WO2012106995A1 - Rorgammat inhibitors - Google Patents
Rorgammat inhibitors Download PDFInfo
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- WO2012106995A1 WO2012106995A1 PCT/CN2012/071017 CN2012071017W WO2012106995A1 WO 2012106995 A1 WO2012106995 A1 WO 2012106995A1 CN 2012071017 W CN2012071017 W CN 2012071017W WO 2012106995 A1 WO2012106995 A1 WO 2012106995A1
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- Prior art keywords
- indazol
- chloro
- trifluoromethyl
- benzoyl
- fluoro
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- 0 *c(cc1)ccc1C(C1=*S)=*N(*c(c(C(F)(F)F)ccc2)c2Cl)C1=**=C1CC1 Chemical compound *c(cc1)ccc1C(C1=*S)=*N(*c(c(C(F)(F)F)ccc2)c2Cl)C1=**=C1CC1 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C Chemical compound CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- HITLBYVWYPUJKB-UHFFFAOYSA-N CC1(C)OB(c(c(F)c2)cc(F)c2C(OC)=O)OC1(C)C Chemical compound CC1(C)OB(c(c(F)c2)cc(F)c2C(OC)=O)OC1(C)C HITLBYVWYPUJKB-UHFFFAOYSA-N 0.000 description 1
- JFBCLLOUVKHZDW-UHFFFAOYSA-N COC(c(cc(c(Cl)c1)F)c1F)=O Chemical compound COC(c(cc(c(Cl)c1)F)c1F)=O JFBCLLOUVKHZDW-UHFFFAOYSA-N 0.000 description 1
- FICFGVPHMSFOHD-UHFFFAOYSA-N COCc(cc1)cc2c1c(I)n[n]2C(c(c(C(F)(F)F)ccc1)c1Cl)=O Chemical compound COCc(cc1)cc2c1c(I)n[n]2C(c(c(C(F)(F)F)ccc1)c1Cl)=O FICFGVPHMSFOHD-UHFFFAOYSA-N 0.000 description 1
- YPHHPEYBWOUYRY-UHFFFAOYSA-N COc(c(C(O)=O)c(cc1B(O)O)F)c1F Chemical compound COc(c(C(O)=O)c(cc1B(O)O)F)c1F YPHHPEYBWOUYRY-UHFFFAOYSA-N 0.000 description 1
- LFXJCALGZMNDHA-UHFFFAOYSA-N COc1c(C(O)=O)c(F)ccc1F Chemical compound COc1c(C(O)=O)c(F)ccc1F LFXJCALGZMNDHA-UHFFFAOYSA-N 0.000 description 1
- HUDMAQLYMUKZOZ-UHFFFAOYSA-N COc1cc(F)ccc1F Chemical compound COc1cc(F)ccc1F HUDMAQLYMUKZOZ-UHFFFAOYSA-N 0.000 description 1
- IPVAXIUJHXJPFN-UHFFFAOYSA-N Cc1cccc(C)c1C([n](c1ccccc11)nc1-c(cc1)ccc1C(O)=O)=O Chemical compound Cc1cccc(C)c1C([n](c1ccccc11)nc1-c(cc1)ccc1C(O)=O)=O IPVAXIUJHXJPFN-UHFFFAOYSA-N 0.000 description 1
- UJWYJYMPIIEMCI-UHFFFAOYSA-N Cc1n[o]c(C)c1S([n](c1c2cccc1)nc2-c(cc1)ccc1-c1nnn[nH]1)(=O)=O Chemical compound Cc1n[o]c(C)c1S([n](c1c2cccc1)nc2-c(cc1)ccc1-c1nnn[nH]1)(=O)=O UJWYJYMPIIEMCI-UHFFFAOYSA-N 0.000 description 1
- MYKGDAQLKXYOHF-UHFFFAOYSA-N OC(c(cc1)ccc1-c(c1ccccc11)n[n]1S(c1ccccc1C(F)(F)F)(=O)=O)=O Chemical compound OC(c(cc1)ccc1-c(c1ccccc11)n[n]1S(c1ccccc1C(F)(F)F)(=O)=O)=O MYKGDAQLKXYOHF-UHFFFAOYSA-N 0.000 description 1
- ZMLMBQCHASQVQR-UHFFFAOYSA-N OC(c(cc1)ccc1-c1n[n](C(C2CCCCC2)=O)c2ccccc12)=O Chemical compound OC(c(cc1)ccc1-c1n[n](C(C2CCCCC2)=O)c2ccccc12)=O ZMLMBQCHASQVQR-UHFFFAOYSA-N 0.000 description 1
- PAHXSXYLIROUER-UHFFFAOYSA-N OC(c1ccc2c(I)n[n](C(c(c(C(F)(F)F)ccc3)c3Cl)=O)c2c1)=O Chemical compound OC(c1ccc2c(I)n[n](C(c(c(C(F)(F)F)ccc3)c3Cl)=O)c2c1)=O PAHXSXYLIROUER-UHFFFAOYSA-N 0.000 description 1
- MHEWCCAXBJEQPU-UHFFFAOYSA-N OCc1ccc2c(I)n[n](C(c(c(C(F)(F)F)ccc3)c3Cl)=O)c2c1 Chemical compound OCc1ccc2c(I)n[n](C(c(c(C(F)(F)F)ccc3)c3Cl)=O)c2c1 MHEWCCAXBJEQPU-UHFFFAOYSA-N 0.000 description 1
- HZPNZUDECDZTLQ-UHFFFAOYSA-N S=C=[Cs]c1ccccc1 Chemical compound S=C=[Cs]c1ccccc1 HZPNZUDECDZTLQ-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- 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
- A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- C07D471/04—Ortho-condensed systems
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Definitions
- T helper cells Upon activation by antigen-presenting cells naive T helper cells undergo clonal expansion and will ultimately differentiate in cytokine secreting effector T cells, such as Thl and Th2 subtypes.
- cytokine secreting effector T cells such as Thl and Th2 subtypes.
- Thl7 Upon activation by antigen-presenting cells naive T helper cells undergo clonal expansion and will ultimately differentiate in cytokine secreting effector T cells, such as Thl and Th2 subtypes.
- This effector T helper cell subset can be distinguished based on its ability to produce large quantities of IL-17/F, IL-21 and IL-22, and is named Thl7 (Miossec et al, New Eng. J. Med. 2361 : 888-898, 2009).
- Thl and Th2 effector cells express Tbet and GATA3, respectively.
- a Thymocyte/T cell specific variant of Retinoic Acid Receptor-related Orphan Receptor (ROR), RORgammaT is highly expressed in Thl7 cells (He et al., Immunity 9: 797-806, 1998).
- RORgammaT belongs to the nuclear hormone receptor superfamily (Hirose et al., Biochem. Biophys. Res. Comm. 205: 1976-1983, 1994). RORgammaT is a truncated form of
- RORgamma lacking the first N-terminal 21 amino acids and is, in contrast to RORgamma which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle), exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science 288: 2369-2372, 2000; Eberl et al., Nat Immunol. 5: 64-73, 2004).
- RORgammaT was shown to play a crucial role in non-Thl7 lymphoid cells.
- RORgammaT was critically important in innate lymphoid cells expressing Thyl, SCA-1 and IL-23R proteins. Genetic disruption of RORgamma in a mouse colitis model dependent on these innate lymphoid cells, prevented colitis development (Buonocore et al., Nature 464: 1371-1375, 2010).
- RORgammaT was shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol. 184: 3336-3340, 2010).
- RORgammaT has been identified as a key mediator in the pathogenesis of several diseases (Louten et al., J Allergy Clin. Immunol. 123: 1004-1011, 2009; Annuziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009). This was confirmed using several disease models
- autoimmune diseases Genetic ablation of the RORgamma gene in mice prevented the development of experimental autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) and colitis (Ivanov et al., Cell 126: 1121-33, 2006; Buonocore et al, Nature 464: 1371-1375, 2010).
- EAE experimental autoimmune encephalomyelitis
- colitis Ivanov et al., Cell 126: 1121-33, 2006; Buonocore et al, Nature 464: 1371-1375, 2010.
- RORgammaT is expected to have a beneficial effect on autoimmune diseases, such as, but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, and asthma (Annunziato et al., Nat. Rev. Immunol. 5: 325-331, 2009; Louten et al., J Allergy Clin. Immunol. 123: 1004-1011, 2009). Inhibition of RORgammaT may also be beneficial in other diseases, which are characterized by increased levels of Thl7 cells and/or elevated levels of Thl7 hallmark cytokines such as IL-17, IL-22 and IL-23.
- autoimmune diseases such as, but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, and asthma (Annunziato et al., Nat. Rev. Immunol. 5: 325-3
- Examples of such diseases are Kawasaki Disease (Jia et al., Clin. Exp. Immunol. 162: 131-137, 2010) and Hashimoto's thyroiditis (Figueroa-Vega et al., J Clin. Endocrinol. Metab. 95: 953-62, 2010).
- Another example includes infectious diseases, such as, but not limited to, mucosal leishmaniasis (Boaventura et al., Eur. J. Immunol. 40: 2830-2836, 2010). In each of the above examples the inhibition may be enhanced by simultaneous inhibition of RORalpha.
- agonists include T0901317 and SR1078 (Wang et al, ACS Chem. Biol. 5: 1029-1034, 2010).
- antagonist have been reported such as 7-oxygenated sterols (Wang et al., J Biol. Chem. 285: 5013-5025, 2009) and compounds described in EP2181710 Al .
- psoriasis One exemplary immue disorder in need of better therapy is psoriasis.
- Various therapeutics have been developed in an attempt to treat psoriasis.
- the present invention provides compounds which inhibit RORgammaT, their use for the treatment of RORgammaT-mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases, as well as pharmaceutical compositions comprising such compounds and pharmaceutical carriers.
- the present invention provides a compound according to Formula I
- X is C(O), SO or S0 2 ,
- Y is CH or N
- n 0, 1, 2, 3 or 4;
- a -A are independently N or CR , CR , CR or CR , respectively, with the proviso that no more than two of the four positions A 4 -A 7 can be simultaneously N;
- R 1 is (i) (C 3 -7)cycloalkyl or (C 3 -5)heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H 2 NC(0)-, (Ci_
- R 2 is C(0)OH, 5-tetrazoylyl, HOC(CF 3 ) 2 , C(0)OH(Ci.io)alkyl, (Ci.
- R 3 is hydrogen, halogen, cyano, nitro, hydroxy, (Cl-3)alkylC(0)0-, (Ci -4 )alkyl, or (Ci_ 4)alkoxy, wherein (Ci -4 )alkyl and (Ci_4)alkoxy are optionally substituted with one or more halogens;
- R 4 -R 7 independently are H, halogen, amino, cyano, hydroxy, (Ci -3 )alkoxy, (Ci -4 )alkyl, (C 0- io)alkyl)aminocarbonyl, (di)(Ci-6)alkylaminocarbonyl or amino(Ci -4 )alkyl, wherein (Ci_ 3 )alkoxy, (Ci -4 )alkyl, (Co-io)alkyl)aminocarbonyl, (di)(Ci.6)alkylaminocarbonyl and amino(Ci.
- 4 )alkyl are optionally substituted with one or more halogen, hydroxyl or (Ci -3 )alkoxy; or a group having the , optionally substituted with one or more of the following: (Ci-io)alkyl, halogen, amino, cyano, hydroxy, (Ci -3 )alkoxy, and wherein m is 1, 2, 3, or 4.
- This invention also provides a compound according to Formula la
- X represents C(O), SO or S0 2 ,
- Y is CH or N
- a -A' are independently N or CR , CR , CR or CR , respectively, with the proviso that no more than two of the four positions A 4 -A 7 can be simultaneously N;
- R 1 is (C 3- 7)cycloalkyl or (C 3- 5)heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, cyano, hydroxy, H 2 NC(0)-, or (Ci -3 )alkoxycarbonyl, (di)(Ci-6)alkylaminocarbonyl, (Ci -4 )alkyl or (Ci -3 )alkoxy, all optionally substituted with one or more halogens or;
- R 1 is (C 2 -9)heteroaryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H 2 NC(0)-, or (Ci -3 )alkoxycarbonyl, (di)(Ci.
- R 1 is (C 6 -i4)aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H 2 NC(0)-, or (Ci -3 )alkoxycarbonyl, (di)(Ci.6)alkylaminocarbonyl, (Ci_ 4 )alkyl or (Ci -3 )alkoxy, all optionally substituted with one or more halogens;
- R 2 is C(0)OH, 5-tetrazoylyl, or HOC(CF 3 ) 2 ;
- R 3 is independently selected from hydrogen, halogen, cyano, nitro or (Ci -4 )alkyl, optionally substituted with one or more halogens;
- R 4 -R 7 independently are H, halogen, amino, cyano, hydroxy, (Ci -3 )alkoxy, (Ci -4 )alkyl, optionally substituted with one or more halogens.
- a 4 , A 5 , A 6 , A 7 are selected from the group consisting of: (i) CR 4 , CR 5 , CR 6 , CR 7 ; (ii) N, CR 5 , CR 6 , CR 7 ; (iii) CR 4 , N, CR 6 , CR 7 ; (iv) CR 4 , CR 5 , N, CR 7 ; (v) CR 4 , CR 5 , CR 6 , N; (vi) N, N, CR 6 ,CR 7 ; (vii) CR 4 , N, N, CR 7 ; (viii) CR 4 , CR 5 , N, N; (ix) N, CR 5 , N, CR 7 ; (x) CR 4 , N, CR 6 , N; and (xi) N, CR 5 , CR 6 , N.
- a 4 , A 5 , A 6 , A 7 are selected from the group consisting of: (i) CR 4 , CR 5 , CR 6 , CR 7 ; (ii) N, CR 5 , CR 6 , CR 7 ; and (iii) CR 4 , N, CR 6 , CR 7 .
- a 4 , A 5 , A 6 , A 7 is (i) CR 4 , CR 5 , CR 6 , CR 7 , or (ii) N, CR 5 , CR 6 , CR 7 ; and Y is N.
- X is C(O) or S0 2 ;
- R 1 is (i) (C 3- 7)cycloalkyl or (C 3- 5)heterocycloalkyl, both optionally substituted with one or more groups selected from (Ci -4 )alkyl or halogen; (ii) (C 2- 9)heteroaryl, optionally substituted with one or more groups selected from halogen, amino or (Ci -4 )alkyl; or (iii) (C 6 -i 4 )aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl, (Ci -3 )alkoxy, wherein (Ci -3 )alkoxycarbonyl, (Ci_ 4 )alkyl and (Ci -3 )alkoxy are optionally substituted with one or more halogens.
- R 1 is (i) (C 3- 7)cycloalkyl or (C
- R 1 is (C 2- 9)heteroaryl or (C 6 -i4)aryl, both optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl or (C ⁇ . 3 )alkoxy, wherein (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl and (Ci -3 )alkoxy are optionally
- Rl is (C 6 -i 4 )aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, or (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl or (Ci -3 )alkoxy, all optionally substituted with one or more halogen.
- R 1 is phenyl, naphthyl, pyridinyl, quinolinyl, benzooxadiazolyl, thiophenyl, or isoxazolyl, each optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (Ci_
- R 1 is phenyl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl or (Ci -3 )alkoxy, wherein (Ci -3 )alkoxycarbonyl, (Ci -4 )alkyl and (Ci -3 )alkoxy are optionally substituted with one or more halogens.
- a tenth subset of the invention relates to compounds according to Formula I and la wherein Y is N.
- X is C(O) or S0 2
- R is selected from halogen, amino, cyano, nitro, hydroxy, H 2 NC(
- x is 0, 1, 2, 3, 4 or 5; and A 4 -A 7 , R J -R 3 , Y and n are defined as set forth hereinabove for Formula I.
- a 4 -A 7 , R 3 , X and n are defined as set forth hereinabove for Formula I.
- la, lb, Ic, Id, and le are compounds wherein
- R 4 is selected from H, halogen, amino, and optionally substituted with one or more halogen;
- R 5 is H
- R 6 is selected from H, dimethylaminocarbonyl, -CH2NH2, cyano, onally substituted with one or more halogen, hydroxyl,
- R7 is selected from H and halogen.
- a still further embodiment of the compounds of Formula I, la, lb, Ic, Id, and le are compounds wherein one of R 4 , R 5 and R 7 is other than hydrogen.
- the invention also relates to those compounds wherein all specific definitions for A 1 through A 4 , R 1 through R 8 , X, Y, n and x and all substituent groups in the various aspects of the inventions defined here above occur in any combination within the definition of the compound of Formula I.
- Non-limiting examples of the compunds of the present invention include:
- alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms.
- an alkyl group contains, for example, from 1 to 6 carbon atoms (Ci- C 6 alkyl) or from 1 to 3 carbon atoms (C 1 -C3 alkyl).
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
- an alkyl group is linear. In another embodiment, an alkyl group is branched.
- alkyl includes both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms; for example, “C 1-6 alkyl” (or “Ci-C 6 alkyl”) includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- Alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments; for example, the term “A-C 4 alkylene-B” represents, for example, A-CH 2 - CH 2 -CH 2 -CH 2 -B, A-CH 2 -CH 2 -CH(CH 3 )-CH 2 -B, A-CH 2 -CH(CH 2 CH 3 )-B, A-CH 2 - C(CH 3 )(CH 3 )-B, and the like.
- Alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example “Ci-Ce alkoxy” includes -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -0(CH 2 ) 5 CH 3 , and the like.
- alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, Ci-C 20 alkyl, CF 3 , NH 2 , N(C C 6 alkyl) 2 , N0 2 , oxo, CN, N 3 , -OH, -0(C C 6 alkyl), C 3 - C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(O) 0-2 -, (C 0 -C 6 alkyl)S(O) 0-2 (C 0 - C 6 alkyl)-, (Co-C 6 alkyl)C(0)NH-, H 2 N-C(NH)-, H 2 N-C(0)(NH)-, -0(Ci-C 6 alkyl
- NHC(0)OCi-C 6 alkyl -NH(Ci-C 6 alkyl)NHS0 2 (Ci-C 6 alkyl), -(C 0 -C 6 alkyl)NHS0 2 (Ci-C 6 alkyl), aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano- heterocyclylalkyl.
- alkenyl means a straight or branched carbon chain having the specified number of carbon atoms with at least one carbon-carbon double bond.
- alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, 2,4-hexadienyl, and the like.
- alkynyl means a straight or branched carbon chain having the specified number of carbon atoms with at least one carbon-carbon triple bond.
- alkynyl include, but are not limited to ethynyl, propargyl, 1-propynyl, 2-butynyl, and the like.
- carbocycle (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C 3 to C 8 monocyclic, saturated or unsaturated ring or (ii) a C 7 to C 12 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either attached via a bond to, or fused (including spirofused) to, the other ring, and each ring is saturated or unsaturated.
- the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
- Saturated carbocyclics form a subset of carbocycles in which the entire ring system (mono- or polycyclic) is saturated.
- Saturated monocyclic carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
- the fused bicyclic carbocycles are a further subset of the carbocycles in which a C 7 to C 10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms (or in the case of spirofused, one carbon atom) are shared by each of the rings in the ring system.
- a saturated bicyclic carbocycle is one in which both rings are saturated.
- An unsaturated bicyclic carbocycle is one in which one ring is unsaturated and the other is unsaturated or saturated. Unless otherwise noted, carbocycle is unsubstituted or substituted with C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, halogen, NH 2 or OH.
- a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound.
- Aromatic carbocycles form another subset of the carbocycles.
- aryl refers to aromatic mono- and poly-carbocyclic ring systems in which the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenyl.
- cycloalkyl means a cyclic ring of an alkane having the specified total ring carbon atoms; for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- heterocycle (and variations thereof such as “heterocyclic” or
- heterocyclyl broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 7- to 12-membered bicyclic ring system, wherein each ring in (ii) is either attached via a bond to, or fused (including spirofused) to, the other ring, and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized.
- heteroatoms e.g., from 1 to 6 heteroatoms, or
- the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
- the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
- saturated heterocyclics form a subset of the heterocycles; i.e., the term “saturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
- saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
- Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, 1 ,4-dioxanyl, 1 ,4-thioxanyl,
- Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
- heteroaryl generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
- heteroaryl refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12- membered bicyclic aromatic ring, and which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
- substituted heteroaryl rings containing at least one nitrogen atom e.g., pyridine
- substitutions can be those resulting in N-oxide formation.
- monocyclic heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
- bicyclic heteroaromatic rings include
- benzotriazolyl indolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, isoindolyl, indazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrazolo[3,4-b]pyridine, imidazo[2,l-b](l,3)thiazole, (i.e., 6-(l-pyrrolyl)-3 -pyridyl, 4-(l-pyrrolyl)phenyl, 4-(pyrid-3-yl)phenyl, and 4- (pyrid-4-yl)phenyl.
- heterocycles are unsaturated heterocycles in which one or both rings are unsaturated (provided the entire ring system is not aromatic).
- unsaturated heterocycles include dihydrofuranyl, dihydrothienyl, dihydropyranyl,
- dihydroimidazolyl indolinyl, isoindolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, 2,3-dihydrobenzofuranyl, 1,4- benzoxazinyl, 1,3-benzoxazolin l 2 3-dih drobenzo-l -dioxinyl (i.e., eft 0 ), and benzo-
- 1,3-dioxolyl i.e., ).
- phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
- groups such as chromone and coumarin.
- cycloalkyl Unless otherwise specifically noted as only unsubstituted or only substituted, cycloalkyl, cycloalkenyl, cycloalkyl, aryl (including phenyl) and heteroaryl groups are unsubstituted or substituted (also referred to as "optionally substituted").
- substituents for substituted or optionally substituted cycloalkyl, cycloalkenyl, aryl (including phenyl, and as an isolated substituent or as part of a substituent such as in aryloxy and aralkyl), heteroaryl (as an isolated substituent or as part of a substituent such as in heteroaryloxy and heteroaralkyl) are one to three groups independently selected from halogen (or halo), Ci-C 6 alkyl optionally substituted with one to five fluorine, NH 2 , N(Ci-C 6 alkyl) 2 , N0 2 , oxo, CN, N 3 , -OH, -0(Ci-C 6 alkyl) optionally substituted with one to five fluorine, C 3 -Cio cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (Co-C 6 alkyl)S(0)
- halogen refers to fluorine, chlorine, bromine and iodine
- fluoro F
- chloro CI
- bromo Br
- iodo I
- haloalkyl means alkyl having the specified number of carbon atoms in which from one to all of the hydrogen atoms have been replaced by a halogen atom.
- aralkyl and “heteroaralkyl” refer to an aryl/heteroaryl linked to the rest of the molecule via a Ci to C 4 alkylene.
- Co as employed in expressions such as "C 0- 6 alkylene” means a direct covalent bond; or when employed in experessions such as "C 0- 6 alkyl” means hydrogen.
- an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond; for example, in the , wherein s is an integer equal to zero, 1 or 2, the structure is when s is zero; or it means that the indicated atom is absent; for example -S(0)o- means -S-.
- an “unsaturated” ring is a partially or fully unsaturated ring.
- an “unsaturated monocyclic C 6 carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
- heterocycle described as containing from “ 1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
- any variable occurs more than one time in any constituent or in any formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- Ri is a defined variable
- Rj is a defined variable
- the value of Ri may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs.
- Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl
- (CRiRj) 2 can be
- the term as used hereinabove means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n- pentyl and n-hexyl. Preferred is (C 1-4 )alkyl.
- the term means a branched or unbranched alkyl group having 1-5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and n-pentyl.
- the term as used herein means a branched or unbranched alkyl group having 1-4 carbon atoms, being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
- the term means an alkoxy group having 1-3 carbon atoms, the alkyl moiety being branched or unbranched.
- the term means an alkoxycarbonyl group having 1-3 carbon atoms in the alkoxy moiety, the alkoxy moiety having the same meaning as previously defined.
- (di)(Ci-6)alkylaminocarbonyl means an alkylaminocarbonyl group, the amino group of which is monosubstituted or disubstituted independently with an alkyl group which contains 1-6 carbon atoms and which has the same meaning as previously defined.
- Preferred alkyl group is (C 1-4 )alkyl.
- (C 3 _7)cycloalkyl means a cycloalkyl group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 5-6 Carbon atoms are preferred.
- heterocycloalkyl means a heterocycloalkyl group having 3-5 carbon atoms, including 1-3 heteroatoms selected from N, O and/or S, which may be attached via a nitrogen if feasible, or a carbon atom.
- Preferred number of heteroatoms is one or two. Most preferred number is one.
- Preferred heteroatoms are N or O. Most preferred are piperazinyl, tetrahydropyranyl, morpholinyl and pyrrolidinyl.
- (C 2 -9)heteroaryl means an aromatic group having 2-9 carbon atoms and 1-3 heteroatoms selected from N, O and S, like imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, thiophenyl or furyl, pyrazolyl, isoxazolyl or quinolyl. Preferred number of heteroatoms is one or two. Preferred heteroaryl groups are pyrazolyl, thiophenyl, isoxazolyl, pyridyl and quinolyl.
- the (C 2 -5)heteroaryl group may be attached via a carbon atom or a nitrogen, if feasible.
- (C 6- i4)aryl means an aromatic hydrocarbon group having 6-14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, anthracyl, More preferred are (C 6- io)aryl groups.
- the most preferred aromatic hydrocarbon group is phenyl.
- X a -Xb shall have the same meaning as the term "X a- b", wherein X is any atom and a and b are any integers.
- C 1 -C4 shall have the same meaning as “C 1-4 ".
- a x shall have the same meaning, and be interchangeable with, “AX”, wherein “A” is any atom and “x” or “X” are any integer.
- R 1 shall have the same meaning, and be
- the attachment point is at the last group.
- substituted means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- Stable compound or “stable structure” is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. When, in the definition of a substituent, is indicated that "all of the alkyl groups" of said substituent are optionally substituted, this also includes the alkyl moiety of an alkoxy group.
- salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
- effective amount refers to an amount of the compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from an RORgammaT-mediated disease or disorder.
- effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
- a “subject” is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a chimpanzee.
- the compounds of this invention include the prodrugs, hydrates or solvates of the compounds.
- the compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
- the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
- Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
- the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
- the above Formula I is shown without a definitive stereochemistry at certain positions.
- the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof.
- Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column.
- any enantiomer or diastereomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g.
- the compounds of Formula (I) may be atropisomers (e.g. substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula I may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
- All stereoisomers for example, geometric isomers, optical isomers and the like
- of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers.
- Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
- Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources.
- organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N'-dibenzyl- ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
- ethanolamine ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
- the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids.
- Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
- Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- the compounds of Formula I can form salts which are also within the scope of this invention.
- Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
- pharmaceutically acceptable salt represents those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are
- salts are well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like.
- the acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium carbonate, ammonium (e.g. diethylamine) or lithium hydroxide.
- solvate refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute.
- solvents include, but are not limited to water, ethanol, and acetic acid.
- the solvent is water
- the solvate is known as hydrate; hydrate includes, but is not limited to, hemi-, mono, sesqui-, di- and trihydrates.
- the compounds of the invention may form hydrates or solvates.
- Solids of the invention may also mean a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
- Solvate encompasses both solution-phase and isolatable solvates.
- suitable solvates include ethanolates, methanolates, and the like.
- the present invention includes within its scope the use prodrugs of the compounds of this invention.
- prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
- the term “administering” shall encompass the treatment of the various conditions described with a compound of formula I or with a compound which may not be a compound of formula I, but which converts to a compound of formula I in vivo after administration to the patient.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.
- prodrugs means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
- prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
- different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- Compounds of the present invention are inhibitors of Retinoic Acid Receptor-related Orphan Receptor gamma t (RORgammaT), and as such are useful in the treatment of diseases and conditions in which inhibition of RORgammaT is desirable, such as autoimmune and inflammatory diseases and disorders.
- RORgammaT Retinoic Acid Receptor-related Orphan Receptor gamma t
- another embodiment of the present invention provides a method for treating a disease or condition mediated by RORgammaT in a subject comprising
- the compounds according to the invention can be used in therapy.
- a further aspect of the invention resides in the use of compounds according to the invention or a pharmaceutically acceptable salt thereof for the treatment of RORgammaT- mediated diseases or RORgammaT mediated conditions.
- Another aspect of the invention resides in the use of compounds or a pharmaceutically acceptable salt thereof having the general formula I for the treatment of autoimmune diseases, in particular those diseases in which Thl7 cells and non-Thl7 cells, which express Thl7 hallmark cytokines play a prominent role.
- autoimmune diseases in particular those diseases in which Thl7 cells and non-Thl7 cells, which express Thl7 hallmark cytokines play a prominent role.
- These include, but are not limited to, the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease and multiple sclerosis.
- compounds or a pharmaceutically acceptable salt thereof having the general formula I can be used for treatment of inflammatory diseases in which Thl7 cells and/or non-Thl7 cells, which express Thl7 hallmark cytokines play a prominent role such as, but not limited to respiratory diseases, osteoarthritis and asthma.
- compounds or a pharmaceutically acceptable salt thereof having the general formula I can be used for treatment of infectious diseases in which Thl7 cells and/or non-Thl7 cells, which express Thl7 hallmark cytokines play a prominent role such as, but not limited to mucosal leishmaniasis.
- Compounds or a pharmaceutically acceptable salt thereof having the general formula I can also be used for treatment of other diseases in which Thl7 cells and/or non-Thl7 cells, which express Thl7 hallmark cytokines play a prominent role such as, but not limited to Kawasaki disease and Hashimoto's thyroiditis.
- the disease or condition is an autoimmune disease or inflammatory disease.
- the disease or condition includes, but is not limited to, multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis or mucosal leishmaniasis.
- the compounds according to the invention can be used in therapies to treat or prevent multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis and mucosal leishmaniasis.
- the compounds according to the invention can be used to treat or prevent psoriasis.
- the compounds according to the invention can be used to treat inflammatory bowel disease.
- This aspect of the present invention further includes the use of a compound of Formula I, la, lb, Ic, Id or Ie, or a pharmaceutically acceptable salt or solvate thereof, in the
- the compounds of this invention can be administered for the treatment or prevention of afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal.
- administration can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral.
- parenteral refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.
- a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
- the compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- the dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
- a daily dosage of active ingredient compound will be from about 1.0-2000 milligrams per day. Ordinarily, from 10 to 500 milligrams per day in one or more applications is effective to obtain desired results.
- These dosages are the effective amounts for the treatment and prevention of afflictions, diseases and illnesses described above, e.g., autoimmune and inflammatory diseases and disorders.
- compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administration, and the like, all in unit dosage forms for administration.
- the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
- the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
- sterile liquid carrier e.g. water
- the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
- the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
- solid dosage units For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
- Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
- aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing
- dispersing agents and/or wetting agents such as propylene glycol or butylene glycol.
- compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable excipients.
- excipient and “carrier” may be used interchangeably.
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
- compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.
- solid dosage forms such as capsules, tablets, troches, dragees, granules and powders
- liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions.
- the active ingredient can also be
- sterile liquid dosage forms such as dispersions, suspensions or solutions.
- Other dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.
- Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene gycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
- Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
- the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
- the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
- the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
- MDI metered dose inhalation
- an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of Formula I in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
- Useful pharmaceutical dosage-forms for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions.
- a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
- a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
- the capsules are washed and dried.
- a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
- Appropriate coatings may be applied to increase palatability or delay absorption.
- a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
- An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S. P., and 0.025 milliliters of vanillin.
- the same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent.
- the dosage form and administration route should be selected depending on the compatibility of the combined drugs.
- coadministration is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents.
- the auxiliaries must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
- the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
- compositions thereof may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered. In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a dosage for humans preferably contains 0.0001-100 mg per kg body weight. The desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day. The dosage as well as the regimen of administration may differ between a female and a male recipient.
- Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent.
- the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
- a compound of formula (I) may be combined with one or more other active agents such as: (1) TNF-a inhibitors; (2) non- selective COX-I/COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for treatment of inflammatory and autoimmune diseases including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine
- the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
- compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
- These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.
- the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions.
- the individual compounds will be administered simultaneously in a combined pharmaceutical composition.
- Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
- compositions of the present invention include those that also comprise at least one additional therapeutically active agent, in addition to the compound of Formula I, la, lb, Ic, Id or Ie.
- the invention further includes a compound of Formula I in combination with one or more other drug(s).
- ferrocene ]dichloropalladium (II); BnBr: Benzyl bromide; DAST: (Diethylamino)sulfur trifluoride; Ac 2 0: Acetic an hydride; LiHMDS: Lithium bis(trimethylsilyl)amide; PhNTf 2 : N- Phenyl-bis(trifluoro methanesulfonimide); S-Phos: 2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl; X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; CPME: Cyclopentyl methyl ether.
- Example i-1 Preparation of methyl 2-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (i-1) Scheme i-1.
- Methyl 4- (benzyloxy)-2-(trifluoromethylsulfonyloxy)benzoate (i-lc) (6.8 g, 17.4 mmol), 4,4,5,5- tetramethyl-2-(prop-l-en-2-yl)-l ,3,2-dioxaborolane (2.9 g, 17.4 mmol), Pd(OAc) 2 (195 mg, 0.87 mmol), S-Phos (71 mg, 0.174 mmol) and K 3 PO 4 (1 1 g, 52 mmol) were mixed in THF (70 ml). The mixture was stirred at 75 °C for 24 h. The mixture was diluted with H 2 0, and extracted with EtOAc. The combined organics were dried and concentrated.
- Example i-4 Preparation of methyl 2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (i-4) i) Preparation of methyl 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2- yl)benzoate (i-4). To a flask was added compound (i-4a) (412 mg, 2.0 mmol), compound (i- 2c) (1.52 g, 6 mmol), X-Phos (95 mg, 0.2 mmol), Pd(OAc) 2 (44 mg, 0.2 mmol) and CPME (20 mL).
- Example i-7 methyl 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)benzoate (i-7)
- heterocyclic derivatives of Formula I wherein A 4 to A 7 , R 1 , R 2 , R 3 , X and Y are as previously defined, can be prepared from compounds II.
- Palladium catalyzed Suzuki- Miyaura arylation of compounds II using appropriately substituted phenylboronic acids Ill-a (corresponding boronic esters Ill-b may also be used) directly affords the desired compounds I.
- aqueous NaOH, K 2 C0 3 or the like) and an aryl boronic acid of general Formula III- a or aryl boronic ester of general formula Ill-b in a suitable solvent such as dioxane or toluene/EtOH, is heated under an atmosphere of nitrogen under microwave irradiation or using conventional heating.
- compound I may be obtained from compounds of Formula IV, in which FG is a functional group (e.g. ester, cyano, protected tetrazole) that can be easily converted to groups defined for R 2 .
- suitable functional groups in compounds IV are a tert-butyl ester or methyl ester or a tetrazole, containing an acid labile group such as a? ra-methoxy benzyl protecting group, which can be treated with acid or base to afford compounds of Formula I-a or I-b in which R 2 is carboxyl or 5-tetrazolyl, respectively.
- Compounds II are prepared by straightforward acylation or sulfonylation of compounds V.
- a strong base such as potassium tert- butoxide or NaH
- a suitable solvent such as DMF or THF
- treatment of V with sulfonyl chlorides and a tertiary amine base e.g. DiPEA or triethylamine
- a solvent such as dichloromethane
- acid chlorides are not available, they can be easily prepared from the corresponding carboxylic acids using known methods (e.g. treatment with SOCl 2 or similar reagents).
- Compounds V are commercially available or prepared by methods know in the art, such as halogenation of compounds VI.
- Compounds VI are also commercially available or easily prepared by standard organic synthesis techniques.
- Compounds IV can be prepared in the same way as compounds I, by Suzuki-Miyaura reaction between compounds of general Formula II and an appropriately substituted arylboronic acid or ester.
- Hal Br, CI, I ⁇ , ⁇ I V-U. A - U
- Electro Spray spectra were recorded on the Applied Biosystems API- 165 single quad MS in alternating positive and negative ion mode using Flow Injection. The mass range was 120-2000 Da and scanned with a step rate of 0.2 Da. and the capillary voltage was set to 5000 V. N2-gas was used for nebulasation.
- UPLC Water acquity UPLC system; Column : BEH C18 1.7 ⁇ , 2.1 x 100 mm, Detector: PDA (200-320 nm), Mass detector: SQD
- step ii) Following a procedure analogous to that described in Example 1, step ii, using 1,1,1,3,3,3- hexafluoro-2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol as the boronic ester, the title compound 1,1,1 ,3 ,3 ,3-hexafluoro-2-(4-(l -(2-
- reaction mixture was stirred at 150 °C in a microwave reactor for lh
- step iii Following a procedure analogous to that described in Example 10, step iii, the title compound, 4-( 1 -(2-(trifluoromethvnphenylsulfonyl -iH-indazol-3-yl)benzoic acid, was prepapred (28 mg)
- step iii Following a procedure analogous to that described in Example 10, step iii, the title compound, 4-(l-(2-cyanophenylsulfonyl)-iH-indazol-3-yl)benzoic acid, was prepapred (13 mg)
- reaction mixture 100 °C in a microwave reactor. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate.
- trimethylsilyl azide (4.02 g, 35 mmol) and dibutyl-stannanone (434 mg, 1.75 mmol) were added into each microwave vessel and the mixtures were irradiated again at 150 °C for 10 min. After cooling to room temperature, the mixtures were combined and purified by column chromatography on florisil (200 g). It was first eluted with 20% dichloromethane in hexane to remove the impurities, then with 10% methanol in dichloromethane to elute the product.
- step ii) (7.92 g, 20.2 mmol) were dissolved in 100 ml of a 1 to 1 mixture of 1,4-dioxane and water under a nitrogen atmosphere.
- step i) To a solution of a mixture of regio-isomers of 3-(4-(l-(4-Methoxybenzyl)-7H-tetrazol-5- yPphenyl H-indazole (Example 20, step i) (50 mg, 0.13 mmol) was dissolved in anhydrous THF (1 ml). After addition of t-BuOK (16 mg, 0.14 mmol,) the reaction mixture was stirred at room temperature for 15 min. Subsequently, 2,6-dichlorobenzoyl chloride (21 ⁇ , 0.14 mmol) was added and the reaction mixture was stirred for another 2h at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in
- step iii Following a procedure analogous to that described in Example 20, step iii, the product obtained in the previous step was converted to the title compound (3-(4-(7H-tetrazol-5- vDphenyl H-indazol- 1 -yl)(2,6-dichlorophenyl)methanone (16 mg).
- A-5 A-6 24A i) Preparation of 4-fluoro-3-iodo-/H-indazole (A-2).
- DMF 80 mL
- h 18.6 g, 73.5 mmol
- KOH 7.73 g, 134 mmol
- the reaction mixture was poured into aq. 10% NaHS0 3 (200 mL) and extracted with EtOAc (200 mL*3).
- the combined organic layers were washed with H 2 0 and brine, dried over Na 2 S0 4 , and concentrated.
- the compounds of the invention inhibit RORgammaT activity. Activation of
- RORgammaT activity can be measured using e.g. biochemical TR-FRET assay.
- TR-FRET interaction of cofactor-derived peptides with human RORgammaT-Ligand Binding Domain (LBD) can be measured.
- LBD RORgammaT-Ligand Binding Domain
- the TR-FRET technique is a sensitive biochemical proximity assay that will give information concerning the interaction of a ligand with the LBD, in the presence of cofactor derived peptides (Zhou et al., Methods 25:54-61, 2001).
- a peptide from Steroid Receptor Co-factor 1 box 2 (SRC 1 2) is aminoterminal biotinylated (biotinyl-CPSSHSSLTERHKILHRLLQEGSPS, NEOMPS, France) and the applied RORgamma-LBD contains a 6-His and GST tag.
- 6His(GST)RORgamma-LBD was expressed and purified from baculovirus infected Sf-21 insect cells (Bac-to-BAC, Invitrogen) and purified using glutathione sepharose
- streptavidin-allophycocyanin Streptavidin-allophycocyanin (Strep-APC, Perkin Elmer, CI 30- 100) and anti-His-Europium Cryptate (Perkin Elmer, AD0111), respectively. Since energy transfer between the streptavidin and His-coupled labels APC and europium cryptate can only take place when these labels are in close proximity, measurement of energy transfer in a mixture of biotinylated peptide, His-GR-LBD, streptavidin- APC and anti-His-Europium Cryptate will be indicative for RORy-LBD/peptide binding.
- Final assay conditions in 50 ⁇ are: TR-FRET buffer [50 mM KC1, 50 mM TRIS, 1 mM Na-EDTA, 0.1 mM DTT, (pH 7.0)];
- Dose-response data are curve-fitted (IBDS Software, ActivityBase) and pEC50 values calculated.
- pEC50 values for Examples 1-23 using Protocol A are provided in Table 6 below. All compounds of the invention have a pEC50 of 4 or higher. Preferred are compounds with a pEC50 of more than 5.
- HIS-tagged RORy-LBD was recombinantly expressed in SF9 cells using a baculovirus expression system. The protein was not purified. Cells were lysed and the lysate was used as a source for RORy-LBD for the assay. A 1 :80 dilution of RORy-LBD lysate in assay buffer (25 mM HEPES pH 7.0, 100 mM NaCl, 0.01% Tween, 0.1% BSA) was prepared and 5 was added to each well (RORy-LBD final concentration ⁇ 10 nM). Control wells received lysate from SF9 cells not expressing RORy-LBD.
- assay buffer 25 mM HEPES pH 7.0, 100 mM NaCl, 0.01% Tween, 0.1% BSA
- a 4x stock of biotinylated-LXXLL peptide from SRC 1-2 was prepared in assay buffer and & 5 ⁇ , aliquot added to each well (450 nM final concentration).
- a 4x solution of europium tagged anti-HIS antibody (2 nM final concentration) and APC conjugated streptavidin (60 nM final concentration) were prepared and & 5 ⁇ , aliquot added to each well.
- IC50 values for test compounds were calculated from the quotient of the fluorescence signal at 665 nm divided by the fluorescence signal at 615 nm using GraphPad Prism software.
- HIS-tagged RORy-LBD protein was expressed in SF9 cells using a baculovirus expression system.
- the RORy-LBD protein was purified by glutathione sepharose chromatography. Separately, SF9 cells not expressing any recombinant protein were lysed and the lysate was added to the purified RORy-LBD at 0.25 ⁇ lysate (from 10,000 SF9 cells)/nM purified protein. The mixture was then diluted in assay buffer (50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT) to obtain RORy-LBD final concentration of 3 nM in 384-well assay plate.
- assay buffer 50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT
- a stock of biotinylated-LXXLL peptide from coactivator SRC1 (Biotin- CPSSHSSLTERHKILHRLLQEGSPS) was prepared in assay buffer and added to each well (100 nM final concentration).
- Table 7 below tabulates the biological data disclosed for Examples 24A-29 as a range of Fret IC 50 values, which was reported as ranges according to the annotation delineated below:
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Abstract
Description
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Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
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US13/983,818 US9095583B2 (en) | 2011-02-11 | 2012-02-10 | RORgammaT inhibitors |
EP12744370.3A EP2683693B1 (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors |
JP2013552823A JP5934721B2 (en) | 2011-02-11 | 2012-02-10 | RORγT inhibitor |
CN201280018025.3A CN103748076A (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors |
KR1020137023663A KR20140044791A (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors |
AU2012214029A AU2012214029A1 (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors |
MX2013009149A MX2013009149A (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors. |
BR112013020352A BR112013020352A2 (en) | 2011-02-11 | 2012-02-10 | compound, pharmaceutical composition, use of a compound and method for treating median rorgamat disease or condition in an individual |
CA2828059A CA2828059A1 (en) | 2011-02-11 | 2012-02-10 | Rorgammat inhibitors |
RU2013141528/04A RU2013141528A (en) | 2011-02-11 | 2012-02-10 | RORGAMMAT RECEPTOR INHIBITORS |
US14/752,195 US9603838B2 (en) | 2011-02-11 | 2015-06-26 | RORgammaT inhibitors |
US15/463,371 US9884043B2 (en) | 2011-02-11 | 2017-03-20 | RORgammaT inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP11154188A EP2487159A1 (en) | 2011-02-11 | 2011-02-11 | RorgammaT inhibitors |
EP11154188.4 | 2011-02-11 |
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US14/752,195 Division US9603838B2 (en) | 2011-02-11 | 2015-06-26 | RORgammaT inhibitors |
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EP (2) | EP2487159A1 (en) |
JP (1) | JP5934721B2 (en) |
KR (1) | KR20140044791A (en) |
CN (1) | CN103748076A (en) |
AU (1) | AU2012214029A1 (en) |
BR (1) | BR112013020352A2 (en) |
CA (1) | CA2828059A1 (en) |
MX (1) | MX2013009149A (en) |
RU (1) | RU2013141528A (en) |
WO (1) | WO2012106995A1 (en) |
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-
2011
- 2011-02-11 EP EP11154188A patent/EP2487159A1/en not_active Withdrawn
-
2012
- 2012-02-10 WO PCT/CN2012/071017 patent/WO2012106995A1/en active Application Filing
- 2012-02-10 AU AU2012214029A patent/AU2012214029A1/en not_active Abandoned
- 2012-02-10 CA CA2828059A patent/CA2828059A1/en not_active Abandoned
- 2012-02-10 CN CN201280018025.3A patent/CN103748076A/en active Pending
- 2012-02-10 MX MX2013009149A patent/MX2013009149A/en unknown
- 2012-02-10 JP JP2013552823A patent/JP5934721B2/en not_active Expired - Fee Related
- 2012-02-10 EP EP12744370.3A patent/EP2683693B1/en active Active
- 2012-02-10 RU RU2013141528/04A patent/RU2013141528A/en not_active Application Discontinuation
- 2012-02-10 KR KR1020137023663A patent/KR20140044791A/en not_active Application Discontinuation
- 2012-02-10 US US13/983,818 patent/US9095583B2/en active Active
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2015
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US9884043B2 (en) | 2018-02-06 |
EP2683693B1 (en) | 2017-04-05 |
JP5934721B2 (en) | 2016-06-15 |
US9095583B2 (en) | 2015-08-04 |
MX2013009149A (en) | 2014-02-17 |
AU2012214029A8 (en) | 2013-10-17 |
EP2683693A4 (en) | 2014-10-08 |
BR112013020352A2 (en) | 2017-08-08 |
US20170340610A1 (en) | 2017-11-30 |
EP2683693A1 (en) | 2014-01-15 |
US20140038942A1 (en) | 2014-02-06 |
AU2012214029A1 (en) | 2013-08-29 |
EP2487159A1 (en) | 2012-08-15 |
CA2828059A1 (en) | 2012-08-16 |
CN103748076A (en) | 2014-04-23 |
KR20140044791A (en) | 2014-04-15 |
JP2014509316A (en) | 2014-04-17 |
US9603838B2 (en) | 2017-03-28 |
RU2013141528A (en) | 2015-03-20 |
US20150297566A1 (en) | 2015-10-22 |
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