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CN-117486888-B - Tricyclic compounds and uses thereof

CN117486888BCN 117486888 BCN117486888 BCN 117486888BCN-117486888-B

Abstract

The invention relates to tricyclic compounds and uses thereof. More particularly, the present invention relates to tricyclic compounds, pharmaceutical compositions containing them, processes for their preparation and their use in medicine.

Inventors

  • SU WEIGUO
  • ZHANG WEIHAN
  • LI JINSHUI

Assignees

  • 和记黄埔医药（上海）有限公司

Dates

Publication Date
20260505
Application Date
20200605
Priority Date
20190606

Claims (20)

  1. 1.A compound of formula (I): Or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 1 and Z 2 are each independently N or C, and Is a5 membered heteroaryl group containing 1,2 or 3 ring heteroatoms selected from N, O or S, said 5 membered heteroaryl group optionally substituted with one or more substituents independently selected from deuterium, halogen, and C 1-6 alkyl, wherein each of said C 1-6 alkyl groups is optionally substituted with one or more deuterium; l is absent, or L is-NR c , O, or S; R c is hydrogen or C 1-6 alkyl; Ar is heteroaryl, wherein the heteroaryl is a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, 1, 2 or 3 of which are independently selected from N, O and S ring heteroatoms, the remaining ring atoms being carbon atoms, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, wherein each of said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl is optionally substituted with one or more deuterium; R 1 is selected from C 1-6 alkyl optionally substituted with one or more deuterium, - (C 1-6 alkyl) -OH, saturated monocyclic C 3-8 cycloalkyl, saturated 3-8 membered monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbyl having 5, 6 or 7 ring atoms of which 1,2 or 3 ring heteroatoms independently selected from 3995 and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbyl having 8, 9 or 10 ring atoms of which 1,2, 3 or 4 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said saturated monocyclic C 3-8 cycloalkyl, saturated monocyclic heterocyclyl containing 1 or 2 ring heteroatoms independently selected from 3996 and S, 3-membered monocyclic heterocyclyl having 1,3 or 4 ring heteroatoms independently selected from 3-to 35C 35 alkyl, 3 or 3-membered monocyclic heterocyclyl independently selected from 3-to 37C 35 alkyl, 3-membered cycloalkyl, saturated monocyclic heterocyclyl having 3-to 37C 35 alkyl, 3-to C35, saturated monocyclic cycloalkyl having 3-to 3-membered cycloalkyl, saturated monocyclic cycloalkyl having 3-3 to O, saturated monocyclic heterocyclyl having 1 to 3, saturated monocyclic heterocyclyl having 3 to saturated monocyclic heterocyclyl having 1 to 3 to O atoms independently selected from 3 and saturated monocyclic heterocyclyl; R 2 is selected from deuterium, halogen, -CN, C 1-6 alkyl optionally substituted with one or more deuterium, C 1-6 haloalkyl, saturated monocyclic C 3-8 cycloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, of which 1, 2 or 3 are independently selected from N, O and S ring heteroatoms, the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 are independently selected from N, O and S ring heteroatoms, the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein each of said saturated monocyclic C 3-8 cycloalkyl, and heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, C 1-6 alkyl, C3776 haloalkoxy, C 1-6 haloalkyl, and oxo, of which is optionally substituted with one or more of which 3, C3798 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkyl, optionally substituted with one or more substituents; R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, C 1-6 alkyl, or R a 、R b together with the carbon atom to which they are attached form a saturated monocyclic C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from deuterium, halogen; represents a double bond or a single bond, and when When representing a double bond, R 3 and R 5 are absent; R 3 、R 4 、R 5 、R 6 、R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, hydroxy, - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -O- (C 1-6 alkyl), C 1-6 alkyl, - (C 1-6 alkyl) -phenyl, C 1-6 alkoxy and C 1-6 haloalkyl, or any two of R 3 、R 4 、R 5 、R 6 、R 7 and R 8 together with the carbon atom to which they are attached and the B ring form an 8-11 membered spiro or bridged ring optionally containing 2 or 3 ring heteroatoms independently selected from N, O or S, said spiro or bridged ring optionally substituted with one or more substituents independently selected from deuterium and halogen; n is 0, 1 or 2; m is 0,1, 2 or 3.
  2. 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Selected from: Wherein R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more deuterium.
  3. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Selected from: Wherein R 10 and R 11 are independently selected from hydrogen, halogen, C 1-6 alkyl.
  4. 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 3, wherein Is that And R 10 and R 11 are independently selected from hydrogen, halogen and C 1-6 alkyl.
  5. 5. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein Ar is a monocyclic heteroaryl group having 5 or 6 ring atoms, 1, 2 or 3 of which are independently selected from N, O and S ring heteroatoms, the remaining ring atoms being carbon atoms, each of which is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, wherein each of said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl is optionally substituted with one or more deuterium.
  6. 6. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein Ar is selected from pyridinyl, pyrimidinyl and 1,3, 5-triazinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl.
  7. 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 6, wherein Ar is: Or (b) Wherein R 20 、R 21 、R 22 、R 23 and R 24 are each independently selected from the group consisting of hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl.
  8. 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein R 1 is selected from C 1-6 alkyl, - (C 1-6 alkyl) -OH, saturated monocyclic C 3-8 cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein the heteroaryl is a monocyclic aromatic hydrocarbyl having 5 or 6 ring atoms, 1,2 or 3 ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbyl having 8 or 9 ring atoms, 1,2,3 or 4 ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring, and when the heteroaryl groups in the ring are independently selected from N, O and S, the total number of ring heteroatoms in the heteroaryl groups is not selected from the group consisting of 1,2 or 3 ring heteroatoms independently selected from N, O and S, or a bicyclic aromatic hydrocarbyl having 8 ring heteroatoms independently selected from the group consisting of 3 and 3456 and S, wherein when the total number of ring atoms in the heteroaryl groups in the ring is not selected from the group consisting of 1, 3 and S, and 3, are independently saturated, and each of the 3 ring heteroatom is selected from the 3; halogen, - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -O- (C 1-6 alkyl), saturated 3-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O or S, C 1-6 alkyl optionally substituted with one or more deuterium, C 1-6 alkoxy or C 1-6 haloalkyl.
  9. 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 8, wherein R 1 is heteroaryl selected from pyrazolyl, pyridinyl, isoxazolyl, 1,2, 4-triazolyl, 1,3, 4-thiadiazolyl, 2,4,5, 6-tetrahydrocyclopenta [ C ] pyrazolyl and 5,6,7, 8-tetrahydro [1,2,4] triazolo [1,5-a ] pyridinyl, wherein each of said heteroaryl groups is optionally substituted with one or more substituents independently selected from C 1-6 alkyl optionally substituted with one or more deuterium, C 1-6 haloalkyl, C 1-6 alkoxy, halogen, - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -O- (C 1-6 alkyl) and a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from N, O or S.
  10. 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as recited in claim 9, wherein R 1 is pyrazolyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen, - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -O- (C 1-6 alkyl) and oxetanyl optionally substituted with one or more deuterium.
  11. 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein R 2 is selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, saturated monocyclic C 3-8 cycloalkyl, phenyl and heteroaryl, said heteroaryl being a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, O and S ring heteroatoms, the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, 1, 2 or 3 of the ring atoms are independently selected from N, O and S ring heteroatoms, the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein the C 3-8 ring is independently substituted with one or more of the following optionally substituted heteroaryl groups: halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and oxo, said phenyl optionally being substituted with one or more substituents independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl.
  12. 12. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R 2 is phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen, -CN and C 1-6 alkoxy.
  13. 13. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R 2 is heteroaryl, selected from the group consisting of 1,2, 5-oxadiazolyl, indolinyl, tetrahydroquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, thiazolyl, benzo [ d ] isoxazolyl, thienyl, indazolyl, and pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, halo, oxo, and-CN.
  14. 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R 2 is a saturated monocyclic C 3-8 cycloalkyl group, optionally substituted with one or more substituents independently selected from C 1-6 haloalkyl.
  15. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein m is 0, 1 or 2.
  16. 16. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-7, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from hydrogen, halogen, hydroxy and C 1-6 alkyl, or R a 、R b together with the carbon atom to which they are attached form a saturated monocyclic C 3-6 cycloalkyl or form a 3-6 membered heterocyclyl, wherein the 3-6 heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of the ring atoms being ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein each of the saturated monocyclic C 3-6 cycloalkyl or 3-6 heterocyclyl is optionally substituted with one or more substituents selected from halogen.
  17. 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein L is absent, or L is NH, O or S.
  18. 18. The compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, or a racemic mixture, enantiomer, diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0, Represents a double bond, R 3 and R 5 are absent, and R 4 and R 6 are each independently selected from hydrogen and C 1-6 alkyl.
  19. 19. A compound of formula (I-1) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, (I-1) Wherein the method comprises the steps of R 1 is heteroaryl optionally substituted with one or more substituents independently selected from C 1-6 alkyl optionally substituted with one or more deuterium; ar is heteroaryl optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkyl; r 2 is selected from C 1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen; R 4 and R 6 are each independently selected from hydrogen and C 1-6 alkyl; R 10 and R 11 are independently selected from hydrogen; m is 0, 1 or 2, R a and R b are each independently selected from hydrogen and C 1-6 alkyl, or R a 、R b together with the carbon atom to which they are attached form a saturated monocyclic C 3-6 cycloalkyl; L is absent or NH, O or S; The heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, 1,2 or 3 of which are independently selected from N, O and S ring heteroatoms, the remaining ring atoms being carbon atoms, and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.
  20. 20. A compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 19, or a racemic mixture, enantiomer, diastereomer of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl; Ar is pyrimidinyl optionally substituted with one or more substituents independently selected from optionally C 1-6 alkyl and halogen; r 2 is selected from C 1-6 haloalkyl or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen; r 10 and R 11 are hydrogen; m is 0 or 1; R a and R b are each independently selected from hydrogen or C 1-6 alkyl, or R a 、R b together with the carbon atom to which they are attached form a saturated monocyclic C 3-6 cycloalkyl, and L is absent or NH or O.

Description

Tricyclic compounds and uses thereof The application is a divisional application, and the main application is a Chinese patent application of International application PCT/CN2020/094692 with the international application date of 2020, 6 and 5 days, entering China, with the application number of 202080041594.4 and the name of tricyclic compound and application thereof. Technical Field The invention relates to tricyclic compounds, pharmaceutical compositions containing them, processes for their preparation and their use in medicine. Background The RAS/RAF/MEK/ERK pathway is an evolutionarily conserved signaling cascade that regulates many processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism and proliferation. It has been widely recognized that abnormal activation of this pathway is closely associated with various cancers. In a high proportion of tumors, ERK signaling pathways are overactivated, mainly due to mutations in the KRAS, NRAS and BRAF genes. About 30% of all human cancers have RAS mutations with a mutation rate of 90% for pancreatic cancer, 50% for colon cancer, 50% for papillary thyroid cancer, 30% for non-small cell lung cancer (NSCLC) and 25% for melanoma, respectively. BRAF mutations have been widely identified in tumors, with a significant proportion (7%) in all human cancers. This mutation is very common in hairy cell leukemia (100%), melanoma (50% -60%), papillary thyroid carcinoma (40% -60%), colon cancer (CRC) (5% -10%), fibroastrocytoma (10% -15%), non-small cell lung carcinoma (NSCLC) (3% -5%). MEK mutations occur predominantly in melanoma, but also in ovarian cancer cell lines and gliomas. In general, all upstream mutations result in the over-activation of ERK proteins, which are responsible for a range of ERK signaling to regulate the activity of the substrate and ultimately associated with various tumors. Targeting the MAPK/ERK pathway has become a hotspot in cancer therapy. The clinical benefit achieved by BRAF and MEK inhibitors has demonstrated that targeting these downstream RAS effectors is a very promising approach to treat cancers with BRAF mutations. However, existing evidence suggests that inhibition of BRAF or MEK alone is insufficient for clinical benefit of cancer producing RAS mutations. Both endogenous and acquired resistance to BRAF and MEK inhibitors are often associated with the sustained presence of ERK signaling in the presence of drugs, which means that it is desirable to target ERK. Preliminary efficacy of ERK inhibitors has been observed in clinical trials. In phase I clinical studies of BVD-523, clinical responses were found in patients with BRAF and NRAS mutations, even in patients who had progressed on prior use of BRAF and/or MEK inhibitor disease. The combined use with ERK inhibitors was studied and preclinical data support a combination strategy with inhibitors of other targets, such as CDK4/6 inhibitors, VEGFR2 inhibitors, PARP inhibitors, poly-ERBB inhibitors and autophagy inhibitors, in KRAS mutant cancer cells. Thus, ERK inhibitors may potentially benefit more patients clinically. Accordingly, there is a need for new compounds and methods for modulating ERK activity and treating related disorders including cancer. The present invention addresses these needs. Brief description of the invention The present invention provides compounds of formula (I): Or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 1 and Z 2 are each independently N or C, and Is a 5-membered heteroaryl containing 1,2, 3 or 4 ring heteroatoms selected from N, O or S, said 5-membered heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2, -CN, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, - (C 1-6 alkyl) -OH and- (C 1-6 alkyl) -O- (C 1-6 alkyl), said C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl each optionally substituted with one or more deuterium; l is absent, or L is-NR c, O, or S; R c is hydrogen or C 1-6 alkyl; Ar is heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2, -CN, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -O- (C 1-6 alkyl), C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more deuterium; R 1 is selected from hydrogen, C 1-6 alkyl optionally substituted with one or more deuterium, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, - (C 1-6 alkyl)