CN118317955A

CN118317955A - 作为cd38抑制剂的n-(4-氨基环己基)嘧啶-4-甲酰胺

作为cd38抑制剂的n-(4-氨基环己基)嘧啶-4-甲酰胺 Download PDF

Info

Publication number: CN118317955A
Authority: CN; China
Prior art keywords: methyl; pyrimidine; imidazol; mmol; cyclohexyl
Prior art date: 2021-11-09
Legal status : Pending

Application number

CN202280073666.2A

Other languages

English (en)

Chinese (zh)

Inventor

R·布利

K·道尔

Current Assignee

Selevens Inc

Original Assignee

Selevens Inc

Priority date

2021-11-09

Filing date

2022-11-09

Publication date

2024-07-09

2022-11-09 Application filed by Selevens Inc filed Critical Selevens Inc

2024-07-09 Publication of CN118317955A publication Critical patent/CN118317955A/zh

Status Pending legal-status Critical Current

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-1 N- (4-aminocyclohexyl) pyrimidine-4-carboxamide Chemical compound 0.000 title claims description 122
229940126634 CD38 inhibitor Drugs 0.000 title description 2
VJQALSOBHVEJQM-UHFFFAOYSA-N COCCOC1CCC(CC1)Nc1cc(=O)n(C)c2ccc(cc12)-c1cncs1 Chemical compound COCCOC1CCC(CC1)Nc1cc(=O)n(C)c2ccc(cc12)-c1cncs1 VJQALSOBHVEJQM-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 182
150000003839 salts Chemical class 0.000 claims abstract description 69
239000000651 prodrug Substances 0.000 claims abstract description 66
229940002612 prodrug Drugs 0.000 claims abstract description 66
239000012453 solvate Substances 0.000 claims abstract description 62
230000000694 effects Effects 0.000 claims abstract description 22
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
238000011282 treatment Methods 0.000 claims abstract description 18
101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims abstract description 5
102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims abstract 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 56
HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 claims description 48
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
229910052757 nitrogen Inorganic materials 0.000 claims description 37
125000001153 fluoro group Chemical group F* 0.000 claims description 35
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
238000000034 method Methods 0.000 claims description 27
201000010099 disease Diseases 0.000 claims description 25
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 20
229910052739 hydrogen Inorganic materials 0.000 claims description 18
125000000217 alkyl group Chemical group 0.000 claims description 17
239000001257 hydrogen Substances 0.000 claims description 16
125000001424 substituent group Chemical group 0.000 claims description 16
208000024827 Alzheimer disease Diseases 0.000 claims description 15
239000003814 drug Substances 0.000 claims description 15
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 13
230000032683 aging Effects 0.000 claims description 12
208000035475 disorder Diseases 0.000 claims description 12
229910052731 fluorine Inorganic materials 0.000 claims description 12
239000011737 fluorine Substances 0.000 claims description 12
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
208000023275 Autoimmune disease Diseases 0.000 claims description 11
208000018737 Parkinson disease Diseases 0.000 claims description 11
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
239000003085 diluting agent Substances 0.000 claims description 11
229910052717 sulfur Inorganic materials 0.000 claims description 11
125000003709 fluoroalkyl group Chemical group 0.000 claims description 10
210000003169 central nervous system Anatomy 0.000 claims description 9
125000005842 heteroatom Chemical group 0.000 claims description 9
208000036110 Neuroinflammatory disease Diseases 0.000 claims description 8
125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 8
230000007850 degeneration Effects 0.000 claims description 8
201000006417 multiple sclerosis Diseases 0.000 claims description 8
230000003959 neuroinflammation Effects 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 7
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
208000001145 Metabolic Syndrome Diseases 0.000 claims description 7
208000008589 Obesity Diseases 0.000 claims description 7
201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 7
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125000001309 chloro group Chemical group Cl* 0.000 claims description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
208000037906 ischaemic injury Diseases 0.000 claims description 7
235000020824 obesity Nutrition 0.000 claims description 7
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
208000012902 Nervous system disease Diseases 0.000 claims description 6
208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 6
208000030886 Traumatic Brain injury Diseases 0.000 claims description 6
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IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 6
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206010003594 Ataxia telangiectasia Diseases 0.000 claims description 5
206010011878 Deafness Diseases 0.000 claims description 5
208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
208000024412 Friedreich ataxia Diseases 0.000 claims description 5
201000011240 Frontotemporal dementia Diseases 0.000 claims description 5
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150000001412 amines Chemical class 0.000 claims description 5
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230000010370 hearing loss Effects 0.000 claims description 5
231100000888 hearing loss Toxicity 0.000 claims description 5
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125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
206010025135 lupus erythematosus Diseases 0.000 claims description 5
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125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
238000002560 therapeutic procedure Methods 0.000 claims description 3
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238000002360 preparation method Methods 0.000 abstract description 13
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 49
229950006238 nadide Drugs 0.000 description 49
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 48
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
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JCDBQDNBEQHDHK-BSLNIGMPSA-N [(2r,3s,4r,5r)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl [[(2r,3s,4r,5r)-3,4-dihydroxy-5-imidazo[2,1-f]purin-3-yloxolan-2-yl]methoxy-hydroxyphosphoryl] phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=C(C5=NC=CN5C=N4)N=C3)O)O2)O)=C1 JCDBQDNBEQHDHK-BSLNIGMPSA-N 0.000 description 8
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