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WO2025016393A1 - 一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物及其在医药上的应用 - Google Patents

一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物及其在医药上的应用 Download PDF

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Publication number
WO2025016393A1
WO2025016393A1 PCT/CN2024/105872 CN2024105872W WO2025016393A1 WO 2025016393 A1 WO2025016393 A1 WO 2025016393A1 CN 2024105872 W CN2024105872 W CN 2024105872W WO 2025016393 A1 WO2025016393 A1 WO 2025016393A1
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Prior art keywords
optionally substituted
alkyl
membered
carbocyclyl
cyclopropyl
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PCT/CN2024/105872
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English (en)
French (fr)
Inventor
张晨
王健民
钱国飞
黄正刚
陈泉龙
钱玫琳
唐平明
李瑶
严庞科
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海思科医药集团股份有限公司
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Publication of WO2025016393A1 publication Critical patent/WO2025016393A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to sGC activity or expression.
  • Nitric oxide (NO) signaling has pleiotropic effects in biology and has a key function 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 many physical stimuli (Int. J. Mol. Sci. 2021, 22, 6029; Molecules 2021, 26, 3418).
  • NA norepinephrine
  • angiotensin adenosine triphosphate
  • bradykinin bradykinin
  • the intracellular mechanism of action of NO is mainly through stimulating the activity of soluble guanylate cyclase (sGC).
  • sGC is a heme-containing enzyme that can increase the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and cause vasodilation (Nat. Rev. Cardiol. 2018, 15, 292-316).
  • cGMP cyclic 3'-5'-guanosine monophosphate
  • the NO/sGC/cGMP regulatory pathway plays an important role in the homeostasis of the cardiovascular and respiratory systems and organs (such as the kidneys, brain and liver).
  • cGMP In addition to smooth muscle cells, cGMP also affects the function of fibroblasts, cardiomyocytes, platelets, neurons and immune cells, regulating fibrosis, inflammatory response and neurotransmission processes (Molecules 2023, 28, 861).
  • sGC modulators and sGC agonists are a class of drugs that can stimulate cGMP formation. These drugs provide tools for studying the regulation of sGC and its role in pathological mechanisms.
  • the development of sGC modulators or agonists makes it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs (Molecules 2023, 28, 861).
  • Riociguat is the first sGC agonist to be marketed. In 2013, Riociguat was approved for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH) (J. Med. Chem. 2017, 60, 5146-5161).
  • the purpose of the present invention is to provide a class of 4-amino-pyrrolo[2,3-d]pyrimidine heterocyclic compounds or pharmaceutically acceptable salts thereof, which are applied as sGC regulators or agonists.
  • the compounds of the present invention can effectively stimulate the activity of soluble guanylate cyclase (sGC) and can be used to treat cardiovascular diseases, kidney diseases or respiratory diseases.
  • sGC soluble guanylate cyclase
  • the compound of the present invention has a good stimulating effect on the cGMP production of LNCap cells and has good lung pharmacokinetic properties, such as lung AUC and/or lung-blood ratio are better than control 1, and has the advantages of lung targeting and reducing systemic side effects.
  • the present invention provides a compound of general formula (I) or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • Formula (I) is selected from Formula (Ia),
  • Z is selected from CH or N;
  • A is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl
  • A is selected from phenyl, benzoC 4-6 carbocycle, 5- to 6-membered heteroaryl, benzo 4- to 7-membered heterocyclyl, or 8-12-membered heteroaryl;
  • A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • A is selected from phenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • A is selected from
  • R 1 is selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;
  • R 1 is selected from -M-(CR 1a R 1b ) r -COOH,
  • M is selected from a bond, a C 3-12 carbocyclyl, or a 4-12 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R m ;
  • M is selected from C 4-12 carbocyclyl or 4-12 membered heterocyclyl, the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R m , and M is not selected from unsubstituted phenyl;
  • M is selected from 4-7 membered heteromonocycle, 5-10 membered heterocyclic ring, 6-12 membered heterospirocycle, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered cycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, said aryl, heteroaryl, cycloalkyl, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heteromonocycle, heterocyclic ring, heterospirocycle or heterobridged ring is optionally substituted with 1 to 4 R m , and M is not selected from unsubstituted phenyl;
  • M is selected from the following groups optionally substituted with 1 to 4 R m : cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • M is selected from M 1 ;
  • R 1 is selected from -M 1 -COOH, -M 1 -CR 1a R 1b -COOH,
  • M 1 is each independently selected from C 4-12 cycloalkyl or 4-12 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 R m ;
  • M 1 is independently selected from the following groups optionally substituted with 1 to 3 R m : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl;
  • B is selected from C 3-8 carbocyclyl, 4-8 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;
  • B is selected from C 3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • B is selected from the following groups optionally substituted with 1 to 4 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • C is selected from C 4-8 carbocyclyl or 4-8 membered heterocyclyl, which is optionally substituted with 1 to 4 R k ;
  • C is selected from C 4-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • C is selected from the following groups optionally substituted with 1 to 4 R k : cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxohexanyl;
  • R is selected from
  • R 2 is selected from C 1-6 alkyl or -C 1-6 alkylene-Q, said alkyl or alkylene being optionally substituted with 1 to 10 R k ;
  • R 2 is selected from C 1-5 alkyl or -C 1-4 alkylene-Q, said alkyl or alkylene being optionally substituted with 1 to 8 R k ;
  • R 2 is selected from C 1-4 alkyl or -C 1-3 alkylene-Q, said alkyl or alkylene being optionally substituted with 1 to 6 R k ;
  • R 2 is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, butylene are optionally substituted with 1 to 6 R k ;
  • R2 is selected from
  • Q is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, which is optionally substituted with 1 to 4 R q ;
  • Q is selected from C 3-11 cycloalkyl, 4 to 11 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally substituted with 1 to 4 R q ;
  • Q is selected from C 3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally substituted with 1 to 4 R q ;
  • Q is selected from the following groups optionally substituted with 1 to 4 Rq : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • Ra , Rc , Rm , Rq, Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2 , C1-6 alkyl, OC1-6 alkyl, SC1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N( C1-6 alkyl) 2 , -OC3-8 carbocyclyl, -O-3 to 8 membered heterocyclyl, -NH- C3-8 carbocyclyl, -NH-3 to 8 membered heterocyclyl, -C0-4 alkylene- C3-8 carbocyclyl, -C0-4 alkylene-3 to 8 membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk
  • Ra , Rc , Rm , Rq, Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2 , C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl , C2-4 alkenyl, C2-4 alkynyl, NHC1-4 alkyl, N( C1-4 alkyl) 2 , -OC3-6 carbocyclyl, -O-3 to 6 membered heterocyclyl, -NH- C3-6 carbocyclyl, -NH-3 to 6 membered heterocyclyl, -C0-2 alkylene- C3-6 carbocyclyl, -C0-2 alkylene-3 to 6 membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , or the following groups optionally substituted with 1 to 4 Rk : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , or the following groups optionally substituted with 1 to 4 Rk : methyl, ethyl, methoxy, cyclopropyl;
  • Ra , Rc , Rb3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , CF3 , CHF2 , CH2F , methyl, ethyl, methoxy, cyclopropyl;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 3-12 carbocyclyl or a 4-12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-11 cycloalkyl group or a 4- to 11-membered heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 R k groups;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-7 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 R k groups;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form the following group optionally substituted by 1 to 4 R k : cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;
  • R b1 , R b2 , R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -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, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -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, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, methoxy, cyclopropyl;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, and cyclopropyl;
  • Selected from Its left side is connected to R 2 ;
  • a, c, r, s are each independently selected from 0, 1, 2, 3, 4;
  • r1 and s are each independently selected from 0, 1, 2, and 3;
  • r1, r, s are each independently selected from 0, 1, 2;
  • a and c are each independently selected from 0, 1, and 2;
  • each R k is 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, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl
  • the general formula (I) satisfies at least one of the following three conditions:
  • M is selected from C 4-12 carbocyclyl or 4-12 membered heterocyclyl and M is not selected from unsubstituted phenyl, the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R m ;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-12 carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 1a , R 1b , R 1c , and R 1d are selected from -OC 3-8 carbocyclyl, -O-3 to 8 membered heterocyclyl, -NH-C 3-8 carbocyclyl, -NH-3 to 8 membered heterocyclyl, -C 0-4 alkylene-C 3-8 carbocyclyl, -C 0-4 alkylene-3 to 8 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k .
  • Z is selected from CH or N
  • A is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl
  • R 1 is selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;
  • M is selected from a bond, a C 3-12 carbocyclyl or a 4-12 membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R m ;
  • R 2 is selected from C 1-6 alkyl or -C 1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 R k ;
  • Q is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted by 1 to 4 R q ;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2 , C1-6 alkyl, OC1-6 alkyl, SC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N( C1-6 alkyl) 2 , -OC3-8 carbocyclyl, -O-3 to 8 membered heterocyclyl, -NH- C3-8 carbocyclyl, -NH-3 to 8 membered heterocyclyl, -C0-4 alkylene- C3-8 carbocyclyl, -C0-4 alkylene-3 to 8 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 3-12 carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • Rb1 , Rb2 , and Rb4 are each independently selected from H, deuterium, OH, CN, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N( C1-6 alkyl) 2 , -NH- C3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C0-4 alkylene- C3-6 carbocyclyl, -C0-4 alkylene R-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • a, c, r, s are each independently selected from 0, 1, 2, 3, 4;
  • M is selected from C 4-12 carbocyclyl or 4-12 membered heterocyclyl and M is not selected from unsubstituted phenyl, the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R m ;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-12 carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 1a , R 1b , R 1c , and R 1d are selected from -OC 3-8 carbocyclyl, -O-3 to 8 membered heterocyclyl, -NH-C 3-8 carbocyclyl, -NH-3 to 8 membered heterocyclyl, -C 0-4 alkylene-C 3-8 carbocyclyl, -C 0-4 alkylene-3 to 8 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k .
  • R1 is selected from -M-( CR1aR1b ) r -COOH,
  • M is selected from C 4-12 carbocyclyl or 4-12 membered heterocyclyl, the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R m , and M is not selected from unsubstituted phenyl;
  • B is selected from C 3-8 carbocyclic group, 4-8 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • C is selected from C 4-8 carbocyclyl or 4-8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • r1 and s are each independently selected from 0, 1, 2, and 3;
  • A is selected from phenyl, benzoC 4-6 carbocyclic ring, 5- to 6-membered heteroaryl, benzo 4- to 7-membered heterocyclyl or 8- to 12-membered heteroaryl;
  • M is selected from 4-7 membered heteromonocycle, 5-10 membered heterocyclic ring, 6-12 membered heterospirocycle, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered cycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heteromonocycle, heterocyclic ring, heterospirocycle or heterobridged ring is optionally substituted with 1 to 4 Rm , and M is not selected from unsubstituted phenyl;
  • R 2 is selected from C 1-5 alkyl or -C 1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 R k ;
  • Q is selected from C 3-11 cycloalkyl, 4 to 11 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 R q ;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2 , C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, NHC1-4 alkyl, N( C1-4 alkyl) 2 , -OC3-6 carbocyclyl, -O-3 to 6 membered heterocyclyl, -NH- C3-6 carbocyclyl, -NH-3 to 6 membered heterocyclyl, -C0-2 alkylene- C3-6 carbocyclyl, -C0-2 alkylene-3 to 6 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-11 cycloalkyl or a 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k ;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -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, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • B is selected from C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 R k ;
  • C is selected from C 4-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 R k ;
  • R 2 is selected from C 1-4 alkyl or -C 1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 R k ;
  • Q is selected from C 3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 R q ;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN , NH2 , NHCH3, N( CH3 ) 2 , or the following groups optionally substituted with 1 to 4 Rk : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;
  • R 1a and R 1b or R 1c and R 1d together with the carbon atom to which they are attached, form a C 4-7 cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k ;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;
  • A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • B is selected from the following groups optionally substituted with 1 to 4 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • C is selected from the following groups optionally substituted with 1 to 4 R k : cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxhexane;
  • M is selected from the following groups optionally substituted with 1 to 4 R m : cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • R 2 is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, butylene are optionally substituted with 1 to 6 R k ;
  • Q is selected from the following groups optionally substituted with 1 to 4 Rq : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • Ra , Rc , Rm , Rq , Rb3 , R1a , R1b , R1c , R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , or the following groups optionally substituted with 1 to 4 Rk : methyl, ethyl, methoxy, cyclopropyl;
  • R 1a and R 1b or R 1c and R 1d together form the following group optionally substituted by 1 to 4 R k : cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, methoxy, and cyclopropyl;
  • r1, r, s are each independently selected from 0, 1, 2;
  • A is selected from phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • R 1 is selected from
  • R 2 is selected from
  • Ra , Rc , and Rb3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , CF3 , CHF2 , CH2F , methyl, ethyl, methoxy, and cyclopropyl;
  • R b1 , R b2 , and R b4 are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, and cyclopropyl;
  • a, c are each independently selected from 0, 1, 2;
  • A is selected from phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; preferably
  • B is selected from the following groups optionally substituted by 1 to 4 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; preferably: cyclopropyl, cyclobutyl, cyclopentyl, oxe
  • R 2 is selected from
  • Ra and Rc are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , CF3 , CHF2, CH2F , methyl, ethyl, methoxy, and cyclopropyl ;
  • R 1a , R 1b are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, methoxy, cyclopropyl;
  • a and c are each independently selected from 0, 1, and 2.
  • the present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:
  • the present invention relates to a pharmaceutical composition, comprising the above compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to the use of the above-mentioned compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing a drug for treating diseases associated with sGC.
  • the present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in preparing drugs for treating cardiovascular diseases, kidney diseases or respiratory diseases (preferably pulmonary arterial hypertension, pulmonary hypertension, chronic obstructive pulmonary disease).
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal and pharmaceutical excipients.
  • the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition.
  • the mammal of the present invention includes a human.
  • Effective amount or “therapeutically effective amount” as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cardiovascular disease) being treated to some extent.
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 0.01-1500 mg, 0.01-1000 mg, 0.01-800 mg, 0.01-600 mg, 0.1-1500 mg, 0.1-1000 mg, 0.1-800 mg, 0.1-600 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-60 0mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-5 00mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg,
  • the pharmaceutical composition includes but is not limited to 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 0.01-1500 mg, and the disease preferably being a cardiovascular disease.
  • a method for treating a disease in a mammal comprising administering to a subject a daily dose of 0.01-1500 mg/day of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the daily dose may be a single dose or divided doses.
  • the daily dose includes but is not limited to 0.01-1500 mg/day, 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day.
  • daily doses include but are not limited to 0.01 mg/day, 0.05 mg/day, 0.1 mg/day, 0.15 mg/day, 0.2 mg/day, 0.3 mg/day, 0.5 mg/day, 1 mg/day, 2 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, and 800 mg/day.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • CN refers to cyano
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc.
  • the cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states.
  • Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, Oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ...
  • alkenyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkynyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain and 2 to 4 carbon atoms in the main chain.
  • alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system.
  • the carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which may be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se, and the C, N, S or Se selectively substituted in the heterocyclyl ring may be oxidized to various oxidation states.
  • the heterocyclyl may be attached to a heteroatom or a carbon atom, and the heterocyclyl may be attached to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl may be optionally a monocyclic, bridged, cyclic or spirocyclic ring.
  • Non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridiny
  • Non-limiting examples include: "Spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like.
  • the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.
  • X-Y membered rings (X, Y are integers, and 3 ⁇ X ⁇ Y, X ⁇ Y ⁇ 20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4....Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1 , Cx+2 , Cx +3 , Cx +4 ...
  • Cy -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl;
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • R d-11 are each independently selected from C 1-6 alkyl
  • R d-12 is selected from halogen, preferably I, Br;
  • the compound of general formula (D-1-5) is subjected to hydrolysis reaction to obtain the compound of general formula (I).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • THF tetrahydrofuran
  • DCM dichloromethane
  • DEA diethanolamine
  • Step 5 Preparation of Compound 1-1, Compound 1-2, Compound 1-3 and Compound 1-4
  • Compound 1 (370 mg) was used for SFC preparation.
  • Sample preparation dissolved in acetonitrile, concentration 3 mg/mL.
  • Compound 1-1 57 mg was obtained under preparation condition A, and the retention time under analysis condition A was 3.871 min.
  • Compound 1-2 52 mg was obtained under preparation condition A, and the retention time under analysis condition A was 4.468 min.
  • Compound 1-3 60 mg was obtained under preparation condition B, and the retention time under analysis condition B was 1.391 min.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 5 Preparation of Compound 2-1, Compound 2-2, Compound 2-3 and Compound 2-4
  • Compound 2 (200 mg) was used for SFC preparation.
  • Preparation condition B Instrument: WATERS150preparative SFC (SFC-26) Column: ChiralCel OJ, 250 ⁇ 30mm I.D., 10 ⁇ m
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Step 3 Preparation of Compound 3-1, Compound 3-2, Compound 3-3 and Compound 3-4
  • Compound 3 (300 mg) was used for SFC preparation.
  • Preparation condition B Instrument: WATERS150preparative SFC (SFC-26) Column: ChiralCel OJ, 250 ⁇ 30mm I.D., 10 ⁇ m
  • the compounds of the present invention have a good stimulating effect on the cGMP production of CHO-KI/sGC cells.
  • the compounds of the present invention have good agonistic and/or activating effects on the activity of guanylate cyclase (sGC).
  • LNCap cells are human prostate cancer cell lines that can express sGC protein. LNCap cells were purchased from ATCC and cultured in complete medium (RPMI-1640+10% FBS+1% PS). On the day of the assay, cells were re-selected in assay buffer (EBSS assay buffer+5mL MgCl2+10mM HEPES+0.05% BSA) at a cell concentration of 2 ⁇ 10 5 /mL. 0.5mM IBMX was added to prevent cGMP degradation.
  • the compounds of the present invention have a good stimulating effect on the cGMP production of LNCap cells.
  • This study administered the test substance to SD rats by single-dose inhalation, determined the concentration of the test substance in rat plasma and lungs, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in rats.
  • mice Male SD rats, 180-200 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the test day, SD rats were randomly divided into 6 groups according to body weight, with 2 rats in each group. The rats were fasted but not watered for 12-16 hours one day before administration, and food was resumed 4 hours after administration.
  • Plasma sampling Blood was collected from the eye socket under isoflurane anesthesia before and after administration and placed in an EDTAK 2 centrifuge tube. The blood was centrifuged at 6000 rpm and 4°C for 10 min to collect plasma. Plasma collection time points: 0, 0.0833, 0.25, 0.5, 1, 2, 4, 7, and 24 h.
  • Lung tissue sampling The experimental animals in each group were euthanized by CO2 inhalation at 0.25, 0.5, 1, 4, 7 and 24 hours after administration. The animals were then dissected, and the lung tissues were collected, rinsed with physiological saline, and then wiped dry with filter paper and weighed using a balance. They were placed on wet ice for 2 hours and homogenized using 6 times the volume of homogenate (50% methanol-water) (i.e., 1 g of tissue was added to 6 mL of homogenate).
  • homogenate 50% methanol-water
  • the compounds of the present invention have good exposure and/or lung-to-blood ratio in the lungs of rats after inhalation administration.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells that stably express hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) using a puller.
  • the tip resistance after perfusing the electrode liquid was about 2-5 M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz.
  • the cell was clamped at -80 mV, and the step voltage to induce the hERG potassium current (I hERG ) was a 2s depolarization voltage from -80 mV to +20 mV, and then repolarized to -50 mV, which lasted for 1 s before returning to the original state.
  • the voltage was set to -80 mV. This voltage stimulation was given every 10 s, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute).
  • Each test concentration of the compound was given for at least 1 minute, and at least 2 cells (n ⁇ 2) were tested for each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention have no significant inhibitory effect on the hERG potassium ion channel.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC 50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the compounds of the present invention have no significant inhibitory effect on CYP450 enzymes or have a weak inhibitory effect.
  • the connective tissue on the surface of the blood vessels was removed to prepare a vascular ring about 3-5 mm long.
  • the vascular ring was hung in an in vitro tissue perfusion bath containing 37°C constant temperature KH solution using a homemade hook, saturated oxygen was introduced, and a tension sensor (Chengdu Instrument Factory, JZ101H) was connected.
  • the tension sensor was connected to a multi-channel electrophysiological signal recorder (Chengdu Instrument Factory, RM6240E).
  • the vascular rings were rinsed with KH solution and allowed to balance for 90 minutes under a 3g basic tension. Then 10 -6 M norepinephrine was added to the bath to pre-contract the vascular rings and reach a stable tension value.
  • test compounds were added to the bath in order from low to high concentration gradient to relax the vascular rings.
  • the interval between each addition of the compound was 5 minutes, and the changes in the tension of the thoracic aorta vascular rings were observed.
  • the relaxation percentage at different concentrations was calculated.

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Abstract

一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物，具体涉及通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与鸟苷酸环化酶(sGC)活性或表达量相关疾病的药物中的应用。

Description

一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物及其在医药上的应用 技术领域
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗sGC活性或表达量相关疾病的药物中的应用。
背景技术
一氧化氮(NO)信号传导在生物学中具有多效性作用，在心血管稳态中具有关键功能。在去甲肾上腺素(NA)、血管紧张素、三磷酸腺苷或缓激肽等介质的影响下，NO的分泌会增加。NO合成也受到许多物理刺激因素的影响(Int.J.Mol.Sci.2021,22,6029；Molecules 2021,26,3418)。
NO的细胞内作用机制主要是通过刺激可溶性鸟苷酸环化酶(sGC)的活性。sGC是含血红素的酶，它能升高平滑肌中环状3’-5’-鸟苷单磷酸(cGMP)水平而导致血管舒张(Nat.Rev.Cardiol.2018,15,292-316)。NO/sGC/cGMP调节通路在心血管系统和呼吸系统以及器官(如肾脏、大脑和肝脏)的稳态中发挥着重要作用。除了平滑肌细胞外，cGMP还影响成纤维细胞、心肌细胞、血小板、神经元和免疫细胞的功能，调节纤维化、炎症反应和神经传递过程(Molecules 2023,28,861)。
sGC调节剂和sGC激动剂是一类可以刺激cGMP形成的药物，这类药物为研究sGC调节机制及其在病理机制中的作用提供了工具。sGC调节剂或激动剂的研发使得直接靶向病变血管、心肌、肾脏和其他器官的药物出现成为可能(Molecules 2023,28,861)。Riociguat是第一个上市的sGC激动剂，2013年Riociguat获批两个适应症：肺动脉高血压(PAH)和慢性血栓栓塞性肺动脉高压(TEPH)(J.Med.Chem.2017,60,5146-5161)。在为期12周的多中心、双盲、随机、安慰剂对照、关键性PATENT-1研究中，与安慰剂相比，riociguat治疗组最常见(≥3％)AEs的发生率是头痛(27％对18％)、消化不良/胃炎(21％对8％)、头晕(20％对13％)、恶心(14％对11％)、腹泻(12％对8％)、低血压(10％对4％)、呕吐(10％对7％)、贫血(7％对2％)、胃食管反流病(5％对2％)和便秘(5％对1％)。研发新型的sGC调节剂或激动剂，以提高治疗效果或减少毒副作用，具有良好的应用前景。
发明内容
本发明的目的就是提供一类4-氨基-吡咯并[2,3-d]嘧啶杂环类化合物或其药学上可接受的盐，将其应用于sGC调节剂或激动剂。本发明中的化合物能有效刺激可溶性鸟苷酸环化酶(sGC)的活性并可用于治疗心血管疾病、肾脏疾病或呼吸系统等疾病。
本发明化合物对LNCap细胞的cGMP产生量具有良好的刺激作用，具有良好的肺部药代动力学性能，如肺部AUC和/或肺血比比对照1更优，具有肺部靶向、降低全身性副作用的优势。
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
在一些实施方案中，通式(I)选自通式(Ia)，
在一些实施方案中，Z选自CH或N；
在一些实施方案中，A选自C3-12碳环基或4-12元杂环基；
在一些实施方案中，A选自苯基、苯并C4-6碳环、5至6元杂芳基、苯并4至7元杂环基或8-12元并环杂芳基；
在一些实施方案中，A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
在一些实施方案中，A选自苯基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
在一些实施方案中，A选自
在一些实施方案中，R1选自-M-(CR1aR1b)r-(CR1cR1d)s-COOH；
在一些实施方案中，R1选自-M-(CR1aR1b)r-COOH、
在一些实施方案中，M选自键、C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rm取代；
在一些实施方案中，M选自C4-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rm取代，M不选自未取代的苯基；
在一些实施方案中，M选自4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基、C6-10芳基或5-10元杂芳基，所述芳基、杂芳基、环烷基、并环烷基、螺环烷基、桥环烷基、杂单环、杂并环、杂螺环或杂桥环任选被1至4个Rm取代，M不选自未取代的苯基；
在一些实施方案中，M选自任选被1至4个Rm所取代的如下基团：环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
在一些实施方案中，M选自M1；
在一些实施方案中，R1选自-M1-COOH、-M1-CR1aR1b-COOH、
在一些实施方案中，M1各自独立的选自C4-12环烷基或4-12元杂环基，所述环烷基或杂环基任选被1至4个Rm取代；
在一些实施方案中，M1各自独立的选自任选被1至3个Rm取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基；
在一些实施方案中，B选自C3-8碳环基、4-8元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，B选自C3-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
在一些实施方案中，B选自任选被1至4个Rk所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
在一些实施方案中，C选自C4-8碳环基或4-8元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，C选自C4-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
在一些实施方案中，C选自任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基；
在一些实施方案中，R1选自
在一些实施方案中，R2选自C1-6烷基或-C1-6亚烷基-Q，所述烷基或亚烷基任选被1至10个Rk取代；
在一些实施方案中，R2选自C1-5烷基或-C1-4亚烷基-Q，所述烷基或亚烷基任选被1至8个Rk取代；
在一些实施方案中，R2选自C1-4烷基或-C1-3亚烷基-Q，所述烷基或亚烷基任选被1至6个Rk取代；
在一些实施方案中，R2选自甲基、乙基、丙基、丁基、-亚甲基-Q、-亚乙基-Q、-亚丙基-Q，所述甲基、乙基、丙基、丁基、亚甲基、亚乙基、亚丁基任选被1至6个Rk取代；
在一些实施方案中，R2选自
在一些实施方案中，Q选自C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rq取代；
在一些实施方案中，Q选自C3-11环烷基、4至11元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
在一些实施方案中，Q选自C3-6环烷基、4至6元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
在一些实施方案中，Q选自任选被1至4个Rq所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
在一些实施方案中，Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、卤素、OH、CN、NH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-8碳环基、-O-3至8元杂环基、-NH-C3-8碳环基、-NH-3至8元杂环基、-C0-4亚烷基-C3-8碳环基、-C0-4亚烷基-3至8元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、卤素、OH、CN、NH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、乙烯基、乙炔基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
在一些实施方案中，Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk取代的如下基团：甲基、乙基、甲氧基、环丙基；
在一些实施方案中，Ra、Rc、Rb3各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2、CF3、CHF2、CH2F、甲基、乙基、甲氧基、环丙基；
在一些实施方案中，R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-11环烷基、4至11元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
在一些实施方案中，R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-7环烷基、4至7元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
在一些实施方案中，R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基；
在一些实施方案中，Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、C1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-NH-C3-6碳环基、-NH-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
在一些实施方案中，Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、或任选被1至4个Rk所取代的如下基团：甲基、乙基、甲氧基、环丙基；
在一些实施方案中，Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、甲基、乙基、甲氧基、环丙基；
在一些实施方案中，选自其左侧与R2相连接；
在一些实施方案中，a、c、r、s各自独立地选自0、1、2、3、4；
在一些实施方案中，r1、s各自独立地选自0、1、2、3；
在一些实施方案中，r1、r、s各自独立地选自0、1、2；
在一些实施方案中，a、c各自独立地选自0、1、2；
在一些实施方案中，Rk各自独立的选自H、氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环基、-NH-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自H、氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、 CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、甲基、乙基、甲氧基、乙氧基的取代基所取代；
任选地，通式(I)至少满足以下三个条件之一：
M选自C4-12碳环基或4-12元杂环基且M不选自未取代的苯基，所述碳环基或杂环基任选被1至4个Rm取代；
R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
r或s不同时为0，且R1a、R1b、R1c、R1d中至少有一个选自-O-C3-8碳环基、-O-3至8元杂环基、-NH-C3-8碳环基、-NH-3至8元杂环基、-C0-4亚烷基-C3-8碳环基、-C0-4亚烷基-3至8元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代。
作为本发明的第一种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
Z选自CH或N；
A选自C3-12碳环基或4-12元杂环基；
R1选自-M-(CR1aR1b)r-(CR1cR1d)s-COOH；
M选自键、C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rm取代；
R2选自C1-6烷基或-C1-6亚烷基-Q，所述烷基或亚烷基任选被1至10个Rk取代；
Q选自C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rq取代；
Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、卤素、OH、CN、NH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-8碳环基、-O-3至8元杂环基、-NH-C3-8碳环基、-NH-3至8元杂环基、-C0-4亚烷基-C3-8碳环基、-C0-4亚烷基-3至8元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C3-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、C1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-NH-C3-6碳环基、-NH-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷 基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
Rk各自独立的选自H、氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环基、-NH-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；
a、c、r、s各自独立地选自0、1、2、3、4；
通式(I)至少满足以下三个条件之一：
M选自C4-12碳环基或4-12元杂环基且M不选自未取代的苯基，所述碳环基或杂环基任选被1至4个Rm取代；
R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
r或s不同时为0，且R1a、R1b、R1c、R1d中至少有一个选自-O-C3-8碳环基、-O-3至8元杂环基、-NH-C3-8碳环基、-NH-3至8元杂环基、-C0-4亚烷基-C3-8碳环基、-C0-4亚烷基-3至8元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代。
作为本发明的第二种实施方案，下述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
R1选自-M-(CR1aR1b)r-COOH、
M选自C4-12碳环基或4-12元杂环基，所述碳环基或杂环基任选被1至4个Rm取代，M不选自未取代的苯基；
B选自C3-8碳环基、4-8元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；
C选自C4-8碳环基或4-8元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
r1、s各自独立地选自0、1、2、3；
其余定义与本发明第一种实施方案相同。
作为本发明的第三种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
A选自苯基、苯并C4-6碳环、5至6元杂芳基、苯并4至7元杂环基或8-12元并环杂芳基；
M选自4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基、C6-10芳基或5-10元杂芳基，所述芳基、杂芳基、环烷基、并环烷基、螺环烷基、桥环烷基、杂单环、杂并环、杂螺环或杂桥环任选被1至4个Rm取代，M不选自未取代的苯基；
R2选自C1-5烷基或-C1-4亚烷基-Q，所述烷基或亚烷基任选被1至8个Rk取代；
Q选自C3-11环烷基、4至11元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、卤素、OH、CN、NH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-11环烷基、4至11元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
Rk各自独立的选自H、氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
其余定义与本发明第一种或第二种实施方案相同。
作为本发明的第四种实施方案，前述通式(I)或(Ia)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
B选自C3-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
C选自C4-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
R2选自C1-4烷基或-C1-3亚烷基-Q，所述烷基或亚烷基任选被1至6个Rk取代；
Q选自C3-6环烷基、4至6元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、乙烯基、乙炔基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-7环烷基、4至7元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基， 所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
其余定义与本发明第一种、第二种或第三种实施方案相同。
作为本发明的第五种实施方案，前述通式(I)或(Ia)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
B选自任选被1至4个Rk所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
C选自任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基；
M选自任选被1至4个Rm所取代的如下基团：环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
R2选自甲基、乙基、丙基、丁基、-亚甲基-Q、-亚乙基-Q、-亚丙基-Q，所述甲基、乙基、丙基、丁基、亚甲基、亚乙基、亚丁基任选被1至6个Rk取代；
Q选自任选被1至4个Rq所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk取代的如下基团：甲基、乙基、甲氧基、环丙基；
或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基；
Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、或任选被1至4个Rk所取代的如下基团：甲基、乙基、甲氧基、环丙基；
Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、 苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、甲基、乙基、甲氧基、乙氧基的取代基所取代；
r1、r、s各自独立地选自0、1、2；
其余定义与本发明第一种、第二种、第三种或第四种实施方案相同。
作为本发明的第六种实施方案，前述通式(I)或(Ia)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
A选自苯基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
R1选自
R2选自
Ra、Rc、Rb3各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2、CF3、CHF2、CH2F、甲基、乙基、甲氧基、环丙基；
Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、甲基、乙基、甲氧基、环丙基；
a、c各自独立地选自0、1、2；
其余定义与本发明第一种、第二种、第三种、第四种或第五种实施方案相同。
作为本发明的第七种实施方案，前述通式(Ia)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
A选自苯基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；优先自
B选自任选被1至4个Rk所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；优选自：环丙基、环丁基、环戊基、氧杂环丁基、氮杂环丁基、吡咯烷基；
R2选自
Ra、Rc各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2、CF3、CHF2、CH2F、甲基、乙基、甲氧基、环丙基；
R1a、R1b各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk取代的如下基团：甲基、乙基、甲氧基、环丙基；
a、c各自独立地选自0、1、2。
本发明涉及一种下述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下表E-1中结构之一：
表E-1






本发明涉及一种药物组合物，包括上述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。
本发明涉及上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物用于制备治疗与sGC相关的疾病的药物中的应用。
本发明涉及上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物用于制备治疗心血管疾病、肾脏疾病或呼吸系统疾病(优选自肺动脉高压、肺性高血压、慢性阻塞性肺病)药物中的应用。
本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐 或共晶和药用赋型剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。
本发明还提供一种用于治疗哺乳动物的疾病的方法，其包括向所述哺乳动物给予治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或药物组合物。一些实施方案中，本发明中所述哺乳动物包括人。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如心血管疾病)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于0.01-1500mg、0.01-1000mg、0.01-800mg、0.01-600mg、0.1-1500mg、0.1-1000mg、0.1-800mg、0.1-600mg、1-1500mg、1-1000mg、1-800mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、0.01-100mg、0.01-10mg、0.01-5mg、0.05-10mg、0.05-5mg、0.1-5mg、1-5mg、0.1-1mg、0.1-5mg；
在一些实施方案中，该药物组合物包括但不限于0.01-1500mg、1-1500mg、1-1000mg、1-800mg、1-600mg、20-400mg、25-200mg、0.01mg、0.05mg、0.1mg、0.15mg、0.2mg、0.3mg、0.5mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选0.01-1500mg，所述的疾病优选心血管疾病。
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以0.01-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于0.01-1500mg/天、10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、 100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于0.01mg/天、0.05mg/天、0.1mg/天、0.15mg/天、0.2mg/天、0.3mg/天、0.5mg/天、1mg/天、2mg/天、5mg/天、10mg/天、20mg/天、25mg/天、50mg/天、100mg/天、125mg/天、150mg/天、200mg/天、400mg/天、600mg/天、800mg/天。
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
除非另有说明，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“CN”是指氰基。
“卤素”是指F、Cl、Br或I。
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；烷基可以是一价、二价、三价或四价。
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至12个碳原子，环烷基可以是单环、并环、桥环和螺环。非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环丁基并环丁基、环丁基螺环丁基、金刚烷等。环烷基可以是一价、二价、三价或四价。
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至12个原子、3至8个原子，包含1至3个选自N、O、S或Se的杂原子，杂环烷基的环上的C、N、S可被氧化成各种氧化态。杂环烷基可以是单环、并环、桥环和螺环。杂环烷基可以连接在杂原子或者碳原子上，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、 噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基、 杂环烷基可以是一价、二价、三价或四价。
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；烯基可以是一价、二价、三价或四价。
“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，包括但不限于在主链上有2至6个碳原子，主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基等；炔基可以是一价、二价、三价或四价。
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。
“碳环基”或“碳环”是指取代的或未取代的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环、10至15元三环、12至18元四元体系，碳环基可以连接在芳香环上或者非芳香环上，环任选为单环、并环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。
“杂环基”或“杂环”是指取代的或未取代的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环、12至18元四元体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O、S或Se的杂原子，杂环基的环中选择性取代的C、N、S或Se可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基任选为单环、桥环、并环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、 苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n(n为0、1或2)的杂原子。非限制性实施例包括：“螺环”或“螺环基”可以是一价、二价、三价或四价。
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括立 方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，
“杂并环”、“杂并环基”“并环杂环基”或“并杂环基”是指含有杂原子的“并环”。
“杂螺环”、“杂螺环基”、“螺环杂环基”或“螺杂环基”是指含有杂原子的“螺环”。
“杂桥环”、“杂桥环基”、“桥环杂环基”或“桥杂环基”是指含有杂原子的“桥环”。
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O、S(＝O)n或Se(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。环上的原子C、N、S任选被氧化(即C(＝O)、NO、S(＝O)n、Se(＝O)n，n为1、2)，杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、硒吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、吡啶酮基等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含 本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于具有芳香性的环上。
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基、Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。
“1至X个选自…..取代基所取代”是指被1、2、3….X个选自…..取代基所取代，X选自1至10之间的任意整数。如“1至4个Rk取代”是指被1、2、3或4个Rk取代。如“1至5个选自…..取代基所取代”是指被1、2、3、4或5个选自…..取代基所取代。如“杂桥环任选被1至4个选自 H或F的取代基所取代”是指杂桥环任选被1、2、3或4个选自H或F的取代基所取代。
X-Y元的环(X、Y为整数，且3≤X＜Y，X＜Y≤20选自4至20之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。
Cx-y碳环(包括芳基、环烷基、单环碳环、螺环碳环、并环碳环或桥环碳环)包括了Cx、Cx+1、Cx+2、Cx+3、Cx+4….Cy元的环(x为整数，且3≤x＜y，y选自4至20之间的任意整数)，例如。如C3-6环烷基”是指C3、C4、C5或C6环烷基；
当某一个基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团连接。当该化学键的连接方式是不定位的，且可连接位点存在氢原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。例如表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，也包括了例如表示该哌啶基上的R基团可以位于C上，可以位于N上，至少包括了
当所列举的连接基团没有指明其连接方向时，其连接方向包括了从左向右和从右向左的读取顺序的方向进行连接，例如A-L-B，L选自-M-W-时，包括了A-M-W-B和A-W-M-B。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对映异构体和构象异构体。
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。
合成方法一：
Rd-11各自独立地选自C1-6烷基；
Rd-12选自卤素，优选自I,Br；
其余基团定义与本发明说明书中所述一致；
通式(D-1-1)化合物与通式(D-1-2)化合物通过加成反应得到通式(D-1-3)化合物；
通式(D-1-3)化合物与通式(D-1-4)化合物通过成环反应得到通式(D-1-5)化合物；
通式(D-1-5)化合物通过水解反应得到通式(I)化合物。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；
试剂缩写：
THF：四氢呋喃；DCM：二氯甲烷；DEA：二乙醇胺；
实施例1：化合物1的制备
第一步：化合物1B的制备
-78℃下将二异丙基氨基锂(8.8mL,2M in THF)滴加到化合物1A(1g,8.76mmol)的四氢呋喃(50mL)溶液中，搅拌0.5h后，加入3-碘苄溴(2.6g,8.76mmol)，缓慢升至室温搅拌1h,加入饱和氯化铵水溶液(60mL)淬灭，乙酸乙酯(40mL×3)萃取，合并有机相，有机相经无水硫酸钠干燥后减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100-1/10)，得化合物1B(1.7g，收率：59％)。
第二步：化合物1C的制备
-78℃下，将异丙基氯化镁氯化锂络合物(4mL,1.3M in THF)滴入化合物1B(1.7g，5.15mmol)的四氢呋喃(40mL)溶液中，搅拌35min后，缓慢加入3,3-二氰基-2-甲基丙烯酸乙酯(CAS：24878-26-0，合成参考Synthesis(1974),(9),669-70.)(1.01g,6.13mmol)，加毕，移至室温搅拌1h,加入饱和氯化铵水溶液(50mL)淬灭，乙酸乙酯(40mL×3)萃取，合并有机相，有机相经无水硫酸钠干燥后减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100-1/10)，得化合物1C(0.4g，收率：21％)。
1H NMR(400MHz,CDCl3)δ7.33(t,1H),7.24-7.10(m,3H),4.50(d,1H),4.36-4.15(m,2H),3.61(d,3H),3.16-3.02(m,1H),3.02-2.86(m,1H),1.98(s,3H),1.93-1.82(m,1H),1.28-1.19(m,3H),1.02-0.90(m,1H),0.58-0.43(m,2H),0.34-0.22(m,1H),0.05--0.04(m,1H).
第三步：化合物1D的制备
将碳酸氢钾(0.33g,3.27mmol)加入至化合物1C(0.4g,1.09mmol)与6-氯-1-(3,3,4,4-五氟丁基)-1H-吲唑-3-羧酰胺(CAS:1350855-88-7，合成参考US20170174693)(0.37g,1.09mmol)的叔丁醇(4mL)溶液中，80℃搅拌16h,加入水(10mL)淬灭，乙酸乙酯(10mL×3)萃取，合并有机相，有机相经无水硫酸钠干燥后减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100-1/10)，得化合物1D(0.5g，收率：69％)。
LCMS m/z＝663.2[M+H]+
第四步：化合物1的制备
将氢氧化锂(0.16g,6.5mmol)加入至化合物1D(430mg,0.65mmol)的1，4-二氧六环(3mL)和水(3mL)混合溶液中，室温搅拌1h,加入冰醋酸(390mg.6.5mmol)淬灭，乙酸乙酯(10mL×3)萃取，合 并有机相，有机相经无水硫酸钠干燥后减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100-1/10)，得化合物1(370mg)。
第五步：化合物1-1、化合物1-2、化合物1-3和化合物1-4的制备
化合物1(370mg)用于SFC制备。
制备条件：仪器:Waters 150Prep-SFC F；柱子:Chiralcel Whelk column流动相:A for CO2；Bfor 0.1％NH3·H2O in MEOH；洗脱:B 40％；流量:100mL/min；背压:100bar；柱温:25℃；波长:220nm；循环时间:3.3min
样品制备:乙腈溶解，浓度3mg/mL.
分析条件：仪器:SHIMADZU LC-30AD；柱子:Chiralcel Whelk column；流动相:A for CO2；Bfor 0.05％DEA in MEOH；洗脱:B 5-40％；流量:3mL/min；背压:100bar；柱温:35℃；波长:220nm
制备分离后，合并相同保留时间的组分，减压浓缩得到化合物1-1、化合物1-2的混合物(183.5mg)和化合物1-3、化合物1-4的混合物(172.5mg)。
化合物1-1、化合物1-2的混合物：分析条件下保留时间1.938min、1.968min。
化合物1-3、化合物1-4的混合物：分析条件下保留时间2.454min、2.506min。
将化合物1-1、化合物1-2的混合物和化合物1-3、化合物1-4的混合物分别再次用SFC进行制备，制备分离后，合并相同保留时间的组分，减压浓缩。
制备条件A：仪器:WATERS150preparative SFC(SFC-26)柱子:ChiralCel OJ,250×30mm I.D.,10μm；流动相:A for CO2 and B for Methanol(0.1％ NH3·H2O)洗脱:B 20％；流量:150mL/min；背压:100bar柱温:38℃；波长:220nm；循环时间:～6min
样品制备:甲醇/二氯甲烷溶解
分析条件A：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:ChiralCel OJ,150×4.6mm I.D.,3μm；流动相:A for CO2 and B for Methanol(0.05％DEA)洗脱:B 5-40％；流量:2.5mL/min；背压:100bar柱温:35℃；波长:220nm
制备条件B：仪器:MGⅡpreparative SFC(SFC-14)柱子:ChiralPak IG,250×30mm I.D.,5μm；流动相:A for CO2 and B for Ethanol(0.1％NH3·H2O)洗脱:B 40％；流量:80mL/min；背压:100bar柱温:38℃；波长:220nm；循环时间:～6min
样品制备:甲醇/二氯甲烷溶解
分析条件B：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:ChiralPak IG,150×4.6mm I.D.,3μm；流动相:A for CO2 and B for Ethanol(0.05％DEA)洗脱:B 40％；流量:2.5mL/min；背压:100bar柱温:35℃；波长:220nm
化合物1-1：制备条件A得到57mg，分析条件A下保留时间3.871min。
LCMS m/z＝649.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.14-10.80(m,1H),8.70(d,1H),8.03(d,1H),7.30-7.03(m,5H),6.53-6.34(m,2H),4.83(t,2H),2.99-2.76(m,4H),1.89-1.74(m,4H),0.92-0.80(m,1H),0.43-0.34(m,2H),0.26-0.18(m,1H),0.06-0.00(m,1H).
化合物1-2：制备条件A得到52mg，分析条件A下保留时间4.468min。
LCMS m/z＝649.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.29-10.79(m,1H),8.70(d,1H),8.03(d,1H),7.30-7.03(m,5H),6.57-6.32(m,2H),4.83(t,2H),3.00-2.77(m,4H),1.89-1.73(m,4H),0.91-0.79(m,1H),0.46-0.30(m,2H),0.25-0.16(m,1H),0.06-0.00(m,1H).
化合物1-3：制备条件B得到60mg，分析条件B下保留时间1.391min。
LCMS m/z＝649.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.70(d,1H),8.03(d,1H),7.40-7.00(m,5H),6.53-6.30(m,2H),4.83(t,2H),3.00-2.75(m,4H),1.89-1.81(m,1H),1.78(s,3H),0.92-0.79(m,1H),0.46-0.32(m,2H),0.26-0.17(m,1H),0.05-0.00(m,1H).
化合物1-4：制备条件B得到58mg，分析条件B下保留时间2.062min。
LCMS m/z＝649.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.70(d,1H),8.03(d,1H),7.38-7.05(m,5H),6.57-6.24(m,2H),4.83(t,2H),3.00-2.76(m,4H),1.87-1.79(m,1H),1.78(s,3H),0.92-0.79(m,1H),0.45-0.32(m,2H),0.25-0.17(m,1H),0.05-0.00(m,1H).
实施例2：
第一步：2A的制备
将2-环丙基乙酸甲酯(2g,17.52mmol)溶于四氢呋喃(20mL)中，氮气置换三次，降温至-70℃，缓慢滴加二异丙基氨基锂的四氢呋喃溶液(10.5mL,2N)。加毕，保持此温度下继续搅拌1h，加入2,3-二溴-1-丙烯(3.85g,19.27mmol)后在-70℃下继续搅拌0.5h。加入20mL饱和氯化铵水溶液淬灭反应，加入100mL水和100mL甲基叔丁基醚搅拌分层，有机层用无水硫酸钠干燥后，减压浓缩，残留物硅胶柱层析纯化(乙酸乙酯/石油醚(V/V)＝0/100-5/100)得到2A(0.75g，收率：18％)。
1H NMR(400MHz,CDCl3)δ5.65-5.61(m,1H),5.42(d,1H),3.70(s,3H),2.97-2.87(m,1H),2.73-2.64(m,1H),2.10-2.00(m,1H),0.98-0.88(m,1H),0.62-0.46(m,2H),0.40-0.32(m,1H),0.29-0.22(m,1H).
第二步：2B的制备
将化合物2B(0.75g,3.22mmol)溶于乙醇(10mL)和水(5mL)的混合溶剂中，冰浴下加入N- 溴代丁二酰亚胺(0.63g,3.54mmol)，加毕，自然升温至室温搅拌1h。缓慢加入10mL饱和碳酸氢钠水溶液淬灭反应，加入20m甲基叔丁基醚搅拌分层，有机相继续用饱和碳酸氢钠水溶液洗涤(10mL x 2)后用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析纯化(乙酸乙酯/石油醚(V/V)＝0/100-5/100)得到2B(0.6g，收率：75％)。
1H NMR(400MHz,CDCl3)δ3.99-3.86(m,2H),3.70(s,3H),3.25-3.15(m,1H),2.94-2.83(m,1H),2.20-2.11(m,1H),0.94-0.82(m,1H),0.62-0.42(m,3H),0.21-0.11(m,1H).
第三步：2C的制备
将化合物2B-1(0.2g,0.41mmol)(合成参考WO2017197555)和2B(0.15g,0.61mmol)混合溶于乙醇(10mL)中，升温至60℃搅拌过夜。冷却至室温，加入30mL乙酸乙酯萃取和20mL饱和碳酸氢钠水溶液，搅拌10min，分层，有机层用10mL饱和食盐水洗，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/1)得到2C(0.25g，收率：95％)。
LCMS m/z＝637.2[M+H]+
第四步：化合物2的制备
将2C(0.10g,0.17mmol)溶于1,4-二氧六环(3mL)和水(2mL)的混合溶剂中，加入氢氧化锂(0.093g,3.90mmol)，升温至60℃搅拌1h。冷却至室温，用1N的盐酸调节反应液pH＝3-4，加入20mL乙酸乙酯，用10mL饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩。残留物用反相柱层析纯化(乙腈/水(含0.1％三氟乙酸)(V/V)＝0/100-50/50)得到化合物2(0.2g)。
第五步：化合物2-1、化合物2-2、化合物2-3和化合物2-4的制备
化合物2(200mg)用于SFC制备。
制备条件A：仪器:WATERS150preparative SFC(SFC-26)柱子:ChiralPak IG,250×30mm I.D.,10μm
流动相:A for CO2 and B for Ethanol(0.1％NH3H2O)洗脱:B 30％；流量:120mL/min背压:100bar柱温:38℃波长:220nm循环时间:～5min
制备条件B：仪器:WATERS150preparative SFC(SFC-26)柱子:ChiralCel OJ,250×30mm I.D.,10μm
流动相:A for CO2 and B for Ethanol(0.1％NH3H2O)洗脱:B 25％；流量:120mL/min背压:100bar柱温:38℃波长:220nm循环时间:～3.2min
分析条件A：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:ChiralPak IG,150×4.6mm I.D.,3μm；流动相:A for CO2 and B for Ethanol(0.05％DEA)洗脱:B 5-40％；流量:2.5mL/min背压:100bar柱温:35℃波长:220nm
分析条件B：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:ChiralCel OJ,150×4.6mm I.D.,3μm；流动相:A for CO2 and B for Ethanol(0.05％DEA)洗脱:B 5-40％流量:2.5mL/min背压:100bar柱温:35℃波长:220nm
经制备条件A分离后，合并相同保留时间的组分，减压浓缩得到化合物2-1、化合物2-2的混合物、化合物2-3(30mg)和化合物2-4(53mg)。化合物2-1、化合物2-2的混合物经制备条件B分离后，合并相同保留时间的组分，减压浓缩得到化合物2-1(43mg)和化合物2-2(21mg)。
化合物2-1，分析条件B下的保留时间：2.830min。
LCMS m/z＝623.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.04(dd,1H),8.64(dd,1H),7.39(dd,1H),7.26(s,1H),6.97(s,2H),4.89(t,2H),3.12-2.90(m,4H),2.02-1.93(m,1H),1.83(s,3H),0.94-0.82(m,1H),0.44-0.32(m,2H),0.30-0.20(m,1H),0.04-0.02(m,1H).
化合物2-2，分析条件B下的保留时间：2.953min。
LCMS m/z＝623.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.04(dd,1H),8.64(dd,1H),7.39(dd,1H),7.26(s,1H),6.96(s,2H),4.89(t,2H),3.12-2.90(m,4H),2.04-1.96(m,1H),1.82(s,3H),0.93-0.81(m,1H),0.46-0.32(m,2H),0.30-0.21(m,1H),0.00-0.05(m,1H).
化合物2-3，分析条件A下的保留时间：3.742min。
LCMS m/z＝623.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.04(dd,1H),8.65(dd,1H),7.39(dd,1H),7.26(s,1H),6.97(s,2H),4.89(t,2H),3.12-2.87(m,4H),2.04-1.95(m,1H),1.82(s,3H),0.94-0.82(m,1H),0.47-0.33(m,2H),0.30-0.20(m,1H),0.03-0.04(m,1H).
化合物2-4，分析条件A下的保留时间：3.890min。
LCMS m/z＝623.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.04(dd,1H),8.65(dd,1H),7.39(dd,1H),7.26(s,1H),6.98(s,2H),4.89(t,2H),3.14-2.88(m,5H),2.02-1.93(m,1H),1.83(s,3H),0.95-0.82(m,1H),0.49-0.32(m,2H),0.30-0.20(m,1H),0.05-0.04(m,1H).
实施例3：
第一步：3A的制备
将3A-1(0.34g,0.65mmol)(合成参考WO2011149921)和2B(0.21g,0.85mmol)混合溶于乙醇(10mL)中，升温至60℃搅拌过夜。冷却至室温，加入30mL乙酸乙酯萃取和20mL饱和碳酸氢钠水溶液，搅拌10min后分层，有机相用10mL饱和食盐水洗，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化(乙酸乙酯/石油醚(V/V)＝1/10-1/3)得到3A(0.32g，收率：73％)。
LCMS m/z＝670.2[M+H]+
第二步：化合物3的制备
将3A(0.32g,0.48mmol)溶于1,4-二氧六环(12mL)和水(4mL)的混合溶剂中，加入氢氧化锂(0.20g,4.80mmol)，升温至60℃搅拌1h。冷却至室温，用1N的盐酸调节反应液pH＝3-4后加入20mL乙酸乙酯搅拌分层，用10mL饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩。残留物用反相柱层析纯化(乙腈/水(含0.1％三氟乙酸)(V/V)＝0/100-50/50)得到化合物3(0.3g)。
第三步：化合物3-1、化合物3-2、化合物3-3和化合物3-4的制备
化合物3(300mg)用于SFC制备。
制备条件A：仪器:WATERS150preparative SFC(SFC-26)柱子:ChiralPak IG,250×30mm I.D.,10μm
流动相:A for CO2 and B for Ethanol(0.1％ NH3H2O)洗脱:B 40％；流量:120mL/min背压:100bar柱温:38℃波长:220nm循环时间:～6min
制备条件B：仪器:WATERS150preparative SFC(SFC-26)柱子:ChiralCel OJ,250×30mm I.D.,10μm
流动相:A for CO2 and B for Ethanol(0.1％ NH3H2O)洗脱:B 25％；流量:120mL/min背压:100bar柱温:38℃波长:220nm循环时间:～3.2min
分析条件A：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:Chiralpak IG-3 100×4.6mm I.D.,3um
流动相:A for CO2 and B for Ethanol(0.05％DEA)洗脱:B 40％；流量:2.5mL/min背压:100bar柱温:35℃波长:220nm
分析条件B：仪器:Waters UPC2 analytical SFC(SFC-H)柱子:ChiralCel OJ,150×4.6mm I.D.,3μm
流动相:A for CO2 and B for Ethanol(0.05％DEA)洗脱:B 30％；流量:2.5mL/min背压:100bar柱温:35℃波长:220nm
经制备条件A分离后，合并相同保留时间的组分，减压浓缩得到化合物3-1、化合物3-2的混合物、化合物3-3(34mg)和化合物3-4(61mg)。化合物3-1、化合物3-2的混合物经制备条件B分离后，合并相同保留时间的组分，减压浓缩得到化合物3-1(73mg)和化合物3-2(76mg)。
化合物3-1，分析条件B下的保留时间：1.876min。
LCMS m/z＝656.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.03(d,1H),7.28(dd,1H),7.25(s,1H),6.94(s,2H),4.83(t,2H),3.12-3.04(m,1H),2.99-2.84(m,3H),2.02-1.93(m,1H),1.82(s,3H),0.96-0.82(m,1H),0.46-0.32(m,2H),0.29-0.21(m,1H),0.05--0.03(m,1H).
化合物3-2，分析条件B下的保留时间：2.413min。
LCMS m/z＝656.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.68(d,1H),8.03(d,1H),7.28(dd,1H),7.26(s,1H),6.93(s,2H),4.83(t,2H),3.14-3.04(m,1H),2.99-2.85(m,3H),2.06-1.95(m,1H),1.81(s,3H),0.94-0.83(m,1H),0.46-0.32(m,2H),0.30-0.22(m,1H),0.01--0.05(m,1H).
化合物3-3，分析条件A下的保留时间：1.585min。
LCMS m/z＝656.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.03(d,1H),7.28(dd,1H),7.26(s,1H),6.93(s,2H),4.83(t,2H),3.14-3.04(m,1H),2.98-2.84(m,3H),2.04-1.96(m,1H),1.81(s,3H),0.95-0.82(m,1H),0.45-0.32(m,2H),0.31-0.22(m,1H),0.03--0.05(m,1H).
化合物3-4，分析条件A下的保留时间：1.813min。
LCMS m/z＝656.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.03(d,1H),7.28(dd,1H),7.26(s,1H),6.94(s,2H),4.83(t,2H),3.14-3.04(m,1H),3.01-2.83(m,3H),2.03-1.93(m,1H),1.82(s,3H),0.94-0.82(m,1H),0.47-0.32(m,2H),0.29-0.21(m,1H),0.06--0.03(m,1H).
生物测试例
1.CHO-KI/sGC细胞cGMP检测实验
构建稳定表达sGCα1/β1异源二聚体的稳转CHO-K1细胞，命名为CHO-KI/sGC。CHO-KI/sGC细胞培养于完全培养基中(FK12+10％FBS+1％双抗+0.5mg/mL潮霉素+0.25mg/mLG418)。检测当天，细胞重选于EAB检测buffer中(EBSS assay buffer+5mL MgCl2+10mM HEPES+0.05％BSA)，细胞浓度为2.25*105/mL。加入0.5mM IBMX用以防止cGMP降解。
细胞预先与1pM二亚乙基三胺/一氧化氮(EDTA-NO)于室温预孵育30分钟后，加入不同浓度的化合物，于37℃继续孵育1h，孵育结束后，终止反应并根据Cisbio试剂盒说明书(CisBio,62GM2PEC)检测细胞内cGMP含量，并根据式(1)计算相对于阳性化合物的最大cGMP产生量，其中RLUcompound为检测化合物的读数，RLUreference为阳性化合物的最大读数。
Activion ％＝RLUcompound/RULreference*100％  式(1)
结论：本发明的化合物，例如实施例化合物对CHO-KI/sGC细胞cGMP产生量具有良好的刺激作用。
2.体外鸟苷酸环化酶(sGC)酶活检测实验
首先用Echo655(LABCYTE，Cat#655)向384反应板(Greiner，Cat.No 784075)中转移100nL不同浓度的化合物，其中DMSO含量在反应终浓度下为1％；将2μL sGC(ICE，Cat.No S2304F-H07SH2)加入到384反应板中，1000rpm离心1min；随后加入1μL DETA NONOate并于37℃孵育10min。孵育结束后，加入2μL GTP，1000rpm离心1min，于37℃反应60min。反应体系中，sGC、GTP、DETA NONOate的终浓度分别为1.5nM、5μM和100μM。反应结束后，加入5μL检测混合物(PerkinElmer，Cat.No 62GM2PEG)于室温下孵育60min，用酶标仪 (BMG，Cat.No PHERAstar FSX)读取TR-FRET信号(Ratio：665/620nm)，运用GraphPad Prism软件进行非线性回归曲线拟合并计算EC50值。以Compound A(WO2010065275中的实施例1)作为阳性参照化合物，激活率计算公式见式2，其中Low control为1μM compound A TR-FRET信号值，High control为DMSO孔TR-FRET信号值。
stimulation％＝(ave High control - cpd well)/(ave High control - ave Low control)*100％   式2
表1测试化合物对鸟苷酸环化酶(sGC)酶学激动和/或激活结果
结论：本发明的化合物，例如实施例化合物对鸟苷酸环化酶(sGC)酶活性具有良好的激动和/或激活作用。
3.LNCap细胞中cGMP检测实验
LNCap细胞为人前列腺癌细胞系，能够表达sGC蛋白。LNCap细胞购置于ATCC，培养于完全培养基中(RPMI-1640+10％FBS+1％PS)。检测当天，细胞重选于检测buffer中(EBSS assay buffer+5mL MgCl2+10mM HEPES+0.05％BSA)，细胞浓度为2×105/mL。加入0.5mM IBMX用以防止cGMP降解。
细胞预先与20μM二乙烯三胺/一氧化氮(DETA-NO)于37℃预孵育30分钟后，加入不同浓度的化合物，于室温继续孵育1h，孵育结束后，终止反应并根据Cisbio试剂盒说明书(CisBio,62GM2PEC)检测细胞内cGMP含量，并根据式(3-1)计算相对于compound A(WO2010065275中的实施例1)的cGMP产生量，并计算EC50值。其中Sample cGMP为检测化合物的读数，Low control GMP为1％DMSO对照，High control cGMP为compound A最大cGMP读数。
％Activity＝(Sample cGMP-Low control GMP)/(High control cGMP-Low control cGMP)*100％   
式(3-1)
表2测试化合物对LNCap细胞cGMP产生的刺激作用结果
结论：本发明的化合物，例如实施例化合物，对LNCap细胞cGMP产生量具有良好的刺激作用。
4：大鼠药代动力学测试(吸入给药)
实验目的：本试验通过单剂量吸入给予受试物于SD大鼠，测定大鼠血浆和肺部中受试物的浓度，评价受试物在大鼠体内药代特征和生物利用度。
试验动物：雄性SD大鼠，180～200g。购自成都达硕实验动物有限公司。
试验方法：试验当天，(每个化合物)SD大鼠按体重随机分成6组，每组2只。给药前1天禁食不禁水12～16h，给药后4h恢复给食。

*剂量以游离碱计；(DMA：二甲基乙酰胺；HS-15(Solutol)：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水)
血浆取样：于给药前及给药后异氟烷麻醉经眼眶取血，置于EDTAK2离心管中。6000rpm，4℃离心10min，收集血浆。血浆采集时间点：0,0.0833,0.25,0.5,1,2,4,7,24h。
肺组织取样：各组试验动物分别在给药后0.25、0.5、1、4、7和24小时用CO2吸入法安乐处死。然后解剖动物，采集肺组织，用生理盐水冲洗，然后用滤纸擦干后使用天平称重，放置在湿冰上2小时内匀浆，采用6倍体积的匀浆液(50％甲醇-水)匀浆(即1g组织加入6mL匀浆液)。
分析检测前，所有样品存于-60℃。用LC-MS/MS对样品进行定量分析。
表3测试化合物在大鼠中的药代动力学参数(吸入给药)
结论：本发明的化合物，例如实施例化合物，经吸入给药后在大鼠肺部具有良好的暴露量和/或肺血比。
5.hERG钾离子通道作用测试
实验平台：电生理手动膜片钳系统
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(IhERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回 到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1-(I/Io)]×100％
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。
结论:本发明化合物，例如实施例化合物，对hERG钾离子通道无明显抑制作用。
6.CYP450酶抑制测试
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。
结论:本发明化合物，例如实施例化合物，对CYP450酶无明显抑制作用或抑制作用较弱。
7.SD大鼠胸主动脉血管环舒张的药效学研究
SPF级别8周龄雄性SD大鼠购自北京维通利华实验动物技术有限公司。到达动物房后适应至少1周。实验前，称取大鼠体重，根据其体重对其进行随机分组。实验当天，用舒泰50(20mg/kg,i.p.)+噻拉嗪(8mg/kg，i.p.)对大鼠进行深度麻醉。后迅速打开胸腔，小心分离主动脉，截取降主动脉，置入盛有饱和氧(95％O2+5％CO2)的K-H液的培养皿中，去掉血管表面的结缔组织，制备约3-5mm左右长的血管环。利用自制的挂钩将血管环悬挂至盛有含37℃恒温K-H液的离体组织灌流浴槽内，通入饱和氧，并连接张力传感器(成都仪器厂，JZ101H)。将张力传感器连接至多通道电生理信号记录仪上(成都仪器厂，RM6240E)。用K-H液冲洗血管环并使其在3g基础拉力的状态下平衡90min，后往浴槽内加入10-6M的去甲肾上腺素以预收缩血管环，并使其达到稳定张力值。然后往浴槽内以浓度梯度自低至高的顺序依次添加受试化合物以舒张血管环，每次添加化合物间隔为5min，观察胸主动脉血管环张力的变化情况。计算在不同浓度下的舒张百分比。
结论：本发明化合物，例如实施例化合物，对大鼠胸主动脉血管环具有显著的舒张作用。
8.SHR大鼠血压遥测
遥测血压植入子植入手术：术前一天，对DSI植入子进行消毒处理(2％戊二醛溶液浸泡8-10h)；称取动物体重，使用噻拉嗪(8mg/kg,ip.)+舒泰50(20mg/kg,ip.)进行麻醉；术前 一天动物禁食；于试验第1天进行植入子埋植手术，其过程如下：大鼠腹部皮肤做无菌消毒，做纵向切口手术，分离腹部脏器，暴露腹主动脉，将植入子的血压敏感探头导管插入腹主动脉，用生物胶止血封闭，然后将植入子体固定在腹壁，并缝合肌肉及皮肤，消毒并皮下给予美洛昔康用于止痛；动物术后放入恒温(37℃)保温箱动物完全清醒(恢复自主运动)后放回饲养笼，并单笼饲养，术后3天内每天皮下注射4-8mg/kg硫酸庆大霉素用于预防感染，皮下注射美洛昔康用于镇痛。
血压监测：术后恢复约10天后进行24h的基础血压测定。根据大鼠的基础血压进行分组，分组后给药(口服或者IT)，单次给药后血压检测24小时，分别记录24小时内大鼠的收缩压、舒张压、平均动脉压和心率的变化情况。原始数据按照一定时间(常规为30min)计算平均收缩压，平均舒张压，平均动脉压，平均心率。P值小于0.05被认为有统计学上显著性差异。
结论：本发明化合物，例如实施例化合物，对大鼠血压具有显著的降低作用；且IT给药后对腹主动脉压力无显著降低作用。

Claims (10)

  1. 一种化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中，
    Z选自CH或N；
    R1选自-M-(CR1aR1b)r-COOH、
    B选自C3-8碳环基、4-8元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；
    C选自C4-8碳环基或4-8元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
    a、c、r各自独立地选自0、1、2、3、4；
    r1、s各自独立地选自0、1、2、3；
    A选自苯基、苯并C4-6碳环、5至6元杂芳基、苯并4至7元杂环基或8-12元并环杂芳基；
    M选自4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基，所述环烷基、并环烷基、螺环烷基、桥环烷基、杂单环、杂并环、杂螺环或杂桥环任选被1至4个Rm取代；
    R2选自C1-5烷基或-C1-4亚烷基-Q，所述烷基或亚烷基任选被1至8个Rk取代；
    Q选自C3-11环烷基、4至11元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
    Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、卤素、OH、CN、NH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
    或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-11环烷基、4至11元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
    Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；
    Rk各自独立的选自H、氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-3至6元杂环基、-NH-C3-6碳环基、-NH-3至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至6 元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。
  2. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，
    B选自C3-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
    C选自C4-6环烷基、4至6元杂环烷基、苯基或5-6元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rk取代；
    R2选自C1-4烷基或-C1-3亚烷基-Q，所述烷基或亚烷基任选被1至6个Rk取代；
    Q选自C3-6环烷基、4至6元杂环烷基、C6-10芳基或5-10元杂芳基，所述环烷基、杂环烷基、芳基、杂芳基任选被1至4个Rq取代；
    Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、乙烯基、乙炔基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
    或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成C4-7环烷基、4至7元杂环烷基，所述环烷基、杂环烷基任选被1至4个Rk取代；
    Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2或任选被1至4个Rk所取代的如下基团：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吗啉基、苯基；
    Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。
  3. 根据权利要求2所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，
    A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
    B选自任选被1至4个Rk所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
    C选自任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂 环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基；
    M选自任选被1至4个Rm所取代的如下基团：环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基；
    R2选自甲基、乙基、丙基、丁基、-亚甲基-Q、-亚乙基-Q、-亚丙基-Q，所述甲基、乙基、丙基、丁基、亚甲基、亚乙基、亚丁基任选被1至6个Rk取代；
    Q选自任选被1至4个Rq所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
    Ra、Rc、Rm、Rq、Rb3、R1a、R1b、R1c、R1d各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk取代的如下基团：甲基、乙基、甲氧基、环丙基；
    或者R1a与R1b或R1c与R1d分别和与其相连的碳原子共同形成任选被1至4个Rk所取代的如下基团：环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基；
    Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、或任选被1至4个Rk所取代的如下基团：甲基、乙基、甲氧基、环丙基；
    Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基、苯基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、甲基、乙基、甲氧基、乙氧基的取代基所取代；
    r1、r、s各自独立地选自0、1、2。
  4. 根据权利要求3所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，
    A选自苯基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
    R1选自
    R2选自
    Ra、Rc、Rb3各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2、CF3、CHF2、CH2F、甲基、乙基、甲氧基、环丙基；
    Rb1、Rb2、Rb4各自独立地选自H、氘、OH、CN、NH2、甲基、乙基、甲氧基、环丙基；
    a、c各自独立地选自0、1、2。
  5. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，通式(I)选自通式(Ia)，
    A选自苯基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；优先自
    B选自任选被1至4个Rk所取代的如下基团：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、1,3-二氧戊烷基、1,4-二氧己烷基、苯基、吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基；优选自：环丙基、环丁基、环戊基、氧杂环丁基、氮杂环丁基、吡咯烷基；
    R2选自
    Ra、Rc各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2、CF3、CHF2、CH2F、甲基、乙基、甲氧基、环丙基；
    R1a、R1b各自独立地选自H、氘、F、Cl、Br、I、OH、CN、NH2、NHCH3、N(CH3)2或任选被1至4个Rk取代的如下基团：甲基、乙基、甲氧基、环丙基；
    a、c各自独立地选自0、1、2。
  6. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中化合物选自表E-1结构之一。
  7. 一种药物组合物，包括权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中含有0.01-1500mg的权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
  8. 根据权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求7所述的药物组合物在用于制备治疗与sGC相关的疾病的药物中的应用。
  9. 根据权利要求8所述的应用，其中所述的疾病选自心血管疾病、肾脏疾病或呼吸系统疾病，优选自肺动脉高压、肺性高血压、慢性阻塞性肺病。
  10. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-6任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可 接受的盐或共晶或权利要求7所述药物组合物，治疗有效量优选0.01-1500mg，所述的疾病优选心血管疾病、肾脏疾病或呼吸系统疾病，优选自肺动脉高压、肺性高血压、慢性阻塞性肺病。
PCT/CN2024/105872 2023-07-17 2024-07-17 一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物及其在医药上的应用 WO2025016393A1 (zh)

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CN103096718A (zh) * 2010-05-27 2013-05-08 默沙东公司 可溶性鸟苷酸环化酶活化剂
CN103906752A (zh) * 2011-07-06 2014-07-02 拜耳知识产权有限责任公司 杂芳基取代的吡唑并吡啶及其用作可溶性鸟苷酸环化酶刺激剂的用途
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CN103096718A (zh) * 2010-05-27 2013-05-08 默沙东公司 可溶性鸟苷酸环化酶活化剂
CN103906752A (zh) * 2011-07-06 2014-07-02 拜耳知识产权有限责任公司 杂芳基取代的吡唑并吡啶及其用作可溶性鸟苷酸环化酶刺激剂的用途
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CN108738320A (zh) * 2015-12-22 2018-11-02 默沙东公司 作为用于治疗心血管疾病的cGMP调节剂的4-氨基-2-(1H-吡唑并[3,4-b]吡啶-3-基)-6-氧代-6,7-二氢-5H-吡咯并[2,3-d]嘧啶衍生物及各自的(1H-吲唑-3-基)衍生物

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