WO2001083445A1 - Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle - Google Patents

Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle Download PDF

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WO2001083445A1
WO2001083445A1 PCT/KR2001/000687 KR0100687W WO0183445A1 WO 2001083445 A1 WO2001083445 A1 WO 2001083445A1 KR 0100687 W KR0100687 W KR 0100687W WO 0183445 A1 WO0183445 A1 WO 0183445A1
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compound
oxo
hydrogen
biphenyl
acid
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PCT/KR2001/000687
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English (en)
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Young-Jun Park
Choon-Ho Ryu
Ji-Uk Yoo
Myeong-Yun Chae
Sang-Hyun Paek
Kyung-Chul Kim
Jeoung-Wook Lee
Hye-Kyung Min
Hae-Young Bae
Eu-Gene Oh
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Samsung Electronics Co., Ltd.
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Priority claimed from KR10-2000-0021835A external-priority patent/KR100405914B1/ko
Priority claimed from KR10-2000-0021834A external-priority patent/KR100405913B1/ko
Application filed by Samsung Electronics Co., Ltd. filed Critical Samsung Electronics Co., Ltd.
Priority to CA002377629A priority Critical patent/CA2377629A1/fr
Priority to JP2001580874A priority patent/JP2003531894A/ja
Priority to AU52759/01A priority patent/AU5275901A/en
Priority to EP01926225A priority patent/EP1189882A1/fr
Publication of WO2001083445A1 publication Critical patent/WO2001083445A1/fr

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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Definitions

  • the present invention relates to biphenyl butyric acid derivatives, more specifically, to novel biphenyl butyric acid derivatives represented as the following general formula (I) , useful as matrix metalloproteinase inhibitor and pharmaceutically acceptable salts thereof and a process for preparing the compounds.
  • Matrix metalloproteinase is a Ca 2+ -dependent proteinase containing zinc ion(Zn 2+ ) at its active site.
  • matrix metalloproteinases including stromelycin, collagenase and a family of gelatinase have been identified in the art.
  • MMP degrades various extracellular matrix components of collagen, laminin, proteoglycan, fibronectin, elastin and gelatin under biological conditions, which, in turn, leads to growth of articulation tissue, bone tissue and connective tissue, and remodeling of the tissues.
  • MMP is secreted as an inactive form of proenzyme, which is subsequently activated in extracellular side, together with a naturally occuring inhibitor, TIMP (tissue inhibitor of metalloproteinase) .
  • TIMP tissue inhibitor of metalloproteinase
  • MMP inhibitor is useful to prevention and treatment of all sorts of diseases caused by overexpression or overactivation of MMP.
  • diseases are, for example, rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis, invasion or growth of tumor cell, autoimmune disease, disease caused by vascular emigration or infiltration of leukocytes, arterialization (s_e_e_: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994).
  • MMP inhibitor has an anti-cancer activity in vivo along with inhibition of basement membrane remodeling in the mouse model bearing ovarian cancer (see: Cancer Res., 53:2087, 1993).
  • MMP-2 and MMP-9 among the above MMP enzymes play an essential role in angiogenesis required for the growth of cancer cells (see: Biochim. Biophys .
  • MMP-1 and MMP- 3 among MMP enzymes play an important role in the progress of arthritis as observed in much higher concentration than normal in the synovium and cartilage of a patient of rheumatoid arthritis ( ⁇ e_£: Arthritis Rheum., 35:35-42, 1992), the selectivity to MMP-l/MMP-2 is considered to play a crucial role in reducing side effects such as arthralgia. Therefore, researches have been made while focusing on the development of selective inhibitors, and many MMP inhibitors have been designed and synthesized in many aspects ( ⁇ e ⁇ : J.
  • MMP are known. In general, they have a zinc binding group (“ZBG") , which is coordinated to the zinc ion of MMP enzymes at the active site of them.
  • ZBGs include hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol and so forth ( ⁇ e_ ⁇ : WO 92/09564; WO
  • the peptide-mimic inhibitors are known to contain a hydroxamic acid as a ZBG and display a broad spectrum for MMP enzymes.
  • non-peptide inhibitors were developed to solve the said problems which are substantially distinguished in terms of chemical structure from the above peptide-mimic inhibitors having simple sulfonyl amino acid derivative represented as a chemical formula below (s_e_e_: USP 5,506,242; J. Med. Chem., 40:2525-2532, 1997).
  • new sulfonamide derivatives have been designed and synthesized, by changing PI' of the above sulfonamide inhibitor which binds to SI' sub-site of the enzymes. While the above sulfonamide inhibitors have relatively high inhibitory activity against MMP, they do not have a higher selectivity to MMP-l/MMP-2 as compared with previous peptide-mimic inhibitors. Some of them have also side effect of arthralgia in clinical trials (s_e_e_: Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery & Development, 3:353-361, 2000; Exp. Opin. Invest.
  • biphenyl butyric acid derivatives as MMP inhibitors have been designed and reported (s_e_e_: USP 5,789,434; USP 5,854,277; USP 5,859,047; USP 5,861,427; USP 5,861,428; USP 5,874,473; USP 5,886,022; USP 5,886,024; USP 5,886,043) .
  • the present inventors have made an effort to develop novel compounds whose inhibitory action on MMP and selectivity to MMP-l/MMP-2 are increased to reduce side effects, and finally found that novel synthetic inhibitors of biphenyl butyric acid derivatives selectively inhibit MMP activity in vitro.
  • a primary object of the present invention is, therefore, to provide biphenyl butyric acid derivatives inhibiting MMP activity.
  • the other object of the invention is to provide a process for preparing the said compounds.
  • the present invention provides biphenyl butyric acid derivatives which inhibit the activity of MMP, represented as the following general formula (I), the isomers and the pharmaceutically acceptable salts thereof, and a process for preparing the said compounds.
  • R_ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF 3 , -OCH 2 F,
  • R 4 and R 4 a which may be the same or different, are alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl
  • R 2 and R 3 which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl
  • n is 1 or 2
  • R 2 and R 3 are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring, which includes the followings:
  • R 8 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, X is 0 or S.
  • R 2 may further include a substituent represented as the following structural formula:
  • R 5 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl; and,
  • R 6 and R 7 which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl.
  • R 3 is not hydrogen
  • R 3 and R 5 of the above formula (I) are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring in which
  • R 6 and R 7 are the same as above;
  • R 9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol or alkylthio
  • R 10 is oxo, hydroxyamine or hydrazone
  • R u and R 12 are hydrogen or C**_ 6 lower alkyl
  • Y is CH 2 , 0 or S.
  • R 6 and R 7 are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring, which includes the followings:
  • the pharmaceutically acceptable salts of the invention include acid-added salts and hydrates.
  • the compound of the invention can be converted to the salts corresponding to them, preferably alkali metal salts (sodium, potassium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), ammonium salts, non- toxic salts of pharmaceutical organic amine and water- soluble salts.
  • the compound of the general formula (I) can be converted to inorganic acid salts (hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.) and organic acid salts (acetate, lactate, tartarate, oxalate, fumarate, glucuronate, etc.), preferably non-toxic salts and water-soluble salts.
  • inorganic acid salts hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.
  • organic acid salts acetate, lactate, tartarate, oxalate, fumarate, glucuronate, etc.
  • the compound of the general formula (I) and its salts can be also converted to the hydrates corresponding to them by the conventionally known method in the art.
  • Step 1 Synthesis of t-butylester compound (IV)
  • a compound (II) is reacted with a compound (III) to give t-butylester compound (IV) :
  • the compound(II) may be commercially available or prepared by the conventionally known methods and the compound (III) may be prepared by partial modification of the conventionally known methods (sj ⁇ e.: B.S. Furniss, et al., VOGEL' s Textbook of Practical Organic Chemistry, 5 th ed., pp942-943, 1988; WO 96/15096) .
  • the t-butylester compound (IV) is deprotected to give a butylester group-free compound (V): the deprotection is preferably accomplished by using TFA or anhydrous HC1.
  • the compound (V) is condensed with an amine compound to give a compound (VI) containing diethylester group: the amine compound comprises R 2 and R 3 defined in the above and condensation with the amine compound can be carried out by a variety of methods such as acid chloride method, active ester method, mixed anhydride method, etc.
  • Step 4 Synthesis of a compound (I)
  • the compounds of the general formula (I) may also be prepared by the following Process 2.
  • R- L , R 2 and R 3 are the same as above.
  • a compound (II) is reacted with a compound (III) to give t-butylester compound (IV) :
  • the compound(II) may be commercially available or prepared by the conventionally known methods and the compound (III) may be prepared by partial modification of the conventionally known methods (s_e_e: B.S. Furniss, et al . , VOGEL' s Textbook of Practical Organic Chemistry, 5 th ed. , pp942-943, 1988; WO 96/15096) .
  • Step 2 Synthesis of a compound (VII '
  • One of ethylester groups of t-butylester compound (IV) is hydrolyzed to a carboxylic group and then decarboxylating the compound to give a compound (VII) : the hydrolysis is carried out in the presence of a base and decarboxylation in the presence of an organic solvent; and, the base includes, but not limited to, preferably 1 equi. of KOH/EtOH and the organic solvent includes preferably 1, 4-dioxane.
  • the compound (VII) is deprotected to give a butylester group-free compound (VIII) : the deprotection is preferably carried out by using TFA or anhydrous HC1.
  • the compound (VIII) is condensed with an amine compound to give a compound (IX) containing ethylester group: the amine compound comprises R 2 and R 3 defined in the above and condensation with the amine compound can be carried . out by a variety of methods such as acid chloride method, active ester method, mixed anhydride method, etc., most preferably, active ester method.
  • Ethylester group of the compound (IX) is hydrolyzed to a carboxylic group to prepare a compound (I) (see: WO 96/15096) .
  • the titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -bromophenyl) - ⁇ -bromoacetophenone (II, R ⁇ Br)
  • the titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -chlorophenyl) - ⁇ -bromoacetophenone (II, R- ⁇ Cl) .
  • the titled compound was prepared in a similar manner as in Example 5, except for employing 5- (4 ' -bromobiphenyl- 4-yl) -5-OXO-3, 3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ⁇ Br) .
  • the titled compound was prepared in a similar manner as in Example 8, except for employing 5- (4 ' -bromobiphenyl- 4-yl) -5-OXO-3, 3-diethoxycarbonylvaleric acid(V, R- ⁇ Br) and piperidine.
  • the titled compound was prepared in a similar manner as in Example 8, except for employing N- benzoylpiperazine (see,: Kondo, K. et al, J. Chem. Soc,
  • the titled compound was prepared in a similar manner as in Example 16, except for employing N-cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3, 3-diethoxycarbonylvaleramide (VI,
  • the titled compound was prepared in a similar manner as in Example 16, except for employing N-phenyl-5- (biphenyl-4-yl ) -5-oxo-3 , 3-diethoxycarbonylvaleramide (VI , R ⁇ OMe) .
  • the titled compound was prepared in a similar manner as in Example 16, except for employing N- [1, 5-dioxo-5- (4 ' - methoxybiphenyl-4-yl) -3, 3-diethoxycarbonylpentane-l-yl] -4- methylpiperazine (VI, R- ⁇ OMe) .
  • the titled compound was prepared in a similar manner as in Example 16, except for employing N-phenyl-5- (4 ' - bromobiphenyl-4-yl) -5-oxo-3, 3-diethoxycarbonylvaleramide (VI,
  • the titled compound was prepared in a similar manner as in Example 25, except for employing 5- (4 ' -bromobiphenyl- 4-yl) -5-OXO-3, 3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ⁇ Br) .
  • the titled compound was prepared in a similar manner as in Example 31, except for employing 5- (- [ (biphenyl-4- yl) ] -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R- ⁇ H) and 2- chloroaniline .
  • the titled compound was prepared in a similar manner as in Example 39, except for employing 5- (biphenyl-4-yl) -5- oxo-3-ethoxycarbonylvaleric acid and D-Ala-CONH-Ph (105mg, 73%) .
  • the titled compound was prepared in a similar manner as in Example 39, except for employing 5- (biphenyl-4-yl) -5- oxo-3-ethoxycarbonylvaleric acid (VIII, R-
  • H) and L-Ala- CONH-m-ClPh.
  • Example 54 In vi tro inhibition on gelatinase A(MMP-2)
  • the present test was accomplished by measuring the fluorescence intensity of a fluorescent material (7- methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced from the cleavage of a fluorescent synthetic peptide substrate ( (7- methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu- ⁇ -(2,4- dinitrophenylamino) Ala-Ala-Arg-NH 2 (Sigma Chem. Co., U.S.A.)) by gelatinase A(Boehringer Manneheim cat# 1782916, from human fibrosarcoma cells) .
  • Enzymatic reaction employing a fluorescent synthetic substrate was accomplished by leaving test compounds, TNBC buffer solution (25mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.01% Brij-35, 5mM CaCl 2 ) , gelatinase A (final concentration in well: 4.17nM) activated with 1 mM of APMA(aminophenylmercuric acetate) for 30 minutes at 37 °C just before the enzymatic reaction, and the substrate, fluorescent synthetic peptide (final concentration in well: 9.15uM) in 96 well plate and then reacting for 30 minutes at 37 °C, and the fluorescence intensity was measured at excitation 328nm and emission 393nm by spectrofluorimeter (Fma (molecular device)).
  • the inhibition rate(%) was calculated from the following equation:
  • A represents fluorescence intensity before the reaction with an inhibitor
  • B represents fluorescence intensity after the reaction with an inhibitor
  • C represents fluorescence intensity before the reaction without an inhibitor
  • D represents fluorescence intensity after the reaction without an inhibitor.
  • MMP-1 In vitro inhibition rate on collagenase (MMP-1) was measured in a similar manner as in Example 54, except for employing collagenase (AngioLab. Co. Ltd) with a final concentration in well of 7.25nM.
  • the present invention provides novel biphenylbutyric acid derivatives which inhibit MMP activity, their isomers and the pharmaceutically acceptable salts thereof, and a process for preparing the compounds. Since the biphenylbutyric acid derivatives of the present invention selectively inhibit MMP activity in vitro, the MMP inhibitors comprising the biphenylbutyric acid derivatives as an active ingredient can be practically applied for the prevention and treatment of diseases caused by overexpression and overactivation of MMP. .

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Abstract

Cette invention, qui a trait à de nouveaux dérivés d'acide diphénylbutirique, à leurs isomères ainsi qu'à leurs sels admissibles du point de vue pharmaceutique, lesquels dérivés se révèlent des plus utiles en tant qu'inhibiteurs de la métalloprotéinase matricielle (MMP), concerne également un procédé de production de ces composés. Dans la mesure où ces dérivés d'acide diphénylbutirique inhibent, de manière sélective, l'activité des MMP in vitro, ils sont administrés dans le cadre du traitement et de la prévention de différents états pathologiques dus à une surexpression et à une suractivation de MMP.
PCT/KR2001/000687 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle WO2001083445A1 (fr)

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CA002377629A CA2377629A1 (fr) 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle
JP2001580874A JP2003531894A (ja) 2000-04-25 2001-04-24 マトリックスメタロプロテアーゼ阻害剤としてのビフェニルブチル酸誘導体
AU52759/01A AU5275901A (en) 2000-04-25 2001-04-24 Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor
EP01926225A EP1189882A1 (fr) 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle

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KR2000-21834 2000-04-25
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KR100405913B1 (ko) * 2000-04-25 2003-11-14 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
KR100405914B1 (ko) * 2000-04-25 2003-11-15 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
WO2007008994A2 (fr) * 2005-07-11 2007-01-18 Wyeth Inhibiteurs de glutamate aggrecanase
WO2008058278A2 (fr) * 2006-11-09 2008-05-15 Wyeth Polymorphes de la n2-(1,1'-biphényl-4-ylcarbonyl)-n1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-α-glutamine
WO2009012656A1 (fr) * 2007-07-24 2009-01-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Inhibiteurs des métalloprotéinases matricielles, compositions pharmaceutiques les contenant et leurs utilisations
US7541485B2 (en) 2005-10-13 2009-06-02 Wyeth Methods for preparing glutamic acid derivatives
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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US20100022582A1 (en) * 2005-03-10 2010-01-28 Kenji Takahashi Tetrahydroisoquinoline Compound and Medicinal Use Thereof
CN104955806B (zh) * 2013-02-06 2018-09-14 默克专利股份公司 用于治疗骨关节炎的作为聚蛋白聚糖酶抑制剂的取代羧酸衍生物

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WO1999018079A1 (fr) * 1997-10-06 1999-04-15 Warner-Lambert Company Acides heteroaryle buturiques et leurs derives en tant qu'inhibiteurs de metalloproteinases matricielles

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WO1993023040A1 (fr) * 1992-05-20 1993-11-25 Merck & Co., Inc. 17-ethers et thioethers de 4-aza-steroides
WO1998009940A1 (fr) * 1996-09-04 1998-03-12 Warner-Lambert Company Acides biphenyl-butyriques et leurs derives, utilises comme inhibiteurs des metalloproteases de matrice
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100405914B1 (ko) * 2000-04-25 2003-11-15 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
KR100405913B1 (ko) * 2000-04-25 2003-11-14 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
WO2007008994A2 (fr) * 2005-07-11 2007-01-18 Wyeth Inhibiteurs de glutamate aggrecanase
WO2007008994A3 (fr) * 2005-07-11 2007-07-12 Wyeth Corp Inhibiteurs de glutamate aggrecanase
US7998965B2 (en) 2005-07-11 2011-08-16 Wyeth Llc Glutamate aggrecanase inhibitors
US7553873B2 (en) 2005-07-11 2009-06-30 Wyeth Glutamate aggrecanase inhibitors
US7541485B2 (en) 2005-10-13 2009-06-02 Wyeth Methods for preparing glutamic acid derivatives
WO2008058278A2 (fr) * 2006-11-09 2008-05-15 Wyeth Polymorphes de la n2-(1,1'-biphényl-4-ylcarbonyl)-n1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-α-glutamine
WO2008058278A3 (fr) * 2006-11-09 2008-07-10 Wyeth Corp Polymorphes de la n2-(1,1'-biphényl-4-ylcarbonyl)-n1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-α-glutamine
WO2009012656A1 (fr) * 2007-07-24 2009-01-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Inhibiteurs des métalloprotéinases matricielles, compositions pharmaceutiques les contenant et leurs utilisations
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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