NOVEL ALK2 INHIBITORS AND METHODS FOR INHIBITING BMP SIGNALING
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
A61K-031/519
A61K-045/06
A61P-019/08
C07D-487/04
C07D-519/00
C07F-009/6561
A61K-031/551
A61K-031/5377
A61K-031/675
출원번호
16608489
(2018-04-26)
공개번호
20200179389
(2020-06-11)
국제출원번호
PCT/US2018/029626
(2018-04-26)
발명자
/ 주소
Yu, Paul B.
Huang, Wenwei
Sanderson, Philip Edward
Jiang, Jian-Kang
Shamim, Khalida
Zheng, Wei
Huang, Xiuli
Tawa, Gregory
Lee, Arthur
Alimardanov, Asaf
Huang, Junfeng
출원인 / 주소
Yu, Paul B.
인용정보
피인용 횟수 :
0인용 특허 :
0
초록▼
The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or co
The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).
대표청구항▼
1. A compound of formula (I): or a pharmaceutically acceptable salt and/or prodrug thereof, whereinA1 is NR4a or CR4bR5;B1 is N or CR2;Z1 is N or CR3;R1 is selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl;R2 is H, CN, NO2, alkyl, or amino;R3 is selected from H, CN, NO2, alkyl, alkoxy, he
1. A compound of formula (I): or a pharmaceutically acceptable salt and/or prodrug thereof, whereinA1 is NR4a or CR4bR5;B1 is N or CR2;Z1 is N or CR3;R1 is selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl;R2 is H, CN, NO2, alkyl, or amino;R3 is selected from H, CN, NO2, alkyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, carbonyl, amino, amido, sulfonyl, sulfonamido, cycloalkyl, aryl, heterocyclyl, and heteroaryl;R4a is selected from alkyl, alkenyl, alkynyl, carbonyl, O−, alkoxycarbonyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;R4b is selected from halo, CN, NO2, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl;R5 is selected from H, halo, hydroxy and alkyl, orR4b and R5 together with A1 form a ring selected from cycloalkyl and heterocyclyl;each R6 is independently selected from H, halo, CN, NO2, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl and oxo;n is 0 or 1;m is 0 or 1; andx is 0, 1, 2, 3, or 4. 2. A compound of formula (I): or a pharmaceutically acceptable salt and/or prodrug thereof, whereinA1 is NR4a or CR4bR5;B1 is N or CR2;Z1 is N or CR3;R1 is selected from aryl, heteroaryl, and heterocyclyl;R2 is H or amino;R3 is H or heterocyclyloxy;R4a is selected from alkyl, O−, aryl, heterocyclyl, and heteroaryl;R4b is selected from alkyl, alkoxy, amino, aryl, heterocyclyl, and heteroaryl;R5 is selected from H and alkyl, orR4b and R5 together with A1 form a ring selected from cycloalkyl and heterocyclyl;each R6 is independently selected from H, halo, alkyl and oxo;n is 0 or 1;m is 0 or 1; andx is 0, 1, 2, 3, or 4. 3. The compound of claim 1 or 2, wherein A1 is NR4a. 4. The compound of claim 1 or 2, wherein A1 is CR4bR5 and R5 is H. 5. The compound of claim 1 or 2, wherein A1 is CR4bR5 and R4b is heterocyclyl. 6. The compound of any one of claims 1-5, wherein B1 is N. 7. The compound of any one of claims 1-5, wherein B1 is CR2, and R2 is H. 8. The compound of any one of claims 1-7, wherein Z1 is CR3 and R3 is H. 9. The compound of any one of claims 1-8, wherein R1 is selected from H, aryl, 5-6 membered heteroaryl, wherein: each E is independently selected from N and CR1d; each G is independently selected from N and CR1e; K1 is N or CH; K2 is NH or S; M is N or CR1a; R1a is selected from H, halo, alkyl, haloalkyl, and amido; R1b is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy; R1c is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino and amido, or R1b and R1c together with the carbon atoms to which they are attached form a heterocyclyl; R1d is selected from H, CN, alkyl, haloalkyl, hydroxy, amido and sulfonamido; R1c is selected from H, alkyl and amino; and R1g is H or halo. 10. The compound of claim 9, wherein R1 is selected from H, pyrrolyl, phenyl, pyridinyl and isoquinolinyl. 11. The compound of claim 9, wherein R1 is 12. The compound of claim 9, wherein R1 is 13. The compound of claim 11 or 12, wherein E is N. 14. The compound of claim 11 or 12, wherein E is CR1d and R1d is selected from H, CONH2, and SO2NH2. 15. The compound of claim 11 or 12, wherein G is CR1e and R1e is selected from H, Me, CN, CHF2, CF3, and NH2. 16. The compound of claim 11, wherein K1 is N. 17. The compound of claim 11, wherein K1 is CH. 18. The compound of claim 12, wherein K2 is NH. 19. The compound of claim 12, wherein K2 is S. 20. The compound of claim 11, wherein M is N. 21. The compound of claim 11, wherein M is CR1a. 22. The compound of claim 11 or 12, wherein R1a is selected from H, F, Me, CF3, and CONH2. 23. The compound of claim 11 or 12, wherein R1b is selected from H, F, Cl, CN, Me, OH, OMe, OEt, CF3, and OCF3. 24. The compound of claim 11, wherein R1c is selected from H, F, Cl, CN, Me, CHF2, CF3, OH, OMe, OCF3, OEt, NH2, NHMe, NMe2, and NHCOMe. 25. The compound of claim 11, wherein R1g is H or F. 26. The compound of any one of claims 1-25, wherein R3 is H or —O-dioxanyl. 27. The compound of any one of claims 1-26, wherein R4a and/or R4b is alkyl. 28. The compound of any one of claims 1-26, wherein A1 is NR4a and R4a is O− (e.g., N-oxide). 29. The compound of any one of claims 1-26, wherein R4b is selected from Me, NH2, NMe2, —CH2—C(Me2)OH, CMe2NH2, OCH2CH2NH2, OCH2CH2NMe2, and N(Me)CH2CH2NMe2. 30. The compound of any one of claims 1-26, wherein R4b is heterocyclyl. 31. The compound of claim 30, wherein the heterocyclyl is selected from pyrrolidinyl, diazolyl, thiomorpholinyl 1,1-dioxide, piperazin-2-onyl, piperidinyl, morpholino, tetrahydropyranyl, diazepanyl, azetidinyl, octahydropyrrolo[3,4-c]pyrrolyl, 3,8-diazabicyclo[3.2.1]octanyl, 8-Me-3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and 4-Me-2,5-diazabicyclo[2.2.1]heptanyl. 32. The compound any one of claims 1-26, wherein R4b is heteroaryl. 33. The compound of claim 32, wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, thiadiazolo, and pyrazolopyridinyl. 34. The compound of any one of claims 30-33, wherein the heterocyclyl or heteroaryl is substituted with one or more substitutents selected from halo, alkyl, alkoxy, carbonyl, amido, amino, oxide and sulfoxide. 35. The compound of claim 34, wherein the heterocyclyl is substituted with one or more substitutents selected from F, Me, Et, OMe, COMe, CONHMe, NH2, —O− (e.g., N-oxide), and SO2. 36. The compound of any one of claims 1-35, wherein R5 is alkyl. 37. The compound of any one of claims 1-35, wherein R5 is selected from H, Me and CH2CN. 38. The compound of any one of claims 1-35, wherein R4b and R5 together with A1 form a ring selected from cyclobutyl, azetidinyl, pyrrolidinyl, and azabicyclohexanyl-6-amine. 39. The compound of claim 38, wherein the ring is substituted by one or more substituents selected from Me, NH2, and NMe2. 40. The compound of any one of claims 1-39, wherein each R6 is independently selected from H, F, Me, and oxo. 41. The compound of any one of claims 1-40, wherein n and m are each 1. 42. The compound of any one of claims 1-40, wherein n is 0 and m is 1. 43. The compound of any one of claims 1-40, wherein n and m are each 0. 44. The compound of any one of claims 1-43, wherein x is 0 or 1. 45. The compound of claim 2, wherein R4a is selected from alkyl, O−, heterocyclyl, and heteroaryl;R4b is selected from alkyl, alkoxy, amino, amido, heterocyclyl, and heteroaryl;R5 is selected from H and alkyl, or R4b and R5 together with A1 form a heterocyclyl; andeach R6 is independently selected from H, halo, and alkyl; andx is 0 or 1. 46. The compound of claim 45, wherein R1 is selected from H, aryl, 5-6 membered heteroaryl, wherein: each E is independently selected from N and CR1d; each G is independently selected from N and CR1e; K1 is N or CH; K2 is NH or S; M is CR1a; R1a is selected from H and amido; R1b is selected from H, halo, alkyl, and alkoxy; R1c is selected from H, alkyl, and alkoxy, or R1b and R1c together with the carbon atoms to which they are attached form a heterocyclyl; R1d is selected from H, alkyl, hydroxy, amido and sulfonamido; R1e is selected from H, alkyl and amino; R1f is H; and R1g is H. 47. The compound of claim 46, wherein R1 is 48. The compound of claim 46, wherein R1 is 49. The compound of claim 47 or 48, wherein E is N. 50. The compound of claim 47 or 48, wherein E is CR1d and R1d is selected from H, CONH2, and SO2NH2. 51. The compound of claim 47 or 48, wherein G is CR1e and R1e is selected from H, Me and NH2. 52. The compound of claim 47, wherein K1 is N. 53. The compound of claim 47, wherein K1 is CH. 54. The compound of claim 48, wherein K2 is NH or S. 55. The compound of claim 47, wherein M is CR1a. 56. The compound of claim 47 or 48, wherein R1a is selected from H and CONH2. 57. The compound of claim 47 or 48, wherein R1b is selected from H, F, Cl, Me, and OMe. 58. The compound of claim 47, wherein R1c is selected from H, Me, OMe, and OEt. 59. The compound of claim 47, wherein R1g is H. 60. The compound of any one of claims 45-59, wherein R3 is H or —O-dioxanyl. 61. The compound of any one of claims 45-59, wherein R4a and/or R4b is alkyl. 62. The compound of any one of claims 45-59, wherein R4b is selected from Me, NH2, NMe2, —CH2—C(Me2)OH, and CMe2NH2. 63. The compound of any one of claims 45-59, wherein R4b is heterocyclyl. 64. The compound of claim 63, wherein the heterocyclyl is selected from pyrrolidinyl, diazolyl, piperazin-2-onyl, piperidinyl, morpholino, tetrahydropyranyl, diazepanyl, azetidinyl, octahydropyrrolo[3,4-c]pyrrolyl, 3,8-diazabicyclo[3.2.1]octanyl, 8-Me-3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and 4-Me-2,5-diazabicyclo[2.2.1]heptanyl. 65. The compound any one of claims 45-59, wherein R4b is heteroaryl. 66. The compound of claim 65, wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, and pyrazolopyridinyl. 67. The compound of any one of claims 63-66, wherein the heterocyclyl or heteroaryl is substituted with one or more substitutents selected from halo, alkyl, carbonyl, amido, amino, oxide and sulfoxide. 68. The compound of claim 67, wherein the heterocyclyl is substituted with one or more substitutents selected from F, Me, Et, COMe, CONHMe, NH2, —O− (e.g., N-oxide), and SO2. 69. The compound of any one of claims 45-68, wherein R5 is alkyl. 70. The compound of any one of claims 45-68, wherein R5 is selected from H, Me and CH2CN. 71. The compound of any one of claims 45-68, wherein R4b and R5 together with A1 form a ring selected from azetidinyl, piperidinyl and pyrrolidinyl. 72. The compound of any one of claims 45-71, wherein R6 is selected from H, F, and Me. 73. The compound of any one of claims 45-72, wherein n and m are each 1. 74. The compound of any one of claims 45-72, wherein n is 0 and m is 1. 75. The compound of any one of claims 45-72, wherein n and m are each 0. 76. The compound of any one of claims 45-75, wherein x is 0. 77. A compound selected from: or a pharmaceutically acceptable salt and/or prodrug thereof. 78. The compound of claim 77, wherein the compound is selected from: or a pharmaceutically acceptable salt and/or prodrug thereof. 79. A compound selected from: or a pharmaceutically acceptable salt and/or prodrug thereof. 80. A pharmaceutical composition comprising a compound according to any one of claims 1-79, or a pharmaceutically acceptable salt and/or prodrug thereof, and one or more pharmaceutically acceptable excipients. 81. A method for treating the formation of abnormal bone in a soft tissue of a subject, the method comprising: administering to the subject a therapeutically effective amount of one or more compounds of any of claims 1-79. 82. The method of claim 81, wherein the subject is determined to have or be at risk of having abnormal bone formation prior to treatment. 83. The method of claim 81, wherein the subject has been subjected to a musculoskeletal trauma, a spinal cord injury or a central nervous system injury. 84. The method of claim 81, wherein the formation of abnormal bone is associated with a heterotopic ossification disease. 85. The method of claim 84, wherein the heterotopic ossification disease is selected from acquired heterotopic ossification, fibrodysplasia ossificans progressive, anklyosing spondylosis, traumatic heterotopic ossification, burn- or blast-injury associated heterotopic ossification, and joint replacement surgery associated heterotopic ossification. 86. The method of claim 81, wherein the soft tissue comprises muscles, tendons, ligaments and/or fascia. 87. The method of claim 81, further comprising administering at least one additional agent to the subject. 88. The method of claim 87, wherein the at least one additional agent comprises a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a lipoxygenase inhibitor, a leukotriene inhibitor, a mast cell stabilizing agent, an anti-histamine, a TNF inhibitor, an IL-23 blocker, or an inhibitor of IL-1 signaling. 89. The method of claim 87, wherein the at least one additional agent comprises an anti-inflammatory agent. 90. The method of claim 89, wherein the anti-inflammatory agent is selected from one or more of an inhibitor of the activity of substance P; an inhibitor of the secretion of substance P; an inhibitor of the effects of substance P; an inhibitor of the activity of histamine; an inhibitor of the secretion of histamine; an inhibitor of the effects of histamine; an inhibitor of mast cell function; an inhibitor of Toll-like receptor signaling; an inhibitor of MyD88; an inhibitor of TRIF; apyrase; and an agent to catalyze hydrolysis of ATP. 91. The method of claim 87, wherein the at least one additional agent comprises an anti-growth factor agent. 92. The method of claim 91, wherein the anti-growth factor agent is selected from one or more of an inhibitor of PDGF ligands; an inhibitor of PDGF-AA; an inhibitor of PDGF-BB; an inhibitor of PDGFR-alpha receptor function; an inhibitor of PDGFR-beta receptor function; a neutralizing antibody against Activin A; a neutralizing antibody against Activin B; a neutralizing antibody against Activin A ligands; a neutralizing antibody against Activin B ligands; a neutralizing antibody against heterodimeric ligands containing Inhibin bA subunits encoded by the INHBA; a neutralizing antibody against heterodimeric ligands containing Inhibin bB subunits encoded by the INHBB gene; a ligand trap of BMP ligands; a ligand trap of Activin ligands; a ligand trap of soluble extracellular domains of a type II Activin receptor ActRIIA; a ligand trap of soluble extracellular domains of a type II Activin receptor ActRIIB; a ligand trap of soluble extracellular domains of a BMP type I receptor ALK2; a ligand trap of soluble extracellular domains of a BMP type I receptor ALK3; and a ligand trap of soluble extracellular domains of a BMP type I receptor ALK6. 93. The method of claim 87, wherein the at least one additional agent comprises an anti-osteogenic signaling agent or an anti-chondrogenic signaling agent. 94. The method of claim 93, wherein the anti-osteogenic signaling agent or the anti-chondrogenic signaling agent is selected from one or more of a RAR-gamma agonist; a nonselective RAR agonist; an agent that inhibits the activity of osteogenic transcription factor Runx2; an agent that inhibits the expression of osteogenic transcription factor Runx2; an agent that promotes the degradation of osteogenic transcription factor Runx2; an agent that inhibits the activity of chondrogenic transcription factor Sox9; an agent that inhibits the expression of chondrogenic transcription factor Sox9; an agent that promotes the degradation of chondrogenic transcription factor Sox9; an inhibitor of HIF-1 alpha activity; and an inhibitor of HIF-1 alpha expression. 95. A method for treating abnormal bone in a soft tissue of a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of a BMP type I serine-threonine kinase receptor to the subject, wherein the inhibitor of a BMP type I serine-threonine kinase receptor is one or more compounds of any of claims 1-79. 96. A method for inhibiting a serine-threonine kinase receptor in a subject, the method comprising: administering an inhibitor of the serine-threonine kinase receptor to the subject under conditions effective to inhibit the serine-threonine kinase receptor, wherein the inhibitor of the serine-threonine kinase receptor is one or more compounds of any of claims 1-79. 97. The method of claim 96, wherein the serine-threonine kinase receptor is a BMP type I receptor, a BMP type II receptor, or a TGF-β type I receptor. 98. A method of treating a subject with Sjogren's syndrome, comprising: administering to the subject a therapeutically effective amount of an inhibitor of BMP6, thereby treating the subject with Sjogren's syndrome, wherein the inhibitor is one or more compounds of any of claims 1-79. 98. The method of claim 97, wherein the salivary gland is a minor labial salivary gland, parotid gland, or a submandibular gland. 99. A method for treating a subject with diffuse intrinsic pontine glioma (DIPG), comprising administering to the subject a therapeutically effective amount of one or more compounds of any of claims 1-79, thereby treating the subject with diffuse intrinsic pontine glioma (DIPG). 100. A method for treating a subject having a cancer selected from adenocarcinoma, prostate carcinoma, breast carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of claims 1-79, thereby treating the subject with cancer.
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