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CN-114616232-B - Azepan pyrimidine derivative and medical application thereof

CN114616232BCN 114616232 BCN114616232 BCN 114616232BCN-114616232-B

Abstract

Relates to azepane pyrimidine derivatives and medical application thereof, and the specific structure is shown in a formula (I). Also relates to a preparation method of the compound, a pharmaceutical composition and application of the compound as a KRAS G12C inhibitor in treating cancers.

Inventors

  • WEI GUOPING
  • Zhao Tanfeng
  • JOHN MCLEAN
  • YANG LING
  • WANG HANJIAN
  • YANG XIA
  • YANG HUA
  • Karum McLaude
  • FU NING
  • LI ZHIWEI
  • BING TIEJUN

Assignees

  • 正大天晴药业集团南京顺欣制药有限公司
  • 正大天晴药业集团股份有限公司

Dates

Publication Date
20260505
Application Date
20200930

Claims (20)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein, the Q is 1, p is 1, and Selected from single bond or double bond; or q is 2, p is 0, and Selected from single bonds; When (when) R 4 and/or R 6 are absent when selected from double bonds; Part A is selected from Each R 1 is substituted on the ring independently selected from C 1-4 alkyl optionally substituted with 1,2 or 3R 0 ; Each R 0 is independently selected from-CN, or C 1-3 alkoxy; m is 0, 1 or 2; Each R 2 is independently selected from-C (O) C≡CR b 、-C(O)C(R a )＝C(R b ) 2 , or-SO 2 C(R a )＝C(R b ) 2 ; Each R a is independently selected from H, halogen, or C 1-4 alkyl; each R b is independently selected from H or a group selected from methyl, dimethylaminomethyl, morpholinylmethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or azetidinylmethyl optionally substituted with 1,2, or 3R c ; each R c is independently selected from fluorine, chlorine, -OH, -NH 2 、-CN、C 1-3 alkyl, C 1-3 alkoxy, or fluoro C 1-3 alkyl; x is selected from single bond, -O-, or-NH-; R 3 is selected from H or a group selected from C 1-4 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl optionally substituted with 1, 2, 3, or 4R d ; Each R d is independently selected from halogen, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino; Y is selected from single bonds; B is selected from phenyl, naphthyl, 5-6 membered heteroaryl, or benzo 5-6 membered heteroaryl optionally substituted with 1,2,3, 4, 5, or 6R e ; Each R e is independently selected from halogen, -CN, -OH, -NH 2 、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or di (halo C 1-6 alkyl) amino; r 4 、R 5 is independently selected from H; R 6 、R 7 is independently selected from H, or R 6 and R 7 together form a carbonyl group; provided that the compound of formula (I) is not
  2. 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 1 is independently selected from methyl, cyanomethyl, or methoxymethyl.
  3. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein the a-R 2 moieties are together selected from
  4. 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R a is independently selected from H, fluoro, chloro, methyl or ethyl.
  5. 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R c is independently selected from fluoro, chloro, methyl, ethyl or trifluoromethyl.
  6. 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 2 is selected from the group consisting of:
  7. 7. a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 2 is selected from the group consisting of:
  8. 8. a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein X is selected from-O-.
  9. 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R 3 is selected from the group consisting of 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl optionally substituted with 1,2,3 or 4R d .
  10. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 3 is selected from H or a group optionally substituted by 1,2,3 or 4R d selected from methyl, ethyl, propyl, 1,2,3, 4-tetrahydroisoquinolinyl, azetidinyl, azetidinylethyl, azetidinylpropyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, tetrahydropyrrolylpropyl, morpholinyl, piperazinyl, piperidinyl, piperidylethyl, piperidylpropyl, morpholinylpropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl,
  11. 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 3 is selected from H or a group consisting of tetrahydropyrrolylmethyl, tetrahydropyrrolethyl, tetrahydropyrrolpropyl, morpholinpropyl,
  12. 12. A compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from tetrahydropyrrolylmethyl optionally substituted by 1,2, 3 or 4R d .
  13. 13. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R d is independently selected from fluoro, oxo, methyl, ethyl, isopropyl, t-butyl, methoxy, dimethylamino, or diethylamino.
  14. 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R d is independently selected from fluoro, or methyl.
  15. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 3 is selected from H,
  16. 16. The compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein B is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, indolyl, or isoindolyl optionally substituted with 1,2, 3, 4, 5, or 6R e .
  17. 17. The compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein B is selected from phenyl, naphthyl, pyridinyl, or benzopyrazolyl optionally substituted with 1,2,3,4, 5, or 6R e .
  18. 18. The compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein B is selected from phenyl, naphthyl, or pyridinyl, optionally substituted with 1, 2, 3, or 4R e .
  19. 19. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R e is independently selected from halogen, -CN, -OH, -NH 2 、C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, C 1-4 alkoxy, C 1-4 alkylamino, or di C 1-4 alkylamino.
  20. 20. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R e is independently selected from fluoro, chloro, bromo, iodo, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, or dimethylamino.

Description

Azepan pyrimidine derivative and medical application thereof Cross-reference to related references The present application claims priority from chinese patent application No. 201910843832.2 entitled "azepan pyrimidine derivatives and their medical uses," filed on 9/6/2019, the entire contents of which are incorporated herein by reference. Technical Field The application relates to azepane pyrimidine derivatives, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound serving as a KRAS G12C inhibitor in treating cancers. Background Ras gene is an important proto-oncogene, named as it is found in the rat sarcoma virus, which encodes a Ras protein that is localized inside the cell membrane, binds to GTP/GDP and hydrolyzes GTP with the aid of GTPase Activating Proteins (GAPs). Ras proteins control the "on" and "off" of signaling processes such as growth factors and cytokines by interconversion between active (GTP-bound) and inactive (GDP-bound) conformations, playing an important role in life processes such as Cell proliferation, differentiation, aging, and apoptosis (Bos J L et al, cell,2007,129 (5): 865-877). There are three members of the human Ras gene family, havi rat sarcoma virus oncogene homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas), and kers Teng Da rat sarcoma virus oncogene homolog (KRas), with KRas expressed primarily in the intestine, lung, and thymus (Rajalingam K et al, biochim Biophys Acta,2007,1773 (8): 1177-1195). Studies have shown that Ras gene mutations are present in more than 30% of human tumors, with KRAS mutations accounting for approximately 86% (Riely G J et al, proc Am Thorac Soc,2009,6 (2): 201-205). For KRAS mutations, the mutation at glycine 12 (G12) accounts for about 80%, whereas the G12C mutation (glycine 12 to cysteine) accounts for about 14% of all G12 mutations (Prior I A et al, CANCER RES,2012,72 (10): 2457-2467; hobbs G A et al, CANCER CELL,2016,29 (3): 251-253). The mutation at G12 reduces the catalytic activity of GAP, eventually promotes Ras to be continuously activated, so that the Ras cannot effectively regulate cell signal transduction, and further promotes the occurrence and development of tumors. In recent years, development of drugs by using the allosteric site of the KRAS G12C mutant has been advanced. Currently, KRAS G12C inhibitors under investigation are ARS-1620, MRTX-1257, AMG-510 and MRTX-849, wherein AMG-510 and MRTX-849 have entered the clinical trial phase. Detailed Description The present application relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof, Wherein, the When q is 0, p is 2,Selected from single bonds; Or when q is 1, p is 1, Selected from single bond or double bond; Or when q is 2, p is 0, Selected from single bonds; When (when) R 4 and/or R 6 are absent when selected from double bonds; Part A is selected from Or (b)Wherein R is selected from H or C 1-6 alkyl; Or the A-R 2 moieties are together selected from Is a 4-10 membered heterocycloalkyl containing at least two N atoms; Is a 4-7 membered heterocycloalkyl containing at least one N atom; Each R 1 is substituted on the ring independently selected from halogen, oxo, -OH, -NH 2, -CN, or a group optionally substituted with 1,2, or 3R 0 C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or di C 1-6 alkylamino; Each R 0 is independently selected from halogen, -OH, -NH 2、-CN、C1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino; m is 0,1, 2, 3,4, 5 or 6; each R 2 is independently selected from C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, -C (O) C≡CR b、-SO2C≡CRb、-C(O)C(Ra)＝C(Rb)2, or-SO 2C(Ra)＝C(Rb)2; Each R a is independently selected from H, halogen, or C 1-4 alkyl; Each R b is independently selected from H or a group optionally substituted with 1, 2, or 3R c C 1-6 alkyl, C 1-4 alkoxyC 1-3 alkyl, C 1-4 alkylamino C 1-3 alkyl, di C 1-4 alkylamino C 1-3 alkyl, 3-7 membered cycloalkyl C 1-3 alkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl; Each R c is independently selected from halogen, -OH, -NH 2、-CN、C1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl; X is selected from single bond, -S-, -O-, -NH-, or-N (C 1-3 alkyl) -; R 3 is selected from H or a group selected from C 1-6 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl optionally substituted with 1,2, 3, or 4R d; Each R d is independently selected from halogen, -OH, oxo, -NH 2、-CN、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl, wherein said C 1-4 alkylamino, di-C 1-4 alkylamino is optionally substituted with a substituent selected from 1 or 2 cyano or 5-6 membered heteroaryl; y is selected from single bond, -CH 2