarbon ring group etc.; R2 is —(CH2)r—CO—R8, etc., wherein r is 0 to 6 and R8 is a C1-6 alkoxy group, etc.; R3 and R4 are the same or different and each is a hydrogen atom, a C1-6 alkyl group, etc.; and R5 is —CO2R21, etc.; R30 and R31 are the same or different and each is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

BICYCLIC UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF PAIN

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome. 2. A compound according to claim 1 , wherein X is O.3. (canceled)4. A compound according to claim 2 , wherein zero to four of R claim 2 , R claim 2 , R claim 2 , R claim 2 , R claim 2 , R claim 2 , Rand Rare independently H claim 2 , OH claim 2 , (1-6C)alkyl [optionally substituted with one to five fluoros] claim 2 , (3-6C)cycloalkyl [optionally substituted with one to five fluoros] claim 2 , (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros] claim 2 , hydroxy(2-6C)alkyl [optionally substituted with one to five fluoros] claim 2 , (2-6C)cyanoalkyl claim 2 , (1-6C)alkoxy [optionally substituted with one to five fluoros] claim 2 , or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros] claim 2 ,{'sup': d', 'e', 'f', 'g', 'h', 'i', 'j', 'k', 'd', 'e', 'f', 'g', 'h', 'i', 'j', 'k', 'd', 'e', 'f', 'g', 'h', 'i', 'j', 'k, 'or one of a pair of Rand R, or Rand R, or Rand R, or Rand R, together with the carbon atom to which they are attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, or one of a pair of Rand R, or Rand R, or Rand R, or Rand Rform an oxo group, and the remainder are hydrogen, wherein only one of Rand Rcan be OH and neither is OH if B is connected to a heteroatom, and only one of Rand Rcan be OH and neither is OH if D is connected to a heteroatom, and only one of Rand Rcan be OH and neither is OH if E is connected to a heteroatom, and only one of Rand Rcan be OH and neither is Oil if F is ...

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof

Process for preparing (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3-ol (formula 14). Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formula 12). Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R)-2-hydroxysuccinate (formula 10) by treating (R)—N—((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (formula 19) with an acid and a reducing agent. (S)—N-(5-((R)-2-(2,5-difluorophenyl ...

Compounds and methods for inhibiting hepatitis C viral replication

Macrocyclic compounds having the structures described herein are useful for inhibiting replication of the hepatitis C virus (HCV). In preferred embodiments, the compounds are active against both the NS3 protease and the NS3 helicase of HCV.

KRas G12C inhibitors

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Fused heterocyclic compounds as RET kinase inhibitors

Provided herein are compounds of the Formula (I): (I) and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein Rx, Ry, W, X, Y, Z, Ring A and (AA) have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the General Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 3. The method of claim 2 , wherein E is:{'sup': '1', '(h) ArC1-C6 alkyl-, or'}{'sup': '2', '(j) hetArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.'}5. The method of claim 4 , wherein E is{'sup': '2', '(j) hetArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, or'}{'sup': '2', '(l) hetArC(═O)—.'}6. The method of claim 3 , wherein B is(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or{'sup': 'a', '(i) (hetCyc)C1-C3 alkyl-.'}7. The method of claim 5 , wherein B is(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,{'sup': 1', '2', '1', '2, '(f) (RRN)C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with OH and wherein Rand Rare independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros),'}{'sup': 1', '1, '(g) hetArC1-C3 alkyl-, wherein hetAris a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or'}{'sup': 'a', '(i) (hetCyc)C1-C3 alkyl-.'}8. The method of claim 1 , wherein Xis N claim 1 , and X claim 1 , Xand Xare CH.9. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;(R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- ...

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal. 1. (canceled)2. A method for attenuating or ameliorating one or more symptoms of a cancerous tumor in a mammal in need thereof , the method comprising:(a) detecting a cancerous tumor that exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase;(b) administering to the mammal a therapeutically effective amount of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3 -hydroxypyrrolidine-1-carboxamide sulfate or a pharmaceutically acceptable salt or solvate thereof; and(c) performing surgery to at least partially resect the tumor in the mammal.3. The method of claim 2 , wherein (c) occurs before (b).4. The method of claim 2 , wherein (b) occurs before (c).5. The method of claim 4 , further comprising claim 4 , after (c) claim 4 , administering to the mammal a therapeutically effective amount of (S)-N-(5-((R)-2-(2 claim 4 ,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1 claim 4 ,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate or a pharmaceutically acceptable salt or solvate thereof.6. The method of claim 2 , further comprising administering to the mammal one or more agents selected from the group consisting of mitotic inhibitors claim 2 , alkylating agents claim 2 , antimetabolites claim 2 , antisense DNA or RNA claim 2 , intercalating antibiotics claim 2 , growth factor inhibitors claim 2 , signal transduction inhibitors claim 2 , cell cycle inhibitors claim 2 , enzyme inhibitors claim 2 , retinoid receptor modulators claim 2 , proteasome inhibitors claim 2 , topoisomerase inhibitors claim 2 , biological response modifiers claim 2 , antihormones claim 2 , angiogenesis inhibitors claim 2 , cytostatic agents anti-androgens claim 2 , targeted antibodies claim 2 , HMG-CoA reductase inhibitors claim 2 , and prenyl-protein transferase ...

MACROCYCLIC COMPOUNDS AS ROS1 KINASE INHIBITORS

Methods for inhibiting a ROS1 kinase with compounds of Formula I: 1. A method for treating a ROS1-associated cancer in a subject in need thereof , wherein the cancer has a fusion selected from the group consisting of: CCDC30-ROS1 , FYN-ROS1 , and MKX-ROS1 , the method comprising administering a compound selected from the group consisting of:(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.02,6.07,12.023,27]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1 (25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02,6.07,12.022,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one; and(6R)-9- ...

Macrocyclic compounds as Trk kinase inhibitors

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula (I) and salts thereof in which R, R, R, R, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 2. A compound of claim 1 , wherein:{'sup': '1', 'Ris H or -(1-6C alkyl);'}{'sup': 2', '1', '1', '2', '2', '1, 'sub': 2', '2', '2', '2', '2, 'Ris H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SONH, -(1-6C alkyl)NHSO(1-3C alkyl), -(1-6C alkyl)NH, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl), -(1-6C alkyl)hetCyc, -(1-6C alkyl)hetAr, hetAr, hetCyc, —O(1-6C alkyl), —O(3-6C cycloalkyl), Cyc, or a bridged 7-membered cycloalkyl ring,'}{'sup': 1', '2, 'sub': 2', '2, 'or NRRforms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —COH and -(1-3C alkyl)COH;'}{'sup': 1', '1, 'hetCycis a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycis optionally substituted with oxo;'}{'sup': 2', '2, 'sub': 2', '2', '2, 'hetCycis a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycis optionally substituted with F, SONH, or SO(1-3C alkyl);'}{'sup': '1', 'hetAris a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with -(1-4C)alkyl;'}{'sup': '2', 'hetAris a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from -(1-4C)alkyl;'}{'sup': '1', 'sub': '2', 'Cycis 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —COH and -(1-4C alkyl) ...

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-a] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or infection in a mammal. 1. (canceled)3. The compound of claim 2 , wherein Y is phenyl optionally substituted with one or more halogen atoms.4. The compound of claim 3 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.5. The compound of claim 2 , wherein n is zero or one.6. The compound of claim 5 , wherein Ris hydrogen.7. The compound of claim 6 , wherein Ris hydrogen.8. The compound of claim 2 , wherein the compound of Formula (I) is a trifluoroacetate salt claim 2 , a sulfate salt or a hydrochloride salt.9. The compound of claim 8 , wherein the compound of Formula (I) is a sulfate salt.10. The compound of claim 2 , wherein the compound of Formula (I) is selected from the group consisting of:(R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)morpholine-4-carboxamide;(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)morpholine-4-carboxamide;(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;(3R,4R)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide;(R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)morpholine-4-carboxamide;(S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate;(S)—N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide;(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-4-isopropylpiperazine-1-carboxamide;(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-4-ethylpiperazine-1-carboxamide;(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-4-methylpiperazine-1-carboxamide;N ...

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the General Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

Method of Treatment Using Substituted Imidazo[1,2b]Pyridazine Compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I 1. (canceled)3. The method of claim 2 , wherein the solid tumor is selected from the group consisting of: breast claim 2 , prostate claim 2 , lung claim 2 , renal claim 2 , thyroid claim 2 , neuroblastoma claim 2 , ovarian cancer claim 2 , breast cancer claim 2 , pancreatic cancer claim 2 , astrocytoma and medulloblastoma claim 2 , glioma claim 2 , melanoma claim 2 , lung adenocarcinoma claim 2 , large cell neuroendocrine tumors claim 2 , colorectal cancer claim 2 , stomach claim 2 , bladder claim 2 , uterus claim 2 , rectum claim 2 , and kidney.4. The method of claim 2 , wherein Ris NRR.5. The method of claim 2 , wherein:{'sup': b', 'c, 'sub': '2', 'NRRforms a 4 membered heterocyclic ring having a ring nitrogen atom optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH, —NHC(═O)O(1-4C alkyl), and (1-4C)hydroxyalkyl,'}{'sup': b', 'c, 'sub': 2', '3', '2', '2', '2, 'or NRRforms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF, (1-4C)alkyl, CO(1-4C alkyl), COH, NH, NHC(═O)O(1-4C alkyl) and oxo,'}{'sup': b', 'c, 'sub': '2', 'or NRRforms a 7-8 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with CO(1-4C alkyl).'}6. The method of claim 2 , wherein:{'sup': 'b', 'Ris H or (1-6C alkyl); and'}{'sup': c', '3, 'sub': '3', 'Ris H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr, or phenyl, wherein said phenyl is optionally substituted with one or more ...

Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

Method of treatment using substituted imidazo[1,2b]pyridazine compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification.

Macrocyclic compounds as TRK kinase inhibitors

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, R 2 , R 2a , R 3 , R 3a , and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors

Compounds of Formula I: and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 2. The compound according to claim 1 , wherein D is hetCyc.3. The compound according to claim 2 , wherein hetCycis a pyrrolidinyl claim 2 , piperidinyl claim 2 , piperazinyl claim 2 , morpholinyl or azetidinyl ring optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl claim 2 , fluoroC1-C3 alkyl claim 2 , difluoroC1-C3 alkyl claim 2 , trifluoroC1-C3 alkyl and OH claim 2 , or hetCycis a piperazinyl ring substituted with a C3-C6 cycloalkylidene ring claim 2 , or hetCycis a piperazinyl ring substituted with an oxo group.4. The compound according to claim 3 , wherein hetCycis piperazinyl.5. The compound according to claim 1 , wherein E is(a) hydrogen,(d) C1-C6 alkyl optionally substituted with one to three fluoros,(e) hydroxyC1-C6 alkyl optionally substituted with one to three fluoros,(i) (C1-C6 alkyl)C(═O)— optionally substituted with one to three fluoros,(j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to three fluoros,(k) (C1-C6 alkoxy)C(═O)—,(l) (C1-C6 alkoxy)(C1-C6 alkyl)C(═O)—,{'sup': '1', '(n) Cyc,'}{'sup': '1', '(o) CycC(═O)—,'}{'sup': 1', 'c', 'd', 'c', 'd, '(p) Cyc(C1-C6 alkyl)C(═O)— wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, fluoro, C1-C3 alkoxy and RRN—, where Rand Rare independently H or C1-C6 alkyl,'}{'sup': '4', '(q) hetCyc,'}{'sup': '4', '(r) hetCycC(═O)—,'}{'sup': '4', '(s) hetCyc(C1-C3 alkyl)C(═O)—,'}{'sup': '4', '(t) (hetCyc)C(═O)C1-C2 alkyl,'}{'sup': '2', '(w) ArC(═O)—,'}{'sup': '2', '(x) ArC1-C6 alkyl,'}{'sup': '2', '(y) (Ar)hydroxy C2-C6 alkyl,'}{'sup': 2', 'e', 'f', 'e', 'f, '(z) Ar(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and RRN—, wherein Rand Rare independently H or C1-C6 ...

Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 1. (canceled)5. The method of claim 2 , wherein Y is F.6. The method of claim 2 , wherein Ris H.7. The method of claim 2 , wherein Ris hydrogen.8. The method of claim 2 , wherein Rand Rare each hydrogen.9. The method of claim 2 , wherein W is CH.10. The method of claim 2 , wherein m is 0.11. The method of claim 2 , wherein m is 1.13. The method of claim 2 , wherein the Trk kinase is selected from the group consisting of TrkA claim 2 , TrkB claim 2 , and TrkC.14. The method of claim 2 , wherein the cancerous tumor is selected from the group consisting of: neuroblastoma claim 2 , ovarian claim 2 , pancreatic claim 2 , colorectal claim 2 , prostate claim 2 , melanoma claim 2 , head and neck cancer claim 2 , gastric carcinoma claim 2 , lung carcinoma claim 2 , breast cancer claim 2 , glioblastoma claim 2 , medulloblastoma claim 2 , secratory breast cancer claim 2 , salivary gland cancer claim 2 , and papillary thyroid carcinoma.15. The method of claim 2 , wherein the cancerous tumor exhibits overexpression of a Trk kinase.16. The method of claim 2 , wherein the cancerous tumor exhibits activation of a Trk kinase.17. The method of claim 2 , wherein the cancerous tumor exhibits amplification of a Trk kinase.18. The method of claim 2 , wherein the cancerous tumor exhibits mutation of a Trk kinase. The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain macrocyclic compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation, ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 4. A compound according to claim 3 , wherein E is{'sup': '2', '(w) ArC(═O)—,'}{'sup': '2', '(x) ArC1-C6 alkyl,'}{'sup': 2', 'e', 'f', 'e', 'f, '(cc) hetAr(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and RRN—, wherein Rand Rare independently H or C1-C6 alkyl,'}{'sup': 1', '2, '(dd) RRNC(═O)—, or'}{'sup': '2', '(oo) hetArC1-C6 alkyl.'}6. The compound according to claim 5 , wherein E is{'sup': 1', '2, '(dd) RRNC(═O)—.'}7. A compound according to claim 1 , wherein Xis N claim 1 , and X claim 1 , X claim 1 , and Xare CH.8. A compound according to claim 1 , wherein Xis CH claim 1 , Xis N claim 1 , and Xand Xare CH.20. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , in admixture with a pharmaceutically acceptable diluent or carrier. This application is a continuation of U.S. application Ser. No. 15/211,702, filed Jul. 15, 2016, which claims priority to U.S. Provisional Application Ser. No. 62/193,448, filed Jul. 16, 2015 and 62/274,018, filed Dec. 31, 2015, both of which are hereby incorporated by reference in their entireties.The present disclosure relates to novel compounds which exhibit Rearranged during Transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, it relates to substituted pyrazolo[1,5-a]pyridine compounds useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation and maintenance of several ...

Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X1, X2, X3, X4, Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Cyclopropane compounds and pharmaceutical use thereof

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R1 is (CH2)mX(CH2)n-A1 etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A1 is a substituted C3-14 hydrocarbon ring group, etc.; R2 and R3 are the same or different and each is a hydrogen atom, (CH2)pX1(CH2)q-A2, etc., wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc. and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc.; R4 is CO2R9, etc., wherein R9 is a hydrogen atom, etc.; and R20 and R21 are the same or different and each is a hydrogen atom, (CH2)m12X12(CH2)m12R30, etc., wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc. and R30 is a hydrogen atom, etc.; or a prodrug thereof or ...

Crystalline forms

Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which exhibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use ...

Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof

In some embodiments, provided herein are processes for preparing a compound of Formula C or a salt thereof, as disclosed herein. In some embodiments, provided herein is a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, provided herein is a solid form of the compound, such as a crystalline form of the compound crystalline Form I.

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or infection in a mammal. This application is a divisional of U.S. Ser. No. 13/125,263 filed Apr. 20, 2011, which is a Section 371(e) filing from PCT/US09/061,519, filed Oct. 21, 2009, which claims the benefit of U.S. provisional patent application No. 61/107,616 filed Oct. 22, 2008, each of which is incorporated herein in its entirety.The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted pyrazolo[1,5-a]pyrimidine compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, inflammation, cancer, and certain infectious diseases.The current treatment regimes for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addictions. Non-steroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members—TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells ( ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 3. The method of claim 2 , wherein E is:{'sup': '1', '(h) ArC1-C6 alkyl-, or'}{'sup': '2', '(j) hetArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.'}5. The method of claim 4 , wherein E is{'sup': '2', '(j) hetArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, or'}{'sup': '2', '(l) hetArC(═O)—.'}6. The method of claim 3 , wherein B is(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or{'sup': 'a', '(i) (hetCyc)C1-C3 alkyl-.'}7. The method of claim 5 , wherein B is(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,{'sup': 1', '2', '1', '2, '(f) (RRN)C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with OH and wherein Rand Rare independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros),'}{'sup': 1', '1, '(g) hetArC1-C3 alkyl-, wherein hetAris a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or'}{'sup': 'a', '(i) (hetCyc)C1-C3 alkyl-.'}8. The method of claim 1 , wherein Xis N claim 1 , and X claim 1 , Xand Xare CH.9. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;(R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- ...

Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors

Compounds of Formula I: and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal. 13.-. (canceled)5. The method of claim 4 , wherein the cancer is mediated by a Trk kinase.6. The method of claim 4 , wherein the cancer is mediated by TrkA.7. The method of claim 4 , wherein the cancer is mediated by TrkB.8. The method of claim 4 , wherein the cancer is mediated by TrkA and TrkB.9. The method of claim 4 , wherein the cancer is associated with one or more of overexpression claim 4 , activation claim 4 , amplification claim 4 , and mutation of a Trk kinase.10. The method of claim 9 , wherein the Trk kinase is selected from one or more of:TrkA, TrkB, and TrkC.11. The method of claim 4 , wherein the cancer is associated with overexpression of a Trk kinase.12. The method of claim 4 , wherein the cancer is associated with activation of a Trk kinase.13. The method of claim 4 , wherein the cancer is associated with amplification of a Trk kinase.14. The method of claim 4 , wherein the cancer is associated with mutation of a Trk kinase.15. The method of claim 4 , wherein the cancer is a hematological malignancy.16. The method of claim 15 , wherein the cancer is selected from the group consisting of myeloma and lymphoma.17. The method of claim 4 , wherein the cancer is a solid tumor.18. The method of claim 17 , wherein the cancer is selected from the group consisting of a breast cancer claim 17 , a lung cancer claim 17 , a renal cancer claim 17 , a thyroid cancer claim 17 , an ovarian cancer claim 17 , a prostate cancer claim 17 , a pancreatic cancer claim 17 , and a colorectal cancer.19. The method of claim 4 , wherein the cancer is selected from the group consisting of a neuroblastoma claim 4 , a multiple myeloma claim 4 , an astrocytoma claim 4 , a medulloblastoma claim 4 , a glioma claim 4 , a melanoma claim 4 , a thyroid carcinoma claim 4 , a lung adenocarcinoma claim 4 , a bone metastasis claim 4 , ...

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS

Provided herein are methods for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal in need thereof a therapeutically effective amount of a compound of Formula I: in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification.

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or infection in a mammal. 1. (canceled)3. The method of claim 2 , wherein Y is phenyl optionally substituted with one or more halogen atoms.4. The method of claim 3 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.5. The method of claim 2 , wherein n is zero or one.6. The method of claim 5 , wherein Ris hydrogen.7. The method of claim 6 , wherein Ris hydrogen.8. The method of claim 2 , wherein the compound of Formula (I) is a trifluoroacetate salt claim 2 , a sulfate salt or a hydrochloride salt.9. The method of claim 8 , wherein the compound of Formula (I) is a sulfate salt.11. The method of claim 10 , wherein the compound is a trifluoroacetate salt claim 10 , a sulfate salt claim 10 , or a hydrochloride salt.13. The method of claim 2 , wherein the dosage form is an oral preparation for oral administration.14. The method of claim 13 , wherein the oral preparation is a solid oral preparation or a liquid oral preparation.15. The method of claim 14 , wherein the oral preparation is a capsule claim 14 , tablet claim 14 , solution claim 14 , dispersion claim 14 , suspension claim 14 , syrup claim 14 , or emulsion.16. The method of claim 2 , wherein the Trk kinase is selected from the group consisting of TrkA claim 2 , TrkB claim 2 , and TrkC.18. The method of claim 17 , wherein Y is phenyl optionally substituted with one or more halogen atoms.19. The method of claim 18 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.20. The method of claim 17 , wherein n is zero or one.21. The method of claim 20 , wherein Ris hydrogen.22. The method of claim 21 , wherein Ris hydrogen.23. The method of claim 17 , wherein the compound of Formula (I) is a trifluoroacetate salt claim 17 , a sulfate salt or a hydrochloride salt.24. The compound of claim 23 , wherein the compound of Formula (I) is a sulfate salt.26. The method ...

Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the General Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

MACROCYCLIC COMPOUNDS AS ROS1 KINASE INHIBITORS

Methods for inhibiting a ROS1 kinase with compounds of Formula I: 1. A method for treating a ROS1-associated cancer in a subject in need thereof , wherein the cancer has a fusion selected from the group consisting of: CCDC30-ROS1 , FYN-ROS1 , MKX-ROS1 , CLTC-ROS1 , NFkB2-ROS1 , and NCOR2-ROS1 , the method comprising administering a compound selected from the group consisting of:{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '23,27, '(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0.0.0]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '21,25, '(6R,15R)-9-fluoro-15- ...

METHOD OF TREATMENT USING SUBSTITUTED IMIDAZO[1,2B]PYRIDAZINE COMPOUNDS

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I 2. The method of claim 1 , wherein Ris NRR.3. The method of claim 2 , wherein:{'sup': b', 'c, 'sub': '2', 'NRRforms a 4 membered heterocyclic ring having a ring nitrogen atom optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH, —NHC(═O)O(1-4C alkyl), and (1-4C)hydroxyalkyl,'}{'sup': b', 'c, 'sub': 2', '3', '2', '2', '2, 'or NRRforms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF, (1-4C)alkyl, CO(1-4C alkyl), COH, NH, NHC(═O)O(1-4C alkyl) and oxo,'}{'sup': b', 'c, 'sub': '2', 'or NRRforms a 7-8 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with CO(1-4C alkyl).'}4. The method of claim 2 , wherein:{'sup': 'b', 'Ris H or (1-6C alkyl); and'}{'sup': c', '3, 'sub': '3', 'Ris H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CFand —O(1-4C alkyl).'}5. The method of claim 1 , wherein Ris (1-4C)alkyl claim 1 , (1-4C)fluoroalkyl claim 1 , CF claim 1 , -(1-4C alkyl)hetAr claim 1 , or -(1-4C alkyl)NH(1-4C alkyl).6. The method of claim 1 , wherein X is null claim 1 , —CH— or —CHCH—.7. The method of claim 1 , wherein Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen claim 1 , (1-4C)alkoxy claim 1 , CFand CHF.9. The method of claim 1 , wherein Ris H.10. ...

Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

Cyclopropane compounds and pharmaceutical use thereof

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R¹ is -(CH₂)_m-X-(CH₂)_n-A¹ etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A¹ is a substituted C_3-14 hydrocarbon ring group, etc.; R² and R³ are the same or different and each is a hydrogen atom, -(CH₂)_p-X₁-(CH₂)_q-A², etc., wherein p and q are the same or different and each is 0 to 6, X₁ is a single bond, etc. and A² is an optionally substituted C_3-14 hydrocarbon ring group, etc.; R⁴ is -CO₂R⁹, etc., wherein R⁹ is a hydrogen atom ...

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 4. The method of claim 3 , wherein E is{'sup': '2', '(w) ArC(═O)—,'}{'sup': '2', '(x) ArC1-C6 alkyl,'}{'sup': 2', 'e', 'f', 'e', 'f, '(cc) hetAr(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and RRN—, wherein Rand Rare independently H or C1-C6 alkyl,'}{'sup': 1', '2, '(dd) RRNC(═O)—, or'}{'sup': '2', '(oo) hetArC1-C6 alkyl.'}6. The method of claim 5 , wherein E is{'sup': '2', '(dd) RIRNC(═O)—.'}7. The method of claim 1 , wherein Xis N claim 1 , and X claim 1 , X claim 1 , and Xare CH.8. The method of claim 1 , wherein Xis CH claim 1 , Xis N claim 1 , and Xand Xare CH.20. The method of claim 1 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL) claim 1 , acute myeloid leukemia (AML) claim 1 , breast cancer claim 1 , cervical cancer claim 1 , colorectal cancer claim 1 , ganglioneuromatosis of the gastroenteric mucosa claim 1 , gastric cancer claim 1 , gastrointestinal stromal tumors claim 1 , glioma claim 1 , leukemia claim 1 , lung cancer claim 1 , lymphoma claim 1 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 1 , respectively) claim 1 , multiple myeloma claim 1 , non-Hodgkin's lymphoma claim 1 , non-small cell lung cancer claim 1 , ovarian cancer claim 1 , papillary renal cell carcinoma claim 1 , paraganglioma claim 1 , parathyroid hyperplasia claim 1 , pheochromocytoma claim 1 , and thyroid cancer.21. The method of claim 20 , wherein the cancer is leukemia.22. The method of claim 1 , wherein the dysregulation of a RET gene claim 1 , a RET kinase claim 1 , or the expression or activity or level of any of the same results in the translation of a RET fusion protein or a mutation of a RET kinase.23. The method of claim 21 , wherein the RET fusion protein is selected from the group consisting of BCR-RET ...

Method of Treatment Using Substituted Imidazo[1,2b]Pyridazine Compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I 1. (canceled)2. A compound selected from the group consisting of:(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide;(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(methyl sulfonamido)benzamide;(S)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;(R)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-hydroxypiperidine-1-carboxamide;(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)piperidine-1-carboxamide;(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(4-methoxyphenyl)urea;(3R,4R)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide;(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,3-difluoropyrrolidine-1-carboxamide;(R)-tert-butyl 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2,2-dimethylpiperazine-1-carboxylate;(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(hydroxymethyl)azetidine-1-carboxamide; and(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide;or a pharmaceutically acceptable salt thereof.3. The compound of claim 2 , wherein the compound is(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide, or a pharmaceutically acceptable salt thereof.4. The compound of claim 2 , wherein the compound is(R)—N-(6-(2 ...

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, RRand Rare as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 1. A compound of the general Formula Ior pharmaceutically acceptable salts thereof, wherein:ring A is selected from rings A-1, A-2 and A-3 having the structures: X is N or CH;', 'Y is H or F;', {'sup': '1', 'Ris H, (1-3C)alkoxy or halogen;'}, 'ring B is selected from rings B-1 and B-2 having the structures:, 'wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;'} [{'sub': 2', '2, 'W is O, NH or CH, wherein when ring A is A-2, then W is CH;'}, 'm is 0, 1 or 2;', {'sup': 2', '2a', '2', '2a', '3', '3a, 'D is carbon, Rand Rare independently H, F, (1-3 C)alkyl or OH (provided that Rand Rare not both OH), and Rand Rare independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl, or'}], 'wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[1,5-a]pyrimidine ring of Formula I;'}{'sup': 2', '3', '2a', '3a, 'D is carbon or nitrogen, Rand Rare absent, and Rand Rtogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;'}{'sup': 4a', '4b', '3, 'sub': '2', 'Z is *—NRC(═O)—, *—ONHC(═O)—, *—NRCH- or *—OC(═O)-, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R;'}{'sup': '4a', 'Ris H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl);'}{'sup': 4b', '1', '2, 'sub': 2', '2', '2', '2, 'Ris H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)-, (3-6C ...

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: 1. (canceled)3. The compound of claim 2 , wherein:{'sub': '2', 'X is CH; and'}{'sup': 3', '3, 'Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc, -(1-4C alkyl)hetCyc, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.'}4. The compound of claim 2 , wherein Ris H.6. The compound of claim 5 , wherein:{'sub': '2', 'X is CH; and'}{'sup': 3', '3, 'Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc, -(1-4C alkyl)hetCyc, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.'}7. The compound of claim 5 , wherein Ris H.9. The compound of claim 8 , wherein:{'sub': '2', 'X is CH; and'}{'sup': 3', '3, 'Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc, -(1-4C alkyl)hetCyc, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.'}10. The compound of claim 8 , wherein Ris H.12. The compound of claim 11 , wherein:{'sup': '1', 'Ris H or -(1-6C alkyl);'}{'sup': 2', '1', '1', '2', '2', '1, 'sub': 2', '2', '2', '2', '2, 'Ris H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SONH, -(1-6C alkyl)NHSO(1-3C alkyl), -(1-6C alkyl)NH, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl), -(1-6C alkyl)hetCyc, -(1-6C alkyl)hetAr, hetAr, hetCyc, —O(1-6C alkyl), —O(3-6C cycloalkyl), or Cyc;'}{'sup': 1', '2, 'sub': 2', '2, 'or ...

COMPOUNDS AND METHODS FOR INHIBITING HEPATITIS C VIRAL REPLICATION

Macrocyclic compounds having the structures described herein are useful for inhibiting replication of the hepatitis C virus (HCV). In preferred embodiments, the compounds are active against both the NS3 protease and the NS3 helicase of HCV.

PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF

In some embodiments, provided herein are processes for preparing a compound of Formula C or a salt thereof, as disclosed herein. In some embodiments, provided herein is a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, provided herein is a solid form of the compound, such as a crystalline form of the compound crystalline Form I. 1227-. (canceled)229. The crystalline form of claim 228 , wherein the crystalline form is characterized by at least one of the following:a. XRPD peaks, in terms of 2-theta, at 9.1, 20.2, and 24.9;b. a DTA thermogram characterized by an endothermal event at about 317° C.;c. a DSC thermogram characterized by an endothermal event at about 317° C.; ord. hygroscopicity characterized by a mass uptake of about 0.7% at 90% relative humidity as determined by dynamic vapor sorption analysis.230. The crystalline form of claim 229 , having one or more additional XRPD peaks claim 229 , at 11.2 claim 229 , 13.4 claim 229 , 14.8 claim 229 , 18.3 claim 229 , 18.6 claim 229 , 23.6 claim 229 , and 29.4.231. The crystalline form of claim 229 , having hygroscopicity characterized by a mass uptake of about 0.3% at 90% relative humidity as determined by dynamic vapor sorption analysis.23222929. The crystalline form of any of claims claim 229 , which is substantially free of the amorphous form.234. The besylate salt of claim 233 , which is in crystalline form characterized by at least one of the following:a. having XRPD peaks, in terms of 2-theta, at 8.1, 13.4, and 21.2;b. a DTA thermogram characterized by an endothermal event at about 248° C.;c. a DSC thermogram characterized by an endothermal event at about 249° C.; ord. hygroscopicity characterized by a mass uptake of about 0.7% at 90% relative humidity as determined by dynamic vapor sorption analysis.235. The crystalline form of claim 234 , having one or more additional XRPD peaks claim 234 , at 12.0 claim 234 , 19.0 claim 234 , 19.4 claim 234 , 19. ...

Cyclopropane compounds and pharmaceutical use thereof

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R1 is —(CH2)m—X—(CH2)n-A1 etc., wherein m and n are the same or different and each is 0 to 6, X1 is a single bond, etc. and A1 is a substituted C3-14 hydrocarbon ring group, etc.; R2 and R3 are the same or different and each is a hydrogen atom, —(CH2)p—X1-(CH2)q-A2, etc., wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc. and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc.; R4 is —CO2R9, etc., wherein R9 is a hydrogen atom, etc.; and R20 and R21 are the same or different and each is a hydrogen atom, —(CH2)m12—X12—(CH2)m12—R30, etc., wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc. and R30 is a hydrogen atom, etc.; or a prodrug ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 1. A method of treating a RET-associated cancer in a subject in need thereof , wherein the cancer has a fusion selected from the group consisting of: KIF5B-RET , CCDC6-RET , CLIP1-RET , PTC1ex9-RET , CEP55-RET , CUX1-RET , ACBD5-RET , MYH13-RET , PIBF1-RET , KIAA1217-RET , MPRIP-RET , NCOA4-RET , BCR-RET , FGFR1OP-RET , MBD1-RET , PRKAR1A-RET , TRIM24-RET , KTN1-RET , GOLGA5-RET , HOOK3-RET , and KIAA1468-RET , the method comprising administering to the subject a compound selected from the group consisting of:((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate;4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide;1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide;4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate);4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;BLU667 ((1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4- ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 6. The method of claim 3 , wherein E is:{'sup': '2', '(e) hetArC1-C6 alkyl-,'}{'sup': '2', '(h) hetAr—O—,'}{'sup': 1', 'g', 'g, '(l) ArC(═O)NR— where Ris H or C1-C6 alkyl, or'}{'sup': 2', 'g', 'g, 'sub': 2', 'p, '(m) hetArC(═O)NR(CH)— where p is 0 or 1 and Ris H or C1-C6 alkyl.'}7. The method of claim 3 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros claim 3 , or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.8. The method of claim 3 , wherein Xis N claim 3 , and X claim 3 , Xand Xare CH.9. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide;6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide;3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide;N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4 ...

NOVEL INHIBITORS OF HEPATITIS C VIRUS REPLICATION

The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

SUBSTITUTED IMIDAZO[1,2b]PYRIDAZINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula (I): in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 4. A compound according to claim 3 , wherein X is CH.5. A compound according to claim 3 , wherein X is N.7. A compound according to claim 1 , wherein W is O.8. A compound according to claim 1 , wherein W is NH.9. A compound according to claim 1 , wherein W is CH.11. A compound according to claim 1 , wherein Y is F.12. A compound according to claim 1 , wherein Y is H.13. A compound according to claim 1 , wherein Ris H.14. A compound according to claim 1 , wherein Ris (1-3 C)alkyl or (1-3C)alkoxy.15. A compound according to claim 14 , wherein Ris methyl or methoxy.16. A compound according to claim 1 , wherein Ris halogen.17. A compound according to claim 16 , wherein Ris fluoro.18. A compound according to claim 1 , wherein Z is *—NRC(═O)—.19. A compound according to claim 18 , wherein Ris hydrogen.20. A compound according to claim 18 , wherein Ris (1-6C)alkyl claim 18 , fluoro(1-6C)alkyl claim 18 , difluoro(1-6C)alkyl claim 18 , trifluoro(1-6C)alkyl claim 18 , hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl).21. A compound according to claim 20 , wherein Ris (1-6C)alkyl.22. A compound according to claim 1 , wherein Z is *—ONHC(═O)—.23. A compound according to claim 1 , wherein Z is *—NRCH—.24. A compound according to claim 23 , wherein Ris H.25. A compound according to claim 23 , wherein Ris selected from (1-6C)alkyl claim 23 , fluoro(1-6C)alkyl claim 23 , difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl.26. A compound according to claim 25 , wherein Ris (1-6C)alkyl.27. A compound according to claim 23 , wherein Ris selected from (1-6C alkyl)C(O)— claim 23 , (3-6C cycloalkyl)C(O)— claim 23 , ArC(O)— and HOCHC(O)—.28. A compound according to claim 27 , wherein Ris (1-6C alkyl)C(O)—.29 ...

PYRROLIDINYL UREA, PYRROLIDINYL THIOUREA AND PYRROLIDINYL GUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R1, R2, Ra, Rb, Rc, Rd, X, Y, B, and Ring C are as defined herein, and wherein the YB moiety and the NHC(X)NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 6. A compound according to claim 3 , wherein E is:{'sup': '2', '(e) hetArC1-C6 alkyl-,'}{'sup': '2', '(h) hetAr—O—,'}{'sup': 1', 'g', 'g, '(l) ArC(═O)NR— where Ris H or C1-C6 alkyl, or'}{'sup': 2', 'g', 'g, 'sub': 2', 'p, '(m) hetArC(═O)NR(CH)— where p is 0 or 1 and Ris H or C1-C6 alkyl.'}7. A compound according to claim 3 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros claim 3 , or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.8. A compound according to claim 3 , wherein Xis N claim 3 , and X claim 3 , Xand Xare CH.9. A compound according to claim 1 , wherein the compound of Formula I is selected from the group consisting of:N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide;6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;N-(1-(5-(3-cyano-6-((3-fluoro-1-methyl azetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide;3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide;N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and3-chloro-N-((3S,4 S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a] ...

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases. 1. (canceled)2. A compound selected from the group consisting of:{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7, 9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '23,27, '(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0.0.0]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-15-methyl-2, 11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17 ...

FORMULATIONS OF A MACROCYCLIC TRK KINASE INHIBITOR

The present application in some embodiments provides a pharmaceutical composition comprising: 2. The pharmaceutical composition of claim 1 , further comprising at least one of citric acid claim 1 , a citrate claim 1 , a lactate claim 1 , a phosphate claim 1 , a maleate claim 1 , a tartrate claim 1 , a succinate claim 1 , a sulfate claim 1 , or an acetate.3. The pharmaceutical composition of claim 2 , wherein the composition comprises trisodium phosphate claim 2 , sodium phosphate claim 2 , citric acid claim 2 , calcium sulfate claim 2 , or a combination thereof.4. The pharmaceutical composition of claim 1 , wherein the composition has a pH of about 3 to about 8.5. The pharmaceutical composition of claim 1 , further comprising a sweetener.6. The pharmaceutical composition of claim 5 , wherein the sweetener comprises sucrose claim 5 , saccharin claim 5 , mannitol claim 5 , sorbitol claim 5 , dextrose claim 5 , acesulfame claim 5 , aspartame claim 5 , fructose claim 5 , maltitol claim 5 , sucralose claim 5 , or a combination thereof claim 5 , wherein the sweetener or at least one sweetener in a combination of sweeteners is optionally in a salt form.7. The pharmaceutical composition of claim 6 , wherein the sweetener comprises sucralose.9. A pharmaceutical composition comprising:Compound 1;about 0.1 wt. % to about 2.0 wt. % of microcrystalline cellulose;about 0.1 wt. % to about 1.0 wt. % of xanthan gum;about 0.01 wt. % to about 1.0 wt. % of carrageenan;and{'sub': '4', 'about 0.01 wt. % to about 1.0 wt. % of CaSO.'}1113.-. (canceled)14. The pharmaceutical composition of claim 10 , wherein Compound 1 is present in a d.e. of at least 96% relative to the compound of formula I′.15. (canceled)16. The pharmaceutical composition of claim 1 , wherein Compound 1 is present as crystalline Form.17. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a suspension.18. A method of treating a Trk-associated cancer in a subject claim 1 , the method ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 2. The method of claim 1 , wherein the compound is ((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridine-3-carbonitrile claim 1 , or a pharmaceutically acceptable salt thereof.3. The method of claim 1 , wherein the compound is 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1 claim 1 ,5-a]pyridine-3-carbonitrile claim 1 , or a pharmaceutically acceptable salt thereof.4. The method of claim 1 , wherein the compound is 4-(6-(4-(2 claim 1 ,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridine-3-carbonitrile 2 claim 1 ,2 claim 1 ,2-trifluoroacetate claim 1 , or a pharmaceutically acceptable salt thereof.5. The method of claim 1 , wherein the compound is 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridin-4-yl)pyridin-2-yl)-N claim 1 ,N-diethylpiperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.6. The method of claim 1 , wherein the compound is 1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide claim 1 , or a pharmaceutically acceptable salt thereof.7. The method of claim 1 , wherein the compound is 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridine-3-carbonitrile bis(2 claim 1 ,2 claim 1 ,2-trifluoroacetate) claim 1 , or a pharmaceutically acceptable salt thereof.8. The method of claim 1 , wherein the compound is 4-(6-(4-(2 claim 1 ,6-difluorobenzyl)piperazin-1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 claim 1 ,5-a]pyridine-3-carbonitrile claim 1 , or a pharmaceutically acceptable salt thereof.9. The method of claim 1 , wherein the compound is 4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- ...

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 6. The method of claim 3 , wherein E is:{'sup': '2', '(e) hetArC1-C6 alkyl-,'}{'sup': '2', '(h) hetAr—O—,'}{'sup': 1', 'g', 'g, '(l) ArC(═O)NR— where Ris H or C1-C6 alkyl, or'}{'sup': 2', 'g', 'g, 'sub': 2', 'p, '(m) hetArC(═O)NR(CH)— where p is 0 or 1 and Ris H or C1-C6 alkyl.'}7. The method of claim 3 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros claim 3 , or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.8. The method of claim 1 , wherein Xis N claim 1 , and X claim 1 , Xand Xare CH.9. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide;6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide;3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide;N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide;6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4 ...

CRYSTALLINE FORMS

Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which exhibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, the application relates to novel crystalline forms of Formula I-IV and pharmaceutically acceptable salts thereof useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors

Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

Method of Treatment Using Substituted Imidazo[1,2b]Pyridazine Compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I 1. (canceled)3. The compound of claim 2 , wherein Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen claim 2 , (1-4C)alkoxy claim 2 , CFand CHF.4. The compound of claim 2 , wherein Y is phenyl optionally substituted with one or more halogen atoms.5. The compound of claim 4 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.6. The compound of claim 2 , wherein X is —CH—.7. The compound of claim 2 , wherein Ris H.8. The compound of claim 2 , wherein n is 0 or 1.9. The compound of claim 2 , wherein:Y is a phenyl ring optionally substituted with halogen;{'sub': '2', 'X is —CH—;'}{'sup': '3', 'Ris H; and'}n is 0.11. The compound of claim 10 , wherein Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen claim 10 , (1-4C)alkoxy claim 10 , CFand CHF.12. The compound of claim 10 , wherein Y is phenyl optionally substituted with one or more halogen atoms.13. The compound of claim 12 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.14. The compound of claim 10 , wherein X is —CH—.15. The compound of claim 10 , wherein Ris H.16. The compound of claim 10 , wherein n is 0 or 1.17. The compound of claim 10 , wherein:Y is a phenyl ring optionally substituted with halogen;{'sub': '2', 'X is —CH—;'}{'sup': '3', 'Ris H; and'}n is 0. This application is a Continuation of U.S. patent application Ser. No. 13/063,894, which is a 371 National Stage filing of PCT/US2009/057729 filed Sep. 21, 2009, which claims priority to U.S. Provisional Application Ser. No. 61/099,030 filed Sep. 22, 2008, each of which is incorporated herein in its entirety.The present ...

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Method of treatment using substituted imidazo[1,2b]pyridazine compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification.

Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.

N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors

Compounds of Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C, X, Ra, Rb, Rc, Rd and n are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 1. A method of treating a RET-associated cancer in a subject in need thereof , wherein the cancer has a RET mutation selected from the group consisting of: S32L , D34S , L40P , P64L , R67H , R114H , V145G , V292M , R330Q , R360W , F393L , A510V , E511K , G513D , C515W , G533S , G550E , V591I , G593E , I602V , K603Q , C609W , C618W , F619F , C620L , E623K , D624N , C630R , C630Y , C630A , D631N , D631A , D631G , D631V , D631E , E632K , E632G , C634A , C634L , C634T , R635G , T636M , A640G , A641S , A641T , V648I , A664D , H665Q , K666M , K666N , S686N , R694Q , M700L , V706M , V706A , E713K , G736R , G748C , A750P , S765P , P766M , E768Q , L769L , R770Q , D771N , N777S , Q781R , E805K , Y806E , Y806F , Y806G , E818K , S819I , G823E , Y826M , Y826S , P841L , P841P , E843D , R844W , M848T , I852M , R873W , A876V , L881V , A883F , A883S , A883T , E884K , R886W , R897Q , D898V , E901K , S904F , K907E , K907M , R908K , G911D , R912Q , M918V , M918L , A919V , E921K , S922Y , F961L , R972G , R982C , M1009V , D1017N , V1041G , M1064T , G321R , C515S , G533C , R600Q , K603E , Y606C , C609S , C609G , C609R , C609F , C609W , C609C , C611S , C611F , C611R , C611G , C611W , C618Y , C618R , C618F , C618G , C620S , C620G , C620F , C620Y , C620W , C630F , C630S , D631Y , T636P , S649L , K666E , G691S , P766S , E768D , V778I , L790F , Y791F , R833C , R844L , R844Q , A866W , S904C , R912P , S922P , and T930M , the method comprising administering to the subject a compound selected from the group consisting of:((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(l-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate;4-(5-(3-cyano-6 ...

Substituted Pyrazolo[1,5-a]Pyrimidine Compounds as TRK Kinase Inhibitors

Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors

Compounds of Formula I: and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

INHIBITORS OF VIRAL REPLICATION

The embodiments provide compounds of the general Formulas I-IV, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

BICYCLIC UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF PAIN

Compounds of Formula I: 1. (canceled)3. The compound according to claim 2 , wherein zero to four of R claim 2 , R claim 2 , R claim 2 , R claim 2 , R claim 2 , R claim 2 , Rand Rare independently H claim 2 , OH claim 2 , or (1-6C)alkyl [optionally substituted with one to five fluoros] claim 2 ,{'sup': d', 'e', 'f', 'g', 'h', 'i', '3', 'k, 'or one of a pair of Rand R, or Rand R, or Rand R, or Rand R, together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring.'}4. The compound according to claim 3 , wherein zero to two of R claim 3 , R claim 3 , R claim 3 , R claim 3 , R claim 3 , R claim 3 , Rand Rare independently H claim 3 , OH claim 3 , or (1-6C)alkyl [optionally substituted with one to five fluoros] claim 3 ,{'sup': d', 'e', 'f', 'g', 'h', 'i', '3', 'k, 'or one of a pair of Rand R, or Rand R, or Rand R, or Rand R, together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring.'}5. The compound according to claim 4 , wherein zero to two of R claim 4 , R claim 4 , R claim 4 , R claim 4 , R claim 4 , R claim 4 , Rand Rare independently OH claim 4 , methyl claim 4 , methoxy claim 4 , CHOCHCHO— claim 4 , or cyclopropyl claim 4 ,{'sup': d', 'e', 'f', 'g', 'h', 'i', '3', 'k, 'or one of a pair of Rand R, or Rand R, or Rand R, or Rand R, together with the carbon atom to which they are attached form a (3-6C)cycloalkylring.'}6. The compound according to claim 5 , wherein B is a bond or CRR claim 5 , D is a bond or CRR claim 5 , E is a bond or CRR claim 5 , and F is CRR claim 5 , provided that the ring formed by B claim 5 , D claim 5 , E claim 5 , and F together with the atoms to which they are attached contains at least five atoms.7. The compound according to claim 5 , wherein B is a bond or CRR claim 5 , D is NR claim 5 , a bond or CRR claim 5 , E is NR claim 5 , a bond or CRR claim 5 , and F is CRR claim 5 , provided that the ring formed by B claim 5 , D claim 5 , E claim 5 , and F together with the atoms to which they are ...

Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds

Provided herein are methods for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal in need thereof a therapeutically effective amount of a compound of Formula I: in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification.

Macrocyclic compounds as TRK kinase inhibitors

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

Method of Treatment Using Substituted Imidazo[1,2b]Pyridazine Compounds

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification.

METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS

Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal. 1. (canceled)7. The process of claim 6 , wherein the standard reducing conditions comprises reacting (R)-5-(2-(2 claim 6 ,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1 claim 6 ,5-a]pyrimidine with zinc dust under acidic conditions.8. The process of claim 7 , wherein acidic conditions comprise performing the reaction in the presence of NHCl claim 7 , HCl claim 7 , or acetic acid.9. The process of claim 6 , wherein the standard reducing conditions comprises reacting (R)-5-(2-(2 claim 6 ,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1 claim 6 ,5-a]pyrimidine under a hydrogen atmosphere in the presence of a precious metal catalyst.11. The process of claim 9 , wherein the activating agent comprises TFA or concentrated sulfuric acid.13. The process of claim 12 , wherein the suitable solvent comprises an alcohol.14. The process of claim 13 , wherein the alcohol comprises n-butanol. This application is a divisional of U.S. Ser. No. 13/125,263 filed Apr. 20, 2011, which is a Section 371(e) filing from PCT/US09/061519, filed Oct. 21, 2009, which claims the benefit of U.S. provisional patent application No. 61/107,616 filed Oct. 22, 2008, each of which is incorporated herein in its entirety.The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted pyrazolo[1,5-a]pyrimidine compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, inflammation, cancer, and certain infectious diseases.The current treatment regimes for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative ...

Substituted Pyrazolo [1,5-A] Pyrimidine Compounds as TRK Kinase Inhibitors

Compounds of Formula I: 2. The method of claim 1 , wherein:{'sup': '1', 'Ris H or -(1-6C alkyl);'}{'sup': 2', '1', '1', '2', '2', '1, 'sub': 2', '2', '2', '2', '2, 'Ris H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SONH, -(1-6C alkyl)NHSO(1-3C alkyl), -(1-6C alkyl)NH, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl), -(1-6C alkyl)hetCyc, -(1-6C alkyl)hetAr, hetAr, hetCyc, —O(1-6C alkyl), —O(3-6C cycloalkyl), Cyc, or a bridged 7-membered cycloalkyl ring,'}{'sup': 1', '2, 'sub': 2', '2, 'or NRRforms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —COH and -(1-3C alkyl)COH;'}{'sup': 1', '1, 'hetCycis a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycis optionally substituted with oxo;'}{'sup': 2', '2, 'sub': 2', '2', '2, 'hetCycis a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycis optionally substituted with F, SONH, or SO(1-3C alkyl);'}{'sup': '1', 'hetAris a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with -(1-4C)alkyl;'}{'sup': '2', 'hetAris a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from -(1-4C)alkyl;'}{'sup': '1', 'sub': '2', 'Cycis 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —COH and -(1-4C alkyl)OH;'}{'sub': 3', '2, 'sup': '3', 'Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, -(1-4C)alkoxy, —CF—CHF, —O(1-4C alkyl)hetCycand —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 2. A compound according to claim 1 , wherein D is a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen.3. A compound according to claim 1 , wherein n is 0 or 1.4. A compound according to claim 1 , wherein E is (a) hydrogen claim 1 , (b) hydroxy claim 1 , (c) C1-C6 alkyl optionally substituted with 1-3 fluoros claim 1 , (d) ArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros claim 1 , (e) hetArC1-C6 alkyl- claim 1 , (g) ArO— claim 1 , (h) hetArO— claim 1 , (i) ArNR— where Ris H or C1-C6 alkyl claim 1 , (j) hetArNR— where Ris H or C1-C6 alkyl claim 1 , (k) RC(═O)NR— where Ris H or C1-C6 alkyl claim 1 , (l) ArC(═O)NR— where Ris H or C1-C6 alkyl claim 1 , (m) hetArC(═O)NR(CH)— where p is 0 or 1 claim 1 , (n) RRNC(═O)— claim 1 , or (s) RRNC(═O)NR— where Ris H or C1-C6 alkyl.5. A compound according to claim 1 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros claim 1 , or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.7. A pharmaceutical composition claim 1 , comprising a compound according to in admixture with a pharmaceutically acceptable diluent or carrier.8. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.9. The method of claim 8 , wherein the cancer is a RET-associated cancer.10. The method of claim 9 , wherein the RET-associated cancer is selected from the group consisting of: lung cancer claim 9 , papillary thyroid cancer claim 9 , medullary thyroid cancer claim 9 , differentiated thyroid cancer claim 9 , recurrent thyroid cancer claim 9 , refractory differentiated thyroid cancer claim 9 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 9 , respectively) claim 9 , pheochromocytoma claim 9 , ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 1. (canceled)2. A compound according to claim 137 , wherein D is hetCyc.37-. (canceled)910-. (canceled)11. The compound according to claim 137 , wherein D is hetCyc.13. The compound according to claim 12 , wherein E is(a) hydrogen,{'sub': 2', 'n, '(c) R′R″N(CH)— wherein R′ is H or C1-C6 alkyl, R″ is H, C1-C6 alkyl or phenyl, and n is 0 or 1;'}{'sup': '6', '(mm) RC(═O)NH—, or'}{'sup': '2', '(oo) hetArC1-C6 alkyl-.'}14. (canceled)15. A compound according to claim 137 , wherein hetAris pyrazolyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl (optionally substituted with one to three fluoros).1617-. (canceled)18. A compound according to claim 137 , wherein A is H.19. A compound according to claim 137 , wherein A is Cl.20. A compound according to claim 137 , wherein A is CN.21. (canceled)22. A pharmaceutical composition claim 137 , comprising a compound according to claim 137 , or a pharmaceutically acceptable salt thereof claim 137 , and a pharmaceutically acceptable carrier or excipient.23. (canceled)24. A method for treating cancer in a patient in need thereof claim 137 , the method comprising administering to the patient an effective amount of a compound of claim 137 , or a pharmaceutically acceptable salt claim 137 , or a pharmaceutical composition according to .2545-. (canceled)46. The method according to claim 24 , wherein the RET-associated cancer is selected from the group consisting of: lung cancer claim 24 , papillary thyroid cancer claim 24 , medullary thyroid cancer claim 24 , differentiated thyroid cancer claim 24 , recurrent thyroid cancer claim 24 , refractory differentiated thyroid cancer claim 24 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 24 , respectively) claim 24 , pheochromocytoma claim 24 , parathyroid hyperplasia claim 24 , breast cancer claim 24 , colorectal cancer claim 24 , papillary renal cell carcinoma ...

Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 4 , Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 2. A compound according to claim 1 , wherein A is CN.3. A compound according to claim 2 , wherein Xis N; X claim 2 , Xand Xare each CH.6. A compound according to claim 4 , wherein B is C1-C6 alkyl- optionally substituted with OH claim 4 , methyl claim 4 , or 1-3 fluoros.7. A compound according to claim 5 , wherein B is methyl or 2-methylpropan-2-ol.9. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , in admixture with a pharmaceutically acceptable diluent or carrier.10. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein the cancer is selected from the group consisting of: lung cancer claim 1 , papillary thyroid cancer claim 1 , medullary thyroid cancer claim 1 , differentiated thyroid cancer claim 1 , recurrent thyroid cancer claim 1 , refractory differentiated thyroid cancer claim 1 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 1 , respectively) claim 1 , pheochromocytoma claim 1 , parathyroid hyperplasia claim 1 , breast cancer claim 1 , colorectal cancer claim 1 , papillary renal cell carcinoma claim 1 , ganglioneuromatosis of the gastroenteric mucosa claim 1 , and cervical cancer.11. A method for treating cancer in a patient in need thereof claim 9 , the method comprising administering to the patient an effective amount of a pharmaceutical composition according to claim 9 , wherein the cancer is selected from the group consisting of: lung cancer claim 9 , papillary thyroid cancer claim 9 , medullary thyroid cancer claim 9 , differentiated thyroid cancer claim 9 , recurrent thyroid cancer claim 9 , refractory differentiated thyroid cancer claim 9 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 9 , ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the General Formula I: 4. The method of claim 3 , wherein E is{'sup': '2', '(w) ArC(═O)—,'}{'sup': '2', '(x) ArC1-C6 alkyl,'}{'sup': 2', 'e', 'f', 'e', 'f, '(cc) hetAr(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and RRN—, wherein Rand Rare independently H or C1-C6 alkyl,'}{'sup': 1', '2, '(dd) RRNC(═O)—, or'}{'sup': '2', '(oo) hetArC1-C6 alkyl.'}6. The method of claim 5 , wherein E is{'sup': 1', '2, '(dd) RRNC(═O)—.'}7. The method of claim 1 , wherein Xis N claim 1 , and X claim 1 , X claim 1 , and Xare CH.8. The method of claim 1 , wherein Xis CH claim 1 , Xis N claim 1 , and Xand Xare CH.20. The method of claim 1 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL) claim 1 , acute myeloid leukemia (AML) claim 1 , breast cancer claim 1 , cervical cancer claim 1 , colorectal cancer claim 1 , ganglioneuromatosis of the gastroenteric mucosa claim 1 , gastric cancer claim 1 , gastrointestinal stromal tumors claim 1 , glioma claim 1 , leukemia claim 1 , lung cancer claim 1 , lymphoma claim 1 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 1 , respectively) claim 1 , multiple myeloma claim 1 , non-Hodgkin's lymphoma claim 1 , non-small cell lung cancer claim 1 , ovarian cancer claim 1 , papillary renal cell carcinoma claim 1 , paraganglioma claim 1 , parathyroid hyperplasia claim 1 , pheochromocytoma claim 1 , and thyroid cancer.21. The method of claim 20 , wherein the cancer is leukemia.22. The method of claim 1 , wherein the dysregulation of a RET gene claim 1 , a RET kinase claim 1 , or the expression or activity or level of any of the same results in the translation of a RET fusion protein or a mutation of a RET kinase.23. The method of claim 21 , wherein the RET fusion protein is selected from the group consisting of BCR- ...

PROCESS FOR THE PREPARATION OF (S)-N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)-PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE AND SALTS THEREOF

Process for preparing (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3-ol (formula 14). Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formula 12). Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R)-2-hydroxysuccinate (formula 10) by treating (R)—N—((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (formula 19) with an acid and a reducing agent. (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing e.g. cancer. 2. The process of claim 1 , wherein the compound of formula 13 or salt thereof is in isolated form prior to the treatment with the compound of formula 14 or salt thereof.4. The process of claim 1 , or claim 1 , wherein X is halogen.5. The process of claim 4 , wherein X is Cl.6. The process of claim 4 , wherein X is Br.7. The process of claim 4 , or claim 4 , wherein X is C-Caryloxy.8. The process of claim 7 , wherein X is phenoxy.9. The process of claim 7 , or claim 7 , wherein X is a 5-membered heteroaryl containing at least one nitrogen directly bonded to the C═O of the compound of formula 13.10. The process of claim 9 , wherein X is imidazolyl.12. The process of claim 11 , wherein the process comprises:forming the compound of formula 13 in a second mixture; andisolating the compound of formula 13 from the second mixture.14. ...

N-(ARYLALKYL)-N'-PYRAZOLYL-UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS

Compounds of Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C, X, Ra, Rb, Rc, Rd and n are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome. 2. A compound according to claim 1 , wherein X is O.3. (canceled)4. A compound according to claim 1 , wherein Ring A is A-1.5. A compound according to claim 4 , wherein G claim 4 , Gand Gare CR.6. A compound according to claim 4 , wherein:{'sup': 1', '2', '3', 'x, 'Gis N and Gand Gare CR; or'}{'sup': 1', '3', 'x', '2, 'Gand Gare CRand Gis N; or'}{'sup': 1', '2', 'x', '3, 'Gand Gare CRand Gis N.'}7. A compound according to claim 4 , wherein:{'sup': 1', '2', '3', 'x, 'Gand Gare N and Gis CR; or'}{'sup': 2', '3', '1', 'x, 'Gand Gare N and Gis CR; or'}{'sup': 1', '3', '2', 'x, 'Gand Gare N and Gis CR.'}8. A compound according to claim 1 , wherein Ris H or F.9. A compound according to claim 1 , where n is 0 and Ris selected from the group consisting of H claim 1 , halogen claim 1 , (1-6C)alkyl [optionally substituted with 1-5 fluoros] claim 1 , (1-6C)alkoxy [optionally substituted with 1-5 fluoros] claim 1 , (1-3C alkoxy)(1-4C)alkyl claim 1 , (3-6C cycloalkyl)CHO— claim 1 , amino(1-3C)alkyl claim 1 , CFCHNHCH claim 1 , HCFCHNHCH claim 1 , a C5-C8 bridged cycloalkyl claim 1 , hetCyc claim 1 , hetCycCH claim 1 , Cyc claim 1 , hetArand Ar.10. A compound according to claim 9 , wherein Ris selected from H claim 9 , (1-6C)alkyl [optionally substituted with 1-5 fluoros] claim 9 , (1-6C)alkoxy [optionally substituted with 1-5 fluoros] claim 9 , (3-6C cycloalkyl)CHO— claim 9 , hetCyc claim 9 , and Cyc.11. A compound according to claim 1 , where n is 1 and ...

KRAS G12C INHIBITORS

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor. 3. The compound of claim 2 , wherein Ris —C(O)C(R) C(R).4. The compound of claim 3 , wherein is a double bond and p is two claim 3 , each Ris hydrogen claim 3 , and Ris deuterium claim 3 , cyano claim 3 , halogen claim 3 , haloalkyl claim 3 , heteroalkyl claim 3 , —C(O)N(R) claim 3 , or hydroxyalkyl.5. The compound of claim 4 , wherein Ris halogen.6. The compound of claim 2 , wherein is a double bond and p is two claim 2 , one Ris hydrogen claim 2 , the second Ris dialkylaminylalkyl claim 2 , and Ris halogen.7. The compound of claim 2 , wherein Y is O.8. The compound of claim 2 , wherein Ris selected from the group consisting of hydroxyalkyl claim 2 , alkylaminylalkyl claim 2 , dialkylaminylalkyl claim 2 , —ZNRR claim 2 , heterocyclyl and heterocyclylalkyl claim 2 , wherein each of the Z claim 2 , heterocyclyl or heterocyclylalkyl are independently optionally substituted with R.9. The compound of claim 8 , wherein Ris heterocyclylalkyl optionally substituted with one or more R.10. The compound of claim 9 , wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl claim 9 , methylazetidinyl claim 9 , N-ethylazetidinyl claim 9 , N-isopropylazetidinyl claim 9 , N-tert-butylazetidinyl claim 9 , fluoroazetidinyl claim 9 , difluoroazetidinyl claim 9 , cyclopropylazetidinyl claim 9 , cyclopentylazetidinyl claim 9 , tetrahydropyranylazetidinyl claim 9 , tetrahydropyranyl claim 9 , pyrrolidinyl claim 9 , methylpyrrolidinyl claim 9 , dimethylpyrrolidinyl claim 9 , (N-methyl)-2-methylpyrrolidinyl claim 9 , (N-methyl)-2-ethylpyrrolidinyl claim 9 , (N-methyl)-3 claim 9 ,3-dimethylpyrrolidinyl claim 9 , isopropylpyrrolidinyl claim 9 , N-tert-butylpyrrolidinyl claim 9 , cycloalkylalkylpyrrolidinyl claim 9 ...

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R, R, R, R, and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases 1. (canceled)5. The compound of claim 2 , wherein Y is F.6. The compound of claim 2 , wherein Ris H.7. The compound of claim 2 , wherein Ris hydrogen.8. The compound of claim 2 , wherein Rand Rare each hydrogen.9. The compound of claim 2 , wherein W is CH.10. The compound of claim 2 , wherein m is 0.11. The compound according of claim 2 , wherein m is 1.12. The compound of claim 2 , selected from the group consisting of:{'sup': 7,11', '2,6', '20,24, '(6R)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1.0.0]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 2,6', '7,12', '22,26, '(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 7,11', '2,6', '20,24, '(6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1.0.0]pentacosa-1(23),7,9,17(24), 18,21-hexaene-16,25-dione;'}{'sup': 2,6', '7,12', '22,26, '(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0.0.0]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;'}{'sup': 7,11', '2,6', '20,24, '(6R,13R)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1.0.0]pentacosa-1(23),7,9,17(24), 18,21-hexaene-16,25-dione;'}{'sup': 2,6', '7,12', '21,25, '(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0.0.0]pentacosa-1(24),7,9,11,18(25), 19,22-heptaen-17-one;'}{'sup': 2,6', '7,12', '23,27, '(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0.0. 0]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;'}{'sup': 7, ...

Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as trka kinase inhibitors

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

SUBSTITUTED PYRAZOLYL[4,3-C]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R, Rand Rhave the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders. 23.-. (canceled)521.-. (canceled)23. A compound according to claim 1 , wherein R is 3-bromo-1 claim 1 ,2 claim 1 ,4-thiadiazole.2532.-. (canceled)33. A compound according to claim 1 , selected from Examples 1-79 claim 1 , or a pharmaceutically acceptable salt thereof.34. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , in admixture with a pharmaceutically acceptable diluent or carrier.35. (canceled)36. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of or a pharmaceutically acceptable salt thereof.37. (canceled)38. The method of claim 34 , wherein the cancer is a RET-associated cancer.3957-. (canceled)58. The method of claim 38 , wherein the RET-associated cancer is selected from the group consisting of: lung cancer claim 38 , papillary thyroid cancer claim 38 , medullary thyroid cancer claim 38 , differentiated thyroid cancer claim 38 , recurrent thyroid cancer claim 38 , refractory differentiated thyroid cancer claim 38 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 38 , respectively) claim 38 , pheochromocytoma claim 38 , parathyroid hyperplasia claim 38 , breast cancer claim 38 , colorectal cancer claim 38 , papillary renal cell carcinoma claim 38 , ganglioneuromatosis of the gastroenteric mucosa claim 38 , and cervical cancer.59. The method of claim 58 , wherein the RET-associated cancer is medullary thyroid cancer.60. The method of claim 58 , wherein the RET-associated cancer ...

SUBSTITUTED PYRROLO[2,3-D]PYRIMIDINES COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: [INSERT FORMULA I] and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2 and Ry have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders. 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Ris a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N and O claim 1 , wherein Ris optionally substituted with 1-2 substituents independently selected from halogen claim 1 , C1-C6 alkyl claim 1 , dihydroxyC2-C6 alkyl- claim 1 , Cyc claim 1 , hetCyc claim 1 , hetArand R′R″NC(═O)— where R′ is hydrogen and R″ is hydrogen C1-C6 alkyl or Cyc.49.-. (canceled)11. (canceled)1318-. (canceled)2023.-. (canceled)24. The compound according to claim 1 , selected from Examples 1-34 claim 1 , or a pharmaceutically acceptable salt thereof.25. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , in admixture with a pharmaceutically acceptable diluent or carrier.26. (canceled)27. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.28. (canceled)29. The method of claim 27 , wherein the cancer is a RET-associated cancer.3048.-. (canceled)49. The method of claim 29 , wherein the RET-associated cancer is selected from the group consisting of: lung cancer claim 29 , papillary thyroid cancer claim 29 , medullary thyroid cancer claim 29 , differentiated thyroid cancer claim 29 , recurrent thyroid cancer claim 29 , refractory differentiated thyroid cancer claim 29 , multiple endocrine neoplasia type 2A or 2B (MEN2A ...

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

Compounds of Formula I: 1. (canceled)3. The compound of claim 2 , wherein X is CH.4. The compound of claim 3 , wherein n is 0.5. The compound of claim 4 , wherein Ris Cycoptionally substituted with one or more substituents selected from methyl claim 4 , —OH claim 4 , —CHOH claim 4 , and —COH.6. The compound of claim 5 , wherein Y is phenyl optionally substituted with one or more substituents independently selected from —F claim 5 , —Cl claim 5 , —OMe claim 5 , —CF claim 5 , —CHF claim 5 , morpholinoethoxy claim 5 , and —OCHCHOMe.7. The compound of claim 5 , wherein Y is pyridyl optionally substituted with one or more substituents independently selected from F claim 5 , OMe claim 5 , and Me.9. The compound of claim 8 , wherein Y is phenyl claim 8 , 3-fluorophenyl claim 8 , 2 claim 8 ,5-difluorophenyl claim 8 , 2-chloro-5-fluorophenyl claim 8 , 2-methoxyphenyl claim 8 , 2-methoxy-5-fluorophenyl claim 8 , 2-trifluoromethyl-5-fluorophenyl claim 8 , 2-difluoromethyl-5-fluorophenyl claim 8 , 3-chloro-5-fluorophenyl claim 8 , 3-fluoro-5-(2-morpholinoethoxy)phenyl claim 8 , 5-fluoro-2-(2-morpholinoethoxy)phenyl claim 8 , 3-fluoro-5-methoxyethoxyphenyl claim 8 , or 5-fluoro-2-methoxyethoxyphenyl.10. The compound of claim 8 , wherein Y is pyrid-2-yl claim 8 , pyrid-3-yl claim 8 , 5-fluoropyrid-3-yl claim 8 , 2-methoxy-5-fluoropyrid-3-yl claim 8 , or 2-methyl-5-fluoropyrid-3-yl.11. A compound of selected from:5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylic acid;(R)—N-cyclopropyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)—N-cyclobutyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;N-((2S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(R)-5-(2-(2,5-difluorophenyl) ...

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: 2. A compound according to claim 1 , wherein D is a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen.3. A compound according to claim 1 , wherein n is 0 or 1.4. A compound according to claim 1 , wherein E is (a) hydrogen claim 1 , (b) hydroxy claim 1 , (c) C1-C6 alkyl optionally substituted with 1-3 fluoros claim 1 , (d) ArC1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros claim 1 , (e) hetArC1-C6 alkyl- claim 1 , (g) ArO— claim 1 , (h) hetArO— claim 1 , (i) ArNR— where Ris H or C1-C6 alkyl claim 1 , (j) hetArNR— where Ris H or C1-C6 alkyl claim 1 , (k) RC(═O)NR— where Ris H or C1-C6 alkyl claim 1 , (l) ArC(═O)NR— where Ris H or C1-C6 alkyl claim 1 , (m) hetArC(═O)NR(CH)— where p is 0 or 1 claim 1 , (n) RRNC(═O)— claim 1 , or (s) RRNC(═O)NR— where Ris H or C1-C6 alkyl.5. A compound according to claim 1 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros claim 1 , or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.7. A pharmaceutical composition claim 1 , comprising a compound according to in admixture with a pharmaceutically acceptable diluent or carrier.8. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.9. The method of claim 8 , wherein the cancer is a RET-associated cancer.10. The method of claim 9 , wherein the RET-associated cancer is selected from the group consisting of: lung cancer claim 9 , papillary thyroid cancer claim 9 , medullary thyroid cancer claim 9 , differentiated thyroid cancer claim 9 , recurrent thyroid cancer claim 9 , refractory differentiated thyroid cancer claim 9 , multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B claim 9 , respectively) claim 9 , pheochromocytoma claim 9 , ...

SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein Rand Rhave the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders. 2. The compound or pharmaceutically acceptably salt thereof according to claim 1 , wherein Ris an isoxazolyl ring substituted with 2 substituents independently selected from halogen claim 1 , C1-C6 alkyl claim 1 , fluoroC1-C6 alkyl claim 1 , hydroxyC1-C6 alkyl claim 1 , (C1-C6 alkoxy)C1-C6 alkyl- claim 1 , C2-C6 alkenyl claim 1 , Cyc claim 1 , hetCyc claim 1 , Ar claim 1 , hetAr claim 1 , (C1-C6 alkyl)C(═O)— claim 1 , (C1-C6 alkyl)-P(═O)— claim 1 , and R′R″NC(═O)— wherein R′ is hydrogen and R″ is hydrogen claim 1 , C1-C alkyl or Cyc.3. The compound or pharmaceutically acceptably salt thereof according to claim 2 , wherein Ris an isoxazolyl ring substituted with 2 substituents independently selected from halogen claim 2 , hydroxyC1-C6 alkyl claim 2 , Cyc claim 2 , hetCyc claim 2 , Arand hetAr.511.-. (canceled)1424.-. (canceled)25. The compound or pharmaceutically acceptably salt thereof according to claim 13 , wherein Ris C1-C6 alkyl.26. The compound or pharmaceutically acceptably salt thereof according to claim 1 , selected from Examples 1-35.27. A pharmaceutical composition claim 1 , comprising a compound or pharmaceutically acceptably salt thereof according to in admixture with a pharmaceutically acceptable diluent or carrier.28. (canceled)29. A method for treating cancer in a patient in need thereof claim 1 , the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.3050.-. (canceled)51. The method of wherein the cancer is selected from the group consisting of: lung cancer claim 29 , papillary thyroid cancer ...

Ret inhibitors

Provided herein are compounds of the Formula (I): and pharmaceutically acceptable salts or solvates thereof, where A, B, Y, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , n and m are as defined in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS

Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

Crystalline forms

Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which exhibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, the application relates to novel crystalline forms of Formula I-IV and pharmaceutically acceptable salts thereof useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors

Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 and R 3 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors

Provided herein are compounds of the Formula I: [INSERT FORMULA I] and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2 and Ry have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Fused heterocyclic compounds as ret kinase inhibitors

Provided herein are compounds of the Formula (I): (I) and tautomers, stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R x , R y , W, X, Y, Z, Ring A and (AA) have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Macrocyclic compounds as ROS1 kinase inhibitors

Methods for inhibiting a ROS1 kinase with compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R 2 , R 2a , R 3 , R 3a , and Z are as defined herein. The compounds and methods provided herein are useful in the treatment of cancer (e.g., ROS1-associated cancers as defined herein).

Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the General Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X 1 , X 2 , X 3 and X 4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors

Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2 and R3 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUND AS TRK KINASE INHIBITOR

【課題】ＴＲＫキナーゼ阻害剤を提供すること。 【解決手段】 式Ｉ の化合物は、Ｔｒｋキナーゼの阻害剤であり、Ｔｒｋキナーゼ阻害剤で治療可能な疾患の治療に有用であり、式中、Ｒ １ 、Ｒ ２ 、Ｒ ３ 、Ｒ ４ 、Ｘ、Ｙ、およびｎは、明細書中に記載される意味を有する。哺乳動物における疼痛、癌、炎症、神経変性疾患、またはクルーズ・トリパノソーマ感染を治療するための方法であって、治療上有効な量の請求項１〜３２のいずれか一項に記載の式Ｉの化合物、またはその薬学的に許容される塩を、前記哺乳動物に投与することを含む、方法もまた提供される。 【選択図】なし

Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors

Provided herein are compounds of the Formula I: (I) or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors

Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

Macrocyclic compounds as trk kinase inhibitors