WO2012034363A1 - 作为hedgehog通路抑制剂的化合物以及包含该化合物的药物组合物及其应用 - Google Patents
作为hedgehog通路抑制剂的化合物以及包含该化合物的药物组合物及其应用 Download PDFInfo
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- WO2012034363A1 WO2012034363A1 PCT/CN2011/001563 CN2011001563W WO2012034363A1 WO 2012034363 A1 WO2012034363 A1 WO 2012034363A1 CN 2011001563 W CN2011001563 W CN 2011001563W WO 2012034363 A1 WO2012034363 A1 WO 2012034363A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- methyl
- nicotinamide
- trifluoromethoxy
- trifluoromethyl
- Prior art date
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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 or sparfloxacin
-
- 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
- A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the present invention relates to a compound, and more particularly to a compound as an inhibitor and a composition comprising the same (C07D 521/00). Background technique
- the functional Hedgehog signaling pathway is essential for the formation of important organs such as the brain, limbs, lungs, skin, prostate, etc. (Ingham PW & McMahon AP (2001) Genes & Development 15, 3059-3087).
- the level of the Hedgehog signaling pathway in adults is much lower than in the embryonic phase, this pathway plays a crucial role in the proliferation and renewal of adult tissues.
- Stem cells are a class of pluripotent cells with self-renewal ability, that is, stem cells remain undirected and proliferative, and can differentiate into multiple functional cells or tissues under appropriate conditions or with appropriate signals.
- the Hedgehog pathway is an important regulator of stem cell activity and stimulates self-renewal and proliferation of stem cells in a variety of tissues (Beachy PA, Karhadkar SS, & Berman DM (2004) Nature 432, 324-331).
- Hedgehog proteins there are three Hedgehog proteins in vertebrate including mammals: Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh).
- Shh protein has received the most attention due to its expression in various tissues.
- These secreted ligands activate the Hedgehog signaling pathway by binding to the 12-transmembrane protein Ptchl.
- Ptchl When not bound to a ligand such as Shh protein, Ptchl inhibits the activity of another transmembrane protein (7 transmembrane proteins) SmoothencUSmo), but when bound to a ligand, Ptchl protein is activated to deactivate its Smo This causes Smo to move to the cell membrane, triggering a series of intracellular signaling (Varjosalo M & Taipale J (2007) Journal of Cell Science 120, 3-6). The signaling cascade triggered by activated Smo results in the activation of Gli transcription factors, which translocate into the nucleus where they control the transcription of the target gene.
- Gli transcription factors of the zinc finger protein family there are three Gli transcription factors of the zinc finger protein family, namely GH1, Gli2 and Gli3.
- GUI and Gli2 are mainly used as transcriptional activators and Gli3 is mainly used as a repressor. Due to the continued overexpression of the GH2 gene, it is generally recognized as the primary target for Smo protein activation.
- Glil The expression is highly correlated with the activation of the Hedgehog pathway, so it is often used as a reading to indicate the activation status of the Hedgehog pathway.
- Gli transcription factor Activation of the Gli transcription factor triggers transcription of Hedgehog target genes such as Glil, Ptch Myc, Bcl-2 (Ferretti E, De Smaele E, Di Marcotullio L, Screpanti I, & Gulino A (2005) Trends in Molecular Medicine 1 1, 537 -545).
- Activation of the Hedgehog pathway is also associated with tumors in other organs.
- tumors include, but are not limited to, prostate cancer (Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, & Beachy PA (2004) Nature 431, 707-712; Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, & Altaba ARI (2004) Proceedings of the National Academy of Sciences of the United States of America 101, 12561-12566 ); Cancer (Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, & Katano M (2004) Cancer Research 64, 6071-6074); Pancreatic Cancer (Thayer SP, di Magliano MP, Heiser PW , Nielsen CM, Roberts DJ, Lauwers GY, Qi Y
- Hedgehog pathway may be closely associated with cancer stem cells (Parisi MJ & Lin H (1998) Cell Res 8, 15-21; Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, et al. (2007) Proceedings of the National Academy of Sciences of the United States of America 104, 4048-4053). Cancer stem cells may play a crucial role in tumor growth and proliferation.
- cancer stem cells have the ability to multiply and become new tumors in the body (Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer Res 66, 9339-9344).
- the hypothesis that the presence of cancer stem cells will have a major impact on the design of anti-tumor drugs, because the complete eradication of tumors requires targeted elimination of all cancer stem cells.
- pancreatic cancer cells are characterized by cancer stem cells and have self-renewal and differentiation properties (Li CW, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Cancer Research 67 , 1030-1037). Feldmann et al. used animal models to demonstrate that Hedgehog inhibitors combined with gemcitabine inhibited the growth of pancreatic cancer, whereas gemcitabine and hedgehog inhibitors were not effective alone.
- the main object of the present invention is to provide a compound as an inhibitor for inhibiting
- the Hedgehog signaling pathway provides new drugs for clinically effective anti-tumor.
- Another object of the present invention is to provide a pharmaceutical composition as an inhibitor comprising as an active ingredient a compound of formula I which is useful for inhibiting the Hedgehog signaling pathway against tumors.
- a further object of the invention is to provide the use of said compounds in the manufacture of a medicament for inhibiting the Hedgehog signaling pathway.
- R u represents hydrogen, cyano, hydroxy, halogen, ( ⁇ _ 6 fluorenyl, d. 6 decyloxy, -C(0) 2 R 14 or -NR 13a R 13b , wherein fluorenyl or decyloxy is not Substituted or substituted by one or more halogen or hydroxy groups;
- R 12 represents hydrogen, C, - 6 alkyl with, C 3 - 8 embankment heterocycloalkyl group, C 3 - 8 embankment heterocyclic group, C 6 _ 1Q aryl, C 5 -io heteroaryl, C 6- 10 aryl-C 1-6 alkyl, C 5 _ 10 heteroaryl, -C(0)2Ri4, -C(0)Ri4 or -S(0) 2 R 14 ;
- R 13A and R 13B independently represent hydrogen, unsubstituted or substituted by one or more halogens, CL 6 fluorenyl, decyloxy - .6 fluorenyl, -C(0) 2 R 14 , -S(0) 2 R 14 , C 6 . 1Q aryl-C ⁇ fluorenyl or C 5 . 1 ⁇ ) heteroaryl
- R 2 independently represent hydrogen or d. 6 fluorenyl; wherein alkyl is unsubstituted or substituted by one or more halogen or hydroxy;
- Y, ⁇ and U independently represent nitrogen or CR 11 ;
- W and V independently represent nitrogen or CR 15;
- R 15 represents hydrogen, -6 fluorenyl or d. 6 fluorenyl, wherein the fluorenyl or decyloxy group is unsubstituted or substituted by one or more halogens;
- R 4 and independently represent hydrogen, halogen, C w alkyl or C 6 methoxy, wherein the fluorenyl or decyloxy group is unsubstituted or substituted by one or more halogens;
- Re and R 7 independently represent hydrogen, halogen, C decyl or .6 alkoxy, wherein the fluorenyl or decyloxy group is unsubstituted or substituted by one or more halogens;
- R 1Q represents hydrogen, halogen, cyano, .6 alkyl with, embankment group, C 6 1Q aryl, C 5 1Q heteroaryl, C 3 -..
- cycloalkyl C 3 8 heterocycloalkyl, C (0) R 14, C ( 0) 2 R 14 , -SR 14 , -S(0) 2 R 14 or NR 13a R 13b , wherein the fluorenyl or decyloxy group is unsubstituted or substituted by one or more halogens, and wherein C 3 - 8 is hetero
- the cycloalkyl group is unsubstituted or substituted by 1 or 2 d- 6 fluorenyl groups, or R 1Q and R 1Q and R 9 form a 5 or 6 membered oxygen-containing saturated heterocyclic ring.
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvent thereof, together with a suitable amount of a pharmaceutically acceptable carrier.
- the invention provides the use of a compound of formula I for the manufacture of a medicament for inhibiting the Hedgehog pathway.
- the invention also provides the use of a compound of formula I for the manufacture of a medicament for the treatment of a tumor associated with abnormal activation of the Hedgehog pathway, wherein the tumor is selected from the group consisting of basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, pancreatic cancer, breast cancer, Meningioma, malignant glioma, melanoma, gastric cancer, esophageal cancer, cholangiocarcinoma, prostate cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, glioma, multiple myeloma, and leukemia.
- the tumor is selected from the group consisting of basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, pancreatic cancer, breast cancer, Meningioma, malignant glioma, melanoma, gastric cancer, esophageal cancer, cholangiocarcinoma, prostate cancer, colon
- a compound of formula I is prepared from a compound of formula la.
- reaction route is:
- the method includes the following steps: 1) preparing a compound of the formula le by a condensation reaction of a compound of the formula lc with a substituted heterocyclic carboxylic acid;
- the methods and compounds of the present invention can be used to inhibit the activated Hedgehog signaling pathway, i.e., to inhibit abnormal growth states due to abnormal activation of Hedgehog.
- a sufficient amount of a compound of Formula I or a compound of Formula I in contact with a pharmaceutical composition formed from a pharmaceutically acceptable carrier can inhibit the abnormally activated Hedgehog pathway and thereby control or reverse abnormal growth conditions. Tumors associated with abnormally activated Hedgehog pathways are effectively treated clinically.
- C 6 fluorenyl represents a fluorenyl group of 1 to 6 carbons including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Amyl, n-hexyl;
- Alkoxy means a group which is bonded to an oxygen atom, and includes, but is not limited to, a methoxy group, an ethoxy group, an isopropoxy group, a cyclopropoxy group and the like.
- Aryl means a monocyclic or fused aromatic ring containing from six to ten carbon atoms. Particular aryl groups include phenyl and naphthyl, with phenyl being preferred.
- Heteroaryl means any fused or non-fused aromatic ring system wherein at least one ring is a five to eight membered ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably at least one hetero The atom is selected from nitrogen.
- Heteroaryl includes, but is not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzo Pyrazolyl, fluorenyl and the like.
- Cycloalkyl refers to a saturated or partially unsaturated monocyclic, fused or bridged ring containing the specified number of carbon atoms.
- C 3 .8 cyclodecyl refers to a cyclic fluorenyl group of three to eight carbons including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- Heterocyclic fluorenyl means a cycloalkyl group as defined in the present invention, wherein the carbonogen on one or more of the rings Subunits are substituted by a group such as oxygen, nitrogen, -NR-, sulfur, -S(0 or -S(0) 2 ; heterocyclic fluorenyl groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, thio Morpholinyl and the like.
- “Pharmaceutically acceptable salt” in the present invention means an acid addition salt.
- “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without other side effects.
- Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, propionate, glycolate, gluconate , lactate, oxalate, maleate, succinate, fumarate, tartrate, citrate, glutamate, aspartate, benzoate, methanesulfonate , p-toluenesulfonate and salicylate.
- solvate as referred to in the present invention means a complex of the compound of the present invention and a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out. For example, a complex formed with water is called a "hydrate.” Solvates of the compounds of formula I are within the scope of the invention.
- Y, ⁇ and U independently represent nitrogen or CRmony, wherein R réelle represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
- W and V are independently representing nitrogen or CH;
- R 3 represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
- R4 and R 5 independently represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy.
- R 7 independently represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
- R 9 independently represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy or trifluoromethoxy
- Ru represents fluorine, chlorine, cyano, methyl, ethyl, isopropyl , difluoromethyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methylsulfonyl, dimethylamino, NHS (0) 2 Me, morpholinyl or piperazinyl, or R 1 () with or 1 1 ⁇ ) with a 5- or 6-membered oxygen-containing saturated heterocyclic ring.
- Y, ⁇ and U independently represent nitrogen, CH or CF.
- - m and 1 represent 1; when n represents 0 or 2, and both are hydrogen;
- R6 and R 7 independently represent hydrogen or chloro
- R 10 represents fluorine, chlorine, methylsulfonyl, methoxy, trifluoromethoxy, trifluoromethyl, difluoromethyl, difluoromethoxy or cyano.
- Step 1 The polysubstituted or monosubstituted phenylboronic acid starting material of the formula Id is substituted with the substituted bromoaniline of the formula lc to prepare the intermediate of the formula lb by a Suzuki coupling reaction.
- the method of the Suzuki coupling reaction can be referred to the method in the literature (Kotha, S.; Lahiri, K and Kashinath, D. Tetrahedron 2002, 48, 9633-9695); the palladium catalyst used may be selected from the group consisting of bistriphenyl groups.
- Palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [1,1'-double (diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) and palladium chloride (PdCl 2 ) ; reaction temperature is from 80 ° C to 160 ° C; the reaction solvent may be selected from 1 , 4-dioxane, toluene, ethanol, and water; the inorganic base may be selected from sodium carbonate, potassium carbonate, and the like.
- phenylboronic acid and 3-aminobromobenzene are heated in a catalyst mixture of tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), an inorganic base of sodium carbonate, and a reaction solvent of toluene, ethanol and water.
- the reaction was carried out for 12 hours at 100 ° C to 130 ° C to obtain the corresponding product.
- Step 2 The substituted heterocyclic carboxylic acid, particularly the substituted nicotinic acid, is condensed with the intermediate of the formula lb to prepare the corresponding amide compound of the formula la.
- the amide-preparing reaction may be carried out by reacting a substituted nicotinic acid with thionyl chloride or oxalyl chloride to prepare a corresponding substituted nicotinyl chloride, followed by condensation with a compound of the formula lb to obtain a corresponding compound of the formula la; (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-trimethylaminopropyl) Carbodiimide), HATU (2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate), TBTU (0-benzotriazine)
- the amide of the formula la is prepared by a condensing agent such as azole, hydrazine, hydrazine, hydrazine, ⁇ '-tetramethyluronium tetrafluoroborate, DIC ( ⁇ , ⁇ '
- the selected base may be selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), etc.
- the reaction solvent may be selected from the group consisting of dichloromethane, tetrahydrofuran, Solvents such as 4-dioxane, N,N-dimethylformamide (DMF);
- the reaction temperature can be selected from 0 ° C to room temperature.
- Step 3 The corresponding compound of formula la can be selected to react with the corresponding amine or other reagent having nucleophilic substitution activity to form a compound of formula I.
- the reaction solvent may be selected from the group consisting of dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N-methylpyrrolidone, ethanol, and isopropanol;
- DMSO dimethyl sulfoxide
- DMF N-dimethylformamide
- N-methylpyrrolidone N-methylpyrrolidone
- ethanol ethanol
- isopropanol ethanol
- a base such as triethylamine, diisopropylethylamine (DIPEA), potassium carbonate, cesium carbonate or sodium carbonate
- DIPEA diisopropylethylamine
- the reaction temperature is between 80 ° C and 240 ° C, and the corresponding compound of the formula la is reacted to prepare a corresponding a compound of formula I.
- Step 1 The substituted heterocyclic carboxylic acid, especially the substituted nicotinic acid, is condensed with the compound of formula lc to prepare the corresponding amide compound of the formula le.
- the amide-preparing reaction may be carried out by reacting a substituted nicotinic acid with thionyl chloride or oxalyl chloride to prepare a corresponding substituted nicotinyl chloride, followed by condensation with a compound of the formula lc to obtain a corresponding formula Compound; DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-trimethylaminopropyl)carbodiimide), 1 ⁇ 1 ⁇ (2-(7-even) Nitrobenzotriazole)-: ⁇ ,>1,: ⁇ , 1'-tetramethylurea hexafluorophosphate), TBTU (0-benzotriazole-oxime, ⁇ , ⁇ , ⁇ '- A condensing agent such as tetramethylurea tetrafluoroborate) or DIC (N,N'-diisopropylcarbodiimide) is used to prepare the corresponding amide of
- the selected base may be selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), etc.;
- the reaction solvent may be selected from dichloromethane, tetrahydrofuran, 1, 4 a solvent such as dioxane or N,N-dimethylformamide (DMF);
- the reaction temperature can be selected from 0 ° C to room temperature.
- Step 2 The corresponding compound of formula le can be selected to react with the corresponding amine or other reagent (A) having nucleophilic substitution activity to form a compound of the formula If.
- the reaction solvent may be selected from the group consisting of dimethyl sulfoxide (DMSO), hydrazine, hydrazine-dimethylformamide (DMF), N-methylpyrrolidone, ethanol, and isopropanol;
- a base such as triethylamine, diisopropylethylamine (DIPEA) potassium carbonate, cesium carbonate or sodium carbonate, the reaction temperature is between 80 ⁇ and 240 V, and reacting with the corresponding compound of formula le to prepare a corresponding compound of the formula If .
- Step 3 The compound of formula I is prepared by a Suzuki coupling reaction of a polysubstituted or monosubstituted phenylboronic acid with an intermediate of the formula If.
- the method of the Suzuki coupling reaction can be referred to the method in the literature (Kotha, S.; Lahiri, K and Kashinath, D. Tetrahedron 2002, 48, 9633-9695); the palladium catalyst used may be selected from the group consisting of bistriphenyl groups.
- reaction temperature is from 80 ° C to 160 ° C;
- the reaction solvent may be selected from 1,4 - Dioxane, Toluene, Ethanol, and Water;
- the inorganic base may be selected from sodium carbonate, potassium carbonate, and the like.
- phenylboronic acid and 3-aminobromobenzene are heated in a catalyst mixture of tetrakis(triphenylphosphine)palladium (Pd(pph 3 ) 4 ), an inorganic base of sodium carbonate, and a reaction solvent of toluene, ethanol and water.
- the reaction was carried out for 12 hours at 100 ° C to 130 ° C to obtain the corresponding product.
- the compounds of the invention may contain one or more chiral carbon atoms and, therefore, the compounds of the invention may exist as enantiomers, diastereomers or mixtures thereof.
- the above compounds may be selected from the racemates, diastereomers or enantiomers as starting materials or intermediates.
- Diastereomeric compounds can be separated by crystallization or chromatography.
- Enantiomers can also be separated via crystallization, chiral chromatography or other known methods.
- Each asymmetric carbon atom can be in the R or S configuration, and both configurations are within the scope of the invention.
- the invention includes prodrugs of the above compounds.
- Prodrugs include known amino protecting groups and carboxy protecting groups, which are hydrolyzed under physiological conditions or released via an enzymatic reaction to give the parent compound; prodrugs of the invention specifically refer to prodrugs formed with an amino group, usually by the active compounds of the invention The nitrogen atom is prepared by reacting with an activated acyl compound.
- Specific prodrug preparation methods can be referred to (Saulnier, MG ; Frennesson, DB; Deshpande, MS; Hansel, S. B and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990. Greenwald, RB; Choe , YH; Conover, CD; Shum, K.; Wu, D .; Royzen, MJ Med. Chem. 2000, 43, 475.).
- the compounds of the invention may be administered in a suitable dosage form with one or more pharmaceutical carriers.
- dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
- dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
- the compounds of the present invention contained in these preparations may be solid powders or granules, aqueous or non-aqueous solutions or suspensions, water-in-oil or oil-in-water emulsions, and the like.
- the above dosage forms can be prepared from the compounds of the invention and one or more carriers or excipients via conventional pharmaceutical methods.
- non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
- Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
- the compounds of the invention may form solutions or suspensions with the above carriers.
- the compounds or dosage forms of the invention are suitable for use in warm-blooded animals; in another aspect, the compounds and dosage forms of the invention are suitable for use in mammals, such as humans.
- the compounds of the present invention inhibit hedgehog signaling and are therefore useful for treating when ptchl is unable or unable to adequately inhibit Smo (Ptchl loss of function phenotype) and/or when Smo is inhibited by Ptchl (Smo function list) Type) A tumor associated with an abnormal Hedgehog pathway.
- the compound of the present invention can be applied to tumors such as basal cell carcinoma and medulloblastoma alone, and can be administered in combination with other drugs (but not limited to) pancreatic cancer, breast cancer, meningioma, glioblastoma, melanoma, gastric cancer. , esophageal cancer, cholangiocarcinoma, prostate cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, glial cell carcinoma, and multiple myeloma.
- other drugs but not limited to) pancreatic cancer, breast cancer, meningioma, glioblastoma, melanoma, gastric cancer.
- esophageal cancer cholangiocarcinoma
- prostate cancer colon cancer
- small cell lung cancer non-small cell lung cancer
- glial cell carcinoma and multiple myeloma.
- Drugs that can be combined with the present compounds include, but are not limited to, gemcitabine, cisplatin, carboplatin, Gleevec, temozolomide, doxorubicin, dacarbazine, tarcoid, etoposide, daunorubicin, and arsenic Glycosides and the like.
- the compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
- the "effective amount" administered to a compound will be dictated by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
- the dosage for parenteral administration is generally from 1 to 200 mg/kg.
- Dosage forms for oral administration may contain from 1 to 1000 mg/kg of a compound of the invention.
- the starting materials used in the experiments in the present invention were either purchased from a reagent supplier or prepared from known starting materials via standard methods. Unless otherwise stated, the examples herein apply the following conditions - the unit of temperature is degrees Celsius (°C); the definition of room temperature is 18-25 ° C;
- the organic solvent is dried over anhydrous magnesium sulfate or anhydrous sodium sulfate; it is spin-dried using a rotary evaporator under reduced pressure (for example: 15 mmHg, 30 ° C);
- Silica gel was used as a carrier for column chromatography purification, and TLC was used to represent a thin layer of silica gel;
- the final product was identified by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
- N-(3-bromo-2-methylphenyl)-6-chloropyridazine-3-carboxamide (100 mg, 0.31 mmol, formula 2-3) , (2R, 6S)-2,6-dimethylmorpholine (0.19 mL, 1.5 mmol, compound of formula 2-4) and potassium carbonate (126.7 mg, 0.92 mmol) are dissolved in 4 mL of N,N- In dimethylformamide, it was reacted at 130 ° C for 10 min in a microwave synthesizer, cooled, and the reaction solution was poured into ice water to precipitate a white solid, which was filtered and dried to give a white solid (122 mg, yield: 98.4%, formula 2 -5 compound).
- N-(3-bromo-2-methylphenyl)-6-[(2R,6S)-2,6-dimethylmorpholine]pyridazin-3-amide (100 mg, under N2) 0.20 mmol, compound of formula 2-5), 4-trifluoromethoxyphenylboronic acid (61.4 mg, 0.30 mmol, compound of formula 2-6), bistriphenylphosphinepalladium dichloride (27.9 mg, 0.04 mmol) and Sodium carbonate (63.3 mg, 0.60 mmol) was added to a mixture of 4 mL of 1,4-dioxane and water (3:1) in a microwave synthesizer at 130 V for 60 min, suction filtration, silica gel column chromatography (The eluent was n-hexane: ethyl acetate 1:4) to give a white solid (50.0 mg, yield: 51.6 %, compound of formula 2-7).
- the insoluble material was filtered, and the filtrate was diluted with water, and ethyl acetate was evaporated.
- the solvent was removed under reduced pressure and the crude crystallijjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- Biological activity screening test (Hedghog signaling pathway Gli-luciferrase reporter gene test) Gli dual luciferase reporter gene detection experimental materials and methods
- Shhlightll cells in logarithmic growth phase were seeded in 96-well plates, 30,000 cells/?L/100 ⁇ , 37 V, 5% C0 2 for two days to maximize cell growth.
- the 96-well plate and kit were equilibrated to room temperature before the start of the experiment.
- the medium containing the inducer and the drug to be tested was aspirated, and a cell-inducing medium equilibrated at room temperature was added at 50 ul/well.
- the 96-well plate was placed in a microplate shaker at room temperature for 10 min.
- the luciferase reporter gene was assayed according to Te C anIF200 instructions. Once assayed, add the new Dual-Glo®Stop & Glo® Reagent, 50 ⁇ 7 wells.
- the 96-well plate was placed in a microplate shaker and the Renilla luciferase reporter gene was assayed at room temperature for 10 min.
- the compounds of the present invention exhibit very good in vitro inhibitory ability against the Hedgehog signaling pathway and are therefore useful for the treatment of tumors associated with abnormal activation of the Hedgehog signaling pathway.
- the compounds and methods of the invention can be used to inhibit the activation of the Hedgehog signaling pathway, i.e., to inhibit abnormal growth due to abnormal activation of Hedgehog.
- contacting a sufficient amount of a compound of Formula I or a compound of Formula I with a pharmaceutical composition to form a pharmaceutical composition with a pharmaceutical carrier inhibits the abnormally activated Hedgehog pathway and thereby controls or reverses abnormal growth conditions. Tumors associated with abnormally activated Hedgehog pathways are effectively treated clinically.
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Description
作为 Hedgehog通路抑制剂的化合物
以及包含该化合物的药物组合物及其应用
技术领域
本发明涉及一种化合物,尤其涉及一种作为抑制剂的化合物以及包含该化 合物的组合物 (C07D 521/00) 。 背景技术
1980年在果蝇中发现的 hedgehog信号通路在动物胚胎形成时期对细胞的 增殖、分化以及决定细胞命运等进程起重要的调节作用。功能正常的 Hedgehog 信号通路是形成脑、四肢、肺、皮肤、前列腺等重要器官所必须的条件(Ingham PW & McMahon AP (2001) Genes & Development 15, 3059-3087 ) 。 尽管 Hedgehog信号通路在成人体内的水平远低于胚胎时期, 该通路在成人组织的 增殖与更新过程中依然起着至关重要的作用。干细胞是一类具有自我更新能力 的多潜能细胞, 即干细胞保持未定向分化状态和具有增殖能力, 在合适的条件 或给予合适的信号, 它可以分化成多种功能细胞或组织器官。 Hedgehog通路 是干细胞活性的重要调节器,它可以刺激多种组织中干细胞的自我更新与增殖 ( Beachy PA, Karhadkar SS, & Berman DM (2004) Nature 432, 324-331 ) 。
在脊椎动物包括哺乳动物中存在三种 Hedgehog 蛋白: Sonic hedgehog (Shh), Desert hedgehog (Dhh)和 Indian hedgehog (Ihh).由于在多种组织中都有表 达, Shh蛋白得到了最多的关注。 这些分泌的配体通过与 12次跨膜蛋白 Ptchl 结合来激活 Hedgehog信号通路。 当未与配体例如 Shh蛋白结合时, Ptchl抑 制另一种跨膜蛋白(7次跨膜蛋白) SmoothencUSmo)的活性, 但当与配体结合 时, Ptchl蛋白被激活而解除其对 Smo的抑制, 从而导致 Smo移动到细胞膜, 引发一系列的细胞内信号传导 (Varjosalo M & Taipale J (2007) Journal of Cell Science 120, 3-6) 。 由激活的 Smo引发的信号传导级联导致 Gli转录因子的活 化, Gli转录因子易位进入细胞核中, 在那里它们控制靶基因的转录。 在脊椎 动物中, 有三种锌指蛋白家族的 Gli转录因子, 分别是 GH1、 Gli2和 Gli3。 其 中 GUI与 Gli2主要作为转录的激活因子而 Gli3则主要作为阻抑因子。 由于 GH2基因的持续过表达, 它通常被认定为 Smo蛋白激活后的主要靶点。 Glil
的表达与 Hedgehog 通路的激活高度相关, 因此它经常被用作读数来指示 Hedgehog通路的激活状态。 Gli转录因子的激活可以引发 Glil、 Ptch Myc、 Bcl-2等 Hedgehog靶基因的转录 (Ferretti E, De Smaele E, Di Marcotullio L, Screpanti I, & Gulino A (2005) Trends in Molecular Medicine 1 1, 537-545 ) 。
近期的研究表明, 肿瘤与 Hedgehog通路的异常激活密切相关。 在大多数 偶发性基底细胞癌中,研究人员发现 Ptchl和 Smo的变异导致了不依赖配体的 Hedgehog 通路激活 (Gailani MR, StahleBackdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, et al. (1996) Nature Genetics 14, 78-81; Xie JW, Murone M, Luoh SM, Ryan A, Gu QM, Zhang CH, Bonifas JM, Lam CW, Hynes M, Goddard A, et al. (1998) Nature 391, 90-92 ),而 Ptchl和 Suf 的变异所引发的 Hedgehog通路的激活也被发现与成 神经管细胞瘤与横纹肌瘤密切相关 (Rubin LL & de Sauvage FJ (2006) Nature Reviews Drug Discovery 5, 1026-1033; Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, & Unden AB (2006) Journal of Pathology 208, 17-25 )。
Hedgehog通路的激活与其他的器官的肿瘤也有关联。 这些肿瘤包括但不限于 前列腺癌 (Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, & Beachy PA (2004) Nature 431, 707-712; Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, & Altaba ARI (2004) Proceedings of the National Academy of Sciences of the United States of America 101, 12561-12566 ) ; 乳腺癌 ( Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, & Katano M (2004) Cancer Research 64, 6071-6074 ) ; 胰腺癌 (Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo CF, Yajnik V, et al. (2003) Nature 425, 851-856 ) ; 消化道 月中瘤( Berman DM, Karhadkar SS, Maitra A, de Oca RM, Gerstenblith MR, Briggs K, Parker A , Shimada Y, Eshleman JR, Watkins DN, et al. (2003) Nature 425, 846-851 ) ; 小细胞肺癌 ( Watkins DN, Berman DM,Burkholder SG, Wang BL, Beachy PA, & Baylin SB (2003) Nature 422, 313-317); 非小细胞肺癌(Yuan Z, Goetz JA, Singh S, Ogden SK, Petty WJ, Black CC, Memoli VA, Dmitrovsky E, & Robbins DJ (2007) Oncogene 26, 1046- 1055)等。
越来越多的证据表明 Hedgehog通路可能与肿瘤干细胞紧密关联 (Parisi MJ & Lin H (1998) Cell Res 8, 15-21; Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, et al. (2007) Proceedings of the National Academy of Sciences of the United States of America 104, 4048-4053)。肿瘤干细胞可能对肿瘤的生长以及增 殖起到至关重要的作用。有研究发现,在白血病以及一些实体瘤例如在脑和胰 腺中, 有一小部分癌细胞有能力大量增殖而在体内成为新的肿瘤 (Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer Res 66, 9339-9344)。肿瘤干细胞存在的假说将会对抗 肿瘤药物设计有重大的影响,因为彻底根除肿瘤需要靶向性地消灭所有的肿瘤 干细胞。
一部分胰腺癌细胞具有肿瘤干细胞的特点,具备自我更新以及分化的性质 (Li CW, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Cancer Research 67, 1030-1037) 。 Feldmann等人利用 动物模型证明, Hedgehog抑制剂与吉西他滨联用可以抑制胰腺癌的生长, 而 吉西他滨和 hedgehog 抑制剂单独的治疗效果都不明显。 该研究表明抑制 Hedgehog通路可能抑制肿瘤干细胞的自我更新与增殖 (Feldmann G, Fendrich V, McGovem K, Bedja D, Bisht S, Alvarez H, Koorstra JBM, Habbe N, Karikari C, Mullendore M, et al. (2008) Molecular Cancer Therapeutics 7, 2725-2735 ) 。 在该 研究中, Feldmann等人还发现, 抑制 Hedgehog通路可以有效地防止癌细胞转 移。
除了调节肿瘤细胞的分化, 增殖和转移, Hedgehog通路正向调节药物转 运蛋白的表达, 导致癌细胞对细胞毒抗肿瘤药物的抗药性(Sims-Mourtada J, Izzo JG, Ajani J, Chao KSC (2007) Oncogene 26, 5674-5679)。 Hedgehog通路还 能够调节肿瘤的血管生成(Klagsbrun M (1991) Annual Review of Physiology 53, 217-239; Cherrington JM, Strawn LM, Shawver LK (2000) Advances in Cancer Research, 79, 1-38)。综上所述,抑制 Hedgehog信号通路的化合物以及其药用 组合物将会有非常好的抗肿瘤临床应用前景。 发明公开
本发明的主要目的在于提供一种作为抑制剂的化合物, 其用于抑制
Hedgehog信号通路, 可为临床有效抗肿瘤提供新的药物。
本发明的另一个目的在于提供作为抑制剂的药物组合物,其包含作为有效 成分的式 I化合物, 可用于抑制 Hedgehog信号通路以抗肿瘤。
本发明的又一个目的在于提供所述化合物在制备用于抑制 Hedgehog信号 通路的药物中的应用。
本发明的再一个目的在于提供所述化合物的制备方法。
根据本发明的一个方面,本发明提供了式 I化合物或其药学上可接受的盐 或溶剂化物:
其中:
X代表 S、 S=0、 S(0)2、 0、 CHR„或者 NR12;
Ru代表氢、 氰基、 羟基, 卤素、 (^_6垸基、 d.6垸氧基、 -C(0)2R14或者 -NR13aR13b, 其中垸基或垸氧基未被取代或者被一个或多个卤素或羟基取代;
R12代表氢、 C,-6垸基、 C3— 8杂环烷基 垸基、 C3-8杂环垸基、 C6_1Q芳基、 C5-io杂芳基、 C6-10芳基 -C1-6烧基、 C5_10杂芳基 烧基、 -C(0)2Ri4、 -C(0)Ri4 或者 -S(0)2R14;
R13A和 R13B独立地代表氢、未被取代或被一个或多个卤素取代的 CL6垸基、 垸氧基 - .6垸基、 -C(0)2R14、 -S(0)2R14、 C6.1Q芳基 -C^垸基或者 C5.1{)杂芳
^和 R2独立地代表氢或者 d.6垸基; 其中烷基未被取代或者被一个或多 个卤素或羟基取代;
Y、 Ζ和 U独立地代表氮或者 CR11 ;
W和 V独立地代表氮或者 CR15;
R15代表氢、 _6垸基或者 d.6垸氧基,其中垸基或垸氧基未被取代或者被 一个或多个卤素取代;
代表氢、 卤素、 氰基、 垸基或者 d_6垸氧基, 其中垸基或者垸氧基 未被取代或被一个或多个卤素取代;
R4和 独立地代表氢、 卤素、 Cw烷基或者 C 6垸氧基, 其中垸基或者 垸氧基未被取代或被一个或多个卤素取代;
Re和 R7独立地代表氢、 卤素、 C 垸基或者 .6烷氧基, 其中垸基或者 垸氧基未被取代或被一个或多个卤素取代;
和 独立地代表氢、 卤素、 d.6垸基或者 d.6烷氧基, 其中垸基或者 垸氧基未被取代或被一个或多个卤素取代, R1Q代表氢、 卤素、 氰基、 .6垸 基、 垸氧基、 C6.1Q芳基、 C5.1Q杂芳基、 C3-8环烷基、 C3.8杂环烷基、 C(0)R14、 C(0)2R14、 -SR14、 -S(0)2R14或者 NR13aR13b, 其中垸基或垸氧基未被取代或被 一个或多个卤素取代, 并且其中 C3-8杂环烷基未被取代或者被 1或 2个 d_6 垸基取代, 或者, R1Q与 或 R1Q与 R9形成 5或 6元的含氧饱和杂环。
根据本发明的另一方面,本发明提供了一种药物组合物,其包含治疗有效 量的式 I化合物或者其药学上可接受的盐或溶剂物以及适量的可药用载体。
根据本发明的另一方面, 本发明提供了式 I 化合物在制备用于抑制 Hedgehog通路的药物中的应用。
本发明还提供了式 I化合物在制备用于治疗与 Hedgehog通路异常激活有 关的肿瘤的药物中的应用, 其中肿瘤选自于基底细胞癌、髓母细胞瘤、橫纹肌 肉瘤、 胰腺癌、 乳腺癌、 脊膜瘤、 恶性胶质瘤、 黑色素瘤、 胃癌、 食道癌、 胆 管癌、 前列腺癌、 结肠癌、 小细胞肺癌、 非小细胞肺癌、 神经胶质细胞癌、 多 发性骨髓瘤以及白血病。
根据本发明的另一个方面,本发明提供了所述化合物的制备方法, 其中, 反应路线为:
其中, 所述方法包括以下步骤-
1 )通过式 Id的化合物与式 lc的化合物进行 Suzuki偶联反应来制备 得到式 lb的化合物;
2)通过式 lb 的化合物与取代杂环羧酸进行缩合反应来制备得到式 la的化合物; 以及
3 ) 从式 la的化合物制备得到式 I的化合物。
或者反应路线为:
其中, 所述方法包括以下步骤:
1 )通过式 lc的化合物与取代杂环羧酸进行缩合反应来制备得到式 le的 化合物; 以及
2 )通过式 le的化合物与亲核试剂(A) 反应制备得到式 If的化合物;
3 )式 If 的化合物与取代的苯硼酸进行 Suzuki偶联反应来制备得到式 I 的化合物。
本发明中的方法以及化合物可以用来抑制激活的 Hedgehog信号通路, 也 就是说可以抑制由于 Hedgehog异常激活所导致的异常生长状态。应用本发明 所描述的方法, 足够量的式 I化合物或者式 I化合物与药用载体所形成的药物 组合物与细胞接触, 可以抑制异常激活的 Hedgehog通路从而控制或逆转异常 的生长状态, 从而可在临床上有效地治疗与异常激活的 Hedgehog通路有关的 肿瘤。 实现本发明的最佳方式
对本发明中所涉及的部分术语定义如下:
"垸基"作为基团或是其他基团的一部分, 例如卤素取代的烷基、羟基取 代的垸基,可以是直链的或是支链的。例如, C 6垸基表示 1到 6个碳的垸基, 包括但不限于甲基、 乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、 正戊基、 正己基;
"烷氧基"是指垸基与氧原子连结后的生成基团, 包括但不限于甲氧基、 乙氧基、 异丙氧基、 环丙氧基等。
"芳基"是指包含六到十个碳原子的单环或稠合的芳环。特定的芳基包括 苯基和萘基, 其中优选苯基。
"杂芳基"是指任何稠合或非稠合的芳环系统, 其中至少一个环是含有 1-4个选自氮、 氧和硫的杂原子的五到八元环, 优选至少一个杂原子选自氮。 杂芳基包括但不限于噻吩基、 咪唑基、 吡唑基、 噻唑基、 恶唑基、 异恶唑基、 吡啶基、 嘧啶基、 吡嗪基、 哒嗪基、 苯并咪唑基、 苯并吡唑基、 吲哚基等。
"环垸基"是指包含指定数目的碳原子的饱和的或部分不饱和的单环、稠 环或桥环。例如, C3.8环垸基是指三到八个碳的环垸基,包括环丙基、环丁基、 环戊基、 环己基等。
"杂环垸基"是指本发明中所定义的环垸基,其中一个或多个环上的碳原
子被氧、 氮、 -NR -、 硫、 -S(0 或 -S(0)2等基团取代; 杂环垸基包括但不限 于吗啉基、 哌嗪基、 哌啶基、 硫代吗啉基等。
"药学上可接受的盐"在本发明中是指酸加成盐。 "药学上可接受的酸加 成盐"是指能够保留游离碱的生物有效性而无其他副作用的,与无机酸或有机 酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等; 有机酸盐包括但不限于甲酸盐、 乙酸盐、 丙酸盐、 乙醇酸盐、 葡糖酸盐、 乳酸 盐、 草酸盐、 马来酸盐、 琥珀酸盐、 富马酸盐、 酒石酸盐、 柠檬酸盐、 谷氨酸 盐、 天冬氨酸盐、 苯甲酸盐、 甲磺酸盐、 对甲苯磺酸盐和水杨酸盐等。
本发明中提及的 "溶剂化物"是指本发明的化合物与溶剂形成的配合物。 它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如,一个与水 形成的配合物称为 "水合物"。 式 I化合物的溶剂化物属于本发明范围之内。
在本发明的优选实施方式中, 在式 I的化合物中,
X代表 S、 0、 S=0、 S(0)2、 CHR16或者 NR12,其中 R16选自于氢、 羟基 或 NR13aR13b;
Y、 Ζ和 U为独立地代表氮或者 CR„, 其中 R„代表氢、 氟、 氯、 溴、 甲 基、 三氟甲基、 甲氧基或者三氟甲氧基;
W和 V为独立地代表氮或者 CH;
R3代表氢、 氟、 氯、 溴、 氰基、 甲基、 三氟甲基、 甲氧基、 乙氧基或者 三氟甲氧基;
R4和 R5独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基、 乙氧基 或者三氟甲氧基。
其中:
或者 R7独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基或者三 氟甲氧基;
和 R9独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基或三氟甲 氧基, Ru)代表氟、 氯、 氰基、 甲基、 乙基、 异丙基、 二氟甲基, 三氟甲基、 甲氧基、异丙氧基、二氟甲氧基,三氟甲氧基、环丙基、 甲磺酰基、二甲胺基、 NHS(0)2Me、吗啉基或哌嗪基, 或者, R1()与 或 1 1{)与 形成 5或 6元的含 氧饱和杂环。
其中-
或者 独立地代表氢、 甲基或者羟基取代的甲基。
其中:
和 独立地代表氢、 氯或者甲基。
其中:
X代表 S、 0、 S=0、 S(0)2、 CHR16或者 NR12, 其中 R12代表甲基、 乙基、 乙酰基、 甲磺酰基、 苄基、 吡啶甲基或者噻唑甲基;
Y、 Ζ和 U独立地代表氮、 CH或者 CF。
其中- m和 1代表 1 ; 当 n代表 0或 2时, 和 同时为氢;
R6和 R7独立地代表氢或者氯;
和 独立地选自氢、 甲基、 氟或者氯;
R10代表氟、 氯、 甲磺酰基、 甲氧基、 三氟甲氧基、 三氟甲基、 二氟甲基、 二氟甲氧基或者氰基。
根据本发明, 更优选的式 I化合物的实例为:
N-{2_甲基 _3_[4,- (三氟甲氧基)苯基] }苯基 -6- (哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-甲基哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-乙基哌嗪 -1-基)烟酰胺;
N-{2_甲基 _3_[4,- (三氟甲氧基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪 -1-基]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-乙酰基哌嗪 -1-基)烟酰胺; N_{2_甲基 _3_[4,- (三氟甲氧基)苯基] }苯基 _6-(4-苄基哌嗪 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N_{2_甲基 _3_[4,- (三氟甲氧基)苯基] }苯基 -6-[(3R,5S)-3,5-二甲基哌嗪 -1-基] 烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基: |}苯基 -6-吗啉烟酰胺;
N-{2-甲基 -3-[4'- (氰基)苯基: J}苯基 -6-吗啉烟酰胺;
N-{2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉基]烟酰胺;
N_{2_甲基 _3_[4,- (三氟甲基)苯基] }苯基 -6-吗啉烟酰胺;
N- {2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6- (哌嗪- 1 -基)烟酰胺;
N_{2_甲基 _3_[4,_ (三氟甲基)苯基] }苯基 _6_(3,5_二甲基哌嗪小基)烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉基]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-{[(3R)-3-N,N-二甲基氨基]四氢 吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-{[(3S)-3-N,N-二甲基氨基]四氢 吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-(4-甲基 -1,4-二氮杂卓 -1-基)烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪小基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-(3,4-甲基哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-(4-苄基哌嗪 -1-基)烟酰胺;
5-{5-{2-甲基 -3-[4,- (三氟甲基)苯基]苯基 -氨基甲酰基 } -吡啶 -2- 基 }-(lS,4S)-2,5-二氮杂卓杂双环 [2.2.1]庚烷基 -2-甲酸叔丁酯;
5-{5-{2-甲基 -[4,- (三氟甲基)苯基]苯基 -氨基甲酰基 } 比啶 -2-基 1,4-二氮 杂卓 -1-甲酸叔丁酯;
N-{2-甲基 -3-[4'- (三氟甲基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[4- (甲磺酰基)哌嗪 -1基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[4- (乙酰基)哌嗪 -1基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-甲基 -1,4-二氮杂卓 -1-基)烟 酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-{[(3R)-3-N,N-二甲基氨基]四 氢吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-{[(3S)-3-N,N-二甲基氨基]四 氢吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰 胺;
N-{2_甲基 _3_[4,_ (三氟甲氧基)苯基] }苯基 _6_(1,4-二氮杂卓 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(2,5-二氮杂卓双环 [2.21]庚烷
基 -2-基)]烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪 -1-基]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[4- (甲磺酰基)哌嗪 -1-基]烟酰 胺;
N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-(4-甲基 -1,4-二氮杂卓 -1-基)烟酰胺; N-{2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-{[(3S)-3-N,N-二甲基氨基]四氢吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-{[(3R)-3-N,N-二甲基氨基]四氢吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰胺; N-(2-甲基 _3-[4,- (氰基)苯基] }苯基 -6-(4-苄基哌嗪小基)烟酰胺;
N-{2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-(3,5-二甲基哌嗪 -1-基)烟酰胺;
N- {2-甲基 -3-[4'- (氰基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-(3,4-二甲基哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-(2,5-二氮杂卓双环 [2.2.1]庚垸基 -2- 基)]烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(1,4-二氮杂卓 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (氰基)苯基] }苯基 -6-[4- (甲磺酰基)哌嗪 -1-基]烟酰胺; Ν·{2-甲基 _3-[4'- (二氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]哒嗪 -3酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[4- (苯基)哌嗪 -1基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基-6-[(21,68)-2,6-二甲基吗啉]烟酰 胺;
N-{2-甲基 -3-[4,- (二氟甲氧基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰 胺;
N-{4-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]烟酰 胺;
N-{2_甲基 _3-[4,- (三氟甲氧基)苯基] }苯基 -6-[4- (吡啶 -3-基)甲基 -哌嗪小基] 烟酰胺;
N_{2_甲基 -3_[4,_ (三氟甲氧基)苯基] }苯基 _6-[4- (吡啶 -4-基)甲基 -哌嗪小基] 烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[4- (吡啶 -2-基)甲基 -哌嗪 -1-基] 烟酰胺;
N-{2-甲基 -3-[4'- (二氟甲氧基)苯基] }苯基 -6-[4-甲磺酰基 -哌嗪 -1-基]烟酰 胺;
N-{2-甲基 -3-[4'- (甲磺酰基)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N-{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[2-甲基 -1,1,-二氧代硫代吗啉 基]烟酰胺;
N-{2-甲基 -3-[4'- (二氟甲氧基)苯基] }苯基 -6-[2-甲基 -1,Γ-二氧代硫代吗啉 基]烟酰胺;
Ν·{4-甲基 -5-[4'- (二氟甲氧基)苯基] }吡啶-3-基 -6-(1,1'-二氧代硫代吗啉基) 烟酰胺;
Ν_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(1,1,-二氧代硫代吗啉基) 烟酰胺;
Ν·{4_甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶 -3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺;
N-[2-甲基 -3-(4'-氟基)苯基]苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰胺;
N-[2-甲基 -3-(3'-氯 -4'-氟)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N-{2-甲基 -3-[2,3-二氢苯并 [b][l,4]-二噁英 -6-基}苯-6-[(28,61 )-2,6-二甲基 吗啉基]烟酰胺;
N- {2-甲基 -3-[3,-氟 -4,- (三氟甲基)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]
烟酰胺;
N-[2-甲基 -3-(3,,4'-二氟)苯基]苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰胺; N-{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(3R)-3-甲基哌嗪 -1-基〗 烟酰胺;
N-{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(3S)-3-甲基哌嗪 -1-基卵 酰胺;
N_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-苄基哌嗪 -1-基)烟酰 胺;
N-{4-甲基 -5-[4,- (三氟甲氧基)苯基; J }吡啶 -3-基 -6-(4-乙酰基哌嗪 -1-基)烟酰 胺;
N_{4_甲基 _5_[4,— (三氟甲氧基)苯基] }吡啶 _3_基 _6_(4_环丙基酰基哌嗪小基) 烟酰胺;
N-{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-甲磺酰基哌嗪 -1-基)烟 酰胺;
N-{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-羟基哌嗪 -1-基)烟酰 胺;
N_{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶 -3-基 -6-(4-甲基 -1,4-二氮杂卓 -1- 基)烟酰胺;
N-{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(3,5-二甲基哌嗪 -1-基)烟 酰胺;
Ν·{2_甲基 _3_[4'- (二氟甲基)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N_[2_甲基 _3_(4'_氟基)苯基]苯基 _6_(U'_二氧代硫代吗啉基)烟酰胺;
N-[2-甲基 -3-(4,-氟基)苯基]苯基 -6-(3,5-二甲基哌嗪小基)烟酰胺;
N_[2_甲基 _3_(4,_氟基)苯基]苯基 _6_(4_环丙基酰基哌嗪小基)烟酰胺;
N-[2-甲基 -3-(4,-氟基)苯基]苯基 -6-(4-羟基哌嗪小基)烟酰胺;
Ν·{4_甲基 _5_[4'_ (二氟甲氧基)苯基] }吡啶 _3_基 _6_[(2S,6R)_2,6_二甲基吗啉 基]烟酰胺;
N-{4-甲基 -5-[4'- (二氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺。
本发明的通式 I化合物合成方法可按照下列反应路线 I或 π所示的步骤进 行制备:
反应路线 I
步骤 1 : 式 Id的多取代或单取代的苯硼酸起始原料与式 lc的取代的溴代 苯胺通过 Suzuki偶联反应制备式 lb的中间体。
其中, Suzuki 偶联反应的方法可以参考文献 (Kotha, S.; Lahiri, K and Kashinath, D. Tetrahedron 2002, 48, 9633-9695)中的方法; 使用的钯催化剂可以 选自于双三苯基磷二氯化钯 (Pd(PPh3)2Cl2)、 四 (三苯基膦)钯(Pd(PPh3)4)、 乙酸 钯(Pd(OAc)2)、 [1,1'-双 (二苯基膦基)二茂铁]二氯化钯 (Pd(dppf)Cl2)以及氯化钯 (PdCl2);反应温度在 80°C至 160°C ;反应溶剂可以选自于 1,4-二氧六环、甲苯、 乙醇以及水; 无机碱可以选择碳酸钠、 碳酸钾等。
例如, 苯硼酸与 3-氨基溴苯在催化剂为四 (三苯基膦)钯 (Pd(PPh3)4), 无机 碱为碳酸钠, 反应溶剂为甲苯、 乙醇以及水的混合溶液中, 加热到 100°C-130 °C, 反应 12小时得到相对应的产物。
步骤 2: 取代杂环羧酸特别是取代烟酸与式 lb的中间体缩合制备相应的 式 la的酰胺化合物。
其中,制备酰胺的反应可选择将取代烟酸与氯化亚砜或者草酰氯反应的方 法制备相应的取代烟酰氯,随后与式 lb的化合物缩合制备得到相应的式 la的 化合物; 也可选择 DCC (二环己基碳二亚胺)、 EDC (1-乙基 -3-(3-三甲氨丙基)
碳二亚胺)、 HATU (2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯)、 TBTU (0-苯并三氮唑 -Ν,Ν,Ν',Ν'-四甲基脲四氟硼酸酯)、 DIC (Ν,Ν'-二异丙基碳 二亚胺)等缩合剂制备相应的式 la的酰胺; 也可选择将取代烟酸与 CDI (Ν,Ν'- 羰基二咪唑)等一些试剂反应制备相应的活泼酰胺,然后制备对应的式 la酰胺。
其中, 所选用的碱可以选自于三乙胺、 二异丙基乙胺 (DIPEA)、 吡啶、 二 甲氨基吡啶 (DMAP)等; 反应溶剂可选自于二氯甲垸、 四氢呋喃、 1,4-二氧六 环、 N,N-二甲基甲酰胺 (DMF)等溶剂; 反应温度可选择 0°C至室温。
步骤 3: 可选择相对应的式 la化合物与对应的胺或其它具有亲核取代活 性的试剂进行反应来生成式 I化合物。
其中, 反应溶剂可选自于二甲基亚砜 (DMSO)、 N,N-二甲基甲酰胺 (DMF)、 N-甲基吡咯垸酮、 乙醇以及异丙醇等溶剂; 在选自于三乙胺、二异丙基乙基胺 (DIPEA)、 碳酸钾、 碳酸铯或碳酸钠等碱的作用下, 反应温度在 80°C-240°C, 与相应的式 la化合物反应制备对应的式 I化合物。
反应路线 II
1f I
反应路线 II中的化合物 I的合成通法详细描述如下。
步骤 1 : 取代杂环羧酸特别是取代烟酸与式 lc化合物缩合制备相应的式 le的酰胺化合物。
其中,制备酰胺的反应可选择将取代烟酸与氯化亚砜或者草酰氯反应的方 法制备相应的取代烟酰氯,随后与式 lc的化合物缩合制备得到相应的式 le的
化合物; 也可选择 DCC (二环己基碳二亚胺)、 EDC(1-乙基 -3-(3-三甲氨丙基) 碳二亚胺)、 1^1^(2-(7-偶氮苯并三氮唑)-:^,>1,:^, 1'-四甲基脲六氟磷酸酯)、 TBTU(0-苯并三氮唑 -Ν,Ν,Ν·,Ν'-四甲基脲四氟硼酸酯)、 DIC(N,N'-二异丙基碳 二亚胺)等缩合剂制备相应的式 le的酰胺; 也可选择将取代烟酸与 CDI(N,N'- 羰基二咪唑)等一些试剂反应制备相应的活泼酰胺,然后制备对应的式 le酰胺。
其中, 所选用的碱可以选自于三乙胺、 二异丙基乙胺 (DIPEA)、 吡啶、 二 甲氨基吡啶 (DMAP)等; 反应溶剂可选自于二氯甲烷、 四氢呋喃、 1,4-二氧六 环、 N,N-二甲基甲酰胺 (DMF)等溶剂; 反应温度可选择 0°C至室温。
步骤 2: 可选择相对应的式 le化合物与对应的胺或其它具有亲核取代活 性的试剂 (A)进行反应来生成式 If化合物。
其中, 反应溶剂可选自于二甲基亚砜 (DMSO)、 Ν,Ν-二甲基甲酰胺 (DMF)、 N-甲基吡咯垸酮、 乙醇以及异丙醇等溶剂; 在选自于三乙胺、二异丙基乙基胺 (DIPEA) 碳酸钾、 碳酸铯以及碳酸钠等的碱的作用下, 反应温度在 80Ό-240 V, 与相应的式 le化合物反应制备对应的式 If化合物。
步骤 3: 多取代或单取代的苯硼酸与式 If的中间体通过 Suzuki偶联反应 制备式 I化合物。
其中, Suzuki 偶联反应的方法可以参考文献 (Kotha, S. ; Lahiri, K and Kashinath, D. Tetrahedron 2002, 48, 9633-9695)中的方法; 使用的钯催化剂可以 选自于双三苯基磷二氯化钯 (Pd(PPh3)2Cl2)、 四 (三苯基膦)钯(Pd(PPh3)4)、 乙酸 钯(Pd(OAc)2)、 [1,Γ-双 (二苯基膦基)二茂铁]二氯化钯 (Pd(dppf)Cl2)以及氯化钯 (PdCl2); 反应温度在 80°C-160°C ; 反应溶剂可以选自于 1,4-二氧六环、 甲苯、 乙醇以及水; 无机碱可以选择碳酸钠、 碳酸钾等。
例如, 苯硼酸与 3-氨基溴苯在催化剂为四 (三苯基膦)钯 (Pd(pph3)4), 无机 碱为碳酸钠, 反应溶剂为甲苯、 乙醇以及水的混合溶液中, 加热到 100°C-130 °C, 反应 12小时得到相对应的产物。
本发明化合物可能含一个或多个手性碳原子, 因此,本发明化合物可以作 为对映异构体、非对映异构体或它们的混合物存在。上述化合物可以选择外消 旋体、非对映异构体或对映异构体作为原料或中间体。非对映化合物可由结晶 或色谱法分离。对映异构体也可经由结晶、手性色谱或其他已知方法分离。每 个不对称碳原子可以是 R或 S构型, 两种构型都在本发明范围之内。
本发明包括上述化合物的前药。 前药包括已知的氨基保护基和羧基保护 基,在生理条件下被水解或经由酶反应释放得到母体化合物;本发明的前药特 指与氨基形成的前药,通常由本发明化合物中的活泼氮原子与活化的酰基化合 物反应制备而得。具体的前药制备方法可参照(Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B and Vysa, D. M. Bioorg. Med. Chem Lett. 1994, 4, 1985-1990. Greenwald, R. B. ; Choe, Y. H.; Conover, C. D.; Shum, K.; Wu, D.; Royzen, M. J. Med. Chem. 2000, 43, 475.) 。
通常,本发明化合物可以与一种或多种药用载体形成适合的剂型施用。这 些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例 如, 皮下、 肌肉、 静脉等) 。 例如, 适合口服给药的剂型包括胶囊、 片剂、 颗 粒剂以及糖浆等。 这些制剂中包含的本发明的化合物可以是固体粉末或颗粒、 水性或非水性的溶液或是混悬液、油包水或水包油的乳剂等。上述剂型可由本 发明化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体 需要与本发明化合物或其他辅料兼容。对于固体制剂,常用的无毒载体包括但 不限于甘露醇、 乳糖、 淀粉、 硬脂酸镁、 纤维素、 葡萄糖、蔗糖等。 用于液体 制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。 本发明化合物可与上述载体形成溶液或是混悬液。
具体的给药方式和剂型取决于化合物本身的理化性质以及所应用疾病的 严重程度等。
一方面, 本发明的化合物或剂型适用于热血动物; 在另一方面, 本发明的 化合物和剂型适用于哺乳动物, 比如人类。
本发明的化合物可抑制 hedgehog信号转导,因此用于治疗当 ptchl不能或 不能充分抑制 Smo (Ptchl失功能表型)时和 /或当 Smo在 Ptchl抑制的情况下 依然具有活性 (Smo获功能表型) 时异常的 Hedgehog通路有关的肿瘤。
本发明化合物可以单独应用于基底细胞癌和髓母细胞瘤等肿瘤,也可以与 其他药物组合施用于(但不限于)胰腺癌、 乳腺癌、 脊膜瘤、 恶性胶质瘤、 黑 色素瘤、 胃癌、 食道癌、 胆管癌、 前列腺癌、 结肠癌、 小细胞肺癌、 非小细胞 肺癌、 神经胶质细胞癌以及多发性骨髓瘤等。
可以与本化合物联用的药物包括但不限于吉西他滨、顺铂、卡铂、格列卫、 替莫唑胺、阿霉素、达卡巴嗪、特罗凯、依托泊苷、柔红霉素以及阿糖胞苷等。
本发明的组合物以符合医学实践规范的方式配制、定量和给药。给予化合 物的 "有效量"由要治疗的具体病症、 治疗的个体、病症的起因、 药物的靶点 以及给药方式等因素决定。通常,一般经胃肠道外给药的剂量是 1 - 200 mg/kg。 口服给药的剂型可以含有 1-1000 mg/kg本发明的化合物。
实施例
下文所描述的实验、合成方法以及所涉及的中间体是对本发明的阐明,并 不限制本发明的范围。
本发明中实验所使用的起始原料或购买自试剂供应商或经由标准方法由 已知原料制备。 除非另有说明, 本文的实施例应用下述条件- 温度的单位是摄氏度 (°C ) ; 室温的定义是 18-25°C ;
有机溶剂使用无水硫酸镁或无水硫酸钠干燥;使用旋转蒸发仪在减压升温 条件下旋干(例如: 15 mmHg, 30°C ) ;
柱层析纯化时使用硅胶作为载体, TLC表示硅胶薄层板;
通常情况下, 反应的进度通过 TLC或 LC-MS监测;
最终产品的鉴定由核磁共振(Bruker AVANCE 300, 300 MHz)和 LC-MS ( Bruker esquine 6000, Agilent 1200 series ) 完成。
制备实施例 1: N-{2-甲基 -3-[4,- (三氟甲基)苯基】}苯基 -6-吗啉烟酰胺的合
1 ) 制备式 1-3的 3-氨基 -2-甲基 -4,-三氟甲基联苯:
称取 3-溴 -2-甲基苯胺 (1.0 g, 5.4 mmol,式 1-1化合物)、 4-三氟甲基苯硼酸 (1.3 g, 6.8 mmol,式 1-2化合物)、双三苯基磷二氯化钯 (0.4 g, 0.54 mmol)以及碳
酸钠 (1.7 g, 16.0 mmol)置于微波合成反应管中, 氮气保护, 微波加热至 120°C 反应 30 min。 反应完毕后过滤除去不溶物, 滤液用水稀释, 乙酸乙酯萃取, 有 机相用盐水洗涤, 无水硫酸钠干燥。减压除去溶剂, 粗品经柱层析纯化(洗脱 剂为正己垸:乙酸乙酯 8:1 ),得黄色固体(1.3 g,得率 90.0%,式 1-3化合物)。
'H-NMR (300 MHz, DMSO-d6) δ: 7.65 (d, 2H, «/ = 8.1 Hz), 7.42 (d, 2H, J =
8.1 Hz), 7.09 (t, 1H, J= 7.8 Hz), 6.75 (d, 1H, J= 7.8 Hz), 6.67 (d, 1H, J= 7.5 Hz), 3.86 (br, 2H), 2.04 (s, 3H).
MS (ESI, m/z): [M+H]+ 251.9
2)制备式 1-5的 6-氯 -N-(2-甲基 -4'-三氟甲基联苯基)烟酰胺:
将 3-氨基 -2-甲基 -4,-三氟甲基联苯(1.3 g, 5.2 mmol,式 1-3化合物)、 6-氯 代烟酸 (1.06 g, 6.73 mmol,式 1-4化合物)和 1-(3-二甲氨基丙基 )-3-乙基碳二亚 胺盐酸盐 (EDCI, 1.5 g, 7.83 mmol)混合溶于 15 mL吡啶中, 于室温搅拌反应 20 ho TLC检测反应, 反应完毕后, 除去溶剂, 油状物溶于乙酸乙酯, 依次用水、 饱和食盐水洗涤, 无水硫酸钠干燥。 除去溶剂的粗品, 经硅胶柱层析纯化(正 己垸:乙酸乙酯 10:1~3:1梯度洗脱) , 得白色固体(1.4 g, 得率 69.2%,式 1-5 化合物) 。
'H-NMR (300 MHz, DMSO-d6) δ: 8.90 (d, 1Η, J= 2.1Hz), 8.21 (dd, 1H, J = 2.1 Hz, J= 8.1Hz), 7.82 (d, 1H, J= 7.8 Hz), 7.69 (d, 3H, J= 8.1 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.35 (t, 1H, J = 7.8 Hz), 7.15 (d, 1H, J = 7.5 Hz), 2.20 (s, 3H).
MS (ESI, m/z) [M+H]+ 391.1
3 )制备式 1-7的 N-[(2-甲基 -4'-三氟甲基联苯基)]烟酰胺基吗啉:
称取 6-氯 -N-(2-甲基 -4'-三氟甲基联苯基)烟酰胺 (50 mg, 0.13 mmol,式 1-5 的化合物)、 吗啡啉 (55 mg, 0.64 mmol, 式 1-6化合物)及碳酸钾 (37 mg, 0.27 mmol)置于微波合成反应管中, 加入 1〜2 mL的 DMSO, 微波加热至 180°C反 应 30 min。 反应完毕后将反应物滴加至 10 mL水中, 收集析出的固体, 用水、 正己垸洗涤, 干燥, 得粗品。 经薄层色谱硅胶制备板纯化, 得类白色固体(37 mg, 得率 64.5%, 式 1-7化合物) 。
!H-NMR (300 MHz, DMSO-d6) δ: 9.81 (s, 1Η), 8.78 (d, 1Η, J= 2.4 Hz), 8.11 (dd, 1H, J= 2.1 Hz, J= 9.0 Hz), 7.83 (d, 2H, J= SA Hz), 7.56 (d, 2H, J= 8.1 Hz), 7.40 (d, 1H, J= 6.9 Hz), 7.32 (t, 1H, J- 7.5 Hz), 7.16 (dd, 1H, J= 7.5Hz), 6.93 (d,
1H, J= 9.0 Hz), 3.71 (t, 4H, J= 4.2 Hz), 3.59 (t, 4H, J= 5.1 Hz), 2.09 (s, 3H).
MS (ESI, m/z): [M+H]+ 442.2
制备实施例 2: N-{2-甲基 -3-[4'- (三氟甲氧基)苯基 1}苯基 -6-[(2R,6S)-2,6-二 甲基吗啉】哒嗪 -3-酰胺的合成
1 )制备式 2-3的 N-(3-溴 -2-甲基苯基) -6-氯哒嗪 -3-酰胺:
冰浴下, 将 3-溴 -2-甲基苯胺 (372.1 mg, 2.0 mmol,式 2-1化合物)、 6-氯哒 嗪 -3-酸 (317.1 mg, 2.0 mmol,式 2-4化合物)、 1-(3-二甲氨基丙基 )-3-乙基碳二亚 胺盐酸盐 (EDCI, 766.8 mg, 4.0 mmol)混合溶于 10 mL吡啶中, 室温搅拌过夜, 减压除去吡啶, 残渣用乙酸乙酯溶解, 有机相用水洗(3次, 每次各 5 mL) , 用无水硫酸钠干燥。 过滤, 浓縮, 硅胶柱层析纯化 (洗脱剂为正己垸:乙酸乙 酯 5:1 ) , 得白色固体(265.0 mg, 得率 40.6%,式 2-3化合物) 。
!H-NMR (300 MHz, CDC13) δ: 9.95 (s, 1Η), 8.48 (d, 1Η, J= 8.7 Hz), 8.05 (d, 1H, J= 8.1 Hz), 7.77 (d, 1H, J= 8.7 Hz), 7.47 (d, 1H, J= 8.1 Hz), 7.16 (t, 1H, J = 8.1 Hz), 2.51 (s, 3H).
MS (ESI, m/z): [M+H]+ 327.9
2)制备式 2-5的 N-(3-溴 -2-甲基苯基) -6-[(2R,6S)-2,6-二甲基吗啉]哒嗪 -3- 酰胺:
将 N-(3-溴 -2-甲基苯基) -6-氯哒嗪 -3-酰胺(100 mg, 0.31 mmol,式 2-3化合
物)、(2R,6S)-2,6-二甲基吗啉 (0.19 mL, 1.5 mmol,式 2-4化合物)和碳酸钾 (126.7 mg, 0.92 mmol)混合溶于 4 mL N,N-二甲基甲酰胺中,在微波合成仪 130 °C 反 应 lO min, 冷却, 反应液倒入冰水中, 析出白色固体, 抽滤, 干燥, 得白色固 体 (122 mg, 得率 98.4%, 式 2-5化合物) 。
'H-NMR (300 MHz, CDC13) δ: 9.81 (s, 1H), 8.12 (t, 2H, J= 3.3 Hz), 7.41 (d,
1H, J= 8.1 Hz), 7.12 (t, 1H, J= 8.1 Hz), 7.02 (d, 1H, J= 9.6 Hz), 4.30 (d, 2H, J= 13.2 Hz), 3.75 (m, 2H), 2.77 (dd, 2H, J= 10.8 Hz, J= 12.9 Hz), 2.50 (s, 3H), 1.30 (d, 6H, J= 6.3 Hz).
MS (ESI, m/z): [M+H]+ 405.2
3 )制备式 2-7的 N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6- 二甲基吗啉]哒嗪 -3-酰胺:
在氮气保护下,将 N-(3-溴 -2-甲基苯基) -6-[(2R,6S)-2,6-二甲基吗啉]哒嗪 -3- 酰胺(100 mg, 0.20 mmol,式 2-5化合物)、 4-三氟甲氧基苯硼酸 (61.4 mg, 0.30 mmol,式 2-6化合物)、双三苯基磷二氯化钯 (27.9 mg, 0.04 mmol)和碳酸钠(63.3 mg, 0.60 mmol)加入到 4 mL 1,4-二氧六环和水(3:1 ) 的混合溶剂中, 在微 波合成仪 130 V 反应 60 min, 抽滤, 硅胶柱层析(洗脱剂为正己垸: 乙酸乙 酯 1 :4) , 得白色固体(50.0 mg, 得率 51.6 %, 式 2-7化合物) 。
!H-NMR (300 MHz, CDC13) δ: 9.85 (s, 1Η), 8.23 (m, 2Η), 7.30 (m, 5H), 7.06 (m, 2H), 4.30 (d, 2H, J= 12.3 Hz), 3.76 (br, 2H), 2.78 (t, 2H, J= 11.4 Hz), 2.25 (s, 3H), 1.30 (m, 6H).
MS (ESI, m/z): [M+H]+ 487.3
制备实施例 3: N-{4-甲基 -3-【4'- (三氟甲氧基)苯基】}苯基 -6-【(2R,6S)-2,6-二 甲基吗啉】烟酰胺的合成
1 )制备式 3-3的 N-(3-溴 -4-甲基苯基) -6-氯-烟酰胺:
将 3-溴 -4甲基苯胺 (169 mg, 1.07 mmol,式 3-1化合物 ),6-氯代烟酸化合物 (200 mg, 1.07 mmol,式 3-2化合物)和 1-(3-二甲氨基丙基 )-3-乙基碳二亚胺盐酸 盐 (EDCI)混合溶于 15 mL吡啶, 于室温搅拌反应 20 h。 TLC检测反应, 反应 完毕后, 除去溶剂, 油状物溶于乙酸乙酯, 依次用水、饱和食盐水洗涤, 无水 硫酸钠干燥。 除去溶剂得黄色固体(300 mg, 得率 85.8%, 式 3-3化合物) 。
Ή-NMR (300 MHz, CDC13) δ: 8.96 (s, 1H), 8.49 (s, 1H), 8.3 l(d, 1H, J= 8.1 Hz), 8.21 (dd, 1H, J= 2.1 Hz, J = 8.4 Hz), 7.50 (d, 1H «7= 8.4 Hz), 7.30 (d, 3H, 7= 7.8 Hz), 7.09 (d, 1H, J= 7.5 Hz), 2.46 (s, 3H).
LC-MS (m/z): [M+H]+ 326.9
2)制备式 3-5的 N-(3-溴 -4-甲基苯基) -6-[(2R,6S)-2,6-二甲基吗啉]烟酰胺: 称取 N-(3-溴 -4-甲基苯基) -6-氯-烟酰胺 (100 mg, 0.31 mmol,式 3-3化合 物), (2R,6S)-2,6-二甲基吗啉 (180 mg, 1.54 mmol,式 3-4化合物)及碳酸钾 (85 mg, 0.61 mmol)置于微波管中,加入 1~2 mL的 DMF,微波加热至 150°C反应 30 min。 反应完毕后将反应物滴加至 10 mL水中, 收集析出的固体, 用水、 正己垸洗 涤, 干燥, 得粗品。 经薄层色谱硅胶预制备板纯化, 得黄色固体 (67 mg, 得 率 53.5%, 式 3-5化合物) , 无需纯化, 直接用于下一步。
LC-MS (m/z): [M+H]+ 406.0
3 )制备式 3-7的 N-{4-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6- 二甲基吗啉]烟酰胺:
称取 N-(3-溴 -4-甲基苯基) -6-[(2R,6S)-2,6-二甲基吗啉]烟酰胺 (67 mg, 0.16 mmol,式 3-5化合物), 4-三氟甲氧基苯硼酸 (51 mg, 0.25 mmol,式 3-6化合物), 双三苯基磷二氯化钯 (11 mg, 0.016 mmol)和碳酸钠 (53 mg, 0.5 mmol)置于微波 合成管中, 加入 4 mL 1,4-二氧六环和水(3:1 ) 的混合溶剂, 加入氮气保护, 在微波合成仪中加热至 120°C反应 30 min。 反应完毕后过滤除去不溶物, 滤液 用水稀释, 乙酸乙酯萃取, 有机相用盐水洗涤, 无水硫酸钠干燥。减压除去溶 剂,粗品经柱层析纯化(洗脱剂为正己垸:乙酸乙酯 =8:1 ),得白色固体(15 mg, 得率 19.3 %, 式 3-7化合物) 。
!H-NMR (300 MHz, CDC13) δ: 8.3 l(d, 1Η, J = 8.1 Hz), 8.20 (d, 1H, J = 2.4 Hz,), 7.57 (dd, 1H, J= 2.1 Hz, J= 9.0 Hz), 7.37 (m, 5H), 7.08 (d, 1H, J= 7.8 Hz), 6.51 (d, 1H, J= 9.3 Hz), 4.13 (m, 2H), 3.66 (m, 2H), 2.58 (t, 2H, J= 10.8 Hz), 2.07 (s, 3H), 1.23 (s, 6H).
LC-MS (m/z): [M+H]+ 486.3
制备实施例 4: N-{4-甲基 -5-【4'- (三氟甲氧基)苯基】 }吡啶 -3-基 -6-(4-甲磺酰 基哌嗪 -1-基)烟酰胺的合成
1 )制备式 4-3的 4-甲基 -3-硝基 -5-[4- (三氟甲氧基)苯基]吡啶:
称取 3-溴 -4-甲基 -5-硝基吡啶 (1.0 g, 4.6 mmol,式 4-1化合物), 4-三氟甲氧 基苯硼酸 (1.2 g, 6.0 mmol,式 4-2化合物),双三苯基磷二氯化钯 (0.4 g, 0.5 mmol)
和碳酸钠 (1.0 g, 9.2 mmol)置于 25 mL反应瓶中, 加入 5 mL 1,4-二氧六环和水 (5:1 ) 的混合溶剂, 通入氮气保护, 微波下 130°C反应 30分钟。 反应完毕后 过滤除去不溶物, 滤液用水稀释, 乙酸乙酯萃取, 有机相用盐水洗涤, 无水硫 酸钠干燥。 减压除去溶剂, 粗品经柱层析纯化 (洗脱剂为正己垸:乙酸乙酯 =8:1 ) , 得黄色固体(0.86 g, 得率 48.1 %, 式 4-3化合物) 。
画 R (300 MHz, CDC13) δ: 9.71 (s, 1H), 8.63 (s, 1H), 7.35-7.26(m, 4H), 2.47 (s, 3H).
LC-MS (m/z): [M+H]+ 299.1
2) 制备式 4-4的 4-甲基 -5-[4- (三氟甲氧基)苯基]吡啶 -3-氨基:
称取 4-甲基 -3-硝基 -5-[4- (三氟甲氧基)苯基]吡啶 (0.86 g, 2.9 mmol,式 4-3 化合物)和钯碳 (0.1 g)置于 100 mL反应瓶中, 以氢气置换空气三次, 在室温下 反应 4小时。 反应完毕后过滤除去不溶物, 滤液蒸干, 得褐色固体 (0.74 g, 得率 95.2 %, 式 4-4化合物) 。
'H-NMR (300 MHz, CDC13) δ: 8.60 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.34-7.17 (m, 4H), 2.06 (s, 3H).
LC-MS (m/z): [M+H]+ 269.1
3 )制备式 4-6的 6-氯 -N-{4-甲基 -5-[(4,-三氟甲氧基)苯基]吡啶 -3-基}烟酰 胺:
将 4-甲基 -5-[4- (三氟甲氧基)苯基] P比啶 -3-氨基 (0.74 g, 2.8 mmol,式 4-4化 合物), 6-氯烟酸 (0.57 g, 3.6 mmol, 式 4-5化合物)和 1 -(3-二甲氨基丙基 )-3-乙 基碳二亚胺盐酸盐 (EDCI) (0.81 g, 4.2 mmol)混合溶于 10 mL吡啶,于室温搅拌 反应 20 h。 TLC检测反应, 反应完毕后, 除去溶剂, 油状物溶于乙酸乙酯, 依次用水、饱和食盐水洗涤, 无水硫酸钠干燥。粗品经柱层析纯化(洗脱剂为 正己垸:乙酸乙酯 =2:1 ) , 得白色固体 (0.65 g,得率 57.0 %,式 4-6化合物) 。
!H-NMR (300 MHz, CDC13) δ: 9.05-9.04 (m, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.29-8.26 (m, 1H), 7.99-7.96 (dd, 1H, J= 2·4Ηζ, J= 8.4Hz), 7.51-7.39 (dd, 2H, J= 8.4Hz, J= 30.3Hz), 7.37-7.35 (m, 3H), 2.45 (s, 3H).
LC-MS (m/z): [M+H]+ 408.1
4) 制备式 4-8 N-{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-甲磺酰
基哌嗪 -1-基)烟酰胺:
将 6-氯 -N-{4-甲基 -5-[(4,-三氟甲氧基)苯基] P比啶 -3-基}烟酰胺 (50 mg, 0.12 mmol,式 4-6化合物 ),1-甲磺酰基哌啶 (101 mg, 0.60 mmol,式 4-7化合物)和 N,N-二异丙基乙胺 (DIPEA) (32 mg, 0.24 mmol)混合溶于 2 mL DMSO中, 微波 下 100°C反应 2小时。 TLC检测反应, 反应完毕后, 加入水到没有固体从反应 液中析出, 过滤, 滤饼真空干燥, 滤饼经制备液相色谱柱纯化得白色固体(11 mg, 得率 17.1 %, 式 4-8化合物) 。
lH NMR (300 MHz, DMSO): δ 13.28 (s, 1 Η), 10.20 (s, 1 Η), 8.13-8.03 (m, 4 Η), 7.56 (s, 0.25 Η), 7.41-7.37 (m, 3 Η), 7.33-7.26 (m, 3.5 Η), 7.17-7.14 (m, 1 H) , 7.07 (s, 0.25 H) , 2.11 (s, 3 H).
LC-MS (m/z): [M+H]+ 536.2 实施例化合物:
下列化合物 (表一)利用类似起始原料通过类似于上述方法而制备:
8.72(s, 1H), 8.36 (s, 1H), 7.97 (m, 1H),
7.84 (s, 1H), 7.54 (d, 1H, J = 7.8 Hz),
7.46 (d, 2H, J= 8.7 Hz), 7.29 (m, 2H),
7.10 (d, 2H, J= 8.7 Hz), 6.52 (d, 1H, J
= 2.4 Hz), 4.10 (d, 2H, J = 13.5Hz),
3.63 (m, 2H), 2.55 (m, 2H), 1.22 (d, 6H,
J = 6.3 Hz). 实验实施例 1
以下, 对本发明的化合物进行试验以评价其对于 Hedgehog信号传导途径 的抑制能力。
生物活性筛选试验: (Hedghog信号传导通路 Gli-luciferrase报道基因试验) Gli双荧光素酶报告基因检测实验材料和方法
1.材料
1.1 细胞株: shhLightll, (ATCC:CRL-2795 )
1.2 96孔板: Corning, Cat#3610
1.3 细胞生长培养基: DMEM (Gibco, 1 1995), 力卩 10% NCS (Gibco),加 0.4mG/mL G418 (invitrogen, 10031035), 力口 0.15mg/mL zeocin (invitrogen, R25001)
1.4 细胞诱导培养基: DMEM (Gibco, 1 1995), 力 B 0.5% NCS, 力卩 5mM HEPES, pH 7.4
1.5 诱导剂: A: 20a-hydroxycholesterol (sigma, Cat. H6378), S: 22(s)-hydroxycholesterol (Sigma, Cat. H5884); 诱导条件: A:S = 1 : 1混合, 使其 终浓度分别为 5 μΜ。
1.6 双报告基因试剂盒: Dual-Glo luciferase assay kit: promega (E2920) 1.7 多道移液器
1.8 微孔板振荡器
1.9 酶标仪: Tecan IF200
2.方法
2.1 细胞接种: 取对数生长期的 Shhlightll细胞, 接种于 96孔板, 30,000 cells/?L/100 μί, 37 V, 5% C02 生长两天, 使细胞达到最大生长密度。
2.2 细胞诱导与给药: 将于 96孔板生长两天的细胞从培养箱取出。 吸去
旧的培养基, 加入含诱导剂 (A:S= 1:1, 各 10 μΜ, 2倍终浓度) 的细胞诱导 培养基, 100 μΙ7孔。 然后, 加入含有不同浓度待测样品的细胞诱导培养基(2 倍待测终浓度) , 100 μΙ7孔。 将给药完毕的 96孔板置于 37 V, 含 5% C02 的培养箱, 孵育 40h。
2.3 报告基因检测: 实验开始前, 将 96孔板、 及试剂盒平衡至室温。 吸 去含诱导剂及待测药物的培养基, 加入室温平衡的细胞诱导培养基 50 ul/孔。 然后按照说明书, 加入 Dual-Glo®Luciferase试剂, 50 μΙ7孔。 将 96孔板置于 微孔板振荡器, 室温 10min。 根据 TeCanIF200说明, 测定荧光素酶报告基因。 测定完成后, 加入新配好的 Dual-Glo®Stop & Glo®试剂, 50 μΙ7孔。将 96孔板 置于微孔板振荡器, 室温 lO min后, 测定海肾荧光素酶报告基因。
2.4 根据试剂盒说明书计算抑制率, origins软件对数拟合得到待测化合 物的 IC5。值。 IC5。越低, 表示待测化合物活性越高。
表一中的化合物对于 Hedgehog信号传导途径的抑制能力参照表二 (Gli双 荧光素酶报告基因检测):
* 表示 IC5。=0.1 nM-lO nM
** 表示 IC5。=10 nM-100 nM
*** 表示 IC5。=100 nM-1000 nM
****表示 IC5o=1000 nM-10000 nM
表二
012 *** 034 056 078 ****
013 **** 035 * * * * 057 *** 079
014 *** 036 **** 058 080
015 ** 037 **** 059 *** 081 **
016 ** 038 **** 060 ** 082
017 **** 039 **** 061 083
018 **** 040 **** 062 084
019 041 *** 063 ** 085
020 042 064 **** 086 #
021 **** 043 065 087 **
022 044 *** 066 **
从表二中可以看出, 本发明的化合物对于 Hedgehog信号传导途径可表现 出非常好的体外抑制能力, 从而可用于与 Hedgehog信号传导途径异常激活有 关的肿瘤的治疗。 工业应用性
本发明化合物以及方法可以用来抑制激活的 Hedgehog信号通路,也就是 说可以抑制由于 Hedgehog异常激活所导致的异常生长状态。应用本发明化合 物以及方法, 将足够量的式 I化合物或者式 I化合物与药用载体所形成的药物 组合物与细胞接触, 可以抑制异常激活的 Hedgehog通路从而控制或逆转异常 的生长状态, 从而可在临床上有效地治疗与异常激活的 Hedgehog通路有关的 肿瘤。
Claims
1. 式 I化合物或其药学上可接受的盐或溶剂化物:
X代表 S、 S=0、 S(0)2、 0、 CHR,, 或者 NR12;
Ru代表氢、 氰基、 羟基, 卤素、 C,.6垸基、 .6烷氧基、 -C(0)2R14或者 NR13aR13b, 其中烷基或烷氧基未被取代或者被一个或多个卤素或羟基取代;
R12代表氢、 6垸基、 C3_8杂环垸基 -C,.6垸基、 C3.8杂环垸基、 C6.1()芳基、 。杂芳基、 C6.1()芳基 -d.6垸基、 。杂芳基 - .6垸基、 -C(0)2Rl4、 -C(0)R14 或者 -S(0)2R14;
R13a和 R13b独立地代表氢、未被取代或被一个或多个卤素取代的 _6垸基、 C1-6垸氧基 - .6垸基、 -C(0)2R14、 -S(0)2R14> 。芳基 - .6垸基、 或者 C5.10 杂芳基 -C卜 6院基;
R14代表未被取代或被一个或多个卤素取代的 — 6垸基;
m和 1独立地代表 1 或 2; n代表 0、 1或 2;
!^和 R2独立地代表氢或者 d.6烷基; 其中垸基未被取代或者被一个或多 个卤素或羟基取代;
Y、 Ζ和 U独立地代表氮或 CR11 ;
W和 V独立地代表氮或 CR15;
R15代表氢、 d.6垸基或者 烷氧基,其中垸基或垸氧基未被取代或者被 一个或多个卤素取代;
R3代表氢、 卤素、 氰基、 -6烷基或者 _6烷氧基, 其中垸基或者烷氧基 未被取代或被一个或多个卤素取代;
和 独立地代表氢、 卤素、 .6烷基或者 d.6垸氧基, 其中垸基或者 垸氧基未被取代或被一个或多个卤素取代;
R6和 R7独立地代表氢、 卤素、 .6烷基或者 d_6垸氧基, 其中垸基或者 垸氧基未被取代或被一个或多个^素取代;
和 独立地代表氢、 卤素、 垸基或者 C 垸氧基, 其中烷基或者 垸氧基未被取代或被一个或多个卤素取代, R1()代表氢、 卤素、 氰基、 .6垸 基、 d.6垸氧基、 C6_1Q芳基、 C5.1Q杂芳基、 C3.8环垸基、 C3.8杂环垸基、 C(0)R14、 C(0)2R14、 -SR14、 -S(0)2Ri4或者 NR13aR13b, 其中垸基或垸氧基未被取代或被 一个或多个卤素取代, 并且其中 C3_8杂环垸基未被取代或者被 1 或 2个 d.6 烷基取代, 或者, R1Q与 或 R1()与 R9形成 5或 6元的含氧饱和杂环。
2. 权利要求 1所述的化合物, 其中:
X代表 S、 0、 S=0、 S(0)2、 CHR16或者 NR12, 其中 R16选自于氢、 羟基 或 NR13aR13b;
Y、 Ζ和 U为独立地代表氮或 CR„, 其中 Rn代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基或者三氟甲氧基;
W和 V独立地代表氮或 CH;
R3代表氢、 氟、 氯、 溴、 氰基、 甲基、 三氟甲基、 甲氧基、 乙氧基或者 三氟甲氧基;
和 R5独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基、 乙氧基 或者三氟甲氧基。
3. 权利要求 2所述的化合物, 其中-
Re和 7独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基或者三氟 甲氧基;
R8和 R9独立地代表氢、 氟、 氯、 溴、 甲基、 三氟甲基、 甲氧基或者三氟 甲氧基, R1()代表氟、 氯、 氰基、 甲基、 乙基、 异丙基、 二氟甲基, 三氟甲基、 甲氧基、异丙氧基、二氟甲氧基、三氟甲氧基、环丙基、 甲磺酰基、二甲胺基、 NHS(0)2Me, 吗啉基或者哌嗪基, 其中吗啉基和哌嗪基未被取代或者被 1或 2 个甲基取代, 或者, Ru)与 或 R1()与 R9形成 5或 6元的含氧饱和杂环。
4. 权利要求 3所述的化合物, 其中: ^和 独立地代表氢、 未被取代的甲基或者羟基取代的甲基。
5. 权利要求 4所述的化合物, 其中- 和 独立地代表氢、 氯或者甲基。
6. 权利要求 5所述的化合物, 其中:
X代表 S、 0、 S=0、 S(0)2、 CHR16 以及 NR12, 其中 R12代表甲基、 乙基、 乙酰基、 甲磺酰基、 苄基、 吡啶甲基或者噻唑甲基;
Y、 Ζ和 U独立地代表氮、 CH或者 CF。
7. 权利要求 6所述的化合物, 其中:
m和 1代表 1 ; 当 n代表 0或 2时, R n R2同时为氢;
R6和 1 7独立地代表氢或者氯;
和 独立地代表氢、 甲基、 氟或者氯;
Ru)代表氟、 氯、 甲磺酰基、 甲氧基、 三氟甲氧基、 三氟甲基、 二氟甲基、 二氟甲氧基或者氰基。
8. 权利要求 6所述的化合物, 其中所述化合物选自于:
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6- (哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-甲基哌嗪 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-乙基哌嗪 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪 -1-基]烟酰
N- {2-甲基 -3- -[4,- 〔三氟甲氧基)苯基] }苯基 -6-(4-乙酰基哌嗪- 1 -基)烟酰胺;
N- {2-甲基 -3- -[4'-1 〔三氟甲氧基)苯基] }苯基 -6-(4-苄基哌嗪- 1 -基)烟酰胺;
N- {2-甲基 -3- -[4'-1 〔三氟甲氧基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N- {2-甲基 -3- -[4,- 〔三氟甲氧基)苯基] }苯基 -6-[(3R,5S)-3,5-二甲基哌嗪 -1-基] 烟酰胺,
N- 甲基 -3- -[4'-< 〔三氟甲氧基)苯基] }苯基 -6-吗啉烟酰胺;
N- {2-甲基 -3· -[4'-< 〔氰基)苯基] }苯基 -6-吗啉烟酰胺;
N- {2-甲基 -3. -[4,-| 〔氰基)苯基] }苯基 -6- [(2R,6S)-2,6-二甲基吗啉基]烟酰胺;
N- 甲基 -3· ■[4Ή 〔三氟甲基)苯基] }苯基 -6-吗啉烟酰胺;
N- (2-甲基 -3. ■[4Ή 〔三氟甲基)苯基] }苯基 -6- (哌嗪- 1 -基)烟酰胺;
N- (2-甲基 -3- -[4,-( 〔三氟甲基)苯基] }苯基 -6-(3,5-二甲基哌嗪- 1 -基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉基]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-{ [(3R)-3-N,N-二甲基氨基]四氢 吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-{[(3S)-3-N,N-二甲基氨基]四氢 吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基-6-(4-甲基 -1,4-二氮杂卓 -1-基)烟酰 胺;
N_{2_甲基 _3-[4,- (三氟甲基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-(3,4-甲基哌嗪 -1-基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基-6-(4-苄基哌嗪小基)烟酰胺; 5-{5-{2-甲基 -3-[4,- (三氟甲基)苯基]苯基 -氨基甲酰基 吡啶 -2- 基}-(18,48)-2,5-二氮杂卓杂双环 [2.2.1]庚垸基 -2-甲酸叔丁酯;
5-{5-{2-甲基 -[4,- (三氟甲基)苯基]苯基-氨基甲酰基 吡啶 -2-基}-1,4-二氮 杂卓 -1-甲酸叔丁酯;
N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰胺; N_{2_甲基 _3_[4,- (三氟甲基)苯基] }苯基 -6-[4- (甲磺酰基)哌嗪 -1基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲基)苯基] }苯基 -6-[4- (乙酰基)哌嗪 -1基]烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(4-甲基 -1,4-二氮杂卓 -1-基)烟 酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-{ [(3R)-3-N,N-二甲基氨基]四 氢吡咯 -1-基}烟酰胺;
Ν·{2_甲基 _3_[4,_ (三氟甲氧基)苯基] }苯基 _6-{[(3S)-3-N,N-二甲基氨基]四 氢吡咯 -1-基}烟酰胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(1,4-二氮杂卓小基)烟酰胺; N-{2-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-(2,5-二氮杂卓双环 [2.21]庚烷 -2-基 ]烟酰胺;
N' 2-甲基 -3-[4, 三氟甲氧基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪 -1-基]烟酰
N- 2-甲基 -3-[4,- 三氟甲氧基)苯基] }苯基 -6-[4- (甲磺酰基)哌嗪 -1-基]烟酰
N- 2-甲基 -3-[4,-氰基)苯基] }苯基 -6-(4-甲基- 1,4-二氮杂卓- 1 -基)烟酰胺; N- 2-甲基 -3-[4,. 氰基)苯基] }苯基 -6-{[(3S)-3-N,N-二甲基氨基]四氢吡咯
1-基}烟酰胺;
N- 2-甲基 -3-[4,-'氰基)苯基] }苯基 -6-{[(3R)-3-N,N-二甲基氨基]四氢吡咯
-1-基}烟酰胺;
N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-[(3S)-3-甲基哌嗪 -1-基]烟酰胺; N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-[(3R)-3-甲基哌嗪- 1 -基]烟酰胺; N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-( 1, 1 -二氧代 -硫代吗啉)烟酰胺; N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-(4-苄基哌嗪- 1 -基)烟酰胺;
N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-(3,5-二甲基哌嗪 -1-基)烟酰胺;
N-{2-甲基 -3-[4,- 基)苯基] }苯基 -6-硫代吗啉烟酰胺;
N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-(3,4-二甲基哌嗪 - 1 -基)烟酰胺;
N-{2-甲基 -3-[4, 氰基)苯基] }苯基 -6-(2,5-二氮杂卓双环 [2.2.1]庚烷基 -2- 基)]烟酰胺;
N-{2-甲基 -3-[4,-三氟甲氧基)苯基] }苯基 -6-( 1,4-二氮杂卓- 1 -基)烟酰胺; N-{2-甲基 -3-[4,-氰基)苯基] }苯基 -6-[4-(甲磺酰基)哌嗪- 1 -基]烟酰胺; N-{2-甲基 -3-[4,-二氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]烟酰
N- 2-甲基 -3-[4,· 三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]哒嗪
-3酰胺;
N- 2-甲基 -3-[4,.三氟甲基)苯基] }苯基 -6-[4- (苯基)哌嗪- 1基]烟酰胺; N- 2-甲基 -3-[4,· 三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]烟酰 胺;
N-{2-甲基 -3-[4, <二氟甲氧基)苯基] }苯基 -6-(1,1-二氧代 -硫代吗啉)烟酰 胺; N-{4-甲基 -3-[4,- (三氟甲氧基)苯基] }苯基 -6-[(2R,6S)-2,6-二甲基吗啉]烟酰 胺;
N-{2-甲基 -3-[4,- (三氟甲氧基)苯基; 1}苯基 -6-[4- (吡啶 -3-基)甲基 -哌嗪 -1-基] 烟酰胺;
N一 {2_甲基 _3-[4,- (三氟甲氧基)苯基] }苯基 -6-[4- (吡啶 -4-基)甲基 -哌嗪 -1-基] 烟酰胺;
N一 {2_甲基 _3_[4,— (三氟甲氧基)苯基] }苯基 _6-[4- (吡啶 -2-基)甲基 -哌嗪 -1-基] 烟酰胺;
N-{2-甲基 -3-[4'- (二氟甲氧基)苯基] }苯基 -6-[4-甲磺酰基 -哌嗪 -1-基]烟酰 胺;
N-{2-甲基 -3-[4'- (甲磺酰基)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N_{4-甲基 _5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺;
N-{2_甲基 _3_[4,- (三氟甲氧基)苯基] }苯基 -6-[2-甲基 -1,1,-二氧代硫代吗啉 基]烟酰胺;
N-{2-甲基 -3-[4'- (二氟甲氧基)苯基] }苯基 -6-[2-甲基 -1,1'-二氧代硫代吗啉 基]烟酰胺;
N-{4-甲基 -5-[4,- (二氟甲氧基)苯基] }吡啶-3-基 -6-(1,1'-二氧代硫代吗啉基) 烟酰胺;
N_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(1,1,-二氧代硫代吗啉基) 烟酰胺;
N_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺;
N-[2-甲基 -3-(4'-氟基)苯基]苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰胺; N-[2-甲基 -3-(3,-氯 -4'-氟)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N-{2-甲基 -3-[2,3-二氢苯并 [b][l,4]-二噁英 -6-基}苯-6-[(28,61 )-2,6-二甲基 吗啉基]烟酰胺;
N-{2-甲基 -3-[3,-氟 -4,- (三氟甲基)苯基] }苯基 -6-[(2S,6R)-2,6-二甲基吗啉基] 烟酰胺;
N_[2_甲基 _3_(3,,4,-二氟)苯基]苯基 -6-[(2S,6R)-2,6-二甲基吗啉基]烟酰胺; N-{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(3R)-3-甲基哌嗪 -1-基] 烟酰胺;
N_{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-[(3S)-3-甲基哌嗪 -1-基]烟 酰胺;
N_{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-苄基哌嗪 -1-基)烟酰 胺;
N-{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-乙酰基哌嗪 -1-基)烟酰 胺;
N-{4_甲基 _5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-环丙基酰基哌嗪 -1-基) 烟酰胺;
N_{4_甲基 _5_[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-甲磺酰基哌嗪 -1-基)烟 酰胺;
Ν·{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-羟基哌嗪 -1-基)烟酰 胺;
Ν_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶-3-基 -6-(4-甲基 -1,4-二氮杂卓 -1- 基)烟酰胺;
Ν_{4-甲基 -5-[4,- (三氟甲氧基)苯基] }吡啶 -3-基 -6-(3,5-二甲基哌嗪 -1-基)烟 酰胺;
Ν_{2_甲基 -3_[4,_ (二氟甲基)苯基] }苯基 _6-[(2S,6R)-2,6-二甲基吗啉基]烟酰 胺;
N-[2-甲基 -3-(4'-氟基)苯基]苯基 -6-(1,1'-二氧代硫代吗啉基)烟酰胺; N-[2-甲基 -3-(4,-氟基)苯基]苯基 -6-(3,5-二甲基哌嗪 -1-基)烟酰胺;
N-[2-甲基 -3-(4'-氟基)苯基]苯基 -6-(4-环丙基酰基哌嗪 -1-基)烟酰胺; N-[2-甲基 -3-(4,-氟基)苯基]苯基 -6-(4-羟基哌嗪 -1-基)烟酰胺;
N-{4-甲基 -5-[4,- (二氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺;
N一 {4-甲基 -5-[4,- (二氟甲氧基)苯基] }吡啶-3-基 -6-[(2S,6R)-2,6-二甲基吗啉 基]烟酰胺。
9. 一种作为抑制剂的药物组合物, 其包含治疗有效量的权利要求 1~8之 一所述的式 I化合物或者其药学上可接受的盐或溶剂化物以及适量的可药用载 体。
10.权利要求 1〜8之一所述的式 I化合物在制备用于抑制 Hedgehog通路 的药物中的应用。
11.权利要求 1~8之一所述的式 I化合物作为用于治疗与 Hedgehog通路 异常激活有关的肿瘤的药物中的应用,其中肿瘤选自于基底细胞癌、髓母细胞 瘤、 横紋肌肉瘤、 胰腺癌、 乳腺癌、 脊膜瘤、 恶性胶质瘤、 黑色素瘤、 胃癌、 食道癌、 胆管癌、前列腺癌、 结肠癌、 小细胞肺癌、 非小细胞肺癌、 神经胶质 细胞癌、 多发性骨髓瘤以及白血病。
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