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HK1128290B - Carbonylamino pyrrolopyrazoles, potent kinase inhibitors - Google Patents

Carbonylamino pyrrolopyrazoles, potent kinase inhibitors Download PDF

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Publication number
HK1128290B
HK1128290B HK09106049.9A HK09106049A HK1128290B HK 1128290 B HK1128290 B HK 1128290B HK 09106049 A HK09106049 A HK 09106049A HK 1128290 B HK1128290 B HK 1128290B
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Hong Kong
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group
compound
alkylene
radical
alkyl
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HK09106049.9A
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Chinese (zh)
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HK1128290A1 (en
Inventor
董利明
创兴．郭
玉峰．洪
玛丽．凯瑟琳．约翰逊
苏珊．伊丽莎白．克帕特
李海涛
英卓恩．詹姆斯．麦考佩恩
贾拉什．吉利什．提赫
杨安乐
俊瑚．张
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辉瑞产品公司
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Priority claimed from PCT/IB2006/003646 external-priority patent/WO2007072153A2/en
Publication of HK1128290A1 publication Critical patent/HK1128290A1/en
Publication of HK1128290B publication Critical patent/HK1128290B/en

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Description

Effective carbonyl amino pyrrolopyrazole kinase inhibitor
This application claims the benefit of U.S. provisional patent application 60/753,349, filed on 21/2005 and 60/864,932, filed on 8/11/2006, the disclosures of which are incorporated herein by reference in their entirety.
Technical Field
The present invention relates generally to a novel chemical compound and a method thereof. More particularly, the present invention provides novel carbonylamino pyrrolopyrazoles compounds having protein kinase activity and analogs thereof, and methods of synthesizing and using the same.
Background
Protein kinases are a class of enzymes that catalyze the phosphorylation of hydroxyl groups in specific tyrosine, serine, or threonine residues in proteins. In general, this phosphorylation can significantly alter the function of proteins, and thus protein kinases can play a key role in regulating various cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. The mechanisms of these cellular processes provide the basis for target protein kinases for the treatment of disease conditions derived from or involving dysregulation of these cellular processes. Examples of such diseases include, but are not limited to, cancer and diabetes.
Protein kinases can be divided into two classes, Protein Tyrosine Kinases (PTKs) and serine-threonine kinases (STKs). Both PTKs and STKs may be receptor protein kinases or non-receptor protein kinases. PAKs are a class of non-receptor STKs. The p-21-activated protein kinase (PAK) among serine/threonine protein kinases plays an important role in the formation of cytoskeleton and in cell morphogenesis (Daniels et al, Trends biochem. Sci.24: 350-355 (1999); Sells et al, Trends cell. biol.7: 162-167 (1997)). PAK proteins were originally identified by interactions with active small gtpases, Cdc42 and Rac, and homologues of the yeast kinase Ste 20. In addition to modulation of actin cytoskeleton and cell adhesion by Cdc42 and Rac mediation (Daniels et al, Trends biochem. Sci.24: 350-355(1999)), it has been determined that some PAK proteins protect cells from apoptosis (Gnesuta et al, J.biol. chem.276: 14414-14419 (2001); Rudel et al, Science 276: 1571-1574 (1997); Schurmann et al, mol.cell.biol.20: 453-461 (2000)); the pathway of mitogen-activated protein (MAP) kinase regulation (Bagrodia et al, J.biol.chem.270: 27995 27998 (1995); Brown et al, curr.biol.6: 598-; mediate the signaling of T-cell antigen receptors (TCRs) (Yablonski et al, EMBO J.17: 5647-5657(1998)) and respond to DNA damage (Roig et al, J.biol. chem.274: 31119-31122 (1999)). Through the various functions described above, PAK proteins regulate cell proliferation and migration.
U.S. Pat. No. 6,013,500 discloses full-length PAK4 nucleic acid and amino acid sequences and is deposited in GenBank under accession numbers AF005046(mRNA) and AAD01210 (amino acids). It has been reported that modulation of the activity of human PAK4 results in alterations in cellular processes that affect cell growth and adhesion. For example, overexpression of PAK4 in fibroblasts results in morphological changes characterized by oncogenic transformation by inducing anchor-independent growth and inhibition of apoptosis (Gnesuta et al, J.biol.chem.276: 14414-14419 (2001); Qu et al, mol.cell.biol.21: 3523-2533 (2001)). In recent years, studies have also shown that: PAK4 was overexpressed in tumor cell lines in various tissue sources in humans; the expression of the active PAK4 mutant has transforming potential, thus leading to anchor-independent growth of the NIH3T3 cell line; inactive kinase (kinase-inactive) PAK4 efficiently blocks transformation by active Ras and inhibits anchor-independent growth of HCT116 colon cancer cells. These data strongly suggest PAK4 in oncogenic transformation and suggest that PAK4 required for Ras-driven anchor-independent growth in human cancer cells is active (Smeal et al, J.biol.chem.277, 550-558 (2002)). The application demonstrates the in vivo efficacy of compounds that inhibit the PAK4 kinase domain in mice with transplanted tumors.
It is therefore apparent that PAK is an attractive target for the development of effective therapeutic agents for the treatment of disorders associated with abnormal cell growth, particularly cancer.
For additional background reference, see U.S. patent application 2003/0171357 and PCT application WO 02/12242.
Disclosure of Invention
In one embodiment, the present invention provides a compound of formula I,
wherein:
R1is ethyl, tert-butyl, R, -L- (C)3-C12Cycloalkyl), -L-phenyl,-L- (5-12 membered heteroaryl), -L- (3-12 membered heterocyclyl) and-L- (C)3-C12Unsaturated non-aromatic carbocyclic ring);
R2and R3Each independently is H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, - (C)1-C3Alkylene radical)m-(C3-C12Cycloalkyl) or- (C)1-C6Perfluoroalkyl group), and R2And R3Each of which is optionally substituted by 1-3 substituents selected from halogen, -CN, oxo, -OH, -NH2、C1-C6Monoalkylamino, and C2-C8The group of dialkylamino is further substituted; or R2And R3And R is2And R3The carbon atoms linked together form a ring selected from a 3-5 membered non-aromatic carbocycle and a 3-5 membered heterocycle, and the ring is optionally substituted with 1-3 substituents selected from C1-C3Alkyl radical, C1-C3Perfluoroalkyl group, oxo group, - (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-CN、-(C1-C3Alkylene radical)m-OH、-(C1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-(C1-C6Monoalkylamino) and- (C)1-C3Alkylene radical)m-(C2-C8Dialkylamino) is further substituted;
R4is selected from-OR5、-O-R6-R7、-O-CH(R8)R9、-N(Rt)-R6-R7、-N(Rt)CH(R8)R9、-CH(Rt)-R6-R7、-CH(Rt)-CH(R8)-R9、-B-(C1-C3Alkylene) -CH (R)8)R9and-B- (C)1-C3Alkylene radical)m-CH(R10)R9And B is-O-, -N (R)t) -or-CH (R)t)-；
R5Is R;
R6is selected from- (C)3-C7A divalent radical of cycloalkylene) -, - (3-to 7-membered heterocyclylene) -and- (5-to 7-membered heteroarylene) -, with the proviso that when R is4is-CH2-R6-R7，R7When it is unsubstituted phenyl, R6Is not unsubstituted thiazolylideneene; r6Optionally 1-4 selected from C1-C3Alkyl, oxo, C1-C3Perfluoroalkyl group, - (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-(C1-C3Alkylamino-, - (C)1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-OH and- (C)1-C3Alkylene radical)m-(C1-C3Alkoxy) is further substituted;
R7selected from phenyl, C10-C12Aryl radical, C3-C12Cycloalkyl radical, C4-C12Unsaturated non-aromatic carbocyclic groups, 3-12 membered heterocyclic groups and 5-12 membered heteroaryl groups;
R8is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H or C1-C6Alkyl, or RpAnd RqAnd R ispAnd RqThe attached nitrogen atoms together form a ring selected from the group consisting of 3-7 membered heterocyclyl and 5-7 membered heteroaryl, and said ring is optionally substituted with 1-6 substituents selected from the group consisting of halogen, C1-C3Alkyl, oxo and C1-C3The group of perfluoroalkyl is further substituted;
R9is selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Perfluoroalkyl group, benzeneRadical, - (L)1) -phenyl, C10-C12Aryl, - (L)1)-(C10-C12Aryl group), C3-C12Cycloalkyl, - (L)1)-(C3-C12Cycloalkyl), C4-C12Unsaturated non-aromatic carbocyclic group, - (L)1)-(C4-C12Unsaturated non-aromatic carbocyclic group), 3-12 membered heterocyclic group, - (L)1) - (3-12 membered heterocyclic group), 5-12 membered heteroaryl and- (L)1) - (5-12 membered heteroaryl);
R10is selected from C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, - (C)1-C6Alkylene radical)m-(C1-C6Alkoxy), - (C)1-C6Alkylene radical)m-(CONRjRk) Wherein R isjAnd RkEach independently is H or C1-C3Alkyl, - (C)1-C3Alkylene radical)m-(C3-C6Cycloalkyl) and- (C)1-C3Alkylene radical)m- (3-to 6-membered heterocyclyl), and R10Optionally substituted by 1-3 substituents selected from halogen, -OH, oxo and C1-C3The radical of alkyl is further substituted with the proviso that when R is4is-B-CH (R)10)R9B is NH or CH2And R is9Is unsubstituted-CH3Or unsubstituted phenyl, R10Not unsubstituted CH3；
Each R is independently selected from methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, C5-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, - (C)1-C3Alkylene radical)m-(C3-C12Cycloalkyl), - (C)1-C3Alkylene radical)m-phenyl, - (C)1-C3Alkylene radical)m- (5-to 12-membered heteroaryl), - (C)1-C3Alkylene radical)m- (3-to 12-membered heterocyclic group), - (C)1-C3Alkylene radical)m-(C3-C12Unsaturated non-aromatic carbocyclic group), - (C)1-C6Perfluoroalkyl group), - (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-CN，-(C1-C3Alkylene radical)m-C(O)Ra、-(C1-C3Alkylene radical)m-C(O)ORa、-(C1-C3Alkylene radical)m-C(O)NRaRb、-(C1-C3Alkylene radical)m-ORa、-(C1-C3Alkylene radical)m-OC(O)Ra、-(C1-C3Alkylene radical)m-OC(O)NRaRb、-(C1-C3Alkylene radical)m-O-S(O)Ra、-(C1-C3Alkylene radical)m-OS(O)2Ra、-(C1-C3Alkylene radical)m-OS(O)2NRaRb、-(C1-C3Alkylene radical)m-OS(O)NRaRb、-(C1-C3Alkylene radical)m-NO2、-(C1-C3Alkylene radical)m-NRaRb、-(C1-C3Alkylene radical)m-N(Ra)C(O)Rb、-(C1-C3Alkylene radical)m-N(Ra)C(O)ORb、-(C1-C3Alkylene radical)m-N(Rc)C(O)NRaRb、-(C1-C3Alkylene radical)m-N(Ra)S(O)2Rb、-(C1-C3Alkylene radical)m-N(Ra)S(O)Rb、-(C1-C3Alkylene radical)m-SRa、-(C1-C3Alkylene radical)m-S(O)Ra、-(C1-C3Alkylene radical)m-S(O)2Ra、-(C1-C3Alkylene radical)m-S(O)NRaRb、-(C1-C3Alkylene radical)m-S(O)2NRaRb、-(C1-C3Alkylene radical)m-O-(C1-C3Alkylene radical)m-NRaRbAnd- (C)1-C3Alkylene radical)m-NRa-(C1-C3Alkylene) -ORb(ii) a Said C is3-C12Cycloalkyl, said phenyl, said 3-12 membered heterocyclyl and said 5-12 membered heteroaryl each independently optionally substituted with 1-3 substituents selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and oxo are further substituted;
each Ra、RbAnd RcEach independently is H, C1-C8Alkyl radical, C2-C8Alkenyl, - (C)1-C3Alkylene radical)m-(C3-C8Cycloalkyl), - (C)1-C3Alkylene radical)m-(C3-C8Cycloalkenyl group), C2-C8Alkynyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)1-C3Alkylene radical)m- (5-to 7-membered heteroaryl) or- (C)1-C3Alkylene radical)m- (3-to 8-membered heterocyclyl), and each Ra、RbAnd RcEach independently optionally substituted by 1-3 substituents selected from halogen, hydroxy, -CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, C1-C6Alkoxy radical, C1-C6The group of alkylamino is further substituted; or, when R isaAnd RbOptionally forming a ring when attached to the same nitrogen, said ring being selected from- (5-7 membered heteroaryl) and- (3-8 membered heterocyclyl), and said ring being optionally substituted with 1-3 substituents selected from halogen, hydroxy, -CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, C1-C6Alkoxy and C1-C6The group of alkylamino is further substituted;
each RtEach independently is H or C1-C3An alkyl group;
each R1、R5、R7And R9Each independently optionally substituted by 1-6 substituents selected from oxo and RxFurther substituted with a group of (a);
each RxEach independently is ethyl, t-butyl or R;
each L is independently selected from- (C)1-C3Alkylene radical)m-(C3-C7Cycloalkylene) -, - (C)2-C8Alkenylene) -, - (C)2-C8Alkynylene) -, -O- (C)1-C3Alkylene radical)m-and-NH- (C)1-C3Alkylene radical)m-a divalent group of (a);
each L1Each independently is selected from- (C)1-C3Alkylene) -, -O-, - (C)1-C3Alkylene) -O-, -N (R)t) -and- (C)1-C3Alkylene) -N (R)t) -a divalent group of (a);
each m is independently 0 or 1;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In the 1 st specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent therewith, each R2And R3Each independently is H, C1-C6Alkyl and C3-C5Cycloalkyl, and each R2And R3Each independently optionally further substituted. More specifically, each R2And R3Each independently optionally substituted by 1-3 substituents selected from-F, oxo, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted. Even more specifically, each R2And R3Each independently of the other is H, unsubstituted C1-C3Alkyl and unsubstituted C3-C5A cycloalkyl group. Even further more specifically, R2Is unsubstituted methyl, R3Is unsubstituted methyl.
In the 2 nd specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent therewith, R2And R3And R is2And R3The carbon atoms linked together form a ring selected from C3-C5Cycloalkylene and 3-5 membered heterocyclylene, and the ring may optionally be further substituted. More specifically, the ring may optionally be substituted by 1-3 groups selected from-F, oxo, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted. Even more particularly, the ring is selected from the group consisting of cyclopropylene, cyclobutylene and cyclopentylene. Even further more specifically, the ring is cyclopropylene. More preferably, the ring is an unsubstituted cyclopropylene.
In the 3 rd specific aspect of this embodiment mode, and in combination with other specific aspects (especially the 1 st or 2 nd specific aspects) which are not inconsistent, R1Is selected from- (C)1-C3Alkylene radical)m-phenyl and-L-phenyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted. More specifically, R1Is optionally substituted by 1-6 substituents selected from oxo and RxPhenyl substituted with the group of (1).
In the 4 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent therewith, R1Is selected from- (C)1-C3Alkylene radical)m-(C3-C12Cycloalkyl) and-L- (C)3-C12Cycloalkyl) and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted. More specifically, R1Is optionally substituted by 1-6 substituents selected from oxo and RxC being further substituted by a group of3-C12A cycloalkyl group. Even more specifically, R1Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 5 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent, R1Is selected from- (C)1-C3Alkylene radical)m- (5-to 10-membered heteroaryl) and-L- (5-to 10-membered heteroaryl), and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted. More specifically, R1Is selected from the group consisting of oxo and R, optionally substituted by 1-6xA 5-10 membered heteroaryl group further substituted with (a) a group (b). Even more specifically, R1Selected from the group consisting of pyridyl, thienyl, thiazolyl and imidazolyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 6 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent, R1Is selected from- (C)1-C3Alkylene radical)m- (3-to 10-membered heterocyclic group) and-L- (3-to 10-membered heterocyclic group), and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted. More specifically, R1Is selected from the group consisting of oxo and R, optionally substituted by 1-6xA 3-to 10-membered heterocyclic group which is further substituted with (a) a group (b). Even more specifically, R1Selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl and morpholinyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 7 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent therewith, R1Is selected from- (C)1-C3Alkylene radical)m-(C3-C12Unsaturated non-aromatic carbocyclic group) and-L- (C)3-C12Unsaturated non-aromatic carbocyclic group), and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted. More specifically, R1Is selected from the group consisting of oxo and R, optionally substituted by 1-6xC being further substituted by a group of3-C12Unsaturated non-aromatic carbocyclic groups.
In the 8 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent, R1Is selected from C1-C8Alkyl radical, C2-C8Alkenyl and C2-C8Alkynyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 9 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent therewith, R1Is selected from-L- (C)1-C8Alkyl), -L- (C)2-C8Alkenyl), -L- (C)2-C8Alkynyl) and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 10 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent, R1Is selected from C1-C8Alkyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)3-C5Cycloalkylene-phenyl, - (C)1-C3Alkylene radical)m- (5-to 6-membered heteroaryl), - (C)3-C5Cycloalkylene) - (5-6 membered heteroaryl), - (C)1-C3Alkylene radical)m-(C3-C10Cycloalkyl), - (C)1-C3Alkylene radical)m-(C5-C10Cycloalkenyl), - (C)1-C3Alkylene radical)m- (3-to 8-membered heterocyclic group) and- (C)3-C5Cycloalkylene) - (3-8 membered heterocyclyl), and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 11 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly the 1 st or 2 nd specific aspects) which are not inconsistent therewith, R1Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene-phenyl, - (cyclopropylene) -phenyl, pyridyl, - (C)1-C3Alkylene) -pyridyl, - (cyclopropylene) -pyridyl, thienyl, thiazolyl, imidazolyl, -cyclopropyl, -cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, and R1Optionally substituted by 1-6 groups selected from oxo and RxIs further substituted.
In the 12 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 11 th specific aspects) which are not inconsistent with each other, R1Optionally 1-6 selected from C1-C3Alkyl radical, C1-C3Perfluoroalkyl group, oxo group, - (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-CN、-(C1-C3Alkylene radical)m-OH、-(C1-C3Alkylene radical)m-ORd、-(C1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-(C1-C6Monoalkylamino group), - (C)1-C3Alkylene radical)m-(C2-C8Dialkylamino), - (C)1-C3Alkylene radical)m-CONRdReWherein each R is further substituteddAnd ReEach independently is H or C1-C3An alkyl group. More specifically, R1Optionally 1-3 selected from-F, C1-C3Alkyl radical, C1-C3Alkoxy and C1-C3The group of perfluoroalkyl is further substituted.
In the 13 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 12 th specific aspects) which are not inconsistent with each other, R4is-OR6-R7。
In the 14 th specific aspect of this embodiment mode, and in a specific party that is not inconsistent with othersIn combination of the faces (particularly, the specific aspects of 2 to 12), R4is-N (R)t)R6-R7Wherein R istIs H or C1-C3An alkyl group. More preferably, R4is-NH-R6-R7。
In the 15 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 12 th specific aspects) which are not inconsistent with each other, R4is-CH (R)t)R6-R7Wherein R istIs H or C1-C3An alkyl group. More preferably, R4is-CH2-R6-R7。
In the 16 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 13 th to 15 th specific aspects) which are not inconsistent with each other, R6Is- (3-7 membered heterocyclylene) -and R6Optionally substituted. More preferably, R6Selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, and R6Optionally further substituted. Even more preferably, R6Optionally 1-4 of the total amino acids are selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and oxo groups are further substituted. Even further more preferably, R6Selected from the group consisting of unsubstituted aziridinyl (aziridyl), unsubstituted azetidinyl (azidinyl), unsubstituted pyrrolidinyl and unsubstituted piperidinyl.
In the 17 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 13 th to 15 th specific aspects) which are not inconsistent with each other, R6Selected from-cyclopropylidene-, -cyclobutylidene-and-cyclopentylidene-, R6Optionally further substituted. More specifically, R6Is optionally substituted by 1-4 substituents selected from oxo, -F, C1-C3Alkyl and C1-C3A-cyclopropylene-group further substituted by a group of the perfluoroalkyl group. Even more specifically, R6Is an unsubstituted sub-ringAnd (4) propyl.
In the 18 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 13 th to 17 th specific aspects) which are not inconsistent with each other, R7Is phenyl, and R7Optionally further substituted.
In the 19 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 13 th to 17 th specific aspects) which are not inconsistent with each other, R7Is a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S and O, and R7Optionally further substituted. More specifically, R7Is a 5-membered heteroaryl group containing 1-2N heteroatoms, and R7Optionally further substituted.
In the 20 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 13 th to 17 th specific aspects) which are not inconsistent with each other, R7Is a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S and O, and R7Optionally further substituted. More specifically, R7Is a 6-membered heteroaryl group containing 1-2N heteroatoms, and R7Optionally further substituted.
In the 21 st specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 18 th to 20 th specific aspects) which are not inconsistent with each other, R7Optionally 1-6 selected from-F, C1-C3Alkyl radical, C1-C3The group of perfluoroalkyl is further substituted. More preferably, R7Optionally substituted by 1-6 substituents selected from halogen and C1-C3The radical of alkyl is further substituted.
In the 22 nd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 12 th specific aspects) which are not inconsistent with each other, R4Is selected from-O-CH (R)8)-R9。
In the 23 rd specific aspect of this embodiment mode, anAnd in combination with other specific aspects not inconsistent with (especially the 2 nd to 12 th specific aspects), R4is-B- (C)1-C3Alkylene) -CH (R)8)-R9Wherein B is-O-, -NRt-or-CH (R)t) -, and RtIs H or C1-C3An alkyl group. More preferably, RtIs H.
In the 24 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 12 th specific aspects) which are not inconsistent with each other, R4Is selected from-N (R)t)CH(R8)R9And wherein R istIs H or C1-C3An alkyl group.
In the 25 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 12 th specific aspects) which are not inconsistent with each other, R4Is selected from-CH (R)t)CH(R8)R9And wherein R istIs H or C1-C3An alkyl group.
In the 26 th particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith (especially the 23 rd, 24 th or 25 th particular aspects), RtIs H.
In the 27 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 26 th specific aspects), R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H or C1-C3An alkyl group. More specifically, R8Is selected from-CH2-N-(CH3)2、-CH2-NH-CH3and-CH2-NH2。
In the 28 th specific aspect of this embodiment mode, and in the group of specific aspects (particularly, the 22 nd to 26 th specific aspects) which are not inconsistent with one anotherIn the reaction, R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein R ispAnd RqTogether with the nitrogen atom to which they are attached form a ring selected from 3-7 membered heterocyclic and 5-7 membered heteroaryl, said ring being optionally substituted with 1-6 selected groups halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 29 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 28 th specific aspects), R9Is phenyl, and R9Optionally further substituted.
In the 30 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 28 th specific aspects), R9Is a 6-membered heteroaryl group containing 1-2N heteroatoms, R9Optionally further substituted. More preferably, R9Is pyridyl, and R9Optionally further substituted.
In the 31 st specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 28 th specific aspects), R9Is a 5-membered heteroaryl group containing 1-2N heteroatoms, and R9Optionally further substituted.
In the 32 nd specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 28 th specific aspects), R9Is C5-C7Cycloalkyl radical, and R9Optionally further substituted.
In the 33 rd specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 28 th specific aspects), R9Is a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, S and O, R9Optionally further substituted.
In the 34 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 22 nd to 33 th specific aspects), R9Optionally 1-6 selected from- (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-hydroxy, - (C)1-C3Alkylene radical)m-CN、C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, mono (C)1-C3Alkylene radical)m-(C1-C6Alkoxy), - (C)1-C3Alkylene radical)m-NH2And- (C)1-C3Alkylene radical)m-(C1-C6Alkylamino) groups. More specifically, R9Optionally 1-6 selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl group, C1-C3Alkoxy and oxo are further substituted.
In the 35 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 1 st to 12 th specific aspects and the 29 th to 34 th specific aspects), R4is-O- (C)1-C3Alkylene radical)m-CH(R10)R9. More specifically, R4is-O-CH (R)10)R9. Even more specifically, R10Is selected from C1-C6Alkyl, - (C)1-C6Alkylene radical)m-(C1-C6Alkoxy) and- (C)1-C3Alkylene radical)m- (3-to 6-membered heterocyclyl), and R10Optionally further substituted.
In the 36 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly the 1 st to 12 th specific aspects and the 29 th to 34 th specific aspects), R4is-NRt-(C1-C3Alkylene radical)m-CH(R10)R9. More specifically, R4is-NRt-CH(R10)R9. Even more specifically, RtIs H. Even further more specifically, R10Is selected from C1-C6Alkyl, - (C)1-C6Alkylene radical)m-(C1-C6Alkoxy) and- (C)1-C3Alkylene radical)m- (3-to 6-membered heterocyclyl), and R10Optionally further substituted.
In the 37 th specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent with each other (particularly, the 1 st to 12 th specific aspects and the 29 th to 34 th specific aspects), R4is-CHRt-(C1-C3Alkylene radical)m-CH(R10)R9. More specifically, R4is-CHRt-CH(R10)R9. Even more specifically, RtIs H. Even further more specifically, R10Is selected from C1-C6Alkyl, - (C)1-C6Alkylene radical)m-(C1-C6Alkoxy) and- (C)1-C3Alkylene radical)m- (3-to 6-membered heterocyclyl), and R10Optionally further substituted.
In the 38 th specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2Is unsubstituted methyl; r3Is unsubstituted methyl; r1Is selected from C1-C8Alkyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)3-C7Cycloalkylene-phenyl, - (C)1-C3Alkylene radical)m-(C3-C12Cycloalkyl), - (C)3-C7Cycloalkylene) - (C3-C12Cycloalkyl), - (C)1-C3Alkylene radical)m-(C3-C12Unsaturated non-aromatic carbocyclic group), - (C)3-C7Cycloalkylene) - (C3-C12Unsaturated non-aromatic carbocyclic group), - (C)1-C3Alkylene radical)m- (5-to 10-membered heteroaryl), - (C)3-C7Cycloalkylene) - (5-10 membered heteroaryl), - (C)1-C3Alkylene radical)m- (3-to 10-membered heterocyclic group) and- (C)3-C7Cycloalkylene) - (3-10 membered heterocyclyl), and R1Optionally 1-6 selected from C1-C3Alkyl, - (C)1-C3Alkylene radical)m-(C3-C5Cycloalkyl), - (C)1-C3Alkylene radical)m- (3-6 membered heterocyclyl optionally further substituted by 1-2 methyl groups), F, Cl, -CN, C1-C3Perfluoroalkyl group, - (C)1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-NH(C1-C4Alkyl), - (C)1-C3Alkylene radical)m-N(C1-C4Alkyl) (C1-C4Alkyl), - (C)1-C3Alkylene radical)m-NH-(C3-C5Cycloalkyl), - (C)1-C3Alkylene radical)m-OH、-(C1-C3Alkylene radical)m-O-(C1-C4Alkyl), - (C)1-C3Alkylene radical)m-O-(C3-C5Cycloalkyl), - (C)1-C3Alkylene radical)m-C(O)-NH2、-(C1-C3Alkylene radical)m-C(O)-NH-(C1-C4Alkyl) and- (C)1-C3Alkylene radical)m-C(O)-N(C1-C4Alkyl) (C1-C4Alkyl) is further substituted.
In the 39 th specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2Is unsubstituted methyl; r3Is unsubstituted methyl; r1Is selected from C1-C8Alkyl radical, C3-C8Cycloalkyl, phenyl, - (C)1-C3Alkylene-phenyl, - (cyclopropylene) -phenyl, pyridyl, - (C)1-C3Alkylene) -pyridyl, - (cyclopropylene) -pyridyl, -pyrimidinyl, - (C)1-C3Alkylene radical) -pyrimidinyl, - (cyclopropylidene) -pyrimidinyl, thienyl, - (C)1-C3Alkylene) -thienyl, - (cyclopropylene) -thienyl, pyrazolyl, - (C)1-C3Alkylene-pyrazolyl, - (cyclopropylene) -pyrazolyl, tetrahydrofuryl, - (C)1-C3Alkylene) -tetrahydrofuranyl, - (cyclopropylidene) -tetrahydrofuranyl, tetrahydropyranyl, - (C)1-C3Alkylene) -tetrahydropyranyl, - (cyclopropylidene) -tetrahydropyranyl, morpholinyl, - (C)1-C3Alkylene) -morpholinyl, - (cyclopropylene) -morpholinyl, imidazolyl, and- (C)1-C3Alkylene-imidazolyl, - (cyclopropylidene) -imidazolyl, thiazolyl, - (C)1-C3Alkylene) -thiazolyl, - (cyclopropylene) -thiazolyl, isothiazolyl, - (C)1-C3Alkylene) -isothiazolyl, - (cyclopropylene) -isothiazolyl, oxazolyl, - (C)1-C3Alkylene) -oxazolyl, - (cyclopropylidene) -oxazolyl, isoxazolyl, - (C)1-C3Alkylene) -isoxazolyl, - (cyclopropylene) -isoxazolyl, benzothienyl, - (C)1-C3Alkylene) -benzothienyl, - (cyclopropylene) -benzothienyl, benzothiazolyl, - (C)1-C3Alkylene) -benzothiazolyl, - (cyclopropylene) -benzothiazolyl, dihydrobenzofuranyl, - (C)1-C3Alkylene) -dihydrobenzofuranyl, - (cyclopropylene) -dihydrobenzofuranyl, pyrazinyl, - (C)1-C3Alkylene) -pyrazinyl, - (cyclopropylene) -pyrazinyl, wherein R1Optionally 1-3 selected from F, Cl, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and C1-C3The radical of alkoxy is further substituted.
In the 40 th particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith, R2And R3An unsubstituted cyclopropylene group is formed.
In another embodiment, the present invention provides a compound of formula II,
wherein:
b is-O-, -NRt-or-CHRt-, wherein RtIs H or C1-C3An alkyl group;
R1is selected from C1-C8Alkyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)3-C5Cycloalkylene-phenyl, - (C)1-C3Alkylene radical)m-(C3-C10Cycloalkyl), - (C)1-C3Alkylene radical)m-(C5-C10Cycloalkenyl), - (C)1-C3Alkylene radical)m- (3-to 10-membered heterocyclic group), - (C)3-C5Cycloalkylene) - (3-10 membered heterocyclic group), - (C1-C3Alkylene radical)m- (5-12 membered heteroaryl) and- (C)3-C5Cycloalkylene) - (5-12 membered heteroaryl), and R1Optionally 1-6 selected from- (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-hydroxy, - (C)1-C3Alkylene radical)m-CN、C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, - (C)1-C3Alkylene radical)m-(C1-C6Alkoxy), - (C)1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-(C1-C6Alkylamino-, - (C)1-C3Alkylene radical)m-(C3-C5Cycloalkyl) and- (C)1-C3Alkylene radical)mThe group of (3-to 5-membered heterocyclic group) is further substituted, and said C3-C5Cycloalkyl and said 3-5 membered heterocyclyl are optionally substituted with 1-3 substituents selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and oxo radicals furtherSubstitution;
each R2And R3Each independently is C1-C3Alkyl, or R2And R3And R is2And R3The carbon atoms bound together form C3-C4A cycloalkylene group;
R6is a divalent radical selected from the group consisting of cyclopropylene, cyclobutylene, cyclopentylene and- (3-6-membered heterocyclylene), R6Optionally 1-6 selected from halogen, C1-C3Alkyl, oxo and C1-C3The group of perfluoroalkyl is further substituted;
R7selected from phenyl, 5-membered heteroaryl, pyridyl, 6-membered heteroaryl containing 2-3 heteroatoms selected from N, S and O, 7-10 membered heteroaryl, and 3-12 membered heterocyclyl, R7Optionally substituted by 1-6 substituents selected from halogen, -C1-C3Perfluoroalkyl group, C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino, -OH, -NH2and-CN is further substituted;
each m is independently 0 or 1; or
Pharmaceutically acceptable salts, solvates, or hydrates of the above compounds are provided.
In a 1 st particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith, B is-O-.
In the 2 nd specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent therewith, B is-NRt-. More specifically, RtIs H. Still more specifically, RtIs C1-C3An alkyl group.
In the 3 rd particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith, B is-CHRt-. More specifically, RtIs H. Yet to be more possessedBody to ground, RtIs C1-C3An alkyl group.
In the 4 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 3 rd specific aspects) which are not inconsistent with each other, R2Is methyl, R3Is methyl.
In the 5 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is C1-C8Alkyl, and R1Optionally further substituted.
In the 6 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is phenyl, and R1Optionally further substituted.
In the 7 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene) -phenyl, and R1Optionally further substituted.
In the 8 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) -phenyl, and R1Optionally further substituted.
In the 9 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is 5-10 membered heteroaryl, and R1Optionally further substituted. More specifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the aspect of this embodimentIn the 10 th specific aspect of the formula (I), and in combination with other specific aspects not inconsistent with (particularly, the 2 nd to 4 th specific aspects), R1Is- (C)1-C3Alkylene) - (5-to 10-membered heteroaryl), and R1Optionally further substituted. More specifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the 11 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) - (5-10 membered heteroaryl), and R1Optionally further substituted. More specifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the 12 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene group) - (C3-C10Cycloalkyl) and R1Optionally further substituted. More specifically, C3-C10Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and R1Optionally further substituted.
In the 13 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is C3-C10Cycloalkyl radical, and R1Optionally further substituted. More specifically, C3-C10Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and R1Optionally further substituted.
In the 14 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene group) - (C5-C10Cycloalkenyl group), and R1Optionally further substituted.
In the 15 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is C5-C10Cycloalkenyl radical, and R1Optionally further substituted.
In the 16 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene) - (3-to 10-membered heterocyclyl), and R1Optionally further substituted. More specifically, the 3-10 membered heterocyclic group is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 17 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) - (3-10 membered heterocyclyl), and R1Optionally further substituted. More specifically, the 3-10 membered heterocyclic group is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 18 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 4 th specific aspects) which are not inconsistent with each other, R1Is a 3-10 membered heterocyclic group, and R1Optionally further substituted. More specifically, the 3-10 membered heterocyclic ring is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 19 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 18 th specific aspects) which are not inconsistent with each other, R1Optionally substituted by 1-6 substituents selected from halogenElement, C1-C3Alkyl radical, C1-C3Perfluoroalkyl group, -OH, C1-C3Alkoxy, -NH2、C1-C3The groups of alkylamino and CN are further substituted.
In the 20 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 19 th specific aspects) which are not inconsistent with each other, R6Is an optionally further substituted cyclopropylene. More specifically, R6Is unsubstituted cyclopropylene.
In the 21 st specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, 2 nd to 19 th specific aspects) which are not inconsistent with each other, R6Is an optionally further substituted cyclobutylene group. More specifically, R6Is unsubstituted cyclobutylidene.
In the 22 nd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 19 th specific aspects) which are not inconsistent with each other, R6Is- (3-6 membered heterocyclylene) -, and R6Optionally substituted. More preferably, R6Selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, and R6Optionally further substituted. Even more preferably, R6Optionally 1-4 of the total amino acids are selected from-F, C1-C3Alkyl and oxo are further substituted. Even further more preferably, R6Unsubstituted aziridinyl, unsubstituted azetidinyl, unsubstituted pyrrolidinyl and unsubstituted piperidinyl.
In the 23 rd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 19 th specific aspects) which are not inconsistent with each other, R6Is cyclopentylene, and R6Optionally substituted. More preferably, R6Is unsubstituted cyclopentylene.
At 24 th of this embodiment modeIn a specific aspect, and in combination with other specific aspects not inconsistent therewith (especially specific aspects 2 to 23), R7Is phenyl, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 25 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 23 th specific aspects) which are not inconsistent with each other, R7Is pyridyl, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 26 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 23 th specific aspects) which are not inconsistent with each other, R7Is a 5-membered heteroaryl group, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 27 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 23 th specific aspects) which are not inconsistent with each other, R7Is a 6-membered heteroaryl group containing 2-3 heteroatoms selected from N, S and O, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 28 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 23 th specific aspects) which are not inconsistent with each other, R7Is a 7-12 membered heteroaryl group, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 29 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 2 nd to 23 th specific aspects) which are not inconsistent with each other, R7Is a 3-10 membered heterocyclic group, and R7Optionally substituted. More specifically, R7Optionally 1-6 selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 30 th specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2Is methyl; r3Is methyl; b is-O-, -NH-or-CH2-；R1Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene) -phenyl, - (cyclopropylene) -phenyl, C3-C10Cycloalkyl, - (C)1-C3Alkylene group) - (C3-C10Cycloalkyl), 3-to 10-membered heterocyclyl, - (C)1-C3Alkylene) - (3-to 10-membered heterocyclic group), - (cyclopropylene) - (3-to 10-membered heterocyclic group), 5-to 12-membered heteroaryl, - (C)1-C3Alkylene) - (5-12 membered heteroaryl) and- (cyclopropylene) - (5-12 membered heteroaryl), and R1Optionally substituted by 1-6 groups selected from F, Cl, hydroxy, CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group and- (C)1-C3Alkylene radical)m-(C1-C6Alkoxy) is further substituted. Preferably, R6Is unsubstituted cyclopropylene or substituted by 1-3 substituents selected from F, Cl, C1-C3Alkyl and C1-C3A cyclopropyl group further substituted with a group of a perfluoroalkyl group. Also preferably, R7Selected from phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and R7Optionally 1-3 selected from F, Cl, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and C1-C3The radical of alkoxy is further substituted.
In the 31 st specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2And R3An unsubstituted cyclopropylene group is formed.
In another embodiment, the present invention provides a compound of formula III,
wherein:
b is-O-, -NRt-or-CHRt-, wherein RtIs H or C1-C3An alkyl group;
R1is selected from C1-C8Alkyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)3-C5Cycloalkylene-phenyl, - (C)1-C3Alkylene radical)m-(C3-C10Cycloalkyl), - (C)1-C3Alkylene radical)m-(C5-C10Cycloalkenyl), - (C)1-C3Alkylene radical)m- (3-to 10-membered heterocyclic group), - (C)3-C5Cycloalkylene) - (3-10 membered heterocyclic group), - (C1-C3Alkylene radical)m- (5-12 membered heteroaryl) and- (C)3-C5Cycloalkylene) - (5-12 membered heteroaryl), and R1Optionally 1-6 selected from- (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-hydroxy, - (C)1-C3Alkylene radical)m-CN、C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, - (C)1-C3Alkylene radical)m-(C1-C6Alkoxy), - (C)1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-(C1-C6Alkylamino-, - (C)1-C3Alkylene radical)m-(C3-C5Cycloalkyl) and- (C)1-C3Alkylene radical)mThe group of (3-to 5-membered heterocyclic group) is further substituted, and said C3-C5Cycloalkyl and said 3-5 membered heterocyclyl are optionally substituted with 1-3 substituents selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and oxo are further substituted;
each R2And R3Each independently is C1-C3Alkyl, or R2And R3And R is2And R3The carbon atoms bound together form C3-C4A cycloalkylene group;
R8is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H, C1-C3Alkyl, or RpAnd RqTaken together with the nitrogen atom to which they are attached, form a ring selected from 3-7 membered heterocyclyl and 5-7 membered heteroaryl, optionally substituted with 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted;
R9is selected from C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, phenyl group, - (C)1-C3Alkylene) -phenyl, C10-C12Aryl radical, C3-C12Cycloalkyl, - (C)1-C3Alkylene group) - (C3-C12Cycloalkyl), C4-C12Unsaturated non-aromatic carbocyclic group, - (C)1-C3Alkylene group) - (C4-C12Unsaturated non-aromatic carbocyclic group), 3-12 membered heterocyclic group, - (C)1-C3Alkylene) - (3-12 membered heterocyclyl), 5-12 membered heteroaryl and- (C)1-C3Alkylene) - (5-12 membered heteroaryl), and each R9Each independently selected from 1-6 selected from halogen, C1-C6Alkyl radical, C1-C6PerfluoroalkanesRadical, -OH, C1-C6Alkoxy, - (C)1-C6Alkylene group) - (C1-C6Alkoxy) -NH2、-(C1-C6Alkylene) -NH2、-(C1-C6Alkylene group) - (C1-C6Alkylamino) and C1-C6The groups of alkylamino and CN are further substituted; and is
Each m is independently 0 or 1; or
Pharmaceutically acceptable salts, solvates, or hydrates of the above compounds are provided.
In a 1 st particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith, B is-O-.
In the 2 nd specific aspect of this embodiment mode, and in combination with other specific aspects not inconsistent therewith, B is-NRt-. More specifically, RtIs H. Still more specifically, RtIs C1-C3An alkyl group.
In the 3 rd particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith, B is-CHRt-. More specifically, RtIs H. Still more specifically, RtIs C1-C3An alkyl group.
In the 4 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 3 rd specific aspects) which are not inconsistent with each other, R2Is methyl, R3Is methyl.
In the 5 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is C1-C8Alkyl, and R1Optionally further substituted.
In the 6 th special case of this embodiment modeIn the aspect, and in combination with other specific aspects not inconsistent (especially, specific aspects 1 to 4), R1Is phenyl, and R1Optionally further substituted.
In the 7 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene) -phenyl, and R1Optionally further substituted.
In the 8 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) -phenyl, and R1Optionally further substituted.
In the 9 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is 5-10 membered heteroaryl, and R1Optionally further substituted. More specifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the 10 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene) - (5-to 10-membered heteroaryl), and R1Optionally further substituted. More specifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the 11 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) - (5-10 membered heteroaryl), and R1Optionally further substituted. Furthermore, the utility modelSpecifically, the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, thienyl, thiazolyl, and imidazolyl, and R1Optionally further substituted.
In the 12 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene group) - (C3-C10Cycloalkyl) and R1Optionally further substituted. More specifically, C3-C10Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and R1Optionally further substituted.
In the 13 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is C3-C10Cycloalkyl radical, and R1Optionally further substituted. More specifically, C3-C10Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and R1Optionally further substituted.
In the 14 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene group) - (C5-C10Cycloalkenyl group), and R1Optionally further substituted.
In the 15 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is C5-C10Cycloalkenyl radical, and R1Optionally further substituted.
In the 16 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)1-C3Alkylene) - (3-to 10-membered heterocyclic group)And R is1Optionally further substituted. More specifically, the 3-10 membered heterocyclic group is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 17 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is- (C)3-C5Cycloalkylene) - (3-10 membered heterocyclyl), and R1Optionally further substituted. More specifically, the 3-10 membered heterocyclic group is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 18 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 4 th specific aspects) which are not inconsistent with each other, R1Is a 3-10 membered heterocyclic group, and R1Optionally further substituted. More specifically, the 3-10 membered heterocyclic ring is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and R is1Optionally further substituted.
In the 19 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 5 th to 18 th specific aspects) which are not inconsistent with each other, R1Optionally 1-6 selected from halogen, C1-C3Alkyl radical, C1-C3Perfluoroalkyl group, -OH, C1-C3Alkoxy, -NH2、C1-C3The groups of alkylamino and CN are further substituted.
In the 20 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 19 th specific aspects) which are not inconsistent with each other, R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H, C1-C3An alkyl group. More specifically, R8Is selected from-CH2-N-(CH3)2、-CH2-NH-CH3and-CH2-NH2。
In the 21 st specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 19 th specific aspects) which are not inconsistent with each other, R8Is- (C)1-C6Alkylene radical)m-NRpRqAnd R ispAnd RqTogether with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl, said 3-7 membered heterocyclyl being optionally substituted with 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 22 nd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 19 th specific aspects) which are not inconsistent with each other, R8Is- (C)1-C6Alkylene radical)m-NRpRqAnd R ispAnd RqTogether with the nitrogen atom to which they are attached, form a 5-7 membered heteroaryl group, said 5-7 membered heteroaryl group optionally being substituted by 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
In the 23 rd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is phenyl, and R9Optionally further substituted.
In the 24 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is a 6-membered heteroaryl group containing 1-2N heteroatoms, and R9Optionally further substituted. More preferably, R9Is pyridyl, R9Optionally further substituted.
In the 25 th specific aspect of this embodiment mode, and in specific aspects (particularly, specific aspects 1 to 22) which are not inconsistent with othersIn combination of R9Is a 5-membered heteroaryl group containing 1-2N heteroatoms, and R9Optionally further substituted.
In the 26 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is C5-C7Cycloalkyl radical, and R9Optionally further substituted. More preferably, R9Is cyclohexyl, and R9Optionally further substituted.
In the 27 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, S and O, and R9Optionally further substituted.
In the 28 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is- (C)1-C3Alkylene) -phenyl, and R9Optionally further substituted. More preferably, R9is-CH2-phenyl, and R9Optionally further substituted.
In the 29 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is- (C)1-C3Alkylene) - (5-to 12-membered heteroaryl), and R9Optionally further substituted.
In the 30 th specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is- (C)1-C3Alkylene group) - (C3-C12Cycloalkyl) and R9Optionally further substituted.
In this embodiment modeIn the 31 st specific aspect, and in combination with other specific aspects not inconsistent with (particularly, the 1 st to 22 th specific aspects), R9Is selected from C1-C6Alkyl radical, C1-C6Perfluoroalkyl and C1-C6Alkoxy, and R9Optionally further substituted.
In the 32 nd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 1 st to 22 th specific aspects) which are not inconsistent with each other, R9Is- (C)1-C3Alkylene) - (3-to 12-membered heterocyclyl), and R9Optionally further substituted.
In the 33 rd specific aspect of this embodiment mode, and in combination with other specific aspects (particularly, the 23 rd to 32 th specific aspects) which are not inconsistent with each other, R9Optionally substituted by 1-6 substituents selected from halogen, hydroxy, -CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, C1-C6Alkoxy and C1-C6The group of alkylamino is further substituted.
In a 34 th particular aspect of this embodiment, and in combination with other particular aspects not inconsistent therewith (especially 1 st to 33 th particular aspects), the compound has the stereochemistry of formula IIIa:
in the 35 th particular aspect of this embodiment, and in combination with other particular aspects not inconsistent (especially the 1 st to 33 th particular aspects), the compound has greater than 80% of the enantiomerically enriched enantiomer of formula IIIa. Preferably, the compound has greater than 90% enantiomerically enriched enantiomer of formula IIIa. Even more preferably, the compound has greater than 95% enantiomerically enriched enantiomer of formula IIIa.
In the 36 th specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2Is methyl; r3Is methyl; b is-O-, -NH-or-CH2-；R1Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene) -phenyl, - (cyclopropylene) -phenyl, C3-C10Cycloalkyl, - (C)1-C3Alkylene group) - (C3-C10Cycloalkyl), 3-to 10-membered heterocyclyl, - (C)1-C3Alkylene) - (3-to 10-membered heterocyclic group), - (cyclopropylene) - (3-to 10-membered heterocyclic group), 5-to 12-membered heteroaryl, - (C)1-C3Alkylene) - (5-12 membered heteroaryl) and- (cyclopropylene) - (5-12 membered heteroaryl), and R1Optionally substituted by 1-6 groups selected from F, Cl, hydroxy, CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group and- (C)1-C3Alkylene radical)m-(C1-C6Alkoxy) is further substituted. Preferably, R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H or C1-C3An alkyl group. Even more preferably, R8Is selected from-CH2-N-(CH3)2、-CH2-NH-CH3and-CH2-NH2. Also preferably, R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein R ispAnd RqTogether with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl, said 3-7 membered heterocyclyl being optionally substituted with 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted. Also preferably, R9Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene) -phenyl, 5-6 membered heteroaryl and 3-7 membered cycloalkyl, and R9Optionally 1-6 selected from F, Cl, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, -OH, C1-C6Alkoxy, - (C)1-C6Alkylene group) - (C1-C6Alkoxy) and CN.
In the 37 th specific aspect of this embodiment, and in combination with other specific aspects not inconsistent therewith, R2And R3An unsubstituted cyclopropylene group is formed.
In another embodiment, the present invention provides a compound selected from the group consisting of,
or pharmaceutically acceptable salts of said compounds.
In another embodiment, the present invention provides a compound selected from the group consisting of,
or a pharmaceutically acceptable salt of said compound.
In another embodiment, the present invention provides a compound selected from the group consisting of,
or a pharmaceutically acceptable salt of the above compound.
In another embodiment, the present invention provides a compound selected from the group consisting of,
or a pharmaceutically acceptable salt of the above compound.
In another embodiment, the invention provides a method of treating abnormal cell growth in a mammal, said method comprising administering to said mammal a compound of the invention. More specifically, the abnormal cell growth is cancer.
In another embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention.
In another embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method of treating a disease condition in a mammal mediated by protein kinase activity, comprising administering to the mammal a therapeutically effective amount of a compound, salt, hydrate or solvate of the present invention. In one aspect of this embodiment, the disease condition in a mammal is tumor growth or abnormal cell proliferation.
In another embodiment, the present invention provides a method of modulating the activity of a protein kinase, comprising contacting the protein kinase with an effective amount of a compound, salt, hydrate or solvate of the present invention. In one aspect of this embodiment, the protein kinase is PAK4 protein kinase.
In some embodiments, the present teachings provide a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable carrier. Examples of such compositions are described below.
In some embodiments, the present teachings provide a method of treating abnormal cell growth in a mammal (including a human being) comprising administering to the mammal any one of the compounds or pharmaceutical compositions of the present teachings.
In some embodiments, the abnormal cell growth is a cancer including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, soft tissue sarcoma, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, chronic or acute leukemia, lymphoma, carcinoma of the bladder, carcinoma of the kidney or urethra, carcinoma of the renal cells, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, chordoma (spinal axis tumor), brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In some embodiments, the abnormal cell growth is a benign proliferative disease including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis (restinosis).
In some embodiments, the method further comprises administering to the mammal an amount of one or more substances selected from the group consisting of: an anti-tumor agent, an angiogenesis inhibiting agent, a signal transduction inhibitor and an anti-proliferative agent, in amounts that together are effective to treat said abnormal cell growth. Such materials include those disclosed in PCT applications WO 00/38715, WO 00/38716, WO00/38717, WO 00/38718, WO 00/38719, WO 00/38730, WO 00/38665, WO 00/37107 and WO 00/38786, the disclosures of which are incorporated herein by reference in their entirety.
Examples of anti-tumour agents include mitotic inhibitors, for example vinblastine derivatives such as vinblastine, vinorelbine, vindesine and vincristine; colchines allochohne, okadamycin (halichondrine), N-benzoyltrimethyl-methylether colchicic acid, dolastatin (dolastatin 10), maytansine (maytansine), rhizobiacin (rhizoxin) taxanes such as taxol, docetaxel (taxotere), 2' -N- [3- (dimethylamino) propyl ] taxane]Glutamate (tyloxanthine) (a taxol derivative), thiocolchicine (thiocolchicine), trityl cysteine, teniposide (teniposide), methotrexate (methotrexate), azathioprine (azathioprine), fluorouricil, cytarabine (cytocine arabine), 2' -difluorodeoxycytidine (gemcitabine), adriamycin (adriamycin) and mitomycin (amimycin), alkylating agents, such as cisplatin (cis-platin), carboplatin (carboplatin), oxthalidomide (oxiptatin), iproplatin, N-acetyl-DL-dodecylsarcosine-L-leucine (leucineor Asalex), 1, 4-cyclohexadiene-1, 4-dicarbamic acid, 2, 5-bis (1-aziridinyl-3, 6-dioxolone, diethyl ester), 1, 5-bis (1-aziridinyl-3, 6-dioxolone (1-dioxolone), 4-bis (methylsulfonyloxy) butane (bisufan or leucosin), chlorouretcin (chlorozotocin), clomethasone (clomesone), hydroxymorpholinodoxorubicin (cytomorpholinodoxorubicin), cyclodissone, dianhydrogalactitol (dianhydrogalactitol), fluorodopa (fluorodopa), hepsfam, mitomycin C (mitomycin C), hypocathenamidomycin C, mitozolamide (mitozolamide), 1- (2-chloroethyl) -4- (3-chloropropyl) -pyrazine dihydrochloride, piperazinedione, bispropionylpiperazine (pipobromonan) norbomycin (porfiromycin), spirohydantostat (tioxolone), tetroxolone (teroxirone), tetrachloroplatinate (tetraplatin), triethylenetetralin (thiophosphamide), tristhiotephospholate (trisporamycin), and mixtures thereofEthylenemelamine (triethyleneamine), uracil mustard (uracilnitrogen mustard), bis (3-methanesulfonyloxypropyl) amine hydrochloride, mitomycin, nitrosourea agents such as cyclohexyl-chloroethylnitrosourea, methylcyclohexyl-chloroethylnitrosourea, 1- (2-chloroethyl) -3- (2, 6-dioxo-3-piperidyl) -1-nitrosourea, bis (2-chloroethyl) nitrosourea, procarbazine, dacarbazine (dacarbazine); nitrogen mustard related compounds such as bis (chloroethyl) methylamine (mechloroethamine), cyclophosphamide (cyclophosphamide), ifosfamide (ifosamide), melphalan (melphalan), chlorambucil (chlorombucil), estramustine sodium phosphate (estramustine sodium phosphate), strptozone and temozolamide; DNA antimetabolites, e.g. 5-fluorouracil, cytosine, arabinoside, hydroxyurea, 2- [ (3-hydroxy-2-pyridonyl) methylene]-hydrazine carbothioamide, deoxyfluorouridine, 5-hydroxy-2-formylpyridine, thiosemicarbazone, α -2' -deoxy-6-thioguanine nucleoside, aphidicolin glycine, 5-azadeoxycytidine, β -thioguanine deoxynucleoside, cyclidine, guanazole, inosine dialdehyde, macbecin ii, pyrazoloimidazole, cladribine (cladribine), butadine (pentostatin), thioguanine, mercaptopurine, bleomycin, 2-chlorodeoxyadenosine; inhibitors of thymidylate synthase, such as raltitrexed and disodium pemetrexed (ramytrexed and pemetrexed disodium), clofarabine (clofarabine), fluorouracil (floxuridine), and fludarabine (fludarabine); DNA/RNA antimetabolites, e.g., L-alanosine, 5-azacitidine, acivicin, aminopterin and derivatives thereof, such as N- [ 2-chloro-5- [ [ (2, 4-diamino-5-methyl-6-quinazolinyl) -methyl ] -5-azacitine]Amino group]Benzoyl radical]-L-aspartic acid, N- [4- [ [ (2, 4-diamino-5-ethyl-6-quinazolinyl) methyl ] amino]Amino group]-benzoyl radical]-L-aspartic acid, N- [ 2-chloro-4- [ [ (2, 4-diaminopterinyl) methyl]Amino group]Benzoyl radical]-L-aspartic acid, soluble Baker's anti-fol, methallyl quinone dichloride, brequinar (brequinar), ftoraf, dihydro-5-azacytidine, methotrexate (methotrexate), N- (phosphonoacetyl) -L-aspartic acid tetrasodium salt, pyrazolofuran, trimetrexate (trimetrexate), plicamycin (p)licamycin), actinomycin D (actinomycin D), candida albicans (cryptophycin) and analogues thereof, such as candida albicans-52, or one of the preferred antimetabolites disclosed in, for example, European patent application 239362, such as N- (5-N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino]-2-thenoyl) -L-glutamic acid; growth factor inhibition; cell cycle inhibitors (cell cycle inhibitors); intercalating antibiotics, such as doxorubicin and bleomycin; proteins, such as interferon; and anti-hormones, e.g. anti-estrogens, such as NolvadexTM(tamoxifen), or, for example, antiandrogens, such as CasodexTM(4 '-cyano-3- (4-fluorobenzenesulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propenanilide). Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components for treatment.
Anti-angiogenic agents include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors. Examples of useful COX-II inhibitors include CELEBREXTM(alecoxib), valdecoxib (valdecoxib), and rofecoxib (rofecoxib). Examples of useful matrix metalloproteinase inhibitors are described in the following patent applications: WO 96/33172 (published 24/10/1996), WO 96/27583 (published 7/3/1996), European patent application 97304971.1 (filed 8/7/1997), European patent application 99308617.2 (filed 29/10/1999), WO 98/07697 (published 26/2/1998), WO 98/03516 (published 29/1/1998), WO 98/34918 (published 13/8/1998), WO 98/34915 (published 13/8/1998), WO 98/33768 (published 6/8/1998), WO 98/30566 (published 16/7/1998), European patent publication 606,046 (published 13/7/1994), European patent publication 931,788 (published 28/7/1999), WO 90/05719 (published 31/1990), WO 99/52910 (published 21/10/1999), WO 99/52889 (published 21/10/1999), WO 99/29667 (published 17.6.1999), PCT International application PCT/IB98/01113 (filed 21.7.1998), European patent application 99302232.1 (filed 25.3.1999), British patent application 9912961.1 (filed 3.3.1999), AmericanNational provisional application 60/148,464 (filed on 12.8.1999), U.S. patent 5,863,949 (granted on 26.1.1999), U.S. patent 5,861, 510 (granted on 19.1.1999), and european patent publication 780,386 (published on 25.6.1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity for inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Examples of MMP inhibitors include AG-3340, RO 32-3555, RS 13-0830 and the following compounds: 3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclopentyl) -amino ] -propionic acid, 3-exo (exo) -3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, (2R, 3R)1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide, 4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide, and pharmaceutically acceptable salts thereof, 3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclobutyl) -amino ] -propionic acid, 4- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide, 3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-3-carboxylic acid hydroxyamide, (2R, 3R)1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide, 3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino ] -propionic acid, 3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (4-hydroxy-carbamoyltetrahydro-pyran-4-yl) -amino ] -propionic acid, 3-exo (exo) -3- [4- (4-chloro-phenoxy) benzene-sulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3- Carboxylic acid hydroxyamide, 3- [4- (4-fluoro-phenoxy) -benzenesulfonamido ] -tetrahydrofuran-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts, solvates and hydrates thereof.
Examples of signal transduction inhibitors include those capable of inhibiting EGFR (Table)Epidermal growth factor receptor) responsive agents, such as EGFR antibodies, EGF antibodies, and EGFR inhibitor molecules; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the receptor of erbB2, e.g. HERCEPTINTM(Genentech，Inc.，South SanFrancisco，California，USA)。
EGFR inhibitors are described, for example, in the following patent applications: WO 95/19970 (published 27/7/1995), WO 98/14451 (published 9/4/1998), WO 98/02434 (published 22/1/1998), and U.S. Pat. No. 5,747,498 (granted 5/1998). EGFR inhibitors include, but are not limited to, monoclonal antibody C225 and anti-EGFR 22Mab (ImCloneSystems Incorporated, New York, New York, USA), compound ZD-1839(AstraZeneca), BIBX-1382(Boehringer Ingelheim), MDX-447 (Metarexinc, Annandale, New Jersey, USA), and OLX-103(Merck & Co., Whitehouse Station, New Jersey, USA), VRCTC-310(Ventech Research), and EGF fusion toxins (Seragen Inc., Hopkinton, Massachusetts).
VEGF inhibitors, such as SU-5416 and SU-6668(Sugen Inc., South san Francisco, California, USA), may also be combined or co-administered with the compositions of the present invention. VEGF inhibitors are described, for example, in the following patent applications: WO 99/24440 (published 20/5/1999), PCT International application PCT/IB99/00797 (filed 3/5/1999), WO95/21613 (published 17/8/1999), WO 99/61422 (published 2/12/1999), US patent 5,834,504 (granted 10/11/1998), WO 98/50356 (granted 12/11/1998), US patent 5,883,113 (granted 16/3/1999), US patent 5,886,020 (granted 23/3/1999), US patent 5,792,783 (granted 11/8/1999), WO 99/10349 (published 4/1999), WO 97/32856 (published 12/1997), WO 97/22596 (published 26/6/1998), WO 98/54093 (published 3/1998), WO 98/02438 (published 22/1/1998), WO 99/16755 (published 4/1999) and WO 98/02437 (published 22/1998), the disclosures of the above-mentioned patent documents are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862(Cytran inc., Kirkland, Washington, USA); the mono-VEGF monoclonal antibodies bevacizumab (Genentech, inc., South San Francisco, California) and vascular enzyme (angiozyme), synthetic ribozymes available from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).
ErbB2 receptor inhibitors, such as GW-282974(Glaxo Wellcome plc) and monoclonal antibodies AR-209(Aronex Pharmaceuticals Inc., The Woodlans, Texas, USA) and 2B-1(Chiron) can be administered in combination with The compositions of The present invention. The erbB2 inhibitors described above include those described in the following patent documents: WO 98/02434 (published 22/1/1998), WO99/35146 (published 15/7/1999), WO 99/35132 (published 15/7/1999), WO 98/02437 (published 22/1/1998), WO 97/13760 (published 17/4/1997), WO 95/19970 (published 27/7/1995), U.S. Pat. No. 5,587,458 (issued 24/12/1996), and U.S. Pat. No. 5,877,305 (issued 2/3/1999), which are incorporated herein by reference in their entirety. erbB2 receptor inhibitors that may be used in the present invention are also described in U.S. provisional application 60/117,341, filed 1-27 1999, and in U.S. provisional patent application 60/117,346, filed 1-27 1999, which are incorporated herein by reference in their entirety.
Other useful antiproliferative agents include inhibitors of farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following U.S. patent applications: 09/221946 (28-day-delivery 12/1998), 09/454058 (2-day-delivery 12/1999), 09/501163 (9-day-delivery 2/2000), 09/539930 (31-day-delivery 3/2000), 09/202796 (22-day-delivery 5/1997), 09/384339 (26-day-delivery 8/1999), and 09/383755 (26-day-delivery 8/1999); and the compounds disclosed and claimed in the following U.S. provisional patent applications: 60/168207 (11/30-day delivery 1999), 60/170119 (12/10-day delivery 1999), 60/177718 (1/21-day delivery 2000), 60/168217 (11/30-day delivery 1999), and 60/200834 (5/1-day delivery 2000). The above-mentioned patent applications and provisional patent applications are incorporated herein by reference in their entirety.
The compounds of the present invention may also be administered with other agents useful in the treatment of abnormal cell growth or cancer, including, but not limited to, agents capable of raising an anti-cancer immune response, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other agents that block CTLA 4; antiproliferative agents, such as other farnesyl protein transferase inhibitors. Specific CTLA4 antibodies useful in the present invention include those described in U.S. provisional application 60/113,647 (filed 12/23 of 1998), which is incorporated herein by reference in its entirety.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings indicated below. Various variables defined in this section, such as R, X, n, are for reference only within this section and are not meant to have the same meaning as can be used outside this defined section. Furthermore, some of the individual groups defined in the present invention may be optionally substituted. The typical substituents listed in the definitions section are exemplary and are not meant to limit the substituents as defined elsewhere in the specification and claims.
The symbol [ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -]When inserted into the chemical structure of a substituent, means [ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -]The atoms attached are the points at which the substituent is attached to some position on another molecule. For example, assume the molecule CH3CH2X in X can be defined as X beingIn the above case, [ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -]By bonded, it is meant that C-1 of the phenyl ring is attached to the methylene carbon.
SymbolAndwhen used together in one molecule without other means (e.g. chemical)Chemical name or the following description) to refer only to the relative stereochemistry in the trans or in the cis (where applicable). Symbols for simultaneous or separate useAnd symbolsIn combination with a symbol representing an absolute stereochemistry (e.g., the symbol "S" or "R" in the corresponding chemical structure or its chemical name), indicates the absolute stereochemistry of the corresponding chiral center.
When a diradical is referred to as, for example, -O-CH2-or- (C)1-C3Alkylene) -NH-, it is understood that each end of the diradical can be equivalently linked to other groups. For example, if K is defined as A-L-B and L is selected from-O-CH2-and- (C)1-C3Alkylene) -, it being understood that K is thus selected from A-O-CH2-B、A-CH2-O-B and A- (C)1-C3Alkylene) -B. Where A and B represent different organic groups.
"aliphatic" means straight, branched or cyclic C1-C12A hydrocarbon which is fully saturated or which contains one or more units of unsaturation, but which is not aromatic. Examples of aliphatic groups include linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl and the like. The aliphatic group is optionally substituted with 1 to 6 substituents. Suitable substituents on the aliphatic radical include: 3-12 membered heterocyclic group, C6-C10Aryl, 5-12 membered heteroaryl, halogen, -NO2、NH2、NR2、-CN、-COR、-COOR、-CONR2、-OH、-OR、-OCOR、-SR、-SOR、-SO2R、-SONR2、-SO2NR2Wherein R is H, C1-C10Alkyl, 3-10 membered heterocyclic group, C6-C10Aryl, 5-12 membered heteroaryl.
“C1-C12Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 12 carbon atoms. C1-C12Alkyl groups are optionally substituted with at least one substituent. C1-C12Suitable substituents on alkyl include, but are not limited to, 3-12 membered heterocyclyl, C6-C10Aryl, 5-12 membered heteroaryl, halogen, -NO2、NH2、NR2、-CN、-COR、-COOR、-CONR2、-OH、-OR、-OCOR、-SR、-SOR、-SO2R、-SONR2、-SO2NR2Wherein each R is independently H, C1-C10Alkyl, 3-10 membered heterocyclic group, C6-C10Aryl, 5-12 membered heteroaryl. C1-C12Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, sec-pentyl, hexyl, heptyl, octyl, and the like, including substituted versions of the foregoing. Furthermore, the term "alkyl" refers to straight or branched chain saturated hydrocarbon groups having 1 to 20 carbon atoms, or 1 to 12 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "lower alkyl" specifically refers to alkyl groups having 1 to 4 carbon atoms. Alkyl groups may be substituted or unsubstituted. Suitable substituents on the alkyl radical may be as defined above for C1-C12Those substituents of the alkyl group are the same.
"cycloalkyl" to cyclic saturated hydrocarbon groups having 3 to 20 carbon atoms. The cyclic alkyl group may be monocyclic and, where permissible, bicyclic or polycyclic. The cycloalkyl group is optionally substituted with at least one substituent. Suitable substituents on the cycloalkyl group are the same as those for the alkyl group described above. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, nobornyl, adamantyl (adamantyl), and the like, including substituted versions of the foregoing.
"non-aromatic carbocyclyl" refers to a 3-12 membered all-carbon monocyclic group, all-carbon bicyclic group, or polycyclic group, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Examples of non-aromatic carbocyclic groups are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadiene, adamantyl, cycloheptyl, cycloheptatrienyl, and the like. The nonaromatic carbocyclic group may be substituted or unsubstituted. Typical substituents are the same as those of alkyl as defined herein. Illustrative examples of non-aromatic carbocycles are derived from alkanes such as (but not limited to) the following:
both "unsaturated non-aromatic carbocyclyl" and "non-aromatic unsaturated carbocyclyl" refer to a non-aromatic carbocyclohexyl, as defined herein, that includes at least one carbon-carbon double bond or one carbon-carbon triple bond.
“C2-C12Alkenyl "means a straight or branched chain unsaturated hydrocarbon group having 2 to 12 carbon atoms. C2-C12Alkenyl groups may have one or more points of unsaturation (i.e., one or more carbon-carbon double bonds). At C2-C12Where the alkenyl group has more than one carbon-carbon double bond, the carbon-carbon double bond may be conjugated or unconjugated. C2-C12The alkenyl group is optionally substituted with at least one substituent. C2-C12Suitable substituents on the alkenyl radicals may be as defined above for C1-C12Those substituents of the alkyl group are the same. C2-C12Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, and the like, including substituted versions of the foregoing. Furthermore, the term "alkenyl" refers to straight or branched chain saturated hydrocarbon groups having 2 to 20 carbon atoms, or 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Alkenyl groups may have one or more points of unsaturation (i.e., one or more carbon-carbon double bonds). Where the alkenyl group has more than one carbon-carbon double bond, the carbon-carbon double bond may be conjugated or non-conjugatedIs conjugated. The alkenyl group may be substituted or unsubstituted. Suitable substituents on the alkenyl radicals may be as defined above for C1-C12Those substituents of the alkyl group are the same.
"alkoxy" means-ORcWherein R iscIs C1-C12Alkyl radical, C2-C12Alkenyl radical, C2-C12Alkynyl, C3-C12Cycloalkyl or (C)1-C6Alkylene group) - (C3-C12Cycloalkyl groups). "C1-C12Alkoxy "refers to an alkoxy group as defined herein, wherein R iscHaving a total of 1-12 carbon atoms.
"alkoxyalkyl" refers to an alkyl group, as defined herein, which is substituted with at least one alkoxy group, as defined herein. "C2-C6Alkylalkoxy "refers to an alkylalkoxy group having from 2 to 6 total carbons in the alkyl group and its alkoxy substituents.
"alkylamino" refers to the radical-NRpRqWherein each R ispAnd RqEach independently is H, C1-C12Alkyl radical, C2-C12Alkenyl radical, C2-C12Alkynyl, C3-C12Cycloalkyl group, (C)1-C6Alkylene group) - (C3-C12Cycloalkyl) with the proviso that RpAnd RqNot all are H. "monoalkylamino" refers to an alkylamino group as defined herein, wherein R ispAnd RqOne of them is H. "dialkylamino" refers to an alkylamino group as defined herein, wherein R ispAnd RqAre not H. "C1-12Alkylamino "refers to alkylamino groups containing 1 to 10 carbon atoms.
“C2-C12Alkynyl "refers to a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms and at least one carbon-carbon triple bond. At C2-C12Where the alkynyl group has more than one carbon-carbon double bond, the carbon-carbon double bond may be conjugated or unconjugated. C2-C12Alkynyl groups are optionally substituted with at least one substituent. C2-C12Suitable substituents on the alkynyl radical may be as defined above for C1-C12Those substituents of the alkyl group are the same. C2-C12Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like, including substituted versions of the foregoing. Furthermore, the term "alkynyl" refers to a straight or branched chain saturated hydrocarbon group having 2 to 20 carbon atoms, or 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and having at least one carbon-carbon triple bond. The alkynyl group may be substituted or unsubstituted. Suitable substituents on the alkynyl radical may be as defined above for C1-C12Those substituents of the alkyl group are the same.
"amino" means-NH2。
“C6-C10Aryl "refers to an all carbon monocyclic or polycyclic ring system of 6 to 10 carbon atoms with a fully conjugated pi-electron system. C6-C10Aryl groups are optionally substituted with at least one substituent. C6-C10Suitable substituents on aryl radicals with C mentioned above1-C12Those substituents of the alkyl group are the same. C6-C10Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Furthermore, the term "aryl" refers to an all-carbon monocyclic or polycyclic ring system of 6 to 20 carbon atoms having a fully conjugated pi-electron system. The aryl group may be substituted or unsubstituted. Examples of aryl groups include, but are not limited to, anthracenyl, phenanthrenyl, and peryleneenyl.
"aralkyl" means C as defined above6-10Aryl-substituted alkyl as defined herein, e.g. -CH2Phenyl, - (CH)2)2Phenyl, - (CH)2)3Phenyl radical, CH3CH(CH3)CH2Phenyl and the like and derivatives thereof. C1-C6Aralkyl means a quilt C6-C10Aryl substituted C1-C6An alkyl group.
"Heteroaralkyl" means an alkyl group as defined herein substituted with a 5-12 membered heteroaryl group, e.g., -CH2Pyridyl, - (CH)2)2Pyrimidinyl, - (CH)2)3Imidazolyl and the like and derivatives thereof. C1-C6Heteroaralkyl means C substituted by a 5-12 membered heteroaryl group1-C6An alkyl group.
"heteroaryl" refers to a monocyclic or fused ring group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S in the 5 to 12 ring atoms, the remaining ring atoms being C, and the group additionally having a fully conjugated pi-electron system. Examples of unsubstituted heteroaryl groups are, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, and carbazolyl. Heteroaryl groups may be substituted or unsubstituted. Typical substituents include, but are not limited to, C1-12Aliphatic radical, 3-10 membered heterocyclic radical, 6-10 membered aryl radical, halogen, -NO2、NH2、NR2、-CN、-COR、-COOR、-CONR2、-OH、-OR、-OCOR、-SR、-SOR、-SO2R、-SONR2、-SO2NR2Wherein R is C1-C10Aliphatic group, 3-10 membered heterocyclic group, C6-C10Aryl, 5-10 membered heteroaryl.
A "pharmaceutically acceptable heteroaryl" is a group that is sufficiently stably attached to a compound of the invention, wherein the compound of the invention is formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof.
Examples of typical monocyclic heteroaryls include, but are not limited to:
pyrrolofuranthiophene pyrazolimidazole
(pyrrolyl) (furanyl) (thienyl) (pyrazolyl) (imidazolyl)
Isoxazole oxazole isothiazole thiazole 1, 2, 3-triazoles
(isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1, 2, 3-triazolyl)
1, 3, 4-triazole 1-oxa-2, 3-diazole 1-oxa-2, 4-diazole 1-oxa-2, 5-diazole
(1, 3, 4-triazolyl) (1-oxa-2, 3-oxadiazolyl) (1-oxa-2, 4-oxadiazolyl) (1-oxa-2, 5-oxadiazolyl)
1-oxa-3, 4-diazole 1-thia-2, 3-diazole 1-thia-2, 4-diazole 1-thia-2, 5-diazoles
(1-oxa-3, 4-oxadiazolyl) (1-thia-2, 3-oxadiazolyl) (1-thia-2, 4-oxadiazolyl) (1-thia-2, 5-oxadiazolyl)
1-thia-3, 4-diazoles tetrazole pyridiniopyridazines
(1-thia-3, 4-oxadiazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl)
Pyrazine 1, 3, 5-triazines
(pyrazinyl) (triazinyl)
Examples of bicyclic heteroaryls include, but are not limited to:
benzofuran benzothiophene indole benzimidazole indazoles
(benzofuranyl) (benzothienyl) (indolyl) (benzimidazolyl) (indazolyl)
Benzotriazolepyrrolo [2, 3-b ] pyridepyrrolo [2, 3-c ] pyridepyrrolo [3, 2-c ] pyridine
(Benzotriazolyl) (pyrrolo [2, 3-b ] pyridinyl) (pyrrolo [2, 3-c ] pyridinyl) (pyrrolo [3, 2-c ] pyridinyl)
Pyrrolo [3, 2-b ] pyridylimidazo [4, 5-c ] pyridylpyrazolo [4, 3-d ] pyridines
(pyrrolo [3, 2-b ] pyridinyl) (imidazo [4, 5-c ] pyridinyl) (pyrazolo [4, 3-d ] pyridinyl)
Pyrazolo [4, 3-c ] pyridylpyrazolo [3, 4-b ] pyridylisoindole
(pyrazolo [4, 3-c ] pyridyl) (pyrazolo [3, 4-b ] pyridyl) (isoindolyl)
Indazolpuroindolizidine imidazo [1, 2-a ] pyridine imidazo [1, 5-a ] pyridine
(indazolyl) (purinyl) (indolizinyl) (imidazo [1, 2-a ] pyridinyl) (imidazo [1, 5-a ] pyridinyl)
Pyrrolo [1, 5-a ] pyrido [1, 2-b ] pyridazine imidazo [1, 2-c ] pyrimidines
(pyrrolo [1, 5-a ] pyridinyl) (pyrrolo [1, 2-b ] pyridazinyl) (imidazo [1, 2-c ] pyrimidinyl)
Thienopyrimidines
(thienopyrimidinyl)
Quinolinoisoquinolinolincinnolinoquinazolines
(quinolinyl) (isoquinolinyl) (cinnolinyl) (azaquinazoline)
Quinoxaline 2, 3-naphthyridine 1, 6-naphthyridine 1, 7-naphthyridine
(quinoxalinyl) (2, 3-naphthyridine) (1, 6-naphthyridinyl) (1, 7-naphthyridinyl)
1, 8-naphthyridine 1, 5-naphthyridine 2, 6-naphthyridine 2, 7-naphthyridine
(1, 8-naphthyridinyl) (1, 5-naphthyridinyl) (2, 6-naphthyridinyl) (2, 7-naphthyridinyl)
Pyrido [3, 2-d ] pyrimido [4, 3-d ] pyrimido [3, 4-d ] pyrimidines
(pyrido [3, 2-d ] pyrimidinyl) (pyrido [4, 3-d ] pyrimidinyl) (pyrido [3, 4-d ] pyrimidinyl)
Pyrido [2, 3-d ] pyrimido [2, 3-b ] pyrimido [3, 4-b ] pyrimidines
(pyrido [2, 3-d ] pyrimidinyl) (pyrido [2, 3-b ] pyrimidinyl) (pyrido [3, 4-b ] pyrimidinyl)
Pyrimido [5, 4-d ] pyrimidinopyrazino [2, 3-b ] pyrazinopyrimidine [4, 5-d ] pyrimidine
(pyrimido [5, 4-d ] pyrimidinyl) (pyrazino [2, 3-b ] pyrazine) (pyrimido [4, 5-d ] pyrimidinyl)
"Heteroalicyclic" or "heterocyclyl" refers to a monocyclic or multicyclic group of 3 to 12 ring atoms in which 1 to 4 ring atoms are heteroatoms selected from N, O and S. "heteroalicyclic" or "heterocyclyl" groups may also have one or more double bonds. However, "heteroalicyclic" or "heterocyclyl" does not have a fully conjugated pi-electron system. A "heteroalicyclic" or "heterocyclic" ring may be substituted or unsubstituted. Typical substituents include, but are not limited to, C1-12Aliphatic radical, 6-10 membered aryl, halogen, -NO2、NH2、NR2、-CN、-COR、-COOR、-CONR2、-OH、-OR、-OCOR、-SR、-SOR、-SO2R, wherein R is C1-C10Alkyl, 3-10 membered heterocyclic group, C6-C10Aryl, 5-10 membered heteroaryl.
Examples of saturated heterocyclic groups include, but are not limited to:
oxirane epithioethane aziridine oxetane thietane azetidine tetrahydrofuran
(oxiranyl) (epithiiranyl) (aziridinyl) (oxetanyl) (thietanyl) (azetidinyl) (tetrahydrofuranyl)
Tetrahydrothienylpyrrolidine tetrahydropyran tetrahydrothiopyrans
(Tetrahydrothienyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl)
Piperidine 1, 4-dioxane 1, 4-oxathiolane morpholine 1, 4-dithiane
(piperidinyl) (1, 4-dioxanyl) (1, 4-oxathianyl) (morpholinyl) (1, 4-dithianyl)
Piperazine 1, 4-azathiane oxepane thiacycloheptane azacycloheptane
(piperazinyl) (1, 4-azathiacylohexyl) (oxacycloheptyl) (thiacycloheptyl) (azepanyl)
1, 4-dioxepane 1, 4-oxathiolane 1, 4-azaoxaheptane 1, 4-dithiacycloheptane
(1, 4-dioxepane) (1, 4-oxathiepanyl) (1, 4-azaxepanyl) (1, 4-dithiacycloheptyl)
1, 4-Azothiaheterocyclic heptane 1, 4-diazacycloheptanes
(1, 4-Azethicycloheptylalkyl) (1, 4-diazepanyl) (tropanyl)
Examples of partially saturated heterocyclic groups include, but are not limited to:
3, 4-dihydro-2H-pyran 5, 6-dihydro-2H-pyran
(3, 4-dihydro-2H-pyranyl) (5, 6-dihydro-2H-pyran (2H-pyranyl)
1, 2, 3, 4-tetrahydropyridine 1, 2, 5, 6-tetrahydropyridine
(1, 2, 3, 4-tetrahydropyridinyl) (1, 2, 5, 6-tetrahydropyridinyl)
"diyl" refers to a group having two open valences and further linking two other groups. Examples of diradicals are, but are not limited to, -CH2-、-O-。
When a "ene" is added to a "radical" at the end of any group previously defined to form a new term, the new term refers to the diradical formed after the removal of one hydrogen atom from the original term in which the new term was formed. For example, alkylene means the removal of a hydrogen atom from an alkyl groupThe "methylene" group refers to the divalent radical-CH formed by removing one hydrogen atom from a methyl group2-. Further examples of such diradicals include, but are not limited to, alkenylene, alkynylene, cycloalkylene, phenylene, heterocyclylene, heteroarylene, and non-aromatic unsaturated carbocyclylene derived from alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl, and non-aromatic unsaturated carbocyclylene, respectively. For example, "cyclopropylene" refers toAndboth of which are described below. For example, "C1-C2Alkylene "means-CH2-、-CH(CH3) -and-CH2-CH2-。
"oxo" refers to an oxygen double bond "═ O" substituent.
"hydroxy" means-OH.
"perfluoroalkyl" refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms.
"optional" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "a heterocyclic group is optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where a heterocyclic group is substituted with an alkyl group and the case where a heterocyclic group is not substituted with an alkyl group.
When a group is "optionally substituted" or "optionally further substituted" with some substituent, this means that, where permissible, the hydrogen atom of the group, unless the group itself is hydrogen, is substituted with some substituent. For example, the definition of a group is "R is H, alkyl and phenyl, and R is substituted with 1-3 substituents selected from-F, oxo and C1-C3The group of perfluoroalkyl groups is further substituted ", which means that R is 1) H (when R is H, R cannot be further substituted);2) optionally substituted by 1-3 groups selected from-F, oxo and C1-C3C in which the radical of the perfluoroalkyl radical is further substituted1-C3An alkyl group; and 3) optionally 1 to 3 substituents selected from the group consisting of-F and C1-C3Phenyl further substituted with perfluoroalkyl groups. When R is phenyl, it cannot be optionally substituted by oxo, since a single atom of phenyl does not have two hydrogen atoms substituted by oxo (i.e., ═ O bond).
"pharmaceutical composition" refers to a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to an organism.
As used herein, "physiologically/pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the compound to be administered.
"pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Examples of the excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The term "pharmaceutically acceptable salts" as used herein refers to those salts which retain the biological effectiveness and properties of the parent compound. The above salts include:
(1) acid addition salts obtainable by reacting the free base of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid, and the like.
(2) Salts formed when an acidic proton present in the parent compound is replaced with a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), or a salt formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like.
"PK" refers to receptor protein tyrosine kinases (RTKs), non-receptor or "cellular" tyrosine kinases (CTKs), and serine-threonine kinases (STKs).
"modulation" refers to altering the catalytic activity of RTKs, CTKs and STKs. Specifically, modulation refers to the catalytic activity of activating RTKs, CTKs, and STKs; preferably, modulation refers to activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTKs, CTKs and STKs are exposed; or more preferably, modulation refers to inhibition of the catalytic activity of RTKs, CTKs and STKs.
"catalytic activity" refers to the rate at which tyrosine of RTKs and/or CTKs phosphorylate under direct or indirect influence, or the rate at which serine and threonine of STKs phosphorylate under direct or indirect influence.
By "contacting" is meant bringing together a compound of the present teachings and a PK of interest in such a way that the compound can affect the catalytic activity of the PK either directly, e.g., by interacting with the kinase itself, or indirectly, e.g., by interacting with other molecules upon which the catalytic activity of the kinase depends. The "contacting" can be done "in vitro" (i.e., in vitro, in a petri dish, etc.). In vitro, the contacting may include the compound and PK of interest alone, or may include whole cells. Cells can also be stored or grown in cell culture dishes and contacted with the compound in such an environment. In the context of the present invention, the ability of a particular compound to affect a PK-related disorder, i.e., the IC of the compound, can be determined before attempting to use the compound in vivo in a more complex living organism50. For cells in vitro, the skilled artisan knows various methods to contact PK with compounds, including, but not limited to, direct cell micromirror injection and various membrane-penetrating carrier technologies.
"in vitro" refers to a process that is performed in an artificial environment, such as, but not limited to, an in vitro or culture medium.
"in vivo" refers to a process that is performed in a living organism, such as, but not limited to, a mouse, rat, or rabbit.
"PK-related disorders," "PK-induced disorders," and "abnormal PK activity" all refer to conditions characterized by inappropriate (i.e., less than or more often greater than) PK catalytic activity, wherein a particular PK may be a RTK, CTK, or STK. Inappropriate catalytic activity may arise from: (1) PK expression in cells that do not normally express PKs; (2) elevated PK expression leading to undesired cell proliferation, differentiation and/or growth; or (3) reduced PK expression resulting in an undesired reduction in cell proliferation, differentiation and/or growth. Low activity of a PK means that amplification of the gene encodes a particular PK or produces a level of PK activity that may be associated with a cell proliferation, differentiation and/or growth disorder (i.e., one or more of the symptoms of a cell disorder increase in severity as PK levels increase). The low activity is of course in contrast to this, where the severity of one or more of the symptoms of the cellular disorder increases with decreasing PK levels.
"treating" refers to a method of alleviating or eliminating a PK related cellular disorder and/or symptoms associated therewith. In particular for cancer, the term is simply understood to mean either an increase in the average lifespan of an individual suffering from cancer, or a reduction in one or more of the symptoms of the disease.
An "organism" refers to any living body consisting of at least one cell. A living organism can be as simple as a eukaryotic cell, and living complex as a mammal, including a human.
"therapeutically effective amount" refers to the amount of the compound administered that will alleviate one or more of the symptoms of the disorder being treated to some extent. With reference to the treatment of cancer, a therapeutically effective amount refers to an amount that has at least one of the following therapeutic effects:
(1) reducing the size of the tumor;
(2) inhibit (i.e., to some extent, preferably prevent) metastasis of the tumor;
(3) inhibit (preferably prevent) to some extent the growth of the tumor;
(4) to some extent alleviate (preferably eliminate) one or more of the symptoms associated with cancer.
"monitoring" inhibits the observation or detection of the effect of a compound in contact with a cell expressing a particular PK. The observed or detected effect may be a change in the phenotype of the cell, a change in the catalytic activity of the PK or a change in the interaction of the PK with a natural binding partner. Techniques for observing or detecting the above-mentioned effects are well known in the art. The effect is selected from the group consisting of a change or lack of change in cell phenotype, a change or lack of change in catalytic activity of the protein kinase, or a change or lack of change in interaction of the protein kinase with a natural binding partner in a final aspect of the invention.
"cellular phenotype" refers to the appearance of a cell or tissue, or the biological function of a cell or tissue. Examples of cellular phenotypes are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis and nutrient uptake and use. The above phenotypic characteristics may be measured by techniques well known in the art.
"native binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners may play a role in signal propagation during PK-mediated signal transduction. As the concentration of the PK/natural binding partner complex increases or decreases, it may appear that the interaction of the natural binding partner with the PK itself changes, and thus a change in the ability of the PK to mediate signal transduction may be observed.
Drawings
Figure 1 shows that compounds of the invention inhibit and retard the growth of HCT116 human colorectal cancer tumor xenografts in athymic mice in vivo.
Detailed Description
The compounds of formulae I, II, III and IIIa may be prepared by some synthetic routes in Scheme 1(Scheme 1) and Scheme 2(Scheme 2). In scheme 1 and scheme 2 and the following description, "BOC", "Boc" or "BOC" means N-tert-butoxycarbonyl, DCM means CH2Cl2DIPEA (also known as Hunig's base) means diisopropylethylamine, DMA means dimethylamine, "DMF" means dimethylformamide, "DMSO" means dimethylsulfoxide, Et means-CH2CH3"MTBE" means methyl tert-butyl ether, NMP means 1-methyl-2-pyrrolidone, TEA means triethylamine, TFA means trifluoroacetic acid, and THF means tetrahydrofuran. Although schemes 1 and 2 and the description refer to compound I, schemes 1 and 2 and the description apply equally to compounds II, II and IIIa
Scheme 1 represents the synthesis of intermediate I (g) for the preparation of compounds of formula I. The amino group of the substituted amino acid I (a) is alkylated to give compound I (b). This can generally be accomplished by treating compound i (a) with an alkylating agent in the presence of a base. Activated electrophilic double bond groups are commonly used alkylating agents. Typical reaction conditions for alkylation of i (a) with an activated electrophilic double bond group are that i (a) is treated with an activated double bond group in the presence of a strong base. Subsequent water work-up gives compound i (b). Then the amino group of compound I (b) is protected with a boc group to give compound I (c). This can generally be accomplished by treating compound i (b) with Boc reagent in the presence of a base. Typically, the compound I (b) is added to Me4In the presence of NOH in MeCN as solventBy (Boc)2And O, treating. The carboxylic acid group of compound i (c) is then converted to the methyl ester of compound i (d). Typical conditions for converting carboxylic acid groups to methyl ester groups are treatment of I (c) with methyl iodide in the presence of a base in DMF. Then, compound i (d) undergoes intramolecular aldol condensation to give compound i (e). This can generally be done by treating compound i (d) with a strong base in an aprotic solvent. Typically, the compound I (d) is treated with t-BuOK in toluene. Subsequent water work-up gives compound i (e). Then, compound i (e) undergoes a 2+3 cyclization reaction with the hydrazine group, thereby forming compound i (f). Typical conditions for the cyclization are reflux of compound i (e) with hydrazine and acetic acid in EtOH. The free base pyrrole nitrogen in compound i (f) is then acylated to give compound i (g). Typical conditions for acylation are the treatment of compound i (f) with chloroethyl carbonate in THF.
More detailed synthesis conditions for compound i (g) of scheme 1 can be found in U.S. patent application 2003/0171357 and PCT application WO02/12242, which are incorporated herein by reference.
Scheme 2 shows two routes for preparing compounds of formula I starting from intermediate I (g). In the first pathway of scheme 2, Compounds I (g) and R1The electrophilic groups undergo nucleophilic reactions. This nucleophilic reaction may be one of an acylation reaction, an alkylation reaction, a sulfonation reaction, a reductive amination reaction, or some other reaction that performs amine functionalization. Typical acylation reaction conditions are to subject compound I (g) to reaction with, for example, R in the presence of a base such as 2 equivalents of DIPEA in a solvent such as dichloromethane1-COCl acylating agent. The reaction mixture was stirred between 0 ℃ and room temperature for 12 hours. Subsequent water work-up gives compound i (h). Then, the Boc group on the pyrrole nitrogen of compound I (h) is removed to give compound IAn item I (i). This can generally be accomplished by treating I (h) with a strong acid. Typical reaction conditions are that compound i (h) is treated with dioxane and 4N HCl in DCM. Subsequent water work-up gives compound i (i). Then, the pyrrole NH in compound i (i) is acylated to give chloroformate i (j). This can be accomplished using phosgene, triphosgene and some equivalents. Typical reaction conditions are that I (i) is treated with 2 equivalents of triphosgene in DCM at 0 ℃ for 4 hours. Subsequently, saturated NaHCO was used3Mild base work-up and purification was carried out to give compound i (j). Then, compound I (j) is taken as R1And (4) processing the nucleophilic group. The nucleophile may be an alcohol, an amine or one of several other functional groups that may react with chloroformate i (j). Typical reactions include: will I (j), at such as K2CO3With a nucleophile such as 1.5 equivalents of an alcohol in a solvent such as DME in the presence of 2 equivalents of a base. The reaction was heated to 80 ℃ for 8 hours and the solvent was removed. Alternatively, i (j) may be treated with 1.5 equivalents of amine in a solvent such as THF in the presence of 1 equivalent of a base such as DIPEA. Subsequent work-up and purification in the presence of a base such as TEA in a protic solvent such as methanol gives the compound of formula I.
Or, the compounds I (i) are then reacted with R4Nucleophilic reaction of the electrophile to give compound i (k). The nucleophilic reaction for carrying out the above-mentioned conversion may be an alkylation reaction, an acylation reaction, a sulfonation reaction, or a reductive amination reaction. The acylation of I (i) is carried out by treating compound I (i) with an acylating agent in the presence of a base to give I (k). Typical reaction conditions are that compound i (i) is mixed with an excess of base such as DIPEA in DCM and the resulting solution is added to the isocyanate at 0 ℃. The reaction was stirred for 2 hours followed by aqueous work-up to give compound i (k). Removing the ethyl ester protecting group from the pyrrole nitrogen of compound I (k) to obtain compound I. This can generally be done by treating compound i (k) with a base. Typical reaction conditions are such that the compound I (k) is present in 2-3 equivalents of LiOHReflux in dioxane and DCM in the presence. Followed by aqueous work-up to give the compounds of the formula I.
In the second route of scheme 2, the Boc group on the pyrrole nitrogen is removed to give compound I (l). This can generally be exemplified by treating compound i (g) with a strong acid. Typical reaction conditions are that compound i (g) is treated with 4N HCl in dioxane and DCM. Followed by water work-up to give compound i (l). Then, the compounds I (l) may be reacted with R4Nucleophilic reaction of the electrophile to give compound i (m). Because of the-NH linkage to the pyrrole in the compounds I (l)2The group is less reactive than the pyrrole nitrogen of I (l), so that the conversion of I (I) to I (m) can be carried out without protecting the pyrrole-NH of the compound I (l)2A group. The nucleophilic reaction used in the above conversion examples may be alkylation, acylation, sulfonation, reductive amination. Relatively mild reaction conditions are preferred to achieve selectivity of the above reaction. The acylation of I (l) is carried out by treating compound I (l) with an acylating agent in the presence of a base to give I (m). Typical reaction conditions are that compound i (l) is mixed with an excess of base such as DIPEA in DCM and the resulting solution is added to the isocyanate at 0 ℃. The reaction was maintained at 0 ℃ for about 2 hours followed by aqueous workup to give compound i (m).
Then, compounds I (m) and R1The electrophilic groups undergo nucleophilic reactions. The nucleophilic reaction may be one of an acylation reaction, an alkylation reaction, a sulfonation reaction, a reductive amination reaction, or some other reaction performed by an amine functional group. Typical acylation reaction conditions are to compound I (m) in the presence of a base such as 2 equivalents of DIPEA in a solvent such as dichloromethane with a base such as R1Treatment with an acylating agent for-NCO for 2 hours. Alternatively, I (m) may be dissolved with a base such as 2 equivalents of DIPEA in a solvent such as 1, 2-dichloroethane1-COOR (wherein, R1An activating group such as p-nitrophenyl). Subsequent water aftertreatmentTo give compound i (n). The ethyl ester protecting group on the pyrazole nitrogen of compound I (n) is typically removed with a base to give the free base compound I. Typical reaction conditions are that compound I (n) is mixed with TEA in a protic solvent such as methanol and purified to give the compound of formula I.
Alternatively, the ethyl ester protecting group on the pyrazole nitrogen of compound i (m) is removed to provide the free base compound i (o). This can generally be done by treating compound i (m) with a base. Typical reaction conditions formula compound i (m) is refluxed in dioxane and DCM in the presence of 2-3 equivalents of LiOH. Followed by aqueous work-up to give compound i (o). Then, compounds I (o) and R1The electrophilic groups undergo nucleophilic reactions. The nucleophilic reaction may be one of an acylation reaction, an alkylation reaction, a sulfonation reaction, a reductive amination reaction, or some other reaction performed by an amine functional group. Typical acylation reaction conditions are to subject compound I (o) to reaction with a base such as 2 equivalents of DIPEA in a solvent such as dichloromethane, with a base such as R1-COCl acylating agent. The reaction mixture was stirred for 4 hours, followed by aqueous workup and purification to give the compound of formula I.
Unless otherwise stated, reference herein to a compound of the invention includes salts, solvates, hydrates and complexes of said compound, as well as solvates, hydrates and complexes of salts of said compound, including polymorphs, stereoisomers and isotopically-labeled forms thereof.
Pharmaceutically acceptable salts include acid addition salts and base salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyacinate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate (pamoate), phosphate/hydrogen phosphate/dihydrogen phosphate, gluconate, stearate, succinate, citrate, salicylate, and salicylate, Tartrate, tosylate, trifluoroacetate.
It is to be understood that when the present invention discloses specific salts of the free base compound B or specific salts of the free acid compound a, the corresponding free base compound B or free acid compound a are also contemplated within the scope of the present invention. The salt of the free base compound B is used with a small amount of aqueous K2CO3The aqueous solution is then extracted with a large amount of organic solvent to give the free base compound B in high yield. If the free base compound B is very soluble in water, it is recommended to dissolve the salt using a suitable organic solvent and then to add the solid K2CO3. Followed by filtration or chromatography to give the free base compound B. The compound a can be obtained from the salt of the free acid compound a in a similar manner.
Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts (benzathine), calcium salts, choline salts, diethylamine salts, dialcohol salts, aminoacetate salts, lysine salts, magnesium salts, meglumine salts, (ethanolamine salts (olamine), potassium salts, sodium salts, tromethamine salts, and zinc salts.
For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use "(Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety.
Pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by the following methods: if appropriate, a solution of the compound is mixed with the desired acid or base. The resulting salt may be precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.
The compounds of the present invention may also exist in unsolvated forms as well as solvated forms. The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates of the invention include hydrates and solvate compounds, wherein the solvent of crystallization may be isotopically substituted, such as D2O、d6-acetone, d6-DMSO。
Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes (where, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts). Also included are complexes of drugs containing two or more organic and/or inorganic components, which may be in a stoichiometric or non-stoichiometric amount. The resulting complex may be ionized, partially ionized, or not ionized. For an overview of the above complexes, see J Pharm Sci, 64(8), 1269-1288 (8/1975) by Haleblian, the disclosure of which is incorporated herein by reference in its entirety.
Also included within the scope of the invention are polymorphs, prodrugs, and isomers (including optical isomers, geometric isomers, and tautomers) of the compounds of the invention.
When a derivative of a compound of the invention, which may have little or no pharmacological activity per se, is administered to a patient, it may be converted to a compound of the invention, for example by hydrolysis. Such derivatives are referred to as "prodrugs". For more information on the use of prodrugs, reference may be made to "Pro-drugs as novel delivery Systems", Vol.14, ACS Symposium Series (T.Higuchi and W.Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987(Ed.E.B.Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety.
Prodrugs of the invention may be prepared, for example, as described in "Design of produgs" by h.mundgarrd (Elsevier, 1985), by substituting certain groups known to those skilled in the art as "precursor groups" for appropriate functional groups present in the compounds of the invention.
Some examples of prodrugs of the invention include:
(i) in the case of compounds containing a carboxylic acid function (-COOH), the esters of said compounds, e.g. hydrogen (-COOH)1-C8) Alkyl substituted compounds;
(ii) in the case of compounds containing an alcohol function (-OH), the esters of said compounds, e.g. hydrogen, are substituted by (C)1-C6) Alkanoyloxymethyl-substituted compounds; and
(iii) in the presence of a primary or secondary amine function (-NH)2or-NHR, where R.noteq.H), amides of said compounds, e.g. one or two hydrogens by (C)1-C10) Alkanoyl substituted compounds.
Other embodiments of the substituent groups in the foregoing embodiments and other types of prodrug examples can be found in the above references.
Finally, certain compounds of the invention may themselves be prodrugs of other compounds of the invention.
The compounds of the present invention containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers. Where the compounds of the present invention comprise an alkenyl or alkenylene group, cis/trans (or Z/E) isomers may be present. In the case of compounds containing keto or oxime groups or aromatic groups, tautomerism may occur. More than one type of isomerism may be present for a single compound.
All stereoisomers, geometric isomers and tautomers of the compounds of the invention and mixtures of one or more thereof, including compounds having more than one type of isomerism, are included within the scope of the invention. Also included are acid addition or base salts wherein the counter ion is optically active, such as d-lactate or l-lysine, or as a racemic mixture, such as dl-tartrate or dl-arginine.
The cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.
Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using chiral High Pressure Liquid Chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or in the case of compounds of the invention containing acidic or basic groups, for example an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or by fractional crystallization and one or both of the diastereomers converted to the corresponding pure enantiomers by techniques known to those skilled in the art.
The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography (typically HPLC) over an asymmetric resin using a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume (typically 2% to 20%) isopropanol and 0 to 5% by volume of an alkylamine (typically 0.1% diethylamine). Concentrating the eluate to obtain an enriched mixture.
Stereoisomeric aggregates can be isolated by conventional techniques known to those skilled in the art, see for example "Stereochemistry of Organic Compounds" (Wiley, 1994) from E.L. Eliel, the disclosure of which is incorporated herein by reference in its entirety.
Compounds of the invention include isotopically-labeled compounds of the invention, in which one or more atoms are replaced by an atom having the same atomic number as the majority of atoms in nature, but a different atomic mass or mass number. Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, such as2H and3h; isotopes of carbon, such as11C、13C and14c; isotopes of chlorine, such as36Cl; isotopes of fluorine, such as18F; isotopes of iodine, such as123I and125i; isotopes of nitrogen, such as13N and15n; isotopes of oxygen, such as15O、17O and18o; isotopes of phosphorus, such as32P and isotopes of sulfur, such as35And S. Certain isotopically-labeled compounds of the present invention, for example those comprising a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. Taking into account the radioactive isotope tritium (i.e. the3H) And carbon-14 (i.e.14C) Easy to add and easy to detect, which is particularly suitable for the above purposes. With heavier isotopes such as deuterium (i.e. deuterium)2H) Instead, certain therapeutic advantages may be obtained due to higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Using positron emitting isotopes such as11C、18F、15O and13n substitution, can be used in Positron Emission Tomography (PET) studies to study the occupancy rate of substrate receptors.
Isotopically-labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the unlabeled reagent previously used.
Pharmaceutically acceptable solvents according to the invention include those which may be isotopically substituted, e.g. D2O、d6-acetone, d6-DMSO。
The compounds of the invention intended for pharmaceutical use may be administered in the form of crystalline or amorphous products. The compounds can be obtained, for example, in the form of solid tablets (solid plugs), powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave drying or radio frequency drying may be used for the above purpose.
The compounds of the present invention may be administered alone or in combination with one or more other compounds of the present invention or with one or more other drugs (or any combination thereof). Generally, they are administered in the form of a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein is used to describe any ingredient other than a compound of the present invention. The choice of excipients depends to a large extent on factors such as the particular mode of administration, the effect of the excipients on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. The above compositions and methods for their preparation can be found, for example, in Remington's pharmaceutical Sciences, 19 th edition, (Mack Publishing Company, 1995), which is incorporated herein by reference in its entirety.
Is administered orally
The compounds of the invention may be administered orally. Oral administration may include swallowing, whereby the compound enters the gastrointestinal tract; and/or buccal or sublingual administration, whereby the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing various granules, liquids or powders, lozenges (including liquid-filled), chewable tablets, microparticles and nanoparticles, gels, solid solutions, liposomes, films (including mucosal patches), ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers for soft or hard capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifying and/or suspending agents. Liquid formulations may also be prepared by reconstituting solids in, for example, sachets.
The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents of Liang and Chen,11(6) 981-986(2001), the disclosure of which is incorporated herein by reference in its entirety.
For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, typically from 5% to 60% by weight. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with a lower alkyl group, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant is present in an amount of from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.
Binders are commonly used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (lactose monohydrate, lactose monohydrate by spray drying, amorphous lactose, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate.
The tablet may optionally include: surfactants such as sodium lauryl sulfate and polysorbate 80; and slip agents such as silica and talc. The surfactant, when present, may comprise from 0.2% to 5% by weight of the tablet and the slip agent may comprise from 0.2% to 1% by weight of the tablet.
Tablets also typically include lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is typically present in an amount of 0.25 to 10% by weight, preferably 0.5 to 3% by weight of the tablet.
Other ingredients may include antioxidants, coloring agents, flavoring agents, preservatives, taste masking agents.
Exemplary tablets comprise up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.
The tablet mixture may be tabletted directly or formed into tablets by roller compaction. The tablet blend or partial blend may be wet granulated, dry granulated, melt frozen or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; or can be made into capsule.
In "Pharmaceutical Dosage Forms" by h.lieberman and l.lachman: tablet formulations are discussed in detail in Tablets, Vol.1 ", Marcel Dekker, N.Y., N.Y., 1980(ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.
Oral solid formulations may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release.
US patent 6,106,864 describes suitable modified release formulations. Other suitable delivery techniques, such as high energy dispersion and penetration, and coating of the particles are described in detail in Verma et al, "Pharmaceutical Technology On-line", 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of the above references are incorporated herein by reference in their entirety.
Parenteral administration
The compounds of the invention may be administered directly into the bloodstream, into muscles or into internal organs. Suitable modes of parenteral administration include intravenous, arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle (including micro-needle) syringes, needleless injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions and may contain excipients such as salts, carbohydrates and buffers (preferably at a pH of 3 to 9), but for some applications are more suitably formulated as sterile non-aqueous solutions, or in dry form for use in conjunction with a suitable vehicle such as sterile pyrogen-free water.
Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The solubility of the compounds of the present invention used in the preparation of parenteral solutions may be enhanced by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents.
Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release. Thus, the compounds of the present invention may be formulated as a solid, semi-solid or thixotropic liquid for administration in an implantable depot form, thereby allowing for modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
Topical administration of drugs
The compounds of the invention may also be administered intradermally orTransdermal administration to the skin or mucous membranes. Typical formulations for the above purposes include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated, see, e.g., j.pharm.sci. by Finnin and Morgan,88(10) 955- "958 (10 months 1999). Other methods of topical administration include delivery by electroporation, iontophoresis, ultrasound introduction, and microneedle injection or needleless injection (e.g., Powderject)TM、BiojectTMEtc.). The disclosures of the above references are incorporated herein by reference in their entirety.
Formulations for topical administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release.
Inhalation/intranasal administration
The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in admixture, e.g. as a dry blend with lactose, or as admixed component particles, e.g. with a phospholipid such as lecithin), administered from a dry powder inhaler; in the form of an aerosol spray, administered by a pressurized container, pump, spray, nebulizer (preferably one that uses electrohydrodynamic pressure to generate a fine mist), or an aerosolizer, with or without the use of a suitable propellant, such as 1, 1, 2, 2-tetrafluoroethane or 1, 1, 1, 2, 3,3, 3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive, such as chitosan or cyclodextrin.
A pressurized container, pump, sprayer, spray or aerosolizer contains a solution or suspension of a compound of the present invention, including, for example, ethanol, aqueous ethanol or other suitable agent for dispersing, dissolving or prolonging the release of the active, a propellant as a solvent, and optionally a surfactant, such as sorbitan trioleate, oleate or oligolactic acid.
Prior to use in dry powder or suspension formulations, the drug substance is micronized into a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any suitable comminution method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate. Lactose can be in anhydrous form or in monohydrate form, preferably in monohydrate form. Other suitable excipients include, glycosides, dextrose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
Suitable solution formulations using electro-hydraulics to generate a fine mist in an aerosolizer may contain 1 μ g to 20mg of a compound of the invention per actuation, and the actuation volume may vary between 1 μ l to 100 μ l. A typical formulation may include a compound of the invention, propylene glycol, sterile water, ethanol, and sodium chloride. Other solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.
Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or saccharin sodium, may be added to those formulations of the invention for inhalation/intranasal administration.
Formulations for inhalation/intranasal administration may be formulated for immediate release and/or modified release, for example, of poly (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release.
In the case of dry powder inhalers and aerosols, the dosage units are determined by a valve delivering a metered dose of medicament. The units of the invention are generally designed to administer a metered dose or "smoke volume" containing the desired amount of the compound of the invention. The total daily dose may be administered in a single dosage form or, more often, in divided daily doses.
Intrarectal/intravaginal administration
The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release.
Ophthalmic drug delivery
The compounds of the invention may also be administered directly to the ear or eye, usually as micronized suspension droplets or as a solution in isotonic, PH-adjusted sterile saline. Other formulations suitable for ophthalmic and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, patches, lenses, and microparticulate or vesicular systems, such as vesicles (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., gelan gum) may be incorporated with preservatives such as benzalkonium chloride. The formulations described above can also be delivered by ionophoresis.
Formulations for ocular/otic administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release.
Other techniques
The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above-described modes of administration.
For example, drug-cyclodextrin complexes are found to be generally useful in most dosage forms and routes of administration. Inclusion and non-inclusion complexes may be used. Another method of direct complexation with drugs is that cyclodextrins may be used as adjuvants, i.e. as carriers, diluents or solubilisers. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which may be found in PCT applications WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference.
Dosage form
The amount of active compound administered will depend on the patient to be treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound and the diagnosis of the physician. However, effective dosages will generally be in the range of about 0.001 to about 100mg/kg body weight per day, preferably 0.01 to about 35mg/kg per day, in single or divided dosage forms. For a 70kg adult, the amount is from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. In some cases dosage ranges below the lower limit of the aforesaid range are more appropriate, while in other cases still higher doses may be employed without causing any harmful side effects, the aforesaid higher doses usually being divided into several lower doses to be taken within a day.
Medicine bag
Since it is desirable to administer a combination of active compounds, for example, for the treatment of a particular disease or condition, it is also within the scope of the present invention that two or more pharmaceutical compositions, at least one of which comprises a compound of the present invention, may conveniently be combined in a kit suitable for simultaneous administration of the compositions. Thus, a kit of the invention comprises two or more separate pharmaceutical compositions (at least one of which comprises a compound of the invention), and means for separately holding the compositions, such as a container, separate bottle or separate tin foil packet. Examples of the above-mentioned kits are common blister packs for packaging tablets, capsules and the like.
The kit of the invention is particularly suitable for administration of different dosage forms (e.g. oral and parenteral dosage forms), for administration of the individual compositions at different dosing intervals, or for the quantitative titration of the individual compositions with one another. To aid compliance, kits often include instructions for taking the medication and may provide so-called memory assistance.
Examples
In the following examples and preparations, "BOC", "Boc" or "BOC" refers to N-tert-butoxycarbonyl, "CBZ" refers to benzyloxyformyl, "DCE" refers to dichloroethane, "DCM" refers to dichloromethane, "DIC" refers to diisopropylcarbodiimide, "DIPEA" or "DIEA" refers to diisopropylethylamine, "DMA" refers to N, N-dimethylacetamide, "DME" refers to 1, 2-dimethoxyethane, "DMF" refers to dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DPPP" refers to 1, 3-bis (diphenylphosphino) propane, "HATU" refers to O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, "HBTU" refers to O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate, "HOAc" refers to acetic acid, "HOBt" refers to 1-hydroxybenzotriazole hydrate, "IPA" refers to isopropanol, "LAH" refers to lithium aluminum hydride, "LiHMDA" refers to lithium bis (trimethylsilyl) amide, "MTBE" refers to methyl tert-butyl ether, "NMP" refers to 1-methyl-2-pyrrolidone, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "TIPS" refers to triisopropylsilyl-, "Trt" refers to triphenylmethyl-.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Route II (tail-first)
Example 1: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester
Preparation of compound 1 a: 5-tert-butyl 2-ethyl 3- (benzoylamino) -6, 6-dimethylpyrrolo [3, 4-c ] pyrazole-2, 5(4H, 6H) -dicarboxylate
A solution of benzoyl chloride (5.75g, 40.7mmol) in dichloromethane (50mL) was added dropwise to a cooled (0 deg.C), stirred solution of I (g) (12.0g, 37.0mmol) and DIPEA (13.0mL, 74.0mmol) in dichloromethane (100 mL). The resulting clear solution was stirred at room temperature for 12 hours. The reaction mixture was washed with water (2X 75mL) and washed with Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (40% ethyl acetate in hexanes) to give amide 1a as an off-white solid (15g, 95.0%). 1H NMR (300MHz, CDCl)3)δ：1.44-1.56(m，12H)1.69(s，3H)1.75(s，3H)4.58(q，J＝7.10Hz，2H)4.74(s，1H)4.79(s，1H)7.44-7.64(m，3H)7.87-7.96(m，2H)10.97-11.11(m，1H)。
Preparation of compound 1 b: 3- (benzoylamino) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester
A4M solution of HCl in hexane (44mL) was added dropwise to a stirred slurry of intermediate 1a (15.0g, 35.0mmol) in ethanol (150 mL). The resulting clear solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo to give a residue, which was stirred with hexane (250mL) for 10 min. The solid product was collected by filtration, washed with hexanes (100mL) and dried under vacuum at 40 ℃ for 15 hours to give the dihydrochloride salt of amine 1b as an off-white solid (13.5g, 96.4%). 1H NMR (300MHz, DMSO-d)6)δppm 1.36(t，J＝6.97Hz，3H)1.67(s，6H)4.47(q，J＝7.16Hz，2H)4.59(s，2H)7.55-7.74(m，3H)7.92(d，J＝7.54 Hz，2H)10.23(s，2H)10.93(s，1H)。
In the table below, compounds 2b and 17b in the table below are HCl salts and compounds 18b, 19b and 20b are free bases.
Preparation of compound 1 c: 3- (benzoylamino) -5- (chlorocarbonyl) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester
A solution of diisopropylethylamine (28.4mL, 162.5mmol) in DCM (50mL) was added dropwise over 15 min to an ice-cold (-10 deg.C), stirred mixture of triphosgene (7.2g, 24.3mmol) and 1b dihydrochloride (13.0g, 32.5mmol) in DCM (150 mL). The resulting reaction mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was washed with water (2X 100mL) and washed with Na2SO4Dried, filtered and concentrated to give the crude product. The crude product was stirred with 25% ethyl acetate in hexane. The resulting precipitate was collected by filtration and dried under vacuum at 40 ℃ to give 1c (12g, 95%) as a white solid. 1H NMR (300MHz, CDCl)3)d ppm 1.51(t，J＝7.06Hz，3H)1.75-1.84(m，6H)4.60(q，J＝7.03Hz，2H)5.08(s，2H)7.46-7.69(m，3H)7.85-7.98(m，2H)11.10(s，1H)。
Preparation of compound 1 d: (1S) -2- (dimethylamino) -1-phenylethanol
Formaldehyde (800mL, 37 wt% in water) was added to a solution of (S) - (+) -2-amino-1-phenyl-ethanol (100.0g, 729.0mmol) in formic acid (400mL) at room temperature. The solution was stirred at 90 ℃ overnight. After cooling to room temperature, the pH of the solution was adjusted to 2 using concentrated HCl. The solution was extracted with ether (3 × 500mL) and then adjusted to pH 10 with solid NaOH. Subjecting the obtained aqueous layer to CH2Cl2(3X 500 mL). The combined organic layers were washed with Na2SO4And drying. Filtration and evaporation followed by flash chromatography (on CH)2Cl25% MeOH in to CH2Cl24.5% MeOH/0.5 NEt in (1)3) Separation was carried out to give (S) -2-dimethylamino-1-phenyl-ethanol (68.0g, 56%) as a pale yellow oil.1H NMR(dmso-d6)δ：2.19(s，6H)，2.31(dd，J＝4.8，12.4Hz，1H)，2.41(dd，J＝8.1，12.4Hz，1H)，4.63(dd，J＝4.8，7.8Hz，1H)，4.97(br s，1H)，7.21(m，1H)，7.31(m，4H)。LCMS(APCI，M+H+)：166.4。
Preparation of compound 1: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester
Potassium carbonate (861mg, 6.23mmol), intermediate 1c (1.218g, 3.12mmol) and alcohol 1d (772mg, 4.67mmol) were reacted in 1, 2-dimethoxyethane (DME,31mL) was stirred in an oil bath at 80 ℃ for 7.5 hours. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between ethyl acetate (25mL) and deionized water (20 mL). The aqueous layer was back-extracted with ethyl acetate (2 × 15mL) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was dissolved in methanol (10mL) and triethylamine (10mL), stirred at room temperature for 19 hours, and concentrated to dryness again. The crude product was purified by silica gel chromatography using a gradient of 5-20% (ethanol + 5% NH) in ethyl acetate4OH) to yield compound 1 as a white foam (561.1mg, 39%).1H NMR(dmso-d6) [ due to the existence of tautomers, some heavy peaks appear]δ: [1.54(s), 1.63(s), 1.72(s)6H in total]In total, [2.20(s), 2.22(s)6H]2.46(d, J ═ 4.8Hz)2.52(d, J ═ 4.8Hz), 1H in total][2.73(dd, J ═ 8.3, 13.1 Hz), 2.82(dd, J ═ 8.3, 12.9Hz)1H in total]In total, [4.46(m), 4.65(br s)2H]Total of 5.80(dd, J ═ 4.6, 8.3Hz, 1H), 7.28(m, 1H), 7.35(m, 4H), 7.50(m, 3H), 7.99(t, J ═ 7.4Hz, 2H), 10.93(br m, 1H), [12.25(br s), 12.48(br s)1H]. Analyzed as (C)25H29N5O3·0.03EtOAc·0.35H2O)C，H，N。HRMS：[M+H]+The calculation result is as follows: 448.2343, respectively; the test results are: 448.2341, respectively; the error was-0.39 ppm.
Example 21: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid 2- (dimethylamino) -1-phenylethyl ester
Preparation of compound 21 a:
(+/-) -2-phenyloxirane (1g, 8.3mmol)1 and 10mL dimethylamine in MeOH (2.0M solution) were heated to 70 ℃ overnight in a sealed tube. The solution was concentrated to dryness in vacuo to give 1.1g of crude product 21a as an oil.
A solution of compound 1c (100mg, 0.25mmol) and 21a (60mg, 0.37mmol) in 5mL of toluene was heated to 100 ℃ in a microwave for 30 minutes. The solution was concentrated to dryness by evaporation under reduced pressure. The residue was dissolved in MeOH (2mL) and Et3N (1mL) was added to the above solution. The solution was stirred at room temperature for 2 hours, concentrated, and purified by HPLC (10-40% CH)3CN/H2O (0.1% TFA)) to afford the TFA salt of 21 in 29% yield. The TFA salt was converted to the HCl salt by treating the above TFA salt in 1N HCl-MeOH. Compound 21(32mg) was prepared as the HCl salt1H NMR(400MHz，DMSO-d6)δppm 1.54(s，3H)1.66(s，3H)2.86(d，J＝4.55Hz，3H)2.89(d，J＝4.55Hz，3H)3.01-3.10(m，2H)4.66(d，J＝13.14Hz，1H)4.96(d，J＝13.14Hz，1H)6.18(d，J＝9.09Hz，1H)7.33-7.40(m，1H)7.45(d，J＝4.29Hz，4H)7.52(t，J＝7.45Hz，3H)7.60(t，J＝7.33Hz，1H)8.02(d，J＝7.33Hz，1H)10.27(s，1H)11.04(s，1H)。MS，m/z：428.2(M+1)。
Example 24: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1R) -2- (dimethylamino) -1-pyridin-2-ylethyl ester
Preparation of compound 24 a: (1R) -2- (dimethylamino) -1-pyridin-2-ylethanol
(1R) -2- (methylamino) -1-pyridin-2-ylethanol (2).25g, 10.0mmol, prepared according to the method of Tanis et al, see WO2004/085414, WO2004/085058 and WO2004/022567), 5.0mL of a mixture of 88% aqueous formic acid and 10.0mL of 37% aqueous formaldehyde, heated while stirring in an oil bath at 95 ℃ for 2 hours, maintaining the internal maximum temperature at 85 ℃. After cooling to room temperature, the solution was extracted with 20mL diethyl ether, and the remaining aqueous layer was basified with aqueous NaOH (5N, 15mL) to give a pH of 10. The basic solution was extracted with dichloromethane (2X 50 mL). The combined dichloromethane extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 1: 4: 20 concentrated aqueous ammonia: EtOH: EtOAc) to give 24a as a pale yellow oil (1.09g, 66%).1H NMR(DMSO-d6)δ：2.19(s，6H)，2.43(dd，J＝8.3，12.4Hz，1H)，2.53(dd，J＝4.3，12.4Hz，1H)，4.67(quint，J＝4.0Hz，1H)，5.18(d，J＝4.0Hz，1H)，7.22(ddd，J＝1.3，4.8，7.6Hz，1H)，7.47(d，J＝8.1Hz，1H)，7.75(doft，Jd＝1.8Hz，Jt＝7.7Hz，1H)，8.46(d of q，Jd＝4.8Hz，Jq0.8Hz, 1H). Analyzed as (C)9H14N2O)C，H，N.LCMS(APCI，M+H+)：167.4。
Intermediate 1c (441mg, 1.13mmol), alcohol 24a (281.5, 1.69mmol) and potassium carbonate (312mg, 2.26mmol) were stirred in a 1, 2-dimethoxyethane (DME, 11.3mL) in an 85 deg.C oil bath under argon for 4 hours. Then, the remaining solution was filtered to remove solids, and the filtrate was concentrated to dryness. The remaining residue was dissolved in methanol (10.0mL), triethylamine (10.0mL) was added, and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent, the crude product was purified by silica gel chromatography (eluting with 1: 4: 20 concentrated aqueous ammonia: EtOH: EtOAc) to give 24 as an orange foam (163.5mg, 32%).1H NMR(DMSO-d6) δ: [ 1.56(s), 1.64(s), 1.67(s), 1.72(s)6H in total]In total, [2.21(s), 2.22(s)6H]2.74(m, 2H), [4.44(m), 4.69(m)2H in total]，5.82(m，1H)，7.30(tofd，Jt＝7.6Hz，Jd＝4.9Hz，1H)，7.41(t，J＝7.7Hz，1H)，7.49-7.56(m，3H)，7.80(qofd，Jq＝7.8Hz，Jd1.5Hz, 1H), 7.99(t, J ═ 6.8 Hz, 2H), 8.55(t, J ═ 4.9Hz, 1H), 10.93(m, 1H), [12.23(brs), 12.46(brs), 12.49(brs)1H in total]. Analyzed as (C)24H28N6O3·0.6H2O)C，H，N。LCMS(APCI，M+H+)：449.4。HRMS：[M+H]+The calculation result is as follows: 449.2296, respectively; the test results are: 449.2287, respectively; the error was-1.95 ppm.
Example 30: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -1-benzyl-2- (dimethylamino) ethyl ester
Preparation of compound 30 a: (S) -2-hydroxy-N, N-dimethyl-3-phenylpropionamide
Diisopropylcarbodiimide (DIC, 3.65mL, 1.1 eq) was added to a solution of (S) -2-hydroxy-3-phenylpropionic acid (3.53g, 21.2mmol), dimethylamine hydrochloride (2.07g, 1.2 eq), 1-hydroxybenzotriazole hydrate (HOBt, 3.25g, 1 eq) and diisopropylethylamine (DIEPA, 4.43mL, 1.2 eq) in THF (60mL) at 0 ℃. The reaction mixture was stirred at room temperature overnight and then under reduced pressureThen concentrated to dryness. The residue was partitioned between ethyl acetate and 1N HCl. The ethyl acetate extract was washed with 1N NaOH, dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to give 30a (2.36g, 62%) as a white solid.1H NMR(400MHz，MeOD)δppm：2.83-2.92(m，7H)，2.93-3.01(m，1H)，4.66(t，J＝6.67Hz，1H)，7.15-7.33(m，5H)。
Preparation of compound 30 b: (S) -1-dimethylamino-3-phenylpropan-2-ol
A solution of intermediate 30a (2.35g, 13.1mmol) in THF (10mL) was added to a stirred suspension of lithium aluminum hydride (1.99g, 52.4mmol) in THF (20mL) at 0 deg.C. The reaction mixture was stirred at room temperature overnight and then saturated Na was used2CO3Quench until bubbling stopped. The resulting mixture was filtered over celite, and the filter cake was washed with dichloromethane. The filtrate was concentrated to dryness. The resulting residue was dissolved in ether. The solution was extracted twice with 2N HCl. The combined aqueous layers were washed with ether and basified with solid NaOH to pH 10. The basic solution was extracted twice with ether. The combined ether extracts are taken in anhydrous K2CO3The residue was dried, filtered and concentrated to give the title compound (1.6g, 74%) as a colorless oil.1H NMR(400MHz，MeOD)δppm：2.24(s，6H)，2.28-2.39(m，2H)，2.63-2.79(m，2H)，3.87-3.99(m，1H)，7.12-7.31(m，5H)。
A solution of intermediate 1c (165mg, 0.42mmol), alcohol 30b (104mg, 1.5 equiv.) and potassium carbonate (117mg, 2 equiv.) in 1, 2-dimethoxyethane (DME, 2mL) was heated to 130 ℃ for 40 minutes in a microwave reactor. Then, the remaining solution was filtered to remove solids, and the filtrate was concentrated to dryness. The remaining residue was dissolved in methanol (1.0mL), triethylamine (1.0mL) was added and the mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the crude product was purified by preparative HPLC and lyophilized to give the title compound 30(90mg) as a white solid in 46% yield.1H NMR(400MHz，MeOD)δppm：1.51(s，3H)，1.66(s，3H)，2.37(s，6H)，2.58(dd, J ═ 13.60, 3.02Hz, 1H), 2.76(dd, J ═ 13.22, 8.69Hz, 1H), 2.82-2.90(m, 1H), 2.92-3.01(m, 1H), 4.49-4.73(m, 2H), 5.18-5.28(m, 1H), 7.14-7.23(m, 1H), 7.23-7.31(m, 4H), 7.53(t, J ═ 7.43Hz, 2H), 7.61(t, J ═ 7.30Hz, 1H), 7.95(t, J ═ 6.42Hz, 2H). Analyzed as (C)26H31N5O3.0.2HOAc.0.2H2O) C, H, N. HPLC: > 95% purity.
Example 31: 3- [ (2-fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -1-benzyl-2- (dimethylamino) ethyl ester
The title compound 31 was prepared in 56% yield by the method of example 30.1H NMR (400MHz, MeOD) δ ppm: 1.50(s, 3H), 1.66(s, 3H), 2.43(s, 6H), 2.63-2.71(m, 1H), 2.79-2.91(m, 2H), 2.97(dd, J ═ 13.72, 5.41Hz, 1H), 4.53-4.74(m, 2H), 5.21-5.31(m, 1H), 7.13-7.22(m, 1H), 7.24-7.31(m, 5H), 7.33(t, J ═ 7.55Hz, 1H), 7.54-7.65(m, 1H), 7.74-7.88(m, 1H). Analyzed as (C)26H30N5O3F.0.2HOAc) C, H, N. HPLC: > 95% purity.
Example 32: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -1-cyclohexane-2- (dimethylamino) ethyl ester
Preparation of compound 32 a: (S) -2-cyclohexyl-2-hydroxy-N, N-dimethylacetamide
The title compound 32a was prepared by the method of example 30a in 75 yield％。1H NMR (400MHz, chloroform-d) delta ppm: 1.09-1.30(m, 4H), 1.38-1.55(m, 3H), 1.64(d, J ═ 11.08Hz, 2H), 1.71-1.87(m, 2H), 3.01(d, J ═ 6.04Hz, 6H), 4.23(d, J ═ 2.77Hz, 1H).
Preparation of compound 32 b: (S) -1-cyclohexyl-2- (dimethylamino) ethanol
The title compound 32b was prepared in 47% yield by the method of example 30 b.1H NMR (400MHz, chloroform-d) delta ppm: 1.04-1.26(m, 6H), 1.58-1.82(m, 5H), 2.90(d, J ═ 5.04Hz, 3H), 2.96(d, J ═ 5.04Hz, 3H), 2.98-3.03(m, 1H), 3.15-3.26(m, 1H), 3.85-3.94(m, 1H), 11.34(br.s., 1H).
The title compound 32 was prepared in 34% yield by the method of example 30.1H NMR (400MHz, MeOD) δ ppm: 1.06-1.36(m, 5H), 1.61-1.84(m, 12H), 2.46(s, 6H), 2.62-2.75(m, 1H), 2.88(dd, J ═ 13.35, 9.06Hz, 1H), 4.58-4.77(m, 2H), 4.89-4.97(m, 1H), 7.52(t, J ═ 7.43Hz, 2H), 7.60(t, J ═ 7.30Hz, 1H), 7.95(d, J ═ 7.30Hz, 2H). Analyzed as (C)25H35N5O3.0.2HOAc.0.7H2O) C, H, N. HPLC: > 95% purity.
Example 35: 3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -1- [ (dimethylamino) methyl ] -3-methylbutyl ester
Preparation of compound 35 a: (S) -2-hydroxy-N, N, 4-trimethylpentanamide
Method of example 30aThe title compound 35a was prepared in 61% yield.1H NMR (400MHz, chloroform-d) delta ppm: 0.94-1.01(m, 6H), 1.27-1.36(m, 1H), 1.38-1.48(m, 1H), 1.95-2.04(m, 1H), 2.70(br.s., 1H), 2.99(d, J ═ 13.35Hz, 6H), 4.40(dd, J ═ 10.07, 2.01Hz, 1H).
Preparation of compound 35 b: (S) -1- (dimethylamino) -4-methylpentan-2-ol
The title compound 35b was prepared in 63% yield by the method of example 30 b.1H NMR (400MHz, chloroform-d) delta ppm: 0.93(dd, J ═ 6.55, 3.78Hz, 6H), 1.05-1.17(m, 1H), 1.32-1.47(m, 1H), 1.75-1.92(m, 1H), 2.16-2.56(m, 8H), 3.73-3.90(m, 1H), 4.39(br.s., 1H).
The title compound 35 was prepared in 54% yield by the method of example 30.1H NMR (400MHz, MeOD) δ ppm: 0.92-1.00(m, 6H), 1.36-1.48(m, 1H), 1.53-1.63(m, 1H), 1.67-1.80(m, 7H), 2.37(s, 6H), 2.48(dd, J ═ 12.84, 3.27Hz, 1H), 2.56-2.74(m, 1H), 4.54-4.78(m, 2H), 5.05-5.16(m, 1H), 7.52(t, J ═ 7.55Hz, 2H), 7.60(t, J ═ 7.18Hz, 1H), 7.94(d, J ═ 7.30Hz, 2H). Analyzed as (C)23H33N5O3.0.1HOAc.0.1H2O) C, H, N. HPLC: > 95% purity.
Example 36: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -1- [ (dimethylamino) methyl ] -3-methylbutyl ester
The title compound 36 was prepared from 2c in 22% yield by the method of example 35.1HNMR (400MHz, MeOD) δ ppm: 0.97(d, J ═ 6.55Hz, 6H), 1.37-1.51(m, 1H), 1.54-1.61(m, 1H), 1.64-1.77(m, 7H), 2.40(s, 6H), 2.44-2.57(m, 1H), 2.59-2.79(m, 1H), 4.52-4.74(m, 2H), 5.05-5.18(m, 1H), 7.25(t, J ═ 8.69Hz, 2H), 7.93-8.09(m, 2H). Analyzed as (C)23H32N5O3F.0.2HOAc) C, H, N. HPLC: > 95% purity.
Example 37: 3- [ (2, 4-difluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-methylethyl ester
The title compound 37 was prepared in 25% yield by a similar method to example 1 using (S) - (+) -1-dimethylamino-2-propanol.1H NMR (400MHz, MeOD) δ ppm: 1.26-1.35(m, 3H), 1.73(s, 6H), 2.47(s, 6H), 2.55-2.66(m, 1H), 2.74-2.91(m, 1H), 4.60-4.75(m, 2H), 5.02-5.17(m, 1H), 7.09-7.18(m, 2H), 7.82-7.92(m, 1H). Analyzed as (C)20H25F2N5O3·0.4H2O·0.3HOAc)C，H，N。LCMS(M+H+)：422.3。
Example 38: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid 2- (dimethylamino) -1- (2-fluorophenyl) ethyl ester
Preparation of compound 38 a: 2-dimethylamino-1- (2-fluoro-phenyl) -ethanol
By the procedure used for the preparation of intermediate 1d, 2-amino-1- (2-fluoro-phenyl) -ethanol (2.18g, 14.1mmol) was methylated to give crude oil 38a (2.26g, 12.3mmol, 88% yield).1H NMR(MeOD)δ：2.54(s，6H)，2.66(dd，J＝9.09，12.88Hz，1H)，2.81(dd，J＝9.09，12.88Hz，1H)，5.33(dd，J＝3.28，9.09Hz，1H)，7.19-7.28(m，1H)，7.33-7.40(m，1H)，7.43-7.51(m，1H)，7.69-7.76(m，1H)。LCMS(APCI，M+H+)：184.2。
Intermediate 2c (298mg, 0.729mmol) and alcohol 38a (200mg, 1.09mmol) were coupled by the method of example 1 to give 38(10mg, 3%) as a white solid.1HNMR (MeOD, mixture of rotamers, only the chemical shifts of the major form are reported) δ: 1.53(s, 3H), 1.65(s, 3H), 2.96(s, 6H), 3.37-3.47(m, 1H), 3.71-3.81(m, 1H), 4.75-4.86(m, 2H), 6.29-6.36(m, 1H), 7.07-7.24(m, 4H), 7.30-7.40(m, 1H), 7.43-7.53(m, 1H), 7.87-7.97(m, 1H). Analyzed as (C)25H27F2N5O31.88TFA 0.88 ethanol) C, H, N, F. LCMS (APCI, M + H)+)：484.2。
Example 39: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid 2- (dimethylamino) -1- (4-fluorophenyl) ethyl ester
Preparation of compound 39 a: 2-dimethylamino-1- (4-fluorophenyl) -ethanol
By the procedure used for the preparation of intermediate 1d, 2-amino-1- (4-fluoro-phenyl) -ethyl ester (2.10g, 13.5mmol) was methylated to give 39a as an oil (1.24g, 6.78mmol, 50% yield).1H NMR(MeOD)δ：2.55(s，6H)，2.62(dd，J＝3.79，12.88Hz，1H)，2.83(dd，J＝9.09，12.88Hz，1H)，5.01(dd，J＝3.54，9.09Hz，1H)，7.28(t，J＝884Hz，2H)，7.61(dd，J＝5.31，8.59Hz，2H)。LCMS(APCI，M+H+)：184.2。
Intermediate 2c (290mg, 0.710mmol) and alcohol 39a (260mg, 1.42mmol) were coupled by the method of example 1 to give compound 39(27mg, 7%) as a white solid.1HNMR(MeOD, mixture of rotamers, only the chemical shifts of the major form are reported) δ: 1.52(s, 3H), 1.64(s, 3H), 2.94(s, 3H), 2.97(s, 3H), 3.32-3.40(m, 1H), 3.66-3.77(m, 1H), 4.77-4.86(m, 2H), 6.04-6.11(m, 1H), 7.04-7.23(m, 4H), 7.40-7.49(m, 2H), 7.87-7.98(m, 2H). Analyzed as (C)25H27F2N5O32.03TFA 0.89 water) C, H, N, F. LCMS (APCI, M + H)+)：484.2。
Example 40: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- [ isopropyl (methyl) amino ] -1-phenylethyl ester
Preparation of compound 40 a: (S) -2-hydroxy-N-isopropyl-N-methyl-2-phenylacetamide
The title compound 40a was prepared by the method of example 30a using isopropyl methylamine in 44% yield.1H NMR (400MHz, chloroform-d) delta ppm: 0.55(d, J ═ 6.55Hz, 1.5H), 1.03(d, J ═ 6.80Hz, 1.5H), 1.16(t, J ═ 6.67Hz, 3H), 2.56(s, 1.5H), 2.86(s, 1.5H), 3.80-3.96(m, 0.5H), 4.87-4.95(m, 0.5H), 5.19(d, J ═ 31.98Hz, 1H), 7.28-7.41(m, 5H).
Preparation of compound 40 b: (S) -2- (isopropyl (methyl) amino) -1-phenylethanol
The title compound 40b was prepared in 84% yield by the method of example 30 b.1H NMR(400MHz，MeOD)δppm：1.02(dd，J＝11.46，6.67Hz，6H)，2.32(s，3H)，2.46-2.63(m，2H)，2.86-2.95(m，1H)，4.70(dd，J＝9.06，3.78Hz，1H)，7.20-7.28(m，1H)，7.29-7.39(m，4H)。
At room temperature, 1.6M butyllithium in hexane (0.73mL) was added to (S) -2- (isopropyl (methyl) amino) -1-benzeneEthanol 40b (227mg, 1.18mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 20 minutes, and then 5- (chlorocarbonyl) -3- [ (4-fluorobenzoyl) amino group was added]-6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c]Pyrazole-2 (4H) -carboxylic acid ethyl ester 2c (200mg, 0.49 mmol). The resulting mixture was heated under reflux for 1 hour and then concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC and lyophilized to give the title compound 40(10mg) as a white solid in 4% yield.1H NMR (400MHz, MeOD) δ ppm: 1.06(dd, J ═ 21.65, 6.55Hz, 6H), 1.62(s, 3H), 1.72(s, 3H), 2.42(s, 3H), 2.62-2.72(m, 1H), 2.88-3.04(m, 2H), 4.82(br.s., 2H), 5.81(dd, J ═ 9.19, 3.40Hz, 1H), 7.21-7.33(m, 3H), 7.34-7.44(m, 4H), 7.97-8.06(m, 2H). Analyzed as (C)27H32N5O3F.0.2HOAc.0.4H2O) C, H, N. HPLC: > 95% purity.
Example 41: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (R) -2- (dimethylamino) -2-phenylethyl ester
Preparation of compound 41 a: (R) -2- (dimethylamino) -2-phenylethanol
The title compound 41a was prepared in 90% yield by the method of example 1d using (R) -2-amino-2-phenylethanol.1H NMR(400MHz，MeOD)δppm：2.21(d，J＝1.26Hz，6H)，3.32-3.39(m，1H)，3.75-3.84(m，1H)，3.90-4.00(m，1H)，7.24-7.39(m，5H)。
Preparation of the title from Compound 2c by the method of example 30Title compound 41 in 18% yield.1H NMR (400MHz, MeOD) δ ppm: 1.65(d, J ═ 11.08Hz, 6H), 2.33(s, 6H), 3.63-3.75(m, 1H), 4.38-4.56(m, 4H), 7.20-7.34(m, 3H), 7.38(t, J ═ 4.53Hz, 4H), 7.93-8.07(m, 2H). Analyzed as (C)25H28N5O3F.0.2HOAc.0.3H2O) C, H, N. HPLC: > 95% purity.
Example 42: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (S) -2- (dimethylamino) -2-phenylethyl ester
Preparation of compound 42 a: (S) -2- (dimethylamino) -2-phenylethanol
The title compound 42a was prepared in 97% yield by the method of example 1d using (S) -2-amino-2-phenylethanol.1H NMR(400MHz，MeOD)δppm：2.20(s，6H)，3.35(t，J＝6.17Hz，1H)，3.79(dd，J＝11.33，6.29Hz，1H)，3.94(dd，J＝11.33，6.04Hz，1H)，7.23-7.37(m，5H)。
The title compound 42 was prepared in 12% yield by the method of example 30.1H NMR (400MHz, MeOD) δ ppm: 1.65(d, J ═ 11.33Hz, 6H), 2.33(s, 6H), 3.61-3.76(m, 1H), 4.37-4.58(m, 4H), 7.25(q, J ═ 8.64Hz, 2H), 7.29-7.34(m, 1H), 7.38(t, J ═ 4.66Hz, 4H), 7.93-8.07(m, 2H). Analyzed as (C)25H28N5O3F.0.4HOAc.) C, H, N. HPLC: > 95% purity.
Example 43: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid 1-phenyl-2-pyrrolidin-1-yl ethyl ester
Preparation of compound 43 a: 1-phenyl-2-pyrrolidin-1-yl-ethanol
Pyrrolidine (1.06mL, 12.8mmol) was added to a solution of (S) - (+) -1-phenyl-1, 2-ethanediol-2-tosylate (745.8mg, 2.55mmol) in dichloromethane (2.55 mL). The mixture was stirred in an oil bath at 40 ℃ for 28 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 mL). Saturated aqueous sodium bicarbonate (5mL) and brine (5mL) were added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2X 20 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated to give a mixture of 1-phenyl-2-pyrrolidin-1-yl-ethanol and 2-phenyl-2-pyrrolidin-1-yl-ethanol (541.2mg) as a yellow oil. Racemization occurs in this reaction because the presence of the isomeric product suggests the formation of an epoxide intermediate. The mixture of alcohols was dissolved in DMF (1.45mL), triisopropylsilyl chloride (154. mu.L, 0.72mmol) and imidazole (99mg, 1.45mmol) were added, and the solution was stirred at room temperature for 42 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate (20mL) and saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was back-extracted with ethyl acetate (2X 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 1/19/80 concentrated aqueous ammonia/EtOH/EtOAc) to give alcohol 43a (155.9mg, 32%) as a white solid and silyl ether 43b (135.8mg, 15%) as a yellow oil. 43 a:1H NMR(DMSO-d6) δ: 1.64(m, 4H), 2.53(m, 5H, partially masked by solvent), 2.60(dd, J ═ 7.8, 12.1Hz, 1H), 4.62(br s, 1H), 5.05(br s, 1H), 7.21(m, 1H), 7.32(m, 4H). Analyzed as (C)12H17NO·0.15H2O)C，H，N。LCMS(APCI，M+H+)：192.4。
Intermediate 2c (210mg, 0.514mmol) and alcohol 43a (147.5mg, 0.771mmol) were coupled by the method of example 1 to give 43 as an off-white powder (57.3mg, 22%).1H NMR(DMSO-d6)δ：1.53(br s，2H) 1.63(m, 8H), 2.52(m, 4H, partially masked by solvent), 2.74(m, 1H), [2.85(m), 3.00(m)1H in total]In total, [4.43(m), 4.64(brs)2H]Total of 5.78(dd, J ═ 5.8, 8.1Hz, 1H), 7.35(m, 7H), 8.07(br s, 2H), 10.97(m, 1H), [12.24(br s), 12.49(br s)1H]. Analyzed as (C)27H30FN5O3·0.7H2O)C，H，N，F。LCMS(APCI，M+H+)：492.4。HRMS：[M+H]+The calculation result is as follows: 492.24054, respectively; the test results are: 492.24017, respectively; the error was-0.76 ppm.
Example 44: 3- [ (4-Fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid 1-methyl-3-phenylpyrrolidin-3-yl ester
Preparation of compound 44 a: 1-methyl-3-phenyl-pyrrolidin-3-ol
A mixture of 3-phenyl-pyrrolidin-3-ol (2.01g, 11.67mmol), 5.8mL of 88% aqueous formic acid and 11.7mL of 37% aqueous formaldehyde were stirred in a 100 ℃ oil bath for 1.5 hours to maintain a maximum internal temperature of 86 ℃. After cooling to room temperature, the solution was extracted with 20mL of diethyl ether, and then the remaining aqueous layer was basified with 50% aqueous sodium hydroxide solution to bring the pH to 8. The basic solution was extracted with ethyl acetate (3X 25 mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 1/19/80 concentrated aqueous ammonia/EtOH/EtOAc) to give 44a as a yellow liquid (260.4mg, 12%).1H NMR(DMSO-d6)δ：2.02(m，1H)，2.08(m，1H)，2.29(s，3H)，2.63(d，J＝9.6Hz，1H)，2.71(m，2H)，2.79(d，J＝9.6Hz, 1H), 5.21(s, 1H), 7.17(t, J ═ 7.2Hz, 1H), 7.29(t, J ═ 7.6Hz, 1H), 7.47(t, J ═ 7.3Hz, 1H). The analysis was (C11H15NO & 0.16H2O) C, H, N. LCMS (APCI, M + H)+)：178.4。
Intermediate 2c (201.1mg, 0.49mmol) and alcohol 44a (131mg, 0.74mmol) were coupled by the method of example 1 to give 44 as a pale yellow solid (72.1mg, 30%).1H NMR(DMSO-d6) δ: [1.52(d, J ═ 9.3Hz), 1.76(J ═ 14.4Hz)6H total]2.24 (septit, J ═ 7.3Hz, 1H), [2.30(s), 2.31(s)3H in total]2.39(m, 1H), 2.57 (quant, J ═ 8.1Hz, 1H), 2.76(m, 1H), 2.85(t, J ═ 11.1Hz, 1H), 3.22(t, J ═ 10.0Hz, 1H), [4.37(br s), 4.69(br s)2H in total]7.21(m, 1H), 7.32(m, 6H), 8.08(m, 2H), 10.97(br m, 1H), 12.48(br m, 1H). Analyzed as (C)26H28FN5O3·0.45H2O)C，H，N，F。LCMS(APCI，M+H+)：478.4。HRMS：[M+H]+The calculation result is; 478.2249, respectively; the test results are: 478.2240, respectively; the error was-1.83 ppm.
Example 45: 3- [ (4-fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S, 2S) -2- (dimethylamino) -1-phenylpropyl ester
1M lithium bis (trimethylsilyl) amide in hexane (1.17mL) was added to a solution of (1S, 2S) -2-dimethylamino-1-phenylpropan-1-ol (210mg, 1.18mmol) in THF (2mL) at room temperature. The reaction mixture was stirred at room temperature for 20 minutes, and then 5- (chlorocarbonyl) -3- [ (4-fluorobenzoyl) amino group was added]-6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c]Pyrazole-2 (4H) -carboxylic acid ethyl ester 2c (200mg, 0.49 mmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated to dryness under reduced pressure. The crude product was purified by preparative-HPLC and freeze-dried, therebyThe title compound 45(20mg) was obtained as a white solid in a yield of 0.4%.1H NMR (400MHz, MeOD) δ ppm: 0.81(d, J ═ 7.05Hz, 3H), 1.58(s, 2H), 1.71(s, 3H), 1.88(d, J ═ 23.42Hz, 1H), 2.48(s, 6H)3.17-3.29(m, 1H), 4.70(br.s., J ═ 13.09Hz, 2H), 5.69(d, J ═ 9.32Hz, 1H), 7.20-7.34(m, 3H), 7.35-7.46(m, 4H), 8.03(dd, J ═ 8.81, 5.29Hz, 2H). Analyzed as (C)26H30N5O3F.0.2HOAc.0.5H2O) C, H, N. HPLC: > 95% purity.
Example 46: 3- (benzoylamino) -N- [ (1S) -2- (dimethylamino) -1-phenylethyl ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Preparation of compound 46 a: [ (1S) -2- (dimethylamino) -2-oxo-1-phenylethyl]-carbamic acid benzyl ester
Potassium carbonate (285g, 2.06mmol) and dimethylamine hydrochloride (84.1g, 1031mmol) were added successively to (2S) - { [ (benzyloxy) carbonyl]Amino } (phenyl) acetic acid (196g, 688mmol), HBTU (261g, 688mmol) and dichloromethane (2.8L). The reaction mixture was heated at 40 ℃ overnight. After cooling to room temperature, the solid was filtered, washed with ethyl acetate (2 × 500mL), and the filtrate was concentrated to a residue. Water (1L) was added to the residue and the solution was held in an ultrasonic cleaner for 2 hours. The precipitated solid was collected, washed with water (4X 300mL), hexane (2X 500mL), and dried under vacuum for 24 hours. The solid crude product was dissolved in chloroform (300mL) and the undissolved solid was filtered off. The filtrate was concentrated to dryness and the residue was dissolved in hexane/ethyl acetate (2)1) (250mL) and left at room temperature overnight. The resulting crystals were collected by filtration, washed with hexane/ethyl acetate (3: 1) (100mL), and dried under high vacuum at 40 ℃ for 24 hours to give 46a as a white crystalline solid (100.0g, 47%).1H NMR(CDCl3)δ：2.88(s，3H)，2.98(s，3H)，5.01(d，J＝12.2Hz，1H)，5.11(d，J＝12.2Hz，1H)，5.58(d，J＝7.5Hz，1H)，6.37(d，J＝7.2Hz，1H)，7.32(m，10H)。
Preparation of compound 46 b: (2S) -2-amino-N, N-dimethyl-2-phenylacetamide
A slurry of Pd/C (10%, 9.0g) in ethyl acetate was added to a solution of 46a (80.0g, 256mmol) in ethanol (1.2L). The reaction mixture was shaken overnight under hydrogen (40psi) in a Parr apparatus. The catalyst was removed by filtration over celite. The filter discs were washed with ethanol (2 × 200mL) and the combined filtrates were concentrated to give 46b as a white solid (40.2g, 88%).1HNMR(CDCl3)δ：2.85(s，3H)，2.99(s，3H)，4.72(s，1H)，7.33(m，5H)。
Preparation of compound 46 c: n- [ (2S) -2-amino-2-phenylethyl ] -N, N-dimethylamine.
The flask containing anhydrous THF (2300mL) under nitrogen atmosphere was frozen with an ice-water bath. Lithium aluminum hydride pellets (59.0g, 1555mmol) were added. A solution of amide 46b (123.0g, 691mmol) in dry THF (800mL) was slowly added to the above LAH suspension over about 1 hour. The resulting reaction mixture was heated to reflux for 5 hours and then cooled to 10 ℃. The cooled reaction mixture was slowly quenched with saturated aqueous sodium sulfate solution (380mL) and stirred overnight. The precipitated solid was filtered off and washed with ethyl acetate (4 × 500 mL). The filtrate was concentrated to a residue, which was purified on a silica gel column (10% methanol in chloroform, 5% triethylamine) to give 46c as a pale yellow liquid (66.7g, 59%).1H NMR(CDCl3)δ：2.24(dd，J＝3.6，12.1Hz，1H)，2.29(s，6H)，2.47(dd，J＝10.6，12.1Hz，1H)，4.07(dd，J＝3.6，10.4Hz，1H)，7.24(m，1H)，7.37(m，4H)。
Diisopropylethylamine (54 μ L, 1.0 eq) was added to 3- (benzoylamino) -5- (chlorocarbonyl) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] at room temperature]Pyrazole-2 (4H) -carboxylic acid ethyl ester 1c (120mg, 0.31mmol) and N- [ (2S) -2-amino-2-phenylethyl]-N, N-dimethylamine (76mg, 1.5 equiv.) in THF (3 mL). The reaction mixture was stirred at reflux for 2 hours and then evaporated to dryness. The residue was dissolved in methanol (1mL) and triethylamine (1mL), stirred at room temperature for 2 hours, and then evaporated to dryness again. The crude product was purified by preparative-HPLC and lyophilized to give the title compound 46(27 mg) as a white foam in 20% yield.1H NMR (400MHz, MeOD) δ ppm: 1.60(s, 3H), 1.67(s, 3H), 2.42(s, 6H), 2.56-2.70(m, 1H), 2.84-3.02(m, 1H), 4.55-4.71(m, 2H), 5.01(dd, J ═ 10.36, 4.04Hz, 1H), 7.16(t, J ═ 7.20Hz, 1H), 7.21-7.34(m, 4H), 7.37-7.54(m, 3H), 7.82-7.92(m, 2H). Analyzed as (C)25H30N6O2.1.0HOAc.0.6H2O) C, H, N. HPLC: > 95% purity.
Example 57: n- [ (1S) -2- (dimethylamino) -1-phenylethyl ] -6, 6-dimethyl-3- [ (2-thienylcarbonyl) amino ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Preparation of compound 57 a: 5- (Chlorocarbonyl) -3- (thiophene-2-carbonylamino) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester
The title compound was prepared in 71% yield from intermediate i (g) by the method of example 1c using thiophene-2-carbonyl chloride.1H NMR (400MHz, chloroform-d) delta ppm: 1.51(t, J ═ 7.07Hz, 3H), 1.56(s, 6H), 4.60(q, J ═ 7.24Hz, 2H), 5.03(s, 2H), 7.17(dd, J ═ 4.93, 3.92Hz, 1H), 7.65(dd, J ═ 4.93, 1.14Hz, 1H), 7.69(dd, J ═ 3.79, 1.26Hz, 1H), 10.98(br.s., 1H).
The title compound was prepared in 53% yield from 57a by a procedure similar to that used in example 46.1H NMR (400MHz, MeOD) δ ppm: 1.70(s, 3H), 1.77(s, 3H), 2.89(s, 6H), 3.27(dd, J ═ 13.01, 4.17Hz, 1H), 3.44-3.53(m, 1H), 4.67(d, J ═ 12Hz, 1H), 4.76(d, J ═ 12Hz, 1H), 5.33(dd, J ═ 11.62, 4.04Hz, 1H), 7.17-7.22(m, 1H), 7.28-7.47(m, 5H), 7.73-7.78(m, 1H), 7.87-7.93(m, 1H). Analyzed as (C)23H28N6O2S·1HCl·1.25HOAc)C，H，N。LCMS(APCI，M+H+)：453.3。
Example 58: 3- (benzoylamino) -6, 6-dimethyl-N- [ trans-2-phenylcyclopropyl ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Trans-2-phenylcyclopropyl isocyanate (54. mu.L, 1.4 equiv.) was added to 3- (benzoylamino) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ]]Pyrazole-2 (4H) -carboxylic acid ethyl ester 1b (85mg, 0.26mmol) and triethylamine (109 μ L, 3 equivalents) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in methanol (1mL) and triethylamine (1mL), stirred at room temperature for 19 hours, and evaporated again to dryness. The crude product was purified by preparative-HPLC and lyophilized to give the title compound 58(63mg) as a white foam in 58% yield.1H NMR (400MHz, MeOD) δ ppm: 1.01-1.16(m, 2H), 1.66(d, J ═ 3.54Hz, 6H), 1.92-2.02(m, 1H), 2.64-2.75(m, 1H), 4.45(s, 2H), 6.99-7.09(m, 3H), 7.09-7.19(m, 2H), 7.37-7.55(m, 3H), 7.80-7.89(m, 2H). Analyzed as (C)24H25N5O2.0.1HOAc.0.6H2O) C, H, N, S. HPLC: > 95% purity.
Example 59: 3- (benzoylamino) -N- (1-benzylpyrrolidin-3-yl) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Various forms of examples 59-63 were generated using the following conventional methods:
A3X 6mm stir bar, appropriate carbamoyl chloride solution 1c (0.1M in THF, 80. mu. mol, 1.0 equiv), appropriate amine solution (0.1M in THF, 80. mu. mol, 1.0 equiv) and DIPEA solution(1M in THF, 80. mu. mol, 1.0 eq.) was added to a 10X 95mm test tube. The reaction was stirred at 80 ℃ for 16 hours. MeOH (500. mu.L) and TEA (500. mu.L) were added and the reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue containing the product and DIPEA-HCl was redissolved in DMSO. Purification by Supercritical Fluid Chromatography (SFC) gave the desired product 59 in 30% yield.1H NMR(500MHz，DMSO)δppm1.59(s，11H)1.92(s，1H)2.48(d，J＝2.47Hz，1H)2.50(s，1H)4.34(s，3H)4.45(s，4H)7.43(s，6H)7.96(s，3H)10.84(s，1H)12.41(s，1H)。LCMS(APCI，M+H+)：459。
Example 64: n- [ (1S) -2-amino-1-phenylethyl ] -3- (benzoylamino) -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Preparation of compound 64 d: 2-amino-2-phenylethylcarbamic acid (S) -benzyl ester
At 0 deg.C, adding SOCl2(785g, 6.6mol) was added dropwise to CH3OH (1.5L), then the reaction mixture was warmed to room temperature and stirred for 2 hours. After addition of L-amino-phenyl-acetic acid (250g, 1.66mol) in portions, the mixture is mixedThe material was stirred at room temperature overnight. The mixture was evaporated to dryness to give a white powdery compound. The white solid was then dissolved in 1.5 liters of toluene. Then NH is added dropwise3H2O (875mL, 28%). The resulting mixture was stirred at room temperature for 30 hours. The mixture was evaporated to a smaller volume and the precipitate was filtered and washed with anhydrous ether to give compound 64a as a white solid (120g, 46%).
Will be in anhydrous CH2Cl2Compound 64a (120g, 0.81mol) and trimethylamine (78g, 0.77mol) in (1.5L) was added dropwise to triphenylmethyl chloride (214g, 0.77mol) in anhydrous CH2Cl2(200 mL). The mixture was stirred at room temperature overnight, TLC (CH)2Cl2MeOH 10: 1) showed that the reaction was complete. The mixture was quenched with water and CH2Cl2(500 mL. times.3) was extracted. The combined organic layers were washed with brine, over Na2SO4Drying above and evaporation gave a pale yellow solid which was washed with ether to give compound 64b as a white solid (300g, 95%).
To compound 64b (300g, 0.70mol) in anhydrous ether (1.5L) LiAlH was added portionwise at 0 deg.C4(300g, 7.89mol) and the reaction mixture was then warmed to room temperature and stirred for 60 hours. TLC (pentane/ethyl acetate 1: 1) indicated that the reaction was complete. At-10 ℃ with H2O (100mL) was slowly added to the reaction mixture, and the resulting mixture was filtered and evaporated to give a pale yellow oil. The pale yellow oil is combined with CH at 0 deg.C2Cl2(1.5L) triethylamine (63.32g, 0.58mol) was added dropwise to CbzCl (98g, 0.58 mol). The reaction mixture was stirred at room temperature overnight. The mixture was washed with water and brine. The organic layer was evaporated to dryness and the residue was purified by column chromatography to give compound 64c (105g, 56%).
Compound 64c (150g, 0.29mol) in CH at 0 deg.C3Solution in OH (200L) was added dropwise to HCl/CH3OH (200mL, 7mol/L), the mixture was stirred overnight. TLC (CH)2Cl2/CH3OH 20: 1) showed that the reaction was complete. The reaction mixture was evaporated until a solid precipitated. The solid was filtered and washed with ethyl acetate to give compound 64d as HCl salt (58.6g, 74%). H1NMR，dmso-d6δppm：8.8-8.6(m，3H，b)，7.55-7.15(m，10H)，4.97(s，2H)，4.45-4.25(m，1H)，3.60-3.40(m，2H)。
The title compound 64 was prepared by a procedure similar to example 46 in 19% yield except that the last step cleaved the Cbz group with 10% Pd-C in MeOH.1HNMR (400MHz, MeOD) ppm: 1.70(s, 3H), 1.77(s, 3H), 1.91(s, 2H), 3.21-3.27(m, 2H), 4.68-4.81(m, 2H), 5.10(dd, J ═ 9.35, 5.31 Hz, 1H), 7.28-7.64(m, 8H)7.93-7.99(m, 2H). Analyzed as (C)23H26N6O2·1.5H2O·1.0HOAc)C，H，N。LCMS(M+H+)：419.2。
Example 65: n- [ (3R) -1-Benzylpyrrolidin-3-yl ] -3- [ (cyclobutylcarbonyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
The title compound 65 was prepared in 98% yield by a similar procedure as example 46 using (R) -1-benzylpyrrolidin-3-ylamine.1H NMR(dmso-d6) δ: 1.52(s, 3H), 1.60(s, 3H), 1.76-1.81(m, 1H), 1.88-1.97(m, 1H), 2.03-2.07(m, 2H), 2.14-2.23(m, 4H), 2.26-2.45(m, 4H), 3.19-3.27(m, 2H), 4.48-4.55(m, 2H), 4.98(s, 1H), 6.38(s, 1H), 7.21(t, J ═ 8.0Hz, 1H), 7.31(t, J ═ 8.0Hz, 2H), 7.38(d, J ═ 8.0Hz, 2H), 10.23(s, 1H), 12.25(s, 1H); analyzed as (C)23H32N6O2.1.5 H2O·0.1 EtOAc)C，H，N。HRMS[M+H]+The calculation and analysis result is as follows: 425.2660, respectively; the test results are: 425.2668.
example 66: n- {5- [4- (dimethylamino) -3-phenylbutyryl ] -6, 6-dimethyl-1, 4,5, 6-tetrahydropyrrolo [3, 4-c ] pyrazol-3-yl } -4-fluorobenzamide
To a mixture of 4- (dimethylamino) -3-phenylbutyric acid (257.1mg, 1.24mmol) (prepared according to Iwao, Junichi, Jpn, Tokkyo Koho (1969), JP 44027218) and HATU (542.2mg, 1.43mmol) in THF (4mL) was added 2b (373.7mg, 1.08mmol) and Et3N (0.53mL, 3.8mmol) in THF (4 mL). The resulting mixture was stirred at room temperature for 6 hours. The solvent was then removed under reduced pressure. The resulting residue was dissolved in MeOH (5mL) and Et3N (5mL) and stirred at room temperature for 4 hours. After removal of the solvent, the residue was subjected to preparative HPLC purification to give 66(100mg, 20%).
1H NMR (400MHz, MeOD) δ ppm: 1.59(s, 3H), 1.75(s, 3H), 2.50(m, 6H), 2.68-2.85(m, 2H), 2.93-3.06(m, 2H), 3.49-3.59(m, 1H), 4.57(d, J ═ 12Hz, 1H), 4.75(d, J ═ 12Hz, 1H), 7.21-7.39(m, 7H), 7.98-8.04(m, 2H). Analyzed as (C)26H30FN5O2·0.8H2O·0.8HOAc)C，H，N。LCMS(M+H+)：464.2。
Example 67: n- {5- [3- (4-chlorophenyl) -4- (dimethylamino) butanoyl ] -6, 6-dimethyl-1, 4,5, 6-tetrahydropyrrolo [3, 4-c ] pyrazol-3-yl } benzamide
The title compound 67 was prepared according to the same procedure as in example 66 in 21% yield. According to Iwao, Junichi, Jpn. Tokkyo Koho (1969), JP44027218 preparation of 4- (dimethylamino) -3- (4-chlorophenyl) butanoic acid. 67:1h NMR (400MHz, MeOD) δ ppm: 1.51(s, 3H), 1.66(s, 3H), 2.41(s, 6H), 2.58-2.65(m, 1H), 2.69-2.77(m, 1H), 2.81-2.94(m, 2H), 3.41-3.49(m, 1H), 4.54(d, J ═ 12.38Hz, 1H), 4.68(d, J ═ 12.38Hz, 1H), 7.22-7.28(m, 4H), 7.40-7.54(m, 3H), 7.82-7.87(m, 2H). Analyzed as (C)26H30ClN5O2·0.95H2O·0.7HOAc)C，H，N。LCMS(M+H+)：482.2。
Example 68: 6, 6-dimethyl-3- [ (1, 3-thiazol-4-ylcarbonyl) amino ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester
Preparation of Compound I (l): 3-amino-6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester dihydrochloride
A solution of 4M HCl in dioxane (155mL) was added dropwise to a stirred slurry of I (g) (40.00g, 123.3mmol) in ethanol (270 mL). The resulting clear solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was stirred with hexane (300mL) for 30 minutes. The solid product was collected by filtration, washed with hexane (2 × 100mL), and dried under vacuum at 40 ℃ to give dihydrochloride i (l) (35.80g, 98%) as a white solid.1H NMR(300MHz，dmso-d6)δ：1.31(t，J＝7.2Hz，3H)，1.59(s，6H)，4.09(t，J＝4.7Hz，2H)，4.36(q，J＝7.1Hz，2H)，10.14(s，2H)。
Preparation of compound 68 a: 5- [ (1S) -2- (dimethylamino) -1-phenylethyl ] 2-ethyl 3-amino-6, 6-dimethylpyrrolo [3, 4-c ] pyrazole-2, 5(4H, 6H) -dicarboxylate
At room temperature under nitrogen atmosphere, triethylamine(26.30g, 260.0mmol) and 4-nitrophenylchloroformate (27.00g, 130.0mmol) were added to a stirred solution of (S) -2-dimethylamino-1-phenyl-ethanol (1d, 21.50g, 130.0mmol) in 1, 2-dichloroethane (500 mL). The solution was stirred at 50 ℃ overnight. Then, a total of 16.8g (130.0mmol) of diisopropylethylamine was added, followed by I (L) (17.90g, 60.25 mmol). Stirring was continued at 50 ℃ for 12 hours. After cooling to room temperature, the solution was diluted with dichloromethane (1.5L), washed with water (2 × 1.0L) and brine (1.0L), and then dried over sodium sulfate. It is also possible to prepare another batch of product on the same scale. During the post-treatment, the two batches were combined. After filtration and evaporation, flash chromatography (4.75% MeOH/0.25% NEt)3/95% DCM) to give 68a as a pale yellow gummy oil (5.00g, 10%).1H NMR(CDCl3Mixture of rotamers, only the chemical shift of the major form is reported) δ: 1.45(t, J ═ 7.1Hz, 3H), 1.63(s, 3H), 1.72(s, 3H), 2.29(s, 3H), 2.36(s, 3H), 2.55-2.63(M, 1H), 2.88(dd, J ═ 13, 8.3Hz, 1H), 4.29(q, J ═ 13Hz, 1H), 4.51(q, J ═ 7.1Hz, 2H0, 5.44(d, J ═ 10.7Hz, 1H), 5.8-5.95(M, 1H), 7.25-7.42(M, 5H), LCMS (APCI, M + H)+)416。
Thiazole-4-carbonyl chloride (1.5 equiv.) was added to (S) -5- (2- (dimethylamino) -1-phenylethyl) 2-ethyl 3-amino-6, 6-dimethylpyrrolo [3, 4-c ] at room temperature]Pyrazole-2, 5(4H, 6H) -dicarboxylate 68a (150mg, 0.36mmol) and triethylamine (100 μ L, 2 equivalents) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in methanol (1mL) and triethylamine (1mL), stirred at room temperature for 19 hours, and evaporated again to dryness. The crude product was purified by preparative-HPLC and lyophilized to give the title compound 68(20mg) as a white foam in 12% yield.1H NMR(400MHz，MeOD)δppm：1.61(s，3H)，1.72(s，3H)，2.43(s，6H)，2.62(dd，J＝13.72，3.15Hz，1H)，3.03(dd，J＝13.60，9.82Hz，1H)，4.77-4.84(m，1H)，4.87-4.94(m，1H)，5.92(dd，J＝9.57，3.02Hz，1H)，7.27-7.34(m，1H)，7.35-7.48(m，4H)，8.43(d, J ═ 1.26Hz, 1H), 9.08(d, J ═ 2.01Hz, 1H). Analyzed as (C)22H26N6O3S.0.1HOAc.0.5H2O) C, H, N, S. HPLC: > 95% purity.
Example 69: 6, 6-dimethyl-3- { [ (1-methyl-1H-imidazol-4-yl) carbonyl ] amino } -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester
Preparation of Compound 69a
Oxalyl chloride (305mg, 0.21mL, 2.4mmol) and 1 drop of DMF were added to 1-methyl-1H-imidazole-4-carboxylic acid (100.9mg, 0.8mmol) in CH, followed by addition of 1-methyl-1H-imidazole-4-carboxylic acid (0.8 mmol) at 0 deg.C2Cl2(8 mL). The mixture was stirred at 25 ℃ for 2 days. All solvents were removed in vacuo to afford crude 69 a.
Reacting (S) -5- (2- (dimethylamino) -1-phenylethyl) 2-ethyl-3-amino-6, 6-dimethylpyrrolo [3, 4-c ]]Pyrazole-2, 5(4H, 6H) -dicarboxylate 68a (100mg, 0.24mmol) and diisopropylethylamine (0.42mL) in CH2Cl2The solution was added to crude 69 a. The mixture was stirred at 25 ℃ for 18 hours. All solvents were removed in vacuo. The residue was redissolved in MeOH-triethylamine co-solvent (2mL, 1: 1 v/v). The solution was stirred at 25 ℃ for 16 hours. All solvents were evaporated. The residue was purified by preparative HPLC to give the title compound 69 as a white solid (40mg, 37% overall yield).1H NMR(dmso-d6)δ：1.44(s，3H)，1.57(s，3H)，2.83-2.86(m，6H)，3.03(m，2H)，3.68(s，3H)，4.60(d，J＝13.3Hz，1H)，4.84(d，J＝13.4Hz，1H)，6.08(d，J＝7.3Hz，1H)，7.3-7.4(m，5H)，7.75(s，1H)，7.78(s，1H)。LCMS[M+H]+: 452. analyzed as (C)23H29N7O3·1.75H2O·1.7TFA)C，H，N。
Example 70: 3- { [ (4-fluorophenyl) acetyl ] amino } -6, 6-dimethyl-N- [ trans-2-phenylcyclopropyl ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carbonamide
Preparation of compound 70 a: 3-amino-6, 6-dimethyl-5- ({ [ trans-2-phenyl-cyclopropyl ] amino } carbonyl) -5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester
Compound I (g) (5.30g, 16.3mmol) was dissolved in 20.4mL of 4.0M HCl/dioxane solution (81.7mmol) and stirred at room temperature for 2.5 h. The solution was then evaporated to dryness and the crude amine hydrochloride i (l) residue was suspended in 50mL dichloromethane. The suspension was cooled in an ice/salt bath (-13 ℃ ice bath temperature). Diisopropylethylamine (9.95mL, 57.1mmol) and trans-2-phenylcyclopropyl isocyanate (2.60g, 16.3mmol) were added sequentially. The resulting mixture was stirred at-10 ℃ for 1 hour. After evaporation of the dichloromethane, the residue was partitioned between ethyl acetate (50mL) and a mixture of saturated aqueous sodium bicarbonate (30mL) and deionized water (20 mL). The aqueous layer was back-extracted with ethyl acetate (20mL) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give 6.67g of crude product as an off-white foam. Trituration in acetonitrile gave pure 70a as a white powder (5.82 g, 86%).1H NMR(dmso-d6) δ: 1.03(m, 1H), 1.19(m, 1H), 1.31(t, J ═ 7.2Hz, 3H), 1.55(d, J ═ 2.8Hz, 6H), 1.91(m, 1H), 2.74(m, 1H), 4.09(d, J ═ 11.6Hz, 1H), 4.13(d, J ═ 11.9Hz, 1H), 4.34(q, J ═ 7.1Hz, 2H), 6.32(d, J ═ 2.8Hz, 1H), 6.52(s, 2H), 7.10(d, J ═ 7.1Hz, 2H), 7.14(d, J ═ 7.3Hz, 1H), 7.24(t, J ═ 7.4Hz, 2H). Analyzed as (C)20H25N5O3·0.6 CH3CN·0.3 H2O)C，H，N。LCMS(APCI，M+H+)：384.2。
Diisopropylethylamine (98.2. mu.L, 0.56mmol) and (4-fluorophenyl) -acetyl chloride (54.5mg, 0.310mmol) were added successively to a room temperature solution of 70a (108.1mg, 0.282mmol) in dichloromethane (0.9 mL). The mixture was stirred at room temperature for 23 hours. Triethylamine (2.5mL) and methanol (2.5mL) were added and stirring was continued for 3 days. After evaporation to dryness, the crude product was purified by silica gel chromatography (eluting with 70% ethyl acetate in hexanes) to give 70 as a white solid (38.9mg, 30%).1H NMR(dmso-d6) δ: 0.99(q, J ═ 7.3Hz, 1H), 1.21 (quant, J ═ 4.7Hz, 1H), 1.58(s, 6H), 1.90(m, 1H), 2.72(m, 1H), 3.59(s, 2H), 4.32(s, 2H), 6.38(d, J ═ 3.0Hz, 1H), 7.11(m, 5H), 7.23(t, J ═ 7.5Hz, 2H), 7.31(dd, J ═ 5.7, 8.3Hz, 2H), 10.65(s, 1H), 12.29(s, 1H). Analyzed as (C)25H26FN5O2·0.55 H2O)C，H，N，F。HRMS：[M+H]+The calculation result is as follows: 448.2143, respectively; the test results are: 448.2138, respectively; the error was 1.12 ppm.
Example 71: n- [ (1S) -2- (dimethylamino) -1-phenylethyl ] -6, 6-dimethyl-3- [ (1, 3-thiazol-2-ylcarbonyl) amino ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Preparation of compound 71 a: (2-isocyanato-2-phenyl-ethyl) -dimethyl-amine
A solution of diisopropylethylamine (23.6g, 182.26mmol) in dichloromethane (50mL) was added dropwise over 20 minutes to a cooled (0 ℃ C.) and stirred solution of triphosgene (27.1g, 91.32mmol) in dichloromethane (250 mL). Then, a solution of amine 46c (15.0g, 91.32mmol) in dichloromethane (100mL) was added dropwise to the brown reaction mixture while maintaining the temperature below 10 ℃. The cooling bath of the resulting mixture was removed and stirred at room temperature for 2 hours. The reaction mixture is added inConcentration in vacuo afforded a residue which was stirred with 10% DCM in hexane (50mL) and then the solid precipitate 71a was isolated by filtration and used for the next reaction without further purification. (Note: the resulting solid product was stored under nitrogen). 1H NMR (300MHz, dmso-d)6)：δ3.29(s，3H)，3.38(s，3H)，3.68(t，J＝10.1Hz，1H)，4.42(dd，J＝11.5，6.5Hz，1H)，5.35(dd，J＝9.6，6.2Hz，1H)，7.4-7.6(m，5H)。
Preparation of compound 71 b: 3-amino-5- ({ [ (1S) -2- (dimethylamino) -1-phenylethyl- ] amino } carbonyl) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c ] pyrazole-2 (4H) -carboxylic acid ethyl ester
Diisopropylethylamine (74mL, 420.1mmol) and 71a (17.1g, 75.71mmol) were added sequentially to a cooled (0 ℃ C.) and stirred slurry of I (L) (25.0g, 84.12 mmol). After stirring at room temperature under nitrogen for 10 hours, the mixture was diluted with dichloromethane (100mL) and washed with water (2X 100 mL). The organic solution was dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting crude product was purified on a silica gel column (10% MeOH/DCM) to give 71b as a light yellow solid (23.0g, 73.7%). M.p: 96-97 ℃.1H NMR(300MHz，dmso-d6)：δ1.32(t，J＝7.1Hz，3H)，1.51(s，3H)，1.57(s，3H)，2.19(s，6H)，2.40(m，1H)，2.60(m，1H)，4.23(m，2H)，4.35(q，J＝6.7Hz，2H)，4.78(m，1H)，6.00(d，J＝6Hz，1H)，6.55(s，2H)，7.18-7.40(m，5H)。LCMS(APCI，M+H+)：415。
Thiazole-2-carbonyl chloride (1.5 equiv.) was added to 3-amino-5- ({ [ (1S) -2- (dimethylamino) -1-phenylethyl-]Amino } carbonyl) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c]Pyrazole-2 (4H) -carboxylic acid ethyl ester 71b (150mg, 0.36mmol) and triethylamine (100 μ L, 2 equivalents) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in methanol (1mL) and triethylamine (1mL), stirred at room temperature for 19 hours, and then evaporated to dryness again. The crude product was purified by preparative-HPLC and freeze-dried fromThus, the title compound 71(70mg) was obtained in 43% yield as a white foam.1H NMR (400MHz, MeOD) δ ppm: 1.68(s, 3H), 1.75(s, 3H), 2.41(s, 6H), 2.55(dd, J ═ 12.84, 4.28Hz, 1H), 2.94(dd, J ═ 12.59, 10.83Hz, 1H), 4.69 to 4.82(m, 2H), 5.05(dd, J ═ 10.70, 4.41Hz, 1H), 7.20 to 7.28(m, 1H), 7.30 to 7.42(m, 4H), 7.94(d, J ═ 3.02Hz, 1H), 8.04(d, J ═ 3.02Hz, 1H). Analyzed as (C)22H27N7O2S.0.2HOAc.1.2H2O) C, H, N, S. HPLC: > 95% purity.
Example 72: n- [ (1S) -2- (dimethylamino) -1-phenylethyl ] -6, 6-dimethyl-3- [ (1, 3-thiazol-4-ylcarbonyl) amino ] -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxamide
Thiazole-4-carbonyl chloride (1.5 equiv.) was added to 3-amino-5- ({ [ (1S) -2- (dimethylamino) -1-phenylethyl-]Amino } carbonyl) -6, 6-dimethyl-5, 6-dihydropyrrolo [3, 4-c]Pyrazole-2 (4H) -carboxylic acid ethyl ester 71b (150mg, 0.36mmol) and triethylamine (100 μ L, 2 equivalents) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in methanol (1mL) and triethylamine (1mL), stirred at room temperature for 19 hours, and then evaporated to dryness again. The crude product was purified by preparative-HPLC and lyophilized to give the title compound 72(55mg) as a white foam in 34% yield.1H NMR (400MHz, MeOD) δ ppm: 1.68(s, 3H), 1.75(s, 3H), 2.49(s, 6H), 2.68(dd, J ═ 12.97, 4.66Hz, 1H), 3.01(dd, J ═ 12.59, 10.83Hz, 1H), 4.69 to 4.81(m, 2H), 5.09(dd, J ═ 10.70, 4.41Hz, 1H), 7.25(t, J ═ 7.05Hz, 1H), 7.30 to 7.44(m, 4H), 8.41(d, J ═ 1.51Hz, 1H), 9.08(d, J ═ 2.01Hz, 1H). Analyzed as (C)22H27N7O2S.0.5HOAc.0.5H2O) C, H, N, S. HPLC: greater than 95% pureAnd (4) degree.
The following examples 73-95 were prepared using a similar method.
Preparation of compound 89 a: (R) -5-tert-butyl-2-ethyl-6, 6-dimethyl-3- (tetrahydrofuran-2-carbonylamino) pyrrolo [3, 4-c ] pyrazole-2, 5(4H, 6H) -dicarboxylate
(R) -tetrahydrofuran-2-carboxylic acid (1.39g, 12.0mmol) was dissolved in dichloromethane (24mL) and cooled to 0 ℃. Oxalyl chloride (4.57g, 36.0mmol) and DMF (25. mu.L) were added dropwise. After stirring at 0 ℃ for 3h, the solution was concentrated to dryness and then rotary evaporated (rotavop) with DME (2X 5mL) to remove residual oxalyl chloride before re-dissolving in DME (8.0 mL). In a separate flask, 5-tert-butyl 2-ethyl 3-amino-6, 6-dimethylpyrrolo [3, 4-c ] was placed]Pyrazole-2, 5(4H, 6H) -dicarboxylate I (G) (1.95g, 6.0mmol) and diisopropylethylamine (2.09mL, 12.0mmol) were dissolved in dichloromethane (8.0mL) and cooled to 0 ℃. The acid chloride solution was added dropwise, which allowed fuming and the internal temperature was raised to 15 ℃. The reaction was carried out at 0 ℃ for 5 hours. Sequentially adopts NaHCO3And DME and water work-up with a silica gel column to give 89a as a white foam (2.2572g, 86%).1HNMR(300MHz，dmso-d6)δ1.35(t，J＝7.1Hz, 3H), [1.42(s), 1.45(s), 9H in total]，1.57(dd，J＝2.8，6.6Hz，6H)，1.86(m，2H)，1.96(m，1H)，2.23(m，1H)，3.91(m，2H)，4.47(m，5H)，10.80(s，1H)。LCMS(APCI，M+H+): 423. analyzed as (C)20H30N4O6·0.15EtOAc)C，H，N。
The following examples were also prepared.
Example 110: (S) -3- (6-chloro-2-fluoro-3-methylbenzamido) -N- (2- (dimethylamino) -1-phenylethyl) -6, 6-dimethylpyrrolo [3, 4-c ] pyrazole-5 (1H, 4H, 6H) -carboxamide
A3X 6mm stir bar, Compound 71b (0.1M CH)2Cl2Solution, 80. mu. mol, 1.0 equiv), DIPEA solution (2M CH)2Cl2Solution, 160. mu. mol, 2.0 equivalents) and 6-chloro-2-fluoro-3-methylbenzoyl chloride (0.1M CH)2Cl2Solution, 160. mu. mol, 2.0 equivalents) was added to a 13X 100mm test tube. The reaction was capped and stirred at RT for 12 h. NaOH (1M, 1000. mu. mol, 12.5 equivalents) was added and the reaction mixture was stirred for 15 minutes. After centrifugation, the top layer was removed. The organic layer was evaporated. MeOH (500. mu.L) and TEA (500. mu.L) were added and the reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was redissolved in DMSO.1H NMR(500 MHz，D2O)dppm1.52(s，3H)1.59(s，3H)2.13(s，6H)2.21(s，3H)2.34(dd，J＝12.22，5.63Hz，1H)2.59(dd，J＝12.91，10.16Hz，1H)4.48(d，J＝11.81Hz，1H)4.52(d，J＝12.09Hz，1H)4.81(q，J＝5.77Hz，1H)6.18(br.s.，1H)7.14(t，J＝7.55Hz，1H)7.21-7.27(m，3H)7.28-7.38(m，3H)。LCMS：M+H+：513.2。
The following compounds were also prepared by the foregoing methods.
Example 121: 3- (4-Fluorobenzoylamino) -6, 6-dimethylpyrrolo [3, 4-c ] pyrazole-5 (1H, 4H, 6H) -carboxylic acid (S) -2- (methylamino) -1-phenylethyl ester
To a solution of compound 2(194mg, 0.406mmol) and 1, 8-bis (dimethylamino) naphthalene (34.8mg, 0.4 equiv.) in 2mL1, 2-dichloroethane was added 1-chloroethyl chloroformate (133. mu.L, 3 equiv.) at 0 ℃. The reaction mixture was stirred at reflux for 1 hour and then evaporated to dryness. The residue was dissolved in 1mL of methanol and 1mL of 2N LiOH, stirred under reflux for 1 hour and evaporated again to dryness. The crude product was purified by preparative HPLC and lyophilized to give the title compound (51mg) as a white foam in 28% yield.1H NMR (400MHz, MeOD) d ppm1.62(s, 3H)1.73(s, 3H)2.59(s, 3H)3.05(dd, J ═ 13.22, 3.40Hz, 1H)3.27(dd, J ═ 13.09, 9.57Hz, 1H)4.75-4.83(m, 1H)4.92(m, 1H)5.91(dd, J ═ 9.57, 3.53Hz, 1H)7.22-7.31(m, 2H)7.31-7.38(m, 1H)7.38-7.48(m, 4H)8.01-8.08(m, 2H). Analyzed as (C)24H26N5O3F.0.4HOAc.0.7H2O)C，H，N。
Bioassay, Ki data, cell assay data and in vivo efficacy data
Cloning, expression and purification of recombinant PAK4 kinase domain (PAK4 KD): the cDNA encoding PAK4 was amplified by PCR from an EST clone (#12) (purchased from Research Genetics). In PCR, P33(ACATATG TCC CATGAGCAGT TCCGGGCTGCCCTGCAGCT) and P34(CTCA TGGGTGCTTC AGCAGCTCGGCTGCCGTGGC) were used as 5 'and 3' primers, respectively. The PCR amplified product was cloned into a Topo vector (Invitrogen Inc.) and verified by DNA sequencing. Then, PAK4KD was subcloned into expression plasmids pET28a (+), pET24a (+) or pGST4.5. The recombinant plasmid containing PAK4KD was transformed into BL21(DE3) cells for recombinant protein expression. The production of PAK4KD was induced by adding IPTG to the cells at 27 ℃. Cells were then harvested and lysed for protein purification. Ni-NTA columns (pET28a (+), pET24a (+)) and glutathione column (pGST4.5) were used for purification. The purified protein was then subjected to a thrombin assay to cleave the inherent N-termination tag from the expression plasmid, thus yielding PAK4KD for the Ki assay of the invention. PAK4 kinase domain enzyme assay conditions: by PAK4KD is determined by the ability of the phosphate residue to be catalyzed by nucleoside triphosphates to be transferred to the amino acid side chain (amino acid sequence EVPRRKSLVGTPYWM) of a commercially available polypeptide. Conversion of ATP to ADP is accompanied by a catalytic reaction. PAK4KD catalyzes the process of ADP production from ATP in association with NADH oxidation by the activation of Pyruvate Kinase (PK) and Lactate Dehydrogenase (LDH). Molecular devices SPECTRAMAX 190 in combination with Biomec FX was used at 340nm (e340 ═ 6.22 cm)-1mM-1) Monitoring NADH to NAD by reduction in absorbance+The transformation of (3). A typical reaction solution comprises 2mM phosphoenolpyruvate (phosphoenol pyruvate), 0.35mM NADH, 10mM MgCl21mM DTT, 0.4mM polypeptide (EVPRRKSLVGTPYWM), 0.04mM ATP, 1 unit/mL PK, 1 unit/mL LDH, 0.01% Tween 20 in 50mM HEPES, pH 7.5. The assay was initiated by the addition of 25nM PAK4 KD. The Ki of the PAK kD for each compound of the invention (inhibitor) was calculated based on the fold of the percent inhibition of the inhibitor at different inhibitor concentrations. The polypeptide (amino acid sequence EVPRRKSLVGTPYWM) was purchased from American Peptide Company. NADH, MgCl2HEPES, DTT, ATP and PK/LDH were purchased from Sigma. Tween 20 was purchased from Calbiochem.
A sandwich ELISA method (sandwich ELISA method) was used to measure the activity of PAK4 kinase in whole cells. The level of PAK 4-dependent phosphorylation of GEF-H1b can be determined by monitoring the binding of phosphospecific antibodies (phosphospecific antibodies) to GEF-H1 b. The modified HEK 293 cell line was used in biological assays and has been designed to overexpress GEF-H1b and the Kinase Domain (KD) of PAK 4. KD of PAK4 in this cell line can be induced by tetracycline (Trex system, Invitrogen). This cell line was named TR-293-KDG. To construct the phosphorylation event in GEF-H1, cells were induced to express PAK4KD using doxycycline. Negative control wells were not induced. The effect of the candidate substance is measured by its ability to block the phosphorylation time.
ELISA plates were prepared by the following method: each plate was precoated with a capture antibody (a-HA-labeled mouse monoclonal antibody), blocked with BSA, and washed in 0.1% tween 20 in tris-buffered saline (TBST). TR-293-KDG cells were seeded on tissue culture plates (pre-coated with poly-D-lysine). TR-293-KDG cells were induced to express PAK4KD overnight with doxycycline and then & concurrently treated with candidate substance or diluent for another 3 hours, exposure was continued. Then, cells were lysed with modified RIPA buffer supplemented with protease inhibitors. Fresh whole cell lysates were then spiked into the ELISA plates for 2 hours. Between all subsequent steps, plates were washed 4 times with TBST. The probe antibody (recognizing the phosphorus-specific epitope on GEF-H1 b) was added for 1 hour followed by the enzyme-linked goat α -rabbit secondary antibody for 45 minutes. The enzyme-linked antibody was stained with peroxide. After 30 minutes of induction, absorbance at 405nm for abts (moss inc) was read using a spectrophotometer. EC50 values were calculated by sigmoidal curve fitting using four parameter analysis.
Ki data for PAK4 kinase domain and EC50 data for PAK4 cell assay of the compounds of examples 1-121.
Example # Ki data (nM) EC50(nM)
1 10.1 10.7
2 16.7 9.7
3 42.1 50.0
4 68.0 14.6
5 14.4 271
6 30.9 27.9
7 314 230
8 124 7.4
9 96.4 13.3
10 75 7.2
11 101 15.7
12 95.5 3.27
13 109 3.9
14 356
15 145 16.1
16 118 17.9
Example # Ki data (nM) EC50(nM)
17 259 110
18 23.3 28.3
19 7.87 67.8
20 8.13 80.2
21 24.8 37.6
22 17.4 14.8
23 122 3.90
24 63.7 140
25 78.6 153
26 278 244
27 82.1 79.9
28 73.2 280
29 27.1 419
30 106 2090
31 858 230
32 57.1 162
33 220
34 510 60
35 92.3 216
36 103 315
37 564
38 43.2 113
39 47.5 15.3
40 64.9 152
41 786
42 955
Example # Ki data (nM) EC50(nM)
43 58.1 439
44 800
45 318 21.1
46 33.6 32.1
47 54.2 34.7
48 98.3 36.4
49 193 90.8
50 33.8 335
51 118 20.3
52 354 242
53 210 28.0
54 41 353
55 13.6 148
56 6.9 37.1
57 11.3 16.0
58 96.0
59 448
60 267
61 444
62 308
63 178
64 19.3 4000
65 849
66 556
67 193
68 48.2 34.1
Example # Ki data (nM) EC50(nM)
69 149 226
70 223
71 101 84.1
72 93.8 362
73 354 200
74 475
75 73.1 115
76 468
77 345 167
78 284
79 96 2120
80 756 12
81 240 104
82 434 301
83A 560
83B 36.2 5
84A 70 16
84B 396
85 143 4
86 68.7 18
87 67.3
88 35.6 88
89 156 10
90 251 4
91 286
92 345 103
Example # Ki data (nM) EC50(nM)
93 335 178
94 161 413
95 137 127
96 12.5 59
97 110 1510
98 19.5 1080
99 67.9 423
100 108 178
101 113 4000
102 621
103 512
104 89 9
105 121 4000
106 412
107 260
108 70 1150
109 176
110 81.7
111 Inhibition of 42% at 1. mu.M
112 Inhibition at 1. mu.M 66%
113 Inhibition at 1. mu.M was 65%
114 Inhibition 70% at 1. mu.M
115 20.8 4000
Example # Ki data (nM) EC50(nM)
116 212 50
117 357 8.8
118 226
119 260 52
120 463
121 16.2 124
The compound 3- [ (4-fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester of example 2 has an in vivo tumor growth inhibiting effect on HCT116 human colorectal cancer tumor xenografts in athymic mice. Details are provided below.
Materials and preparation: the HCT116 cell line was obtained from American Type CultureCo (ATCC, Bethesda, Md.). The cells were grown as individual monolayers in McCoy media supplemented with 10% FBS (from Life Technologies, Inc., Bethesda, Md.) and 5% CO maintained at 37 deg.C2Under a humid atmosphere. Tumor cells were harvested near fusion by culture with 0.05% insulin-EDTA and transplanted into athymic mice. The cells were pelleted at 450Xg for 5-10 minutes and the cell pellets were resuspended in serum-free McCoy medium supplemented with 50% matrigel. On day 0, tumor cells (1 × 106 cells/animal) were transplanted into the hind flank region of each mouse and grown to the indicated size before administration of the compounds of each experiment.
Inhibiting tumor growth: when the tumor reaches about 200mm3At size (d), treatment is initiated. The compound or vehicle of example 2 (methylcellulose, MC) was administered in oral gavage 10mL/kg daily or every other day. Tumors were measured using a Vernier caliper and the formula length x width2X 0.4 to calculate the tumor volume. Tumor volumes were measured on selected days and the median tumor volume for each group of 12 animals was expressed as median ± SEM. Grinding machineAt the end of the study (day 39), the highest percentage of tumor growth inhibition was calculated as 100 x (tumor volume final-tumor volume initial) for each group treated with example 2 and was settled as 100 x (tumor volume initial) for the vehicle groupFinally, the product is processedTumor volumeInitial) And when the median tumor volume reached 1250mm3Tumor growth delay was calculated as: median tumor volumeMedicine for curing diabetes Therapeutic groupMedian tumor volumeControl group。
And (3) tumor growth delaying: when the tumor reached-200 mm on day 113Treatment with the compound of example 2 was started and continued for 28 days until tumors of the control group reached the evaluation size (1250 mm)3). To assess the retardation of tumor growth, tumor measurements were continued until tumors in the treated group reached the assessment size (1250 mm)3). The compound of example 2 was administered to tumor-bearing mice as a 10mL/kg volume solution of MC by oral gavage and compared to vehicle alone at the same volume. Oral administration of the compound of example 2 at 50 mg/kg/day or 75 mg/kg/alternate day, statistically had 50% or 37% significant tumor growth inhibition (p 0.05), respectively, compared to vehicle-treated controls (fig. 1). In addition, a delay in tumor growth of 12.2 days or 9.8 days at a dose level of 50 mg/kg/day or 75 mg/kg/alternate day, respectively, was observed. Mice administered the compound of example 2 throughout the 28 day treatment cycle generally appeared healthy and continued to gain weight.
The tumor growth inhibitory effect and tumor growth retardation results of the compound 3- [ (4-fluorobenzoyl) amino ] -6, 6-dimethyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (1H) -carboxylic acid (1S) -2- (dimethylamino) -1-phenylethyl ester of example 2 are summarized in the following table and fig. 1.
Terminal point Parameter(s) 50mg/Kg QD 75mg/Kg/QOD
Inhibiting Tumor Growth (TGI) ％TGImaxd39 50.0 36.6
Delay tumor growth T-C1250mm3(sky) 12.2 9.8
As can be seen in figure 1, the compound of example 2 inhibited/delayed the growth of HCT116 human colorectal cancer tumor xenografts in athymic mice. When the mean tumor size reached 200mm on day 113The compound of example 2 was orally administered initially at 50 mg/kg/day (QD) or 75 mg/kg/alternate day (QOD) and continued until day 39 to stop treatment. Tumor volumes were measured on selected days, with median tumor volumes for 10 animals per group being median ± SEM. At selected time points, 50&ANOVA p < 0.01 in the 75mg/kg group compared to the vehicle control group.

Claims (14)

1. A compound of the formula III,
wherein:
b is-O-, -NRt-or-CHRt-, wherein RtIs H or C1-C3An alkyl group;
R1is selected from C1-C8Alkyl, - (C)1-C3Alkylene radical)m-phenyl, - (C)3-C5Cycloalkylene-phenyl, - (C)1-C3Alkylene radical)m-(C3-C10Cycloalkyl), - (C)1-C3Alkylene radical)m-(C5-C10Cycloalkenyl), - (C)1-C3Alkylene radical)m- (3-to 10-membered heterocyclic group), - (C)3-C5Cycloalkylene) - (3-10 membered heterocyclic group), - (C1-C3Alkylene radical)m- (5-12 membered heteroaryl) and- (C)3-C5Cycloalkylene) - (5-12 membered heteroaryl), and R1Optionally 1-6 selected from- (C)1-C3Alkylene radical)m-halogen, - (C)1-C3Alkylene radical)m-hydroxy, - (C)1-C3Alkylene radical)m-CN、C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, - (C)1-C3Alkylene radical)m-(C1-C6Alkoxy), - (C)1-C3Alkylene radical)m-NH2、-(C1-C3Alkylene radical)m-(C1-C6Alkylamino-, - (C)1-C3Alkylene radical)m-(C3-C5Cycloalkyl) and- (C)1-C3Alkylene radical)mThe group of (3-to 5-membered heterocyclic group) is further substituted, and said C3-C5Cycloalkyl and said 3-5 membered heterocyclyl are optionally substituted with 1-3 substituents selected from-F, C1-C3Alkyl radical, C1-C3Perfluoroalkyl and oxo are further substituted;
each R2And R3Each independently is C1-C3Alkyl, or R2And R3And R is2And R3The carbon atoms bound together form C3-C4A cycloalkylene group;
R8is- (C)1-C6Alkylene) m-NRpRqWherein each R ispAnd RqEach independently is H, C1-C3Alkyl, or RpAnd RqNitrogen atom to which they are attachedTogether, form a ring selected from 3-7 membered heterocyclyl and 5-7 membered heteroaryl, said ring optionally substituted with 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted;
R9is selected from C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, phenyl group, - (C)1-C3Alkylene) -phenyl, C10-C12Aryl radical, C3-C12Cycloalkyl, - (C)1-C3Alkylene group) - (C3-C12Cycloalkyl), C4-C12Unsaturated non-aromatic carbocyclic group, - (C)1-C3Alkylene group) - (C4-C12Unsaturated non-aromatic carbocyclic group), 3-12 membered heterocyclic group, - (C)1-C3Alkylene) - (3-12 membered heterocyclyl), 5-12 membered heteroaryl and- (C)1-C3Alkylene) - (5-12 membered heteroaryl), and each R9Each independently selected from 1-6 selected from halogen, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, -OH, C1-C6Alkoxy, - (C)1-C6Alkylene group) - (C1-C6Alkoxy) -NH2、-(C1-C6Alkylene) -NH2、-(C1-C6Alkylene group) - (C1-C6Alkylamino), C1-C6The groups of alkylamino and CN are further substituted; and is
Each m is independently 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2Is methyl; r3Is methyl; b is-O-, -NH-or-CH2-；R1Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene) -phenyl, - (cyclopropylene) -phenyl, C3-C10Cycloalkyl, - (C)1-C3Alkylene group) - (C3-C10Cycloalkyl), 3-to 10-membered heterocyclic group, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier,-(C1-C3Alkylene) - (3-to 10-membered heterocyclic group), - (cyclopropylene) - (3-to 10-membered heterocyclic group), 5-to 12-membered heteroaryl, - (C)1-C3Alkylene) - (5-12 membered heteroaryl) and- (cyclopropylene) - (5-12 membered heteroaryl), and R1Optionally substituted by 1-6 groups selected from F, Cl, hydroxy, CN, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group and- (C)1-C3Alkylene radical)m-(C1-C6Alkoxy) is further substituted.
3. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R8Is- (C)1-C6Alkylene radical)m-NRpRqWherein each R ispAnd RqEach independently is H or C1-C3An alkyl group.
4. A compound or pharmaceutically acceptable salt according to claim 3, wherein R is8Is selected from-CH2-N-(CH3)2、-CH2-NH-CH3and-CH2-NH2。
5. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R8Is- (C)1-C6Alkylene radical)m-NRpRqAnd R ispAnd RqTogether with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl, said 3-7 membered heterocyclyl being optionally substituted with 1-6 substituents selected from halogen, C1-C3Alkyl and C1-C3The group of perfluoroalkyl is further substituted.
6. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R9Is selected from C1-C8Alkyl, phenyl, - (C)1-C3Alkylene) -phenyl, 5-6 membered heteroaryl and 3-7 membered cycloalkyl, and each R9Each independently of the otherOptionally 1-6 selected from F, Cl, C1-C6Alkyl radical, C1-C6Perfluoroalkyl group, -OH, C1-C6Alkoxy, - (C)1-C6Alkylene radical)m-(C1-C6Alkoxy) and CN.
7. A compound selected from the group consisting of,
or a pharmaceutically acceptable salt thereof.
8. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. A compound which is a mixture of a compound having a structure represented by formula (I),
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.
12. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a therapeutic agent for treating abnormal cell growth in a mammal.
13. A method of inhibiting a PAK4 protein kinase, the method comprising: contacting the PAK4 kinase with a compound of claim 1 or a pharmaceutically acceptable salt thereof, for non-therapeutic purposes.
14. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a therapeutic agent for inhibiting PAK4 protein kinase.
HK09106049.9A 2005-12-21 2006-12-12 Carbonylamino pyrrolopyrazoles, potent kinase inhibitors HK1128290B (en)

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