WO2022089444A1 - 一种含氮杂环化合物及其应用 - Google Patents
一种含氮杂环化合物及其应用 Download PDFInfo
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- WO2022089444A1 WO2022089444A1 PCT/CN2021/126482 CN2021126482W WO2022089444A1 WO 2022089444 A1 WO2022089444 A1 WO 2022089444A1 CN 2021126482 W CN2021126482 W CN 2021126482W WO 2022089444 A1 WO2022089444 A1 WO 2022089444A1
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- heteroatoms
- membered
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- alkyl
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Definitions
- R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, the heteroatom is N, monocyclic or bicyclic 5-membered to 8-membered heterocycloalkyl" or “substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic or bicyclic 5- to 8-membered Heterocycloalkyl";
- R 5 is independently hydroxyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;
- R 6 is independently C 1 -C 6 alkyl
- X is CH
- R 3 is hydrogen or -CN.
- n 0;
- R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl" or “substituted by 1, 2 or 3 R6, The number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl";
- X is CH
- R 6 is independently C 1 -C 6 alkyl
- R 3 is hydrogen or CN.
- the ring A when the ring A is "5-membered or 6-membered cycloalkenyl", the ring A can be
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the halogen can be fluorine, chlorine, bromine or iodine, or is fluorine.
- the C 3 -C 6 cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, It can also be cyclobutane, cyclopentane or cyclohexane.
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group or a methyl group.
- ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl also methyl or ethyl.
- the C 3 -C 6 cycloalkyl may be Cyclopropane, cyclobutane, cyclopentane or cyclohexane can be cyclobutane, cyclopentane or cyclohexane.
- bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms, and the heteroatom is N said “the number of heteroatoms is 1 or 2
- bicyclic 5- to 8-membered heterocycloalkyl with a heteroatom of N can be 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or can be
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the R when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5-membered to 8-membered
- the monocyclic 5- to 8-membered heterocycloalkyl can be pyrrolidinyl or piperidinyl , can also be
- a bicyclic 5- to 8-membered heteroatom cycloalkyl when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, and the heteroatom is N, a bicyclic 5- to 8-membered heteroatom cycloalkyl", the "bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and the heteroatom is N" may be 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or
- said halogen when said R7 is independently halogen, said halogen can be fluorine, chlorine, bromine or iodine, and can also be bromine.
- the nitrogen-containing heterocyclic compound shown in formula I can be any of the following compounds:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising substance X and pharmaceutical excipients
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof.
- the substance X may be a therapeutically effective amount of the substance X.
- the present invention also provides the application of a substance X in preparing a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof.
- the present invention also provides the application of a substance X in preparing a medicine for treating and/or preventing diseases related to CDK7 kinase;
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof.
- said "disease associated with CDK7 kinase” may be a proliferative disease.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides the application of a substance X in the preparation of a medicine for treating and/or preventing proliferative diseases
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof.
- the present invention also provides a nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof;
- R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1, 2 or 3 R 1-1 ", "the number of heteroatoms is 1 or 2" , the heteroatom is selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl” or “substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl";
- R 1-1 is independently halogen, hydroxyl, NHR 1-1-1 , cyano or C 1 -C 6 alkyl; R 1-1-1 is independently C 1 -C 6 alkyl;
- R 1-2 is independently halogen, hydroxyl, NHR 1-2-1 , cyano or C 1 -C 6 alkyl;
- R 1-2-1 is independently C 1 -C 6 alkyl;
- R 2 is hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;
- X is N or CH
- R 1 is "C 4 -C 6 cycloalkyl substituted with 1 , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2" 5-membered or 6-membered heterocycloalkyl group with heteroatoms selected from one or more of N, O and S" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, the heteroatoms are selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl".
- R 1 is "a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or "are A 5- or 6-membered heterocycloalkyl group substituted with 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.
- R 1-2 is independently hydroxy or C 1 -C 6 alkyl.
- R 2 is chlorine or C 1 -C 3 alkyl substituted with 1-3 fluorine atoms.
- R 3 is
- R4 is hydrogen, halogen or cyano.
- R4 is cyano or hydrogen.
- R 1-2 is independently hydroxyl or C 1 -C 6 alkyl
- X is CH
- R 4 is hydrogen, halogen or cyano.
- R 1 is "a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or “are 1 or 2 R 1-2 substituted, the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.
- 5-membered or 6-membered heterocycloalkyl is “a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or “are 1 or 2 R 1-2 substituted, the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.
- R 2 is chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms
- X is CH
- the C 4 -C 6 cycloalkane is The radical can be cyclobutane, cyclopentane or cyclohexane.
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or may is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the heteroatoms are selected from 5-membered or 6-membered heterocycloalkyl group of one or more of N, O and S.
- the heteroatom number is 1 or 2
- the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl
- the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S. or more 5-membered or 6-membered heterocycloalkyl”, the “heteroatoms are 1 or 2, and the heteroatoms are selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl" can be pyrrolidinyl or piperidinyl, or can be
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group or a methyl group , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the R 1 when the R 1 is "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S. or multiple 5-membered or 6-membered heterocycloalkyl", the "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S 5- or 6-membered heterocycloalkyl" can be
- the C 1 -C 3 alkyl group can be methyl, ethyl, n- propyl or isopropyl.
- the C 1 -C 3 alkyl group substituted with 1-3 fluorine atoms can be trifluoromethyl.
- the nitrogen-containing heterocyclic compound shown in formula II can be any of the following compounds:
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof.
- the substance Z may be a therapeutically effective amount of the substance Z.
- the present invention also provides the application of a substance Z in the preparation of a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof.
- the present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof.
- said "disease associated with CDK7 kinase” may be a proliferative disease.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing proliferative diseases
- the present invention provides a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;
- Ring A is "5-membered or 6-membered heteroaryl group with 1 to 3 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered cycloalkenyl” or “5-membered or 6-membered heterocycloalkenyl with 1 to 3 heteroatoms selected from one or more of N, O and S";
- n 0, 1 or 2;
- R 1 is independently halogen, C 1 -C 6 alkyl or "C 1 -C 6 alkyl substituted with one or more halogens";
- R is C 3 -C 6 cycloalkyl, "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, and the heteroatom is N , monocyclic or bicyclic 5- to 8-membered heterocycloalkyl "or "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the single 5- to 8-membered cyclic or bicyclic heterocycloalkyl";
- R 5 is independently hydroxyl, C 1 -C 6 alkyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;
- R 6 is independently C 1 -C 6 alkyl
- X is N or CH
- Z is N or CR 7 ;
- R 3 is hydrogen, -CN, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl or amino.
- Ring A is "the number of heteroatoms is 1 to 2, and the heteroatoms are selected from N, O and 5-membered heteroaryl” or "5- or 6-membered cycloalkenyl" of one or more of S.
- n is 0 or 1.
- n is zero.
- R is "monocyclic or bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and N heteroatoms" or "with 1, 2 or 3 heteroatoms"
- R 6 A monocyclic or bicyclic 5- to 8-membered heterocycloalkyl group substituted with R 6 , the number of heteroatoms is 1 or 2, and the heteroatom is N.”
- X is CH.
- R3 is hydrogen or -CN.
- ring A is a "5-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered ring” Alkenyl” or “5-membered heterocyclic alkenyl with one heteroatom selected from one of N, O and S";
- n 0 or 1
- R 1 is independently halogen, C 1 -C 6 alkyl or "C 1 -C 6 alkyl substituted with one or more halogens";
- R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, the heteroatom is N, monocyclic or bicyclic 5-membered to 8-membered heterocycloalkyl" or “substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic or bicyclic 5- to 8-membered Heterocycloalkyl";
- R 5 is independently hydroxyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;
- R 6 is independently C 1 -C 6 alkyl
- X is CH
- Z is CR 7 ;
- n 0;
- R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl" or “substituted by 1, 2 or 3 R6, The number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl";
- X is CH
- R 6 is independently C 1 -C 6 alkyl
- Z is CR 7 ;
- R 3 is hydrogen or CN.
- the ring A when the ring A is "5-membered or 6-membered heteroaryl with 1 to 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S" , the ring A can be Its upper end is connected with N atom.
- the ring A when the ring A is "5-membered or 6-membered cycloalkenyl", the ring A can be
- the halogen can be fluorine, chlorine, bromine or iodine, or is fluorine.
- the C 1 -C 6 alkyl may be C 1 -C 4 Alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and also methyl or ethyl.
- the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.
- the R when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5-membered to 8-membered
- the monocyclic 5- to 8-membered heterocycloalkyl can be pyrrolidinyl or piperidinyl , can also be
- a bicyclic 5- to 8-membered heteroatom cycloalkyl when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, and the heteroatom is N, a bicyclic 5- to 8-membered heteroatom cycloalkyl", the "bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and the heteroatom is N" may be 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or
- said halogen when said R7 is independently halogen, said halogen can be fluorine, chlorine, bromine or iodine, and can also be bromine.
- the C 1 -C 3 alkyl group may be methyl, ethyl, n-propyl or isopropyl.
- the C 1 -C 3 alkoxy may be methoxy, ethoxy, n-propoxy or iso- propoxy.
- the nitrogen-containing heterocyclic compound shown in formula I can be any of the following compounds:
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the present invention also provides the application of a substance X in preparing a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the present invention also provides the application of a substance X in preparing a medicine for treating and/or preventing diseases related to CDK7 kinase;
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- said "disease associated with CDK7 kinase” may be a proliferative disease.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides the application of a substance X in the preparation of a medicine for treating and/or preventing proliferative diseases
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides a method of treating and/or preventing a disease associated with CDK7 kinase, comprising administering to a patient a therapeutically effective amount of Substance X;
- the "disease associated with CDK7 kinase” may be a proliferative disease.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1, 2 or 3 R 1-1 ", "the number of heteroatoms is 1 or 2" , the heteroatom is selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl” or “substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl";
- R 1-2 is independently halogen, hydroxyl, NHR 1-2-1 , cyano or C 1 -C 6 alkyl;
- R 1-2-1 is independently C 1 -C 6 alkyl;
- R 4 is hydrogen, hydroxyl, cyano or halogen
- R 1 is "a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or "are A 5- or 6-membered heterocycloalkyl group substituted with 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.
- R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl.
- R 2 is hydrogen, chlorine, or C 1 -C 3 alkyl substituted with 1-3 fluorine atoms.
- R4 is hydrogen, halogen or cyano.
- R4 is cyano or hydrogen.
- R 3 is
- R 3 is
- R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl;
- X is CH
- the R 1 when the R 1 is "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S. or multiple 5-membered or 6-membered heterocycloalkyl", the "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S 5- or 6-membered heterocycloalkyl" can be
- the C 1 -C 3 alkyl group substituted with 1-3 fluorine atoms can be trifluoromethyl.
- the nitrogen-containing heterocyclic compound shown in formula II can be any of the following compounds:
- the present invention also provides a pharmaceutical composition, which comprises substance Z and pharmaceutical excipients;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the substance Z may be a therapeutically effective amount of the substance Z.
- the present invention also provides the application of a substance Z in the preparation of a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- said "disease associated with CDK7 kinase” may be a proliferative disease.
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing proliferative diseases
- the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease.
- the cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .
- the present invention also provides a method of treating and/or preventing a disease associated with CDK7 kinase, comprising administering to a patient a therapeutically effective amount of Substance Z;
- the present invention also provides a method of treating and/or preventing a proliferative disease comprising administering to a patient a therapeutically effective amount of Substance Z;
- the present invention provides a nitrogen-containing heterocyclic compound of formula III or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclic compound is selected from the group consisting of:
- R 2 is hydrogen or C 1 -C 3 alkyl substituted with 1-3 fluorine atoms.
- R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1 , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2, heteroatoms Atoms selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl" or “substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2 , the heteroatom is selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl";
- the present invention also provides a pharmaceutical composition, which comprises substance Z and pharmaceutical excipients;
- the pharmaceutical composition comprises a therapeutically effective amount of Substance Z.
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula III or formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating and/or preventing a disease associated with CDK7 kinase, comprising administering to a patient a therapeutically effective amount of Substance Z;
- the substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula III or formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- Described organic base can be various organic bases that can form salts conventional in the field, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines. kind.
- the tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine.
- the aniline organic base is preferably N,N-dimethylaniline.
- the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
- the inorganic base can be various inorganic bases that can form salts in the field, preferably alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , one or more of potassium bicarbonate and sodium bicarbonate.
- Said alkali metal hydride is preferably sodium hydride and/or potassium hydride.
- the alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
- the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
- solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
- the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
- “Pharmaceutically acceptable salts” and “solvates” in the term “solvates of pharmaceutically acceptable salts” are as described above, and refer to compounds of the present invention in combination with 1, a relatively non-toxic, pharmaceutically acceptable compound. 2. A substance formed in combination with a stoichiometric or non-stoichiometric solvent. Said “solvates of pharmaceutically acceptable salts” include, but are not limited to, hydrochloric acid monohydrates of the compounds of the present invention.
- crystalline form As used herein, the terms "crystalline form,” “polymorphic form,” and “polymorph” are used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) crystallizes in different crystal packings, which All have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility, etc. Recrystallization solvent, rate of crystallization, storage temperature and other factors may cause one crystalline form to dominate. Polymorphic forms of a compound can be prepared by crystallization under various conditions.
- Isotopes of atoms include atoms with the same atomic number but different mass numbers.
- hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the compounds of the present application also include isotopes thereof, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35Cl , 37Cl , 79Br , 81Br , 127I and 131I .
- the hydrogen includes protium, deuterium, tritium, or a combination thereof.
- the carbon includes12C,13C , or a combination thereof.
- the abundance of various isotopic atoms of an element may be the state in which the element naturally occurs in nature, or may be in a state enriched for a certain isotope.
- prevention refers to a reduced risk of acquiring or developing a disease or disorder.
- terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein.
- a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.
- the reagents and raw materials used in the present invention are all commercially available.
- compound 5b (129 mg) was obtained by one-step reaction from compound 5a (200 mg, 1.13 mmol).
- compound 5 (20 mg) was obtained by one-step reaction from compound 5c (53 mg, 0.08 mmol).
- compound 6a (112 mg) was obtained by one-step reaction from compound 3a (500 mg, 1.25 mmol) and 4b (275 mg, 1.25 mmol).
- compound 6b 43 mg was obtained by one-step reaction from compound 6a (100 mg, 0.25 mmol).
- compound 6 (15 mg) was obtained by one-step reaction from compound 6b (30 mg, 0.08 mmol).
- compound 7b (118 mg) was obtained by one-step reaction from compound 7a (200 mg, 1.14 mmol).
- compound 7c (134 mg) was obtained by one-step reaction starting from compound 7b (85 mg, 0.39 mmol).
- compound 5 (45 mg) was obtained by one-step reaction from compound 5c (70 mg, 0.18 mmol).
- CDK7/CyclinH/MAT1 kinase was purchased from Carna Company.
- Substrate (MBP) and other detection reagents were purchased from Promega.
- Nivo Multilabel Analyzer PerkinElmer.
- Dilute enzyme, substrate (MBP), adenosine triphosphate and inhibitor with the kinase buffer included in the kit Dilute enzyme, substrate (MBP), adenosine triphosphate and inhibitor with the kinase buffer included in the kit.
- the compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, from 50 ⁇ M to 0.65 nM, and the DMSO concentration was 5%, and a double-well experiment was set up.
- the reaction system was placed at 25 degrees for 120 minutes.
- the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).
- Table 1 provides the enzymatic inhibitory activity of the compounds of the present invention on CDK7/CyclinH/MAT1.
- the compounds of the present invention possess potent kinase inhibitory activity.
Abstract
一种含氮杂环化合物或其药学上可接受的盐及其应用,该化合物对CDK7激酶具有较高的抑制作用。
Description
本发明提供了一种含氮杂环化合物及其应用。
属于丝氨酸/苏氨酸激酶家族的细胞周期蛋白依赖性激酶(cyclin dependent kinases,CDKs)与其相对应的细胞周期蛋白(cyclins)结合所形成的二聚体复合物在细胞周期的不同阶段发挥各种关键的调节作用,如细胞的分化,DNA的转录等。研究发现,异常高表达的CDKs发现于各种肿瘤细胞中,因此靶向CDKs被认为可以提供一种高效可行的肿瘤治疗手段。目前已发现的CDKs接近20种,按照功能区分可以将其大致分为两大类:调控细胞周期的CDKs和控制细胞转录的CDKs。其中,与细胞周期相关的主要是CDK1/2/4/6,而与细胞DNA转录相关的有CDK7/8/9/10/12等(Nature Review Drug Discovery,2015(2):130-146)。到目前为止,已有三个靶向CDK4/6的小分子抑制剂被批准在临床上用于治疗各种肿瘤(Future Med Chem.2018,10:1369-1388)。而与DNA转录相关的CDKs虽然仍然处于较前期的开发阶段,但是越来越多的基础研究表明靶向这一类CDKs可能提供一种更有效和更安全的肿瘤治疗手段。
在细胞质中,CDK7作为CDK7/Cyclin H/MAT1异源三聚体形式存在,并被认为作为必须的CDK1/2激活激酶(CDK1/2-activating kinase,CAK)可以磷酸化其保守氨基酸残基而实现其激酶催化活性和细胞周期进程。在细胞核中,CDK7形成RNA聚合酶II通用转录因子复合物的激酶核心,负责RNA聚合酶II碳端区域(C-terminal domain,CTD)的磷酸化,这是基因转录起始的必要步骤。总的来说,CDK7的两大功能,催化CAK和CTD的磷酸化在细胞增殖、细胞周期和DNA转录方面起到关键作用。另外,扰乱RNA聚合酶II CTD的磷酸化将会首先影响短半衰期的蛋白,例如抗凋亡的BCL-2家族蛋白。肿瘤细胞可以通过上调BCL-2家族蛋白逃避正常的促细胞死亡信号而达到存活、增殖的目的。因此,抑制CDK7激酶活性可能会产生抗肿瘤细胞增殖和促肿瘤细胞凋亡的作用。
但是由于与CDKs同族激酶序列和结构的相似性,选择性CDK7抑制剂的研发遭遇了巨大的挑战。到目前为止,还没有选择性CDK7抑制剂被批准在临床上使用,因此有必要继续开发成药性高的选择性抑制剂。本发明报道了一系列高活性,高选择性的CDK7激酶抑制剂,有望在未来的临床上为相关肿瘤病人带来新的治疗手段。
发明内容
本发明所要解决的技术问题是针对现有技术中CDK7激酶抑制剂结构较为单一,为此,本发明提供了一种含氮杂环化合物及其应用。该化合物对CDK7激酶具有较高的抑制作用。
本发明提供了一种如式I所示的含氮杂环化合物或其药学上可接受的盐;
环A为“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂芳基”、“5元或6元环烯基”或“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烯基”;
n为0、1或2;
R
1独立地为卤素、C
1~C
6烷基或“被一个或多个卤素取代的C
1~C
6烷基”;
R为C
3~C
6环烷基、“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;
R
5独立地为羟基、C
1~C
6烷基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基;
R
6独立地为C
1~C
6烷基;
X为N或CH;
Z为N或CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3;
R
3为氢、-CN、卤素、C
1~C
3烷基、C
1~C
3烷氧基、羟基或氨基。
在某一方案中,如式I所示的含氮杂环化合物或其药学上可接受的盐里,某些基团的定义可如下所述,其他基团的定义可如上任一方案所述(以下简称“在某一方案中”):环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”。
在某一方案中,n为0或1。
在某一方案中,n为0。
在某一方案中,R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”。
在某一方案中,R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”。
在某一方案中,R
5独立地为羟基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基。
在某一方案中,X为CH。
在某一方案中,Z为CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3。
在某一方案中,Z为CR
7;R
7为卤素或-P(=O)(CH
3)
2。
在某一方案中,R
3为氢或-CN。
在某一方案中,环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”、“5元或6元环烯基”或“杂原子数为1个,杂原子选自N、O和S中的一种的5元杂环烯基”;
n为0或1;
R
1独立地为卤素、C
1~C
6烷基或“被一个或多个卤素取代的C
1~C
6烷基”;
R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;
R
5独立地为羟基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基;
R
6独立地为C
1~C
6烷基;
X为CH;
Z为CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3;
R
3为氢或-CN。
在某一方案中,环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”;
n为0;
R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双 环的5元到8元杂环烷基”;
X为CH;
R
6独立地为C
1~C
6烷基
Z为CR
7;R
7为卤素或-P(=O)(CH
3)
2;
R
3为氢或CN。
在某一方案中,当所述的R
1独立地为卤素时,所述的卤素可为氟、氯、溴或碘,又可为氯。
在某一方案中,当所述的R
1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可 为甲基或乙基。
在某一方案中,当所述的R
1独立地为“被多个卤素取代的C
1~C
6烷基”时,所述的多个可为2个或3个。
在某一方案中,当所述的R
1独立地为“被一个或多个卤素取代的C
1~C
6烷基”时,所述的卤素可为氟、氯、溴或碘,又可为氟。
在某一方案中,当所述的R
1独立地为“被一个或多个卤素取代的C
1~C
6烷基”时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1独立地为“被多个卤素取代的C
1~C
6烷基”时,所述的“被多个卤素取代的C
1~C
6烷基”可为三氟甲基。
在某一方案中,当所述的R为C
3~C
6环烷基时,所述的C
3~C
6环烷基可为环丙烷、环丁烷、环戊烷或环己烷,又可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
5独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
5-1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”时,所述的C
3~C
6环烷基可为环丙烷、环丁烷、环戊烷或环己烷,又可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R为“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”可为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基,又可为
在某一方案中,当所述的R
6独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”可为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基,又可为
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”时,所述的“被1个、2个或3个 R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”可为
在某一方案中,当所述的R
7独立地为卤素时,所述的卤素可为氟、氯、溴或碘,又可为溴。
在某一方案中,当所述的R
3为卤素时,所述的卤素可为氟、氯、溴或碘,又可为溴或氟。
在某一方案中,当所述的R
3为C
1~C
3烷基时,所述的C
1~C
3烷基可为甲基、乙基、正丙基或异丙基。
在某一方案中,当所述的R
3为C
1~C
3烷氧基时,所述的C
1~C
3烷氧基可为甲氧基、乙氧基、正丙氧基或异丙氧基。
在某一方案中,所述的如式I所示的含氮杂环化合物可为下述任一化合物:
本发明还提供了一种药物组合物,其包含物质X和药用辅料;
所述的物质X为上述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
所述的药物组合物中,所述的物质X可为治疗有效量的物质X。
本发明还提供了一种物质X在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;
所述的物质X为上述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
本发明还提供了一种物质X在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;
所述的物质X为上述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
在所述的应用中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种物质X在制备治疗和/或预防增殖性疾病的药物中的应用;
所述的物质X为上述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
在所述的应用中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种如式II所示的含氮杂环化合物或其药学上可接受的盐;
其中,R
1为C
4~C
6环烷基、“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
1-1独立地为卤素、羟基、NHR
1-1-1、氰基或C
1~C
6烷基;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为卤素、羟基、NHR
1-2-1、氰基或C
1~C
6烷基;R
1-2-1独立地为C
1~C
6烷基;
或者,同碳或相邻碳上的R
1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
或者,同碳或相邻碳上的R
1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
R
2为氢、卤素、C
1~C
3烷基或被1-3个氟原子取代的C
1~C
3烷基;
X为N或CH;
R
4为氢、羟基、氰基或卤素。
在某一方案中,如式II所示的含氮杂环化合物或其药学上可接受的盐里,某些基团的定义可如下所述,其他基团的定义可如上任一方案所述(以下简称“在某一方案中”):R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某一方案中,R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某一方案中,R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基。
在某一方案中,R
1-2独立地为羟基或C
1~C
6烷基。
在某一方案中,R
2为氢、氯或被1-3个氟原子取代的C
1~C
3烷基。
在某一方案中,R
2为氯或被1-3个氟原子取代的C
1~C
3烷基。
在某一方案中,X为CH。
在某一方案中,R
4为氢、卤素或氰基。
在某一方案中,R
4为氰基或氢。
在某一方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”
R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为羟基或C
1~C
6烷基;
R
2为氢、氯或被1-3个氟原子取代的C
1~C
3烷基;
X为CH;
R
4为氢、卤素或氰基。
在某一方案中,R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
2为氯或被1-3个氟原子取代的C
1~C
3烷基;
X为CH;
R
4为氰基或氢。
在某一方案中,当所述的R
1为C
4~C
6环烷基时,所述的C
4~C
6环烷基可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”时,所述的C
4~C
6环烷基可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
1-1-1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R
1为“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R
1-2独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1为“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为
在某一方案中,当所述的R
2为被1-3个氟原子取代的C
1~C
3烷基时,所述的C
1~C
3 烷基可为甲基、乙基、正丙基或异丙基。
在某一方案中,当所述的R
2为被1-3个氟原子取代的C
1~C
3烷基时,所述的被1-3个氟原子取代的C
1~C
3烷基可为三氟甲基。
在某一方案中,所述的如式II所示的含氮杂环化合物可为以下任一化合物:
本发明还提供了一种药物组合物,其包含物质Z和药用辅料;
所述的物质Z为上述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
所述的药物组合物中,所述的物质Z可为治疗有效量的物质Z。
本发明还提供了一种物质Z在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;
所述的物质Z为上述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
本发明还提供了一种物质Z在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;
所述的物质Z为上述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
在所述的应用中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症 可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种物质Z在制备治疗和/或预防增殖性疾病的药物中的应用;
所述的物质Z为上述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
在所述的应用中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明提供了一种如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物;
环A为“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂芳基”、“5元或6元环烯基”或“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烯基”;
n为0、1或2;
R
1独立地为卤素、C
1~C
6烷基或“被一个或多个卤素取代的C
1~C
6烷基”;
R为C
3~C
6环烷基、“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;
R
5独立地为羟基、C
1~C
6烷基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基;
R
6独立地为C
1~C
6烷基;
X为N或CH;
Z为N或CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3;
R
3为氢、-CN、卤素、C
1~C
3烷基、C
1~C
3烷氧基、羟基或氨基。
在某一方案中,如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物里,某些基团的定义可如下所述,其他基团的定义可如上任一方案所述(以下简称“在某一方案中”):环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”。
在某一方案中,n为0或1。
在某一方案中,n为0。
在某一方案中,R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”。
在某一方案中,R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”。
在某一方案中,R
5独立地为羟基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基。
在某一方案中,X为CH。
在某一方案中,Z为CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3。
在某一方案中,Z为CR
7;R
7为卤素或-P(=O)(CH
3)
2。
在某一方案中,R
3为氢或-CN。
在某一方案中,环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”、“5元或6元环烯基”或“杂原子数为1个,杂原子选自N、O和S中的一种的5元杂环烯基”;
n为0或1;
R
1独立地为卤素、C
1~C
6烷基或“被一个或多个卤素取代的C
1~C
6烷基”;
R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;
R
5独立地为羟基或“R
5-1-NH-”;R
5-1独立地为C
1~C
6烷基;
R
6独立地为C
1~C
6烷基;
X为CH;
Z为CR
7;R
7为卤素、-P(=O)(CH
3)
2或-S(=O)
2-CH
3;
R
3为氢或-CN。
在某一方案中,环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”;
n为0;
R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;
X为CH;
R
6独立地为C
1~C
6烷基
Z为CR
7;R
7为卤素或-P(=O)(CH
3)
2;
R
3为氢或CN。
在某一方案中,当所述的R
1独立地为卤素时,所述的卤素可为氟、氯、溴或碘,又可为氯。
在某一方案中,当所述的R
1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1独立地为“被多个卤素取代的C
1~C
6烷基”时,所述的多个可为2个或3个。
在某一方案中,当所述的R
1独立地为“被一个或多个卤素取代的C
1~C
6烷基”时,所述的卤素可为氟、氯、溴或碘,又可为氟。
在某一方案中,当所述的R
1独立地为“被一个或多个卤素取代的C
1~C
6烷基”时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1独立地为“被多个卤素取代的C
1~C
6烷基”时,所述的“被多个卤素取代的C
1~C
6烷基”可为三氟甲基。
在某一方案中,当所述的R为C
3~C
6环烷基时,所述的C
3~C
6环烷基可为环丙烷、环丁烷、环戊烷或环己烷,又可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
5独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
5-1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R为“被1个、2个或3个R
5取代的C
3~C
6环烷基”时,所述的C
3~C
6环烷基可为环丙烷、环丁烷、环戊烷或环己烷,又可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R为“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”可为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基,又可为
在某一方案中,当所述的R
6独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或 2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”可为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基,又可为
在某一方案中,当所述的R为“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”时,所述的“被1个、2个或3个R
6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”可为
在某一方案中,当所述的R
7独立地为卤素时,所述的卤素可为氟、氯、溴或碘,又可为溴。
在某一方案中,当所述的R
3为卤素时,所述的卤素可为氟、氯、溴或碘,又可为溴或氟。
在某一方案中,当所述的R
3为C
1~C
3烷基时,所述的C
1~C
3烷基可为甲基、乙基、正丙基或异丙基。
在某一方案中,当所述的R
3为C
1~C
3烷氧基时,所述的C
1~C
3烷氧基可为甲氧基、乙氧基、正丙氧基或异丙氧基。
在某一方案中,所述的如式I所示的含氮杂环化合物可为下述任一化合物:
本发明还提供了一种药物组合物,其包含物质X和药用辅料;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
所述的药物组合物中,所述的物质X可为治疗有效量的物质X。
本发明还提供了一种物质X在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
本发明还提供了一种物质X在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种物质X在制备治疗和/或预防增殖性疾病的药物中的应用;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾 病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防与CDK7激酶相关疾病的方法,其包括向患者施用治疗有效量的物质X;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防增殖性疾病的方法,其包括向患者施用治疗有效量的物质X;
所述的物质X为上述的如式I所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物;
其中,R
1为C
4~C
6环烷基、“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
1-1独立地为卤素、羟基、NHR
1-1-1、氰基或C
1~C
6烷基;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为卤素、羟基、NHR
1-2-1、氰基或C
1~C
6烷基;R
1-2-1独立地为C
1~C
6烷基;
或者,同碳或相邻碳上的R
1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
或者,同碳或相邻碳上的R
1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
R
2为氢、卤素、C
1~C
3烷基或被1-3个氟原子取代的C
1~C
3烷基;
X为N或CH;
R
4为氢、羟基、氰基或卤素;
在某一方案中,如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物里,某些基团的定义可如下所述,其他基团的定义可如上任一方案所述(以下简称“在某一方案中”):R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某一方案中,R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某一方案中,R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基。
在某一方案中,R
1-2独立地为羟基或C
1~C
6烷基。
在某一方案中,R
2为氢、氯或被1-3个氟原子取代的C
1~C
3烷基。
在某一方案中,R
2为氯或被1-3个氟原子取代的C
1~C
3烷基。
在某一方案中,X为CH。
在某一方案中,R
4为氢、卤素或氰基。
在某一方案中,R
4为氰基或氢。
在某一方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”
R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为羟基或C
1~C
6烷基;
R
2为氢、氯或被1-3个氟原子取代的C
1~C
3烷基;
X为CH;
R
4为氢、卤素或氰基;
在某一方案中,R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
2为氯或被1-3个氟原子取代的C
1~C
3烷基;
X为CH;
R
4为氰基或氢;
在某一方案中,当所述的R
1为C
4~C
6环烷基时,所述的C
4~C
6环烷基可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”时,所述的C
4~C
6环烷基可为环丁烷、环戊烷或环己烷。
在某一方案中,当所述的R
1-1-1独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R
1为“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为吡咯烷基或哌啶基,又可为
在某一方案中,当所述的R
1-2独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为C
1~C
4烷基,又可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,还可为甲基或乙基。
在某一方案中,当所述的R
1为“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”可为
在某一方案中,当所述的R
2为被1-3个氟原子取代的C
1~C
3烷基时,所述的C
1~C
3烷基可为甲基、乙基、正丙基或异丙基。
在某一方案中,当所述的R
2为被1-3个氟原子取代的C
1~C
3烷基时,所述的被1-3个氟原子取代的C
1~C
3烷基可为三氟甲基。
在某一方案中,所述的如式II所示的含氮杂环化合物可为以下任一化合物:
本发明还提供了一种药物组合物,其包含物质Z和药用辅料;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
所述的药物组合物中,所述的物质Z可为治疗有效量的物质Z。
本发明还提供了一种物质Z在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
本发明还提供了一种物质Z在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症 可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种物质Z在制备治疗和/或预防增殖性疾病的药物中的应用;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防与CDK7激酶相关疾病的方法,其包括向患者施用治疗有效量的物质Z;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防增殖性疾病的方法,其包括向患者施用治疗有效量的物质Z;
所述的物质Z为上述的如式II所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明提供了一种如式III所示的含氮杂环化合物或其药学上可接受的盐;
其中,
W,Y和Z各自独立地为N或C(R
2);
R
1为C
4~C
6环烷基、“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
1-1独立地为卤素、羟基、NHR
1-1-1、氰基或C
1~C
6烷基;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为卤素、羟基、NHR
1-2-1、氰基或C
1~C
6烷基;R
1-2-1独立地为C
1~C
6烷基;
或者,同碳或相邻碳上的R
1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
或者,同碳或相邻碳上的R
1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
R
2为氢、卤素、C
1~C
3烷基或被1-3个氟原子取代的C
1~C
3烷基;
R
4为氢、羟基、氰基或卤素。
在某些方案中,本发明提供了一种如式III所示的含氮杂环化合物或其药学上可接受的盐,其中所述含氮杂环化合物选自下组:
在某些方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某些方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某些方案中,R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基。
在某些方案中,R
1-2独立地为羟基或C
1~C
6烷基。
在某些方案中,R
1为被1个、2个或3个R
1-1取代的环戊烷或环己烷,或被1个或2个R
1-2取代的哌啶基。
在某些方案中,R
1为被1个、2个或3个R
1-1取代的环戊烷或环己烷,R
1-1为羟基。
在某些方案中,R
1为被1个或2个R
1-2取代的哌啶基,R
1-2为C
1~C
6烷基。
在某些方案中,R
2为氢、氯或被1-3个氟原子取代的C
1~C
3烷基。
在某些方案中,R
2为氢或被1-3个氟原子取代的C
1~C
3烷基。
在某些方案中,R
2为氢或三氟甲基。
在某些方案中,R
4为氢、卤素或氰基。
在某些方案中,R
4为氰基或氢。
在某些方案中,R
4为氰基。
在某些方案中,所述的如式III所示的含氮杂环化合物可为以下任一化合物:
本发明提供了一种如式IV所示的含氮杂环化合物或其药学上可接受的盐;
其中,
W,Y和Z各自独立地为N或C(R
2);
R
1为C
4~C
6环烷基、“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;
R
1-1独立地为卤素、羟基、NHR
1-1-1、氰基或C
1~C
6烷基;R
1-1-1独立地为C
1~C
6烷基;
R
1-2独立地为卤素、羟基、NHR
1-2-1、氰基或C
1~C
6烷基;R
1-2-1独立地为C
1~C
6烷基;
或者,同碳或相邻碳上的R
1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
或者,同碳或相邻碳上的R
1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;
R
2为氢、卤素、C
1~C
3烷基或被1-3个氟原子取代的C
1~C
3烷基;
R
4为氢、羟基、氰基或卤素。
在某些方案中,本发明提供了一种如式IV所示的含氮杂环化合物或其药学上可接受的盐,其中所述含氮杂环化合物具有下式:
在某些方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某些方案中,R
1为“被1个、2个或3个R
1-1取代的C
4~C
6环烷基”或“被1个或2个R
1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”。
在某些方案中,R
1-1独立地为羟基、NHR
1-1-1;R
1-1-1独立地为C
1~C
6烷基。
在某些方案中,R
1-2独立地为羟基或C
1~C
6烷基。
在某些方案中,R
1为被1个或2个R
1-2取代的哌啶基。
在某些方案中,R
1为被1个或2个R
1-2取代的哌啶基,R
1-2为C
1~C
6烷基。
在某些方案中,R
4为氢、卤素或氰基。
在某些方案中,R
4为氰基或氢。
在某些方案中,R
4为氰基。
在某些方案中,所述的如式IV所示的含氮杂环化合物可为如下:
本发明还提供了一种药物组合物,其包含物质Z和药用辅料;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某些方案中,所述的药物组合物包含治疗有效量的物质Z。
本发明还提供了一种物质Z在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
本发明还提供了一种物质Z在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种物质Z在制备治疗和/或预防增殖性疾病的药物中的应用;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的应用中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防与CDK7激酶相关疾病的方法,其包括向患者施用治疗有效量的物质Z;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的“与CDK7激酶相关疾病”可为增殖性疾病。所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
本发明还提供了一种治疗和/或预防增殖性疾病的方法,其包括向患者施用治疗有效量的物质Z;
所述的物质Z为上述的如式III或式IV所示的含氮杂环化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的方法中,所述的增殖性疾病可为癌症、良性赘生物、血管生成、炎症性疾病或自身免疫性疾病。所述的癌症可为白血病、黑色素瘤、多发性骨髓瘤、乳腺癌、脑癌、肺癌、结直肠癌、肝癌、胰腺癌、***癌、子宫癌、卵巢癌和胃癌中的一种或多种。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C
1~C
6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简 化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
术语“多个”是指2个、3个、4个或5个。
术语“卤素”是指氟、氯、溴或碘。
术语“环烷基”是指仅由碳原子组成的饱和的单环基团,优选具有3-7个环碳原子、更优选3-6个碳原子的饱和的单环基团,例如环丙基、环丁基、环戊基或环己基。
术语“杂环烷基”表示由3至7个碳原子及1~3个杂原子(选自氮、氧和硫中的一种或多种)组成的稳定的4元至11元的饱和的环状基团。除非本说明书中另外特别指明,否则杂环烷基可以为单环或双环的环体系,其可包括螺环、桥环体系。杂环烷基可以经由碳原子或杂原子并通过单键与分子其余部分连接。就本发明的目的而言,杂环烷基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、哌啶基、氮杂环丁烷基、八氢环戊[b]吡咯基、2-氮杂螺[3.3]庚烷或1-氮杂螺[3.3]庚烷和1-氮杂螺[3.4]辛烷基等。
术语“环烯基”是指仅由碳原子组成的不饱和的、非芳香性的单环基团,优选具有3-7个环碳原子的不饱和的、非芳香性的单环基团,例如环戊烯基。
术语“杂环烯基”表示由3至5个碳原子及1~2个杂原子(选自氮、氧和硫中的一种或多种)组成的稳定的5元或6元的不饱和的、非芳香性的环状基团。杂环烯基可以经由碳原子或杂原子并通过单键与分子其余部分连接。就本发明的目的而言,杂环烯基的实例包括但不限于二氢噻吩等。
术语“杂芳基”是指含有杂原子的芳香基团,优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环,例如呋喃基、吡啶基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、异噻唑基、噻二唑基等。
本文提供的化合物可以以多种不同的形式或衍生物存在,所有均包括在本申请的范围内。这些形式或衍生物包括,例如,互变异构体、立体异构体、外消旋混合物、位置异构体、盐、前药、溶剂化形式、不同的晶型或多晶型,和活性代谢物。
本文提供的化合物可包含一个或多个不对称中心,因此可以以多种立体异构体形式存在。因此,本文描述的化合物还意在包括所述化合物的所有异构(例如,对映异构、非对映异构和几何异构)形式,例如包括针对每个不对称中心的R和S构型、Z和E双键异构体及Z和E构象异构体。因此,本申请还涵盖作为基本上不含其他异构体的单独的异构体的化合物,或者作为各种异构体的混合物(例如对映异构体的外消旋混合物)的化合物。
在一些实施方案中,当优选一种特定的对映异构体时,本申请的化合物可以提供为 基本上不含相反的对映异构体,并可称为“光学富集的”。本文所述的“光学富集的”意指化合物由明显更大比例的一种对映异构体组成。在一些实施方案中,化合物由至少约90重量%的优选对映异构体组成。在一些实施方案中,化合物由至少约95重量%,98重量%或99重量%的优选对映异构体组成。优选对映异构体可通过本领域已知的任意方法从外消旋混合物中分离,包括手性高压液相色谱(HPLC)、手性盐的形成和结晶,或不对称合成法。参见,例如,Jacques等人,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Wilen,S.H.等人,Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)。
本申请的化合物也包括前药、活性代谢衍生物(活性代谢物)、活性中间体,及其药学上可接受的盐。
本文所用的术语“前药”是指化合物或其药学上可接受的盐,当其在生理条件下代谢时或当其通过溶剂分解而转化时,其生成所需的活性化合物。前药包括但不限于活性化合物的酯、酰胺、氨基甲酸酯、碳酸酯、酰脲、溶剂化物或水合物。通常,前药为无活性的,或者比活性化合物的活性更低,但可提供一种或多种有利的处理、施用,和/或代谢性质。例如,一些前药为活性化合物的酯,在代谢过程中,酯基裂解而产生活性药物。而且,一些前药被酶活化而产生活性化合物,或产生在进一步化学反应时会生成活性化合物的化合物。前药可在单个步骤中由前药形式转变为活性形式,或者可具有一种或多种中间体形式,所述中间体形式本身可具有活性或不具有活性。前药的制备和使用在T.Higuchi和V.Stella,“Pro-drugs as Novel Delivery Systems”,Vol.14 of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design,Edward B.Roche编辑,American Pharmaceutical Association and Pergamon Press,1987中描述。
本文所用的术语“代谢物”,例如活性代谢物,是指药理学活性的化合物或者进一步代谢为药理学活性的化合物(其为获自受试者体内的代谢过程的衍生物)的化合物。例如,这种代谢物可获自所施用化合物或盐或前药的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯化、酶解等。其中,活性代谢物为这种药理学活性的衍生物化合物。对于前药,前药化合物通常为无活性的或者具有比代谢产物更低的活性。对于活性代谢物,母体化合物可为活性化合物或可为无活性的前药。
可使用本领域的常规技术鉴定前药和活性代谢物。参见例如Bertolini等人,1997,J Med Chem 40:2011-2016;Shan等人,J Pharm Sci 86:756-757;Bagshawe,1995,DrugDev Res 34:220-230。
本文所用的术语“活性中间体”是指在合成过程中的中间体化合物,其显示出与最终合成的化合物相同或基本上相同的生物活性。
本申请的化合物可配制为药学上可接受的盐或者是药学上可接受的盐的形式。除非相反指出,否则本文提供的化合物包括该化合物的药学上可接受的盐。
本文所用的术语“药学上可接受的”是指适用于接触人类或动物的组织而不会产生过度的毒性、刺激、过敏反应、其他问题或并发症,具有合理的效益/风险比的化合物、材料、组合物和/或剂型。在一些实施方案中,药学上可接受的化合物、材料、组合物和/或剂型是指由监管机构(如美国食品和药物管理局、中国国家药品监督管理局、欧洲药品管理局)批准的或列在公认药典(如美国药典、中国药典、欧洲药典)中的用于动物,特别是人类的那些化合物、材料、组合物和/或剂型。
本文所用的术语“药学上可接受的盐”表示由适宜的非毒性有机酸、无机酸、有机碱或无机碱与如式I或II所示的含氮杂环化合物形成的盐,其保留如式I或II所示的含氮杂环化合物的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸,优选甲磺酸、三氟甲磺酸、苯甲磺酸、对甲苯磺酸、马来酸、富马酸、琥珀酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、苯乙酸、羟乙基磺酸、1-萘磺酸、2-萘磺酸、扁桃酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸,优选盐酸、氢溴酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱,优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱,优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。
还应理解本申请的化合物可以以非溶剂化形式、溶剂化形式(例如水合形式)和固体形式(例如晶体或多晶型形式)存在,本申请旨在涵盖所有这些形式。
本文所用的术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述,是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
本文所用的术语“晶型”、“多晶型形式”和“多晶型”可相互交换使用,并意指化合物(或其盐或溶剂化物)以不同的晶体堆积方式结晶的晶体结构,其均具有相同的元素组成。不同的晶型通常具有不同的X射线衍射图谱、红外谱、熔点、密度、硬度、晶体形状、光学和电学性质、稳定性和溶解度等。重结晶溶剂、结晶速率、储存温度和其他因素可能导致一种晶型占优。化合物的多晶型可通过在不同条件下结晶而制得。
本申请还旨在包括化合物中原子的所有同位素。原子的同位素包括具有相同原子序数但不同质量数的原子。例如,除非另外指出,本申请的化合物中的氢、碳、氮、氧、磷、硫、氟、氯、溴或碘也包括其同位素,例如但不限于
1H、
2H、
3H、
11C、
12C、
13C、
14C、
14N、
15N、
16O、
17O、
18O、
31P、
32P、
32S、
33S、
34S、
36S、
17F、
19F、
35Cl、
37Cl、
79Br、
81Br、
127I和
131I。在一些实施方案中,氢包括氕、氘、氚或其组合。在一些实施方案中,碳包括
12C、
13C或其组合。在一些实施方案中,某元素的各种同位素原子的丰度可以是该元素在自然界中天然存在的状态,也可以是某种同位素富集的状态。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优,人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等, 以人类为最优。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:初步活性显示本发明化合物对CDK7激酶具有较高的抑制作用。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
第一步
在氮气保护下,将化合物1a(100mg,0.49mmol)和AlCl
3(130mg,0.98mmol)的无水1,2-二氯乙烷(5mL)溶液置于80℃反应30分钟后将化合物1b(115mg,0.59mmol)的1,2-二氯乙烷(1mL)溶液滴加到上述反应液中。所得反应液在80℃反应过夜。反应结束,冷却,用水淬灭(30mL),乙酸乙酯(30mL x 3)萃取,合并有机相,无水硫酸钠干燥,过了,浓缩,得到粗产品用甲醇(2mL)打浆,过滤,得到化合物1c (50mg,28%)。
1H NMR(400HMz,DMSO-d6)δ12.52(s,1H),8.64-8.58(m,2H),8.37(s,1H),7.66(d,J=4.8Hz,1H),7.56(d,J=4.8Hz,1H),7.26(t,J=8Hz,1H)。
第二步
氮气保护下,将化合物1c(50mg,0.14mmol),化合物1d(28mg,0.14mmol)和DIEA(88mg,0.69mmol)的NMP(1mL)溶液加热至150℃并反应3小时。反应结束,冷却至室温,加入水(20mL),乙酸乙酯萃取(20mL x 2),合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,浓缩得到1e粗品(50mg)。
第三步
室温下,向化合物1e(上一步粗品,50mg)的无水DCM(5mL)溶。中滴加TFA(0.5mL)。滴加完毕后继续反应2小时。反应结束,浓缩,粗品经反向制备HPLC得到目标化合物1(5mg,两步收率9%)。
1H NMR(400HMz,CDCl
3)δ8.70(s,1H),8.49(d,J=8.0Hz,1H),8.08(d,J=2.4Hz,1H),7.00-7.85(m,1H),7.40(d,J=7.6Hz,1H),7.20-7.10(m,2H),4.66-4.53(m,2H),3.23-3.18(m,1H),3.02-2.93(m,2H),2.00-1.96(m,1H),1.82-1.79(m,1H),1.39-1.26(m,2H)。
LCMS(M+H)+m/z:428/430
实施例2
第一步
在氮气保护下,将化合物2a(300mg,1.59mmol)和AlCl
3(232mg,1.74mmol)的无水1,2-二氯乙烷(5mL)溶液至于80℃反应30分钟。将化合物1b(312mg,1.59mmol)的1,2-二氯乙烷(1mL)溶液滴加到上述反应液中。所得反应液在80℃反应过夜。反应结束,冷却,用水淬灭(30mL),乙酸乙酯(30mL x 3)萃取,合并有机相,无水硫酸钠干燥,过了,浓缩,得到粗产品用甲醇(2mL)打浆,过滤,得到化合物2b(150mg,27%)。
第二步
氮气保护下,将化合物2b(150mg,0.43mmol),化合物1d(86mg,0.43mmol)和DIEA(277mg,2.15mmol)的NMP(2mL)溶液加热至150℃并反应3小时。反应结束,冷却至室温,加入水(20mL),乙酸乙酯萃取(20mL x 2),合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,浓缩得到2c粗品(150mg)。
第三步
室温下,向化合物2c(上一步粗品,150mg)的无水DCM(5mL)溶。中滴加TFA(0.5mL)。滴加完毕后继续反应2小时。反应结束,浓缩,粗品经反向制备HPLC得到目标化合物2(20mg,两步收率11%)。
1H NMR(400HMz,CDCl
3)δ8.64(d,J=8.0Hz,1H),7.74(d,J=2.4Hz,1H),7.46(d,J=7.6Hz,1H),7.18(t,J=8.0Hz,H),4.68-4.54(m,2H),3.25-3.04(m,1H),3.02-2.90(m,6H),2.17-1.85(m,4H),1.44-1.28(m,2H)。
LCMS(M+H)+m/z:412/414
实施例3
第一步
按照实施例1的合成方法,由化合物3a和化合物1b出发经两步反应得到化合物3b。
第二步
在氮气保护下,将化合物3b(300mg,0.56mmol),K
3PO
4(130mg,0.61mmol),Xantphos(97mg,0.17mmol),Pd2(dba)3(77mg,0.084mmol)和二甲基氧化膦(52mg,0.67mmol)的DMF(2mL)溶液加热至140℃并反应2小时。反应结束,冷却至室温,加入水(20mL)淬灭反应,乙酸乙酯(20mL x 2)萃取,合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,浓缩得粗品经柱层析(MeOH/DCM=0-100%)得到目标化合物3c(190mg,64%)。
第三步
在氮气保护下,将化合物3c(100mg,0.19mmol)和劳森试剂(136mg,0.34mmol)的甲苯溶液加热回流3小时。反应结束,冷却至室温,除去溶剂,经制备硅胶板(石油醚/乙酸乙酯=2/1)得到化合物3d(60mg,53%)。
第四步,
按照实施例1第三步的合成方法,由化合物3d(60mg,0.11mmol)得到化合物3(23mg,47%)。
1H NMR(400HMz,CDCl
3)δ11.54(s,1H),8.61-8.45(m,2H),7.90(s,1H),7.34-7.25(m,2H),6.29(br s,1H),4.35-4.15(m,2H),3.28-3.19(m,1H),3.02-2.85(m,3H),2.13(s,3H),2.10(s,3H),1.95-1.85(m,2H),1.77-1.60(m,2H)。
LCMS(M+H)+m/z:454
实施例4
第一步
在氮气保护下,将化合物4a(300mg,1.39mmol)和AlCl
3(202mg,1.52mmol)的无水1,2-二氯乙烷(5mL)溶液至于80℃反应30分钟。将化合物4b(306mg,1.39mmol)的1,2-二氯乙烷(5mL)溶液滴加到上述反应液中。反应液在80℃反应过夜。反应结束,冷却,用水淬灭(30mL),乙酸乙酯(30mL x 3)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,得到粗产品用甲醇(5mL)打浆,过滤,得到化合物4c(150mg)。
第二步
在氮气保护下,将化合物4c(100mg,0.19mmol),K
3PO
4(43mg,0.20mmol),Xantphos(32mg,0.06mmol),Pd
2(dba)
3(26mg,0.028mmol)和二甲基氧化膦(18mg,0.22mmol)的DMF(2mL)溶液加热至140℃并反应2小时。反应结束,冷却至室温,加入水(20mL)淬灭反应,乙酸乙酯(20mL x 2)萃取,合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,浓缩得粗品经柱层析(MeOH/DCM=0-100%)得到目标化合物4d(63mg)。
第三步
氮气保护下,将化合物4d(50mg,0.13mmol),化合物4e(17mg,0.13mmol) 和DIEA(84mg,0.65mmol)的NMP(2mL)溶液加热至150℃并反应3小时。反应结束,冷却至室温,加入水(20mL),乙酸乙酯萃取(20mL x 2),合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,经柱层析(MeOH/DCM=0-100%)得到目标化合物4(30mg)。
1H NMR(400HMz,CDCl
3)δ8.86-8.73(m,2H),8.53-8.28(m,2H),7.79-7.78(m,1H),4.42-4.21(m,1H),3.42-3.24(m,1H),3.10-3.08(s,1H),2.06-2.03(m,7H),1.90-1.82(m,2H),1.75-1.70(m,1H),1.59-1.36(s,6H)。
LCMS(M+H)+m/z:494
实施例5
第一步
按照化合物4d的合成方法,由化合物5a(200mg,1.13mmol)出发经一步反应得到化合物5b(129mg)。
第二步
在氮气保护下,将化合物5b(100mg,0.46mmol),K
2CO
3(126mg,0.91mmol),Xantphos(58mg,0.10mmol),Pd
2(dba)
3(45mg,0.05mmol)和3a(99mg,0.46mmol)的DMF(5mL)溶液加热至140℃并反应2小时。反应结束,冷却至室温,加入水(20mL)淬灭反应,乙酸乙酯(20mL x 2)萃取,合并有机相,依次用水(20mL x 1)和饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,浓缩得粗品经柱层析(MeOH/DCM=0-100%)得到目标化合物5c(74mg)。
第三步
参照化合物4e的合成方法,由化合物5c(53mg,0.08mmol)出发经一步反应得到化合物5(20mg)。
1H NMR(400HMz,CDCl
3)δ8.86-8.73(m,2H),8.53-8.28(m,2H),7.79-7.78(m,1H),4.42-4.21(m,1H),3.42-3.24(m,1H),3.10-3.08(s,1H),2.06-2.03(m,7H),1.90-1.82(m,2H),1.75-1.70(m,1H),1.59-1.36(s,6H)。
LCMS(M+H)+m/z:492
实施例6
第一步
按照化合物4c的合成方法,由化合物3a(500mg,1.25mmol)和4b(275mg,1.25mmol)出发经一步反应得到化合物6a(112mg)。
第二步
按照化合物4d的合成方法,由化合物6a(100mg,0.25mmol)出发经一步反应得到化合物6b(43mg)。
第三步
参照化合物4e的合成方法,由化合物6b(30mg,0.08mmol)出发经一步反应得到化合物6(15mg)。
1H NMR(400HMz,CDCl
3)δ11.89(s,1H),8.57(s,2H),8.04(s,1H),7.59-7.56(m,1H),5.52-5.51(m,1H),3.91-3.89(m,1H),3.59-3.48(m,2H),3.64-3.46(m,1H),2.13-2.01(m,8H),1.81-1.78(m,2H),1.37-1.32(m,4H)。
LCMS(M+H)+m/z:478
实施例7
第一步
按照化合物4d的合成方法,由化合物7a(200mg,1.14mmol)出发经一步反应得到化合物7b(118mg)。
第二步
按照化合物5c的合成方法,由化合物7b(85mg,0.39mmol)出发经一步反应得到化合物7c(134mg)。
第三步
参照化合物4的合成方法,由化合物5c(70mg,0.18mmol)出发经一步反应得到化合物5(45mg)。
1H NMR(400HMz,CDCl
3)δ8.86-8.73(m,2H),8.34-8.23(m,2H),7.83-7.75(m,1H),7.51-7.42(m,1H),4.34-4.15(m,1H),3.38-3.19(m,1H),3.05-2.97(s,1H),2.16-2.08(m,7H),1.85-1.80(m,2H),1.79-1.72(m,1H),1.55-1.32(s,6H)。
LCMS(M+H)+m/z:491
细胞试验
实验材料:
CDK7/CyclinH/MAT1激酶购自Carna公司。底物(MBP)及其他检测试剂购自Promega公司。Nivo多标记分析仪(PerkinElmer)。
实验方法:
使用试剂盒里的激酶缓冲液稀释酶,底物(MBP),三磷酸腺苷和抑制剂。
将待测化合物用排枪进行5倍稀释至第8个浓度,即从50μM稀释至0.65nM,DMSO浓度为5%,设置双复孔实验。向微孔板中加入1μL抑制剂各浓度梯度,2μl CDK7/CyclinH/MAT1酶(共20ng),2μl底物和ATP的混合物(125uM三磷酸腺苷,0.1μg/μl底物),此时化合物终浓度梯度为10μM稀释至0.13nM。反应体系置于25度反应120分钟。反应结束后,每孔加入5μl ADP-Glo试剂,25度继续反应40分钟,结束反应后每孔加入10μL的激酶检测试剂,25度反应30分钟后采用多标记分析仪读数化学发光,积分时间0.5秒。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。
表1提供了本发明的化合物对CDK7/CyclinH/MAT1酶学抑制活性。
实施例 | IC 50(nM) |
化合物1 | 232 |
化合物2 | 2327 |
化合物3 | 3.6 |
化合物4 | 29.18 |
化合物5 | 4.8 |
化合物6 | 2189 |
化合物7 | 7.1 |
本发明的化合物具有强效的激酶抑制活性。
Claims (45)
- 一种如式I所示的含氮杂环化合物或其药学上可接受的盐,其特征在于:环A为“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂芳基”、“5元或6元环烯基”或“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烯基”;n为0、1或2;R 1独立地为卤素、C 1~C 6烷基或“被一个或多个卤素取代的C 1~C 6烷基”;R为C 3~C 6环烷基、“被1个、2个或3个R 5取代的C 3~C 6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;R 5独立地为羟基、C 1~C 6烷基或“R 5-1-NH-”;R 5-1独立地为C 1~C 6烷基;R 6独立地为C 1~C 6烷基;X为N或CH;Z为N或CR 7;R 7为卤素、-P(=O)(CH 3) 2或-S(=O) 2-CH 3;R 3为氢、-CN、卤素、C 1~C 3烷基、C 1~C 3烷氧基、羟基或氨基。
- 如权利要求1所述的如式I所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”;和/或,n为0或1;和/或,R为“被1个、2个或3个R 5取代的C 3~C 6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;和/或,R 5独立地为羟基或“R 5-1-NH-”;R 5-1独立地为C 1~C 6烷基;和/或,X为CH;和/或,Z为CR 7;R 7为卤素、-P(=O)(CH 3) 2或-S(=O) 2-CH 3;和/或,R 3为氢或-CN。
- 如权利要求2所述的如式I所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,n为0;和/或,R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;和/或,Z为CR 7;R 7为卤素或-P(=O)(CH 3) 2。
- 如权利要求1所述的如式I所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,其定义如下任一方案所述:方案1:环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”、“5元或6元环烯基”或“杂原子数为1个,杂原子选自N、O和S中的一种的5元杂环烯基”;n为0或1;R 1独立地为卤素、C 1~C 6烷基或“被一个或多个卤素取代的C 1~C 6烷基”;R为“被1个、2个或3个R 5取代的C 3~C 6环烷基”、“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;R 5独立地为羟基或“R 5-1-NH-”;R 5-1独立地为C 1~C 6烷基;R 6独立地为C 1~C 6烷基;X为CH;Z为CR 7;R 7为卤素、-P(=O)(CH 3) 2或-S(=O) 2-CH 3;R 3为氢或-CN;方案2:环A为“杂原子数为1~2个,杂原子选自N、O和S中的一种或多种的5元杂芳基”或“5元或6元环烯基”;n为0;R为“杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”或“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环或双环的5元到8元杂环烷基”;X为CH;R 6独立地为C 1~C 6烷基Z为CR 7;R 7为卤素或-P(=O)(CH 3) 2;R 3为氢或CN。
- 如权利要求1~4中任一项所述的如式I所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,当所述的环A为“杂原子数为1~3个,杂原子选自N、O和S中的一种或多种的5元或6元杂芳基”时,所述的环A为 其上端与N原子连接;和/或,当所述的R 1独立地为卤素时,所述的卤素为氟、氯、溴或碘;和/或,当所述的R 1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R 1独立地为“被多个卤素取代的C 1~C 6烷基”时,所述的多个为2个或3个;和/或,当所述的R 1独立地为“被一个或多个卤素取代的C 1~C 6烷基”时,所述的卤素为氟、氯、溴或碘;和/或,当所述的R 1独立地为“被一个或多个卤素取代的C 1~C 6烷基”时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙烷、环丁烷、环戊烷或环己烷;和/或,当所述的R 5独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R 5-1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R为“被1个、2个或3个R 5取代的C 3~C 6环烷基”时,所述的C 3~C 6环烷基为环丙烷、环丁烷、环戊烷或环己烷;和/或,当所述的R为“杂原子数为1个或2个,杂原子为N的,单环的5元到8 元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”为吡咯烷基或哌啶基;和/或,当所述的R为“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基;和/或,当所述的R 6独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R为“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的,单环的5元到8元杂环烷基”为吡咯烷基或哌啶基;和/或,当所述的R为“被1个、2个或3个R 6取代的,杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子为N的双环的5元到8元杂环烷基”为1-氮杂螺[3.4]辛烷基或八氢环戊[b]吡咯基;和/或,当所述的R 7独立地为卤素时,所述的卤素为氟、氯、溴或碘;和/或,当所述的R 3为卤素时,所述的卤素为氟、氯、溴或碘;和/或,当所述的R 3为C 1~C 3烷基时,所述的C 1~C 3烷基为甲基、乙基、正丙基或异丙基;和/或,当所述的R 3为C 1~C 3烷氧基时,所述的C 1~C 3烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基。
- 和/或,当所述的R 1独立地为卤素时,所述的卤素为氯;和/或,当所述的R 1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R 1独立地为“被一个或多个卤素取代的C 1~C 6烷基”时,所述的卤 素为氟;和/或,当所述的R 1独立地为“被一个或多个卤素取代的C 1~C 6烷基”时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丁烷、环戊烷或环己烷;和/或,当所述的R 5独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R 5-1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R为“被1个、2个或3个R 5取代的C 3~C 6环烷基”时,所述的C 3~C 6环烷基为环丁烷、环戊烷或环己烷;和/或,当所述的R 6独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R 7独立地为卤素时,所述的卤素为溴;和/或,当所述的R 3为卤素时,所述的卤素为氟或溴。
- 一种药物组合物,其包含物质X和药用辅料;所述的物质X为如权利要求1~9中任一项所述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质X在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;所述的物质X为如权利要求1~9中任一项所述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质X在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;所述的物质X为如权利要求1~9中任一项所述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质X在制备治疗和/或预防增殖性疾病的药物中的应用;所述的物质X为如权利要求1~9中任一项所述的如式I所示的含氮杂环化合物或其药学上可接受的盐。
- 一种如式II所示的含氮杂环化合物或其药学上可接受的盐,其特征在于:其中,R 1为C 4~C 6环烷基、“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;R 1-1独立地为卤素、羟基、NHR 1-1-1、氰基或C 1~C 6烷基;R 1-1-1独立地为C 1~C 6烷基;R 1-2独立地为卤素、羟基、NHR 1-2-1、氰基或C 1~C 6烷基;R 1-2-1独立地为C 1~C 6烷基;或者,同碳或相邻碳上的R 1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;或者,同碳或相邻碳上的R 1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;R 2为氢、卤素、C 1~C 3烷基或被1-3个氟原子取代的C 1~C 3烷基;X为N或CH;R 4为氢、羟基、氰基或卤素。
- 如权利要求14所述的如式II所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;和/或,R 1-1独立地为羟基、NHR 1-1-1;R 1-1-1独立地为C 1~C 6烷基;和/或,R 1-2独立地为羟基或C 1~C 6烷基;和/或,R 2为氢、氯或被1-3个氟原子取代的C 1~C 3烷基;和/或,X为CH;和/或,R 4为氢、卤素或氰基。
- 如权利要求14所述的如式II所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,其定义如下任一方案所述:方案A:R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”R 1-1独立地为羟基、NHR 1-1-1;R 1-1-1独立地为C 1~C 6烷基;R 1-2独立地为羟基或C 1~C 6烷基;R 2为氢、氯或被1-3个氟原子取代的C 1~C 3烷基;X为CH;R 4为氢、卤素或氰基;方案B:R 1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;R 2为氯或被1-3个氟原子取代的C 1~C 3烷基;X为CH;R 4为氰基或氢。
- 如权利要求14~17中任一项所述的如式II所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,当所述的R 1为C 4~C 6环烷基时,所述的C 4~C 6环烷基为环丁烷、环戊烷或环己烷;和/或,当所述的R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”时,所述的C 4~C 6环烷基为环丁烷、环戊烷或环己烷;和/或,当所述的R 1-1-1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R 1为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”为吡咯烷基或哌啶基;和/或,当所述的R 1为“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”为吡咯烷基或哌啶基;和/或,当所述的R 1-2独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为C 1~C 4烷基;和/或,当所述的R 2为被1-3个氟原子取代的C 1~C 3烷基时,所述的C 1~C 3烷基为甲基、乙基、正丙基或异丙基。
- 如权利要求18所述的如式II所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,当所述的R 1-1-1独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R 1为“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”时,所述的“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”为和/或,当所述的R 1-2独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;和/或,当所述的R 2为被1-3个氟原子取代的C 1~C 3烷基时,所述的被1-3个氟原子取代的C 1~C 3烷基为三氟甲基。
- 一种药物组合物,其包含物质Z和药用辅料;所述的物质Z为如权利要求14~22中任一项所述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;所述的物质Z为如权利要求14~22中任一项所述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;所述的物质Z为如权利要求14~22中任一项所述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备治疗和/或预防增殖性疾病的药物中的应用;所述的物质Z为如权利要求14~22中任一项所述的如式II所示的含氮杂环化合物或其药学上可接受的盐。
- 一种如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于:其中,W,Y和Z各自独立地为N或C(R 2);R 1为C 4~C 6环烷基、“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;R 1-1独立地为卤素、羟基、NHR 1-1-1、氰基或C 1~C 6烷基;R 1-1-1独立地为C 1~C 6烷基;R 1-2独立地为卤素、羟基、NHR 1-2-1、氰基或C 1~C 6烷基;R 1-2-1独立地为C 1~C 6烷基;或者,同碳或相邻碳上的R 1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;或者,同碳或相邻碳上的R 1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;R 2为氢、卤素、C 1~C 3烷基或被1-3个氟原子取代的C 1~C 3烷基;R 4为氢、羟基、氰基或卤素。
- 如权利要求27或28所述的如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;和/或,R 1-1独立地为羟基、NHR 1-1-1;R 1-1-1独立地为C 1~C 6烷基;和/或,R 1-2独立地为羟基或C 1~C 6烷基;和/或,R 2为氢、氯或被1-3个氟原子取代的C 1~C 3烷基;和/或,R 4为氢、卤素或氰基。
- 如权利要求27或28所述的如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;和/或,R 2为氢或被1-3个氟原子取代的C 1~C 3烷基;和/或,R 4为氢或氰基。
- 如权利要求27或28所述的如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为被1个、2个或3个R 1-1取代的环戊烷或环己烷,或被1个或2个R 1-2取代的哌啶基。
- 如权利要求31所述的如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1-1为羟基。
- 如权利要求31所述的如式III所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1-2为C 1~C 6烷基。
- 一种如式IV所示的含氮杂环化合物或其药学上可接受的盐,其特征在于:其中,W,Y和Z各自独立地为N或C(R 2);R 1为C 4~C 6环烷基、“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;R 1-1独立地为卤素、羟基、NHR 1-1-1、氰基或C 1~C 6烷基;R 1-1-1独立地为C 1~C 6烷基;R 1-2独立地为卤素、羟基、NHR 1-2-1、氰基或C 1~C 6烷基;R 1-2-1独立地为C 1~C 6烷基;或者,同碳或相邻碳上的R 1-1以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环 烷基”;或者,同碳或相邻碳上的R 1-2以及与其相连接的C原子共同形成3元到6元的碳环或“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3元到6元杂环烷基”;R 2为氢、卤素、C 1~C 3烷基或被1-3个氟原子取代的C 1~C 3烷基;R 4为氢、羟基、氰基或卤素。
- 如权利要求35或36所述的如式IV所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”、“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;和/或,R 1-1独立地为羟基、NHR 1-1-1;R 1-1-1独立地为C 1~C 6烷基;和/或,R 1-2独立地为羟基或C 1~C 6烷基;和/或,R 2为氢、氯或被1-3个氟原子取代的C 1~C 3烷基;和/或,R 4为氢、卤素或氰基。
- 如权利要求37所述的如式IV所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为“被1个、2个或3个R 1-1取代的C 4~C 6环烷基”或“被1个或2个R 1-2取代的,杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5元或6元杂环烷基”;和/或,R 2为氢或被1-3个氟原子取代的C 1~C 3烷基;和/或,R 4为氰基或氢。
- 如权利要求38所述的如式IV所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1为被1个或2个R 1-2取代的哌啶基。
- 如权利要求39所述的如式IV所示的含氮杂环化合物或其药学上可接受的盐,其特征在于,R 1-2为C 1~C 6烷基。
- 一种药物组合物,其包含物质Z和药用辅料;所述的物质Z为如权利要求27~41中任一项所述的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备CDK7激酶抑制剂中的应用,所述的CDK7激酶抑制剂在体外使用;所述的物质Z为如权利要求27~41中任一项所述的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备治疗和/或预防与CDK7激酶相关疾病的药物中的应用;所述的物质Z为如权利要求27~41中任一项所述的含氮杂环化合物或其药学上可接受的盐。
- 一种物质Z在制备治疗和/或预防增殖性疾病的药物中的应用;所述的物质Z为如权利要求27~41中任一项所述的含氮杂环化合物或其药学上可接受的盐。
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