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CN-121986093-A - Pyrazolecarboxylic acid derivatives and their use in medicine

CN121986093ACN 121986093 ACN121986093 ACN 121986093ACN-121986093-A

Abstract

A pyrazolo carboxylic acid derivative and application thereof in medicine, in particular to a compound shown in a formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and application thereof in preparing medicines for treating diseases related to sGC.

Inventors

  • ZHANG CHEN
  • WANG JIANMIN
  • CHEN TENGFEI
  • HUANG LONGBIN
  • CHEN QUANLONG
  • QIAN MEILIN
  • Tang Pingming
  • LI YAO
  • YAN PANGKE

Assignees

  • 海思科医药集团股份有限公司

Dates

Publication Date
20260505
Application Date
20240927
Priority Date
20230927

Claims (10)

  1. A compound or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the compound being selected from compounds of formula (I), wherein, X 1 is selected from CR 1 or N, X 2 is selected from CR 2 or N, X 3 is selected from CR 3 or N, X 4 is selected from CR 4 or N, X 5 is selected from CR 5 or N, X 6 is selected from CR 6 or N, X 7 is selected from CR 7 or N, and X 8 is selected from CR 8 or N; selected from C 3-12 carbocyclyl or 4-to 12-membered heterocyclyl, optionally substituted with 1 to 4R a ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, halogen, OH, CN, NH 2 、C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N (C 1-6 alkyl) 2 、-O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally substituted with 1 to 4R k ; Or R 7 taken together with R a and the atoms to which it is attached form a 4-8 membered carbocycle or a 4-8 membered heterocycle, said carbocycle or heterocycle optionally being substituted with 1 to 4R k ; R k is each independently selected from deuterium, halogen, OH, =o, CN, NH 2 、COOH、CONH 2 、C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N (C 1-6 alkyl) 2 、-O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from deuterium, halogen, = O, CN, OH, NH 2 、C 1-6 alkyl, C 1-6 alkoxy; n is selected from 0,1,2,3, 4; provided that the conditions are that, 1) R 2 is not Cl, CF 3 ; or 2) at least one of X 1 、X 2 、X 3 、X 4 、X 5 、X 8 is selected from N; or 3) at least one of R 1 、R 3 、R 4 is other than H; Or 4) Not selected from M is selected from 0,1,2,3, 4; Or 5) R 7 together with R a and the atoms to which it is attached form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring being optionally substituted with 1 to 4R k ; Or 6) when R b1 is selected from CHF 2 ,R b2 is selected from H, Selected from the group consisting of R c are each independently selected from H or halogen, Selected from the group consisting of M is selected from 0, 1, 2,3, 4, X 1 is selected from CH, X 3 is selected from CH, X 4 is selected from CH, X 2 is selected from CR 2 ,R 2 is selected from Cl or CF 3 ,X 6 or X 7 is selected from CH, CF or N, X 5 is selected from CR 5 ,X 8 is selected from CR 8 , at least one of R 5 or R 8 is other than H or C 1-4 alkyl; Or 7) when Selected from the group consisting of When R a is not C 1-4 alkylcarbonyl or optionally substituted C 3-6 cycloalkyl.
  2. The compound according to claim 1, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, A group selected from the group consisting of C 3-6 monocycloalkyl, C 3-6 monocycloalkenyl, C 5-11 spirocycloalkyl, C 4-10 and cycloalkyl, C 5-10 bridged cycloalkyl, 4 to 6 membered monocycloheterocycloalkyl, 4 to 6 membered monocycloalkenyl, C 5-11 spiroheterocycloalkyl, C 4-10 and heterocycloalkyl, or C 5-10 bridged heterocycloalkyl optionally substituted with 1 to 4R a ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, halogen, OH, CN, NH 2 、C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N (C 1-4 alkyl) 2 、-O-C 3-6 carbocyclyl, -O-3 to 6 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 6 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-3 to 6 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally substituted with 1 to 4R k ; or R 7 taken together with R a and the atoms to which it is attached form a 4-6 membered carbocycle or a 4-6 membered heterocycle, said carbocycle or heterocycle optionally being substituted with 1 to 4R k ; R k is each independently selected from deuterium, halogen, OH, =o, CN, NH 2 、COOH、CONH 2 、C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N (C 1-4 alkyl) 2 、-O-C 3-6 carbocyclyl, -O-3 to 6 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 6 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-3 to 6 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from deuterium, halogen, = O, CN, OH, NH 2 、C 1-6 alkyl, C 1-6 alkoxy.
  3. The compound according to claim 2, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, Selected from the following optionally substituted with 1 to 4R a : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, S1, s2, s3, s4, s5 are each independently selected from 0 or 1; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, cl, br, I, OH, CN, NH 2 、NHCH 3 、NHCH 3 , Or optionally substituted with 1 to 4R k groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl; Or R 7 together with R a and the atoms to which it is attached form a 5-6 membered carbocycle or a 5-6 membered heterocycle, said carbocycle or heterocycle being optionally substituted with 1 to 4R k ; R k is each independently selected from deuterium, F, cl, br, I, OH, =o, CN, NH 2 、COOH、CONH 2 、NHCH 3 、N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, = O, CN, OH, NH 2 、C 1-4 alkyl, C 1-4 alkoxy.
  4. A compound according to claim 3, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, Selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with 1 to 4R a , Or R 7 together with R a and the atoms to which it is attached form a 5-6 membered heterocyclyl.
  5. The compound according to claim 4, wherein the compound represented by the general formula (I) is selected from the group consisting of compounds represented by the general formulae (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h) and (II-I), R 2a is selected from H, deuterium, F, br, CHF 2 , methyl, ethyl, isopropyl, cyclopropyl; x 1a is selected from N or CR 1a ; x 3a is selected from N or CR 3a ; X 4a is selected from N or CR 4a ; R 1a 、R 3a or R 4a are each independently selected from deuterium, F, cl, br, CHF 2 , methyl, ethyl, isopropyl, cyclopropyl; Selected from the following optionally substituted with 1 to 4R a : r a is selected from H, deuterium, F, cl, br, I, OH, CN, NH 2 、NHCH 3 、NHCH 3 , Methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, -CH 2 -cyclopropyl; r a1 is selected from H, deuterium, F, cl, br, I, OH, CN, NH 2 、NHCH 3 、NHCH 3 , Methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl; R 8a is selected from deuterium, F, br, CF 3 、CHF 2 , cyclopropyl; Selected from the group consisting of The remaining definitions are the same as in claim 4.
  6. The compound of claim 1, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures of table E-1.
  7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably wherein the pharmaceutical composition comprises 0.01 to 1500mg of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
  8. Use of a compound according to any one of claims 1-6 or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of a disease associated with sGC.
  9. Use according to claim 8, wherein said disease is selected from cardiovascular disease, kidney disease or respiratory disease, preferably pulmonary arterial hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, chronic kidney disease or nonproliferative diabetic retinopathy.
  10. A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-6, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition of claim 7, preferably 0.01-1500mg, said disease being preferably cardiovascular disease, kidney disease or respiratory disease.

Description

Pyrazolecarboxylic acid derivatives and their use in medicine Technical Field The invention belongs to the field of medicinal chemistry, relates to a pyrazole carboxylic acid derivative and application thereof in medicine, and particularly provides a pyrazole carboxylic acid derivative and application thereof in medicine, and particularly relates to a compound shown in a formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and application thereof in preparation of medicines for treating diseases related to sGC. Background Nitric Oxide (NO) signaling has pleiotropic effects in biology and critical functions in cardiovascular homeostasis. NO secretion is increased under the influence of mediators such as Norepinephrine (NA), angiotensin, adenosine triphosphate or bradykinin. NO synthesis is also affected by a number of physical stimuli. The intracellular mechanism of action of NO is mainly by stimulating the activity of soluble guanylate cyclase (sGC). sGC is a heme-containing enzyme that increases cyclic 3'-5' -guanosine monophosphate (cGMP) levels in smooth muscle leading to vasodilation. The NO/sGC/cGMP regulatory pathways play an important role in the homeostasis of the cardiovascular and respiratory systems and organs such as the kidneys, brain and liver. In addition to smooth muscle cells, cGMP also affects the function of fibroblasts, cardiomyocytes, platelets, neurons and immune cells, regulating the processes of fibrosis, inflammatory response and neurotransmission. SGC modulators and sGC agonists are a class of drugs that stimulate cGMP formation, and these drugs provide tools for studying the mechanism of sGC modulation and its role in the pathogenesis. The development of sGC modulators or agonists has made possible the emergence of drugs that target directly diseased blood vessels, cardiac muscles, kidneys and other organs. The novel sGC regulator or agonist is developed, the therapeutic value and the wider therapeutic potential of the sGC target point in different indications are explored, and the sGC regulator or agonist has good application prospect. Disclosure of Invention The invention aims to provide a compound shown in a general formula (I) with a novel structure, or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound or the stereoisomer, the deuteride, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal in preparation of medicines for treating diseases related to sGC. The compound has good drug substitution performance, better liver microsome stability, oral performance and good safety. The invention provides a compound shown in a general formula (I) or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof, In some embodiments, the compound of formula (I) is selected from compounds of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h) or (II-I), In some embodiments of the present invention, in some embodiments,Represents an aromatic ring or a non-aromatic ring; In some embodiments, C1 is selected from 5-6 membered heterocycles; in some embodiments of the present invention, in some embodiments, Selected from the group consisting of In some embodiments, X 1 is selected from CR 1 or N; In some embodiments, X 2 is selected from CR 2 or N; In some embodiments, X 3 is selected from CR 3 or N; In some embodiments, X 4 is selected from CR 4 or N; In some embodiments, X 5 is selected from CR 5 or N; In some embodiments, X 6 is selected from CR 6 or N; in some embodiments, X 7 is selected from CR 7 or N; In some embodiments, X 8 is selected from CR 8 or N; in some embodiments, X 1 is selected from CR 1 or N, X 2 is selected from CR 2 or N, X 3 is selected from CR 3 or N, X 4 is selected from CR 4 or N, X 5 is selected from CR 5 or N, X 6 is selected from CR 6 or N, X 7 is selected from CR 7 or N, and X 8 is selected from CR 8 or N; in some embodiments of the present invention, in some embodiments, Selected from C 3-12 carbocyclyl or 4-to 12-membered heterocyclyl, optionally substituted with 1 to 4R a; in some embodiments of the present invention, in some embodiments, A group selected from the group consisting of C 3-6 monocycloalkyl, C 3-6 monocycloalkenyl, C 5-11 spirocycloalkyl, C 4-10 and cycloalkyl, C 5-10 bridged cycloalkyl, 4 to 6 membered monocycloheterocycloalkyl, 4 to 6 membered monocycloalkenyl, C 5-11 spiroheterocycloalkyl, C 4-10 and heterocycloalkyl, or C 5-10 bridged heterocycloalkyl optionally substituted with 1 to 4R a; in some embodiments of the present invention, in some embodiments, Selected from the following optionally substituted with 1 to 4R a: cy