WO2020020377A1 - 用作fgfr4抑制剂的稠环衍生物 - Google Patents
用作fgfr4抑制剂的稠环衍生物 Download PDFInfo
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- WO2020020377A1 WO2020020377A1 PCT/CN2019/098076 CN2019098076W WO2020020377A1 WO 2020020377 A1 WO2020020377 A1 WO 2020020377A1 CN 2019098076 W CN2019098076 W CN 2019098076W WO 2020020377 A1 WO2020020377 A1 WO 2020020377A1
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- membered
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- WQYAJFWNJROGBX-UHFFFAOYSA-N CCC(CCCCN1Cc(cc2CCC3)c(C(OC)OC)nc2N3C(Nc(cc2F)ncc2[IH]N)=O)CC1=O Chemical compound CCC(CCCCN1Cc(cc2CCC3)c(C(OC)OC)nc2N3C(Nc(cc2F)ncc2[IH]N)=O)CC1=O WQYAJFWNJROGBX-UHFFFAOYSA-N 0.000 description 1
- 0 CCSCCNC1=CC(C)=C*C=C1* Chemical compound CCSCCNC1=CC(C)=C*C=C1* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further 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
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention provides a fused ring derivative compound, its use for inhibiting FGFR4, and a method for treating diseases using the compound.
- Fibroblast growth factor receptor belongs to the family of receptor protein tyrosine kinases. Through receptor binding to ligands, it can activate many signaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase C. These pathways Growth, proliferation, and survival all play important roles.
- FGFR4 is a tyrosine kinase receptor in the human body encoded by the gene FGFR4 and is highly conserved in evolution. It needs to bind to its specific ligand FGF19 to function.
- FGFR4 activation and FGF19 overexpression have important effects on the occurrence and development of liver cancer, and inhibition of FGFR4 can effectively reduce the incidence of liver cancer.
- FGFR4 ligand FGF19 and coreceptor KLB are highly expressed in tumors of about one-third of liver cancer patients.
- changes in FGFR4-FGF19 signal axis are also related to the occurrence of colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.
- fibroblast growth factor receptor 4 (FGFR4) inhibitors have great potential for treating liver cancer, and have better specificity and effectiveness than similar drugs.
- Liver cancer is the most common malignant tumor and fatal disease after lung cancer, and China has the largest number of liver cancer patients in the world.
- Sorafenib can only increase the average survival time of patients by 3 months, and because it is a multi-target tyrosine kinase inhibitor, it has strong toxic side effects. Therefore, the development of more effective liver cancer drugs has become an urgent need worldwide, and FGFR4 inhibitors provide a possibility for breakthroughs in this regard.
- FGFR4 inhibitors are a popular research direction in the field of global liver cancer treatment research and a market direction that the world's biopharmaceutical companies are vying for, but due to the limitations of experimental methods, research cycles and other factors, there is currently no FGFR4 inhibitor drug. Go to market. China, as the country with the highest incidence of liver cancer and the largest number of liver cancer patients in the world, a breakthrough in this direction will have strong clinical application significance. At present, no similar drugs have entered clinical research in China, and they are all in the early stage of clinical research internationally. Therefore, breakthroughs in this direction will also greatly enhance the international competitiveness of China's new drug research and development.
- the present invention relates to fused ring compounds for use as FGFR4 inhibitors for the treatment of diseases mediated by FGFR4.
- the present invention first provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof:
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0, 1, 2 or 3;
- R X1 and R X2 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -C 1-6 alkyl; substituted with 1, 2 or 3 substituents C 1-6 alkyl; C 1-6 alkoxy or substituted with 1,2 or 3 substituents of C 1-6 alkoxy; each of the substituents at each occurrence is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or -C 1-3 alkoxy;
- Y is independently selected at each occurrence from O or S;
- R 2 and R 3 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NH 2 ; -NO 2 ; -N 3 ; -C 1-6 alkyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH,- -C 1-6 alkyl substituted by C 1-3 alkyl or C 1-3 alkoxy; C 1-6 alkoxy; substituted by 1, 2 or 3 -D, -F, -Cl, -Br , -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-6 alkoxy; substituted or unsubstituted C 3-8 cycloalky
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2 -or O; m is 0, 1, 2, 3 or 4;
- Each R G1 and R G2 are independently at each occurrence selected from H; D; -C 1-6 alkyl; 2 or 3 substituents of -C 1-6 alkyl; -C 1-6 alkoxy; -C 1-6 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy;
- Q is independently selected at each occurrence from -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 or 4;
- R 4 and R 4 ′ are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; substituted C 1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; is 1 C 3-8 cycloalkyl substituted with 2, 3 or 2 substituents; 3-8 membered heterocyclic group; 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents At each occurrence is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring or a -5-10 membered heteroaromatic ring, each ring system can be independent at each occurrence Optionally substituted with one or more substituents, or unsubstituted;
- R 5 and R 5 ' are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; substituted with -C 1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of -C 1-6 alkoxy; -C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic group; 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said The substituents are each independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy Base; or
- R 5 and R 5 ′ form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring, a 5-10 membered heteroaromatic ring with the carbon atom to which they are commonly connected, each heterocyclic group and each heteroaromatic group
- Each radical independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and each of said ring systems can independently be optionally Multiple substituents substituted or unsubstituted; or
- R 4 and R 5 together with the atoms to which they are connected form a 5-10 membered aromatic ring, a -C 3-10 carbocyclic ring, and a 4-10 membered heterocyclic ring.
- Optionally contains 1 or 2 heteroatoms selected from N, O or S, each of said ring systems being independently optionally substituted with one or more substituents on each occurrence ;
- W is independently selected at each occurrence from- (CR w1 R w2 ) n -S-,-(CR w1 R w2 ) n -SO- or-(CR w1 R w2 ) n -SO 2- , n is selected From 0, 1, 2, 3 or 4;
- R w1 and R w2 are each independently selected from H; D; -F; -Cl; -Br; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1 substituent; methoxy; ethoxy; propoxy; isopropoxy; -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-membered heterocyclyl; 4-membered heterocyclyl; 5-membered heterocyclic A cyclic group; a 6-membered heterocyclic group or a 3-6-membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D,- F, -Cl, -Br, -I, -
- R 6 at each occurrence is independently selected from H; D; -F; -Cl; -Br; -I; -C 1-3 alkyl; -C 1 substituted with 1 , 2 or 3 substituents -3 alkyl; -C 1-3 alkoxy; 2 or 3 substituents of -C 1-3 alkoxy; -C 1-3 alkyl group -COO-C 1-3, -C 3-6 cycloalkyl, or two or three substituents -C 3-6 cycloalkyl; each of said substituents are independently selected from optionally D, halo, -OH, - CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy; or
- Q and R 6 together with the carbon atom and W to which they are respectively connected form a 4-6 membered heterocyclic ring, said heterocyclic ring is optionally optionally substituted with one or more substituents, and said heterocyclic ring is independently optionally containing 1, 2 or 3 heteroatoms selected from N, O or S, each of said substituents optionally selected from group D is independently, halo, -OH, -CN, -NH 2, -NO 2 , -COOH, -C 1-3 alkyl, or -C 1-3 alkoxy; or
- R 4 and R 6 form a 5-8 membered monocyclic heterocyclic group, a 5-10 membered spirocyclic heterocyclic group, a 5-10 membered condensed ring heterocyclic group, a 5-10 membered bridged heterocyclic ring together with the atoms to which they are connected
- Each R 9 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2-4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH-C 1-3 alkane Group, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide group;
- Each R 10 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3-6 cycloalkyl, -C 5-10 aryl, halo C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- Each R 11 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -C 3-6 ring Alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl, C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, substituted Or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or C 1-3 alkanoyl;
- t is independently selected at each occurrence from 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0, 1 or 2;
- R X1 and R X2 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -C 1-3 alkyl; substituted with 1, 2 or 3 substituents C 1-3 alkyl; a C 1-3 alkoxy group or substituted with 1,2 or 3 substituents of a C 1-3 alkoxy group; each of said substituents are independently selected from optionally D, - F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy;
- Y is independently selected at each occurrence from O or S;
- R 7 at each occurrence is independently selected from H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-5 cycloalkyl, or 3-8 membered heterocyclyl
- the heterocyclic group independently optionally comprises 1, 2 or 3 heteroatoms selected from N, O or S
- each R 9 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2 -4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH -C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3 -6 cycloalkyl, -C 5-10 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkane Radical, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are each independently selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 Alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkane Group, substituted or unsubstituted C 5-10 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group or -C 1-3 alkanoyl group;
- t 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0 or 1;
- R X1 and R X2 are each independently selected from H; D; -F; -Cl; -Br; -I; methyl; ethyl; propyl; isopropyl; C 1-3 alkyl substituted with 1 substituent; methoxy; ethoxy; propoxy; isopropoxy or C 1-3 alkoxy substituted with 1, 2 or 3 substituents; said each optionally substituted group independently selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2, -NO 2, -COOH, methyl, ethyl, propyl , Isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
- Y is independently O at each occurrence
- R 8 is independently selected at each occurrence from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 2- 4 -alkenyl, -C 2-4 alkynyl, -C (O) R 11 , -methyl-C (O) R 11 , -ethyl-C (O) R 11 , -propyl-C ( O) R 11 , -isopropyl-C (O) R 11 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, and the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O, or S, and R 8 independently
- R 7 and R 8 form a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 5-membered spirocyclic heterocyclic group, 6 7-membered spirocyclic heterocyclyl, 7-membered spirocyclic heterocyclyl, 8-membered spirocyclic heterocyclyl, 9-membered spirocyclic heterocyclyl, 10-membered spirocyclic heterocyclyl, 5-membered fused ring heterocyclyl, 6-membered fused Cycloheterocyclyl, 7-membered fused ring heterocyclyl, 8-membered fused ring heterocyclyl, 9-membered fused ring heterocyclyl, 10-membered fused ring heterocyclyl, 5-membered bridged heterocyclic ring, 6-membered bridged heterocyclic ring A
- each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1-3 alkoxy , -C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclyl, halogenated C 1-3 alkyl, phenyl , P-methylphenyl, amino, -NH-C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy -C 3-6 cycloalkyl, -C 5-10 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy , Isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, Hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are each independently selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or -C 1-3 alkanoyl;
- t 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -CH (CH 3 )-, -C (CH 3 ) 2- , -CHF-, -CHBr- or -CH (OH)-; and p is 0 or 1;
- Y is independently O at each occurrence
- R 8 is independently selected at each occurrence from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 2- 4 -alkenyl, -C 2-4 alkynyl, -C (O) H, -methyl-C (O) H, -ethyl-C (O) H, -propyl-C (O) H , -Isopropyl-C (O) H, -C (O) -methyl, -methyl-C (O) -methyl, -ethyl-C (O) -methyl, -propyl-C (O) -methyl, -isopropyl-C (O) -methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclic A
- R 1 is selected from:
- R 1 is selected from:
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NH 2 ; -NO 2 ;- N 3 ; -C 1-3 alkyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted -C 1-3 alkyl; -C 1-3 alkoxy; substituted by 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted or Unsubstituted C 3-6 cycloal
- each R 9 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2 -4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH -C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3 -6 cycloalkyl, -C 5-8 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkane Radical, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, or hydroxy substituted C 1-3 alkoxy;
- each of R 12 and R 13 is each independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
- t 0, 1, or 2.
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NO 2 ; -N 3 ; A Ethyl; propyl; isopropyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH , -C 1-3 alkyl or a C 1-3 alkoxy-substituted -C 1-3 alkyl; methoxy; ethoxy; propoxy; isopropoxy; 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted
- each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy , -C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclyl, halogenated C 1-3 alkyl, phenyl , P-methylphenyl, amino, -NH-C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy Cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 5-8 aryl, halo C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy , Isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, Hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- each of R 12 and R 13 is each independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1- 3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 chain Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
- t 0 or 1.
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NO 2 ; -N 3 ; A Ethyl; propyl; isopropyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH , -C 1-3 alkyl or a C 1-3 alkoxy-substituted -C 1-3 alkyl; methoxy; ethoxy; propoxy; isopropoxy; 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted
- R 2 and R 3 are each independently selected from H, D, -F, -Cl, -Br, -I, -OH, -SH, -CN, -NO 2 , -N 3 , a Group, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
- R 2 and R 3 are each independently selected from H, D, -F, or methyl.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2, 3 or 4;
- Each R G1 and R G2 are independently selected from H; D; -C 1-3 alkyl; 2 or 3 substituents of -C 1-3 alkyl; -C 1-3 alkoxy -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, halogen, -OH, -CN, -NH 2 ,- NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2 or 3;
- Each R G1 and R G2 are independently selected from H; D; -C 1-3 alkyl; 2 or 3 substituents of -C 1-3 alkyl; -C 1-3 alkoxy Or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2 or 3;
- Each R G1 and R G2 is independently selected from H; D; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy Ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D , -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , Propoxy, or isopropoxy.
- G is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -NH-, -S-, -SO-, -SO 2- , or O; m is 0, 1, or 2.
- G is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -NH-, -S-, -SO-, -SO 2- , or O; m is 0 or 1.
- G is independently selected at each occurrence from -NH- or O; m is 0 or 1.
- G is independently selected at each occurrence from -NH- or O; m is 1.
- G is independently selected at each occurrence from -NH-; m is 0 or 1.
- G is independently selected at each occurrence from -NH-; m is 1.
- m is 0.
- Q is independently selected at each occurrence from -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ' are independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; C substituted with 1, 2 or 3 substituents C1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; by 1, 2 or 3 C 3-8 cycloalkyl substituted with a substituent; a 3-8 membered heterocyclic group; a 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a -C 3-8 carbocyclic ring, a -3-8-membered heterocyclic ring or a -5-10-membered heteroaromatic ring, each ring system can be independently selected Is substituted or unsubstituted with one or more substituents.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ' are independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; C substituted with 1, 2 or 3 substituents C1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; by 1, 2 or 3 C 3-8 cycloalkyl substituted with a substituent; a 3-8 membered heterocyclic group; a 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring or a -5-10 membered heteroaromatic ring, each ring system can be optionally optionally One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring or a 5-8 membered heteroaromatic ring, each of said heterocyclic rings and each heteroaromatic ring
- the rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atoms to which they are attached form a -C 3-6 carbocyclic ring, a 3-6-membered heterocyclic ring, or a -5-8-membered heteroaromatic ring, each of said heterocyclic rings and each Heteroaryl rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atoms to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring or a 5-8 membered heteroaromatic ring
- the rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, ethy
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; 6-membered carbocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, ethy
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; a 6-membered carbocyclic ring; a 3-membered heterocyclic ring; a 4-membered heterocyclic ring; a 5-membered heterocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, eth
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; a 6-membered carbocyclic ring; a 3-membered heterocyclic ring; a 4-membered heterocyclic ring; a 5-membered heterocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; substituents of -C 1-3 alkyl; -C 1-3 alkoxy; 2 or 3 substituents of -C 1-3 alkoxy; -C 3-6 cycloalkyl, ; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; said each Each substituent is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 5 and R 5 ′ form a C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, and a 5-8 membered heteroaromatic ring with the carbon atom to which they are commonly connected, each heterocyclic ring and each heteroaromatic ring described
- R 4 and R 5 together with the atoms to which they are respectively connected form a 5-10 membered aromatic ring, a -C 3-8 carbocyclic ring, and a 4-8 membered heterocyclic ring, each of said heterocyclic groups optionally optionally comprises 1 or 2 heteroatoms selected from N, O or S, each of said ring systems can be independently optionally substituted with one or more substituents.
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; -C 1- substituted with 1, 2 or 3 substituents 3 alkoxy; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic group; 4 membered heterocyclic Cyclic group; 5-membered heterocyclic group; 6-membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said heterocyclic groups optionally independently contains 1 Or 2 heteroatoms selected from N, O, or S; each of
- R 5 and R 5 ′ form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6 A heterocyclic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 7-membered heteroaromatic ring, or an 8-membered heteroaromatic ring. 2 heteroatoms selected from N, O or S, and each of said ring systems is independently optionally substituted with 1, 2 or 3 substituents; or
- R 4 and R 5 together with the atoms to which they are connected form a 5-membered aromatic ring, a 6-membered aromatic ring, a 7-membered aromatic ring, an 8-membered aromatic ring, a 9-membered aromatic ring, a 10-membered aromatic ring, a 4-membered carbon ring, and a 5-membered ring Carbocycle, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring or 8-membered heterocyclic ring, each of said heterocyclic rings
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; -C 1- substituted with 1, 2 or 3 substituents 3 alkoxy; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic group; 4 membered heterocyclic Cyclic group; 5-membered heterocyclic group; 6-membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said heterocyclic groups optionally independently contains 1 Or 2 heteroatoms selected from N, O, or S; each of
- R 4 and R 5 together with the atoms to which they are attached form benzene, naphthalene, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, piperidine, piperazine, oxopiperazine, oxo Piperidine, tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole, tetrahydrooxazole, tetrahydropyran, tetrahydropyrrole or azapentyl ring, each of said ring systems is optionally optionally 1, 2, or 3 D, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -COOH, -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, prop
- R 6 is independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents -Methyl-COO-methyl; -ethyl-COO-ethyl; -propyl-COO-propyl; -isopropyl-COO-isopropyl; cyclopropyl; cyclobutyl; cyclopentyl Cyclohexyl; -C 3-6 carbocyclyl substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br,- I, -OH, -NH 2 , -
- Q and R 6 together with the carbon atom and W to which they are respectively connected form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a 7-membered heterocyclic ring, which heterocyclic ring is optionally optionally substituted by one or more Group is substituted or unsubstituted, the heterocyclic ring optionally optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the substituents is optionally optionally selected from D,- F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy; or R 4 and R 6 Forms a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, an 8-membere
- the compound is selected from:
- the compound is selected from:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of the general formula represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides a compound of the general formula represented by Structural Formula I or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition in the preparation of a medicament.
- the medicament is used to treat, prevent or prevent a disease or condition mediated by FGFR4 activity.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- the present invention also provides a method for treating, preventing or preventing a disease or condition mediated by FGFR4 activity, which comprises administering to a patient an effective dose of a compound represented by Formula I or a pharmaceutically acceptable salt thereof. , Or the pharmaceutical composition.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- the present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for treating, preventing or preventing a disease or condition mediated by FGFR4 activity.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- halogen means fluorine, chlorine, bromine or iodine.
- Preferred halogen radicals are fluorine, chlorine and bromine.
- haloC 1-6 alkyl halo C 2-6 alkenyl
- halo C 2-6 alkynyl halo C 1-6 alkoxy
- fluorinated C 1-6 alkyl, fluorinated C 2-6 alkenyl, fluorinated C 2-6 alkynyl, and fluorinated C 1-6 alkoxy especially fluorinated C 1 -3 alkyl, such as -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 ; fluorinated C 1-3 alkoxy, such as- OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CH 2 F, -OCH 2 CHF 2 or -OCH 2 CF 3 ; especially -CF 3 , -OCF 3 and -OCHF 2 .
- alkyl includes a saturated monovalent hydrocarbon group having a linear, branched, or cyclic moiety.
- alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2 -Methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
- a C 1-8 alkyl group is defined in the present invention as a group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
- the alkylene group refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above.
- methylene i.e. -CH 2-
- ethylene i.e. -CH 2 -CH 2 -or -CH (CH 3 )-
- propylene i.e. -CH 2 -CH 2 -CH 2- , -CH (-CH 2 -CH 3 )-or -CH 2 -CH (CH 3 )-).
- alkoxy refers to a straight-chain or branched-chain alkoxy group containing a specific number of carbon atoms.
- C 1-6 alkoxy means a straight or branched chain alkoxy group containing at least 1 and up to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, Prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, hexyloxy, cyclopentyl Oxy or methylcyclopropoxy and the like.
- alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond
- C 2-8 alkenyl refers to a group containing 2-8 A linear or branched alkenyl group of one carbon.
- alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
- C 2-8 alkynyl means containing 2-8 Carbon straight or branched chain alkynyl.
- ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
- aryl refers to a monocyclic or polycyclic aromatic hydrocarbon by itself or as part of another substituent. Phenyl and naphthyl are preferred aryl. The most preferred aryl is phenyl.
- heterocyclic ring refers to an unsubstituted and substituted monocyclic or polycyclic non-aromatic containing one or more heteroatoms, and some are not Saturated or fully saturated ring systems.
- Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
- the ring is three to eight members and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two or three degrees of substitution.
- heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, azacycloheptyl, tetrahydrofuran Base, dioxolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, oxadioxane An azole, oxazepine, pyridazinyl, indolyl, pyrimidinyl, pyrazinyl, isothiazolyl, diazanaphthyl, or midazinyl.
- Heterocyclyl includes, but is not limited to, monocyclic heterocyclyl and / or polycyclic heterocyclyl.
- Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyranyl, piperazinyl, morpholinyl, thiomorpholinyl, or homopiperazinyl, etc., preferably pyrrolidinyl, tetrahydrofuran Or pyranyl.
- Polycyclic heterocyclyls include, but are not limited to, spiro, fused and bridged heterocyclyls.
- a "spiroheterocyclyl” refers to a polycyclic heterocyclic atom that shares one atom (a spiro atom) between single rings, where one or more ring atoms are selected from nitrogen, oxygen, and S (O) r (where r is an integer 0 , 1, 2), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system.
- Spirocycloalkyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl based on the number of spiro atoms shared between the rings.
- Spirocycloalkyl includes but is not limited to:
- fused heterocyclyl refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of them
- the ring has a completely conjugated ⁇ -electron system, in which one or more ring atoms are selected from nitrogen, oxygen, heteroatoms of S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl.
- the fused heterocyclyl includes but is not limited to:
- Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but none of the rings have a completely conjugated pi electron system.
- One or more ring atoms are selected from the group consisting of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings.
- the bridged cycloalkyl includes but is not limited to:
- heteroaryl refers to an aromatic ring system containing carbon and at least one heteroatom.
- Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, and a polycyclic heteroaryl group may contain 1 to 10 heteroatoms.
- Polycyclic heteroaryl rings may contain fused spiro or bridged rings, for example, a ring heteroaryl is a polycyclic heteroaryl.
- a bicyclic heteroaryl ring may contain 8 to 12 member atoms.
- a monocyclic heteroaryl ring may contain 5 to 8 member atoms (carbon number and heteroatoms).
- heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl gland Purinyl, quinolinyl or isoquinolinyl.
- cycloalkyl refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon group, which An alkylene linker is optionally included through which a cycloalkyl group can be attached.
- exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- oxo refers to the formation of oxygen with the carbon atoms to which it is attached
- R- or S-isomer When a compound described herein is specifically designated as the R- or S-isomer by its chemical name, it should be understood that the main configuration is the R-isomer or the S-isomer, respectively.
- R- or S-designated isomers may be substantially free (less than 5%, less than 1%, or undetectable as determined by chiral HPLC) of each Another isomer at the chiral center.
- the R- or S-isomers can be prepared by the methods exemplified in this application, for example by using a chiral auxiliary such as R- or S-tert-butylsulfinamide during the synthesis.
- R- or S-isomers include, but are not limited to, chiral HPLC purification of a mixture of stereoisomers (e.g., a racemic mixture).
- chiral HPLC purification of a mixture of stereoisomers e.g., a racemic mixture.
- General methods for separating stereoisomers, such as enantiomers and / or diastereomers, using HPLC are known in the art.
- the compounds described herein may exist in isotopically labeled or enriched forms that contain one or more atoms having an atomic mass or mass number different from the most abundant atomic mass or mass number in nature.
- the isotope can be a radioactive or non-radioactive isotope.
- Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 C1 and 125 I.
- Compounds containing other isotopes of these and / or other atoms are within the scope of the invention.
- one or more hydrogen atoms of any of the compounds described herein can be replaced with deuterium to provide the corresponding labeled or enriched compound.
- the term "subject” refers to an animal, preferably a mammal, most preferably a human, who has been the subject of a treatment, observation, or experiment.
- ring system (may also be referred to as “ring system”) as used herein includes, but is not limited to, carbocycles, heterocycles, heteroaryl rings, etc., and may also include only heterocycles and / or Heteroaryl rings, and specifically include which rings are determined as the context requires.
- composition in the present invention is intended to include a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition containing the compound in the present invention as an active ingredient and a method for preparing the same are also the contents of the present invention. Moreover, the crystalline forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
- the compounds provided by the present invention may also exist in the form of pharmaceutically acceptable salts.
- the salt of the compound provided by the present invention refers to a non-toxic "pharmaceutically acceptable salt".
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anionic or base / cationic salts.
- Pharmaceutically acceptable acid / anionic salts generally exist in the form of a basic nitrogen that is protonated with an inorganic or organic acid.
- Typical organic or inorganic acids include hydrochloric acid, hydrofluoric acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, and malic acid , Tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, acetic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid, water Salicylic acid, saccharinic acid or trifluoroacetic acid.
- Pharmaceutically acceptable base / cationic salts including, but not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium Salt and
- Prodrugs of the compounds of the invention are included within the scope of the invention.
- the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the method of treatment provided by the present invention includes administering a compound disclosed in the present invention, or, although not explicitly disclosed, it can be converted into the compound disclosed in the present invention after administration to a subject.
- Various diseases Conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
- any substituent or variable at a particular position is independent of the definition of the substituent or variable at other positions in the molecule. It should be understood that the substituents and substituted forms on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art and those methods proposed herein.
- the compounds according to the invention may contain one or more asymmetric centers and may result in diastereomers and optical isomers.
- the invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.
- the above formula (I) does not precisely define the stereo structure of a certain position of the compound.
- the present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific stereoisomers isolated are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization methods known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
- the present invention includes any possible tautomer and a pharmaceutically acceptable salt thereof, and mixtures thereof.
- the present invention includes any possible solvate and polymorph.
- the type of the solvate-forming solvent is not particularly limited as long as the solvent is pharmacologically acceptable.
- water, ethanol, propanol, acetone and the like can be used.
- pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
- pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
- Salts derived from inorganic bases include salts such as aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium and sodium.
- Non-toxic organic bases capable of deriving into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
- non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N ', N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphamine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine , Lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
- the compound provided by the present invention is a base
- its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionate , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, acetic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.
- citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicament, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
- the pharmaceutical composition provided by the present invention comprises, as an active ingredient, a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient, and other optional therapeutic components or Excipients.
- a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
- a pharmaceutically acceptable excipient or other optional therapeutic components or Excipients.
- the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical composition for parenteral (including subcutaneous, intramuscular, intravenous) administration.
- the pharmaceutical composition of the present invention can be conveniently prepared in the form of unit dosage forms known in the art and any preparation method known in the pharmaceutical field.
- the compound represented by formula (I), or a prodrug, or a metabolite, or a pharmaceutically acceptable salt of the present invention can be mixed with a drug carrier to form a drug combination as an active ingredient.
- a drug carrier can take a variety of forms depending on the mode of administration desired, for example, oral or injection (including intravenous). Therefore, the pharmaceutical composition of the present invention may be in the form of a separate unit suitable for oral administration, such as a capsule, cachet, or tablet containing a predetermined dose of the active ingredient.
- the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be administered by a controlled release manner and / or a delivery device.
- the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier that makes up one or more of the necessary ingredients.
- the pharmaceutical composition is prepared by uniformly and intimately mixing an active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. The product can then be conveniently prepared to the desired appearance.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a compound having a therapeutic activity in combination with one or more other compounds are also included in the pharmaceutical composition of the present invention.
- the pharmaceutical carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier.
- Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid.
- Liquid carriers including syrup, peanut oil, olive oil, and water.
- Gas carriers including carbon dioxide and nitrogen.
- any convenient pharmaceutical medium can be used.
- water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants and the like can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used for oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are preferred for oral formulations.
- the tablet coating may use standard aqueous or non-aqueous formulation techniques.
- Tablets containing a compound or pharmaceutical composition of the invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- the active ingredients are mixed in a free-flowing form, such as a powder or granules, with lubricants, inert diluents, surfactants or dispersants, and compressed tablets can be made by compression in a suitable machine.
- a powdered compound or pharmaceutical composition is wetted with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
- each tablet contains about 0.05 mg to 5 g of active ingredient
- each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
- a dosage form intended for oral administration in humans contains from about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and conveniently metered auxiliary material that accounts for about 5% to 95% of the total pharmaceutical composition.
- Unit dosage forms generally contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active ingredient to water to prepare an aqueous solution or suspension.
- a suitable surfactant such as hydroxypropyl cellulose may be included.
- Dispersion systems can also be prepared in glycerol, liquid polyethylene glycols, and their mixtures in oils. Further, a preservative may be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
- the invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions.
- the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for instant preparation of a sterile injection solution or dispersion.
- the final injection form must be sterile and, for easy injection, it must be easy to flow.
- the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
- the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- the pharmaceutical composition provided by the present invention may be in a form suitable for topical application, for example, an aerosol, an emulsion, an ointment, a lotion, a dusting powder, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention may be in a form suitable for use in a transdermal drug delivery device.
- These preparations can be prepared by a conventional processing method using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof.
- an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 to 10% by weight of the above-mentioned compound to obtain an emulsion or ointment having a desired consistency.
- the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier.
- a preferred dosage form is that the mixture forms a unit dose suppository.
- Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, and then cooling and moulding.
- the above pharmaceutical preparations may also include, as appropriate, one or more additional excipient components such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants, preservatives (including antioxidants), etc.
- additional excipient components such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants, preservatives (including antioxidants), etc.
- other adjuvants may include penetration enhancers that regulate the isotonic pressure of the drug and blood.
- a pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or a concentrated solution.
- the dosage level of the drug is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day.
- inflammation, cancer, psoriasis, allergies / asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS) effective dosages of drugs for treatment from 0.01 mg / kg to 50 mg / kg body weight per day, 0.5mg to 3.5g per patient per day.
- the specific dose level for any particular patient will depend on a number of factors, including age, weight, general health, gender, diet, timing of administration, route of administration, excretion rate, status of combination medications and acceptance The severity of the specific disease being treated.
- Dimethoxyethyl acetate (147.59 g, 1.00 mol) was dissolved in EtOAc (150.23 g, 1.71 mol), Na (33.42 g, 1.45 mol) was added at 60 ° C, and the mixture was stirred at reflux overnight. It was cooled to room temperature, diluted with EtOAc (500 mL), concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound A1-1 (135.47 g, 0.71 mol).
- the method for preparing compound E1-1 is the same as the method for synthesizing D1-1 in the preparation of intermediate D1.
- the method for preparing compound F1-1 is the same as the method for synthesizing D1-1 in the preparation of intermediate D1.
- the method for preparing compound F1 refers to the synthetic steps of E1-3 in preparing intermediate E1.
- This experiment employed a method of changing the mobility (mobility shift assay) test compound inhibition of FGFR4 kinase activity, and inhibition rate of the compound obtained FGFR4 kinase activity or on the half maximal inhibitory concentration IC 50.
- the test compound is configured as a concentration gradient in 100% DMSO, and a buffer solution (pH of the buffer solution is 7.5, which contains 50 mM HEPES (N- (2-hydroxyethyl) piperazine-N'-2 sulfonic acid) ), 0.00015% (ml / ml) Brij-35 (dodecyl polyethylene glycol ether) and the balance of water) were diluted to 10% DMSO, and added to a 384-well plate.
- a buffer solution pH of the buffer solution is 7.5, which contains 50 mM HEPES (N- (2-hydroxyethyl) piperazine-N'-2 sulfonic acid)
- 0.00015% ml / ml
- Brij-35 diodecyl polyethylene glycol ether
- FGFR4 enzyme (Invitrogen, Cat. No. PR4380A, Lot. No. 1856505A) buffer (the buffer pH is 7.5, which contains 50mM HEPES, 0.00015% (ml / ml) Brij-35, 2mM DTT (disulfide Threitol) and the balance of water) were diluted to the optimal concentration (final concentration 12.5 nM). Transfer 10 ⁇ l to a 384-well plate and incubate with the test compound for 10-15 minutes;
- the reference compound in the present invention has the following structure:
- the MTS method was used to test the inhibitory effect of the compound on the proliferation of hepatocellular carcinoma cells Hep3B (high expression of FGFR4 and FGF19), and the IC 50 of the inhibitory concentration of the compound on Hep3B was obtained.
- Hep3B cell line was purchased from ATCC, and its complete medium was MEM + 10% FBS + 1% PS.
- MEM cell culture medium, fetal bovine serum, trypsin were purchased from Gibco, cell culture bottles were purchased from Greiner, disposable cell counting plates, and trypan blue solution were purchased from Bio-Rad.
- the microplate reader measures the chemiluminescence signal value of each plate at a wavelength of 492nm;
- SD rats (Vitalone) are used to perform compound pharmacokinetic experiments on compounds.
- Mode of administration single intragastric administration and intravenous injection;
- Oral administration before administration, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h;
- Intravenous injection before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h;
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 5 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 3 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 10 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 2 ⁇ L.
- Q1, Q3, DP, EP, CE, and CXP in the table respectively represent Q1: parent ion; Q3: product ion; DP: declustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision chamber outlet voltage.
- p.o. refers to oral administration.
- Example D NOD-SCID mouse PK / PD
- This experiment is an in vivo pharmacodynamic experiment. Blood and tumor are taken at different time points to administer intragastric administration to detect the blood concentration and the drug concentration in the tumor.
- Blood sample sampling time points Compound 4, reference compound sampling points were before administration, 1h, 2h, 4h, and 6h, and each sampling point was 3 mice.
- Tumor sample sampling time points Compound 4, reference compound sampling points were 4h, 6h each sampling point was 3 mice.
- Tumor sample collection 200-300mg of each tumor tissue was taken to indicate the tumor weight. After quick freezing in liquid nitrogen, it was tested in a refrigerator at -80 °C.
- the chromatographic separation conditions and mass spectrometry analysis conditions are as follows:
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 2 ⁇ L.
- Q1, Q3, DP, EP, CE, and CXP in the table respectively represent Q1: parent ion; Q3: product ion; DP: declustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision chamber outlet voltage.
- p.o. refers to oral administration.
- Example E In vivo efficacy
- Hep3B cell line was purchased from ATCC, MEM cell culture medium, fetal bovine serum, trypsin was purchased from Gibco, cell culture bottles were purchased from Greiner, disposable cell counting plates and trypan blue solution were purchased from Bio-Rad. Disposable sterile syringes were purchased from Changzhou Jinlong Medical Plastic Equipment Co., Ltd. Ophthalmic surgical scissors and ophthalmic surgical tweezers were purchased from Shanghai Medical Instrument (Group) Co., Ltd. Surgical Instrument Factory. Viton Lihua.
- tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm) / 2
- the tumor grows to an average volume of 100-150 mm 3 , it is randomly divided into two groups for administration according to tumor size and mouse weight. Each group has 9 animals, one of which is the control group and the rest are the administration group.
- the method of administration is gavage.
- the control group is administered with 10% DMSO + 90% ddH 2 O.
- the dosages of the administration group are compound 4: 15/30 / 60mg / kg, which are administered once a day.
- Compound 4 15 mg / kg, twice daily, reference compound: 60 mg / kg, once daily.
- the solvent of compound 4 is: 10% DMSO + 90% ddH 2 O, and the solvent of the reference compound is: 100% ddH 2 O. Tumors were measured and weighed twice a week after the start of administration.
- TGI (Tumor growth inhibition)% (1-tumor weight of experimental group / tumor weight of control group) ⁇ 100%.
- the compound 4 of the present invention has an excellent tumor suppressing effect, and the effect of 60 mg / kg QD of the reference compound can be achieved by administering 15 mg / kg BID. The same effect is achieved, but the dosage is reduced by half, which results in less toxic and side effects and higher safety.
Abstract
Description
DCM | 二氯甲烷 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
THF | 四氢呋喃 |
DMF | N,N-二甲基甲酰胺 |
CH 3CN | 乙腈 |
TFA | 三氟乙酸 |
MnO 2 | 二氧化锰 |
DPPF | 1,1'-双(二苯基膦)二茂铁 |
DIEA/DIPEA | N,N-二异丙基乙胺 |
Pd 2(dba) 3 | 三(二亚苄基丙酮)二钯 |
Zn(CN) 2 | 氰化锌 |
NIS | 碘代琥珀酰亚胺 |
Na | 钠 |
Na 2SO 4 | 硫酸钠 |
NaCl | 氯化钠 |
HATU | 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 |
Boc 2O | 二碳酸二叔丁酯 |
化合物 | Hep3B(IC 50μM) | 化合物 | Hep3B(IC 50μM) |
化合物1 | 0.023 | 化合物64 | 0.018 |
化合物2 | 0.028 | 化合物68 | 0.026 |
化合物4 | 0.014 | 化合物69 | 0.067 |
化合物6 | 0.049 | 化合物71 | 0.049 |
化合物7 | 0.011 | 化合物72 | 0.282 |
化合物8 | 0.008 | 化合物73 | 0.039 |
化合物9 | 0.009 | 化合物74 | 0.060 |
化合物11 | 0.035 | 化合物75 | 0.028 |
化合物16 | 0.029 | 化合物76 | 0.006 |
化合物20 | 0.021 | 化合物82 | 0.020 |
化合物27 | 0.282 | 化合物83 | 0.068 |
化合物56 | 0.013 | 参照化合物 | 0.024 |
化合物62 | 0.054 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.20 | 95.0 | 5.00 |
1.00 | 0.00 | 100 |
2.20 | 0.00 | 100 |
2.21 | 95.0 | 5.00 |
4.00 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.15 | 95.0 | 5.00 |
1.50 | 0.00 | 100 |
2.50 | 0.00 | 100 |
2.60 | 95.0 | 5.00 |
3.80 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.15 | 95.0 | 5.00 |
1.50 | 0.00 | 100 |
2.50 | 0.00 | 100 |
2.60 | 95.0 | 5.00 |
3.80 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.30 | 95.0 | 5.00 |
1.80 | 5.00 | 95.0 |
2.50 | 5.00 | 95.0 |
2.51 | 95.0 | 5.00 |
3.00 | 95.0 | 5.00 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物1 | 523.252 | 175.100 | 96 | 10 | 35 | 16 |
化合物7 | 508.287 | 175.100 | 96 | 10 | 35 | 16 |
化合物16 | 538.278 | 175.000 | 111 | 10 | 37 | 12 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物4 | 537.083 | 175.100 | 76 | 10 | 37 | 14 |
化合物5 | 535.095 | 174.900 | 71 | 10 | 39 | 12 |
化合物20 | 549.071 | 175.100 | 71 | 10 | 37 | 12 |
化合物56 | 546.026 | 175.100 | 36 | 10 | 35 | 12 |
化合物71 | 537.078 | 175.000 | 146 | 10 | 37 | 14 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
参照化合物 | 507.252 | 175.100 | 56 | 10 | 25 | 14 |
Dexamethasone | 393.171 | 373.000 | 96 | 10 | 13 | 10 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.30 | 95.0 | 5.00 |
1.80 | 5.00 | 95.0 |
2.50 | 5.00 | 95.0 |
2.51 | 95.0 | 5.00 |
3.00 | 95.0 | 5.00 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
参照化合物 | 507.252 | 175.100 | 56 | 10 | 25 | 14 |
Dexamethasone | 393.171 | 373.000 | 96 | 10 | 13 | 10 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物4 | 537.083 | 175.100 | 76 | 10 | 37 | 14 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
组别 | TGI% |
化合物4 15mg/kg BID | 96.7 |
参照化合物60mg/kg QD | 97.7 |
Claims (50)
- 结构式I所示的化合物或其药学上可接受的盐:其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0、1、2或3;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;C 1-6烷氧基或被1、2或3个取代基取代的C 1-6烷氧基;所述每个取代基在每次出现时独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Y在每次出现时均独立地选自O或S;R 7在每次出现时均独立地选自H、D、-C 1-6烷基、-C 1-6烷氧基、-C 3-8环烷基或3-8元杂环基,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、-C 1-6烷基、-C 1-6烷氧基、-C 2-6链烯基、-C 2-6链炔基、-C(O)R 11、-C 1-6烷基-C(O)R 11、-C 3-6环烷基、3-8元杂环基,R 8在每次出现时均独立 地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5-10元单环杂环基、5-12元螺环杂环基、5-12元稠环杂环基或5-12元桥环杂环基,所述每个环系在每次出现时均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 2和R 3在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NH 2;-NO 2;-N 3;-C 1-6烷基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-6烷基;C 1-6烷氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-6烷氧基;取代或未取代的C 3-8环烷基;取代或未取代的3-8元杂环基;取代或未取代的3-8元杂环氧基;取代或未取代的3-8元杂环硫基;-S(O) tR 9;-C 1-6烷基-S(O) tR 9;-O-R 10;-C 1-6烷基-O-R 10;-C(O)OR 10;-C 1-6烷基-C(O)OR 10;-C(O)R 11;-C 1-6烷基-C(O)R 11;-O-C(O)R 11;-C 1-6烷基-O-C(O)R 11;-NR 12R 13;-C 1-6烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-6烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2、3或4;每个R G1和R G2在每次出现时均独立地选自H;D;-C 1-6烷基;被1、2或3个取代基取代的-C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的-C 1-6烷氧基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Q在每次出现时均独立地选自-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成C 3-8碳环、3-8元杂环或-5-10元杂芳环,每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;R 5和R 5’在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的-C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的-C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 5和R 5’与它们共同连接的碳原子形成-C 3-8碳环、3-8元杂环、5-10元杂芳环,所述的每个杂环基和每个杂芳基在每次出现时均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5-10元芳环、-C 3-10碳环、4-10元杂环,所述的每个杂环基在每次出现时均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;W在每次出现时均独立地选自-(CR w1R w2) n-S-、-(CR w1R w2) n-SO-或-(CR w1R w2) n-SO 2-,n选自0、1、2、3或4;R w1和R w2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;R 6在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-3烷基;被1、2或3个 取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧;-C 1-3烷基-COO-C 1-3烷基、-C 3-6环烷基或被1、2或3个取代基取代的-C 3-6环烷基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或Q和R 6与它们分别连接的碳原子和W一起形成4-6元杂环,所述杂环独立地任选地被一个或多个取代基取代或不取代,所述的杂环独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或-C 1-3烷氧基;或R 4和R 6与它们分别相连的原子一起形成5-8元单环杂环基、5-10元螺环杂环基、5-10元稠环杂环基、5-10元桥环杂环基或5-10元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基或-C 1-3烷氧基取代或不取代;或R 5和R 6与它们分别连接的碳原子和W一起形成4-6元杂环或5-8元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基、-C 1-3烷氧基取代或不取代;每个R 9在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;每个R 10在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;每个R 11在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;R 12和R 13在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或C 1-3烷酰基;t在每次出现时均独立地选自0、1或2。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0、1或2;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;C 1-3烷氧基或被1、2或3个取代基取代的C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Y在每次出现时均独立地选自O或S;R 7在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-5环烷基或3-8元杂环基,且所述的杂环基独立地任选地包含1、2或3个选自N、O或S的杂原子,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)R 11、-C 1-3烷基-C(O)R 11、-C 3-6环烷基、3-8元杂环基,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5-7元单环杂环基、5-10元螺环杂环基、5-10元稠环杂环基或5-10元桥环杂环基,所述的每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4 链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;在R 7和R 8中,每个R 9均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 7和R 8中,每个R 10均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 7和R 8中,每个R 11均独立地任选地选自选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 7和R 8中,R 12和R 13各自独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或-C 1-3烷酰基;t为0、1或2。
- 根据权利要求1或2所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0或1;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基或被1、2或3个取代基取代的C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;Y在每次出现时均独立地为O;R 7在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、5元杂 环基、6元杂环基、7元杂环基、8元杂环基,且所述每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、5元杂环基、6元杂环基、7元杂环基、8元杂环基,且所述杂环基独立地任选地包含1或2个选自N、O或S的杂原子,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、-异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5元单环杂环基、6元单环杂环基、7元单环杂环基、5元螺环杂环基、6元螺环杂环基、7元螺环杂环基、8元螺环杂环基、9 元螺环杂环基、10元螺环杂环基、5元稠环杂环基、6元稠环杂环基、7元稠环杂环基、8元稠环杂环基、9元稠环杂环基、10元稠环杂环基、5元桥环杂环基、6元桥环杂环基、7元桥环杂环基、8元桥环杂环基、9元桥环杂环基或10元桥环杂环基,所述的每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、-异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;在R 7和R 8中,每个R 9均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 7和R 8中,每个R 10均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 7和R 8中,每个R 11均独立地任选地选自选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 7和R 8中,R 12和R 13各自独立地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、环丙基、环丁基、环戊基、环己基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或-C 1-3烷酰基;t为0、1或2。
- 根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-CH(CH 3)-、-C(CH 3) 2-、-CHF-、-CHBr-或-CH(OH)-;且p是0或1;Y在每次出现时均独立地为O;R 7在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、二氧戊环基、氮杂环丁烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、四氢咪唑基、四氢噻唑基、四氢噁唑基、四氢吡喃基、吗啉基、硫代吗啉基或恶二唑,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O)H、-S(O)CH 3、-甲基-S(O)H、-甲基-S(O)CH 3、-乙基-S(O)H、-乙基-S(O)CH 3、-丙基-S(O)H、-丙基-S(O)CH 3、-异丙基-S(O)H、-异丙基-S(O)CH 3、-甲基-OH、-甲基-OCH 3、-乙基-OH、-乙基-OCH 3、-丙基-OH、-丙基-OCH 3、-异丙基-OH、-异丙基-OCH 3、-C(O)OH、-C(O)OCH 3、-甲基-C(O)OH、-甲基-C(O)OCH 3、-乙基-C(O)OH、-乙基-C(O)OCH 3、-丙基-C(O)OH、-丙基-C(O)OCH 3、-异丙基-C(O)OH、-异丙基-C(O)OCH 3、-C(O)H、-C(O)CH 3、-甲基-C(O)H、-甲基-C(O)CH 3、-乙基-C(O)H、-乙基-C(O)CH 3、-丙基-C(O)H、-丙基-C(O)CH 3、-异丙基-C(O)H、-异丙基-C(O)CH 3、-O-C(O)H、-O-C(O)CH 3、-甲基-O-C(O)H、-甲基-O-C(O)CH 3、-乙基-O-C(O)H、-乙基-O-C(O)CH 3、-丙基-O-C(O)H、-丙基-O-C(O)CH 3、-异丙基-O-C(O)H、-异丙基-O-C(O)CH 3、-NH 2、-N(CH 3) 2、-甲基-NH 2、-甲基-N(CH 3) 2、-乙基-NH 2、-乙基-N(CH 3) 2、-丙基-NH 2、-丙基-N(CH 3) 2、-异丙基-NH 2、-异丙基-N(CH 3) 2、-C(O)NH 2、-C(O)N(CH 3) 2、-甲基-C(O)NH 2、-甲基-C(O)N(CH 3) 2、-乙基-C(O)NH 2、-乙基-C(O)N(CH 3) 2、-丙基-C(O)NH 2、-丙基-C(O)N(CH 3) 2、-异丙基-C(O)NH 2、-异丙基-C(O)N(CH 3) 2、-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)H、-甲基-C(O)H、-乙基-C(O)H、-丙基-C(O)H、-异丙基-C(O)H、-C(O)-甲基、-甲基-C(O)-甲基、-乙基-C(O)-甲基、-丙基-C(O)-甲基、-异丙基-C(O)-甲基、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、 5元杂环基、6元杂环基、7元杂环基、8元杂环基,且所述杂环基独立地任选地包含1或2个选自N、O或S的杂原子,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O)H、-S(O)CH 3、-甲基-S(O)H、-甲基-S(O)CH 3、-乙基-S(O)H、-乙基-S(O)CH 3、-丙基-S(O)H、-丙基-S(O)CH 3、-异丙基-S(O)H、-异丙基-S(O)CH 3、-甲基-OH、-甲基-OCH 3、-乙基-OH、-乙基-OCH 3、-丙基-OH、-丙基-OCH 3、-异丙基-OH、-异丙基-OCH 3、-C(O)OH、-C(O)OCH 3、-甲基-C(O)OH、-甲基-C(O)OCH 3、-乙基-C(O)OH、-乙基-C(O)OCH 3、-丙基-C(O)OH、-丙基-C(O)OCH 3、-异丙基-C(O)OH、-异丙基-C(O)OCH 3、-C(O)H、-C(O)CH 3、-甲基-C(O)H、-甲基-C(O)CH 3、-乙基-C(O)H、-乙基-C(O)CH 3、-丙基-C(O)H、-丙基-C(O)CH 3、-异丙基-C(O)H、-异丙基-C(O)CH 3、-O-C(O)H、-O-C(O)CH 3、-甲基-O-C(O)H、-甲基-O-C(O)CH 3、-乙基-O-C(O)H、-乙基-O-C(O)CH 3、-丙基-O-C(O)H、-丙基-O-C(O)CH 3、-异丙基-O-C(O)H、-异丙基-O-C(O)CH 3、-NH 2、-N(CH 3) 2、-甲基-NH 2、-甲基-N(CH 3) 2、-乙基-NH 2、-乙基-N(CH 3) 2、-丙基-NH 2、-丙基-N(CH 3) 2、-异丙基-NH 2、-异丙基-N(CH 3) 2、-C(O)NH 2、-C(O)N(CH 3) 2、-甲基-C(O)NH 2、-甲基-C(O)N(CH 3) 2、-乙基-C(O)NH 2、-乙基-C(O)N(CH 3) 2、-丙基-C(O)NH 2、-丙基-C(O)N(CH 3) 2、-异丙基-C(O)NH 2、-异丙基-C(O)N(CH 3) 2、-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成二氧戊环、氮杂环丁烷、哌啶、哌嗪、氧代哌嗪、氧代哌啶、四氢呋喃、四氢咪唑、四氢噻唑、四氢噁唑、四氢吡喃、四氢吡咯、氮杂戊环、吗啉基、硫代吗啉基、7元氮氧杂环或7元氮氧螺环,所述每个环系均独立地任选地被一个或者多个选自D、-F;-Cl;-Br;-I;-OH;氧代;=O;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;甲氧基;乙氧基;丙氧基;异丙氧基;C 2-4链烯基;C 2-4链炔基;卤代C 1-3烷基;环丙基;环丁基;环戊基;环己基;哌嗪基;被1、2或3个F、Cl、Br、-OH、-CH 3取代的哌嗪基;3-6元杂环基氧基;3-6元杂环基硫基;C 5-8芳基;C 5-8芳基氧基;C 5-8芳基硫基;5-8元杂芳环;5-8元杂芳基氧基;5-8元杂芳基硫基;-S(O)H;-S(O)CH 3;-甲基-S(O)H;-甲基-S(O)CH 3;-乙基-S(O)H;-乙基-S(O)CH 3;-丙基-S(O)H;-丙基-S(O)CH 3;-异丙基-S(O)H;-异丙基-S(O)CH 3;-甲基-OH;-甲基-OCH 3;-乙基-OH;-乙基-OCH 3;-丙基-OH;-丙基-OCH 3;-异丙基-OH;-异丙基-OCH 3;-C(O)OH;-C(O)OCH 3;-甲基-C(O)OH;-甲基-C(O)OCH 3;-乙基-C(O)OH;-乙基-C(O)OCH 3;-丙基-C(O)OH;-丙基-C(O)OCH 3;-异丙基-C(O)OH;-异丙基-C(O)OCH 3;-C(O)H;-C(O)CH 3; -甲基-C(O)H;-甲基-C(O)CH 3;-乙基-C(O)H;-乙基-C(O)CH 3;-丙基-C(O)H;-丙基-C(O)CH 3;-异丙基-C(O)H;-异丙基-C(O)CH 3;-O-C(O)H;-O-C(O)CH 3;-甲基-O-C(O)H;-甲基-O-C(O)CH 3;-乙基-O-C(O)H;-乙基-O-C(O)CH 3;-丙基-O-C(O)H;-丙基-O-C(O)CH 3;-异丙基-O-C(O)H;-异丙基-O-C(O)CH 3;-NH 2;-N(CH 3) 2;-甲基-NH 2;-甲基-N(CH 3) 2;-乙基-NH 2;-乙基-N(CH 3) 2;-丙基-NH 2;-丙基-N(CH 3) 2;-异丙基-NH 2;-异丙基-N(CH 3) 2;-C(O)NH 2;-C(O)N(CH 3) 2;-甲基-C(O)NH 2;-甲基-C(O)N(CH 3) 2;-乙基-C(O)NH 2;-乙基-C(O)N(CH 3) 2;-丙基-C(O)NH 2;-丙基-C(O)N(CH 3) 2;-异丙基-C(O)NH 2;-异丙基-C(O)N(CH 3) 2;-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代。
- 根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NH 2;-NO 2;-N 3;-C 1-3烷基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、 -C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O) tR 9;-C 1-3烷基-S(O) tR 9;-O-R 10;-C 1-3烷基-O-R 10;-C(O)OR 10;-C 1-3烷基-C(O)OR 10;-C(O)R 11;-C 1-3烷基-C(O)R 11;-O-C(O)R 11;-C 1-3烷基-O-C(O)R 11;-NR 12R 13;-C 1-3烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-3烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;在R 2和R 3中,每个R 9均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 2和R 3中,每个R 10均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-8芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 2和R 3中,每个R 11均独立地任选地选自选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 2和R 3中,每个R 12和R 13各自独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-8芳基、取代或未取代的5-8元杂芳基或C 1-3烷酰基;t为0、1或2。
- 根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O) tR 9;-C 1-3烷基-S(O) tR 9;-O-R 10;-C 1-3烷基-O-R 10;-C(O)OR 10;-C 1-3烷基-C(O)OR 10;-C(O)R 11;-C 1-3烷基-C(O)R 11;-O-C(O)R 11;-C 1-3烷基-O-C(O)R 11;-NR 12R 13;-C 1-3烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-3烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;在R 2和R 3中,每个R 9均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6 元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 2和R 3中,每个R 10均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、环丙基、环丁基、环戊基、环己基、-C 5-8芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 2和R 3中,每个R 11均独立地任选地选自选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 2和R 3中,每个R 12和R 13各自独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、环丙基、环丁基、环戊基、环己基、取代或未取代的C 5-8芳基、取代或未取代的5-8元杂芳基或C 1-3烷酰基;t为0或1。
- 根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O)H;-S(O)CH 3;-甲基-S(O)H;-甲基-S(O)CH 3;-乙基-S(O)H;-乙基-S(O)CH 3;-丙基-S(O)H;-丙基-S(O)CH 3;-异丙基-S(O)H;-异丙基-S(O)CH 3;-甲基-OH;-甲基-OCH 3;-乙基-OH;-乙基-OCH 3;-丙基-OH;-丙基-OCH 3;-异丙基-OH;-异丙基-OCH 3;-C(O)OH;-C(O)OCH 3;-甲基-C(O)OH;-甲基-C(O)OCH 3;-乙基-C(O)OH;-乙基-C(O)OCH 3;-丙基-C(O)OH;-丙基-C(O)OCH 3;-异丙基-C(O)OH;-异丙基-C(O)OCH 3;-C(O)H;-C(O)CH 3;-甲基-C(O)H;-甲基-C(O)CH 3;-乙基-C(O)H;-乙基-C(O)CH 3;-丙基-C(O)H;-丙基-C(O)CH 3;-异丙基-C(O)H;-异丙基-C(O)CH 3;-O-C(O)H;-O-C(O)CH 3;-甲基-O-C(O)H;-甲基-O-C(O)CH 3;-乙基-O-C(O)H;-乙基-O-C(O)CH 3;-丙基-O-C(O)H;-丙基-O-C(O)CH 3;-异丙基-O-C(O)H;-异丙基-O-C(O)CH 3;-NH 2;-N(CH 3) 2;-甲基-NH 2;-甲基-N(CH 3) 2;-乙基-NH 2;-乙基-N(CH 3) 2;-丙基-NH 2;-丙基-N(CH 3) 2;-异丙基-NH 2;-异丙基-N(CH 3) 2;-C(O)NH 2;-C(O)N(CH 3) 2;-甲基-C(O)NH 2;-甲基-C(O)N(CH 3) 2;-乙基-C(O)NH 2;-乙基-C(O)N(CH 3) 2;-丙基-C(O)NH 2; -丙基-C(O)N(CH 3) 2;-异丙基-C(O)NH 2;-异丙基-C(O)N(CH 3) 2;-NH-C(O)H或-NH-C(O)OH。
- 根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H、D、-F、-Cl、-Br、-I、-OH、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H、D、-F或甲基。
- 根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2、3或4;每个R G1和R G2均独立地选自H;D;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2或3;每个R G1和R G2均独立地选自H;D;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2或3;每个R G1和R G2均独立地选自H;D;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-14中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-NH-、-S-、-SO-、-SO 2-或O;m是0、1或2。
- 根据权利要求1-15中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-NH-、-S-、-SO-、-SO 2-或O; m是0或1。
- 根据权利要求1-16中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-或O;m是0或1。
- 根据权利要求1-17中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-或O;m是1。
- 根据权利要求1-18中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-;m是0或1。
- 根据权利要求1-19中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-;m是1。
- 根据权利要求1-20中任一项所述的化合物或其药学上可接受的盐,其中:m是0。
- 根据权利要求1-21中任一项所述的化合物或其药学上可接受的盐,其中:Q在每次出现时均独立地选自-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-8碳环、-3-8元杂环或-5-10元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-22中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成C 3-8碳环、3-8元杂环或-5-10元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-23中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-24中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-26中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、 -NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-27中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、-3-6元杂环或-5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-28中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-29中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2 或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环;3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-30中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环;3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-31中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环; 3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-32中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 5和R 5’与它们共同连接的碳原子形成-C 3-6碳环、3-6元杂环、5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系均可独立地任选地被一个或多个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5-10元芳环、-C 3-8碳环、4-8元杂环,所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-33中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基或R 5和R 5’与它们共同连接的碳原子形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环或8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5元芳环、6元芳环、7元芳环、8元芳环、9元芳环、10元芳环、4元碳环、5元碳环、6元碳环、7元碳环、8元碳环、4元杂环、5 元杂环、6元杂环、7元杂环或8元杂环,所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-34中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 5和R 5’与它们共同连接的碳原子形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环、8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个D、-F、-Cl、-Br、-I、-OH、氧代、=O、-NH 2、-CN、-COOH、-NO 2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成苯、萘、3元碳环、4元碳环、5元碳环、6元碳环、哌啶、哌嗪、氧代哌嗪、氧代哌啶、四氢呋喃、四氢咪唑、四氢噻唑、四氢噁唑、四氢吡喃、四氢吡咯或氮杂戊环,所述的每个环系均独立地任选地被1、2或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、-NO 2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基取代或不取代。
- 根据权利要求1-35中任一项所述的化合物或其药学上可接受的盐,其中:R 6在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的C 1-3烷氧基;-甲基-COO-甲基;-乙基-COO-乙基;-丙基-COO-丙基;-异丙基-COO-异丙基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的-C 3-6碳环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或Q和R 6与它们分别连接的碳原子和W一起形成4元杂环、5元杂环、6元杂环或7元 杂环,所述杂环独立地任选地被一个或多个取代基取代或不取代,所述的杂环独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 6与它们分别相连的原子一起形成5元单环杂环基、6元单环杂环基、7元单环杂环基、8元单环杂环基、5元杂螺环、6元杂螺环、7元杂螺环、8元杂螺环、9元杂螺环、10元杂螺环、5元稠环杂环基、6元稠环杂环基、7元稠环杂环基、8元稠环杂环基、9元稠环杂环基、10元稠环杂环基、5元桥环杂环基、6元桥环杂环基、7元桥环杂环基、8元桥环杂环基、9元桥环杂环基、10元桥环杂环基、5元杂芳环、6元杂芳环、7元杂芳环、8元杂芳环、9元杂芳环或10元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基或-C 1-3烷氧基取代或不取代;或R 5和R 6与它们分别连接的碳原子和W一起形成4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环或8元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代或不取代。
- 一种药物组合物,其包括至少一种权利要求1-40中任一项所述的化合物或其药学上可接受的盐,和至少一种药学上可接受的辅料。
- 权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求40中所述的药物组合物在制备用于治疗、阻止或预防由FGFR4活性介导的疾病或病症的药物中的用途。
- 根据权利要求42所述的用途,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求42或43所述的用途,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
- 一种治疗、阻止或预防由FGFR4活性介导的疾病或病症的方法,其包括向患者给药有效剂量的权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求41中所述的药物组合物。
- 根据权利要求45中所述的方法,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求45或46中所述的方法,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
- 权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求41中所述的药物组合物用于治疗、阻止或预防由FGFR4活性介导的疾病或病症。
- 根据权利要求48中所述的化合物或其药学上可接受的盐或所述的药物组合物,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求49中所述的化合物或其药学上可接受的盐或所述的药物组合物,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
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BR112021003949-0A BR112021003949A2 (pt) | 2018-07-27 | 2019-07-29 | derivado de anel fundido usado como inibidor de fgfr4 |
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KR102559624B1 (ko) | 2023-07-24 |
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PH12021550406A1 (en) | 2021-09-20 |
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