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WO2025016393A1 - Dérivé de 4-amino-pyrrolo[2,3-d]pyrimidin-6-one et son utilisation médicale - Google Patents

Dérivé de 4-amino-pyrrolo[2,3-d]pyrimidin-6-one et son utilisation médicale 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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Chinese (zh)
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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Haisco Pharmaceutical Group Co Ltd
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Haisco Pharmaceutical Group Co Ltd
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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

La présente invention concerne un dérivé de 4-amino-pyrrolo [2,3-d]pyrimidin-6-one, et en particulier un composé représenté par la formule générale (I), un stéréoisomère, un composé deutéré, un solvate, un promédicament, un métabolite ou un sel ou un co-cristal pharmaceutiquement acceptable de celui-ci, un intermédiaire de celui-ci et son procédé de préparation, et son utilisation dans la préparation d'un médicament pour le traitement de maladies liées au niveau d'activité ou d'expression de la guanylate cyclase (sGC).
PCT/CN2024/105872 2023-07-17 2024-07-17 Dérivé de 4-amino-pyrrolo[2,3-d]pyrimidin-6-one et son utilisation médicale Pending WO2025016393A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104812762A (zh) * 2012-01-11 2015-07-29 拜耳药业股份公司 取代的环状嘧啶和三嗪以及它们的用途
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104812762A (zh) * 2012-01-11 2015-07-29 拜耳药业股份公司 取代的环状嘧啶和三嗪以及它们的用途
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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