HK1153691A - Indazole derivatives - Google Patents
Indazole derivatives Download PDFInfo
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- HK1153691A HK1153691A HK11107954.6A HK11107954A HK1153691A HK 1153691 A HK1153691 A HK 1153691A HK 11107954 A HK11107954 A HK 11107954A HK 1153691 A HK1153691 A HK 1153691A
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Description
Technical Field
The present invention provides pharmaceutically active indazole compounds and analogs. The above compounds have Cannabinoid (CB)1 receptor binding activity. The invention also relates to pharmaceutical compositions, methods of treatment and uses comprising the above derivatives for the treatment of diseases mediated by CB1 receptor binding activity.
Background
Cannabinoid receptors, endocannabinoids and enzymes that synthesize and degrade endocannabinoids constitute the endocannabinoid system. CB1 and CB2 are two subtypes of cannabinoid receptors. CB1 and CB2 are both G protein-coupled receptors. CB1 receptors are found primarily in the central nervous system, but can also be found in several peripheral tissues including the pituitary gland, immune cells, reproductive tissues, gastrointestinal tissues, sympathetic ganglia, heart, lung, urinary bladder, and adrenal gland. The CB2 receptor is found primarily in immune cells. Cannabinoid agonists are said to be useful in the treatment of pain and several other signs.
There is a need to provide a novel CB1 ligand as a good candidate drug. They should be well absorbed from the gastrointestinal tract, metabolically stable and have favorable pharmacokinetic properties. In addition, the ideal drug candidate exists in a physical form that is stable, non-hygroscopic, and easily formulated.
Disclosure of Invention
The present invention relates to pharmaceutically active indazole compounds. The above compounds are useful as CB1 agonists.
The present invention relates in part to compounds falling generally within the structure of formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1is that
R4 1-5-aryl- (CH)2)n-or
R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently is H, halogen, cyano, or,
NH2-C(O)-、C1-C6Alkoxy-, trifluoromethyl or C1-C6alkoxy-C (O) -;
each R5Independently is H or C1-C6An alkyl group;
R2is that
NR11R12-C(O)-R13CH-、
R14-C(O)-NR15-(CH2)n-R13CH-、
R16-C(O)-R13CH-、
C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、
R20-SO2-NR21-(CH2)n-R13CH-、
R22R23CH-、
R24 1-5-a heteroaryl group,
R24 1-5-heteroaryl-R13CH-、
R24 1-5-heteroaryl-NR15-C(O)-R13CH-、
R25 1-5-a heterocyclic group,
R25 1-5-heterocyclyl- (CH)2)n-、
R26 1-5-C3-C7A cycloalkyl group, a,
NR27R28-(CH2)n-NR29-C(O)-R13CH-、
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、
R30-SO2-(CH2)n-NR31-C(O)-R13CH-、
R32-C(O)-R33CH-NR34-C(O)-R13CH-、
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、
R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl-C (O) -R13CH-、
R38 1-5-aryl-R39C-NR40-C(O)-R13CH-、
R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-、
R41 1-5-aryl- (CH)2)n-、
NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-, or
R43-CH(OH)-CH2-NR19-C(O)-R13CH-；
Wherein
R11And R12Independently H, OH, C1-C6Alkyl radical, C1-C6Haloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, (OH)3-C4-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, benzo-fused C3-C7Cycloalkyl, cyano-C1-C6Alkyl, NH2-C(NH)-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, OH-C3-C7cycloalkyl-C1-C6alkoxy-C (O) -C3-C7Cycloalkyl-, (C)1-C6Alkoxy-aryl) -C3-C7Cycloalkyl-, NH2-C(O)-C3-C7Cycloalkyl-, OH-aryl, or R24 1-5-heteroaryl-O- (CH)2)n-；
R13Is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R14is (C)1-C6Alkyl radical)2N-, aryl, C1-C6Alkyl, or C3-C7A cycloalkyl group;
R15、R21、R29、R31、R34and R40Independently is H or C1-C6An alkyl group;
R16is OH or C1-C6An alkoxy group;
R17and R18Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, or R24 1-5-heteroaryl-;
each R19Independently is H or C1-C6An alkyl group;
R20is C1-C6Alkyl radical, C1-C6Haloalkyl, or (C)1-C6Alkyl radical)2N-；
R22And R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、OH-C1-C6Alkyl, aryl, or aryl-OH-C1-C6An alkylene group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, OH, NH2、C1-C6alkoxy-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, OH-C1-C6alkyl-NH-C(O) -, or C3-C7cycloalkyl-C (O) -NH-;
each R25Independently is H or oxo;
each R26Independently is H, OH-C1-C6Alkyl, aryl- (CH)2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -;
R27and R28Independently is H, NH2-C(O)-、C3-C7cycloalkyl-C (O) -, or R24 1-5-heteroaryl-;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl, NH2、C1-C6alkyl-NH-, C3-C7Cycloalkyl- (CH)2)n-NH-, morpholin-4-yl, or R38 1-5-a phenyl group;
R32is OH or C1-C6Alkoxy-;
each R33Independently is H, C1-C6Alkyl, or OH-C1-C6An alkyl group;
each R35Independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -, C3-C7Cycloalkyl, OH, phenyl, or heteroaryl, or two adjacent R35Radicals may together form- (CH)2)3-6-；
Each R36Independently is H, C1-C6Alkyl radical, C1-C6Alkoxy-, or NH2-C(O)-；
Each R37Independently is H, NH2C (O) -, OH, halogen, cyano, oxo, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, NH2C(O)-(CH2)n-、NH2C(O)-(CH2)n-C(O)-、NH2C(O)-NH-(CH2)n-、C1-C6alkyl-NH-C (O) -O-, (OH) -C1-C6alkyl-NH-C (O) -, (OH)2-C1-C6alkyl-NH-C (O) -, C1-C6alkyl-C (O) -, C1-C6alkoxy-C (O) -, C3-C7cycloalkyl-C (O) -NH- (CH)2)n-、C1-C6alkyl-SO2-、C3-C7cycloalkyl-SO2-, or C3-C7cycloalkyl-SO2-NH-(CH2)n-；
Each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -, or C1-C6alkoxy-C (O) -;
each R39Independently is H, C1-C6Alkyl, or OH-C1-C6An alkyl group;
each R41Independently is H, C1-C6Alkoxy or halogen;
R42is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-or NH2-C(O)-CH2；
R43Is OH-C (O) -, C1-C6alkoxy-C (O) -, NH2-C (O) -or R44R45NCH2-; and
R44and R45Independently is C1-C6Alkyl or OH-C1-C6Alkyl, or
R44And R45Together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine or morpholine ring;
n is an integer from 1 to 6; and
each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl.
The invention also includes pharmaceutically acceptable salts, solvates, and hydrates. The invention also includes all tautomers and stereochemically isomeric forms of these compounds.
The invention also relates in part to a method for treating a CB1 mediated disorder in a mammal. The CB1 mediated disorders described above include pain, rheumatoid arthritis and osteoarthritis. Such methods comprise administering to the mammal an amount of a compound described above or a pharmaceutically acceptable salt thereof that is therapeutically effective for treating the above-described conditions.
Other benefits of the present invention will become apparent to those of ordinary skill in the art upon reading this specification.
Detailed Description
The invention will be more closely understood from the following description, which is given by way of example only. This invention relates to a class of indazole compounds. In particular, the present invention relates to indazole compounds useful as CB1 agonists. The present invention is not so limited and various aspects of the invention will be appreciated through the following discussion and examples given below.
Definition of
The definitions of various terms used herein are listed below:
symbolRepresenting a connection point.
The term "alkane" refers to a saturated acyclic hydrocarbon, which may be straight-chain or branched.
The term "alkyl" refers to a straight or branched chain monovalent radical derived from an alkane by the removal of one hydrogen. Examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl and the like.
The term "alkylene" refers to a straight or branched chain divalent group resulting from the removal of H from each of the two terminal carbons of an alkyl group. Examples include methyleneEthylene radicalPropylene radicalIsopropylideneAnd so on.
The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Examples of the above substituent include methoxy (CH)3-O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term "cycloalkyl" refers to a saturated carbocyclic substituent containing from 3 to about 20 carbon atoms. Cycloalkyl is a single ring or multiple fused rings. The above cycloalkyl group includes, for example: monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like; or polycyclic structures such as adamantyl and the like.
The term "aryl" refers to an aromatic carbocyclic group containing 6 to 14 carbon ring atoms. The term aryl encompasses monocyclic and polycyclic rings. Examples of aryl groups include phenyl, naphthyl, and indenyl.
The term "aralkyl" refers to an alkyl group substituted with an aryl group, wherein alkyl and aryl are as defined above.
The term "carboxy" or "carboxyl" refers to OH-c (o) -, which may also be represented as:
the term "formyl" refers to hc (o) -, which may also be represented as:
the symbol "C (O)" means C ═ O, which can also be represented as:
the term "oxo" refers to a keto group, which may be represented as ═ O.
The term "hydroxy" or "hydroxy" refers to OH-.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein hydroxyl and alkyl are as defined above.
The term "halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
The term "oxygen" refers to an ether substituent, which may be represented as-O-.
The term "sulfonyl" refers to SO2-。
The term "thio" refers to SH-.
The term "alkylthio" refers to an alkyl group substituted with a thio group, which may be represented as:
wherein thio and alkyl are as defined above.
The term "heterocyclyl" refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), wherein the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
A heterocyclyl group may be a monocyclic ring, which typically contains 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, and diazepinyl (diazepanyl).
The term "heteroaryl" refers to an aromatic heterocyclic group containing 5 to 14 ring atoms, which may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include isoxazolyl, pyridyl, furyl, oxadiazolyl, tetrazolyl, dihydroimidazolyl, thiadiazole, oxazolyl, triazolyl, and dihydroisoxazolyl.
The terms "substituent" and "group" are used interchangeably.
If a substituent is described as being "independently selected from" a group, each substituent is selected in a manner independent of the other substituents. Thus each substituent may be the same or different from the others.
The term "pharmaceutically acceptable" is used herein in the form of a adjective, which means that the modified noun is suitable for use as, or as part of, a pharmaceutical product.
Compounds of the invention
In a first embodiment, the present invention relates to a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1is that
R4 1-5-aryl- (CH)2)n-or
R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently of each other H, halogen, cyano, NH2-C(O)-、C1-C6Alkoxy-, trifluoromethyl or C1-C6alkoxy-C (O) -;
each R5Independently is H or C1-C6An alkyl group;
R2is that
NR11R12-C(O)-R13CH-、
R14-C(O)-NR15-(CH2)n-R13CH-、
R16-C(O)-R13CH-、
C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、
R20-SO2-NR21-(CH2)n-R13CH-、
R22R23CH-、
R24 1-5-a heteroaryl group,
R24 1-5-heteroaryl-R13CH-、
R24 1-5-heteroaryl-NR15-C(O)-R13CH-、
R25 1-5-a heterocyclic group,
R25 1-5-heterocyclyl- (CH)2)n-、
R26 1-5-C3-C7A cycloalkyl group, a,
NR27R28-(CH2)n-NR29-C(O)-R13CH-、
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、
R30-SO2-(CH2)n-NR31-C(O)-R13CH-、
R32-C(O)-R33CH-NR34-C(O)-R13CH-、
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、
R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl-C (O) -R13CH-、
R38 1-5-aryl-R39C-NR40-C(O)-R13CH-、
R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-、
R41 1-5-aryl- (CH)2)n-、
NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-, or
R43-CH(OH)-CH2-NR19-C(O)-R13CH-；
Wherein
R11And R12Independently H, OH, C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
C1-C6Haloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, (OH)3-C4-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, benzo-fused C3-C7Cycloalkyl, cyano-C1-C6Alkyl, NH2-C(NH)-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, OH-C3-C7cycloalkyl-C1-C6alkoxy-C (O) -C3-C7Cycloalkyl-, (C)1-C6Alkoxy-aryl) -C3-C7Cycloalkyl-, NH2-C(O)-C3-C7Cycloalkyl-, OH-aryl, or R24 1-5-heteroaryl-O- (CH)2)n-；
R13Is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R14is (C)1-C6Alkyl radical)2N-, aryl, C1-C6Alkyl, or C3-C7A cycloalkyl group;
R15、R21、R29、R31、R34and R40Independently is H or C1-C6An alkyl group;
R16is OH or C1-C6An alkoxy group;
R17and R18Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl or R24 1-5-heteroaryl-;
each R19Independently is H or C1-C6An alkyl group;
R20is C1-C6Alkyl radical, C1-C6Haloalkyl or (C)1-C6Alkyl radical)2N-；
R22And R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、OH-C1-C6Alkyl, aryl, or aryl-OH-C1-C6An alkylene group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, OH, NH2、C1-C6alkoxy-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, OH-C1-C6alkyl-NH-C (O) -, or C3-C7cycloalkyl-C (O) -NH-;
each R25Independently is H or oxo;
each R26Independently is H, OH-C1-C6Alkyl, aryl- (CH)2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -;
R27and R28Independently is H, NH2-C(O)-、C3-C7cycloalkyl-C (O) -, or R24 1-5-heteroaryl-;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl, NH2、C1-C6alkyl-NH-, C3-C7Cycloalkyl- (CH)2)n-NH-, morpholin-4-yl, or R38 1-5-a phenyl group;
R32is OH or C1-C6Alkoxy-;
each R33Independently is H, C1-C6Alkyl, or OH-C1-C6An alkyl group;
each R35Independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -, C3-C7Cycloalkyl, OH, phenyl, or heteroaryl, or two adjacent R35Radicals may together form- (CH)2)3-6-；
Each R36Independently is H, C1-C6Alkyl radical, C1-C6Alkoxy-, or NH2-C(O)-；
Each R37Independently is H, NH2C (O) -, OH, halogen, cyano, oxo, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, NH2C(O)-(CH2)n-、NH2C(O)-(CH2)n-C(O)-、NH2C(O)-NH-(CH2)n-、C1-C6alkyl-NH-C (O) -O-, (OH) -C1-C6alkyl-NH-C (O) -, (OH)2-C1-C6alkyl-NH-C (O) -, C1-C6alkyl-C (O) -, C1-C6alkoxy-C (O) -, C3-C7cycloalkyl-C (O) -NH- (CH)2)n-、C1-C6alkyl-SO2-、C3-C7cycloalkyl-SO2-, or C3-C7cycloalkyl-SO2-NH-(CH2)n-；
Each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -, or C1-C6alkoxy-C (O) -;
each R39Independently is H, C1-C6Alkyl, or OH-C1-C6An alkyl group;
each R41Independently is H, C1-C6Alkoxy or halogen;
R42is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-or NH2-C(O)-CH2；
R43Is OH-C (O) -, C1-C6alkoxy-C (O) -, NH2-C (O) -or R44R45NCH2-; and
R44and R45Independently is C1-C6Alkyl or OH-C1-C6Alkyl, or
R44And R45Together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine or morpholine ring;
n is an integer from 1 to 6; and
each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl.
In some other embodiments, the invention includes a compound having the structure of formula I as follows:
wherein
X is CH or N;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently is H, halogen, cyano or NH2-C(O)-；
Each R5Independently is H or C1-C6An alkyl group;
R2is NR11R12C(O)-R13CH-、R14-C(O)-NR15-(CH2)n-R13CH-、R16-C(O)-R13CH-、C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、R20-SO2-NR21-(CH2)n-R13CH-、R22R23CH-、R24 1-5-heteroaryl, R24 1-5-heteroaryl-R13CH-、R24 1-5-heteroaryl-NR15-C(O)-R13CH-、R25 1-5-heterocyclyl, R25 1-5-heterocyclic ringRadical- (CH)2)n-、R26 1-5-C3-C7Cycloalkyl, NR27R28-(CH2)n-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、R30-SO2-(CH2)n-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl-C (O) -R13CH-、R38 1-5-aryl-R39C-NR40-C(O)-R13CH-、R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-or R41 1-5-aryl- (CH)2)n-; wherein
R11And R12Independently is H, C1-C6Alkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, cyano-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, or OH-aryl;
R13is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R14is (C)1-C6Alkyl radical)2N-, aryl, C1-C6Alkyl, or C3-C7A cycloalkyl group;
R15、R21、R29、R31、R33、R34、R36、R39and R40Independently is H or C1-C6An alkyl group;
R16is OH or C1-C6An alkoxy group;
R17、R18and R19Independently is H or C1-C6An alkyl group;
R20is C1-C6Alkyl radical, C1-C6Haloalkyl, or (C)1-C6Alkyl radical)2N-；
R22And R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、OH-C1-C6Alkyl, aryl, or aryl-OH-C1-C6An alkylene group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, NH2、C1-C6alkoxy-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, or OH-C1-C6alkyl-NH-C (O) -;
each R25Independently is H or oxo;
each R26Independently is H, OH-C1-C6Alkyl, aryl-(CH2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -;
R27and R28Independently is H, NH2-C (O) -, or C3-C7cycloalkyl-C (O) -;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl or NH2；
R32Is OH;
R35independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -or C3-C7A cycloalkyl group;
each R37Independently is H, NH2C (O) -or OH;
each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -, or C1-C6alkoxy-C (O) -;
each R41Independently selected from H, C1-C6Alkoxy or halogen;
n is an integer from 1 to 6; and
each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl.
In another embodiment, X is CH or N;
R1is R4 1-5-benzyl, R5 1-5-isoxazolyl-CH2-or R5 1-5-pyridyl-CH2-; wherein
Each R4Is H, fluorine, cyano, NH2-C(O)-；
Each R5Independently is H or CH3；
R2Is NR11R12-C(O)-R13CH-、R14-C(O)-NR15-CH2-R13CH-、R16-C(O)-R13CH-、(CH3)3C-O-C(O)-CH2-NR15-C(O)-R13CH-、NR17R18-C(O)-CH2-NR19-C(O)-R13CH-、NR17R18-C(O)-(CH2)2-NR19-C(O)-R13CH-、R20-SO2-NR21-CH2-R13CH-、R22R23CH-、R24 1-5-dihydroimidazolyl, R24 1-5-isoxazolyl, R24 1- 5Thiadiazole, R24 1-5-isoxazolyl-R13CH-、R24 1-5-oxazolyl-R13CH-、R24 1-5-furyl-R13CH-、R24 1-5-oxadiazolyl-R13CH-、R24 1-5-triazolyl-R13CH-、R24 1-5-dihydroisoxazolyl-R13CH-、R24 1-5-tetrazolyl-R13CH-、R24 1-5-isoxazolyl-NR15-C(O)-R13CH-、R24 1-5Thiadiazole NR15-C(O)-R13CH-、R25 1-5-tetrahydrofuranyl, R25 1-5-tetrahydrofuryl-CH2-、R26 1-5-cyclohexyl radical, R26 1-5-tetrahydronaphthyl, R26 1-5-indanyl radical, NR27R28-(CH2)2-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)2-NR15-C(O)-R13CH-、R30-SO2-(CH2)2-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R32-C(O)-(CH2)2-NR34-C(O)-R13CH-、R35 1-5-oxadiazole- (CH)2)2-NR36-C(O)-R13CH-、R35 1- 5-oxadiazole-CH2-NR36-C(O)-R13CH-、R35 1-5-pyridyl-CH2-NR36-C(O)-R13CH-、R35 1-5-tetrazolyl-CH2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl-CH2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl-C (O) -R13CH-、R37 1-5pyrrolidinyl-C (O) -R13CH-、R37 1- 5-morpholinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperazinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl- (CH)2)2-NR36-C(O)-R13CH-、R38 1-5-phenyl-R39C-NR40-C(O)-R13CH-、R38 1-5-phenyl- (CH)2)2-NR40-C(O)-R13CH-、R38 1-5-phenyl- (CH)2)3-NR40-C(O)-R13CH-or R41 1-5-a benzyl group; wherein
R11And R12Independently is H, CH3、(CH3)2CH-, cyclobutyl, cyclopropyl, CH3O(CH2)2-, OH-ethyl, OH-propyl, (OH)2-propyl, cyano-CH2-、(OH-CH2)2-CH-, OH-cyclopropyl-CH2-, OH-cyclopentyl-CH2-OH-methyl-cyclopropyl or OH-phenyl;
R13is H, (CH)3)3C-、(CH3)2CHCH2-、(CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R14is (CH)3CH2)2N-, phenyl, (CH)3)3C-, or cyclopropyl;
R15、R21、R29、R31、R33、R34、R36、R39and R40Independently is H or CH3；
R16Is OH or CH3O；
R17、R18And R19Independently is H or CH3；
R20Is (CH)3)2CH-、CH3、CF3Or (CH)3)2N-；
R22And R23Independently is (CH)3)3C-、(CH3)2CH-, cyclohexyl-CH2-、OHCH2Phenyl, OH-isopropyl, OH-ethyl, or phenyl-OHCH-;
each R24Independently is H, CH3、CH3CH2-、(CH3)3C-, cyclopropyl, CF3Oxo, NH2、CH3CH2-O-C(O)-、NH2-C(O)-CH2-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-CH2-NH-C(O)-、(OH)2-propyl-NH-c (o) -or OH-ethyl-NH-c (o) -;
each R25Independently is H or oxo;
each R26Independently is H, OH, OHCH2benzyl-O-, NH2-C (O) -or CH3CH2-O-C(O)-；
R27And R28Independently is H, NH2-C (O) -, or cyclopropyl-C (O) -;
R30is CH3Cyclopropyl or NH2；
R32Is OH;
each R35Independently is H, CH3、NH2-C(O)-、CH3CH2-O-c (O) -, or cyclopropyl;
each R37Independently is H, NH2C (O) -or OH;
each R38Independently is H, NH2SO2-, cyano, tetrazolyl, OH, chlorine, CH3-O-, OH-C (O) -, or CH3-O-C(O)-；
Each R41Independently is H, CH3O or fluorine; and
each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O, pyridyl or oxazolyl.
In another embodiment, X is CH or N;
R1is that
R2Is that
Each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O-, 3-pyridyl, 4-pyridyl, or 2-oxazolyl.
In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, is as follows:
x is CH or N;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently is H, halogen, cyano or NH2-C(O)-；
Each R5Independently is H or C1-C6An alkyl group;
R2is NR11R12-C(O)-R13CH-、R16-C(O)-R13CH-、NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-heteroaryl-R13CH-、R26 1-5-C3-C7Cycloalkyl, NR27R28-(CH2)n-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)n-NR19-C(O)-R13CH-、R30-SO2-(CH2)n-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl-C (O) -R13CH-or R41 1-5-aryl- (CH)2)n-; wherein
R11And R12Independently is H, C1-C6Alkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl, OH-aryl, alkyl, aryl, heteroaryl,
R13Is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R16is OH or C1-C6An alkoxy group;
R17、R18and R19Independently is H or C1-C6An alkyl group;
R22and R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、OH-C1-C6An alkyl group, or an aryl group;
each R24Independently is H, C1-C6Alkyl, NH2、NH2-C(O)-NH-、NH2-C(O)-、NH2-C(O)-(CH2)n-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, or OH-C1-C6alkyl-NH-C (O) -;
each R26Independently is H, OH-C1-C6Alkyl, aryl- (CH)2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -;
R27and R28Independently is H or NH2-C(O)-；
R29R33、R34、R36And R38Independently is H or C1-C6An alkyl group;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl or NH2；
R31Is H;
R32is OH;
each R35Independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -, or C3-C7A cycloalkyl group;
each R37Independently is H, NH2C (O) -or OH;
each R41Independently selected from H, C1-C6Alkoxy or halogen;
n is an integer from 1 to 6; and
each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl.
In another embodiment, X is CH or N;
R1is R4 1-5-benzyl, R5 1-5-isoxazolyl-CH2-or R5 1-5-pyridinepyridyl-CH2-; wherein
Each R4Is H, fluorine, cyano, NH2-C(O)-；
Each R5Independently is H or CH3；
R2Is NR11R12-C(O)-R13CH-、R16-C(O)-R13CH-、NR17R18-C(O)-CH2-NR19-C(O)-R13CH-、NR17R18-C(O)-(CH2)2-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-furyl-R13CH-、R24 1-5-oxadiazolyl-R13CH-、R24 1-5-tetrazolyl-R13CH-、R26 1-5-cyclohexyl radical, R26 1-5-tetrahydronaphthyl, R26 1-5-indanyl radical, NR27R28-(CH2)2-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)2-NR19-C(O)-R13CH-、R30-SO2-(CH2)2-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R35 1-5-oxadiazole-CH2-NR36-C(O)-R13CH-、R35 1-5-oxadiazole- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-morpholinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperazinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl-C(O)-R13CH-、R37 1-5pyrrolidinyl-C (O) -R13CH-or R41 1-5-a benzyl group; wherein
R11And R12Independently is H, CH3、(CH3)2CH-, cyclobutyl, cyclopropyl, CH3O(CH2)2-, OH-ethyl, OH-propyl, (OH)2-propyl, (OH-CH)2)2-CH-, OH-cyclopropyl-CH2-, OH-cyclopentyl-CH2-、OH-CH2-cyclopropyl, or OH-phenyl;
R13is H, (CH)3)3C、(CH3)2CHCH2-、(CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R16is OH or CH3O；
R17、R18And R19Independently is H or CH3；
R22And R23Independently is (CH)3)3C-、(CH3)2CH-, cyclohexyl-CH2-、OHCH2Phenyl, OH-isopropyl, or OH-ethyl;
each R24Independently is H, CH3、NH2、NH2-C(O)-NH-、NH2-C(O)-、NH2-C(O)-CH2-、OH-C(O)-、NH2-C(O)-CH2-NH-C(O)-、(OH)2-propyl-NH-c (o) -, or OH-ethyl-NH-c (o) -;
each R26Independently is H, OH, OHCH2benzyl-O-, NH2-C (O) -or CH3CH2-O-C(O)-；
R27And R28Independently is H or NH2-C(O)-；
R29R33、R34、R36And R38Independently is H or CH3；
R30Is CH3Cyclopropyl or NH2；
R31Is H;
R32is OH;
each R35Independently is H, CH3、NH2-C(O)-、CH3CH2-O-c (O) -, or cyclopropyl;
each R37Independently is H, NH2C (O) -or OH;
each R41Independently is H, CH3O or fluorine; and
each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O, pyridyl or oxazolyl.
In another embodiment, X is CH or N;
R1is that
R2Is that
And
each R3Independently is H, CH3Chlorine, bromine, fluorinePhenyl, NH2-C(O)-、CH3O, 3-pyridyl, 4-pyridyl, or 2-oxazolyl.
In another embodiment, X is CH.
In another embodiment:
x is CH;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently H, halogen, cyano, or NH2-C(O)-；
Each R5Independently is H or C1-C6An alkyl group;
R2is NR11R12-C(O)-R13CH-、NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-heteroaryl-R13CH、R30-SO2-NR31-(CH2)n-NR19-C(O)-R13CH-、R30-SO2-(CH2)n-NR31-C(O)-R13CH-or R32-C(O)-R33CH-NR34-C(O)-R13CH-; wherein
R11And R12Independently H, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C3-C7Cycloalkyl or (OH-C)1-C6Alkyl radical)2-(CH2)n-；
R13Is C1-C6An alkyl group;
R17、R18and R19Independently is H;
R22and R23Independently is C1-C6Alkyl or OH-C1-C6An alkyl group;
each R24Independently is H or NH2；
R30Is C3-C7Cycloalkyl or NH2；
R31Is H;
R32is OH;
R33is H;
R34is H;
n is an integer from 1 to 6; and
R3is H, halogen or C1-C6An alkyl group.
In another embodiment, X is CH;
R1is that
R2Is that
R3Is H, F, Cl or CH3。
In one embodiment, X is N;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently H, halogen, cyano, or NH2-C(O)-；
Each R5Independently is H;
R2is NR11R12-C(O)-R13CH-、R22R23CH-or R16-C(O)-R13CH-; wherein R is11And R12Independently is H;
R13is C1-C6Alkyl or OH-C1-C6An alkyl group;
R16is OH;
R22and R23Independently is C1-C6Alkyl or OH-C1-C6An alkyl group; n is an integer from 1 to 6; and
R3is H.
In another embodiment, X is N;
R1is R4 1-5-benzyl or R5 1-5-pyridyl-CH2-; wherein each R4Is H or fluorine;
each R5Independently is H;
R2is NR11R12-C(O)-R13CH-、R22R23CH-or R16-C(O)-R13CH-; wherein R is11And R12Independently is H;
R13is (CH)3)3C、(CH3)2CHCH2、(CH3)2CH. OH-ethyl;
R16is OH;
R22and R23Independently is (CH)3)3C or OHCH2(ii) a And R3Is H.
In another embodiment, X is N;
R1is that
R2Is that
R3Is H.
In another embodiment, the compound has the general formula:
wherein
R2AIs selected from
NR11R12-C(O)-R13CH-、
C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、
R24 1-5-heteroaryl-NR15-C(O)-R13CH-、
NR27R28-(CH2)n-NR29-C(O)-R13CH-、
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、
R30-SO2-(CH2)n-NR31-C(O)-R13CH-、
R32-C(O)-R33CH-NR34-C(O)-R13CH-、
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、
R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl-C (O) -R13CH-、
R38 1-5-aryl-R39C-NR40-C(O)-R13CH-, or
R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-
Wherein
R11And R12Independently is H, C1-C6Alkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, cyano-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, or OH-aryl;
R13is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R15、R29、R31、R33、R34、R36、R39and R40Independently is H or C1-C6An alkyl group;
R17、R18and R19Independently is H or C1-C6An alkyl group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, NH2、C1-C6alkoxy-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, or OH-C1-C6alkyl-NH-C (O) -;
each R25Independently is H or oxo;
R27and R28Independently is H, NH2-C (O) -, or C3-C7cycloalkyl-C (O) -;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl or NH2；
R32Is OH;
R35independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -or C3-C7A cycloalkyl group;
each R37Independently is H, NH2C (O) -or OH;
each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -, or C1-C6alkoxy-C (O) -;
n is an integer from 1 to 6;
R3Aand R3BIndependently selected from H and halogen;
R4Aselected from F and CN; and
R4Bselected from H and F.
Preferably, R13Is C1-C6An alkyl group. More preferably, it is branched C3-C6An alkyl group. Most preferably, it is tert-butyl.
In another embodiment, the compound has the general formula:
wherein R is3ASelected from H, F and Cl, R4ASelected from F and CN, R4BSelected from H and F, R11ASelected from H, OH-C1-C6Alkyl and (OH)2-C1-C6An alkyl group.
In another embodiment, the compound has the general formula:
wherein R is3ASelected from H, F and Cl, R4ASelected from F and CN, R4BSelected from H and F, R11ASelected from the group consisting of H, 2-hydroxyethyl and 2, 3-dihydroxypropyl.
In one embodiment, the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-bromo-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-pyridin-3-yl-1H-indazole-3-carboxamide;
1- [3- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-bromo-1H-indazole-3-carboxamide;
1- [2- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5- (1, 3-oxazol-2-yl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-pyridin-4-yl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-pyridin-4-yl-1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valine methyl ester;
1-benzyl-N- (4-methoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2-methoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2, 3-dimethoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (3-methoxybenzyl) -1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-pyridin-3-yl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-methoxy-1H-indazole-3-carboxamide;
n-3- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-indazole-3, 5-dicarboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-phenyl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-phenyl-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (2, 5-dimethyl-3-furanyl) methyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valine;
1-benzyl-N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1-benzyl-N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1-benzyl-N- [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valylglycine;
n- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- {5- [ (cyclopropyl carbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1-benzyl-1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-cyano-2-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [2- (methylsulfonyl) ethyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [2- (methylsulfonyl) ethyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (aminosulfonyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (aminosulfonyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -7-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1H-indazole-3-carboxamide
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- ({ [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- {5- [ (aminocarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [4- (aminocarbonyl) -5-methyl-1, 3-oxazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [5- (2-amino-2-oxoethyl) -1, 3, 4-oxadiazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
2- [ (1S) -1- ({ [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } amino) -2, 2-dimethylpropyl ] -5-methyl-1, 3-oxazole-4-carboxylic acid;
- Λ/- { (1S) -1- [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (4- { [ (2-amino-2-oxoethyl) amino ] carbonyl } -5-methyl-1, 3-oxazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [4- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -5-methyl-1, 3-oxazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- (4- { [ (2-hydroxyethyl) amino ] carbonyl } -5-methyl-1, 3-oxazol-2-yl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
ethyl 5- { [ (N- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 3, 4-oxadiazole-2-carboxylate;
ethyl 5- { [ (N- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 3, 4-oxadiazole-2-carboxylate;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- { (1S) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
3- { [ (N- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester;
3- { [ (N- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- { [ (2-morpholin-4-ylethyl) amino ] carbonyl } propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [2- (4-hydroxypiperidin-1-yl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (4-methylpiperazin-1-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (5-methyl-1, 3, 4-oxadiazol-2-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3R) -3-hydroxypyrrolidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3R) -3-hydroxypyrrolidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopropyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- (([ (1-hydroxycyclopropyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- { [ (3-hydroxyphenyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- { [ (3-hydroxyphenyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopentyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopentyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [1- (hydroxymethyl) cyclopropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- { [3- (aminocarbonyl) piperidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1- (cyclohexylmethyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- { [3- (aminocarbonyl) piperidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1- (4-cyanobutyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -5-fluoro-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -5-fluoro-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -5-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -5-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -5-fluoro-1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -5-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- { [1- (4-cyanobenzyl) -5-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -5-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -5-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
5-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 5-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
5-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-chloro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
- Λ/- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
7-chloro-N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-chloro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-chloro-1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
7-chloro-1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
n- { [1- (3-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [1- (2-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [1- (2, 4-difluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine; or
N- { [1- (3, 4-difluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine.
In one embodiment, the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
1- (2-fluorobenzyl) -N- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1-benzyl-1H-pyrazolo [3, 4-b ] pyridin-3-yl) carbonyl ] -3-methyl-L-valine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
1-benzyl-N- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide; or
N- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
In one embodiment, the present invention relates to a method for treating a CB1 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises: administering to the subject an amount of a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein the amount of the compound is effective to treat or prevent the CB1 mediated disorder.
In one embodiment, the CB1 mediated disorder is pain.
Salts of the compounds of the invention
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compound are preferred for reasons of one or more of its physical properties, such as enhanced pharmaceutical stability at different temperatures and humidities, or suitable solubility in water or oil. In some cases, the compound salt may also assist in the isolation, purification, and/or dissolution (resolution) of the compound.
Where the salt is intended to be administered to a patient (as opposed to, for example, in vitro use), the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include those salts commonly used to form alkali metal salts and those used to form free acid or free base addition salts. In general, these salts can be generally prepared by conventional means using the compounds of the present invention by: for example, by reacting an appropriate acid or base with a compound of the invention.
Pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic organic acids, alicyclic organic acids, aromatic organic acids, araliphatic organic acids, heterocyclic organic acids, carboxylic organic acids, and sulfonic organic acids. Specific examples of suitable organic acids include acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid (anthranilic acid), methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonate or pamoate, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, aminobenzenesulfonic acid (Sufanilate), cyclohexylsulfamic acid, alginic acid (algenic acid), beta-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, alginic acid, bisulfate, butyric acid, camphorsulfonic acid, cyclohexanepropionic acid, dodecylsulfuric acid, Ethylene glycol heptanoic acid, glycerophosphoric acid, hemisulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid (palmoate), pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, methanesulfonic acid, undecanoic acid, and naphthalene-1, 5-disulfonic acid.
Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts and organic salts. Preferred metal salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiologically acceptable metal salts. The salt can be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts may be made from tertiary amines and quaternary ammonium salts, such as tromethamine (tromethamine), diethylamine, NN' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C)1-C6) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, methyl, ethyl, propyl, and butyl bromides, and methyl, ethyl, propyl, and butyl iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, di-inorganic sulfate), long chain halides (e.g., decyl, dodecyl, tetradecyl, and octadecyl chlorides, decyl, dodecyl, tetradecyl, and octadecyl bromides, and decyl, dodecyl, tetradecyl, and octadecyl iodides), aralkyl halides (e.g., phenyl and phenethyl bromides), and others.
The scope of the present invention also includes the so-called "prodrugs" of the compounds of formula (I). Thus, a particular derivative of a compound of formula (I) which itself has little or no pharmacological activity may be converted to a compound of formula (I) having the desired activity by, for example, hydrolysis, upon administration to the body or body surface. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs Novel Delivery Systems", Vol.14, ACS Symposium Series (T Higuchi and WStela) and "Bioreversible Carriers in Drug Delivery", Pergamon Press, 1987(ed. EB Roche, American Pharmaceutical Association).
Prodrugs of the invention may be prepared, for example, by substituting the corresponding functional groups present in a compound of formula (I) with specific moieties known to those skilled in the art, which are described as "precursor moieties" in, for example, HBundgaard "Design of produgs" (Elsevier, 1985).
Examples of prodrugs of the invention include:
(i) if the compounds of the formula (I) contain an alcohol function (-OH), for example with (C)1-C6) Alkanoyloxymethyl substitutionEthers formed by hydrogen;
(ii) if the compounds of the formula (I) contain carboxylic acid functions, for example with (C)1-C8) Esters formed by alkyl groups substituting for hydrogen;
(iii) if the compound of formula (I) contains a primary or secondary amino function (-NH)2or-NHR and R.noteq.H), for example with (C)1-C10) Amides formed by the substitution of one or two hydrogens with an alkanoyl group.
Further examples of substituents for the above examples and for examples of other prodrug types can be found in the above-mentioned documents.
Finally, certain compounds of formula (I) may themselves be prodrugs of other compounds of formula (I).
The compounds of formula (I) containing one or more asymmetric carbon atoms may exist in two or more stereoisomeric forms. Where the compounds of formula (I) contain, for example, keto or oxime groups or aromatic moieties, tautomers ("tautomerism") may be present. A single compound may exhibit more than one isomerism.
The scope of the present invention includes all stereoisomers, geometric isomers and tautomers of the compounds of formula (I) including compounds having more than one isomeric type, as well as mixtures of one or more thereof. Also included within the scope of the invention are acid addition or base salts with optically active counterions, such as D-lactate, L-lysine, or the racemate of, for example, DL-tartrate or DL-arginine.
Conventional techniques for the preparation/separation of single enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure gas chromatography (HPLC).
Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, in the case of compounds of formula (I) comprising an acidic or basic moiety, an acid or base, for example tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization and one or both of the diastereomers converted to the corresponding pure enantiomers by methods well known to those skilled in the art.
The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form on asymmetric resins using chromatography (typically HPLC) with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) comprising 0-50% isopropanol (typically 2-20%) and 0-5% alkylamine (typically 0.1% diethylamine). Concentrating the eluate to obtain an enriched mixture.
Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art, see, for example, E L Eliel, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) in which one or more atoms are replaced by an atom having the same atomic number, but a different atomic mass or mass number than the atom usually found in nature.
Examples of suitable isotopes that are suitable for inclusion in the compounds of the invention include hydrogen isotopes, for example2H and3h; isotopes of carbon, e.g.11C，13C and14c; isotopes of chlorine, e.g.36Cl; isotopes of fluorine, e.g.18F; iodine isotopes, e.g.123I and125i; isotopes of nitrogen, e.g.13N and15n; isotopes of oxygen, e.g.15O，17O and18o; isotopes of phosphorus, e.g.32p; isotopes of sulfur, e.g.35S。
Certain isotopically-labeled compounds of formula (I), for example those incorporating a radioisotope, are useful in drug and/or substrate tissue distribution studies. Due to the ease of incorporation and the convenient means of detection, the radioactive isotope tritium (i.e., tritium)3H) And carbon-14 (i.e.14C) Particularly suitable for this purpose.
With, for example, deuterium (i.e. deuterium)2H) The heavier isotope substitution may provide specific therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and thus such substitution may be preferred in some circumstances.
Using positron-emitting isotopes (e.g. of the type11C，18F，15O and13n) can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, by substituting an appropriate isotopically-labelled reagent for the unlabelled reagent previously used.
All compounds of formula (I) can be prepared by procedures described in the general methods presented below or by specific methods described in the examples section and the preparation section or by routine modification thereof. The present invention encompasses one or more of these processes for preparing compounds of formula (I) in addition to any novel intermediates used herein.
Treatment of disorders with compounds of the invention
The methods of the invention are useful for treating disorders mediated by CB1 in a subject, but are not limited thereto. For example, the compounds described herein may be used to treat any of the symptoms associated with CB1 mediated disorders as described below.
The term "treatment" as used herein is used interchangeably with verbs, nouns, participles or infinitive forms. "treatment" includes palliative, prophylactic and therapeutic treatment. Palliative treatment includes reducing, eliminating the focus of pain and/or inflammation associated with CBI-mediated disorders. Prophylactic treatment refers to preventing or slowing the appearance of a condition associated with a CB1 mediated disorder. For the method of prevention, the subject is any subject, preferably a subject in need of prevention of CB1 mediated disorders.
The term "subject" for therapeutic purposes includes any human or animal subject in need of prophylaxis or suffering from a TNF α -mediated inflammatory disease or disorder. The subject is typically a human.
In some embodiments, the methods and compositions of the invention encompass the treatment of conditions including pain and degenerative disorders of nervous tissue. (see Annu. Rev. Pharmacol. Toxicol. (2006) 46: 101-22; Clinical Neuroscience Research (2005) 5185-.
In some embodiments, the methods and compositions of the present invention encompass the treatment of pain including, but not limited to, chronic pain, acute pain, joint pain, nociceptive pain, neuropathic pain, allodynia, hyperalgesia, burn pain, dysmenorrhea, kidney stones, headache, migraine, sinus headache, pressure headache, dental pain, myasthenia gravis, rheumatic joint pain, osteoarticular pain, back pain, cancer pain, multiple sclerosis, sarcoidosis, Behcet's syndrome, myositis, polymyositis, gingivitis, hypersensitivity, swelling after injury, closed head injury, endometriosis, stroke, and the like.
In other embodiments, the methods and compositions of the invention encompass the treatment of connective tissue and joint disorders selected from the group consisting of: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, fibromyalgia, spondyloarthropathies, gouty arthritis, lumbar facet degeneration, carpal tunnel syndrome, psoriatic arthritis, scleroderma, canine hip dysplasia, systemic lupus erythematosus, juvenile arthritis, osteoarthritis, tendonitis, and bursitis.
In other embodiments, the methods and compositions of the present invention encompass the treatment of neurological disorders including neuroinflammatory and neurodegenerative disorders selected from the group consisting of: neuritis, Alzheimer's disease, Multiple Sclerosis (MS), Parkinson's disease, Touette's syndrome, stiffness and epilepsy.
In other embodiments, the methods and compositions of the present invention encompass the treatment of neurological disorders including HIV-associated neurological disorders, nerve damage, spinal cord damage, sciatica, neuropathic pain, diabetic neuropathy, neuropathic pain, and some peripheral neuropathies and neurodegenerative disorders.
In another embodiment, the methods and compositions of the present invention encompass the treatment of a respiratory disorder selected from the group consisting of: cough, asthma, bronchitis, Chronic Obstructive Pulmonary Disease (COPD), bronchospasm, cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory disease syndrome, occult fibrosing alveolitis, and emphysema.
In other embodiments, the methods and compositions of the present invention encompass the treatment of dermatological disorders selected from the group consisting of: acne, psoriasis, eczema, burns, poison ivy dermatitis, poison oak dermatitis and dermatitis.
In other embodiments, the methods and compositions of the present invention encompass the treatment of a surgical disorder selected from the group consisting of: postoperative pain and swelling, postoperative infection, and postoperative inflammation.
In other embodiments, the methods and compositions of the present invention encompass the treatment of gastrointestinal disorders selected from the group consisting of: colitis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome, diarrhea, constipation, dysentery, ulcerative colitis, gastroesophageal reflux, gastric ulcer, gastric varices, ulcers, functional gastrointestinal disorders, and heartache.
In other embodiments, the methods and compositions of the present invention encompass the treatment of an ocular disorder selected from the group consisting of: retinopathy, uveal eye, photophobia, acute damage to eye tissue, conjunctivitis, age-related macular degeneration diabetic retinopathy, retinal detachment, glaucoma, vitelliform macular dystrophy, choroidal and retinal swirl atrophy, conjunctivitis, corneal infections, Fuch dystrophy, iridocorneal endothelial syndrome, retinitis, keratoconus, lattice degeneration, corneal epithelial basement membrane dystrophy, ocular herpes, pterygium, myopia, hyperopia, and cataracts.
We believe that cannabinoid agonists may be useful in the treatment of diseases including other diseases including acute cerebral ischemia, neuroprotection, anxiety, cerebrovascular ischemia, cachexia, motion sickness, emesis, chemotherapy-induced emesis, cutaneous T-cell lymphoma, diabetes, osteoporosis, glomerulonephritis, renal injury, nephritis, hepatitis, cerebral stroke, vasodilation, hypertension, vasculitis, myocardial infarction, and cerebral ischemia.
Pharmaceutical compositions comprising the compounds of the invention
The present invention also relates to pharmaceutical compositions (or "medicaments") comprising the above-described compounds (including tautomers of the above-described compounds and pharmaceutically acceptable salts of the above-described compounds and tautomers), and to processes for the manufacture of pharmaceutical compositions, said processes comprising: bringing the compounds into association with one or more non-toxic pharmaceutically acceptable carriers, diluents, wetting or dispersing agents, carriers and/or adjuvants (which carriers, diluents, wetting or dispersing agents, carriers and/or adjuvants are sometimes collectively referred to herein as "carrier materials"); and/or other active ingredient combinations. The preferred composition depends on the method of administration. Methods of formulation of pharmaceutical products are generally discussed in, for example, Hoover, John E., Remington's pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975) (incorporated herein by reference). See also Liberman, h.a., Lachman, l., editors, Pharmaceutical document Forms (Marcel Decker, New York, n.y., 1980) (incorporated herein by reference).
In some embodiments, the pharmaceutical composition is prepared in a form in which a dosage unit contains a specific amount of the active ingredient. Typically, the pharmaceutical composition comprises from about 0.1 to 1000mg (more typically 7.0 to 350mg) of the compound.
The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler, alone, as a mixture (e.g. in a dry mixture with lactose) or as admixed component particles (e.g. admixed with a phospholipid such as lecithin), or as a spray from a pressurised container, pump, nebuliser (preferably one utilising electro-hydrodynamics to generate a fine mist) or nebuliser, with or without the use of a suitable propellant (e.g. 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-hexafluoropropane). For intranasal use, the powder may comprise a bioadhesive, such as chitosan or cyclodextrin.
The pressurized container, pump, sprayer, atomizer or sprinkler contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or an optional agent for dispersing, dissolving or prolonging the release of the active substance, a propellant as a solvent and optionally a surfactant (e.g., sorbitan trioleate, oleic acid or oligomeric lactic acid).
Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for administration by inhalation (typically less than 5 microns). This may be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters (blisters), and kits for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base (for example, lactose or starch), and a modifier (for example, l-leucine, mannitol, or magnesium stearate). Lactose can be in anhydrous form or in monohydrate form, the latter being preferred. Other suitable excipients include dextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
Suitable solution formulations for use in nebulisers which utilise electro-hydrodynamic generation of fine mist may contain from 1 μ g to 20mg of a compound of the invention (per actuation), and the volume ejected per actuation may be from 1 μ l to 100 μ l. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents to propylene glycol include glycerol and polyethylene glycol.
Suitable flavouring agents (e.g. menthol and levomenthol) or sweetening agents (e.g. saccharin or saccharin sodium) may be added to the formulations of the invention for inhalation/intranasal administration.
Formulations for inhalation/intranasal administration may be formulated for immediate release and/or modified controlled release, for example with poly DL-lactic-co-glycolic acid (PGLA). Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.
In the case of dry powder inhalers and aerosols, the dosage units are determined by means of a valve for dosing. The dosage unit used in the present invention is generally arranged to administer a dose or "puff" comprising 1 μ g-10mg of a compound of the invention. The total daily dose will generally be in the range 0.001mg to 40mg and may be administered as a single dose or, more generally, in divided doses throughout the day.
Solid dosage forms for oral administration include, for example, hard or soft capsules, tablets, pills, powders, and granules. In the above solid dosage forms, the compounds are often combined with one or more adjuvants. If administered by mouth, the compounds may be combined with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for administration. The capsules and tablets described above may contain controlled release formulations which may be provided as a dispersion of the compound of the present invention in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents such as sodium citrate, or magnesium or calcium carbonate, or magnesium or calcium bicarbonate. Tablets and alkyl groups may additionally be prepared as enteric coatings. Liquid polarities for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, in the form of inert diluents commonly used in the art (e.g., water). The compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and/or perfuming agents.
"parenteral administration" includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting and/or suspending agents. Acceptable carrier materials include, for example, water, 1, 3-butanediol, Ringer's solution, isotonic sodium chloride solution, mild non-volatile oils (e.g., synthetic mono-or di-esters of monoglycerides), dextrorotatory grape-like, mannitol, fatty acids (e.g., oleic acid), dimethylacetamide, surfactants (e.g., ionic and nonionic detergents), and/or polyethylene glycols (e.g., PEG 400).
Formulations for parenteral administration may be prepared, for example, from sterile powders or granules having one or more of the above-described carrier materials for use in formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. The pH can be adjusted as desired using an appropriate acid, base or buffer.
Universal synthesis methodMethod of
The compounds of formula (I) illustrated in the examples hereinafter, as well as the intermediates necessary for the preparation of the compounds of formula (I), may be prepared using the procedures described in schemes a and B below. Those skilled in the art will recognize that: the compounds of the present invention may be prepared by methods other than those specifically described herein, for example by adapting the methods described herein according to known techniques. In the following methods, unless otherwise stated, group X, R1、R2And R3 1-4As described above for the compounds of formula (I).
Schematic diagram A
Starting compound 1, wherein X is carbon or nitrogen and R is a carboxy protecting group such as alkyl or aralkyl, may be treated with a base and an alkylating agent. Exemplary bases include sodium hydride, potassium t-butoxide, sodium hexamethyldisilazane and potassium carbonate, and exemplary alkylating agents include R1-L, wherein L is a leaving group, such as halogen, mesylate or tosylate, R1As described in the description of formula (I). This reaction typically produces a mixture of regioisomers, where alkylation typically occurs at the N1 position or at the N2 position of the indazole ring, depending on the base and alkylating agent. The desired N1-alkylated regioisomer is isolated in pure form by chromatographic separation or recrystallization of the crude product mixture. The alkylation product is saponified with an aqueous base such as sodium hydroxide, potassium hydroxide or lithium hydroxide to give compound 2.
Reaction conditions for polypeptide bond synthesis known to those of ordinary skill in the art [ see for example Bodanszky and Bodanszky,The Practice of Peptide Chemistry，Springer-Verlag(1984)；Bodanszky，Principles of Peptide Synthesis，Springer-Verlag(1984)；Han，S-Y and Kim，Y-A，Tetrahedron，vol.60，pp 2447-2467(2004)]coupling compound 2 with amine 3 to give a compound of formula (I). Exemplary reagents that activate the carboxyl group of compound 2 to react with an amine include carbodiimide reagents such as N, N' -Dicyclohexylcarbodiimide (DCC) and 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide, used alone or in combination with 1-hydroxybenzotriazole (HOBt); and uronium (uronium) reagents such as O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HBTU), and O- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU).
Scheme B
May be according to Johnson, b.l.; the procedure in Rodgers, j.d.syn.comm.2005, 35, 2681-2684 prepares starting compound 1 from compound 4 as shown in scheme B, wherein X is carbon and R is a carbonyl protecting group such as alkyl or aralkyl. Thus, compound 4 is converted to compound 5 by a base-catalyzed ring-opening reaction followed by diazotization. Compound 5 is reduced to produce compound 6, followed by ring closure to give compound 7. Compound 7 is esterified using an appropriate alcohol of the formula R-OH and an acid catalyst to give compound 1.
Can be prepared according to the following literature [ see, for example, Lynch, B.M. et alCanadian Journal of ChemistryVol.66, pp 420-428 (1988); huang, S. et alBioorganic& Medicinal Chemistry LettersVol.17, pp1243-1245 (2007); lin, R, et alBioorganic&Medicinal Chemistry Letters，vol.17，pp 4297-4302(2007)]By the known methods ofStarting from compound 1, wherein X is nitrogen and R is a carbonyl protecting group, such as alkyl or aralkyl.
Amine Compound 3 (R)2-NH2) Are commercially available or can be readily prepared by methods known in the art as described in the schemes for representative preparations herein.
The compounds of the present invention can be prepared by the methods described in the methods, examples and preparation examples section herein, or can be prepared by methods appropriately modified by methods known in the art. It will be appreciated that the synthetic transformations referred to herein may be performed in a variety of different orders in order to efficiently assemble the desired compounds. The most efficient reaction sequence for the synthesis of a particular target compound is empirically determined by those skilled in the chemical arts.
The compounds, salts and solvent compounds (including hydrates) of the present invention can be isolated and purified by conventional methods.
Separation of the diastereomers may be achieved by conventional techniques, for example by chromatographic or HPLC separation of a stereoisomeric mixture of the compound of formula (I) or an appropriate salt or derivative thereof. The various enantiomers of the compounds of formula (I) may also be prepared from the corresponding optically pure intermediates, or may be prepared by resolution, such as chromatographic separation of the corresponding racemate using a suitable chiral support, or fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base.
Biological evaluation
Methods for evaluating biological activity:
the binding affinity and other biological activities of the compounds of the invention to the human CB1 receptor were determined by the following procedure.
Film preparation method: transcriptional modulation of Human Embryonic Kidney (HEK) cells expressing the human CB1 receptor in tetracycline induction promotersGrowth was performed sublingually in Dulbecco's Modified minimal medium (Invitrogen, Carlsbad, Calif.) containing 10% tetracycline-free fetal bovine serum (Clonetech, Mountain View, Calif.), 100. mu.g/ml hygromycin (Calbiochem, San Diego, Calif.) and 5ug/ml blasticidin (Invitrogen) without sodium pyruvate. CB1 receptor expression was induced by: doxycycline (Calbiochem) was added at 1. mu.g/ml and incubated for an additional 24 hours. Cells were released from the flasks using cell division buffer (Invitrogen). Cells were centrifuged at 500XG for 5 minutes to form pellets. The membranes were prepared by resuspending the cells in ice-cold TEE buffer (25mM Tris pH7.4, 5mM EDTA, 5mM EGTA, holoprotease inhibitor (Roche, Basel, Switzerland)). The cells were lysed by 12 strokes using a Dounce homogenizer (dounecemogenizer). The unlysed cells were pelleted by centrifugation at 500XG for 5 minutes. The films were pelleted by centrifugation at 25000XG for 30 minutes. The film was resuspended in TEE, 12 Dunes strokes, and then re-pelleted at 25000XG for 30 minutes. The membrane spheres were resuspended in 50mM Tris pH7.4, 100mM NaCl, 3mM MgCl20.2mM EGTA, holoprotease inhibitor (Roche). Protein concentration was determined using a Micro-BCA protein kit (Pierce, Rockford, IL) using BSA as a standard. The films were snap frozen and then stored at-80 degrees celsius for later use.
Binding experiments: 50 μ l of the test compound and 50 μ l of [ mu ] l of a [ sic ]3H]CP-55, 940(Perkinelmer, Boston, Mass.) (final concentration 500pM) was incubated with 150. mu.l of membrane homogenate (1. mu.g/well) in a polypropylene 96-well plate (Corning, Acton, Mass.). The final reaction conditions were 50mM Tris pH7.4, 100mM NaCl, 3mM MgCl20.2mM EGTA, 0.04% BSA. Non-specific binding was determined by incubation with 50. mu.M WIN-55, 212-2(Tocris, Ellisville, Mo.). After incubation at room temperature for 60 min, the reactions were harvested by vacuum filtration using a FilterMate Plate Harvester (Perkin Elmer) through a Unifilter GF/B-96 filter (Perkin Elmer) that had been pre-soaked in assay buffer (Sigma, St. Louis, Mo.) containing 0.5% BSA) In (1). The filters were rinsed four times with 50mM Tris pH7.4, 0.025% Tween-20 and dried at 50 deg.C for at least 30 minutes. Mu.l of Microscint-20(Perkin Elmer) was added to each well and counted using a Top-Count Microplate Scintillation counter (Perkin Elmer). Binding data was analyzed and EC was calculated using Graph Pad Prism 4.0 software50And KiNumerical values.
GTP γ S binding
Film preparation method: CHO cells expressing the human CB1 receptor were grown to 80% confluence in Ham's F-12 nutrient medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), 1% double antibody (pen/strep) (Invitrogen), 1% non-essential amino acids (Invitrogen) and 500 μ G/ml G418 (Invitrogen). Cells were released from the flasks using cell division buffer (Invitrogen). Cells were centrifuged at 500XG for 5 minutes to form pellets. The membrane was prepared by resuspending the cells in ice-cold assay buffer (25mM Tris pH7.4, 5mM EDTA, 5mM EGTA, holoprotease inhibitor (Roche)). The cells were lysed by 12 strokes using a Dounce homogenizer (dounce homogen). The unlysed cells were pelleted by centrifugation at 500XG for 5 minutes. The films were pelleted by centrifugation at 25000XG for 30 minutes. The film was resuspended in TEE, 12 Dunes strokes, and then re-pelleted at 25000XG for 30 minutes. The membrane spheres were resuspended in 50mM Tris pH7.4, 100mM NaCl, 3mM MgCl20.2mM EGTA, holoprotease inhibitor (Roche). Protein concentration was determined using a Micro-BCA protein kit (Pierce, Rockford, IL) using BSA as a standard. The films were snap frozen and then stored at-80 degrees celsius for later use.
GTP γ S binding:40 μ l of the test compound and 20 μ l of [ mu ] l of a [ sic ]35S]GTP γ S (Perkin Elmer) (1250 Ci/mmol) was incubated with 140. mu.l of membrane homogenate (5. mu.g/well) in a polypropylene 96-well plate (Corning). The final reaction conditions were 50mM Tris pH7.4, 100mM NaCl, 3mM MgCl20.2mM EGTA, 0.04% BSA. In 3After incubation for 45 minutes at 7 degrees Celsius, the reaction was harvested by vacuum filtration through a UnifilterGF/B-96 filter (Perkin Elmer) using a FilterMate Plate Harvester (Perkin Elmer). The filters used ice-cold 50mM TrispH 7.4, 3mM MgCl2Four washes with 0.2mM EGTA and drying at 50 degrees celsius for at least 30 minutes. Mu.l of Microscint-20(Perkin Elmer) was added to each well and counted using a Top-Count Microplate Scintillation counter (Perkin Elmer). Binding data was analyzed and EC was calculated using Graph Pad Prism 4.0 software50Numerical values.
The above protocol was used to determine biological activity. We measured ki for certain compounds of the invention at the human CB1 receptor to be between 0.01 and 1000 nM. Certain compounds of the invention measured by the present invention have an EC50 of 0.1-5000nM at the human CB1 receptor in the GTP γ S assay. Table 1 shows some biological activities of some exemplary compounds.
Table 1: CB1 binding affinity and agonism
| Example number | CB1Ki(nM) | GTPγS EC50(nM) |
| 1 | 0.36 | 0.98 |
| 2 | 0.9 | 23.2 |
| 3 | 49.9 | 298 |
| 4 | 708 | ND* |
| 5 | 954 | ND* |
| 6 | 12.6 | 160 |
| 7 | 2.04 | 12.9 |
| 8 | 118 | 209 |
| 9 | 84.2 | ND* |
| 10 | 1.91 | 37.5 |
| 11 | 0.29 | 0.55 |
| 12 | 11.5 | 302 |
| 13 | 0.73 | 11.9 |
| 17 | 4.69 | 149 |
| 19 | 2.57 | 20.5 |
| 20 | 51.1 | 216 |
| 27 | 0.33 | 14.7 |
| 28 | 2.05 | 121 |
| 30 | 9.22 | 78.9 |
| 33 | 0.24 | 0.92 |
| 34 | 154 | ND* |
| 35 | 35.3 | 271 |
| 38 | 0.14 | 2.42 |
| 43 | 27.1 | 101 |
| 45 | 8.79 | 21.4 |
| 65 | 3.85 | 90 |
| 67 | 46.5 | 827 |
| 68 | 4.61 | 90.1 |
| 69 | 18.8 | 183 |
| 71 | 8.85 | 314 |
| 73 | 22.9 | 217 |
| 77 | 5.39 | 48.1 |
| 78 | 0.59 | 2.88 |
| 79 | 2.02 | 27.1 |
| 80 | 0.21 | 1.82 |
| 81 | 0.32 | 0.98 |
| 82 | 1.12 | 22.1 |
| 83 | 15.3 | 720 |
| 85 | 1.72 | 16.1 |
| 86 | 2.75 | 34.2 |
| 87 | 2.26 | 46.1 |
| 88 | 15.4 | 132 |
| 89 | 63.4 | 539 |
| 90 | 27.4 | 385 |
| 91 | 1.87 | 53.8 |
| 92 | 14.1 | 265 |
| 93 | 14.3 | 41.8 |
| 94 | 27.5 | 77 |
| 95 | 2.22 | 13.7 |
| 96 | 1.18 | 16.9 |
| 97 | 1.04 | 16.7 |
| 98 | 0.98 | 8.63 |
| 99 | 0.18 | 0.5 |
| 103 | 2.68 | 9.08 |
| 108 | 3.78 | 27 |
| 109 | 8.14 | 110 |
| 110 | 28.9 | 237 |
| 111 | 0.72 | 9.73 |
| 112 | 0.51 | 31.8 |
| 113 | 7.79 | 188 |
| 115 | 1.09 | 8.72 |
| 116 | 13.5 | 49.6 |
| 117 | 9.54 | 168 |
| 118 | 0.7 | 23.8 |
| 120 | 3.05 | 40 |
| 122 | 0.73 | 13.1 |
| 126 | 0.97 | 2.55 |
| 127 | 32.8 | 136 |
| 128 | 0.97 | 3.58 |
| 129 | 12.6 | 106 |
| 130 | 14.7 | 72.7 |
| 131 | 0.6 | 13.2 |
| 133 | 0.55 | 6.35 |
| 134 | 32.7 | 326 |
| 135 | 3.47 | 14.3 |
| 136 | 10.7 | 115 |
| 137 | 0.69 | 1.69 |
| 139 | 0.82 | 6.36 |
| 140 | 39.3 | 645 |
| 141 | 9.42 | 41.1 |
| 148 | 1.8 | 32.2 |
| 151 | 1.63 | 6.3 |
| 154 | 0.53 | 4.81 |
| 160 | 1.45 | 32.3 |
| 163 | 4.45 | 180 |
| 166 | 5.14 | 132 |
| 170 | 0.27 | 0.7 |
| 171 | 0.42 | 0.44 |
| 172 | 0.42 | 0.42 |
| 173 | 2.37 | 5.12 |
| 174 | 1.1 | 1.81 |
| 175 | 0.19 | 0.64 |
| 176 | 0.22 | 0.51 |
| 177 | 0.28 | 0.31 |
| 178 | 0.56 | 1.61 |
| 179 | 0.87 | 5.41 |
| 180 | 0.37 | 3.81 |
| 181 | 0.1 | 0.33 |
| 182 | 0.34 | 2.23 |
| 183 | 0.26 | 0.83 |
| 184 | 0.37 | 3.94 |
| 185 | 0.51 | 10.2 |
| 186 | 0.19 | 1.03 |
| 187 | 0.09 | 1.09 |
| 198 | 1.19 | 7.07 |
| 199 | 1.32 | 8.94 |
| 200 | 4.8 | 35 |
| 201 | 14.2 | 70.1 |
| 202 | 0.8 | 3.07 |
| 203 | 10.2 | 63.2 |
| 211 | 3.08 | 18.3 |
| 212 | 52.1 | |
| 213 | 15.7 | 57.7 |
| 214 | 3.87 | 23.4 |
| 215 | 7.69 | 41.3 |
| 216 | 225 | |
| 217 | ＞400 | |
| 218 | 7.92 | 360 |
| 219 | ＞400 | |
| 220 | 1.26 | 3.78 |
| 221 | 87.5 | |
| 222 | 21.4 | |
| 223 | 1.12 | 4.76 |
| 224 | 6.77 | 19.3 |
| 225 | 6.3 | 26.9 |
| 226 | 0.18 | 0.73 |
| 227 | ＞400 | |
| 228 | 4.26 | 15.1 |
| 229 | 31.3 | |
| 230 | 6.5 | 31.4 |
| 231 | 2.25 | 5.12 |
| 232 | 54.2 | |
| 233 | 2.45 | 11.5 |
| 234 | 13.4 | 36.1 |
| 235 | 222 | |
| 236 | 0.94 | 3.91 |
| 237 | ＞400 | |
| 238 | 6.46 | 25.7 |
| 239 | 46.8 | |
| 240 | 152 | |
| 241 | 1.65 | 5.72 |
| 242 | 0.36 | 3.37 |
| 243 | 11.3 | 91.3 |
| 244 | 2.42 | 16.2 |
| 245 | 2.61 | 12.4 |
| 246 | 6.58 | 69 |
| 247 | 0.65 | 0.95 |
| 248 | 108 | |
| 249 | 2.51 | 16.3 |
| 250 | 3.72 | 18.1 |
| 251 | 0.51 | 2.33 |
| 252 | 205 | |
| 253 | 4.5 | 26 |
| 254 | 12.3 | 153 |
| 255 | 13.1 | 130 |
| 256 | 98.6 | |
| 257 | 224 | |
| 258 | ＞400 | |
| 259 | 132 | |
| 260 | ＞400 | |
| 261 | 76.7 | |
| 262 | 8.25 | 38.9 |
| 263 | 8.36 | 100 |
| 264 | 6.75 | 103 |
| 265 | 13.1 | 82 |
| 266 | 0.94 | 4.34 |
| 267 | 78 | |
| 268 | ＞400 | |
| 269 | 23.8 | |
| 270 | 0.76 | 2.62 |
| 271 | 2.91 | 24.9 |
| 272 | ＞400 | |
| 273 | ＞400 | |
| 274 | ＞400 | |
| 275 | ＞400 | |
| 276 | ＞400 | |
| 277 | 31.7 | |
| 278 | 68.8 | |
| 279 | 54.1 | |
| 280 | 176 | |
| 281 | 4.83 | 37.4 |
| 282 | 0.17 | 0.78 |
| 283 | ＞400 |
| 284 | 1.03 | 12.3 |
| 285 | 27.9 | |
| 286 | 5.74 | 36.1 |
| 287 | ＞400 | |
| 288 | 1.18 | 9.53 |
| 289 | 5.13 | 35.8 |
| 290 | 92 | |
| 291 | 1.2 | |
| 292 | 5.25 | 19 |
| 293 | ＞400 | |
| 294 | ＞400 | |
| 295 | 9.17 | 64.3 |
| 296 | 64.1 | |
| 297 | 124 | |
| 298 | 182 | |
| 299 | 8.56 | 23.8 |
| 300 | 5.85 | 121 |
| 301 | 70.3 | |
| 302 | 5.41 | 33.1 |
| 303 | 2.27 | 11 |
| 304 | 152 |
| 305 | 18 | 86.4 |
| 306 | 0.78 | 1.39 |
| 307 | 1.27 | 1.56 |
| 308 | 2.63 | 5.55 |
| 309 | 1.59 | 2.59 |
| 310 | 1.48 | 2.1 |
| 311 | 147 | |
| 312 | 178 | |
| 313 | 273 | |
| 314 | 130 | |
| 315 | 2.91 | 8.67 |
| 316 | 243 | |
| 317 | 31.1 | |
| 318 | 68.7 | |
| 319 | 45.8 | |
| 320 | 12 | 63.2 |
| 321 | 1.58 | 16.6 |
| 322 | 8.89 | 109 |
| 323 | 2.99 | 22.5 |
| 324 | 0.15 | 2.6 |
| 325 | 1.97 | 5.33 |
| 326 | 15.8 | 53.2 |
| 327 | 4.19 | 18.1 |
| 328 | 0.71 | 1.7 |
| 329 | 2.93 | 8 |
| 330 | 0.2 | 0.41 |
| 331 | 2.2 | 9.9 |
| 332 | 15 | 27.3 |
| 333 | 1.49 | 3.75 |
| 334 | 1.72 | 9.41 |
| 335 | 3.21 | 14.9 |
| 336 | 0.11 | 0.52 |
| 337 | 3.48 | 21.1 |
| 338 | 3.43 | 24.9 |
| 339 | 5.36 | 21.6 |
| 340 | 2.59 | 7.22 |
| 341 | 3.74 | 13.9 |
| 342 | 20.5 | |
| 343 | 216 | |
| 344 | 10.1 | 60.2 |
| 345 | 0.61 | 1.69 |
| 346 | 5.14 | 12.1 |
| 347 | 24.4 | |
| 348 | 7.83 | 19.7 |
| 349 | 101 | |
| 350 | 229 | |
| 351 | 24.3 | |
| 352 | 4.14 | 49.5 |
| 353 | 72.8 | |
| 354 | 11.7 | ＞500 |
| 355 | 52.9 | |
| 356 | 32.6 | |
| 357 | 2.93 | 48.6 |
| 358 | 4.89 | 7.46 |
| 359 | 47.2 | |
| 360 | 73.5 | |
| 361 | 41.6 | |
| 362 | 125 | |
| 363 | 57.8 | |
| 364 | 20.9 | |
| 365 | 11.9 | 34.8 |
| 366 | 241 | |
| 367 | 41.4 |
| 368 | 2 | 4.55 |
| 369 | 28.1 | |
| 370 | 132 | |
| 371 | 54.8 | |
| 372 | 22.6 | |
| 373 | 14.6 | 11.6 |
| 374 | 7.33 | 12.5 |
| 375 | 7.92 | 31.4 |
| 376 | 1.52 | 4.4 |
| 377 | 22.5 | |
| 378 | 158 | |
| 379 | ＞400 | |
| 380 | ＞400 | |
| 381 | 15.3 | 26.9 |
| 382 | 238 | |
| 383 | ＞400 | |
| 384 | 286 | |
| 385 | 166 | |
| 386 | 209 | |
| 387 | ＞400 | |
| 388 | ＞400 |
| 389 | ＞400 | |
| 390 | ＞400 | |
| 391 | ＞400 | |
| 392 | ＞400 | |
| 393 | ＞400 | |
| 394 | ＞400 | |
| 395 | 41.2 | 30.8 |
| 396 | 239 | |
| 397 | 243 | |
| 398 | 5.8 | 26.6 |
| 399 | ＞400 | |
| 400 | 12.3 | 28.1 |
| 401 | ＞400 | |
| 402 | 277 | |
| 403 | ＞400 | |
| 404 | 13.1 | 38.2 |
| 405 | 48.1 | |
| 406 | 89.7 | |
| 407 | 36.2 | |
| 408 | ＞400 | |
| 409 | 73 |
| 410 | 104 | |
| 411 | 3.73 | 21.3 |
| 412 | ＞400 | |
| 413 | 14 | 52 |
| 414 | 7.61 | 38.6 |
| 415 | 8.69 | 10.8 |
| 416 | 9.26 | 47.1 |
| 417 | 7.84 | 25.7 |
| 418 | 0.78 | 4.07 |
| 419 | 110 | |
| 420 | 11.2 | 43.7 |
| 421 | 2.88 | 17.2 |
| 422 | 4.67 | 19.6 |
| 423 | 5.19 | 30.8 |
| 424 | 1.28 | 10.2 |
| 425 | 0.92 | 3.36 |
| 426 | 90 | |
| 427 | 15 | 50.5 |
| 428 | 0.89 | |
| 429 | 0.44 | |
| 430 | 18.2 |
| 431 | 13.6 | |
| 432 | 15.7 | 101 |
| 433 | 35.5 | |
| 434 | 55.1 | |
| 435 | 6.5 | |
| 436 | 1.13 | |
| 437 | 2.79 | |
| 438 | 10.9 | 20 |
| 439 | 3.26 | |
| 440 | 104 | |
| 441 | ＞400 | |
| 442 | ＞400 | |
| 443 | ＞400 | |
| 444 | ＞400 | |
| 445 | ＞400 | |
| 446 | 168 | |
| 447 | 170 | |
| 448 | ＞400 | |
| 449 | ＞400 | |
| 450 | 241 | |
| 451 | ＞400 |
| 452 | ＞400 | |
| 453 | ＞400 | |
| 454 | ＞400 | |
| 455 | 33.6 | |
| 456 | 43.8 | |
| 457 | 1.77 | 108 |
| 458 | 120 | |
| 459 | 2.78 | 17.7 |
| 460 | 24.6 | |
| 461 | ＞400 | |
| 462 | 2.29 | 13 |
| 463 | 274 | |
| 464 | 58 | |
| 465 | ＞400 | |
| 466 | ＞400 | |
| 467 | 53.8 | |
| 468 | 23.5 | |
| 469 | 80.7 | |
| 470 | 11.2 | 33.7 |
| 471 | ＞400 | |
| 472 | 19.6 | 52.7 |
| 473 | 17 | 41.8 |
| 474 | 41.2 | |
| 475 | 141 | |
| 476 | 6.48 | 31.4 |
| 477 | 28.3 | |
| 478 | 21.3 | 23.7 |
| 479 | 13.4 | 131 |
| 480 | 15.3 | 42.6 |
| 481 | 52.6 | |
| 482 | 12.1 | 22.2 |
| 483 | 84 | |
| 484 | ＞400 | |
| 485 | 152 | |
| 486 | 43.9 | |
| 487 | 109 | |
| 488 | 5.61 | 21.4 |
| 489 | 127 | |
| 490 | 12.4 | 63.1 |
| 491 | 88.5 | |
| 492 | 1.32 | 9.71 |
| 493 | 0.95 | 9.94 |
| 494 | 0.34 | 1.17 |
| 495 | 130 | |
| 496 | 16.5 | 30.2 |
| 497 | 16.7 | 59.5 |
| 498 | 16.4 | 38.3 |
| 499 | 18.3 | 204 |
| 500 | 10.1 | 47.4 |
| 501 | 24.2 | 16.8 |
| 502 | 17.3 | 36.9 |
| 503 | 321 | |
| 504 | 21.3 | 132 |
| 505 | 301 | |
| 506 | 1.3 | 8.97 |
| 507 | 212 | |
| 508 | 2.71 | 16.2 |
| 509 | 0.45 | 7.55 |
| 510 | 6.87 | 24.8 |
| 511 | 0.68 | 6.7 |
| 512 | 8.4 | 31.4 |
| 513 | 2.3 | 13.7 |
| 514 | 3.03 | 33.3 |
| 515 | 37.5 | |
| 516 | 4.28 | 44.6 |
| 517 | 15.9 | 111 |
| 518 | 1.8 | 13.6 |
| 519 | 0.95 | 5.77 |
| 520 | 1.88 | 10.1 |
| 521 | ＞400 | |
| 522 | ＞400 | |
| 523 | 5.22 | 2.8 |
ND not tested
Examples and preparation examples
The invention is illustrated by the following non-limiting examples and preparations, in which all operations are carried out at room or ambient temperature, i.e. in the range of 18 to 25 degrees celsius, unless otherwise stated; evaporation of the solvent was carried out using a rotary evaporator under reduced pressure at a bath temperature of at most 60 ℃; the reaction was monitored by Thin Layer Chromatography (TLC), the reaction time was for illustration only; are listed belowUncorrected (polymorphism can lead to different melting points); the structure and purity of all isolated compounds was determined by at least one of the following techniques: TLC (through Merck silica gel 60F)254Precoated TLC plates or Merck NH2Gel (amine-coated silica gel) F254sPre-coated TLC plates), mass spectrometry, Nuclear Magnetic Resonance (NMR), infrared absorption spectroscopy (IR), or micro-separations. The yields are given for illustration only. The cation exchange column treatment was carried out using SCX cartridges (Varian BondElute), which were preconditioned with methanol. Flash column chromatography was performed using Merck SILICA gel 60(63-200 □ m), Wako SILICA gel 300HG (40-60 □ m), Fuji Silysia NH gel (amine-coated SILICA gel) (30-50 □ m), Biotage KP-SIL (32-63 □ m), or Biotage aminosilicA (amine-coated SILICA gel) (40-75 □ m). Preparative TLC was performed using Merck silica gel 60F254Precoated TLC plates (0.5 or 1.0mm thick). Low resolution mass spectral data (EI) were obtained on an Integration (Waters) mass spectrometer. Low resolution mass spectral data (ESI) in ZMDTMOr ZQTM(Waters) and on a mass spectrometer. NMR data were obtained on 270MHz (JEOL JNM-LA 270 chromatograph), 300MHz (JEOL JNM-LA300 chromatograph) or 600MHz (Bruker AVANCE 600 chromatograph) using deuterated chloroform (99.8% D) and dimethylsulfoxide (99.9% D) as solvents in parts per million (ppm) relative to Tetramethylsilane (TMS) as internal standard, unless otherwise stated; the conventional abbreviations used are: s is singlet, d is doublet, t is triplet, q is quartet, quint is quintet, m is multiplet, bs is broad singlet, etc. The IR spectrum was measured by Fourier transform infrared spectrometer (Shimazu FTIR-8300). Chemical symbols have their usual meaning: bp (boiling point), mp (melting point), rt (room temperature), L (L), mL (mL), g (g), mg (mg), mol (mol), mmol (mmol), eq. (eq.), quant. (quantitative yield). The following abbreviations may be used in the examples: CDI (N, N' -carbonyldiimidazole), DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), edc.hcl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), HATU [2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea]TBTU [2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyltetrafluoroboric acid urea]EtOH (ethanol), HOBt (1)-hydroxy-1H-benzotriazole), MeOH (methanol), THF (tetrahydrofuran) and TFA (trifluoroacetic acid). Rf means the retention time determined by LC/MS (Waters 2790) under the following conditions:
column: xterra, C18, 5 μm, 4.6X 50mm (40 degrees Celsius)
Flow rate: 2.0mL/min
Gradient: Water/MeOH/1% HCO2H aq.＝90/5/5to 0/95/5
Total run time: 2.5 minutes
Example 1: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
Step 1: 1- (4-Fluorobenzyl) -1H-indazole-3-carboxylic acid methyl ester
To a solution of indazole-3-carboxylic acid methyl ester (1.0g, 5.67mmol) in anhydrous THF (30ml) cooled in an ice bath was slowly added solid potassium tert-butoxide (694mg, 6.18 mmol). Then, the mixture was stirred at room temperature for 1 hour, and then 4-fluorobenzyl bromide (1.1ml, 8.96mmol) was added at 0 ℃. The reaction mixture was stirred at room temperature for 5 hours, then quenched by addition of water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate-hexane as eluent to give the pure product methyl 1- (4-fluorobenzyl) -1H-indazole-3-carboxylate (1.5g, 92% yield).
1H NMR(400MHz，CDCl3)δ：4.04(s，3H)、5.66(s，2H)、6.95-7.00(m，2H)、7.18-7.22(m，2H)、7.28-7.39(m，3H)、8.22-8.24(m，1H)。FIA-MS：285.2[M+H]+、307.2[M+H+Na]+。
Step 2: 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid
To a solution of methyl 1- (4-fluorobenzyl) -1H-indazole-3-carboxylate (300mg, 1.05mmol) dissolved in methanol was added 1M NaOH (2 mL). The mixture was stirred at ambient temperature for 12 hours. After completion of the reaction, the mixture was evaporated to dryness. The residue was dissolved in water and neutralized with 1n hcl, then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the desired product 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (280mg, 98% yield) as a white solid.
1H NMR(400MHz，DMSO-d6)δ：5.76(s，2H)、7.14-7.18(m，2H)、7.29-7.35(m，3H)、7.45-7.49(m，1H)、7.85(d，J＝8.4Hz，1H)、8.09(d，J＝8.0Hz，1H)、13.1(br s，1H)。FIA-MS：271.3[M+H]+、293.3[M+H+Na]+。
And step 3: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
A mixture of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (100mg, 0.37mmol), L-tert-leucinamide (preparation 1, 73.5mg, 0.56mmol), EDC.HCl (108mg, 0.56mmol), HOBt (76mg, 0.56mmol) and N, N-diisopropylethylamine (0.33mL, 1.88mmol) in dry DMF (5mL) was stirred at room temperature for 18H. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (100 mesh 200) using 50% ethyl acetate-hexane as eluent to give the pure product N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide (70mg, 49% yield) as a white solid.
1H NMR(400MHz，CD3OD)δ：1.10(s，9H)、4.53(s，1H)、5.71(s，2H)、7.02-7.06(m，2H)、7.26-7.32(m，3H)、7.40-7.44(m，1H)、7.59(d，J＝8.8Hz，1H)、8.21(d，J＝8.0Hz，1H)。FIA-MS：383.2[M+H]+、405.1[M+H+Na]+。
Example 2: n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
A mixture of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (example 1, step 2, 100mg, 0.37mmol), L-tert-leucinamide (65.5mg, 0.56mmol), EDC.HCl (108mg, 0.56mmol), HOBt (76mg, 0.56mmol) and N, N-diisopropylethylamine (0.33mL, 1.88mmol) in anhydrous DMF (5mL) was stirred at room temperature for 18H. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel using 50% ethyl acetate-hexane as eluent to give the pure product N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide as a white solid (88mg, 64% yield).
1H NMR(400MHz，CD3OD)δ：1.03(d，J＝6.8Hz，3H)、1.05(d，J＝6.8Hz，3H)、2.14-2.24(m，1H)、4.50(d，J＝6.4Hz，1H)、5.71(s，2H)、7.02-7.06(m，2H)、7.26-7.32(m，3H)、7.40-7.44(m，1H)、7.59(d，J＝8.8Hz，1H)、8.21(d，J＝8.0Hz，1H)。FIA-MS：369.2[M+H]+、391.3[M+H+Na]+。
Example 3: n- [ (1S) -2-amino-2-oxo-1-phenylethyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
A mixture of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (example 1, step 2, 100mg, 0.37mmol), (S) -2-amino-2-phenyl-acetamide (84.7mg, 0.56mmol), EDC.HCl (108mg, 0.56mmol), HOBt (76mg, 0.56mmol) and N, N-diisopropylethylamine (0.33mL, 1.88mmol) in anhydrous DMF (5mL) was stirred at room temperature for 18H. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel using 50% ethyl acetate-hexane as eluent to give the pure product N- [ (1S) -2-amino-2-oxo-1-phenylethyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide (90mg, 60% yield) as a white solid.
1H NMR(400MHz，CD3OD)δ：5.68(s，1H)、5.70(s，2H)、7.01-7.05(m，2H)、7.24-7.43(m，7H)、7.53-7.59(m，3H)、8.18(d，J＝8.4Hz，1H)。FIA-MS：403.3[M+H]+、425.1[M+H+Na]+。
Example 4: n-alpha- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -L-phenylalanine amide
A mixture of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (example 1, step 2, 100mg, 0.37mmol), L-phenylalanine amide (92mg, 0.56mmol), EDC.HCl (108mg, 0.56mmol), HOBt (76mg, 0.56mmol) and N, N-diisopropylethylamine (0.33mL, 1.88mmol) in anhydrous DMF (5mL) was stirred at room temperature for 18H. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel using 50% ethyl acetate-hexane as eluent to give N- α - { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -L-phenylalanine amide (55mg, 32% yield) as a white solid.
1H NMR(400MHz，CD3OD)δ：3.08-3.26(m，3H)、5.67(s，2H)、7.02-7.06(m，2H)、7.17-7.30(m，8H)、7.38-7.42(m，1H)、7.58(d，J＝8.8Hz，1H)、8.14(d，J＝8.4Hz，1H)。FIA-MS：417.2[M+H]+。
Example 5: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxamide
Step 1: 1- [ (5-Methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylic acid methyl ester
To a solution of indazole-3-carboxylic acid methyl ester (200mg, 1.14mmol) in anhydrous THF (6ml) cooled in an ice bath was slowly added solid potassium tert-butoxide (138.8mg, 1.23 mmol). Then, the mixture was stirred at room temperature for 1 hour, and then 3-chloromethyl-5-methylisoxazole (235mg, 1.79mmol) was added at 0 ℃. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 15% ethyl acetate-hexane as eluent to give methyl 1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylate (150mg, 42% yield).
1H NMR(400MHz，CDCl3)δ：2.32(s，3H)、4.05(s，3H)、5.70(s，2H)、5.84(s，1H)、7.30-7.34(m，1H)、7.41-7.45(m，1H)、7.53(d，J＝8.4Hz，1H)、8.20-8.22(m，1H)。FIA-MS：272.3[M+H]+、294.1[M+H+Na]+。
Step 2: 1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylic acid
To a solution of methyl 1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylate (500mg, 1.84mmol) in methanol (3mL) was added 1M NaOH (3 mL). The mixture was stirred at ambient temperature for 4 hours. After completion of the reaction, the mixture was evaporated to dryness. The residue was dissolved in water and acidified to pH 6 with 1N HCl, then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give 1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylic acid as a white solid (450mg, 95% yield).
1H NMR(400MHz，DMSO-d6)δ：2.32(s，3H)、5.83(s，2H)、6.05(s，1H)、7.34(t，J＝7.6Hz，1H)、7.48-7.83(m，1H)、7.82(d，J＝8.4Hz，1H)、8.09(d，J＝8.0Hz，1H)、13.1(br s，1H)。FIA-MS：258.3[M+H]+、280.2[M+H+Na]+。
And step 3: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxamide
A mixture of 1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxylic acid (100mg, 0.39mmol), L-tert-leucinamide (preparation 1, 77.48mg, 0.59mmol), EDC.HCl (114.25mg, 0.59mmol), HOBt (80.5mg, 0.59mmol) and N, N-diisopropylethylamine (0.35mL, 2.01mmol) in anhydrous DMF (5mL) was stirred at room temperature for 18 hours. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (100-200 mesh) using 70% ethyl acetate-hexane as eluent to give N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- [ (5-methylisoxazol-3-yl) methyl ] -1H-indazole-3-carboxamide (45mg, 30% yield) as a white solid.
1H NMR(400MHz，CD3OD)δ：1.09(s，9H)、2.34(s，3H)、4.52-4.54(m，1H)、5.75(s，2H)、6.01(s，1H)、7.28-7.32(m，1H)、7.45-7.48(m，1H)、7.65(d，J＝8.8Hz，1H)、8.22(d，J＝8.0Hz，1H)。FIA-MS：370.4[M+H]+、392.3[M+H+Na]+。
Example 6: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxamide
Step 1: 1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxylic acid methyl ester
To a solution of indazole-3-carboxylic acid methyl ester (200mg, 1.14mmol) in anhydrous THF (6ml) cooled in an ice bath was slowly added solid potassium hydride (840mg, 7.5 mmol). The mixture was then stirred at room temperature for 2 hours, then a solution of 2- (chloromethyl) pyridine hydrochloride (294mg, 1.79mmol) in DMF (1mL and 1mL triethylamine) was added at 0 deg.C the reaction mixture was stirred at room temperature for 12 hours then at 60 deg.C the reaction was quenched by addition of water and extracted with ethyl acetate the organic layer was dried over sodium sulfate and concentrated under reduced pressure the residue was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate-hexane as eluent to give methyl 1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxylate (100mg, 33% yield).
1H NMR(400MHz，DMSO-d6)δ：3.91(s，3H)、5.89(s，2H)、7.17(d，J＝8.0Hz，1H)、7.29-7.38(m，2H)、7.49(t，J＝7.2Hz，1H)、7.74-7.83(m，2H)、8.10(d，J＝8.0Hz，1H)、8.47(br s，1H)。MS 268.1[M+H]+。
Step 2: 1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxylic acid
To a solution of methyl 1-pyridin-2-ylmethyl-1H-indazole-3-carboxylate (350mg, 1.31mmol) in methanol (3mL) was added 1M NaOH (3 mL). The mixture was stirred at ambient temperature for 6 hours. After completion of the reaction, the mixture was evaporated to dryness. The residue was dissolved in water and acidified to pH 6 with 1n hcl, then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the desired product 1-pyridin-2-ylmethyl-1H-indazole-3-carboxylic acid (150mg, 45% yield) as a yellowish solid.
1H NMR(400MHz，DMSO-d6)δ：5.87(s，2H)、7.15(d，J＝8.0Hz，1H)、7.29-7.34(m，2H)、7.46(t，J＝7.6Hz，1H)、7.74-7.79(m，2H)、8.10(d，J＝8.4Hz，1H)、8.48(d，J＝4.4Hz，1H)、13.1(br s，1H)。FIA-MS：254.3[M+H]+、276.2[M+H+Na]+。
And step 3: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxamide
A mixture of 1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxylic acid (100mg, 0.39mmol), L-tert-leucinamide (preparation 1, 78.4mg, 0.60mmol), EDC.HCl (115.6mg, 0.60mmol), HOBt (81.4mg, 0.60mmol) and N, N-diisopropylethylamine (0.35mL, 2.01mmol) in anhydrous DMF (5mL) was stirred at room temperature for 18H. Then, after completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and then concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel using 70% ethyl acetate-hexane as eluent to give N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-indazole-3-carboxamide as a white solid (105mg, 73% yield).
1H NMR(400MHz，DMSO-d6)δ：0.97(s，9H)、4.45(d，J＝9.6Hz，1H)、5.89(br s，2H)、7.16(d，J＝7.6Hz，1H)、7.27-7.31(m，3H)、7.43-7.45(m，1H)、7.57(d，J＝9.6Hz，1H)、7.71-7.76(m，3H)、8.18(d，J＝8.0Hz，1H)、8.48(d，J＝4.8Hz，1H)。FIA-MS：366.4[M+H]+、388.3[M+H+Na]+。
Example 7: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-bromo-1H-indazole-3-carboxamide
Step 1: 1-benzyl-5-bromo-1H-indazole-3-carboxylic acid methyl ester
To a slurry of 60% sodium hydride (0.157g, 3.92mmol) in anhydrous THF (15mL) was added methyl 6-bromo-1H-indazole-3-carboxylate (1.0g, 3.92 mmol). During the addition, gas is generated. After stirring at room temperature under nitrogen for 30 minutes, benzyl bromide (0.68g, 3.98mmol) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between brine and ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (70g) using 30% ethyl acetate-hexane as eluent to give 0.996g (73.6%) of the title compound:1H NMR(400MHz，CDCl3)δppm 4.08(s，3H)5.68(s，2H)7.24(dd，J＝7.51、1.71Hz，2H)7.31-7.38(m，3H)7.43(dd，J＝8.53、1.37Hz，1H)7.54-7.58(m，1H)8.13(d，J＝8.53Hz，1H)。
step 2: 1-benzyl-5-bromo-1H-indazole-3-carboxylic acid
To a solution of methyl 1-benzyl-5-bromo-1H-indazole-3-carboxylate (0.907g, 2.63mmol) in methanol (30mL) was added 1N NaOH (5.0mL, 50 mmol). The mixture was heated to 50 ℃ and held for 2 hours, then cooled to room temperature. The mixture was acidified to pH 4 with 1N HCl and then extracted twice with ethyl acetate (30 mL). The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.7969g (91.6%) of the title compound.1H NMR(400MHz，DMSO-d6)δppm 5.59(d，J＝3.07Hz，2H)7.10-7.17(m，3H)7.18-7.26(m，4H)7.31-7.37(m，1H)8.33-8.40(m，1H)。
And step 3: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-bromo-1H-indazole-3-carboxamide
To a mixture of 1-benzyl-5-bromo-1H-indazole-3-carboxylic acid (0.7969g, 2.406mmol) in THF was added L-tert-leucinamide hydrochloride (preparation 1, 0.401g, 2.41mmol), diisopropylethylamine (1.5mL, 2.41mmol), and HATU (0.915g, 2.41 mmol). The mixture was stirred at room temperature for 3 hours and then partitioned between brine and ethyl acetate. The layers were separated and the organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The mixture contained some tetramethylurea from HATU. The residue was dissolved in dichloromethane and washed 6 times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (70g) using 50: 40: 10 ethyl acetate: dichloromethane: hexane as eluent to give 0.7598g (71%) of the title compound.1H NMR(400MHz，CDCl3)δppm 1.17(s，9H)4.57(d，J＝9.22Hz，1H)5.57(br.s.，1H)5.63(s，2H)6.02(br.s.，1H)7.16-7.25(m，3H)7.30-7.38(m，3H)7.44(dd，J＝8.88，1.71Hz，1H)7.70(d，J＝9.56Hz，1H)8.54(d，J＝1.71Hz，1H)。
Example 8: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-pyridin-3-yl-1H-indazole-3-carboxamide
To N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl radical]To a mixture of-1-benzyl-5-bromo-1H-indazole-3-carboxamide (example 25, 0.1011g, 0.228mmol) in 1, 4-dioxane (5.0mL) and water (2.0mL) was added potassium hydrogen phosphate (0.12g, 0.684mmol) and 3-pyridineboronic acid (0.0841g, 0.684 mmol). Nitrogen was bubbled through the mixture for 5 minutes, at which time 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (0.018g, 0.025mmol) was added, and then the mixture was heated to 80 ℃ under nitrogen overnight. The heating of the mixture was stopped and allowed to cool to room temperature. The mixture was partitioned between brine and ethyl acetate, then the layers were separated and the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate extracts were washed four times with brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20g) using ethyl acetate as eluent to give 0.0633g (63%) of the title compound: MS (ESI +) M/z 442.2243(M + H) C26H27N5O2+；1H NMR(400MHz，DMSO-d6)δppm 0.97(s，9H)4.44(d，J＝10.25Hz，1H)5.79(s，2H)7.17(br.s.，1H)7.21-7.27(m，3H)7.27-7.34(m，2H)7.45(dd，J＝8.05，5.12Hz，1H)7.61(d，J＝9.52Hz，1H)7.66(br.s.，1H)7.76(dd，J＝8.79，2.20Hz，1H)7.82-7.90(m，1H)8.00-8.08(m，1H)8.37(s，1H)8.49-8.59(m，1H)8.85(d，J＝1.46Hz，1H)。
Example 9: n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl]Carbonyl } -3-methyl-L-valylglycine
Step 1: ((S) -2- { [1- (4-Fluorobenzyl) -1H-indazole-3-carbonyl ] -amino } -3, 3-dimethylbutyryl-amino) acetic acid benzyl ester
To a solution of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (example 1, step 2, 114mg, 0.42mmol) in anhydrous DMF (5mL) was added N, N-diisopropylethylamine (0.5mL, 2.96mmol), edc.hcl (121mg, 0.63mmol), HOBT (86mg, 0.63mmol), and then it was stirred at room temperature under nitrogen atmosphere for 1 hour. Then, (2-amino-3, 3-dimethylbutyrylamino) acetic acid benzyl ester hydrochloride (preparation 3, 200mg, 0.63mmol) was added and stirring was continued at room temperature for 18 hours. Upon completion of the reaction (monitored by TLC, Rf ═ 0.5; solvent system: 30% ethyl acetate in hexane, spots visible with UV or iodine), the solution was diluted with water (50mL), extracted with ethyl acetate (50mL) and washed with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (200 mg). The crude product was subjected to column chromatography using 100-mesh 200-mesh silica gel eluting with 15-20% ethyl acetate-hexane to give ((S) -2- { [1- (4-fluorobenzyl) -1H-indazole-3-carbonyl) as a viscous semi-solid]-amino } -3, 3-dimethylbutyrylamino) acetic acid benzyl ester (193mg, yield 83%).1H NMR(400MHz，DMSO-d6)δ：0.99(s，9H)、3.87-3.93(dd，J＝8.4，17.2Hz，1H)、3.99-4.05(dd，J＝6，17.6Hz，1H)、4.57(d，J＝10Hz，1H)、5.12(s，2H)、5.78(s，2H)、7.15(t，J＝8.8Hz，2H)、7.28-7.35(m，8H)、7.46(t，J＝8Hz，1H)、7.61(d，J＝9.6Hz，1H)、7.79(d，J＝8.8Hz，1H)、8、17(d，J＝8Hz，1H)、8.80(t，J＝6Hz，1H)。FIA-MS：531.0[M+H]+、553.3[M+H+Na]+。
Step 2: n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine
To already((S) -2- { [1- (4-fluorobenzyl) -1H-indazole-3-carbonyl) flushed with nitrogen]To a solution of benzyl-amino) -3, 3-dimethylbutyrylamino) acetate (96mg, 0.181mmol) in pure ethanol (5mL) was added 10% palladium on carbon (10mg), and the resulting mixture was stirred under hydrogen (1atm) at room temperature for 5 hours. On completion of the reaction (monitored by TLC, Rf ═ 0.1; solvent system: ethyl acetate, spots visible with UV or iodine), the mixture was filtered through a bed of celite and the filtrate was evaporated to give N- { [1- (4-fluorobenzyl) -1H-indazol-3-yl as a white solid]Carbonyl } -3-methyl-L-valylglycine (40mg, 50.6% yield).1H NMR(400MHz，DMSO-d6)δ：1.00(s，9H)、3.75(dd，J＝6，18Hz，1H)、3.85(dd，J＝6，17Hz，1H)、4.56(d，J＝10Hz，1H)、5.78(s，2H)、7.16(m，2H)、7.27-7.33(m，3H)、7.46(t，J＝8Hz，1H)、7.62(d，J＝10Hz，1H)、7.80(d，J＝9Hz，1H)、8.17(d，J＝8Hz，1H)、8.67(t，J＝6Hz，1H)。FIA-MS：441.2[M+H]+、463.2[M+H+Na]+。
Example 10: 1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide
Step 1: 7-fluoro-1H-indazole-3-carboxylic acid
This compound was according to Johnson, b.l.; rodgers, J.D.Syn.Comm.2005, 35, 2681-2684. While stirring, a suspension of 5.28g of 7-fluoroisatin in 30mL of water was added to a solution of 1.30g of NaOH in 10 mL. The resulting dark red solution was stirred until all the solids were dissolved, and then cooled in an ice-water bath. Then, willThis solution was slowly added to 2.21g of NaNO2In an ice-cold (ice-bath) solution in 10mL of water. These combined solutions were then slowly added to an ice-cold (ice bath) aqueous sulfuric acid solution (3.4mL H2SO4In 60mL of water). Ice was added to maintain a temperature of about 0 ℃. After stirring for about 10 minutes, the dark red diazonium solution was slowly added to 18g SnCl22H2O was in a30 mL solution of concentrated HCl in cold (0 ℃ C., ice bath). Ice was added again to maintain a temperature of about 0 ℃. After stirring for about 1 hour, the reaction mixture was filtered, and the resulting residue was dissolved in 1N NaOH (60mL) and washed with ether (2 × 50 mL). The resulting brown-yellow solution was cooled in an ice bath and acidified to pH-3 with concentrated HCl (litmus paper), which resulted in the formation of a dark yellow precipitate. The precipitate was collected by filtration and washed with water and then dried in an oven overnight to give 3.69g (47%) of 7-fluoro-1H-indazole-3-carboxylic acid as an orange solid.1H NMR(400MHz，DMSO-d6)δ14.35(br s，1H)、13.22(br s，1H)、7.89-7.87(m，1H)、7.26-7.21(m，2H)。MS(ESI)m/z 181(M+H)+。
Step 2: 7-fluoro-1H-indazole-3-carboxylic acid methyl ester
A solution of 30g of 7-fluoro-1H-indazole-3-carboxylic acid in 1200mL of anhydrous methanol was added to 8mL of concentrated sulfuric acid. The resulting mixture was heated to reflux and refluxed overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (1000 mL). The organic solution was washed with saturated NaHCO3Washed (2X 250mL), brine (2X 250mL), dried (MgSO4) Filtered and concentrated to a brown solid. The crude reaction was purified by MPLC (5% -30% diethyl ether/heptane) to give 20.74g (64%) methyl 7-fluoro-1H-indazole-3-carboxylate as a bright yellow solid.1H NMR(400MHz，DMSO-d6)δ14.49(br s，1H)、7.85-7.83(m，1H)、7.28-7.21(m，2H)、3.92(s，3H)。MS(ESI)m/z 195(M+H)+。
And step 3: 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylic acid methyl ester
A suspension of 1.67g of 60% sodium hydride in 134.0mL of anhydrous DMF was added dropwise by syringe to a solution of 7g of methyl 7-fluoro-1H-indazole-3-carboxylate in 10mL of anhydrous DMF at room temperature. The mixture was stirred at room temperature for about 1 hour, then a solution of 8.02g of 4-cyanobenzyl bromide in 56mL of DMF was added dropwise via syringe. The resulting mixture was then heated to 60 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and quenched by the careful addition of water (500 mL). The aqueous solution was extracted with ethyl acetate (4 × 150 mL). The organic solution was washed with brine (2 × 200mL), dried (MgSO)4) Filtered and concentrated to an oil. The crude product was purified by MPLC (25% -50% ethyl ether/heptane) to give 7.68g (68.8%) of methyl 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylate as a light yellow solid.1H NMR(400MHz，CDCl3)δ8.01(d，J＝8.0Hz，1H)、7.60(d，J＝7.8Hz，2H)、7.36(d，J＝8.0Hz，2H，7.20-7.28(m，1H)、7.06-7.14(m，1H)、5.85(s，2H)、4.06(s，3H)。MS(ESI)m/z310(M+H)+。
And 4, step 4: 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylic acid
A solution of 6.07g of methyl 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylate in 100mL THF was added to 20mL of 2.5M sodium hydroxide at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with 150mL of water and the aqueous solution was washed with diethyl ether (3 × 50 mL). The aqueous solution was placed in an ice bathCooled and acidified with concentrated HCl to pH-3 to give a white precipitate. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 5.42g (94%) of 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylic acid as a white solid.1H NMR(400MHz，DMSO-d6)δ13.38(br s，1H)、7.93-7.92(m，1H)、7.79(d，J＝8.2Hz，2H)、7.33-7.26(m，4H)、5.90(s，2H)。MS(ESI)m/z195(M+H)+。
And 4, step 4: 1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide
While stirring, a solution of 1.05g 1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxylic acid and 3.1mL N, N-diisopropylethylamine in 18mL DMF was added to 1.66g HATU. The resulting mixture was stirred for 10 minutes, and then 908mg of (S) -2-amino-N- (2-hydroxyethyl) -3, 3-dimethylbutanamide hydrochloride (preparation example 4) was added. The resulting brown-yellow solution was stirred at room temperature overnight. The dark brown reaction mixture was diluted with water (100 mL). The aqueous solution was extracted with ethyl acetate (3 × 25 mL). The combined organic solutions were washed with brine (2 × 25mL) and dried (MgSO)4) Filtered and concentrated under reduced pressure to give a dark brown oil. The crude reaction product was purified by MPLC (25-50% ethyl acetate/heptane) to yield 1.27g (80%) of 1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] as an off-white solid]Carbonyl } -2, 2-dimethylpropyl radical]-1H-indazole-3-carboxamide.1H NMR(400MHz，DMSO-d6)δppm 8.32(t，J＝5.5Hz，1H，)、7.99-8.06(m，1H)、7.81(d，J＝8.2Hz，1H)、7.66(d，J＝9.7Hz，1H)、7.22-7.37(m，3H)、5.94(s，2H)、4.69(t，J＝5.1Hz，1H)、4.51(d，J＝9.7Hz，1H)、3.41(q，J＝5.7Hz，2H)、3.07-3.27(m，2H)、0.97(s，9H)。MS(ESI)m/z 195(M+H)+。MS(ESI)m/z 452(M+H)+。
Example 11: n- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
To a solution of 1- (4-fluorobenzyl) -1H-indazole-3-carboxylic acid (example 1, step, 200mg, 0.74mmol) in dichloromethane (2mL) were added TBTU (356mg, 1.11mmol) and triethylamine (0.52mL, 3.70 mmol). After stirring for 15 minutes at ambient temperature, (S) -5- ((2-amino-3, 3-dimethylbutyrylamino) methyl) -1, 3, 4-oxadiazole-2-carboxamide trifluoroacetate (preparation 27, 328mg, 0.89mmol) is added and stirring is continued for 1 hour. The reaction mixture was extracted with water, and then the two-phase solution was filtered through a phase separation tube. The resulting organic solution was concentrated to give the crude product as an oil. The crude material was purified by chromatography on silica gel (heptane/ethyl acetate) to give/\/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluoro-benzyl) -1H-indazole-3-carboxamide (95mg, 25% yield) as a colorless oil.
1H NMR(400MHz，DMSO-d6)δppm 0.98(s，9H)4.47-4.73(m，3H)5.77(s，2H)7.15(t，J＝8.79Hz，2H)7.23-7.38(m，3H)7.45(t，J＝7.69Hz，1H)7.62(d，J＝10.25Hz，1H)7.79(d，J＝8.79Hz，1H)8.16(d，J＝8.79Hz，1H)8.19(br.s.，1H)8.59(s，1H)9.16(t，J＝5.49Hz，1H)；LC-MS：508[M+H]+
Example 12: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide
Step 1: 1H-pyrrolo [3, 4-b ] pyridine-3-carboxylic acid ethyl ester
1H-pyrrolo [3, 4-b ] is reacted with]Pyridine-3-carboxylic acid (prepared according to Can.J.chem.1988, 66, 420-428 of Lynch, B.M. et al; 2g, 9mmol) was suspended in ethanol (60mL) and flushed with HCl gas for 5 minutes. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water, and washed with 2M Na2CO3The solution was neutralized and extracted with ethyl acetate (3 × 20 mL). The combined organics were concentrated and the residue was purified by chromatography using 40-60% ethyl acetate/hexanes as the eluent to give 1H-pyrrolo [3, 4-b ] as a light brown solid]Pyridine-3-carboxylic acid ethyl ester (904mg, 40%). LC-MS; 228, [ M + H ]]+。
Step 2: 1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxylic acid ethyl ester
1H-pyrrolo [3, 4-b ] is reacted with]A solution of pyridine-3-carboxylic acid ethyl ester (1.19g, 5.23mmol) in DMF (10mL) was added dropwise to a suspension of NaH (230mg, 5.75mmol) in DMF (10 mL). The reaction mixture was heated to 50 ℃ for 45 minutes, then a solution of benzyl bromide (1.79g, 10.5mmol) in 10mL of DMF was added dropwise. The reaction mixture was stirred at 50 ℃ overnight. The reaction mixture was quenched by addition of water while cooling in an ice bath, which was then extracted with ethyl acetate. The organic layer was washed with brine, over Na2SO4Dried and concentrated. The residue was purified by chromatography on silica gel using 40-60% ethyl acetate-hexanes as eluent to give 1-benzyl-1H-pyrrolo [3, 4-b ] as a white solid]Pyridine-3-carboxylic acid ethyl ester (620mg, 42.2%).
1H NMR(400MHz，DMSO-d6)δppm 1.34(t，J＝7.12Hz，3H)4.37(q，J＝7.25Hz，2H)5.78(s，2H)7.21-7.33(m，5H)7.45(dd，J＝8.06、4.57Hz，1H)8.47(dd，J＝8.06、1.61Hz，1H)8.68(dd，J＝4.56、1.61Hz，1H)。LC-MS；282[M+H]+、304[M+Na]+。
And step 3: 1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxylic acid
Ethyl 1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxylate (620mg, 2.2mmol), 1N NaOH (5mL), THF (5mL), and ethanol (5mL) were stirred at room temperature for 4 hours. The reaction mixture was concentrated, diluted with water, and neutralized with 1N HCl solution. The resulting precipitate was collected by filtration and air dried to give 1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxylic acid (525mg, 94%) as a white solid.
LC-MS；254[M+H]+、276[M+Na]+。
And 4, step 4: n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide
A mixture of 1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxylic acid (50mg, 0.20mmol), L-tert-leucinamide (preparation 1, 49.4mg, 0.30mmol), EDC.HCl (57mg, 0.30mmol), HOBt (40mg, 0.30mmol) and N, N-diisopropylethylamine (0.17mL, 0.98mmol) in anhydrous DMF (2mL) was stirred at 50 ℃ overnight. The crude reaction mixture was purified by reverse phase HPLC to give N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide as a viscous solid (7.4mg, 10%).
1H NMR(400MHz，DMSO-d6)δppm 0.99(s，8H)4.46(d，J＝9.52Hz，1H)5.80(d，J＝2.93Hz，2H)7.22(br.s.，1H)7.25-7.34(m，3H)7.41(dd，J＝8.05，4.39Hz，1H)7.63(d，J＝9.52Hz，1H)7.68(br.s.，1H)8.56(d，J＝9.15Hz，1H)8.68(d，J＝4.39Hz，1H)；LC-MS：365[M+H]+。
Preparation example:
preparation example 1: l-tert-leucinamide
Step 1: [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] carbamic acid benzyl ester
At room temperature to N- [ (benzyloxy) carbonyl]To a solution of tert-leucine (prepared according to Tetrahedron 2001, 57, 5303-5320, Emily, M.S. et al; 3.7g, 14mmol) in DMF (80mL) were added ammonium chloride (900mg, 17mmol), triethylamine (5.9mL, 42mmol), HOBt (2.8g, 18mmol), and EDC (3.1g, 18 mmol). After 17 h, the reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (100mL) and then extracted with ethyl acetate (100mL × 3). The combined organic layers were washed with water (100mL x 3), brine (50mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to give 3.0g (82%) of the title compound. MS (ESI) M/z 265(M + H)+。
Step 2: l-tert-leucinamide
To [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl group]To a solution of benzyl carbamate (3.7g, 14mmol) in THF (40mL) was added 10% Pd/C (710 mg). The flask was evacuated and washed with H2 gas and the process was repeated three times. By H2The flask was filled with gas (4atm), and stirred at room temperature for 3 hours. Then, the reaction mixture was filtered through a celite pad, and concentrated in vacuo to give the title compound (crude product; 1.8g) as a white solid.1H-NMR(300MHz，DMSO-d6)δ6.59(bs，1H)、5.92(bs，1H)、3.12(s，1H)、1.02(s，1H)。MS(ESI)m/z 131(M+H)+。
Preparation example 2: (S) -2-amino-N-carbamoylmethyl-3, 3-dimethylbutanamide hydrochloride
Step 1: [ (S) -1- (carbamoylmethylcarbamoyl) -2, 2-dimethylpropyl ] carbamic acid tert-butyl ester
To a solution of N-Boc-L-t-tert-leucine (1.0g, 4.327mmol) in anhydrous DMF (10ml) was added N, N-diisopropylethylamine (5.1ml, 30.3mmol), EDC.HCl (1.23g, 6.5mmol), HOBT (880mg, 6.5mmol) and stirred at room temperature under nitrogen for 30 min. Glycinamide hydrochloride (720mg, 6.5mmol) was then added thereto and stirring was continued at room temperature for 18 h. At the completion of the reaction (monitored by TLC, R)f0.3; solvent system 40% ethyl acetate in hexanes by KMnO4Or spots are visible with iodine)The solution was diluted with distilled water (100ml), which was then extracted with ethyl acetate (100ml), washed with brine (50ml), over anhydrous Na2SO4Dried above and concentrated under reduced pressure to give a crude product (1.6 g). The crude mixture was subjected to column chromatography using 100-200 mesh silica gel eluting with 30-50% ethyl acetate-hexane to give the desired product [ (S) -1- (carbamoylmethylcarbamoyl) -2, 2-dimethylpropyl ] as a viscous cake]Tert-butyl carbamate (1.09g, yield 87.9%).
Step 2: (S) -2-amino-N-carbamoylmethyl-3, 3-dimethylbutanamide hydrochloride:
reacting [ (S) -1- (carbamoylmethylcarbamoyl) -2, 2-dimethyl-propyl]Tert-butyl carbamate (1.09g, 3.79mmol) was dissolved in 40ml of 4N 1, 4-dioxane-HCl solution and stirred at room temperature under nitrogen for 4 hours. At the completion of the reaction (monitored by TLC, R)f0.1; solvent system 50% ethyl acetate in hexane, spots visible by UV) and then the dioxane was removed under reduced pressure to give the desired product (S) -2-amino-N-carbamoylmethyl-3, 3-dimethylbutanamide hydrochloride as a viscous semi-solid (750mg, 88% yield).1H NMR(400MHz，DMSO-d6)δ：0.99(s，9H)、3.56-3.59(m，1H)、3.69-3.72(m，2H)、7.10(br s，1H)、7.47(br s，1H)、8.25(br s，3H)、8.73(br s，1H)。FIA-MS：188.2[M+H]+。
Preparation example 3: ((S-2-amino-3, 3-dimethyl-butyrylamino) acetic acid benzyl ester hydrochloride
Step 1: ((S) -2-tert-Butoxycarbonylamino-3, 3-dimethylbutyrylamino) acetic acid benzyl ester
To a solution of N-Boc-L-tert-leucine (1.5g, 6.48mmol) in anhydrous DMF (40mL) was added N, N-diisopropylethylamine (8.0mL, 45.34mmol), EDC.HCl (1.89g, 9.89mmol) and HOBt (1.34g, 9.89mmol) under a nitrogen atmosphere, followed by stirring at room temperature for 1 h. Benzyl glycinate (as p-toluenesulfonate salt) (3.33g, 9.89mmol) was then added to the reaction mixture and stirred at room temperature for a further 18 hours. After completion of the reaction (monitored by TLC, 30% ethyl acetate in hexane, R of the productf0.5, spots were visible with UV and iodine), water (400ml) was added to the reaction mixture and extracted with ethyl acetate (400 ml). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material (2.7g) which was purified by column chromatography, silica gel column (100-200 mesh) using 20% ethyl acetate-hexane as an eluent to give benzyl ((S) -2-tert-butoxycarbonylamino-3, 3-dimethylbutyrylamino) acetate (2.0g, yield 82%) as a white solid.
1H NMR(400MHz，CDCl3)δ：0.99(s，9H)、1.41(s，9H)、3.87(d，J＝8.8Hz，1H)、3.93-3.97(m，1H)、4.17-4.21(m，1H)、5.14-5.23(m，3H)、6.19(s，1H)、7.31-7.38(m，5H)。FIA-MS：379.0[M+H]+、396.1[M+H+NH3]+、401.2[M+H+NH3]+。
Step 2: ((S) -2-amino-3, 3-dimethylbutyrylamino) acetic acid benzyl ester hydrochloride
Benzyl ((S) -2-tert-butoxycarbonylamino-3, 3-dimethylbutyrylamino) acetate (2.0g, 5.29mmol) was dissolved in 16ml of 4N HCl-1, 4-dioxane solution and stirred at room temperature under nitrogen for 4 hours. At the completion of the reaction (monitored by TLC, R)f0.1; solvent system 30% ethyl acetate in hexanes with a spot visible by UV) then the dioxane was removed under reduced pressure to give benzyl ((S) -2-amino-3, 3-dimethylbutyrylamino) acetate hydrochloride as an off-white solid (1.6g, 96% yield).
1H NMR(400MHz，CDCl3)δ：1.09(s，9H)、3.69(m，3H)、5.10(s，2H)、7.30-7.36(m，5H)、8.01(brs，3H)、8.60(br s，1H).
The following intermediates were prepared in a similar manner:
preparation example 21: (S) -5- ((2-amino-3, 3-dimethylbutanamide) methyl) -1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester trifluoroacetate salt
Step 1: (S) -5- ((2- (tert-butoxycarbonylamino) -3, 3-dimethylbutanamide) methyl) -1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester
To a solution of N-Boc-L-tert-leucine (4.91g, 21.2mmol) in dichloromethane (50mL) was added TBTU (10.2g, 31.9mmol) and triethylamine (8.88mL, 63.7 mmol). After stirring for 15 minutes at ambient temperature, ethyl 5- (aminomethyl) -1, 3, 4-oxadiazole-2-carboxylate (prepared according to Kolb, H.C. et al, U.S. Pat. No. 6951946.; 4.0g, 23.0mmol) was added and stirring continued for 18 hours. The organic layer was washed with water (100mL) and saturated sodium chloride (100mL) and dried over magnesium sulfate. Filtered and concentrated to give the crude product as a brown oil. The product was purified by normal phase chromatography (heptane/ethyl acetate) to give the title compound as a colorless oil (5.72g, 64% yield).
1H NMR(400MHz，DMSO-d6)δppm 0.91(s，9H)1.32(t，3H)1.38(s，9H)3.89(d，J＝9.38Hz，2H)4.41(q，J＝7.04Hz，2H)4.50-4.70(m，1H)6.54(d，J＝8.99Hz，1H)8.77(t，J＝5.08Hz，1H)
Step 2: (S) -5- ((2-amino-3, 3-dimethylbutyrylamino) methyl) -1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester trifluoroacetate salt
To a solution of ethyl (S) -3- ((2- (tert-butoxycarbonylamino) -3, 3-dimethylbutyrylamino) methyl) -1, 2, 4-oxadiazole-5-carboxylate (900mg, 2.34mmol) in dichloromethane (3mL) was added trifluoroacetic acid (3 mL). The solution was stirred for 1 hour and concentrated in vacuo to give the title compound as a brown oil (900mg, quantitative yield). 1H NMR (400MHz, DMSO-d)6)δppm 1.00(s，9H)1.34(t，J＝7.23Hz，3H)3.53(d，J＝5.47Hz，2H)4.43(q，J＝7.03Hz，2H)4.48-4.77(m，1H)8.09(br.s.，2H)9.07-9.22(m，1H).MS：285(M+H)
The following intermediates were prepared in a similar manner:
preparation example 27: (S) -5- ((2-amino-3, 3-dimethylbutyrylamino) methyl) -1, 3, 4-oxadiazole-2-carboxamide trifluoroacetate salt
Step 2: (S) -1- ((5-carbamoyl-1, 3, 4-oxadiazol-2-yl) methylamino) -3, 3-dimethyl-1-oxobutan-2-ylcarbamic acid tert-butyl ester
Ethyl (S) -5- ((2- (tert-butoxycarbonyl) -3, 3-dimethylbutyrylamino) methyl) -1, 3, 4-oxadiazole-2-carboxylate (5.72g, 14.9mmol) was dissolved in methanol (20mL), and a solution of 2N ammonia in methanol (15mL) was added. The solution was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo to give the desired material as a white foam (quantitative yield); 1H NMR (400MHz, DMSO-d)6)δppm 0.90(s，9H)1.38(s，9H)3.89(d，J＝9.77Hz，2H)4.46-4.66(m，1H)6.52(d，J＝8.99Hz，1H)8.18(s，1H)8.56(s，1H)8.73(t，J＝4.89Hz，1H)
And step 3: (S) -5- ((2-amino-3, 3-dimethylbutyrylamino) methyl) -1, 3, 4-oxadiazole-2-carboxamide trifluoroacetate salt
Tert-butyl (S) -1- ((5-carbamoyl-1, 3, 4-oxadiazol-2-yl) methylamino) -3, 3-dimethyl-1-oxobutan-2-ylcarbamate (5.7g, 14.9mmol) was dissolved in dichloromethane (20mL) and then triacetic acid (10mL) was added. The solution was stirred at ambient temperature for 1 hour. Concentration was then carried out in vacuo and titrated with diethyl ether to give the desired product as a white solid (5.21g, 95% yield).
1H NMR(400MHz，DMSO-d6)δppm 1.00(s，9H)3.54(d，J＝5.47Hz，2H)4.62-4.78(m，1H)8.11(br.s.，2H)8.23(s，1H)8.61(s，1H)9.21(t，1H)
Preparation example 28: 5- ((S) -1-amino-2, 2-dimethylpropyl) - [1, 3, 4] oxadiazol-2-ylamine dihydrochloride
Step 1: ((S) -1-Hydrazinocarbonyl-2, 2-dimethylpropyl) carbamic acid tert-butyl ester
To a solution of N-Boc-L-tert-leucine (2.0g, 8.647mmol) in anhydrous THF (20mL) was added N, N-Carbonyldiimidazole (CDI) (1.54g, 9.511mmol) and stirred at room temperature under nitrogen for 1.5 h. Then, hydrazine hydrate (1.3ml, 26.6mmol) was added thereto, and stirring was continued at room temperature for 18 hours. At the completion of the reaction (monitored by TLC, R)f0.3; solvent system 40% ethyl acetateIn hexane), THF was evaporated until dry, and the residue was dissolved in 1, 4-dioxane (50mL) and filtered. The filtrate was concentrated under reduced pressure and the residual cake (as a white viscous mass) was redissolved in DCM. The solution was washed with distilled water, brine and dried over anhydrous Na2SO4The mixture was dried and concentrated under reduced pressure to give tert-butyl ((S) -1-hydrazinocarbonyl-2, 2-dimethylpropyl) carbamate (2.3g) as a viscous mass containing imidazole.
1H NMR(400MHz，DMSO-d6) δ: 0.87(s, 9H), 1.37(s, 9H), 3.80(d, J ═ 9.6Hz, 1H), 6.35(d, J-9.6Hz, 1H), 9.10(s, 1H) + imidazole: 7.01(s, 2H), 7.63(s, 1H).1H NMR(400MHz，DMSO-d6-D2O exchange) δ: 0.88(s, 9H), 1.35(s, 9H), 3.77(s, (1H) + imidazole: 7.01(2H, 7.65(s, 1H). FIA-MS: 246.3[ M + H ]]+、268.3[M+H+Na]+
Step 2: [1- (5 amino- [1, 3, 4] oxadiazol-2-yl) - (S) -2, 2-dimethylpropyl ] carbamic acid tert-butyl ester
To a clear solution of tert-butyl ((S) -1-hydrazinocarbonyl-2, 2-dimethylpropyl) carbamate (1.5g, 6.117mmol) in 1, 4-dioxane (50mL) was added NaHCO3(0.515g, 6.117mmol) in distilled water (15mL) to form a white suspension. Cyanogen bromide (0.65g, 6.117mmol) was added to the reaction mixture in portions and stirred at room temperature for 18 hours. When the reaction was complete (monitored by TLC, R)f0.5; solvent system 50% ethyl acetate in hexanes), dioxane was evaporated under reduced pressure, and ethyl acetate (100mL) was added. This solution was then washed twice with distilled water (2X 100mL), brine, and over anhydrous Na2SO4Dried above and concentrated under reduced pressure. The resulting residue cake was washed with hexane to obtain an off-white colorDesired product [1- (5-amino- [1, 3, 4] as solid]Oxadiazol-2-yl) - (S) -2, 2-dimethylpropyl radical]Tert-butyl carbamate (0.7g, 42% yield).
1H NMR(400MHz，CDCl3)δ：1.01(s，9H)、1.27(s，9H)、4.65(d，J＝9.6Hz，1H)、5.44(d，J＝8.4Hz，1H)、8.92(br s，2H).MS，271.4[M+H]+
And step 3: 5- ((S) -1-amino-2, 2-dimethylpropyl) - [1, 3, 4] oxadiazol-2-ylamine dihydrochloride
Tert-butyl [1- (5-amino- [1, 3, 4] oxadiazol-2-yl) - (S) -2, 2-dimethylpropyl ] carbamate (4.0g, 14.81mmol) was added to 75mL of 4N HCl dioxane solution, and the solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give 5- ((S) -1-amino-2, 2-dimethylpropyl) - [1, 3, 4] oxadiazol-2-ylamine dihydrochloride as a white solid (3.5g, 98.59% yield).
1H NMR(400MHz，DMSO-d6)δ：0.95(s，9H)、4.31(d，J＝5.6Hz，1H)、6.34(br s，3H)、7.60(br s，1H)、8.86(d，J＝4.0Hz，3H)。LC-MS，171.1[M+H]+
Preparation example 29: n- {5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazol-2-yl } cyclopropane-carboxamide hydrochloride
Step 1: [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] carbamic acid tert-butyl ester
To [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl radical]To a mixture of tert-butyl carbamate (preparation 28, step 2, 500mg, 1.85mmol) in pyridine (20ml) was added cyclopropanecarbonyl chloride (202. mu.l, 2.22mmol) dropwise. The resulting mixture was allowed to stir at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated to a residue. By SiO2Chromatographic purification, eluting with 0-50% ethyl acetate/heptane, gave 503mg (80%) of the desired product.1H NMR(400MHz，DMSO-d6)δppm 0.80-0.88(m，4H)0.92(s，9H)1.19-1.29(m，1H)1.35(s，9H)1.79-1.89(m，1H)4.55(d，J＝8.86Hz，1H)7.50(d，J＝8.59Hz，1H)11.77(s，1H)；FIA-MS：339.2[M+H]+。
Step 2: n- {5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazol-2-yl } cyclopropane-carboxamide hydrochloride
To [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino group at ambient temperature]-1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl radical]To a solution of tert-butyl carbamate (502mg, 1.48mmol) in dioxane (5ml) was added HCl (4.0M in dioxane, 3 ml). The resulting mixture was allowed to stir at ambient temperature. The reaction mixture was concentrated to a solid. The solid was suspended in ethyl ether and then collected by filtration. The hygroscopic solid was placed in a vacuum oven overnight to dryness. Yield 408mg (94%).1H NMR(400MHz，DMSO-d6)δppm 0.81-0.93(m，4H)0.96-1.02(m，9H)1.92(t，J＝4.57Hz，1H)3.36(t，J＝6.98Hz，1H)4.51(s，1H)5.73(s，1H)8.83(br.s.，2H)12.14(s，1H).FIA-MS：237.3[M+H]+.
Preparation example 30: 1- {5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazol-2-yl } urea hydrochloride
Step 1: [ (1S) -1- {5- [ (aminocarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] carbamic acid tert-butyl ester
Stirring [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl at 0 DEG C]To a solution of tert-butyl carbamate (preparation 28, step 2, 250mg, 0.9mmol) in anhydrous THF (5ml) was slowly added trichloroacetyl isocyanate (240ul, 2mmol) dropwise. The cooling bath was removed after the addition was complete and the reaction mixture was then allowed to stir at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in methanol (3ml) and flushed with ammonia gas for 3 minutes. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated by rotary evaporator. The resulting solid was powdered with diethyl ether and collected by filtration to give 115.5mg (40%).1H NMR(400MHz，DMSO-d6)δppm 0.96(s，9H)1.38(s，9H)4.54(d，J＝8.99Hz，1H)7.10(br.s.，2H)7.51(d，J＝8.79Hz，1H)10.59(s，1H)。FIA-MS：314.1[M+H]+。
Step 2: 1- {5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazol-2-yl } urea hydrochloride
To [ (1S) -1- {5- [ (aminocarbonyl) amino group]-1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl radical]To a solution of tert-butyl carbamate (115mg, 0.37mmol) in dioxane (2ml) was added HCl (4N in dioxane, 1.5 ml). The resulting mixture was allowed to stir at ambient temperature overnight. The mixture was concentrated under a stream of nitrogen and placed under high vacuum to give 125.4mg of the desired starting material.1H NMR(400MHz，DMSO-d6)δppm 1.03(s，9H)4.48(d，J＝5.47Hz，1H)7.08(br.s.，2H)8.90(d，J＝4.30Hz，3H)。FIA-MS：214.2[M+H]+。
Preparation example 31: 5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazole-2-carboxamide hydrochloride
Step 1: [ N' - ((S) -2-tert-Butoxycarbonylamino-3, 3-dimethyl-butyryl) -hydrazino ] -oxo-acetic acid ethyl ester
To a solution of ((S) -hydrazinocarbonyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (preparation 28, step 1, 500mg, 2.0mmol) and sodium bicarbonate (197mg, 2.3mmol) in THF (10ml) was added ethyl oxalyl chloride (239 μ l, 2.1mmol) dropwise over 10 min at 0 ℃. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was filtered through a cake of seaweed soil, which was eluted with THF. The cloudy filtrate was concentrated to an oily residue. Toluene (. about.2 ml) was added and powdered with diethyl ether. The ether solution was concentrated to a residue and passed through SiO2Chromatographic purification, eluting with 30-100% ethyl acetate/heptane, gave 653.7mg (93%).1H NMR(400MHz，DMSO-d6)δppm 0.90(s，9H)1.25(t，J＝7.12Hz，3H)1.35(s，9H)3.91(d，J＝9.67Hz，1H)4.22(q，2H)6.56(d，J＝9.67Hz，1H)10.08(s，1H)10.74(s，1H)。FIA-MS：368.2[M+Na]+。
Step 2: 5- { (1S) -1- [ (tert-Butoxycarbonyl) amino ] -2, 2-dimethylpropyl } -1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester
Triethylamine (600. mu.l, 4.2mmol) and [ N' - ((S) -2-tert-Butoxycarbonylamino-3, 3-dimethyl-butyryl) -hydrazino at ambient temperature]A solution of oxo-acetic acid ethyl ester (350mg, 1.0mmol) in dry dichloromethane (5ml) was added sequentially to an agitated solution of triphenylphosphine (548mg, 2.0mmol) and iodine (851mg, 2.0mmol) in dichloromethane (10 ml). The reaction was completed within 2 hours. The reaction mixture was extracted with saturated sodium thiosulfate (2 × 30 ml). Concentrating the organic layer and passing through SiO2The resulting residue was chromatographed, eluting with 0-75% ethyl acetate/heptane. The oily residue was placed under high vacuum to give 151.3mg (46%).1H NMR(400MHz，DMSO-d6)δppm 0.97(s，9H)1.36(q，3H)1.34(s，9H)4.42(q，J＝7.04Hz，2H)4.73(d，J＝8.60Hz，1H)7.73(d，J＝8.60Hz，1H)。FIA-MS：350.1[M+Na]+。
And step 3: { (1S) -1- [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] -2, 2-dimethylpropyl } carbamic acid tert-butyl ester
To 5- { (1S) -1- [ (tert-butoxycarbonyl) amino group]A solution of ethyl (150mg, 0.46mmol) of 2, 2-dimethylpropyl } -1, 3, 4-oxadiazole-2-carboxylate in ethanol (3ml) was bubbled with ammonia gas for 2 min. The tube was sealed and heated at 50 ℃ overnight. Concentrating the mixture to obtain residueAnd dissolved in dichloromethane. Passing the raw material through SiO2Chromatographic purification, eluting with 0-15% methanol/dichloromethane. The fractions were separated, and the residue of the layer was concentrated to give 123.9mg (91%).1H NMR(400MHz，DMSO-d6)δppm 0.97(s，9H)1.38(s，9H)4.71(d，J＝8.60Hz，1H)7.67(d，J＝8.60Hz，1H)8.21(s，1H)8.57(br.s.，1H)。FIA-MS：321.1[M+Na]+。
And 4, step 4: 5- [ (1S) -1-amino-2, 2-dimethylpropyl ] -1, 3, 4-oxadiazole-2-carboxamide hydrochloride
To { (1S) -1- [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl]To a solution of tert-butyl (2, 2-dimethylpropyl) carbamate (120mg, 0.40mmol) in dioxane (2ml) was added 4N HCl dioxane solution (1 ml). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to a residue. The residue was powdered with ethyl ether and collected by filtration to give 72.0mg (76%).1H NMR(400MHz，DMSO-d6)δppm 1.04(s，9H)3.42(br.s.，1H)8.33(s，1H)8.71(s，1H)8.92(br.s.，3H)。FIA-MS：199.1[M+H]+。
Preparation example 32: (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propan-1-amine hydrochloride
Step 1: [ (1S) -1-cyano-2, 2-dimethylpropyl ] carbamic acid benzyl ester
To [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl group at-10 deg.C]To a solution of benzyl carbamate (preparation 1, step 1, 2.8g, 10.9mmol) in pyridine (25ml) was added dropwise a solution of phosphorus oxychloride (1.2ml, 2.0g, 13.1mmol) in dichloromethane (15 ml). The resulting mixture was stirred for 3 hours. The reaction mixture was poured onto ice water (. about.100 ml). The layers were separated and the organic layer was washed with 1X 30ml of 1.0M CuSO4Solution, 2 × 50ml water 1 × 50ml brine extraction. The organic layer was washed with Na2SO4Dried and concentrated in vacuo. The oily residue was passed through SiO2Chromatography (70g) eluting with 0-10% methanol in dichloromethane. The oil was used in subsequent reactions without additional purification and/or characterization. LC/MS 247.1(M + H).
Step 2: [ (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propyl ] carbamic acid benzyl ester
Sodium azide (633mg, 9.7mmol) and ammonia chloride (544mg, 10.2mmol) were added simultaneously to [ (1S) -1-cyano-2, 2-dimethylpropyl ester]Benzyl carbamate (2.2g, 8.8mmol) in DMF (35 ml). The resulting reaction mixture was heated to 95 ℃ for 3 hours. Additional sodium azide (633mg, 9.7mmol) and NH were added4Cl (544mg, 10.2mmol) and the reaction mixture was heated to 95 ℃. The incomplete reaction mixture was cooled to ambient temperature and quenched by pouring onto ice water (-100 ml). The pH of the solution was adjusted to 2 with 4N HCl. The acidic solution was treated with 3X30ml CH2Cl2And (4) extracting. The organic layer was washed with brine (1X 30ml) and over MgSO4And drying. By SiO2Purification was performed by chromatography (Flashmaster 70g) using 10-60% ethyl acetate/hexane as eluent. 646.7mg, 25% yield. 1H NMR (400MHz, DMSO-d)6)δppm 0.89(s，10H)4.77(d，J＝8.59Hz，1H)4.99(d，J＝7.25Hz，2H)7.22-7.35(m，5H)7.90(d，J＝8.59Hz，1H)。LC/MS 290.1(M+H)。
And step 3: (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propan-1-amine hydrochloride
5% Palladium on carbon catalyst (20mg) was added to anhydrous [ (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propyl ] in a domed flask]Benzyl carbamate (600mg, 2.1 mmol). Methanol (10ml) was added to the flask under nitrogen atmosphere. The atmosphere was evacuated and flushed twice with hydrogen, and then a hydrogen balloon was fixed to the flask. The reaction was maintained at ambient pressure and ambient temperature overnight. The reaction mixture was flushed with nitrogen and then filtered through a celite cake. The celite was washed with methanol and the filtrate was concentrated to a light tan solid. 320.1mg, 99% yield. 1H NMR (400MHz, DMSO-d)6)δppm 0.90(s，10H)4.13(s，1H)7.99(br.s.，2H)。LC/MS 156.1(M+H)。
The following examples were synthesized according to the general procedures used in the representative examples and representative preparations described above.
Claims (30)
1. A compound having the formula I
Or a pharmaceutically acceptable salt thereof, wherein:
x is CH or N;
R1is that
R4 1-5-aryl- (CH)2)n-or
R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently of each other H, halogen, cyano, NH2-C(O)-、C1-C6Alkoxy-, trifluoromethyl or C1-C6alkoxy-C (O) -;
each R5Independently is H or C1-C6An alkyl group;
R2is that
NR11R12-C(O)-R13CH-、
R14-C(O)-NR15-(CH2)n-R13CH-、
R16-C(O)-R13CH-、
C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、
R20-SO2-NR21-(CH2)n-R13CH-、
R22R23CH-、
R24 1-5-a heteroaryl group,
R24 1-5-heteroaryl-R13CH-、
R24 1-5-heteroaryl-NR15-C(O)-R13CH-、
R25 1-5-a heterocyclic group,
R25 1-5-heterocyclyl- (CH)2)n-、
R26 1-5-C3-C7A cycloalkyl group,
NR27R28-(CH2)n-NR29-C(O)-R13CH-、
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、
R30-SO2-(CH2)n-NR31-C(O)-R13CH-、
R32-C(O)-R33CH-NR34-C(O)-R13CH-、
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、
R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl-C (O) -R13CH-、
R38 1-5-aryl-R39C-NR40-C(O)-R13CH-、
R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-、
R41 1-5-aryl- (CH)2)n-、
NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-or R43-CH(OH)-CH2-NR19-C(O)-R13CH-；
Wherein
R11And R12Independently H, OH, C1-C6Alkyl radical, C1-C6Haloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, (OH)3-C4-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, benzo-fused C3-C7Cycloalkyl, cyano-C1-C6Alkyl, NH2-C(NH)-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, OH-C3-C7cycloalkyl-C1-C6alkoxy-C (O) -C3-C7Cycloalkyl-, (C)1-C6Alkoxy-aryl) -C3-C7Cycloalkyl-, NH2-C(O)-C3-C7Cycloalkyl-, OH-aryl or R24 1-5-heteroaryl-O- (CH)2)n-；
R13Is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-or C3-C7A cycloalkyl group;
R14is (C)1-C6Alkyl radical)2N-, aryl, C1-C6Alkyl or C3-C7A cycloalkyl group;
R15、R21、R29、R31、R34and R40Independently is H or C1-C6An alkyl group;
R16is OH or C1-C6An alkoxy group;
R17and R18Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl or R24 1-5-heteroaryl-;
each R19Independently is H or C1-C6An alkyl group;
R20is C1-C6Alkyl radical, C1-C6Haloalkyl, or (C)1-C6Alkyl radical)2N-；
R22And R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、
OH-C1-C6Alkyl, aryl or aryl-OH-C1-C6An alkylene group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, OH, NH2、C1-C6Alkoxy radical
radical-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、
NH2-C(O)-NH-、OH-C(O)-、
NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6Alkane (I) and its preparation method
The radicals-NH-C (O) -, OH-C1-C6alkyl-NH-C (O) -or C3-C7cycloalkyl-C (O) -NH-;
each R25Independently is H or oxo;
each R26Independently is H, OH-C1-C6Alkyl, aryl
Radical- (CH)2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -; r27And R28Independently is H, NH2-C(O)-、C3-C7Cycloalkanes
radical-C (O) -, or R24 1-5-heteroaryl-;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl, NH2、C1-C6alkyl-NH-, C3-C7Cycloalkyl- (CH)2)n-NH-, morpholin-4-yl or R38 1-5-a phenyl group;
R32is OH or C1-C6Alkoxy-;
each R33Independently is H, C1-C6Alkyl or OH-C1-C6An alkyl group;
each R35Independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -, C3-C7Cycloalkyl, OH, phenyl or heteroaryl,
or two adjacent R35The radicals may be taken togetherForm- (CH)2)3-6-；
Each R36Independently is H, C1-C6Alkyl radical, C1-C6Alkoxy-or NH2-C(O)-；
Each R37Independently is H, NH2C (O) -, OH, halogen, cyano, oxo, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
NH2C(O)-(CH2)n-、NH2C(O)-(CH2)n-C(O)-、
NH2C(O)-NH-(CH2)n-、C1-C6alkyl-NH-C (O) -O-,
(OH)-C1-C6alkyl-NH-C (O) -, (OH)2-C1-C6Alkane (I) and its preparation method
radical-NH-C (O) -, C1-C6alkyl-C (O) -, C1-C6Alkoxy radical
radical-C (O) -, C3-C7cycloalkyl-C (O) -NH- (CH)2)n-、C1-C6
alkyl-SO2-、C3-C7cycloalkyl-SO2-or C3-C7Cycloalkanes
radical-SO2--NH-(CH2)n-；
Each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -or C1-C6alkoxy-C (O) -;
each R39Independently is H, C1-C6Alkyl or OH-C1-C6An alkyl group;
each R41Independently is H, C1-C6Alkoxy or halogen;
R42is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-or NH2-C(O)-CH2；
R43Is OH-C (O) -, C1-C6alkoxy-C (O) -, NH2-C (O) -or R44R45NCH2-; and
R44and R45Independently is C1-C6Alkyl or OH-C1-C6Alkyl, or
R44And R45Together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine or morpholine ring;
n is an integer from 1 to 6; and is
Each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl.
2. The compound of claim 1, wherein
X is CH or N;
R1is R4 1-5-benzyl, R5 1-5-isoxazolyl-CH2-or R5 1-5-pyridyl-CH2-; wherein
Each R4Is H, fluorine, cyano, NH2-C(O)-；
Each R5Independently is H or CH3；
R2Is NR11R12-C(O)-R13CH-、R14-C(O)-NR15-CH2-R13CH-、R16-C(O)-R13CH-、(CH3)3C-O-C(O)-CH2-NR15-C(O)-R13CH-、NR17R18-C(O)-CH2-NR19-C(O)-R13CH-、NR17R18-C(O)-(CH2)2-NR19-C(O)-R13CH-、R20-SO2-NR21-CH2-R13CH-、R22R23CH-、R24 1-5-dihydroimidazolyl, R24 1-5-isoxazolyl, R24 1-5Thiadiazole, R24 1-5-isoxazolyl-R13CH-、R24 1-5-oxazolyl-R13CH-、R24 1-5-furyl-R13CH-、R24 1-5-oxadiazolyl-R13CH-、R24 1-5-triazolyl-R13CH-、R24 1-5-dihydroisoxazolyl-R13CH-、R24 1-5-tetrazolyl-R13CH-、R24 1-5-isoxazolyl-NR15-C(O)-R13CH-、R24 1-5Thiadiazole NR15-C(O)-R13CH-、R25 1-5-tetrahydrofuranyl, R25 1-5-tetrahydrofuryl-CH2-、R26 1-5-cyclohexyl radical, R26 1-5-tetrahydronaphthyl, R26 1-5-indanyl radical, NR27R28-(CH2)2-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)2-NR15-C(O)-R13CH-、R30-SO2-(CH2)2-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R32-C(O)-(CH2)2-NR34-C(O)-R13CH-、R35 1-5-dioxazole- (CH)2)2-NR36-C(O)-R13CH-、R35 1-5-oxadiazole-CH2-NR36-C(O)-R13CH-、R35 1-5-pyridyl-CH2-NR36-C(O)-R13CH-、R35 1-5-tetrazolyl-CH2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl-CH2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl-C (O) -R13CH-、R37 1-5pyrrolidinyl-C (O) -R13CH-、R37 1-5-morpholinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperazinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl- (CH)2)2-NR36-C(O)-R13CH-、R38 1-5-phenyl-R39C-NR40-C(O)-R13CH-、R38 1-5-phenyl- (CH)2)2-NR40-C(O)-R13CH-、R38 1-5-phenyl- (CH)2)3-NR40-C(O)-R13CH-or R41 1-5-a benzyl group; wherein
R11And R12Independently is H, CH3、(CH3)2CH-, cyclobutyl, cyclopropyl, CH3O(CH2)2-, OH-ethyl, OH-propyl, (OH)2-propyl, cyano-CH2-、(OH-CH2)2-CH-, OH-cyclopropyl-CH2-, OH-cyclopentyl-CH2-OH-methyl-cyclopropyl or OH-phenyl;
R13is H, (CH)3)3C-、(CH3)2CHCH2-、(CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R14is (CH)3CH2)2N-, phenyl, (CH)3)3C-, or cyclopropyl;
R15、R21、R29、R31、R33、R34、R36、R39and R40Independently is H or CH3；
R16Is OH or CH3O；
R17、R18And R19Independently is H or CH3；
R20Is (CH)3)2CH-、CH3、CF3Or (CH)3)2N-；
R22And R23Independently is (CH)3)3C-、(CH3)2CH-, cyclohexyl-CH2-、OHCH2Phenyl, OH-isopropyl, OH-ethyl, or phenyl-OHCH-;
each R24Independently is H, CH3、CH3CH2-、(CH3)3C-, cyclopropyl, CF3Oxo, NH2、CH3CH2-O-C(O)-、NH2-C(O)-CH2-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-CH2-NH-C(O)-、(OH)2-propyl-NH-c (o) -or OH-ethyl-NH-c (o) -;
each R25Independently is H or oxo;
each R26Independently is H, OH, OHCH2benzyl-O-, NH2-C (O) -or CH3CH2-O-C(O)-；
R27And R28Independently is H, NH2-C (O) -, or cyclopropyl-C (O) -;
R30is CH3Cyclopropyl or NH2；
R32Is OH;
each R35Independently is H, CH3、NH2-C(O)-、CH3CH2-O-c (O) -, or cyclopropyl;
each R37Independently is H, NH2C (O) -or OH;
each R38Independently is H, NH2SO2-, cyano, tetrazolyl, OH, chlorine, CH3-O-, OH-C (O) -, or CH3-O-C(O)-；
Each R41Independently is H, CH3O or fluorine; and
each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O, pyridyl or oxazolyl.
3. The compound of claim 2, wherein
X is CH or N;
R1is that
R2Is that
Each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O-, 3-pyridyl, 4-pyridyl, or 2-oxazolyl.
4. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently is H, halogen, cyano or NH2-C(O)-；
Each R5Independently is H or C1-C6An alkyl group;
R2is NR11R12-C(O)-R13CH-、R16-C(O)-R13CH-、NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-heteroaryl-R13CH-、R26 1-5-C3-C7Cycloalkyl, NR27R28-(CH2)n-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)n-NR19-C(O)-R13CH-、R30-SO2-(CH2)n-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、R37 1-5-heterocyclyl-C (O) -R13CH-or R41 1-5-aryl- (CH)2)n-; wherein
R11And R12Independently is H, C1-C6Alkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl, OH-aryl;
R13is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R16is OH or C1-C6An alkoxy group;
R17、R18and R19Independently is H or C1-C6An alkyl group;
R22and R23Independently is C1-C6Alkyl radical, C3-C7Cycloalkyl- (CH)2)n-、OH-C1-C6An alkyl group, or an aryl group;
each R24Independently is H, C1-C6Alkyl, NH2、NH2-C(O)-NH-、NH2-C(O)-、NH2-C(O)-(CH2)n-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, or OH-C1-C6alkyl-NH-C (O) -;
each R26Independently is H, OH-C1-C6Alkyl, aryl- (CH)2)n-O-、NH2-C (O) -or C1-C6alkoxy-C (O) -;
R27and R28Independently is H or NH2-C(O)-；
R29、R33、R34、R36And R38Independently is H or C1-C6An alkyl group;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl or NH2；
R31Is a compound of formula (I) wherein the compound is H,
R32is OH;
each R35Independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -, or C3-C7A cycloalkyl group;
each R37Independently is H, NH2C (O) -or OH;
each R41Independently is H, C1-C6Alkoxy or halogen;
n is an integer from 1 to 6; and
each R3Independently of each other is H, halogen, C1-C6Alkyl, aryl, NH2-C(O)-、C1-C6Alkoxy or heteroaryl radicals。
5. The compound of claim 4, wherein
X is CH or N;
R1is R4 1-5-benzyl, R5 1-5-isoxazolyl-CH2-or R5 1-5-pyridyl-CH2-; wherein
Each R4Is H, fluorine, cyano, NH2-C(O)-；
Each R5Independently is H or CH3；
R2Is NR11R12-C(O)-R13CH-、R16-C(O)-R13CH-、NR17R18-C(O)-CH2-NR19-C(O)-R13CH-、NR17R18-C(O)-(CH2)2-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-furyl-R13CH-、R24 1-5-oxadiazolyl-R13CH-、R24 1-5-tetrazolyl-R13CH-、R26 1-5-cyclohexyl radical, R26 1-5-tetrahydronaphthyl, R26 1-5-indanyl radical, NR27R28-(CH2)2-NR29-C(O)-R13CH-、R30-SO2-NR31-(CH2)2-NR19-C(O)-R13CH-、R30-SO2-(CH2)2-NR31-C(O)-R13CH-、R32-C(O)-R33CH-NR34-C(O)-R13CH-、R35 1-5-oxadiazole-CH2-NR36-C(O)-R13CH-、R35 1-5-oxadiazole- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-morpholinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperazinyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-tetrahydropyranyl- (CH)2)2-NR36-C(O)-R13CH-、R37 1-5-piperidinyl-C (O) -R13CH-、R37 1-5pyrrolidinyl-C (O) -R13CH-or R41 1-5-a benzyl group; wherein
R11And R12Independently is H, CH3、(CH3)2CH-, cyclobutyl, cyclopropyl, CH3O(CH2)2-, OH-ethyl, OH-propyl, (OH)2-propyl, (OH-CH)2)2-CH-、
OH-cyclopropyl-CH2-, OH-cyclopentyl-CH2-、OH-CH2-cyclopropyl, or OH-phenyl;
R13 isH、(CH3)3C、(CH3)2CHCH2-、(CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R16is OH or CH3O；
R17、R18And R19Independently is H or CH3；
R22And R23Independently is (CH)3)3C-、(CH3)2CH-, cyclohexyl-CH2-、OHCH2Phenyl, OH-isopropyl, or OH-ethyl;
each R24Independently is H, CH3、NH2、NH2-C(O)-NH-、NH2-C(O)-、NH2-C(O)-CH2-、OH-C(O)-、NH2-C(O)-CH2-NH-C(O)-、(OH)2-propyl-NH-c (o) -, or OH-ethyl-NH-c (o) -;
each R26Independently is H, OH, OHCH2benzyl-O-, NH2-C (O) -or CH3CH2-O-C(O)-；
R27And R28Independently is H or NH2-C(O)-；
R29、R33、R34、R36And R38Independently is H or CH3；
R30Is CH3Cyclopropyl or NH2；
R31Is H;
R32is OH;
each R35Independently is H, CH3、NH2-C(O)-、CH3CH2-O-c (O) -, or cyclopropyl;
each R37Independently is H, NH2C (O) -or OH;
each R41Independently is H, CH3O or fluorine; and
each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O, pyridyl or oxazolyl.
6. The compound of claim 5, wherein
X is CH or N;
R1is that
R2Is that
Each R3Independently is H, CH3Chlorine, bromine, fluorine, phenyl, NH2-C(O)-、CH3O, 3-pyridyl, 4-pyridyl, or 2-oxazolyl.
7. The compound of claim 4, wherein X is CH.
8. The compound of claim 7, wherein
X is CH;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently H, halogen, cyano, or NH2-C(O)-；
Each R5Independently is H or C1-C6An alkyl group;
R2is NR11R12-C(O)-R13CH-、NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、R22R23CH-、R24 1-5-heteroaryl-R13CH、R30-SO2-NR31-(CH2)n-NR19-C(O)-R13CH-、R30-SO2-(CH2)n-NR31-C(O)-R13CH-or R32-C(O)-R33CH-NR34-C(O)-R13CH-; wherein
R11And R12Independently H, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C3-C7Cycloalkyl or (OH-C)1-C6Alkyl radical)2-(CH2)n-；
R13Is C1-C6An alkyl group;
R17、R18and R19Independently is H;
R22and R23Independently is C1-C6Alkyl or OH-C1-C6An alkyl group;
each R24Independently is H or NH2；
R30Is C3-C7Cycloalkyl or NH2；
R31Is H;
R32is OH;
R33is H;
R34is H;
n is an integer from 1 to 6; and
R3is H, halogen or C1-C6An alkyl group.
9. The compound of claim 8, wherein
X is CH;
R1is that
R2Is that
R3Is H, F, Cl or CH3。
10. The compound of claim 4, wherein X is N;
R1is R4 1-5-aryl- (CH)2)n-or R5 1-5-heteroaryl- (CH)2)n-; wherein
Each R4Independently H, halogen, cyano, or NH2-C(O)-；
Each R5Independently is H;
R2is NR11R12-C(O)-R13CH-、R22R23CH-or R16-C(O)-R13CH-; wherein
R11And R12Independently is H;
R13is C1-C6Alkyl or OH-C1-C6An alkyl group;
R16is OH;
R22and R23Independently is C1-C6Alkyl or OH-C1-C6An alkyl group; n is an integer from 1 to 6; and
R3is H.
11. The compound of claim 10, wherein X is N;
R1is R4 1-5-benzyl or R5 1-5-pyridyl-CH2-; wherein
Each R4Is H or fluorine;
each R5Independently is H;
R2is NR11R12-C(O)-R13CH-、R22R23CH-or R16-C(O)-R13CH-; wherein
R11And R12Independently is H;
R13is (CH)3)3C、(CH3)2CHCH2、(CH3)2CH. OH-ethyl;
R16is OH;
R22and R23Independently is (CH)3)3C or OHCH2(ii) a And R3Is H.
12. The compound of claim 11, wherein X is N;
R1is that
R2Is that
R3Is H.
13. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-bromo-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-pyridin-3-yl-1H-indazole-3-carboxamide;
1- [3- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-bromo-1H-indazole-3-carboxamide;
1- [2- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5- (1, 3-oxazol-2-yl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-pyridin-4-yl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-di-methylpropyl ] -1-benzyl-6-pyridin-4-yl-1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valine methyl ester;
1-benzyl-N- (4-methoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2-methoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (2, 3-dimethoxybenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- (3-methoxybenzyl) -1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-pyridin-3-yl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-methoxy-1H-indazole-3-carboxamide;
n-3- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-indazole-3, 5-dicarboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-6-phenyl-1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-5-phenyl-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (2, 5-dimethyl-3-furanyl) methyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- (2H-tetrazol-5-yl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valine;
1-benzyl-N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1-benzyl-N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1-benzyl-N- [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1-benzyl-1H-indazol-3-yl) carbonyl ] -3-methyl-L-valylglycine;
n- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- {5- [ (cyclopropyl carbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1-benzyl-1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- {5- [ (cyclopropylcarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-cyano-2-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [ (aminocarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1-benzyl-N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
n- { (1S) -1- [ ({2- [ (cyclopropylcarbonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [2- (methylsulfonyl) ethyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
1- (4-cyano-2-fluorobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [2- (methylsulfonyl) ethyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (aminosulfonyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (aminosulfonyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-cyano-2-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -7-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
n- [ (1S) -1- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1H-indazole-3-carboxamide
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -7-fluoro-1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -7-fluoro-N- [ (1S) -1- ({ [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- {5- [ (aminocarbonyl) amino ] -1, 3, 4-oxadiazol-2-yl } -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [4- (aminocarbonyl) -5-methyl-1, 3-oxazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [5- (2-amino-2-oxoethyl) -1, 3, 4-oxadiazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
2- [ (1S) -1- ({ [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } amino) -2, 2-dimethylpropyl ] -5-methyl-1, 3-oxazole-4-carboxylic acid;
- Λ/- { (1S) -1- [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (4- { [ (2-amino-2-oxoethyl) amino ] carbonyl } -5-methyl-1, 3-oxazol-2-yl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [4- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -5-methyl-1, 3-oxazol-2-yl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- (4- { [ (2-hydroxyethyl) amino ] carbonyl } -5-methyl-1, 3-oxazol-2-yl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
ethyl 5- { [ (N- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 3, 4-oxadiazole-2-carboxylate;
ethyl 5- { [ (N- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 3, 4-oxadiazole-2-carboxylate;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- { (1S) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
ethyl 3- { [ (N- { [1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 2, 4-oxadiazole-5-carboxylate;
ethyl 3- { [ (N- { [1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl) amino ] methyl } -1, 2, 4-oxadiazole-5-carboxylate;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -2, 2-dimethyl-1- ({ [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] amino } carbonyl) propyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- { [ (2-morpholin-4-ylethyl) amino ] carbonyl } propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [2- (4-hydroxypiperidin-1-yl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (4-methylpiperazin-1-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({2- [5- (aminocarbonyl) -1, 2, 4-oxadiazol-3-yl ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -2, 2-dimethyl-1- ({ [2- (5-methyl-1, 3, 4-oxadiazol-2-yl) ethyl ] amino } carbonyl) propyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [2- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) ethyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3R) -3-hydroxypyrrolidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3R) -3-hydroxypyrrolidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopropyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopropyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- { [ (3-hydroxyphenyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- { [ (3-hydroxyphenyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopentyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobutyl) -N- [ (1S) -1- ({ [ (1-hydroxycyclopentyl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (cyclohexylmethyl) -N- [ (1S) -1- ({ [1- (hydroxymethyl) cyclopropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-fluorobenzyl) -N- [ (1S) -1- ({ [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- { [3- (aminocarbonyl) piperidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1- (cyclohexylmethyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- { [3- (aminocarbonyl) piperidin-1-yl ] carbonyl } -2, 2-dimethylpropyl ] -1- (4-cyanobutyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (4-cyanobenzyl) -5-fluoro-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -N- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -5-fluoro-1H-indazole-3-carboxamide;
1- [4- (aminocarbonyl) benzyl ] -5-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -5-fluoro-N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -5-fluoro-1H-indazole-3-carboxamide;
n- { [1- (4-cyanobenzyl) -5-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- { [1- (4-cyanobenzyl) -5-fluoro-1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -5-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -5-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
5-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 5-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
5-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-fluoro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-chloro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-fluorobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
- Λ/- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
n- { [ 7-fluoro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
7-chloro-N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
7-chloro-N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -7-fluoro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
- Λ/- { (1S) -1- [ ({ [5- (aminocarbonyl) -1, 3, 4-oxadiazol-2-yl ] methyl } amino) carbonyl ] -2, 2-dimethylpropyl } -7-chloro-1- (4-fluorobenzyl) -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -7-chloro-1- (4-cyanobenzyl) -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- { (1S) -1- [ (cyclopropylamino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (2-hydroxyethyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- { [ (3-hydroxypropyl) amino ] carbonyl } -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl glycinamide;
7-chloro-1- (4-cyanobenzyl) -N- { (1S) -1- [ ({2- [ (cyclopropylsulfonyl) amino ] ethyl } amino) carbonyl ] -2, 2-dimethylpropyl } -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2S) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
7-chloro-1- (4-cyanobenzyl) -N- [ (1S) -1- ({ [ (2R) -2, 3-dihydroxypropyl ] amino } carbonyl) -2, 2-dimethylpropyl ] -1H-indazole-3-carboxamide;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [ 7-chloro-1- (4-cyanobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valyl-D-alanine;
n- { [1- (3-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [1- (2-fluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine;
n- { [1- (2, 4-difluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine; and
n- { [1- (3, 4-difluorobenzyl) -1H-indazol-3-yl ] carbonyl } -3-methyl-L-valylglycine.
14. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
1- (2-fluorobenzyl) -N- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1-benzyl-1H-pyrrolo [3, 4-b ] pyridin-3-yl) carbonyl ] -3-methyl-L-valine;
n- [ (1S) -1- (aminocarbonyl) -2, 2-dimethylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide:
n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
1-benzyl-N- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (aminocarbonyl) -3-methylbutyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1-benzyl-1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S) -1- (hydroxymethyl) -2, 2-dimethylpropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide;
n- [ (1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl ] -1- (pyridin-2-ylmethyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide; and
n- [ (1S) -1- (aminocarbonyl) -2-methylpropyl ] -1- (2-fluorobenzyl) -1H-pyrrolo [3, 4-b ] pyridine-3-carboxamide.
15. A compound according to claim 1 having the formula:
or a pharmaceutically acceptable salt thereof, wherein
R2ASelected from:
NR11R12-C(O)-R13CH-、
C1-C6alkoxy-C (O) - (CH)2)n-NR15-C(O)-R13CH-、
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-、
R24 1-5-heteroaryl-NR15-C(O)-R13CH-、
NR27R28-(CH2)n-NR29-C(O)-R13CH-、
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-、
R30-SO2-(CH2)n-NR31-C(O)-R13CH-、
R32-C(O)-R33CH-NR34-C(O)-R13CH-、
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-、
R35 1-5-heteroaryl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl- (CH)2)n-NR36-C(O)-R13CH-、
R37 1-5-heterocyclyl-C (O) -R13CH-、
R38 1-5-aryl-R39C-NR40-C(O)-R13CH-, or
R38 1-5-aryl- (CH)2)n-NR40-C(O)-R13CH-
Wherein
R11And R12Independently is H, C1-C6Alkyl, OH-C1-C6Alkyl, (OH)2-C1-C6Alkyl radical, C1-C6Alkoxy- (CH)2)n-、C3-C7Cycloalkyl, cyano-C1-C6Alkyl, (OH-C)1-C6Alkyl radical)2-C1-C6Alkylene, OH-C3-C7Cycloalkyl- (CH)2)n-、OH-(CH2)n-C3-C7Cycloalkyl-, or OH-aryl;
R13is H, C1-C6Alkyl, OH-C1-C6Alkyl, aryl- (CH)2)n-, or C3-C7A cycloalkyl group;
R15、R29、R31、R33、R34、R36、R39and R40Independently is H or C1-C6An alkyl group;
R17、R18and R19Independently is H or C1-C6An alkyl group;
each R24Independently is H, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C1-C6Haloalkyl, oxo, NH2、C1-C6alkoxy-C (O) -, NH2-C(O)-(CH2)n-、NH2-C(O)-、NH2-C(O)-NH-、OH-C(O)-、NH2-C(O)-(CH2)n-NH-C(O)-、(OH)2-C1-C6alkyl-NH-C (O) -, or OH-C1-C6alkyl-NH-C (O) -;
each R25Independently is H or oxo;
R27and R28Independently is H, NH2-C (O) -, or C3-C7cycloalkyl-C (O) -;
R30is C1-C6Alkyl radical, C3-C7Cycloalkyl or NH2；
R32Is OH;
R35independently is H, C1-C6Alkyl, NH2-C(O)-、C1-C6alkoxy-C (O) -or C3-C7A cycloalkyl group;
each R37Independently is H, NH2C (O) -or OH;
each R38Independently is H, NH2SO2-, cyano, heteroaryl, OH, halogen, C1-C6Alkoxy, OH-C (O) -, or C1-C6alkoxy-C (O) -;
n is an integer from 1 to 6;
R3Aand R3BIndependently selected from H and halogen;
R4Aselected from F and CN; and
R4Bselected from H and F.
16. A compound according to claim 15, wherein R is13Is C1-C6An alkyl group.
17. A compound according to claim 16, wherein R is13Is branched C3-C6An alkyl group.
18. A compound according to claim 17, wherein R is13Is a tert-butyl group.
19. A compound according to claim 1 having the formula:
or a pharmaceutically acceptable salt thereof, wherein
R3ASelected from H, F and Cl;
R4Aselected from F and CN;
R4Bselected from H and F; and
R11Aselected from H, OH-C1-C6Alkyl and (OH)2-C1-C6An alkyl group.
20. A compound according to claim 1 having the formula:
or a pharmaceutically acceptable salt thereof, wherein
R3ASelected from H, F and Cl;
R4Aselected from F and CN;
R4Bselected from H and F; and
R11Aselected from the group consisting of H, 2-hydroxyethyl and 2, 3-dihydroxypropyl.
21. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, for use as a medicament.
23. A compound of claim 22 for use in the treatment of a CB1 mediated disorder.
24. A compound according to claim 23 for use in the treatment of pain.
25. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament for the treatment of CB1 mediated disorders.
26. The use of claim 25, wherein the CB1 mediated disorder is pain.
27. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, for the treatment of CB1 mediated disorders.
28. The use of claim 27, wherein the CB1 mediated disorder is pain.
29. A method for treating a CB1 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein the amount of the compound is effective to treat or prevent the CB1 mediated disorder.
30. The method of claim 29, wherein the CB1 mediated disorder is pain.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/032,657 | 2008-02-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1153691A true HK1153691A (en) | 2012-04-05 |
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