CN115785083A - Cathepsin C small-molecule inhibitor and preparation method thereof - Google Patents
Cathepsin C small-molecule inhibitor and preparation method thereof Download PDFInfo
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- CN115785083A CN115785083A CN202211691228.0A CN202211691228A CN115785083A CN 115785083 A CN115785083 A CN 115785083A CN 202211691228 A CN202211691228 A CN 202211691228A CN 115785083 A CN115785083 A CN 115785083A
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Abstract
The disclosure relates to a cathepsin C small-molecule inhibitor and a preparation method thereof, in particular to amide nitrile compounds shown as a formula I, which have certain cathepsin C inhibition effect.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a cathepsin C small-molecule inhibitor and a preparation method thereof.
Background
Cathepsins are a class of proteolytic enzymes that are widely present in a variety of tissue cell lysosomes, and are classified according to their structure and catalytic type into serine proteases (cathepsins a and G), aspartic proteases (cathepsins D and E), and cysteine protease 3 classes. Among them, cysteine proteases are the largest cathepsin family, including 11 proteases, cathepsin B, C, F, H, K, L, O, S, W, V and Z.
Cathepsin C (cathepsin C) is also known as dipeptidyl peptidase i or "DPPI", DPP1 is constitutively expressed in many tissues, with highest levels in the lung, kidney, liver and spleen. Some recently published studies have begun to describe the role cathepsin C plays in certain inflammatory processes. For example: j Clin invest.2002Feb, adkison et al; 109 363-71; 160-170, archives of Biochemistry and Biophysics, 2002, published by Tinh et al; from these studies, cathepsin C is co-expressed with certain serine proteases in granules and serves to process the precursor forms of these proteases into active forms, which are then released from the granules of inflammatory cells recruited to the site of inflammation. Once activated, these proteases have a number of functions, including degradation of various extracellular matrix components, which together can spread tissue damage and chronic inflammation.
WO 2004/110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.
WO 2009/074829 relates to peptidyl nitriles and their use as DPP1 inhibitors.
WO 2010/128324 relates to α -aminoamide nitriles and their use as DPP1 inhibitors.
WO 2012/119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.
WO 2013/041497 relates to N- [ 1-cyano-2- (phenyl) ethyl ] -2-azabicyclo [2.2.1] heptane-3-carboxamide and its use as DPP1 inhibitor.
WO 2001/096285 and WO 2003/048123 relate to beta-aminoamide nitriles having inhibitory activity against cysteine proteases.
WO 2015/110826 relates to α -amino amide nitriles and their use as DPP1 inhibitors.
However, the amide nitriles of formula I of this disclosure are not disclosed in any literature.
Disclosure of Invention
The disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof
Wherein
A is C 1-6 Alkylene of (a), said C 1-6 Optionally substituted with one or more deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a Substitution;
b is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, said 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b Substitution;
R 1 independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5e Substitution;
n is an integer from 0 to 3;
R 2 selected from deuterium, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
R 3 is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkene oxideBase, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy, or a fused ring, optionally substituted with one or more R 5c Substituted;
or R 3 And R 2 Form a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, said 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with one or more deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution;
or R 3 And R 2 Form a 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl, said 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl with C 6-10 Aryl or 5-10 membered heteroaryl fused to form a fused ring, said fused ring optionally substituted with 1-3R 5d Is substituted by
R 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-to 10-membered aryl or 5-to 10-membered heteroaryl, methanesulfonyl, methyl ethyl phenyl,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl;
R 5a independently selected from halogenElement, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl, 5-10 membered heteroaryl, or methanesulfonyl;
R 5b independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl;
R 5c independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl;
R 5e independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl;
* The carbon atom is labeled with S or R.
In some embodiments, a is C in a compound of formula I or a pharmaceutically acceptable salt thereof 1-6 Alkylene of (a), said C 1-6 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amidoAcyl group, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, a is C in a compound of formula I or a pharmaceutically acceptable salt thereof 1-4 Alkylene of (a), said C 1-4 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, a is C in a compound of formula I or a pharmaceutically acceptable salt thereof 1-4 Alkylene of (b), said C 1-4 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, a in the compound of formula I or a pharmaceutically acceptable salt thereof is methylene optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, a is C in a compound of formula I or a pharmaceutically acceptable salt thereof 1-4 Alkylene of (a), said C 1-4 Is optionally substituted by oneOne or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxy, oxo, nitro, cyano, amino substitutions; the methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, a in the compound of formula I or a pharmaceutically acceptable salt thereof is methylene optionally substituted with one or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxy, oxo, nitro, cyano, amino; the methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl is optionally substituted with 1-3R 5a And (4) substitution.
In some embodiments, B in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, said 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b And (4) substitution.
In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, B is selected from 3-15 membered heterocycloalkyl, said 3-15 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b And (4) substitution.
In some embodiments, B is selected from 3-15 membered heterocycloalkyl in the compounds of formula I or pharmaceutically acceptable salts thereof, said 3-15 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, B is selected from 3-15 membered heterocycloalkyl containing 1-3 heteroatoms, said 3-15 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b Substitution; the heteroatom is selected from a nitrogen atom or an oxygen atom.
In some embodiments, B is selected from 5-10 membered heterocycloalkyl containing 1-3 heteroatoms, said 5-10 membered heterocycloalkyl optionally substituted with 1-3 heteroatoms selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b Substitution; the heteroatom is selected from a nitrogen atom or an oxygen atom.
In some embodiments, B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl-substituted
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl-substituted
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl-substituted
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxyCycloalkenyloxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl condensed to form a condensed ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings optionally substituted with one or more R 5c Substituted;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl condensed to form a condensed ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy or fused ring optionally substituted with one or more R 5c Substituted;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy or
Is substituted by C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy optionally substituted with one or more R 5c Substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said fused ring optionally substituted with one or more R 5c And (4) substituting.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a 6-10 membered fused ring, said 6-10 membered fused ring optionally substituted with one or more R 5c And (4) substituting.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl radical, said C 6-10 Aryl is fused to a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms to form a 6-10 membered fused ring, said 6-10 membered fused ring optionally substituted with one or more R 5c And (4) substituting.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 Is selected from C 6-10 Aryl radical, said C 6-10 Aryl is fused with a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms to form a 6-10 membered fused ring, said 6-10 membered fused ring optionally substituted with one or more R 5c Substituted; the heteroatoms are independently selected from nitrogen atoms, oxygen atoms.
The disclosure also provides a compound of formula II or a pharmaceutically acceptable salt thereof
Of which A, B, R 1 、n、R 5c As defined in formula I;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
X 1 、X 2 independently selected from nitrogen atom, oxygen atom, sulfur atom; preferably X 1 、X 2 Independently selected from nitrogen atom, oxygen atom; more preferably X 1 Is an oxygen atom, X 2 Is a nitrogen atom.
In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 2 Selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl optionally substituted by 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
preferably R 2 Selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro;
more preferably R 2 Selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 And R 2 Form a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, said 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with 1-3 deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 And R 2 Form a 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl, said 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl being optionally substituted with 1-3 deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 And R 2 Form a 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl, said 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl with C 6-10 Aryl or 5-10 membered heteroaryl fused to form a fused ring, said fused ring optionally substituted with 1-3R 5d And (4) substitution.
The disclosure also provides a compound of formula III or a pharmaceutically acceptable salt thereof
Of which A, B, R 1 、n、R 5d As defined in claim 1;
X 3 、X 4 independently selected from nitrogen atom, oxygen atom, sulfur atom, carbon atom; preferably X 3 、X 4 Independently selected from nitrogen atom, oxygen atom, carbon atom; preferably X 3 、X 4 Independently selected from oxygen atoms, carbon atoms; more preferably X 3 Is an oxygen atom, X 4 Is a carbon atom.
In some embodiments, the configuration of the carbon atom marked by the symbol in formula I, formula II, formula III is S, in particular the structure of the compound shown in formula IV, V, VI:
in some embodiments, R in a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof 1 Independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, C 1-6 An alkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy is optionally substituted with 1-3R 5e Substitution;
preferably R 1 Independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy is optionally substituted with 1-3R 5e And (4) substitution.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI or a pharmaceutically acceptable salt thereof 5a Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acylAmide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof 5a Independently selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI or a pharmaceutically acceptable salt thereof 5a Independently selected from halogen, deuterium, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof 5a Independently selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclopropyl.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI or a pharmaceutically acceptable salt thereof 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
In some embodiments, R in a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
In some embodiments, formulas I, II, III, IV, VOr R in the compound shown in VI or the pharmaceutically acceptable salt thereof 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, methyl, ethyl, n-propyl, cyclopropyl.
In some embodiments, R in a compound of formula I, II, IV or V, or a pharmaceutically acceptable salt thereof 5c Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, methanesulfonyl.
In some embodiments, R in the compound of formula I, II, IV or V, or a pharmaceutically acceptable salt thereof 5c Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, methanesulfonyl.
In some embodiments, R in the compound of formula I, II, IV or V, or a pharmaceutically acceptable salt thereof 5c Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, methyl, ethyl, cyclopropyl, methylcyclopropyl, methanesulfonyl.
In some embodiments, R in a compound of formula I, III, V, or VI or a pharmaceutically acceptable salt thereof 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl, or a pharmaceutically acceptable salt thereof,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy is optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, R in a compound of formula I, III, V, or VI, or a pharmaceutically acceptable salt thereof 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, methanesulfonyl,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, R in a compound of formula I, III, V, or VI, or a pharmaceutically acceptable salt thereof 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, R in a compound of formula I, III, V, or VI, or a pharmaceutically acceptable salt thereof 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
In some embodiments, R in a compound of formula I, III, V, or VI or a pharmaceutically acceptable salt thereof 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, methyl, ethyl, cyclopropyl, propyl, said methyl, ethyl, cyclopropyl, propyl being optionally substituted with 1-3 groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, R in a compound of formula I, III, V, or VI, or a pharmaceutically acceptable salt thereof 5e Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3 to6-membered heterocyclic alkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl.
In some embodiments, R in a compound of formula I, III, V, or VI or a pharmaceutically acceptable salt thereof 5e Independently selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
In some embodiments, R in a compound of formula I, III, V, or VI, or a pharmaceutically acceptable salt thereof 5e Independently selected from halogen, deuterium, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
In some embodiments, R in a compound of formula I, III, V, or VI or a pharmaceutically acceptable salt thereof 5e Independently selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclopropyl.
Typical compounds of formula I, or pharmaceutically acceptable salts thereof, include, but are not limited to:
the present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof, or prepared by the foregoing methods, and a pharmaceutically acceptable excipient.
In some embodiments, the unit dose of the pharmaceutical composition is 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises from 0.01 to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.
The present disclosure also provides a method of preventing and/or treating a patient having a disorder associated with cathepsin C by administering to the patient a therapeutically effective amount of a compound as shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.
In some embodiments, the cathepsin C-related disorders include, but are not limited to, respiratory diseases such as asthma, obstructive pulmonary disease, bronchiectasis, and the like, and autoimmune diseases such as ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.
The present disclosure also provides a method of preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis in a patient by administering to the patient a therapeutically effective amount of a compound as shown in formula I, II, III, IV, V or VI, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.
The present disclosure also provides a use of a compound as shown in formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the prevention and/or treatment of a disorder associated with cathepsin C.
The disclosure also provides use of a compound as shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, antitrypsin a deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis.
The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.
The disclosed compounds may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
In the chemical structure of the compound of the present invention, a bond
Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure
Can be that
Or
Or at the same time contain
And
two configurations. In the chemical structure of the compounds described in the present disclosure, a bond
The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.
Although all of the above structural formulae are drawn as certain isomeric forms for the sake of simplicity, the present invention may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
Tautomers are structural isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction often results in formal migration of hydrogen atoms or protons, with the concomitant conversion of single and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactam equilibrium is between A and B as shown below.
All compounds of the present invention can be drawn as form a or form B. All tautomeric forms are within the scope of the invention. The naming of the compounds does not exclude any tautomers.
Any isotopically-labeled derivative of a compound described in this disclosure or a pharmaceutically acceptable salt thereof, or an isomer thereof, is encompassed by this disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. Each of which can be isotopically-labelled 2 H(D)、 3 H、 11 C、 13 C、 14 C、 15 N、 18 F、 31 P、 32 P、 35 S、 36 Cl, 125I and the like. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).
The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, tri-deuterated boranes tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.
Optionally "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. For example "C optionally substituted by halogen or cyano 1 -C 6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
Interpretation of terms:
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
An "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy、C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C 2-6 Alkenyl "denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl groups. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected fromHalogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, are substitutedThe substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7A ring atom. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
the heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring joined together with the parent structure is heterocycloalkyl, non-limiting examples of which include:
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,
and so on.
The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more ofA group independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are as defined above for "alkoxy".
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" refers to the = O substituent.
"monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "subunit" refers to a compound that "formally" eliminates two monovalent or one divalent formed atoms or groups of atoms. Examples "alkyl" refers to the moiety remaining after removal of 1 hydrogen atom from an alkane molecule, and includes straight and branched chain monovalent groups of 1 to 20 carbon atoms. "alkylene (-CH) 2 - "then denotes the remaining part of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. Alkylene groups having 1 to 6 carbon atoms, non-limiting examples of which include methylene (-CH) 2 -), ethylene (e.g. -CH) 2 CH 2 -or-CH (CH) 3 ) -), propylene (e.g. -CH) 2 CH 2 CH 2 -or-CH (CH) 2 CH 3 ) -) butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -). The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and are conventional reagents purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 The units in (ppm) are given. NMR was measured by Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated Methanol (Methanol-d) 4 ) Internal standard is Tetramethylsilane (TMS).
The HPLC assay used an Agilent1100 high pressure liquid chromatograph, GAS15B DAD uv detector, water Vbridge C18 x 4.6mm 5um column.
MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, waters Xbridge C184.6 x 50mm,5um chromatography column, scanning in positive/negative ion mode with a mass scan range of 80-1200.
The silica gel plate for thin layer chromatography is HSGF254 silica gel plate from yellow sea of cigarette platform, and the specification for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification for thin layer chromatography separation and purification product is 0.4mm-0.5mm.
The flash column purification system used either Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of Taiwan yellow sea as carrier, or uses the ultra-pure forward phase silica gel column (40-63 μm,60g,24g,40g,120g or other specifications) pre-filled by Santai in Changzhou.
Known starting materials in this disclosure can be synthesized by or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoshi Chemical technology (Accela ChemBio Inc), biddy medicine, and the like.
The reactions can all be carried out under a nitrogen atmosphere without specific reference in the examples.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogen was produced by QPH-1L model hydrogen generator, shanghai Quanpu scientific instruments.
The nitrogen atmosphere or the hydrogen atmosphere is usually evacuated, and nitrogen or hydrogen is charged, and the operation is repeated 3 times.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC).
Example 1
Synthesis of Compound 2
(S) -2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) acetic acid (62mg, 0.27mmol), N, N-diisopropylethylamine (143mg, 1.10mmol) and the solvent N, N-dimethylformamide (3 mL) were charged into a 25mL eggplant-shaped flask at 15 ℃. O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (124mg, 0.327mmol) was added continuously at 15 ℃. After stirring for 5 minutes, a solution of Compound 1 (80mg, 0.273 mmol) in N, N-dimethylformamide (0.5 mL) was added. After 5 hours reaction at 15 ℃ water (20 mL) was added and extraction was carried out with ethyl acetate (3X 10 mL). The extract was washed with saturated brine (15 mL. Times.1) and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and purifying the residue by column chromatography (SiO) 2 50% ethyl acetate/petroleum ether) to give compound 2 (90 mg). MS (ESI) M/z =449.4 (M + H-56) + 。
Synthesis of example 1
To a 10mL three-necked flask, compound 2 (80mg, 0.16mmol) and formic acid (1.5 mL) were added at 15 ℃. Stirring was carried out at 30 ℃ for 0.5 hour. Concentration and purification of the residue on a C18 reverse phase column (30-80%, acetonitrile/water (0.1% ammonium bicarbonate) system) gave example 1 (25 mg). MS (ESI) M/z =405.1 (M + H) + 。
1 H NMR(400MHz,DMSO-d 6 ):δ7.66(d,J＝8.0Hz,2H),7.57(s,1H),7.42-7.38(m,4H),4.99(t,J＝8.0Hz,1H),3.40(s,3H),3.22-3.06(m,4H),2.81-2.75(m,1H),2.71-2.63(m,1H),2.25-2.11(m,2H),1.71-1.48(m,3H),1.16-1.04(m,1H).
Biological evaluation
The present disclosure is further described and explained below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.
Test example 1In vitro CatC enzyme Activity detection assay
1. Experimental materials
Control drug AZD7986
The specific synthesis method can refer to the preparation method in CN105980367 for preparation:
2. experimental procedure
The inhibition of the rhCatC in vitro enzyme activity by the compound and the positive control was evaluated by AMC fluorescence assay. The rhCatC can catalyze the reaction of a substrate peptide fragment H-Gly-Arg-AMC and release AMC to generate fluorescence. The assay was performed in 384 well black-backed plates, starting at a maximum concentration of typically 30uM, and enzyme activity was tested by 8-point semilogarithmic dilution. 1) Preparation of test compound plates: test compounds and positive control AZD7986 were dissolved in 100% DMSO to make up a stock solution of compound at a final concentration of 10 mM. Compounds were diluted with DMSO into 384-well Echo plates at 100X of the highest concentration at the start of the experiment. 0.2ul of the diluted compound was transferred to a 384-well black-bottomed plate and prepared for use. Negative control wells were DMSO.
2) Activating rhCatC: rhCatC and rhCatL were added to the activation buffer to give a final rhCatC concentration of 100ug/ml and a final rhCatL concentration of 20ug/ml, and incubated at room temperature for 1 hour. 3) Enzyme activity reaction: activated rhCatC was diluted to 0.4ug/ml with reaction buffer. Add black-bottom 384-well plates, 10ul per well. The blank control group was added with 10ul of buffer. Incubate with the compounds in the wells for 30 minutes at room temperature. H-Gly-Arg-AMC was diluted to 97uM with reaction buffer and 10ul was added per well. 4) Fluorescence detection: envision measured the fluorescence intensity, ex355 nM, em460nM. 5) Inhibition and IC50 calculation: inhibition ratio: formula (1) Inh% = (Max-Signal)/(Max-Min) × 100; IC50 value: formula (2) Y = Bottom + (Top-Bottom)/(1 + (IC 50/X) — HillSlope), where Y is% inhibition and X is compound concentration.
RLU data and calculated inhibition, and IC50 values were calculated from concentration and inhibition fitted curves, where the maximum is the reading of the DMSO control and the minimum is the reading of the no enzyme active control.
In vitro inhibition of CatC enzyme Activity by the examples of the present disclosure IC was determined by the above assay 50 The values are shown in Table 1.
TABLE 1
| Compound (I) | Biological Activity IC50 (nM) |
| Example 1 | 88 |
| AZD7986 | 7.4 |
。
Claims (54)
1. A compound of formula I or a pharmaceutically acceptable salt thereof
Wherein
A is C 1-6 Alkylene of (2), aC is 1-6 Optionally substituted with one or more deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a Substitution;
b is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, said 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b Substitution;
R 1 independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5e Substitution;
n is an integer from 0 to 3;
R 3 is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic alkoxyAlkyl, cycloalkenyloxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings optionally substituted with one or more R 5c Substituted;
R 2 selected from deuterium, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
or R 3 And R 2 Form a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, said 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with one or more deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution;
or R 3 And R 2 Form a 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl, said 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl with C 6-10 Aryl or 5-10 membered heteroaryl fused to form a fused ring, said fused ring optionally substituted with 1-3R 5d Substituted;
R 5d selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical,C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-to 10-membered aryl or 5-to 10-membered heteroaryl, methanesulfonyl, methyl ethyl phenyl,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl;
R 5a independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl, 5-10 membered heteroaryl or methanesulfonyl;
R 5b independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-to 10-membered aryl or 5-to 10-membered heteroaryl, methanesulfonyl;
R 5c independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl;
R 5e independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl;
* The carbon atom is labeled with S or R.
2. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is C 1-6 Alkylene of (a), said C 1-6 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
3. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is C 1-4 Alkylene of (a), said C 1-4 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
4. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is C 1-4 Alkylene of (a), said C 1-4 Optionally substituted with one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
5. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is methylene, optionally substituted by one or more deuterium, C 1-4 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy substitution; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3R 5a And (4) substitution.
6. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is C 1-4 Alkylene of (a), said C 1-4 Optionally substituted with one or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxy, oxo, nitro, cyano, amino; said methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl group being optionally substituted with 1-3R 5a And (4) substitution.
7. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is methylene optionally substituted with one or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxy, oxo, nitro, cyano, amino; the methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcycloPropyl is optionally substituted by 1-3R 5a And (4) substitution.
8. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, said 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b And (4) substitution.
9. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from 3-15 membered heterocycloalkyl, said 3-15 membered heterocycloalkyl being optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy or C 1-6 Alkoxy substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy or C 1-6 Alkoxy is optionally substituted with 1-3R 5b And (4) substitution.
10. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from 3-15 membered heterocycloalkyl, said 3-15 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
11. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from 3-15 membered heterocycloalkyl containing 1-3 heteroatoms, said 3-15 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b Substitution; the heteroatom is selected from a nitrogen atom or an oxygen atom.
12. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of 5-10 membered heterocycloalkyl containing 1-3 heteroatoms, said 5-10 membered heterocycloalkyl optionally substituted with 1-3 substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Cycloalkyl substitution; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b Substitution; the heteroatom is selected from a nitrogen atom or an oxygen atom.
13. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted by 1-3 substituents 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
14. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted by 1-3 substituents 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
15. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted by 1-3 substituents 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
16. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C, optionally substituted by 1-3 substituents 1-6 Alkyl radical, C 3-6 Cycloalkyl-substituted
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
17. A compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of optionally substituted by 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, amino, oxo, C 1-6 Alkyl radical, C 3-6 Substituted by cycloalkyl radicals
Said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted by 1-3R 5b And (4) substitution.
18. A compound as claimed in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings optionally substituted with one or more R 5c Substituted;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
19. A compound as claimed in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy or
Substituted, and/or said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy or fused ring optionally substituted with one or more R 5c Substituted;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
20. A compound as claimed in claim 18, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, amino, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy or
Is substituted by C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy optionally substituted with one or more R 5c Substituted;
R 4 independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.
21. A compound as claimed in claim 18, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-to 10-membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a fused ring, said fused ring optionally substituted with one or more R 5c And (4) substituting.
22. A compound as claimed in claim 18, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl with C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl fused to form a 6-10 membered fused ring, said 6-10 membered fused ring optionally substituted with one or more R 5c And (4) substituting.
23. A compound as claimed in claim 18, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl radical, said C 6-10 Aryl is fused with a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms to form a 6-10 membered fused ring, said 6-10 membered fused ring optionally substituted with one or more R 5c Substituted; the heteroatoms are independently selected from nitrogen, oxygen or sulfur atoms.
24. A compound as claimed in claim 18, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is selected from C 6-10 Aryl radical, said C 6-10 The aryl group being condensed with a 3-to 6-membered heterocycloalkyl group containing 1 to 3 hetero atoms 6-10 Condensed rings of elements, said 6-10 The condensed rings of the elements being optionally substituted by one or more R 5c Substituted; the heteroatoms are independently selected from nitrogen atoms, oxygen atoms.
25. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, which is
Of which A, B, R 1 、n、R 5c (ii) as defined in claim 1;
R 2 selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
X 1 、X 2 independently selected from nitrogen atom, oxygen atom, sulfur atom; preferably X 1 、X 2 Independently selected from nitrogen atom, oxygen atom; more preferably X 1 Is an oxygen atom, X 2 Is a nitrogen atom.
26. The compound of any one of claims 18-25, or a pharmaceutically acceptable salt thereof, wherein
R 2 Selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl optionally substituted by 1-3 of deuterium, halogen, cyano, nitro, C 3-6 Cycloalkyl radical, C 1-6 Alkyl substituted;
preferably R 2 Selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted with 1-3 of deuterium, halogen, cyano, nitro;
more preferably R 2 Selected from deuteriumHalogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino.
27. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein
R 3 And R 2 Form a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, said 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with 1-3 deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution.
28. A compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein
R 3 And R 2 Form a 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl, said 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl being optionally substituted with 1-3 deuterium, C 1-6 Alkyl, halogen, hydroxy, oxo, nitro, cyano, C 3-6 Cycloalkyl, amino, amido, acyl, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy substitution.
29. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein
R 3 And R 2 Form a 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl, said 5-to 10-membered cycloalkyl or 5-to 10-membered heterocycloalkyl with C 6-10 Aryl or 5-10 membered heteroaryl fused to form a fused ring, said fused ring optionally substituted with 1-3R 5d And (4) substitution.
30. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
Of which A, B, R 1 、n、R 5d (iii) as defined in claim 1;
X 3 、X 4 independently selected from nitrogen atom, oxygen atom, sulfur atom, carbon atom; preferably X 3 、X 4 Independently selected from nitrogen atom, oxygen atom, carbon atom; preferably X 3 、X 4 Independently selected from oxygen atoms, carbon atoms; more preferably X 3 Is an oxygen atom, X 4 Is a carbon atom.
31. The compound of any one of claims 1, 25, 30, or a pharmaceutically acceptable salt thereof, wherein the configuration of the carbon atom labeled in formula I, formula II, formula III is S.
32. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 1 Independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, amino, C 1-6 An alkoxy group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy is optionally substituted with 1-3R 5e Substitution;
preferably R 1 Independently selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group; said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy is optionally substituted with 1-3R 5e And (4) substitution.
33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R 5a Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl.
34. A compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereofWith a salt of formula wherein R 5a Independently selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
35. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R 5a Independently selected from halogen, deuterium, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
36. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R 5a Independently selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclopropyl.
37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R 5b Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R 5c Independently selected from halogen, deuterium, hydroxy, oxo,Nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, methanesulfonyl.
41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R 5c Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, methanesulfonyl.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl, or a pharmaceutically acceptable salt thereof,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy is optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, methanesulfonyl,
Said C is 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R 5d Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R 5e Independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, methylsulfonyl.
46. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R 5e Independently selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
47. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R 5e Independently selected from halogen, deuterium, nitro, cyano, C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
48. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R 5e Independently selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclopropyl。
49. A compound of structure according to claim 1 or a pharmaceutically acceptable salt thereof, selected from
50. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
51. A method of preventing and/or treating a patient having a disorder associated with cathepsin C by administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-49 or a pharmaceutical composition according to claim 50.
52. A method for preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis by administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 50.
53. Use of a compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 50, in the manufacture of a medicament for the prevention and/or treatment of a disorder associated with cathepsin C.
54. Use of a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 50, in the manufacture of a medicament for the prevention and/or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211691228.0A CN115785083A (en) | 2022-12-27 | 2022-12-27 | Cathepsin C small-molecule inhibitor and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211691228.0A CN115785083A (en) | 2022-12-27 | 2022-12-27 | Cathepsin C small-molecule inhibitor and preparation method thereof |
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