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US-12617784-B2 - AKT inhibitor

US12617784B2US 12617784 B2US12617784 B2US 12617784B2US-12617784-B2

Abstract

An AKT inhibitor is provided, which specifically relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof. The present invention further provides a preparation method thereof, and the use thereof in prevention and/or treatment of a disease mediated by AKT protein kinase.

Inventors

  • CHANGYOU MA
  • He Tian
  • Jie An
  • Jianliang Zhao
  • Donghui Chen
  • Jian Wu
  • Dan Xu
  • Chunxia Zhu
  • Zhoushan Tian

Assignees

  • NANJING CHIA TAI TIANQING PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20200122
Priority Date
20190129

Claims (20)

  1. 1 . A compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by halogen or OH; R 2 and R 3 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 1 and R 2 , together with the atoms to which R 1 and R 2 are attached, form a 4-7 membered nitrogen-containing heterocyclic ring; m is 1 or 2, n is 0; R 4 and R 5 form ═O together; is selected from the group consisting of R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of H and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by halogen; R 10 is H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by halogen, OH or CN; L is selected from the group consisting of and is optionally substituted by one or more R 12 ; wherein a single wavy line is a position where L is connected to carbonyl, and a double wavy line is a position where L is connected to pyrimidine; and wherein R 12 is C 1 -C 6 alkyl; G is a 6-10 membered aryl optionally substituted by 1-5 R 11 ; R 11 is halogen; provided that neither R 1 nor R 2 is H if R 1 and R 2 , together with the atoms to which R 1 and R 2 are attached, form a 4-7 membered nitrogen-containing heterocyclic ring; and when L is is not
  2. 2 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is H.
  3. 3 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of H, isopropyl and cyclopropyl.
  4. 4 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 and R 2 , together with the atoms to which R 1 and R 2 are attached, form
  5. 5 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein is selected from the group consisting of
  6. 6 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of H, methyl and CF 3 .
  7. 7 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 10 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CN, CH 2 CH 2 CN, CH 2 OH and CH 2 CH 2 OH.
  8. 8 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein L is optionally substituted by methyl.
  9. 9 . The compound or a pharmaceutically acceptable salt thereof according to claim 8 , wherein L is selected from the group consisting of:
  10. 10 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein G is phenyl optionally substituted by 1-5 R 11 ; wherein R 11 is independently selected from the group consisting of F, Cl, Br and I.
  11. 11 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of: cis-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, and trans-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein L is selected from the group consisting of and wherein L is optionally substituted by methyl.
  13. 13 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein L is selected from the group consisting of and wherein L is optionally substituted by methyl.
  14. 14 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has the structure represented by Formula IV: wherein R 2 , L, G, and are as defined in claim 1 .
  15. 15 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has the structure represented by Formula V, Formula VIII, or Formula XI: wherein R 2 , R 6 , R 8 , R 10 , L and G are as defined in claim 1 .
  16. 16 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has the structure represented by Formula VI, Formula IX, or Formula XII: wherein R 2 , R 6 , R 8 , R 10 , R 11 and L are as defined in claim 1 , and d is 0, 1 or 2.
  17. 17 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has the structure represented by Formula VII: wherein, R 2 , R 6 , R 8 , R 11 and L are as defined in claim 1 , d is 0, 1 or 2.
  18. 18 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and/or R 3 is H.
  19. 19 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is isopropyl or cyclopropyl; and/or R 3 is H.
  20. 20 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 6 is methyl or CF 3 ; and/or R 7 is H; and/or R 8 is H; and/or R 9 is H; and/or R 10 is methyl.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National-Stage entry under 35 U.S.C. § 371 based on International Application No. PCT/CN2020/073798, filed Jan. 22, 2020, which was published under PCT Article 21(2) and which claims the priority of the Chinese patent application with the application number 201910084801.3 filed with the China National Intellectual Property Administration on Jan. 29, 2019, the entire content of which are incorporated in their entirety by reference. FIELD OF THE INVENTION The present invention belongs to the field of medicinal chemistry, and specifically relates to an AKT inhibitor, and a preparation method and medical use thereof. BACKGROUND OF THE INVENTION The PI3K/AKT/mTOR pathway composed of phosphatidylinositol 3-kinase (PI3K) and its downstream protein AKT (also known as protein kinase B, PKB) and mammalian target of rapamycin (mTOR), as a very important signal transduction pathway in cells, plays an extremely important biological function in the process of cell growth, survival, proliferation, apoptosis, angiogenesis, and autophagy. Abnormal activation of this pathway can cause a series of diseases, including cancer, neuropathy, autoimmune diseases and hemic and lymphatic system diseases. AKT, a type of serine/threonine kinase, affects cell survival, growth, metabolism, proliferation, migration and differentiation through numerous downstream effectors. Over 50% of human tumors have over-activation of AKT, especially prostate cancer, pancreatic cancer, bladder cancer, ovarian cancer, and breast cancer. Over-activation of AKT can lead to tumorigenesis, tumor metastasis and drug resistance development. AKT has three subtypes: AKT1, AKT2 and AKT3. As a typical protein kinase, each subtype is composed of an amino-terminal PH domain (Pleckstrin homology domain), a kinase domain that binds ATP in the middle, and a carboxy-terminal regulatory domain. About 80% of the amino acid sequences of the three subtypes are homologous, with large changes only in the junction region of the PH domain and the kinase domain. Currently, the targeting drugs for the PI3K/AKT/mTOR signal pathway are mainly PI3K inhibitors and mTOR inhibitors, while AKT is at the core of the signal transduction pathway. Inhibition of AKT activity can not only avoid the serious side effects caused by inhibiting upstream PI3K, but also avoid the negative feedback mechanism caused by inhibiting downstream mTOR, which affects the efficacy of the drug. Therefore, searching for effective and selective AKT inhibitors is an important direction of current tumor-targeted drug research and development. CN101631778A discloses a class of cyclopenta[D]pyrimidine derivatives, CN101578273A discloses a class of hydroxylated and methoxylated cyclopenta[D]pyrimidine derivatives, CN101511842A discloses a class of dihydrofuro pyrimidine derivatives, and CN101970415A discloses a class of 5H-cyclopenta[d]pyrimidine derivatives. These compounds have an IC50 of inhibiting AKT1 of less than 10 μM. SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound represented by formula I or pharmaceutically acceptable salts thereof, whereinR1 is selected from the group consisting of H, OH, halogen, CN, NH2, NO2, or C1-C6 alkyl optionally substituted by halogen or OH;R2 and R3 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)—, (C3-C6 cycloalkyl)-(CH2CH2)—, benzyl, phenethyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)— or (C3-C6 cycloalkyl)-(CH2CH2)— is optionally substituted by halogen, OH, CN, NH2 or C1-C3 alkoxy, the benzyl or phenethyl is optionally substituted by halogen, OH, CN, NO2, NH2, C1-C3 alkoxy, halogenated C1-C3 alkoxy, C1-C3 alkyl or halogenated C1-C3 alkyl, the pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl is optionally substituted by halogen, OH, C1-C3 alkyl, cyclopropylmethyl or C1-C4 alkanoyl; orR1 and R2, together with the atoms to which R1 and R2 are attached, form a 4-7 membered nitrogen-containing heterocyclic ring;m and n are each independently 0, 1, 2 or 3;R4 and R5 both are hydrogen or R4 and R5 form ═O together; is selected from the group consisting of R6, R7, R8, and R9 are each independently selected from the group consisting of H, CN, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by halogen, OH, CN or C1-C3 alkoxy;R10 is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by halogen, OH, CN or C1-C3 alkoxy;L is an optionally substituted 5-12 membered saturated heterocyclic ring containing 1-2 nitrogen atoms;G is a 6-10 membered aryl or a 5-10 membered heteroaryl optionally substituted by 1-5 R11;R11 is independently selected from the group consisting of halogen, OH, CN, NH2, NO2, benzyloxy, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)NH2, —C(═O)NH(C1-C6 alkyl),