CN114057733A - Fused heterocyclic derivative and application thereof in medicine - Google Patents
Fused heterocyclic derivative and application thereof in medicine Download PDFInfo
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- CN114057733A CN114057733A CN202110860850.9A CN202110860850A CN114057733A CN 114057733 A CN114057733 A CN 114057733A CN 202110860850 A CN202110860850 A CN 202110860850A CN 114057733 A CN114057733 A CN 114057733A
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- alkyl
- substituted
- halogen
- cyano
- alkoxy
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- 125000000623 heterocyclic group Chemical group 0.000 title claims description 187
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
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- 229940002612 prodrug Drugs 0.000 claims abstract description 32
- 239000000651 prodrug Substances 0.000 claims abstract description 32
- 239000012453 solvate Substances 0.000 claims abstract description 28
- 239000002207 metabolite Substances 0.000 claims abstract description 27
- 239000013078 crystal Substances 0.000 claims abstract description 26
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
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- 150000003254 radicals Chemical class 0.000 claims description 173
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 95
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
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- 125000003118 aryl group Chemical group 0.000 claims description 32
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
Abstract
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to JAK kinase activity or expression quantity.
Description
Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to JAK kinase activity or expression quantity.
Background
Inflammatory Bowel Disease (IBD), an idiopathic inflammatory bowel disease affecting the ileum, rectum, and colon. The clinical manifestations are diarrhea, abdominal pain and even bloody stool. Including Ulcerative Colitis (UC) and Crohn's Disease (CD). Ulcerative colitis is a continuous inflammation of the mucosal layer and submucosa of the colon, the disease usually affects the rectum first and gradually spreads to the whole colon, Crohn's disease can affect the whole digestive tract and is a discontinuous whole-layer inflammation, and the most frequently affected parts are the terminal ileum, colon and perianal.
The incidence of inflammatory bowel disease worldwide is high, with incidence rates in north america and europe of over 0.3%, and has increased year by year since 1990 in africa, asia and south america.
Janus kinase \ signal transduction and transcription activator (Janus-activated kinase) is a cell signaling pathway closely related to cell factors newly discovered in recent years, and participates in a plurality of important biological processes such as cell proliferation, differentiation, apoptosis, immunoregulation and the like. Janus kinase is a non-receptor tyrosine protein kinase. There are 4 family members, JAK1, JAK2, TYK2 and JAK3, respectively. The JAK/STAT signaling pathway is an important intracellular signal transduction pathway in the growth, activation, differentiation, apoptosis and function of various cells, and is activated by many cytokines such as Interferon (IFN) family, glycoprotein 130(gp130) family, γ -C family and single chain family. The signal transduction chain of the cytokine receptor is provided with JAK tyrosine protein kinase, after the cytokines are combined with a cell surface specific receptor, JAK molecules on the signal transduction chain are polymerized and are mutually phosphorylated to be activated, tyrosine residues (Y) on an intracellular segment of another receptor chain are phosphorylated to be PY by releasing phosphate radical (P), the phosphorylated tyrosine sites form 'docking sites' with surrounding amino acid sequences, so that a transcription factor STAT with a SH2 structural domain is recruited, tyrosine in the STAT is also activated by obtaining phosphate radical from the activated JAK to form homodimer, after the STAT is separated from the receptor, a nuclear localization signal of the STAT is exposed to enter a nucleus and is combined with a target gene to regulate the transcription of the gene. JAK-STAT intracellular signaling is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors.
The exact pathogenesis of UC is not clear, but the proinflammatory cytokines play a key role in the immune response (georger et al, gastroentol, 2011,140, 1756-. Many of the proinflammatory cytokines most commonly elevated in UC (e.g., IL-4, IL-6, IL-13, IL-15, IL-23, IL-24, IFN γ, and leptin) rely on the JAK family of tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) for signal transduction, and inhibition of the JAK enzyme family inhibits signaling of a number of key proinflammatory cytokines. Thus, inhibition of the JAK enzyme family is expected to have therapeutic benefits for ulcerative colitis and other inflammatory diseases.
Disclosure of Invention
The invention aims to provide a compound capable of inhibiting JAK kinase or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing medicines for treating diseases related to JAK activity or expression.
The compound has the advantages of good selectivity, excellent drug effect, high bioavailability, low toxicity, safety and higher pharmacokinetic performance, and is used for treating JAK kinase-related diseases.
The compound has good JAK kinase inhibitory activity, anti-inflammatory activity, good safety, skin targeting and/or intestinal targeting.
The invention provides a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein
In certain embodiments, L is selected from a bond or NRn2；
In certain embodiments, L is selected from NRn2；
In certain embodiments, L is selected from a bond;
in certain embodiments, Rn1、Rn2Each independently selected from H, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF3OH, cyano, NH2、C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
in certain embodiments, Rn1、Rn2Is selected from H;
in certain embodiments, ring A is selected from a 5-6 membered monocyclic heteroaryl ring or an 8-10 membered fused heteroaryl ring, said heteroaryl ring optionally further substituted with 0 to 3Ra(ii) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N;
in certain embodiments, ring a is selected from an 8-10 membered fused-ring heteroaryl ring optionally further substituted with 0 to 3Ra(ii) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N;
in certain embodiments, ring a is selected from a substituted or unsubstituted 6 and 6 membered fused heteroaryl, preferably one of the following substituted or unsubstituted: isoquinolinyl, naphthyridinyl, pyridopyrazinyl, pyridopyrimidinyl, quinazolinyl, pteridinyl, quinoxalinyl, dihydropyranopyrimidinyl or dihydrodioxadienopyrimidinyl, when substituted, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, ring a is selected from substituted or unsubstitutedSubstituted 5 and 6 membered fused heteroaryl, preferably substituted or unsubstituted, one of the following groups: thienopyrimidinyl or pyrazolopyrimidinyl, benzopyrolyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, imidazopyridazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, triazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyridazinyl, imidazopyrazinyl, triazolopyrazinyl, pyrrolotriazinyl, imidazotriazinyl or imidazopyrazinone, when substituted, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, ring a is selected from substituted or unsubstituted
X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N, ring C selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N, when substituted, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, ring a is selected from substituted or unsubstituted
X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N, ring C selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring or benzene ring, when substituted, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted groups:
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted groups:
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted groups:
left side with-NH-R1Directly linked, to the right of L, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, ring a is selected from
Left side with-NH-R1Directly linked, to the right of L, optionally further substituted with 0 to 3RaSubstitution;
in certain embodiments, RaEach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, RaEach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C3-6Carbocyclic ring or- (CH)2)q-3 to 6 membered heterocycle, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2Or- (CH)2)qNRa1C(＝O)-Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, RaEach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, NHRa2、-CH2NHRa2、-C(＝O)NHRa2、-CH2C(＝O)NHRa2、-NHC(＝O)Ra2、-CH2NHC(＝O)Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, RaEach independently selected from H, F, cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (═ O) NH2、-C(＝O)NHCH3、-C(＝O)NHCH2CH3-C (═ O) NH-cyclopropyl, -C (═ O) NH-cyclobutyl, -C (═ O) NH-cyclopentyl, -C (═ O) NH-cyclohexyl, -C (═ O) NH-phenyl, -NHC (═ O) H, -NHC (═ O) CH-phenyl3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl or phenyl being optionally further substituted by 0 to 4 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
in certain embodiments, RaEach independently selected from H, F, CF3Cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2、-NHC(＝O)H、-NHC(＝O)CH3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl or phenyl being optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
in certain embodiments, RaEach independently selected from H, F, CF3Methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
in certain embodiments, RaIs selected from Rc，RcEach independently selected from H, F, CF3OH, cyano, methylEthyl, methoxy, ethoxy,
Or
In certain embodiments, ring B is selected from non-aromatic C3-12Carbocycle, said carbocycle is optionally selected from monocyclic, fused, bridged or spiro ring, said carbocycle, monocyclic, fused, bridged or spiro ring is optionally further substituted with 0 to 3RbSubstituted by a substituent;
in certain embodiments, ring B is selected from C3-8Monocycloalkyl radical, C4-10And cycloalkyl group, C4-12Spiro cycloalkyl, C5-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent;
in certain embodiments, ring B is selected from C5-8Monocycloalkyl radical, C8-10And cycloalkyl group, C8-12Spiro cycloalkyl, C8-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent;
in certain embodiments, ring B is selected from C5-7Monocycloalkyl radical, C9-10And cycloalkyl group, C9-12Spiro cycloalkyl, C9-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent;
in certain embodiments, ring B is selected from C5Monocycloalkyl radical, C6Monocycloalkyl radical, C7Monocycloalkyl radical, C6And cycloalkyl group, C7And cycloalkyl group, C8And cycloalkyl group, C9And cycloalkyl group, C10And cycloalkyl group, C6Spiro cycloalkyl, C7Spiro cycloalkyl, C8Spiro cycloalkyl, C9Spiro cycloalkyl, C10Spiro cycloalkyl, C11Spiro cycloalkyl, C12Spiro cycloalkyl, C5Bridged cycloalkyl radical, C6Bridged cycloalkyl radical, C7Bridged cycloalkyl radical, C8Bridged cycloalkyl radical, C9Bridged cycloalkyl radicals、C10Bridged cycloalkyl radical, C11Bridged cycloalkyl radical, C12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent;
in certain embodiments, ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexylcyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylpropenyl, cyclohexylspirocyclohexyl, bicyclo [ 1.1.1.1]Pentyl alkyl, bicyclo [2.1.1]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3 substituents selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
in certain embodiments, ring B is selected from
in certain embodiments, ring B is selected from
Or
Right side and R2Direct connection;
in certain embodiments, ring B is selected from
Or
Right side and R2Direct connection;
in certain embodiments, ring B is selected from
Or
Right side and R2Direct connection;
in certain embodiments, ring B is selected from
Right side and R2Direct connection;
in certain embodiments, RbEach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, RbEach independently selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-4Cycloalkyl, substituted with a substituent;
in certain embodiments, RbEach independently selected from H, halogen, cyano, OH, O, and O, and O, and O,C1-4Alkyl or C1-4An alkoxy group;
in certain embodiments, RbEach independently selected from H, F, cyano, OH, methyl, ethyl, methoxy, ethoxy, or hydroxymethyl;
in certain embodiments, R1Selected from 5 to 10 membered heteroaryl or phenyl, optionally further substituted with 0 to 4R1aSubstitution;
in certain embodiments, R1Selected from one of the following substituted or unsubstituted groups: selected from 5 to 6 membered monocyclic heteroaryl, 6 and 6 membered heteroaryl, 5 and 6 membered heteroaryl or phenyl, when substituted, optionally further substituted with 0 to 4R1aSubstitution;
in certain embodiments, R1Selected from one of the following substituted or unsubstituted groups: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, benzopyrazolyl, benzopyrrole, benzimidazolyl, benzothienyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzisothiazolyl or benzisoxazolyl, when substituted, is optionally further substituted with 0 to 4R1aSubstitution;
in certain embodiments, R1Is selected from
in certain embodiments, R1Is selected from
In certain embodiments, R1Is selected from
In certain embodiments, R1Is selected from
In certain embodiments, R1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-4Cycloalkyl), C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R1aEach independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R1bEach independently selected from C1-6Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R1bEach independently selected from C1-4Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R1bEach independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in certain embodiments, R2Selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R2Selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 10 membered heterocycle, said-CH2-, alkyl, alkoxyThe radical, carbocycle or heterocycle is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R2Selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, -NH-C3-6Carbocyclic, -NH-3 to 6 membered heterocyclic ring or-NHC1-4Alkyl, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R2Selected from F, cyano, OH, -OCH3Methyl, ethyl, CF3、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2CH2CH2CH2CN、-NHCH2CN、-NHCH2CH2CN、-NHCH2CH2CH2CN、-NHCH2CH2CH2CH2CN、
In certain embodiments, R2Selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN；
In certain embodiments, R2Selected from CN, -CH2CN、-CH2CH2CN；
In certain embodiments, Ra1、Ra2、R2a、R2bEach independently selected from H, C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, Ra1、Ra2、R2a、R2bEach independently selected from H, C1-4Alkyl radical, C3-10Carbocyclyl or 3 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, Ra2Selected from H, C1-4Alkyl radical, C3-6Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocycleThe radical or the heterocyclic radical is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, Ra2Selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl or isoxazolyl, said methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl or isoxazolyl being optionally further substituted by 0 to 4 groups selected from H, halogen, OH, cyano, NH2、-NHCH3、-NHCH2CH3、-N(CH3)2、-N(CH2CH3)2-NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, halogen-substituted methyl, halogen-substituted ethyl, cyano-substituted methyl, cyano-substituted ethyl, methoxy, ethoxy;
q is each independently selected from 0,1, 2, 3 or 4.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
l is selected from a bond or NRn2；
Rn1、Rn2Each independently selected from H, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF3OH, cyano, NH2、C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
ring A is selected from 8-10 membered fused heteroaromatic rings optionally further substituted with 0 to 3Ra(ii) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N;
Raeach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
ring B is selected from non-aromatic C3-12Carbocycle, said carbocycle is optionally selected from monocyclic, fused, bridged or spiro ring, said carbocycle, monocyclic, fused, bridged or spiro ring is optionally further substituted with 0 to 3RbSubstituted by a substituent;
Rbeach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1selected from 5 to 10 membered heteroaryl or phenyl, optionally further substituted with 0 to 4R1aSubstitution;
R1aeach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected fromH、C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0,1, 2, 3 or 4.
As a second embodiment of the present invention, a compound represented by the following general formula (Ia) or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein
When the N atom in ring C is attached to L, L is selected from a bond;
when the C atom in the ring C is connected with L, L is selected from NH;
X1、X2、X3or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N;
provided that X is1、X2、X3、X4Y, Z at least 1 is selected from N;
ring C is selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N or a benzene ring;
Raeach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
p is selected from 0,1, 2 or 3;
ring B is selected from C3-8Monocycloalkyl radical, C4-10And cycloalkyl group, C4-12Spiro cycloalkyl, C5-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent;
Rbeach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1is selected from
Or R1Is selected from
R1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
m is selected from 0,1 or 2;
R1beach independently selected from C1-6Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Substituent of alkoxy(iii) substituted, said heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected from H, C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0,1, 2, 3 or 4.
As a third embodiment of the present invention, a compound represented by the aforementioned general formula (Ia) or a stereoisomer, a tautomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
R1aeach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-4Cycloalkyl), C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1beach independently selected from C1-4Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
ring C is selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N or a benzene ring;
p is selected from 0,1 or 2 or 3;
Raeach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C3-6Carbocyclic ring or- (CH)2)q-3 to 6 membered heterocycle, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2Or- (CH)2)qNRa1C(＝O)-Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Rbeach independently selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-4Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 10 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocyclic or heterocyclic, optionally further substituted by 0 to4 are selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected from H, C1-4Alkyl radical, C3-10Carbocyclyl or 3 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
the remaining groups are defined in accordance with either the first or second embodiment of the present invention.
As a fourth embodiment of the present invention, a compound represented by the aforementioned general formula (Ia) or a stereoisomer, a tautomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
R1aeach independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1beach independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally further substituted by 0 to 4 substituents selected fromH. Halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
ring C is selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring or benzene ring;
the ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexylcyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylpropenyl, cyclohexylspirocyclohexyl, bicyclo [ 1.1.1.1]Pentyl alkyl, bicyclo [2.1.1]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3 substituents selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, -NH-C3-6Carbocyclic, -NH-3 to 6 membered heterocyclic ring or-NHC1-4Alkyl, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
the remaining groups are defined in accordance with any of the first, second and third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (Ia) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal thereof,
ring B is selected from
R2selected from F, cyano, OH, -OCH3Methyl, ethyl, CF3、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2CH2CH2CH2CN、-NHCH2CN、-NHCH2CH2CN、-NHCH2CH2CH2CN、-NHCH2CH2CH2CH2CN、
In the general formula (Ia)
Is selected from
Left side with-NH-R1Direct connection, right side is connected with L directly;
R1is selected from
RaEach independently selected from H, F, cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentylHexyl radical, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (═ O) NH2、-C(＝O)NHCH3、-C(＝O)NHCH2CH3-C (═ O) NH-cyclopropyl, -C (═ O) NH-cyclobutyl, -C (═ O) NH-cyclopentyl, -C (═ O) NH-cyclohexyl, -C (═ O) NH-phenyl, -NHC (═ O) H, -NHC (═ O) CH-phenyl3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl or phenyl being optionally further substituted by 0 to 4 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy；
The remaining groups are defined in accordance with any one of the first, second, third and fourth embodiments of the present invention.
As a sixth embodiment of the present invention, a compound represented by the aforementioned general formula (Ia) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal thereof,
ring B is selected from
Or
Right side and R2Direct connection;
R2selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN；
In the general formula (Ia)
Is selected from
R1is selected from
The remaining groups are defined in accordance with any one of the first, second, third, fourth and fifth embodiments of the present invention.
As a seventh embodiment of the present invention, a compound represented by the following general formula (Ia-1), (Ia-2), (Ia-3) or (Ia-4) or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,
wherein the content of the first and second substances,
ring B is selected from
Or
Right side and R2Direct connection;
R2selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN；
R1Is selected from
Or
RaEach independently selected from H, F, cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2、-NHC(＝O)H、-NHC(＝O)CH3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl or phenyl being optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
the remaining groups are defined in accordance with any one of the first, second, third, fourth, fifth, and sixth embodiments of the present invention.
As an eighth embodiment of the present invention, a compound represented by the aforementioned general formula (Ia-1), (Ia-2), (Ia-3) or (Ia-4) or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,
ring B is selected from
Or
Right side and R2Direct connection;
R2selected from CN, -CH2CN、-CH2CH2CN；
R1Is selected from
Or
RaEach independently selected from H, F, CF3Methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
the remaining groups are defined in accordance with any one of the first, second, third, fourth, fifth, sixth, and seventh embodiments of the present invention.
As a ninth embodiment of the present invention, a compound represented by the following general formula (Ib-1) or a stereoisomer, tautomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,
wherein the content of the first and second substances,
ring B is selected from
Right side and R2Direct connection;
R2selected from CN, -CH2CN、-CH2CH2CN；
R1Is selected from
Or
RaEach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
Rceach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy,
Or
The remaining groups are defined in accordance with any one of the first, second, third, fourth, fifth, sixth, seventh and eighth embodiments of the present invention.
The present invention relates to a compound as shown below, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
in some embodiments of the general formulae (I), (Ia), L is selected from a bond or NRn2。
In some embodiments of the general formulae (I), (Ia), L is selected from NRn2。
In some embodiments of the general formulae (I), (Ia), L is selected from a bond.
In some embodiments of the general formula (I), Rn1、Rn2Each independently selected from H, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF3OH, cyano, NH2、C1-6Alkyl or C1-6Substituted by a substituent of alkoxy.
In some embodiments of the general formula (I), Rn1、Rn2Each independently selected from H.
In some embodiments of formula (I), Ring A is selected from a 5-6 membered monocyclic heteroaryl ring or an 8-10 membered fused heterocyclic heteroaryl ring, said heteroaryl ring optionally further substituted with 0 to 3RaAnd (b) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N.
In some embodiments of formula (I), ring A is selected from an 8-10 membered fused heteroaromatic ring optionally further substituted with 0 to 3RaAnd (b) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N.
In some embodiments of formula (I), ring a is selected from substituted or unsubstituted 6 and 6 membered fused heteroaryl, preferably one of the following substituted or unsubstituted: isoquinolinyl, naphthyridinyl, pyridopyrazinyl, pyridopyrimidinyl, quinazolinyl, pteridinyl, quinoxalinyl, dihydropyranopyrimidinyl or dihydrodioxadienopyrimidinyl, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of formula (I), ring a is selected from substituted or unsubstituted 5 and 6 membered fused heteroaryl, preferably one of the following substituted or unsubstituted: thienopyrimidinyl or pyrazolopyrimidinyl, benzopyrolyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, imidazopyridazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, triazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyridazinyl, imidazopyrazinyl, triazolopyrazinyl, pyrrolotriazinyl, imidazotriazinyl or imidazopyrazinone, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of formula (I), ring A is selected from substituted or unsubstituted
X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N, ring C selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of formula (I), ring A is selected from substituted or unsubstituted
X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N, ring C selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring or benzene ring, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of formula (I), ring A is selected from one of the following substituted or unsubstituted groups:
In some embodiments of formula (I), ring A is selected from one of the following substituted or unsubstituted groups:
left side with-NH-R1Directly linked, to the right of L, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of formula (I), ring A is selected from one of the following substituted or unsubstituted groups:
left side with-NH-R1Directly linked, to the right of L, optionally further substituted with 0 to 3RaAnd (4) substitution.
The present invention relates to certain embodiments of formula (Ia) wherein when the N atom in ring C is attached to L, L is selected from a bond.
In some embodiments of formula (Ia), when the C atom in ring C is attached to L, L is selected from NH.
In some embodiments of the general formula (Ia), X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N; provided that X is1、X2、X3、X4At least 1 of Y, Z is selected from N.
In some embodiments of formula (Ia), p is selected from 0,1, 2, or 3.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RaEach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) wherein RaEach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C3-6Carbocyclic ring or- (CH)2)q-3 to 6 membered heterocycle, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2Or- (CH)2)qNRa1C(＝O)-Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RaEach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, NHRa2、-CH2NHRa2、-C(＝O)NHRa2、-CH2C(＝O)NHRa2、-NHC(＝O)Ra2、-CH2NHC(＝O)Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RaEach independently selectsFrom H, F, cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (═ O) NH2、-C(＝O)NHCH3、-C(＝O)NHCH2CH3-C (═ O) NH-cyclopropyl, -C (═ O) NH-cyclobutyl, -C (═ O) NH-cyclopentyl, -C (═ O) NH-cyclohexyl, -C (═ O) NH-phenyl, -NHC (═ O) H, -NHC (═ O) CH-phenyl3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolylThiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidyl or phenyl optionally further substituted by 0 to 4 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RaEach independently selected from H, F, CF3Cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2、-NHC(＝O)H、-NHC(＝O)CH3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2,4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidyl or phenyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RaEach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
In some embodiments of the general formula (Ib-1), RcEach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
In some embodiments of the general formula (Ib-1), RcEach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy,
Or
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from non-aromatic C3-12Carbocycle, said carbocycle is optionally selected from monocyclic, fused, bridged or spiro ring, said carbocycle, monocyclic, fused, bridged or spiro ring is optionally further substituted with 0 to 3RbSubstituted by a substituent.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from C3-8Monocycloalkyl radical, C4-10And cycloalkyl group, C4-12Spiro cycloalkyl, C5-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from C5-8Monocycloalkyl radical, C8-10And cycloalkyl group, C8-12Spiro cycloalkyl, C8-12Bridged cycloalkyl, said cycloalkyl being optionally substitutedOne step by 0 to 3RbSubstituted by a substituent.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from C5-7Monocycloalkyl radical, C9-10And cycloalkyl group, C9-12Spiro cycloalkyl, C9-12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from C5Monocycloalkyl radical, C6Monocycloalkyl radical, C7Monocycloalkyl radical, C6And cycloalkyl group, C7And cycloalkyl group, C8And cycloalkyl group, C9And cycloalkyl group, C10And cycloalkyl group, C6Spiro cycloalkyl, C7Spiro cycloalkyl, C8Spiro cycloalkyl, C9Spiro cycloalkyl, C10Spiro cycloalkyl, C11Spiro cycloalkyl, C12Spiro cycloalkyl, C5Bridged cycloalkyl radical, C6Bridged cycloalkyl radical, C7Bridged cycloalkyl radical, C8Bridged cycloalkyl radical, C9Bridged cycloalkyl radical, C10Bridged cycloalkyl radical, C11Bridged cycloalkyl radical, C12Bridged cycloalkyl optionally further substituted with 0 to 3RbSubstituted by a substituent.
In some embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ib-1), Ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexylcyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylpropenyl, cyclohexylspirocyclohexyl, bicyclo [ 1.1.1.1]Pentyl alkyl, bicyclo [2.1.1]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl radicalBicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3 substituents selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from
Or
Right side and R2And (4) direct connection.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from
Or
Right side and R2And (4) direct connection.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from
Or
Right side and R2And (4) direct connection.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ring B is selected from
Right side and R2And (4) direct connection.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RbEach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl substituents.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RbEach independently selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-4Cycloalkyl substituents.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), RbEach independently selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4An alkoxy group.
The invention relates to compounds of the general formula (I), (Ia-1)In some embodiments of (Ia-2), (Ia-3), (Ia-4), or (Ib-1), RbEach independently selected from H, F, cyano, OH, methyl, ethyl, methoxy, ethoxy, or hydroxymethyl.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Selected from 5 to 10 membered heteroaryl or phenyl, optionally further substituted with 0 to 4R1aAnd (4) substitution.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Selected from one of the following substituted or unsubstituted groups: selected from 5 to 6 membered monocyclic heteroaryl, 6 and 6 membered heteroaryl, 5 and 6 membered heteroaryl or phenyl, when substituted, optionally further substituted with 0 to 4R1aAnd (4) substitution.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Selected from one of the following substituted or unsubstituted groups: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, benzopyrazolyl, benzopyrrole, benzimidazolyl, benzothienyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzisothiazolyl or benzisoxazolyl, when substituted, is optionally further substituted with 0 to 4R1aAnd (4) substitution.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Is selected from
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Is selected from
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Is selected from
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1Is selected from
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl substituents.
The invention relates toAnd of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1)1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-4Cycloalkyl), C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1aEach independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl substituents.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1bEach independently selected from C1-6Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1bEach independently selected from C1-4Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R1bEach independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
in some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 10 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, -NH-C3-6Carbocyclic, -NH-3 to 6 membered heterocyclic ring or-NHC1-4Alkyl, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from F, cyano, OH, -OCH3Methyl, ethyl, CF3、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2CH2CH2CH2CN、-NHCH2CN、-NHCH2CH2CN、-NHCH2CH2CH2CN、-NHCH2CH2CH2CH2CN、
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN。
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), R2Selected from CN, -CH2CN、-CH2CH2CN。
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ra1、Ra2、R2a、R2bEach independently selected from H, C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3 to12-membered heterocyclic group, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ra1、Ra2、R2a、R2bEach independently selected from H, C1-4Alkyl radical, C3-10Carbocyclyl or 3 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ra2Selected from H, C1-4Alkyl radical, C3-6Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
In some embodiments of the general formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4) or (Ib-1), Ra2Selected from H, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutylA group selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl, said methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl being optionally further substituted with 0 to 4 substituents selected from the group consisting of H, halogen, OH, cyano, NH, halogen, OH, and heteroaryl2、-NHCH3、-NHCH2CH3、-N(CH3)2、-N(CH2CH3)2NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ring, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, halogen-substituted methyl, halogen-substituted ethyl, cyano-substituted methyl, cyano-substituted ethyl, methoxy, ethoxy.
In some embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ib-1), q is each independently selected from 0,1, 2, 3, or 4.
In some embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ib-1), q is each independently selected from 0,1, or 2.
In some embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ib-1), each m is independently selected from 0,1, 2, or 3.
In some embodiments of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ib-1), each m is independently selected from 0,1, or 2.
In some embodiments of the general formula (Ia), X1、X2、X3Or X4Each independentlySelected from CH, C or N, Y, Z are each independently selected from C or N, ring C is selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
In some embodiments of the general formula (Ia), X1、X2、X3Or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N, ring C selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring or benzene ring, when substituted, optionally further substituted with 0 to 3RaAnd (4) substitution.
The present invention relates to certain embodiments of formula (Ia),
selected from one of the following substituted or unsubstituted groups:
The present invention relates to certain embodiments of formula (Ia),
selected from the group consisting of substituted or unsubstitutedFirstly, the method comprises the following steps:
The present invention relates to certain embodiments of formula (Ia),
selected from one of the following substituted or unsubstituted groups:
left side with-NH-R1Directly linked, to the right of L, optionally further substituted with 0 to 3RaAnd (4) substitution.
The present invention relates to a pharmaceutical composition comprising any of the above compounds or a stereoisomer, tautomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to the use of any of the above compounds or a stereoisomer, tautomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof for the manufacture of a medicament for the treatment of a disease associated with JAK kinase activity or expression, preferably said disease is selected from inflammatory diseases.
References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.
Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.
Synthesis method
To accomplish the objects of the present invention, the compounds of the present invention can be prepared by the following scheme:
the first scheme is as follows:
x is selected from Cl, Br, I, OTs (p-toluenesulfonyl) or benzenesulfonate group;
PG is selected from the group consisting of amine protecting group and hydroxyl protecting group, preferably
R1、R2、Ra、RcThe same as the definition of the substituent in the compound represented by the general formula ((Ib-1));
converting the compound of the general formula (M-1) and the compound of the general formula (M-2) into a compound of the general formula (M-3) through a conventional nucleophilic substitution reaction; carrying out reduction reaction on the compound with the general formula (M-3) to obtain a compound with a general formula (M-4); carrying out a ring closure reaction on the compound of the general formula (M-4) to obtain a compound of a general formula (M-5); carrying out nucleophilic substitution reaction or coupling reaction on the compound of the general formula (M-5) to obtain a compound of the general formula (M-6); the compound of the general formula (M-6) is subjected to deprotection reaction to obtain a compound of a general formula (Ib-1).
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F include17F and19isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"halogen" means F, Cl, Br or I.
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; the alkyl group may be optionally further substituted with 0 to 6 groups selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, carboxy, or carboxylate, wherein alkyl is as defined herein.
"alkylene" refers to a straight and branched chain divalent saturated hydrocarbon radical, including- (CH)2)v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like; the alkylene group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkylene groups, as used herein, are defined in accordance with the present definition.
"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically of 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Cycloalkyl as found herein, is as defined above.
"alkenyl" means a straight and branched chain monovalent unsaturated hydrocarbon group having at least 1, and usually 1,2 or 3 carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain, examples of alkenyl 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-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, and the like, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; the alkenyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkenyl groups are present herein, the definition of which is consistent with the present definition.
"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, and a backbone containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, with examples of alkynyl including, but 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-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-butynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkynyl groups are presented herein, and their definitions are consistent with this definition.
"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkoxy group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkoxy groups, as used herein, are defined in accordance with the present definition.
"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. 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, and mixtures thereof,
Or
The carbocycle may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Carbocyclic or carbocyclic groups, as used herein, are defined in accordance with the present definition.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and contain 1 to 3 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclyl, the optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]NonaneOxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,
Or
The heterocyclic group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"spiro" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (called spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 substituents selected from N, O or S (═ O)nA heteroatom of (a). Preferably 6 to 14, more preferably 6 to 12, more preferably 6 to 10, non-limiting examples of which include:
"fused" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 rings selected from N, S (═ O)nOr a heteroatom of O. Preferably 5 to 20, more preferably 5 to 14, more preferably 5 to 12, and even more preferably 5 to 10 yuan. Non-limiting examples include:
when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0,1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. The definition of fused rings appearing herein is consistent with this definition.
"bridged ring" means any two polycyclic group of carbon atoms not directly linked, which may contain 0 or more double bonds and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 heteroatoms or groups selected from N, S (═ O) n or O (where n is 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include
"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The definition of "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as used herein, is consistent with the present definition. "carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. The definition of "carbocyclic", "fused carbocyclic", or "fused carbocyclic" appearing herein is consistent with the present definition.
"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. The definition of "carbocycle", "carbocyclyl", "bridged carbocyclyl", or "carbocyclyl" as used herein is consistent with the present definition.
"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and the definition of heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein is consistent with the present definition.
"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The definition of heterocyclo, "" heterocyclo, "or" heterocyclo "as used herein is consistent with the present definition.
"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospirocyclic, "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" as used herein is consistent with the present definition.
"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The definition of heterobridged ring, "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group," as used herein, is consistent with this definition.
"aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single ring or fused rings, typically 6 to 12 carbon atoms, and which may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0,1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Aryl or aromatic rings are present herein, and the definition is consistent with the present definition.
"heteroaryl" refers to a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S (═ O) n, preferably a 5 to 10 membered heteroaromatic ring, more preferably 5 to 6 membered aromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together to the parent structure is a heteroaryl ring, non-limiting examples of which include
And
when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0,1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxyOr a group selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereofbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heteroaryl, as used herein, is defined in accordance with the present definition.
"contains 1 to 5 heteroatoms selected from O, S, N" means containing 1,2, 3, 4 or 5 heteroatoms selected from O, S, N.
"substituted with 0 to X substituents" means substituted with 0,1, 2, 3 … X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0,1, 2, 3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0,1, 2, 3, 4, or 5 substituents. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0,1, 2, 3 or 4 substituents selected from H or F.
X-Y membered rings (X is selected from integers less than Y greater than 3 and Y is selected from any integer between 4 and 12) include X +1, X +2, X +3, X +4 … Y membered rings. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"tautomer" refers to functional group isomers resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-enol isomers, and the like.
"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.
“IC50"is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto. The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from compounds described in the commercial chemicals and/or chemical literature. "commercial chemicals" are obtained from regular commercial sources, and suppliers include: tatan science and technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical engineering, Shaoshao chemical technology, Nanjing Yashi, Yaogongkang and Bailingwei science and technology.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;
the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.
EXAMPLE 1 trans-2- [4- [5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile; 2,2, 2-Trifluoroacetate (Compound 1)
trans-2-[4-[5-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]cyclohexyl]acetoni trile；2,2,2-trifluoroacetic acid
First step trans-2- [4- [ (6-chloro-3-nitro-2-pyridyl) amino ] cyclohexyl ] acetonitrile (Compound 1b)
Trans-2-[4-[(6-chloro-3-nitro-2-pyridyl)amino]cyclohexyl]acetonitrile
2, 6-dichloro-3-nitropyridine (1a) (1.50g,7.77mmol) was dissolved in EtOH (30mL), DIPEA (5mL) and trans-2- (4-aminocyclohexyl) acetonitrile hydrochloride (1.36g,7.77mmol) (prepared according to the synthetic method of patent WO2019/239387, starting with trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid) were added and the mixture was allowed to react overnight at 80 ℃ until LCMS indicated completion. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:0-3:1) to give trans-2- [4- [ (6-chloro-3-nitro-2-pyridyl) amino ] cyclohexyl ] acetonitrile (1b) (1.2g, 52%) as a white solid.
LCMS m/z＝295[M+1]+。
Second step trans-2- [4- [ (3-amino-6-chloro-2-pyridyl) amino ] cyclohexyl ] acetonitrile (1c)
Trans-2-[4-[(3-amino-6-chloro-2-pyridyl)amino]cyclohexyl]acetonitrile
Trans-2- [4- [ (6-chloro-3-nitro-2-pyridyl) amino ] cyclohexyl ] acetonitrile (1b) (1.50g,5.10mmol) was dissolved in EtOH (30mL), Zn (1.65g,25.4mmol) and NH4Cl (1.35g,25.5mmol) were added and the mixture reacted at 50 ℃ until LCMS indicated completion of the reaction. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:0-1:1) to give trans-2- [4- [ (3-amino-6-chloro-2-pyridyl) amino ] cyclohexyl ] acetonitrile (1c) (1.2g, 89%) as a gray solid.
LCMS m/z＝265[M+1]+。
The third step is trans-2- [4- (5-chloroimidazo [4,5-b ] pyridin-3-yl) cyclohexyl ] acetonitrile (1d)
Trans-2-[4-(5-chloroimidazo[4,5-b]pyridin-3-yl)cyclohexyl]acetonitrile
Trans-2- [4- [ (3-amino-6-chloro-2-pyridinyl) amino ] cyclohexyl ] acetonitrile (1c) (100mg,0.38mmol) was dissolved in HCOOH (3mL) and the mixture reacted at 100 ℃ until LCMS indicated completion of the reaction. The residue was adjusted to PH 8 with aqueous NaOH, extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution method: petroleum ether: ethyl acetate ═ 1:0-2:1) to give trans-2- [4- (5-chloroimidazo [4,5-b ] pyridin-3-yl) cyclohexyl ] acetonitrile (1d) (50mg, 48%).
LCMS m/z＝275[M+1]+。
The fourth step is trans-3- [ [ [3- [4- (cyanomethyl) cyclohexyl ] imidazo [4,5-b ] pyridin-5-yl ] amino ] -5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (1e)
trans-tert-butyl3-[[3-[4-(cyanomethyl)cyclohexyl]imidazo[4,5-b]pyridin-5-yl]amino]-5-methyl-pyrazole-1-carboxyl ate
Trans-2- [4- (5-chloroimidazo [4,5-b ]]Pyridin-3-yl) cyclohexyl]Acetonitrile (1d) (16mg,0.058mmol) and tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate (7.72mg,0.039mmol) were dissolved in 1,4-dioxane (2mL), and Pd2(dba)3(2.60mg,0.0028mmol), Brettphos (2.80mg,0.0052mmol), Cs were added2CO3(17mg,0.052mmol) of the mixture in N2The reaction was protected at 100 ℃ overnight and TLC indicated completion. The mixture was added with water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution method: dichloromethane: methanol ═ 100:1-30:1) to give trans-3- [ [ [3- [4- (cyanomethyl) cyclohexyl ] amino acid]Imidazo [4,5-b ]]Pyridyl-5-yl]Amino group]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (1e) (16mg, 63%).
LCMS m/z＝436[M+1]+。
The fifth step: trans-2- [4- [5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile; 2,2, 2-Trifluoroacetate (Compound 1)
trans-2-[4-[5-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]cyclohexyl]acetoni trile；2,2,2-trifluoroacetic acid
Trans-3- [ [ [3- [4- (cyanomethyl) cyclohexyl ] imidazo [4,5-b ] pyridin-5-yl ] amino ] -5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (1e) (16.00mg,0.037mmol) was dissolved in dichloromethane (2mL), TFA (1mL) was added and after 1h reaction at room temperature, the reaction was concentrated under reduced pressure to give an oil, which was adjusted to pH 9 with sodium hydroxide solution (1M), extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Pre-HPLC (instrument and preparative column: liquid phase was prepared using Waters2767, preparative column model XBridge, 5 μm, 19mm x 250mm in internal diameter x length). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% trifluoroacetic acid). Gradient elution method: acetonitrile is subjected to gradient from 10% to 50% (elution time is 16min), and trans-2- [4- [5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile is obtained after freeze-drying; 2,2, 2-Trifluoroacetate (Compound 1) (5.00mg, 30%).
LCMS m/z＝336[M+1]+。
1H NMR(400MHz,CD3OD)δ9.02(s,1H),7.96(d,1H),7.15(d,1H),6.38(s,1H),4.76-4.69(m,1H),2.59-2.52(m,2H),2.41-2.32(m,5H),2.18-2.10(m,4H),1.97-1.85(m,1H),1.57-1.46(m,2H)。
Example 2 trans-2- [4- [ (3R) -2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile; 2,2, 2-Trifluoroacetate (Compound 2)
Trans-2-[4-[(3R)-2-(hydroxymethyl)-5-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]cyclohexyl]acetonitrile；2,2,2-trifluoroacetic acid
The first step is as follows: trans-2-benzyloxy-N- [ 6-chloro-2- [ [4- (cyanomethyl) cyclohexyl ] amino ] -3-pyridinyl ] acetamide (2a)
Trans-2-benzyloxy-N-[6-chloro-2-[[4-(cyanomethyl)cyclohexyl]amino]-3-pyridyl]acetamide
Trans-2- [4- [ (3-amino-6-chloro-2-pyridinyl) amino ] cyclohexyl ] acetonitrile (1c) (510mg,1.93mmol) was dissolved in DCM (10mL), Et3N (0.55mL) and 2-benzyloxyacetyl chloride (0.36mL) were added and the mixture reacted at room temperature until LCMS indicated completion of the reaction. The mixture was concentrated, the residue was extracted with water and ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution method: petroleum ether: ethyl acetate ═ 1:0-5:1) to give trans-2-benzyloxy-N- [ 6-chloro-2- [ [4- (cyanomethyl) cyclohexyl ] amino ] -3-pyridinyl ] acetamide (2a) (450mg, 57%).
LCMS m/z＝413[M+1]+。
The second step is that: trans-2- [4- [2- (benzyloxymethyl) -5-chloro-imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile (2b)
Trans-2-[4-[2-(benzyloxymethyl)-5-chloro-imidazo[4,5-b]pyridin-3-yl]cyclohexyl]acetonitrile
trans-2-benzyloxy-N- [ 6-chloro-2- [ [4- (cyanomethyl) cyclohexyl ] amino ] -3-pyridinyl ] acetamide (2a) (130mg,0.31mmol) was dissolved in HCOOH (5mL) and the mixture reacted at 100 ℃ until LCMS indicated completion of the reaction. The residue was adjusted to PH 8 with aqueous NaOH, extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution method: petroleum ether: ethyl acetate ═ 1:0-3:1) to give trans-2- [4- [2- (benzyloxymethyl) -5-chloro-imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile (2b) (50mg, 40%).
LCMS m/z＝395[M+1]+。
The third step is trans-3- [ [ [2- (benzyloxymethyl) -3- [4- (cyanomethyl) cyclohexyl ] imidazo [4,5-b ] pyridin-5-yl ] amino ] -5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (2c)
trans-tert-butyl3-[[2-(benzyloxymethyl)-3-[4-(cyanomethyl)cyclohexyl]imidazo[4,5-b]pyridin-5-yl]amino]-5-methy l-pyrazole-1-carboxylate
Reacting trans-2- [4- [2- (benzyloxymethyl) -5-chloro-imidazo [4,5-b ]]Pyridin-3-yl]Cyclohexyl radical]Acetonitrile (2b) (16mg,0.041mmol) and 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (7.72mg,0.039mmol) were dissolved in 1,4-dioxane (2mL) and Pd was added2(dba)3(2.60mg,0.0028mmol),Brettphos(2.80mg,0.0052mmol),Cs2CO3(17mg,0.052mmol) of the mixture in N2The reaction was protected at 100 ℃ overnight and TLC indicated completion. The mixture was added with water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution method: dichloromethane: methanol ═ 100:1-50:1) to give trans-3- [ [ [2- (benzyloxymethyl) -3- [4- (cyanomethyl) cyclohexyl ] amino acid]Imidazo [4,5-b ]]Pyridin-5-yl]Amino group]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (2c) (16mg, 71%).
LCMS m/z＝556[M+1]+。
The fourth step: trans-2- [4- [ (3R) -2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile; 2,2, 2-Trifluoroacetate (Compound 2)
Trans-2-[4-[(3R)-2-(hydroxymethyl)-5-[(5-methyl-1H-pyrazol-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]cyclohexyl]acetonitrile；2,2,2-trifluoroacetic acid
Tert-butyl trans-3- [ [ [2- (benzyloxymethyl) -3- [4- (cyanomethyl) cyclohexyl ] imidazo [4,5-b ] pyridin-5-yl ] amino ] -5-methyl-pyrazole-1-carboxylate (2c) (16mg,0.029mmol) was dissolved in dichloromethane (2mL), replaced with nitrogen, and a solution of boron tribromide (36mg,0.15mmol) in dichloromethane (1mL) was slowly added dropwise in an ice bath, and after completion of dropwise addition, the reaction was carried out at room temperature for 5 min. The reaction was then quenched with methanol (1mL) in ice bath, adjusted to pH 7-8 with triethylamine, concentrated under reduced pressure to give a residue, which was purified by Pre-HPLC (instrument and preparative column: liquid phase prepared using Gilson Gx-281, model Sunfire, 5 μm, internal diameter x length 30mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). Gradient elution method: eluting acetonitrile with 10% gradient 60% (elution time 16min), and lyophilizing to obtain trans-2- [4- [ (3R) -2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] imidazo [4,5-b ] pyridin-3-yl ] cyclohexyl ] acetonitrile; 2,2, 2-Trifluoroacetate (Compound 2) (5mg, 36%).
LCMS m/z＝366[M+1]+。
1H NMR(400MHz,CD3OD)δ7.89(d,1H),7.11(d,1H),6.46(s,1H),5.07(s,2H),4.57-4.44(m,1H),2.91-2.78(m,2H),2.53(d,2H),2.35(s,3H),2.18-2.05(m,4H),2.03-1.86(m,1H),1.53-1.36(m,2H)。
Example 3: trifluoroacetate salt of Trans-4- (2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] -3H-imidazo [4,5-b ] pyridin-3-yl) adamantan-1-ol (Compound 3)
Trans-4-(2-(hydroxymethyl)-5-[(5-methyl-1H-pyrazol-3-yl)amino]-3H-imidazo[4,5-b]pyridin-3-yl)adamantan-1-ol trifluoroacetate
Compound 3 the trifluoroacetate salt of Trans-4- (2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] -3H-imidazo [4,5-b ] pyridin-3-yl) adamantan-1-ol (Compound 3) was obtained by the synthesis method of example 2 starting with hydrochloride of 2, 6-dichloro-3-nitropyridine (1a) and Trans-4-amino-1-hydroxyadamantane (Compound 3)
LCMS m/z＝395.2[M+1]+
1H NMR(400MHz,CD3OD)δ7.89(d,1H),7.14(d,1H),6.12(s,1H),5.08(s,2H),4.78-4.76(m,1H),3.03-2.96(m,2H),2.42-2.35(m,2H),2.31(s,3H),2.19-2.14(m,1H),2.09-2.02(m,2H),1.95-1.89(m,2H),1.85-1.80(m,2H),1.60-1.52(m,2H).
Example 4: trifluoroacetate salt of Cis-4- (2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] -3H-imidazo [4,5-b ] pyridin-3-yl) adamantan-1-ol (Compound 4)
Cis-4-(2-(hydroxymethyl)-5-[(5-methyl-1H-pyrazol-3-yl)amino]-3H-imidazo[4,5-b]pyridin-3-yl)adamantan-1-ol trifluoroacetate
Compound 4 starting with 2, 6-dichloro-3-nitropyridine (1a), Cis-4-amino-1-hydroxyadamantane hydrochloride, the synthesis of Cis-4- (2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] -3H-imidazo [4,5-b ] pyridin-3-yl) adamantan-1-ol (Compound 4) was carried out according to the method of example 2 to give the trifluoroacetate salt of Cis-4- (2- (hydroxymethyl) -5- [ (5-methyl-1H-pyrazol-3-yl) amino ] -3H-imidazo [4,5-b ] pyridin-3-yl) adamantan-1-ol (Compound 4)
LCMS m/z＝395.2[M+1]+
1H NMR(400MHz,CD3OD)δ7.90(d,1H),7.31(d,1H),6.08(s,1H),5.08(s,2H),4.69-4.65(m,1H),3.05-2.97(m,2H),2.60-2.53(m,2H),2.32(s,3H),2.28-2.23(m,1H),2.06-1.97(m,2H),1.96-1.88(m,2H),1.84-1.79(m,2H),1.73-1.65(m,2H).
Biological test example
Test example 1: inhibitory Activity against JAK1, JAK2, JAK3 and Tyk2 kinase
The detection was carried out using HTRF KinEASE-TKkit (cat # 62TK0PEC) from Cisbio as follows:
diluting the compound with 1x kinase buffer to 2.5 times the final concentration; the enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15. mu.g/mL, 0.185. mu.g/mL, 1.665. mu.g/mL and 5. mu.g/mL, respectively; ATP was diluted to 19.6. mu.M (JAK1), 19.8. mu.M (JAK2), 7.15. mu.M (JAK3) and 25.3. mu.M (Tyk2), respectively; TK Substrate-biotin stock was diluted to 10. mu.M.
10 μ L of kinase reaction with 1x kinase buffer: example Compounds or 1x kinase buffer 4. mu.L + TK Substrate-biotin 2. mu.L + enzyme 2. mu.L + ATP 2. mu.L, mixed and incubated at room temperatureAfter incubation for 2 hours (JAK1), 30 minutes (JAK2 vs JAK3) or 50 minutes (Tyk2), 5. mu.L of Streptavidin-XL665(500nM) and 5. mu.L of TK Antibody-cryptate (1X) were added and incubation continued at room temperature for 1 hour. The fluorescence values at 665nm and 620nm were measured with a microplate reader (PHERAstar FSX). Signal Ratio was calculated according to equation (1), and IC was calculated and analyzed using Origin 9.250。
Ratio＝[Signal665]/[Signal620]*104Formula (1)
The inhibitory activity of the compounds of the present invention, JAK1, JAK2, JAK3 and Tyk2 kinase, was determined by the above experiment.
TABLE 1 inhibitory Activity of Compounds against JAK1, JAK2, JAK3 and Tyk2 kinase
And (4) conclusion: the compounds of the invention have inhibitory effects on JAK1, JAK2, JAK3 and Tyk2 kinase.
Claims (12)
1. A compound or a stereoisomer, a tautomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, the compound being selected from a compound represented by the general formula (I), wherein,
l is selected from a bond or NRn2；
Rn1、Rn2Each independently selected from H, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF3OH, cyano, NH2、C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
ring A is selected from 8-10 membered fused heteroaromatic rings optionally further substituted with 0 to 3Ra(ii) substituted, said heteroaromatic ring containing 1 to 5 heteroatoms selected from O, S, N;
Raeach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
ring B is selected from non-aromatic C3-12Carbocycle, said carbocycle is optionally selected from monocyclic, fused, bridged or spiro ring, said carbocycle, monocyclic, fused, bridged or spiro ring is optionally further substituted with 0 to 3RbSubstituted by a substituent;
Rbeach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1selected from 5 to 10 membered heteroaryl or phenyl, optionally further substituted with 0 to 4R1aSubstitution;
R1aeach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected from H, C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0,1, 2, 3 or 4.
2. The compound of claim 1, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein compound is selected from formula (Ia),
X1、X2、X3or X4Each independently selected from CH, C or N, Y, Z each independently selected from C or N;
provided that X is1、X2、X3、X4Y, Z at least 1 is selected from N;
when the N atom in ring C is attached to L, L is selected from a bond;
when the C atom in the ring C is connected with L, L is selected from NH;
ring C is selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N or a benzene ring;
Raeach independently selected from H, halogen, cyano, OH, C1-6Alkyl radical, C1-6Alkoxy, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2、-(CH2)qNRa1C(＝O)-Ra2、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
p is selected from 0,1, 2 or 3;
ring B is selected from C3-8Monocycloalkyl radical, C4-10And cycloalkyl group, C4-12Spiro cycloalkyl, C5-12Bridged cycloalkyl, said cycloalkyl being optionally substitutedOne step by 0 to 3RbSubstituted by a substituent;
Rbeach independently selected from H, halogen, cyano, OH, C1-6Alkyl or C1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1is selected from
Or R1Is selected from
R1aEach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
m is selected from 0,1 or 2;
R1beach independently selected from C1-6Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl radical, C1-6Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 12 membered heterocycle, said-CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected from H, C1-6Alkyl radical, C3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-6Alkyl radical, C3-12Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or C1-6Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0,1, 2, 3 or 4.
3. The compound of claim 2, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
R1aeach independently selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-4Cycloalkyl), C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1beach independently selected from C1-4Alkyl radical, C3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
ring C is selected from a 5-6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, N or a benzene ring;
p is selected from 0,1 or 2 or 3;
Raeach independently selected from H, halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C3-6Carbocyclic ring or- (CH)2)q-3 to 6 membered heterocycle, - (CH)2)q-C(＝O)-NRa1Ra2、-(CH2)q-NRa1Ra2Or- (CH)2)qNRa1C(＝O)-Ra2said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Rbeach independently selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl radical, C1-4Alkoxy or C3-4Cycloalkyl, substituted with a substituent;
R2selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)q-C(＝O)-R2a、-(CH2)q-C(＝O)O-R2a、-(CH2)q-S(＝O)2-R2a、-(CH2)q-NR2aS(＝O)2-R2b、-(CH2)q-C(＝O)-NR2aR2b、-(CH2)q-NR2aR2b、-(CH2)qNR2aC(＝O)-R2b、-(CH2)q-C3-10Carbocyclic ring or- (CH)2)q-3 to 10 membered heterocycle, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
Ra1、Ra2、R2a、R2beach independently selected from H, C1-4Alkyl radical, C3-10Carbocyclyl or 3 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-NH(C3-6Cycloalkyl), C1-4Alkyl radical, C3-8Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
4. The compound of claim 3, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
R1aeach independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R1beach independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2Halogen-substituted C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
ring C is selected from pyrazole ring, thiazole ring, imidazole ring, oxazole ring, thiophene ring, furan ring, pyrrole ring, isoxazole ring, isothiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring or benzene ring;
the ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexylcyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylpropenyl, cyclohexylspirocyclohexyl, bicyclo [ 1.1.1.1]Pentyl alkyl, bicyclo [2.1.1]Hexane radical, bicyclo [2.2.1 ]]Heptylalkyl, bicyclo [3.3.2]Decyl, bicyclo [2.2.2]Octyl radical, bicyclo [ alpha ], [ beta ], [ alpha ], [ beta ]3.2.1]Octyl, bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3 substituents selected from H, halogen, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Carbocyclic, 3-to 6-membered heterocyclic, -CH2-C3-6Carbocyclic ring, -CH2-3 to 6 membered heterocycle, -NH-C3-6Carbocyclic, -NH-3 to 6 membered heterocyclic ring or-NHC1-4Alkyl, said-CH2-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH2、C1-4Alkyl, halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N.
5. The compound of claim 4, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
ring B is selected from
R2selected from F, cyano, OH, -OCH3Methyl, ethyl, CF3、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2CH2CH2CH2CN、-NHCH2CN、-NHCH2CH2CN、-NHCH2CH2CH2CN、-NHCH2CH2CH2CH2CN、
In the general formula (Ia)
Is selected from
Left side with-NH-R1Direct connection, right side is connected with L directly;
R1is selected from
RaEach independently selected from H, F, cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (═ O) NH2、-C(＝O)NHCH3、-C(＝O)NHCH2CH3-C (═ O) NH-cyclopropyl, -C (═ O) NH-cyclobutyl, -C (═ O) NH-cyclopentyl, -C (═ O) NH-cyclohexyl, -C (═ O) NH-phenyl, -NHC (═ O) H, -NHC (═ O) CH-phenyl3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl,the methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidyl or phenyl are optionally further substituted by 0 to 4 groups selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
6. The compound of claim 5, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
ring B is selected from
Right side and R2Direct connection;
R2selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN；
In the general formula (Ia)
Is selected from
R1is selected from
7. The compound of claim 6, or a stereoisomer, tautomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from (Ia-1), (Ia-2), (Ia-3) or (Ia-4),
wherein the content of the first and second substances,
ring B is selected from
Right side and R2Direct connection;
R2selected from F, OH, CN, -OCH3、-CH2OH、-CH2CN、-CH2CH2CN、-NHCH2CN、-NHCH2CH2CN；
R1Is selected from
RaEach independently selected from H, F, CF3Cyano, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NH-Ph-CH2F、-CH2C(＝O)NH-Ph-CHF2、-CH2C(＝O)NH-Ph-CF3、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2-cyclopentyl, -CH2C(＝O)NHCH2-cyclohexyl, -CH2C(＝O)NHCH2CH2NH2、-CH2C(＝O)NHCH2CH2NHCH3、-CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2、-NHC(＝O)H、-NHC(＝O)CH3、-NHC(＝O)CH2CH3、-NHC(＝O)CH2CH2CH3-NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl, -NHC (═ O) -cyclohexyl or-NHC (═ O) -phenyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isoxazolyl, isothioenyl, pyridyl, pyrimidinyl or phenyl being optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy.
8. The compound of claim 7, or a stereoisomer, tautomer, deutero-derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from (Ib-1),
wherein the content of the first and second substances,
ring B is selected from
Right side and R2Direct connection;
R2selected from CN, -CH2CN、-CH2CH2CN；
R1Is selected from
RaEach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, -CH2NHCH2CH2CN、-CH2NHCH2CN、-CH2NHCH2CH2CH2CN、-CH2C(＝O)NH-Ph-CH2OH、-CH2C(＝O)NH-Ph-CH2CN、-CH2C(＝O)NHCH2-cyclopropyl, -CH2C(＝O)NHCH2-cyclobutyl, -CH2C(＝O)NHCH2CH2N(CH3)2、-CH2C(＝O)NHCH2CH2N(CH2CH3)2-NHC (═ O) -cyclopropyl or-NHC (═ O) -cyclobutyl, said methyl, ethyl, pyrazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl optionally further substituted by 0 to 2 substituents selected from H, F, CF3OH, cyano, NH2Methyl, ethyl, methoxy or ethoxy;
Rceach independently selected from H, F, CF3OH, cyano, methyl, ethyl, methoxy, ethoxy,
9. The compound of claim 1, or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:
10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.
11. Use of a compound according to any one of claims 1-9, or a stereoisomer, tautomer, deutero-solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with JAK kinase activity or expression.
12. The use according to claim 11, wherein the disease is selected from inflammatory diseases.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114746413A (en) * | 2019-11-29 | 2022-07-12 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
| WO2022184130A1 (en) * | 2021-03-03 | 2022-09-09 | 成都先导药物开发股份有限公司 | Nuak inhibitor and use thereof |
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2021
- 2021-07-30 CN CN202110860850.9A patent/CN114057733A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114746413A (en) * | 2019-11-29 | 2022-07-12 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
| CN114746413B (en) * | 2019-11-29 | 2024-02-23 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
| WO2022184130A1 (en) * | 2021-03-03 | 2022-09-09 | 成都先导药物开发股份有限公司 | Nuak inhibitor and use thereof |
| CN115141195A (en) * | 2021-03-03 | 2022-10-04 | 成都先导药物开发股份有限公司 | NUAK inhibitor and application thereof |
| CN115141195B (en) * | 2021-03-03 | 2024-02-06 | 成都先导药物开发股份有限公司 | NUAK inhibitor and application thereof |
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