WO2013085890A1 - Therapeutic methods - Google Patents

Therapeutic methods Download PDF

Info

Publication number
WO2013085890A1
WO2013085890A1 PCT/US2012/067735 US2012067735W WO2013085890A1 WO 2013085890 A1 WO2013085890 A1 WO 2013085890A1 US 2012067735 W US2012067735 W US 2012067735W WO 2013085890 A1 WO2013085890 A1 WO 2013085890A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
alkoxy
amino
methyl
Prior art date
Application number
PCT/US2012/067735
Other languages
French (fr)
Inventor
Erkan Baloglu
Shomir Ghosh
Mercedes Lobera
Darby Schmidt
Yonghui Wang
Original Assignee
Glaxo Group Limited
Tempero Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited, Tempero Pharmaceuticals, Inc. filed Critical Glaxo Group Limited
Publication of WO2013085890A1 publication Critical patent/WO2013085890A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to methods of treatment of diseases mediated by retinoid- related orphan receptor gamma (RORy).
  • RORy retinoid- related orphan receptor gamma
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR ), and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB, and RORC, respectively).
  • RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2).
  • RORy is a term used to describe both RORyl and/or RORyt.
  • Thl7 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines. Thl7 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
  • EAE experimental autoimmune encephalomyelitis
  • CIA collagen-induced arthritis
  • Thl7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7:e003; Manel et al. (2008) Nat. Immunol. 9:641-649).
  • the pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues.
  • Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205: 1517- 1522; Leung et al. (2010) Cell. Mol. Immunol. 7: 182- 189). There is evidence that Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev. Immunol. 27:485-517).
  • RORyt plays a critical role in the pathogenic responses of Thl7 cells (Ivanov et al. (2006) Cell 126: 1 121-1 133). RORyt deficient mice produce few Thl7 cells. In addition, RORyt deficiency resulted in amelioration of EAE. Further support for the role of RORyt in the pathogenesis of autoimmune or inflammatory diseases can be found in the following references: Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355; Meier et al. (2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217; Jager et al. (2009) J. Immunol.
  • the invention is directed to methods treatment of diseases mediated by RORy.
  • the invention is directed to a method of treatment of a disease mediated by RORy which comprises administering to a human in need thereof an effective amount of a compound accordin to Formula (I):
  • n 0, 1, or 2;
  • n 0, 1, 2, or 3;
  • one of Y 1 and Y 2 is O or NR 8 and the other is a bond;
  • Cy is (C 3 -Cg)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
  • a 1 , A 2 , A 3 , and A 4 are each independently selected from N, NR 6 , O, S, CH, and CR 10 , wherein one of A 1 , A 2 , A 3 , and A 4 is NR 6 , O, or S, 0-2 of A 1 , A 2 , A 3 , and A 4 are CR 10 , and 0-3 of A 1 , A 2 , A 3 , and A 4 are CH or N;
  • R 1 is (C 3 -C 6 )alkyl, (C 3 -C 6 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 6 )alkoxy,
  • R 2 is hydrogen, (C C 6 )alkyl, or (C C 6 )haloalkyl
  • R 1 and R 2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R 5 ;
  • R 3 and R 3a are each independently hydrogen, hydroxyl, (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, (Ci-C6)alkoxy, amino, (d -Chalky lamino, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino;
  • each R 4 is independently selected from hydrogen, halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -C0 2 R 7 , -CONR 7 R 8 , -OR 9 , and -NR 8 R 9 , wherein said (C C 6 )alkyl or (C C 6 )haloalkyl is optionally substituted by hydroxyl, -OR 9 , -C0 2 R 7 , -CONR 7 R 8 , or -NR 8 R 9 ;
  • each R 4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
  • R 4 and R 4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl,
  • each R 5 is independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, aryl, heteroaryl, aryl(Ci-C 6 )alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
  • R 6 is hydrogen, (C C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, hydroxy(Ci-C 6 )alkyl, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, -((C 0 -C 3 )alkyl)CO 2 R 7 , -((C 0 -C 3 )alkyl)CONR 7 R 8 , aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
  • R 7 is hydrogen, (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl,
  • R 8 is hydrogen, (C C 6 )alkyl, or (C C 6 )haloalkyl; or R 7 and R 8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 -C 6 )cycloalkyl, -C0 2 H, -C0 2 (Ci-C 4 )alkyl, hydroxyl, hydroxy(C C 6 )alkyl, (C C 4 )alkoxy, (Ci-C4)alkoxy(Ci-C 6 )alkyl, amino, (Ci-C 4 )alkylamino, or ((Ci-C4)alkyl)((Ci-C 4 )alkyl)amino;
  • R 9 is -C(0)R 7 , -C0 2 R 7 , -C(0)NR 7 R 8 , (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, aryl(Ci-C 6 )alkyl, heteroaryl(Ci-C 6 )alkyl, or heterocycloalkyl, wherein said (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, aryl(C C 6 )alkyl,
  • heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -CO 2 R 7 , -CONH 2 ,
  • R 8 and R 9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 -C 6 )cycloalkyl, -C0 2 H, -C0 2 (C C 4 )alkyl, -CONR 7 R 8 , hydroxyl, hydroxy(Ci-C 6 )alkyl,
  • R 10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (C C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, -((C 0 -C 3 )alkyl)CO 2 R 7 ,
  • R 11 is hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, amino,
  • (Ci-C 4 )alkylamino ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
  • this invention provides for the use of the compounds of Formula (I) for the treatment of diseases mediated by RORy.
  • diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, uveitis, dry eye, glomerulonephritis, Crohn's disease and asthma.
  • autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, uveitis, dry eye, glomerulonephritis, Crohn's disease and asthma.
  • alkyl represents a saturated, straight, or branched hydrocarbon moiety.
  • (Ci-C6)alkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, ?-butyl, pentyl, and hexyl.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl”, “hydroxyalkyl”, “alkoxyalkyl”, “arylalkyl”, or “heteroarylalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by, for example, the bonding arrangement present in a benzyl group (-CH 2 -phenyl);
  • halo(Ci-C 4 )alkyl is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical, and is represented by, for example, a trifluoromethyl group (-CF 3 ).
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C3-C8)cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms.
  • Exemplary "(C3-C8)cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom.
  • (Ci-Cz alkoxy) refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and ?-butoxy.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, to which may be fused one or more cycloalkyl rings.
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl,
  • benzimidazolyl dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
  • heteroaryl groups present in the compounds of this invention are
  • Selected 5-membered and/or 6-memebred monocyclic heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms.
  • 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, hexahydro-lH-l,4-diazepinyl, azabicylo[3.2.1]octyl,
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro- 1H- 1 ,4-diazepinyl.
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazol
  • Hydroxo or "hydroxyl” is intended to mean the radical -OH.
  • RORy refers to all isoforms encoded by the RORC gene which include RORyl and
  • RORy modulator refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy.
  • RORy modulators include antagonists and inverse agonists of RORy.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term "compound(s) of the invention” means a compound of Formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof
  • any physical form thereof e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrate
  • the term "optionally substituted” indicates that a group, such as alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
  • n is 0, 1, 2, or 3. In another embodiment of this invention, n is 1 or 2.
  • one of Y 1 and Y 2 is O or NR 8 and the other is a bond.
  • one of Y 1 and Y 2 is O, NH, or N((Ci-C 4 )alkyl) and the other is a bond.
  • Y 1 is NH or NCH 3 and Y 2 is a bond.
  • Y 1 is NH and Y 2 is a bond.
  • Y 1 is a bond and Y 2 is NH.
  • Cy is (C 3 -C 8 )cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one to three times, independently, by
  • (Ci-C4)alkylamino ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl.
  • Cy is heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one or two times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, cyano, (Ci-C 4 )alkoxy, ((Ci-C 4 )alkyl)amino ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -((C 0 -C 3 )alkyl)CO 2 R 7 ,
  • Cy is (C 3 -C6)cycloalkyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, piperidinyl, piperazinyl, morpholinyl,
  • thiomorpholinyl tetrahydropyranyl, dihydropyranyl, dioxanyl, oxathianyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
  • (Ci-C 4 )alkylamino ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl.
  • Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
  • Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one or two times, independently, by (d-d)alkyl, (d-d)haloalkyl, halogen, cyano, (d-d)alkoxy, (d-C 4 )alkyl)((d-C 4 )alkyl)amino, -((C 0 -C 3 )alkyl)CO 2 H,
  • Cy is phenyl, which is optionally substituted one to three times, independently, by (Crd)alkyl, (d-d)haloalkyl, (C 3 -d)cycloalkyl, halogen, oxo, cyano, hydroxyl,
  • (Ci-d)alkylamino ((Ci-d)alkyl)((C d)alkyl)amino, aryl, heteroaryl, aryl(d-C 6 )alkyl, heteroaryl(d-d)alkyl, or heterocycloalkyl.
  • Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-C 4 )alkyl, (d-C 4 )haloalkyl, cyano, (C C 4 )alkoxy, -((C 0 -C 3 )alkyl)CO 2 R 7 , or -((C 0 -C 3 )alkyl)CONR 7 R 8 or ((Ci-C )alkyl)((Ci-C )alkyl)amino.
  • Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-C 4 )alkyl,
  • Cy is phenyl.
  • Z is a bond, O, or NH. In another embodiment of this invention, Z is O or NH. In a specific embodiment of this invention, Z is O.
  • a 1 , A 2 , A 3 , and A 4 are each independently selected from N, NR 6 , O, S, CH, and CR 10 , wherein one of A 1 , A 2 , A 3 , and A 4 is NR 6 , O, or S, 0-2 of A 1 , A 2 , A 3 , and A 4 are CR 10 , and 0-3 of A 1 , A2 , A 3 , and A 4 are CH or N.
  • a 1 , A 2 , A 3 , and A are each independently selected from N, N((Ci-C 4 )alkyl), O, S, CH, and C((C C 4 )alkyl), wherein one of A 1 , A 2 , A 3 , and A 4 is N((d-C 4 )alkyl), O, or S, 0-2 of A 1 , A 2 , A 3 , and A 4 are
  • a 1 and A 4 are each independently selected from CH and CR 10 , and one of A 2 and A 3 is NR 6 , O, or S and the other is N or CH.
  • a 1 and A 4 are each independently selected from CH and C((Ci-C 4 )alkyl), and one of A 2 and A 3 is N((C C 4 )alkyl), O, or S and the other is N or CH.
  • a 1 and A 4 are each independently selected from CH and C((Ci-C 4 )alkyl), and one of A 2 and A 3 is N((C C 4 )alkyl), O, or S and the other is N or CH.
  • a 1 and A 4 are each independently selected from CH and C((Ci-C 4 )alkyl), and one of A 2 and A 3 is O or S and the other is N.
  • R 1 is (C 3 -C 6 )alkyl, (C 3 -C 6 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 6 )alkoxy,
  • R 1 is (C 3 -C6)alkyl, (C 3 -Cg)cycloalkyl,
  • R 1 is (C 3 -C6)alkyl, (C 3 -C6)cycloalkyl, (Ci-C6)alkoxy(Ci-C2)alkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl
  • R 5 is halogen, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, cyano, (Ci-C 4 )alkoxy, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino).
  • R 1 is (C 3 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl,
  • R 1 is (C 3 -C6)alkyl. In another embodiment of this invention, R 1 is (C 5 -C6)alkyl. In another embodiment of this invention, R 1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, cyano, (Ci-C 4 )alkoxy, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino.
  • R 1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-Cz alkyl, (Ci-Cz alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
  • R 1 is phenyl optionally substituted one or two times, independently, by halogen,
  • R 1 is phenyl or pyridinyl. In another specific embodiment of this invention, R 1 is phenyl.
  • R 2 is hydrogen, (Ci-C 6 )alkyl, or (Ci-C 6 )haloalkyl. In another embodiment of this invention, hydrogen or (Ci-C 4 )alkyl. In another embodiment of this invention, R 2 is hydrogen or methyl. In a specific embodiment of this invention, R 2 is hydrogen.
  • R 1 and R 2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R 5 .
  • R 1 and R 2 taken together represent -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • R 3 and R 3a are each independently hydrogen, hydroxyl, (Ci-C6)alkyl,
  • R 3 and R 3a are each independently hydrogen or methyl. In a specific embodiment of this invention, R 3 and R 3a are each independently hydrogen.
  • each R 4 is independently selected from hydrogen, halogen, (Ci-C6)alkyl,
  • each R 4 is independently selected from hydrogen
  • each R 4 is independently selected from hydrogen, halogen, (Ci-C 4 )alkyl,
  • each R 4 is independently selected from hydrogen, halogen, (Ci-C 4 )alkyl, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino,
  • each R is independently selected from hydrogen, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, (Ci-C 4 )alkoxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkoxy, -0((Ci-C 3 )alkyl)C0 2 H, -0((Ci-C 3 )alkyl)C0 2 (Ci-C 4 )alkyl, -0((Ci-C 3 )alkyl)CONH 2 , -0((Ci-C 3 )alkyl)CONH(Ci-C 4 )alkyl, and -0((C 1 -C 3 )alkyl)CON((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl).
  • each R 4 is independently selected from hydrogen, (Ci-C 4 )
  • each R 4 is independently selected from (Ci-C 4 )alkoxy, -0((Ci-C 3 )alkyl)C0 2 H,
  • each R 4 is independently selected from (Ci-C 4 )alkyl and (Ci-C 4 )alkoxy. In a specific embodiment of this invention, each R 4 is hydrogen.
  • each R 4a is independently selected from hydrogen, halogen, hydroxyl, amino, and (Ci-C6)alkyl. In another embodiment of this invention, each R 4a is independently selected from hydrogen, halogen, and (Ci-C 4 )alkyl. In another embodiment of this invention, each R 4a is independently selected from is hydrogen, fluorine, and methyl. In another embodiment of this invention, each R 4a is independently selected from is hydrogen and methyl. In a specific embodiment of this invention, each R 4a is hydrogen. In a specific embodiment of this invention, each R 4a is methyl.
  • R 4 and R 4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano,
  • R 4 and R 4a taken together represent -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • R 11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C 4 )alkoxy(Ci-C6)alkyl, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl.
  • R 11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C 4 )alkoxy(Ci-C6)alkyl, amino, (Ci-C 4 )alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
  • R 11 is hydrogen, (Ci-C 4 )alkyl, -CF 3 , F, CI, Br, cyano, hydroxyl, or (Ci-C 4 )alkoxy.
  • One articular embodiment of the invention is a compound of Formula (la):
  • m 1 ;
  • n 1 or 2;
  • Y 1 is NH or NCH 3 and Y 2 is a bond
  • K 1 , K 2 , K 3 , and K 4 are each independently selected from N, N -0 ⁇ , CH, and CR 10 , wherein 0-2 of K 1 , K 2 , K 3 , and K 4 are N or N + -0 " and 0-2 of K 1 , K 2 , K 3 , and K 4 are CR 10 ;
  • Z is O, NR 6 , or a bond
  • a 1 , A 2 , A 3 , and A 4 are each independently selected from N, NR 6 , O, S, CH, and CR 10 , wherein one of A 1 , A 2 , A 3 , and A 4 is NR 6 , O, or S, 0-2 of A 1 , A 2 , A 3 , and A 4 are CR 10 , and 0-3 of A 1 , A 2 , A 3 , and A 4 are CH or N;
  • R 1 is (C 3 -C 6 )alkyl, (C 3 -C 6 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 6 )alkoxy,
  • R 2 is hydrogen, (C C 6 )alkyl, or (Ci-C 6 )haloalkyl
  • R 1 and R 2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R 5 ;
  • R 3 and R 3a are each independently hydrogen, hydroxyl, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, halogen, (Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino;
  • each R 4 is independently selected from hydrogen, halogen, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, -OR 9 , and -NR 8 R 9 , wherein said (Ci-C 4 )alkyl or (Ci-C 4 )haloalkyl is optionally substituted by hydroxyl, -OR 9 , -C0 2 R 7 , -CONR 7 R 8 , or -NR 8 R 9 ;
  • each R 4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
  • each R 5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C 6 )alkyl, and heterocycloalkyl;
  • R 6 is hydrogen, (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 6 )alkyl, -((C 0 -C 3 )alkyl)CO 2 R 7 , -((C 0 -C 3 )alkyl)CONR 7 R 8 , aryl, heteroaryl, aryl(Ci-C 6 )alkyl, heteroaryl(Ci-C 6 )alkyl, or heterocycloalkyl;
  • R 7 is hydrogen, (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl,
  • R 8 is hydrogen, (C C 6 )alkyl, or (C C 6 )haloalkyl
  • R 7 and R 8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C 3 -C 6 )cycloalkyl, -C0 2 H, -C0 2 (Ci-C 4 )alkyl, hydroxyl, hydroxy(Ci-C 6 )alkyl, (C C 4 )alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
  • R 9 is -C(0)R 7 , -C0 2 R 7 , -C(0)NR 7 R 8 , (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, aryl(Ci-C 6 )alkyl,
  • heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -C0 2 R 7 , -CONH 2 ,
  • R 8 and R 9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 -C 6 )cycloalkyl, -C0 2 H, -C0 2 (Ci-C 4 )alkyl, -CONR 7 R 8 , hydroxyl, hydroxy(Ci-C 6 )alkyl,
  • R 10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (C C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, -((C 0 -C 3 )alkyl)CO 2 R 7 ,
  • R 11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (C
  • Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;
  • n 1 or 2;
  • Y 1 is NH or NCH 3 and Y 2 is a bond
  • K 1 , K 2 , K 3 , and K 4 are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C 4 )alkyl, (C C 4 )alkoxy, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, wherein 2-4 of K 1 , K 2 , K 3 , and K 4 are a carbon atom substituted by hydrogen;
  • Z is O, NH, -N(Ci-C 4 )alkyl, -N((C 0 -C 3 )alkyl)CO 2 R 7 , -N((C 0 -C 3 )alkyl)CONR 7 R 8 , or a bond;
  • a 1 and A 4 are each independently selected from CH and CR 10 , and one of A 2 and A 3 is NR 6 , O, or S and the other is N or CH;
  • R 1 is (C 3 -C 6 )alkyl, (C 3 -C 6 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 6 )alkoxy,
  • R 2 is hydrogen
  • R 3 and R 3a are each independently hydrogen or methyl
  • each R 4 is independently selected from hydrogen, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy,
  • each R 4a is independently selected from hydrogen, hydroxyl, amino, and (Ci-C 4 )alkyl; each R 5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C 3 -C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C 4 )alkoxy(Ci-C6)alkyl, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
  • R 7 is hydrogen, (C C 6 )alkyl, (C C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl,
  • R 8 is hydrogen, (C C 6 )alkyl, or (C C 6 )haloalkyl;
  • R is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (C C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, -((C 0 -C 3 )alkyl)CO 2 R 7 ,
  • R 11 is hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 4 )alkoxy(Ci-C 6 )alkyl, amino,
  • Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;
  • n 1 or 2;
  • Y 1 is NH and Y 2 is a bond
  • K 1 , K 2 , K 3 , and K 4 are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C 4 )alkyl, (C C 4 )alkoxy, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, wherein 2-4 of K 1 , K 2 , K 3 , and K 4 are a carbon atom substituted by hydrogen;
  • Z is O, NH, -N(C C 4 )alkyl, or a bond
  • a 1 and A 4 are each independently selected from CH and C((Ci-C 4 )alkyl), and one of A and A 3 is O or S and the other is N;
  • R 2 is hydrogen
  • R 3 and R 3a are each independently hydrogen or methyl
  • each R 4 is independently selected from hydrogen, (d-d)alkyl, (d-d)alkylamino, ((d-C 4 )alkyl)((d-C 4 )alkyl)amino, and (d-d)alkoxy;
  • each R 4a is independently selected from hydrogen, hydroxyl, amino, and (d-C 4 )alkyl; and R 11 is hydrogen, (d-C 4 )alkyl, -CF 3 , F, CI, Br, cyano, hydroxyl, or (Ci-C 4 )alkoxy;
  • the compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • stereochemistry of a chiral center present in Formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula (I) containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure means products whose enantiomeric excess is 99% ee or greater.
  • the compound or salt, including solvates (particularly, hydrates) thereof may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or salt, or solvates (particularly, hydrates) thereof may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as
  • polymorphs It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof.
  • Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • solvates of the compounds of the invention, or salts thereof, that are in crystalline form may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • salts of the compounds of Formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1- 19. Salts encompassed within the term “pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha- hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesul
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
  • phenylpropionates phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthalene-2-sulfonates.
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
  • dehydroabietylamine N,N-Z?z ' sdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.
  • non-pharmaceutically acceptable salts e.g. trifluoroacetate
  • Other non-pharmaceutically acceptable salts e.g. trifluoroacetate, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula (I).
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK a than the free acid form of the compound.
  • the invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride or sodium borodeuteride).
  • deuterated reagents e.g. lithium aluminum deuteride or sodium borodeuteride
  • the compounds of the invention are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases and cancer.
  • the inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Behcets disease, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, dry eye and glomerulonephritis, myocarditis.
  • the cancer diseases of the invention include lytic bone disease in multiple myelom
  • AML myelogenous leukemia
  • bladder carcinoma gastric cancer
  • hepatocellular carcinoma melanoma
  • medulloblastoma colon cancer.
  • the invention is directed to methods of treating such diseases.
  • the methods of treatment of the invention futher comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • treatment in reference to a condition means: (1) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • an “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • patient refers to a human or animal.
  • the compounds of the invention may be administered by any suitable route of
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.
  • pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as
  • pro-moieties for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate
  • Preferred "pro-moieties" for compounds of the invention include: ester, carbonate ester, hemi-ester, phosphate ester, nitro ester, sulfate ester, sulfoxide, amide, carbamate, azo-, phosphamide, glycoside, ether, acetal, and ketal derivatives of the compounds of Formula (I).
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • the invention includes the use of compounds of the invention for the preparation of a composition for treating or ameliorating diseases mediated by RORy in a subject in need thereof, wherein the composition comprises a mixture of one or more of the compounds of the invention and an optional pharmaceutically acceptable excipient.
  • the invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by RORy.
  • the invention relates to the use of compounds of the invention in the preparation of a medicament for the treatment of diseases mediated by RORy.
  • diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, Dry Eye, glomerulonephritis, myocarditis and cancer diseases including lytic bone disease in multiple myeloma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, bladder carcinoma, gastric cancer, hepatocellular carcinoma, melanoma,
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to methods of treatment of diseases mediated by RORy which comprise administering to a human in need thereof pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient(s).
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition, or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain
  • pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose).
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the reaction sequences provided in these Schemes are applicable for producing compounds of the invention having a variety of different R 1 , R 3 , R 3a , R 4 , R 4a , R 11 , ⁇ ⁇ 4 , and A 1 -A 4 groups employing appropriate precursors.
  • the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de -protecting different substituents using such suitable protecting groups are well known to those skilled in the art;
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • the compounds according to Formula (I) are RORy modulators, and are useful in the treatment of diseases mediated by RORy.
  • the biological activities of the compounds according to Formula (I) can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models.
  • This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner.
  • RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co-activators.
  • LBD ligand binding domain
  • the sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC 1(2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co- activator.
  • the assay measures ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) to indirectly assess ligand binding.
  • RORy has a basal level of interaction with the co-activator SRC 1(2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRCl(2) interaction.
  • RORy-LBD Human RORy Ligand Binding Domain
  • BL21(DE3) as an amino-terminal polyhistidine tagged fusion protein.
  • DNA encoding this recombinant protein was sub-cloned into a modified pET21 a expression vector (Novagen).
  • a modified polyhistidine tag (MKKHHHHHHLVPRGS) (SEQ ID No: 1) was fused in frame to residues 263-518 of the human RORy sequence.
  • E.coli cell pellet was resuspended in 300 mL of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCl). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 min at 20,000 g at 4 °C. The cleared supernatant was filtered through a 0.45 ⁇ cellulose acetate membrane filter. The clarified lysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (InVitrogen), pre-equilibrated with 30 mM imidazole pH 7.0 and 150 mM NaCl.
  • lysis buffer 30 mM imidazole pH 7.0 and 150 mM NaCl
  • the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0.
  • Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mL.
  • the concentrated protein was loaded onto a Superdex 200 column pre- equilibrated with 20 mM Tris-Cl pH 7.2 and 200 mM NaCl.
  • the fractions containing the desired RORy-LBD protein were pooled together.
  • Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [100 mM NaPhosphate, pH 8 and 150 mM NaCl].
  • the concentration of RORy-LBD was approximately 30 ⁇ in PBS.
  • Five-fold molar excess of NHS- LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 min at ambient rt.
  • the modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5 mM DTT, 2 mM EDTA and 2% sucrose - each at least 20 times of the volume.
  • the modified protein was distributed into aliquots, frozen on dry ice and stored at -80 °C.
  • the biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent. In general, approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five.
  • biotinylated SRC 1(2) solution was prepared by adding an appropriate amount of biotinylated SRC 1(2) from the 100 ⁇ stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM.
  • An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC 1(2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 min at rt. Twenty- fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 min at rt.
  • biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM.
  • An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy-LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 min at rt. Twenty- fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 min at rt.
  • Equal volumes of the above-described Europium labeled SRC 1 (2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20 nM RORy-LBD, 10 nM APC- Strepavidin, 20 nM SRC 1(2) and 5 nM Europium- Streptavidin.
  • the reaction mixtures were incubated for 5 min.
  • 25 ⁇ ⁇ of the reaction mixtures per well was added to the 384-well assay plates containing 1 ⁇ ⁇ of test compound per well in 100% DMSO. The plates were incubated for 1 h and then read on ViewLux in Lance mode for EU/APC.

Abstract

The present invention relates to methods of treatment of diseases mediated by RORϒ.

Description

THERAPEUTIC METHODS
The present invention relates to methods of treatment of diseases mediated by retinoid- related orphan receptor gamma (RORy).
Background of the Invention
Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355). The ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR ), and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB, and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2). RORy is a term used to describe both RORyl and/or RORyt.
While RORyl is expressed in a variety of tissues including thymus, muscle, kidney and liver, RORyt is exclusively expressed in the cells of the immune system. RORyt has been identified as a key regulator of Thl7 cell differentiation. Thl7 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines. Thl7 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7:e003; Manel et al. (2008) Nat. Immunol. 9:641-649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205: 1517- 1522; Leung et al. (2010) Cell. Mol. Immunol. 7: 182- 189). There is evidence that Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev. Immunol. 27:485-517).
RORyt plays a critical role in the pathogenic responses of Thl7 cells (Ivanov et al. (2006) Cell 126: 1 121-1 133). RORyt deficient mice produce few Thl7 cells. In addition, RORyt deficiency resulted in amelioration of EAE. Further support for the role of RORyt in the pathogenesis of autoimmune or inflammatory diseases can be found in the following references: Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355; Meier et al. (2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217; Jager et al. (2009) J. Immunol. 183:7169- 7177; Serafmi et al. (2004) Brain Pathol. 14: 164- 174; Magliozzi et al. (2007) Brain 130: 1089- 1104; Barnes (2008) Nat. Rev. Immunol. 8: 183- 192.
In light of the role RORy plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORy activity, which can be used in the treatment of diseases mediated by RORy.
Summary of the Invention The invention is directed to methods treatment of diseases mediated by RORy.
Specifically, the invention is directed to a method of treatment of a disease mediated by RORy which comprises administering to a human in need thereof an effective amount of a compound accordin to Formula (I):
Figure imgf000003_0001
wherein:
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
one of Y1 and Y2 is O or NR8 and the other is a bond;
Cy is (C3-Cg)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy, -((C0-C3)alkyl)NHCO2R7, -((Co-C3)alkyl)N((Ci-C4)alkyl)C02R7,
-((C0-C3)alkyl)NHC(O)R7, -((Co-C3)alkyl)N((Ci-C4)alkyl)C(0)R7, -((Co-C3)alkyl)C02R7,
-((C0-C3)alkyl)CONR7R8, -((C0-C3)alkyl)C(O)R7, (Ci-C4)alkoxy(Ci-C6)alkyl, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
Z is O, S, S02, C=0, NR6, or a bond; A1, A2, A3, and A4 are each independently selected from N, NR6, O, S, CH, and CR10, wherein one of A1, A2, A3, and A4 is NR6, O, or S, 0-2 of A1, A2, A3, and A4 are CR10, and 0-3 of A1, A2, A3, and A4 are CH or N;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5;
R2 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, (Ci-C6)alkoxy, amino, (d -Chalky lamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
each R4 is independently selected from hydrogen, halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -C02R7, -CONR7R8, -OR9, and -NR8R9, wherein said (C C6)alkyl or (C C6)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
(C1-C6)alkyl;
or R4 and R4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl,
(C3-C6)cycloalkyl, -C02R7, -CONR7R8, hydroxyl, hydroxy(C C6)alkyl, (C C4)alkoxy,
(Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((CrC4)alkyl)C02R7, -NHC(0)R7, or -N((C C4)alkyl)C(0)R7;
each R5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(Ci-C6)alkyl, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl,
(Ci-C4)alkoxy(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl; or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(Ci-C4)alkyl, hydroxyl, hydroxy(C C6)alkyl, (C C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
R9 is -C(0)R7, -C02R7, -C(0)NR7R8, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(C C6)alkyl,
heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -CO2R7, -CONH2,
-CONH(Ci-C4)alkyl, -CON((Ci-C4)alkyl)((Ci-C4)alkyl), hydroxyl, (C C4)alkoxy, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((Ci-C4)alkyl)C02R7, -NHC(0)R7, or -N((C C4)alkyl)C(0)R7;
or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(C C4)alkyl, -CONR7R8, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((C C4)alkyl)C02R7, -NHC(0)R7, or
-N((Ci-C4)alkyl)C(0)R7;
R10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (C C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, aminoCd-Qalkyl, ((C C^alky CCd-C^alky aminoCC Qalkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl; and
R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides for the use of the compounds of Formula (I) for the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, uveitis, dry eye, glomerulonephritis, Crohn's disease and asthma. Detailed Description of the Invention
As used herein, the term "alkyl" represents a saturated, straight, or branched hydrocarbon moiety. The term "(Ci-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, ?-butyl, pentyl, and hexyl.
When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl", "hydroxyalkyl", "alkoxyalkyl", "arylalkyl", or "heteroarylalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by, for example, the bonding arrangement present in a benzyl group (-CH2-phenyl); "halo(Ci-C4)alkyl" is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical, and is represented by, for example, a trifluoromethyl group (-CF3).
As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C3-C8)cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary "(C3-C8)cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
"Alkoxy" means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom. The term "(Ci-Cz alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary
Figure imgf000006_0001
groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and ?-butoxy.
"Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, to which may be fused one or more cycloalkyl rings.
Generally, in the compounds of this invention, aryl is phenyl.
Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl,
dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl,
benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
Generally, the heteroaryl groups present in the compounds of this invention are
5-membered and/or 6-memebred monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, hexahydro-lH-l,4-diazepinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and 1,5,9-triazacyclododecyl.
Generally, in the compounds of this invention, heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro- 1H- 1 ,4-diazepinyl.
"Oxo" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C=0). The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH.
"RORy" refers to all isoforms encoded by the RORC gene which include RORyl and
RORyt.
"RORy modulator" refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy. RORy modulators include antagonists and inverse agonists of RORy.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
As used herein, the term "compound(s) of the invention" means a compound of Formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
As used herein, the term "optionally substituted" indicates that a group, such as alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The alternative definitions for the various groups and substituent groups of Formula (I) provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions. Suitably, m is 0, 1, or 2. In a specific embodiment of this invention, m is 1.
Suitably, n is 0, 1, 2, or 3. In another embodiment of this invention, n is 1 or 2.
Suitably, one of Y1 and Y2 is O or NR8 and the other is a bond. In another embodiment of this invention, one of Y1 and Y2 is O, NH, or N((Ci-C4)alkyl) and the other is a bond. In a specific embodiment of this invention, Y1 is NH or NCH3 and Y2 is a bond. In another specific embodiment of this invention, Y1 is NH and Y2 is a bond. In another specific embodiment of this invention, Y1 is a bond and Y2 is NH.
Suitably, Cy is (C3-C8)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one to three times, independently, by
(Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl,
hydroxy(Ci-C6)alkyl, (C C6)alkoxy, -((C0-C3)alkyl)NHCO2R7,
-((C0-C3)alkyl)N((Ci-C4)alkyl)C02R7, -((Co-C3)alkyl)NHC(0)R7,
-((Co-C3)alkyl)N((Ci-C4)alkyl)C(0)R7, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8,
-((C0-C3)alkyl)C(O)R7, (Ci-C4)alkoxy(Ci-C6)alkyl, amino(Ci-C6)alkyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one or two times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, cyano, (Ci-C4)alkoxy, ((Ci-C4)alkyl)amino ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -((C0-C3)alkyl)CO2R7,
or -((Co-C3)alkyl)CONR7R8. In another embodiment of this invention, Cy is (C3 -C6)cycloalkyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, dioxanyl, oxathianyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy, -((C0-C3)alkyl)NHCO2R7, -((C0-C3)alkyl)N((Ci-C4)alkyl)CO2R7,
-((C0-C3)alkyl)NHC(O)R7, -((C0-C3)alkyl)N((Ci-C4)alkyl)C(O)R7, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, -((C0-C3)alkyl)C(O)R7, (Ci-C4)alkoxy(Ci-C6)alkyl, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy, -((C0-C3)alkyl)NHCO2R7, -((Co-C3)alkyl)N((Ci-C4)alkyl)C02R7,
-((C0-C3)alkyl)NHC(O)R7, -((Co-C3)alkyl)N((C1-C4)alkyl)C(0)R7, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8, -((C0-C3)alkyl)C(O)R7, (d-C^alkoxyCd-Qalkyl, amino(C1-C6)alkyl, ((C C^alky^CCd-C^alky^aminoCC Qalkyl, (d-C^alkylaminoCd-d^lkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(d-d)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one or two times, independently, by (d-d)alkyl, (d-d)haloalkyl, halogen, cyano, (d-d)alkoxy, (d-C4)alkyl)((d-C4)alkyl)amino, -((C0-C3)alkyl)CO2H,
-((d-C3)alkyl)C02(Ci-C6)alkyl, or -((C0-C3)alkyl)CONH(Ci-C6)alkyl. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one to three times, independently, by (Crd)alkyl, (d-d)haloalkyl, (C3-d)cycloalkyl, halogen, oxo, cyano, hydroxyl,
hydroxy(Ci-d)alkyl, (d-d)alkoxy, -((C0-C3)alkyl)NHCO2R7,
-((d-C3)alkyl)N((Ci-d)alkyl)CO2R7, -((C0-C3)alkyl)NHC(O)R7,
-((d-C3)alkyl)N((Ci-d)alkyl)C(0)R7, -((d-C3)alkyl)C02R7, -((d-C3)alkyl)CONR7R8,
-((C0-C3)alkyl)C(O)R7, (d-C4)alkoxy(d-d)alkyl, amino(Ci-d)alkyl,
((Ci-d)alkyl)((Ci-d)alkyl)amino(Ci-d)alkyl, (Ci-d)alkylamino(Ci-d)alkyl, amino,
(Ci-d)alkylamino, ((Ci-d)alkyl)((C d)alkyl)amino, aryl, heteroaryl, aryl(d-C6)alkyl, heteroaryl(d-d)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (d-C4)haloalkyl, cyano, (C C4)alkoxy, -((C0-C3)alkyl)CO2R7, or -((C0-C3)alkyl)CONR7R8 or ((Ci-C )alkyl)((Ci-C )alkyl)amino. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl,
(Ci-C4)haloalkyl, cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In a specific embodiment of this invention, Cy is phenyl.
Suitably, Z is O, S, S02, C=0, NR6, or a bond. In another embodiment of this invention, Z is O, NR6, or a bond. In another embodiment of this invention, Z is O, NH,
-N(Ci-C4)alkyl, -N((C0-C3)alkyl)CO2R7, -N((C0-C3)alkyl)CONR7R8 or a bond. In another embodiment of this invention, Z is a bond, O, or NH. In another embodiment of this invention, Z is O or NH. In a specific embodiment of this invention, Z is O.
Suitably, A1, A2, A3, and A4 are each independently selected from N, NR6, O, S, CH, and CR10, wherein one of A1, A2, A3, and A4 is NR6, O, or S, 0-2 of A1, A2, A3, and A4 are CR10, and 0-3 of A 1 , A2 , A 3 , and A 4 are CH or N. In another embodiment of this invention, A 1 , A 2 , A 3 , and A are each independently selected from N, N((Ci-C4)alkyl), O, S, CH, and C((C C4)alkyl), wherein one of A1, A2, A3, and A4 is N((d-C4)alkyl), O, or S, 0-2 of A1, A2, A3, and A4 are
C((Ci-C4)alkyl), and 0-3 of A1, A2, A3, and A4 are CH or N. In another embodiment of this invention, A1 and A4 are each independently selected from CH and CR10, and one of A2 and A3 is NR6, O, or S and the other is N or CH. In another embodiment of this invention, A1 and A4 are each independently selected from CH and C((Ci-C4)alkyl), and one of A2 and A3 is N((C C4)alkyl), O, or S and the other is N or CH. In another embodiment of this invention, A1 and A4 are each independently selected from CH and C((Ci-C4)alkyl), and one of A2 and A3 is O or S and the other is N.
Suitably, R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5. In another embodiment of this invention, R1 is (C3-C6)alkyl, (C3-Cg)cycloalkyl,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, or heteroaryl, each of which is optionally substituted one to three times, independently, by R5. In another embodiment of this invention, R1 is (C3-C6)alkyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy(Ci-C2)alkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino (i.e. wherein R5 is halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino). In another embodiment of this invention, R1 is (C3-C6)alkyl, (C3-C6)cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R1 is (C3-C6)alkyl. In another embodiment of this invention, R1 is (C5-C6)alkyl. In another embodiment of this invention, R1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-Cz alkyl, (Ci-Cz alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R1 is phenyl optionally substituted one or two times, independently, by halogen,
(Ci-C4)alkyl, (C C4)haloalkyl, cyano, (C C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In a specific embodiment of this invention, R1 is phenyl or pyridinyl. In another specific embodiment of this invention, R1 is phenyl.
Suitably, R2 is hydrogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl. In another embodiment of this invention, hydrogen or (Ci-C4)alkyl. In another embodiment of this invention, R2 is hydrogen or methyl. In a specific embodiment of this invention, R2 is hydrogen.
In another embodiment of this invention, R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R5. In another embodiment of this invention, R1 and R2 taken together represent -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-.
Suitably, R3 and R3a are each independently hydrogen, hydroxyl, (Ci-C6)alkyl,
(Ci-C6)haloalkyl, halogen, (Ci-C6)alkoxy, amino, (Ci-C4)alkylamino, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R3 and R3a are each independently hydrogen or methyl. In a specific embodiment of this invention, R3 and R3a are each independently hydrogen.
Suitably, each R4 is independently selected from hydrogen, halogen, (Ci-C6)alkyl,
(C C6)haloalkyl, -C02R7, -CONR7R8, -OR9, and -NR8R9, wherein said (C C6)alkyl or
(C C6)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9. In another embodiment of this invention, each R4 is independently selected from hydrogen,
(C C4)alkyl, (C C4)haloalkyl, -OR9, and -NR8R9, wherein said (C C4)alkyl or (Q^haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9. In another embodiment of this invention, each R4 is independently selected from hydrogen, halogen, (Ci-C4)alkyl,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, (Ci-C4)alkoxy(Ci-C4)alkylamino,
-NHC02(C C4)alkyl, (C C4)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, -0((Ci-C4)alkyl)C02R7, -0((d-C4)alkyl)CONH2,
-0((Ci-C4)alkyl)CONH(Ci-C4)alkyl, -0((Ci-C4)alkyl)CON((Ci-C4)alkyl)((Ci-C4)alkyl), and C02R7. In another embodiment of this invention, each R4 is independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino,
(Ci-C4)alkoxy(Ci-C4)alkylamino, (Ci-C4)alkoxy, hydroxy(C2-C4)alkoxy,
(Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, -0((Ci-C3)alkyl)C02H,
-0((Ci-C3)alkyl)C02(Ci-C4)alkyl, -0((Ci-C3)alkyl)CONH2, -0((Ci-C3)alkyl)CONH(Ci-C4)alkyl, and -0((Ci-C3)alkyl)CON((Ci-C4)alkyl)((Ci-C4)alkyl). In another embodiment of this invention, each R is independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, -0((Ci-C3)alkyl)C02H, -0((Ci-C3)alkyl)C02(Ci-C4)alkyl, -0((Ci-C3)alkyl)CONH2, -0((Ci-C3)alkyl)CONH(Ci-C4)alkyl, and -0((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl). In another embodiment of this invention, each R4 is independently selected from (Ci-C4)alkoxy, hydroxy(C2-C4)alkoxy,
(CrC4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, -0((C C3)alkyl)C02H,
-0((C1-C3)alkyl)C02(C1-C4)alkyl, -0((C C3)alkyl)CONH2, -0((C1-C3)alkyl)CONH(C1-C4)alkyl, and -0((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl). In another embodiment of this invention, each R4 is independently selected from (Ci-C4)alkoxy, -0((Ci-C3)alkyl)C02H,
-0((C C3)alkyl)C02(Ci-C4)alkyl, -0((C C3)alkyl)CONH2, -0((Ci-C3)alkyl)CONH(C C4)alkyl, and -0((Ci-C3)alkyl)CON((Ci-C4)alkyl)((C C4)alkyl). In another embodiment of this invention, each R4 is independently selected from (Ci-C4)alkyl and (Ci-C4)alkoxy. In a specific embodiment of this invention, each R4 is hydrogen.
Suitably, each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and (Ci-C6)alkyl. In another embodiment of this invention, each R4a is independently selected from hydrogen, halogen, and (Ci-C4)alkyl. In another embodiment of this invention, each R4a is independently selected from is hydrogen, fluorine, and methyl. In another embodiment of this invention, each R4a is independently selected from is hydrogen and methyl. In a specific embodiment of this invention, each R4a is hydrogen. In a specific embodiment of this invention, each R4a is methyl.
In another embodiment of this invention, R4 and R4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano,
(C C4)alkyl, (C C4)haloalkyl, (C3-C6)cycloalkyl, -C02R7, -CONR7R8, hydroxyl,
hydroxy(Ci-C6)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((C C^alky^CCd-C^alky amino, -NHC02R7, -N((C C4)alkyl)C02R7, -NHC(0)R7, or
-N((Ci-C4)alkyl)C(0)R7. In another embodiment of this invention, R4 and R4a taken together represent -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-.
Suitably, R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl. In another embodiment of this invention, R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R11 is hydrogen, (Ci-C4)alkyl, -CF3, F, CI, Br, cyano, hydroxyl, or (Ci-C4)alkoxy.
One articular embodiment of the invention is a compound of Formula (la):
Figure imgf000014_0001
wherein:
m is 1 ;
n is 1 or 2;
Y1 is NH or NCH3 and Y2 is a bond;
K1, K2, K3, and K4 are each independently selected from N, N -0~, CH, and CR10, wherein 0-2 of K1, K2, K3, and K4 are N or N+-0" and 0-2 of K1, K2, K3, and K4 are CR10;
Z is O, NR6, or a bond;
A1, A2, A3, and A4 are each independently selected from N, NR6, O, S, CH, and CR10, wherein one of A1, A2, A3, and A4 is NR6, O, or S, 0-2 of A1, A2, A3, and A4 are CR10, and 0-3 of A1, A2, A3, and A4 are CH or N;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5;
R2 is hydrogen, (C C6)alkyl, or (Ci-C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (Ci-C4)alkyl, (Ci-C4)haloalkyl, halogen, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
each R4 is independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, -OR9, and -NR8R9, wherein said (Ci-C4)alkyl or (Ci-C4)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
(CrC4)alkyl; each R5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy(C1-C6)alkyl, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl,
(Ci-C4)alkoxy(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(Ci-C4)alkyl, hydroxyl, hydroxy(Ci-C6)alkyl, (C C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
R9 is -C(0)R7, -C02R7, -C(0)NR7R8, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl,
heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -C02R7, -CONH2,
-CONH(Ci-C4)alkyl, -CON((Ci-C4)alkyl)((Ci-C4)alkyl), hydroxyl, (Ci-C4)alkoxy, amino,
(C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, -NHC02R7, -N((CrC4)alkyl)C02R7, -NHC(0)R7, or -N((C C4)alkyl)C(0)R7;
or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(Ci-C4)alkyl, -CONR7R8, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((Ci-C4)aikyl)C02R7, -NHC(0)R7, or
-N((Ci-C4)alkyl)C(0)R7;
R10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (C C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl; and R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;
n is 1 or 2;
Y1 is NH or NCH3 and Y2 is a bond;
K1, K2, K3, and K4 are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C4)alkyl, (C C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, wherein 2-4 of K1, K2, K3, and K4 are a carbon atom substituted by hydrogen;
Z is O, NH, -N(Ci-C4)alkyl, -N((C0-C3)alkyl)CO2R7, -N((C0-C3)alkyl)CONR7R8, or a bond;
A1 and A4 are each independently selected from CH and CR10, and one of A2 and A3 is NR6, O, or S and the other is N or CH;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5;
R2 is hydrogen;
R3 and R3a are each independently hydrogen or methyl;
each R4 is independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkoxy,
hydroxy(C2-C4)alkoxy, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino,
(Ci-C4)alkoxy(Ci-C4)alkylamino, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
-0((C C3)alkyl)C02H, -0((C1-C3)alkyl)C02(C1-C4)alkyl, -0((C C3)alkyl)CONH2,
-0((C1-C3)alkyl)CONH(C1-C4)alkyl, and -0((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl);
each R4a is independently selected from hydrogen, hydroxyl, amino, and (Ci-C4)alkyl; each R5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
R7 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl,
(Ci-C4)alkoxy(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl; R is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (C C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl; and
R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(d-C4)alkylamino, or ((d-C^alkylXCd-C^alky amino;
or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;
n is 1 or 2;
Y1 is NH and Y2 is a bond;
K1, K2, K3, and K4 are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C4)alkyl, (C C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, wherein 2-4 of K1, K2, K3, and K4 are a carbon atom substituted by hydrogen;
Z is O, NH, -N(C C4)alkyl, or a bond;
A1 and A4 are each independently selected from CH and C((Ci-C4)alkyl), and one of A and A3 is O or S and the other is N;
R1 is phenyl optionally substituted one or two times, independently, by halogen,
(C C4)alkyl, (C C4)haloalkyl, cyano, (C C4)alkoxy, or ((d-C^alkylXCd-C^alky^amino;
R2 is hydrogen;
R3 and R3a are each independently hydrogen or methyl;
each R4 is independently selected from hydrogen, (d-d)alkyl, (d-d)alkylamino, ((d-C4)alkyl)((d-C4)alkyl)amino, and (d-d)alkoxy;
each R4a is independently selected from hydrogen, hydroxyl, amino, and (d-C4)alkyl; and R11 is hydrogen, (d-C4)alkyl, -CF3, F, CI, Br, cyano, hydroxyl, or (Ci-C4)alkoxy;
or a pharmaceutically acceptable salt thereof.
Specific compounds used in this invention include:
N-(bis(4-methoxcyphenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- methoxyphenyl)(phenyl)methyl)acetamide; N-((4-(dimethylamino)phenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl) methoxy)phenyl)acetamide;
N-((2,3-dihydrobenzo[Z7] [l ,4]dioxin-6-yl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- fluorophenyl)(phenyl)methyl)acetamide;
N-(bis(4-fluorophenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide;
N-(di-/j-tolylmethyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- isopropylphenyl)(phenyl)methyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -(p-tolyl)cyclohexyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -phenylcyclohexyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -phenyl- 1 -(p-tolyl)ethyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3- fluorophenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-2- fluorophenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(((3,5-dimethylisoxazol-4- yl)methyl)(methyl)amino)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(thiazol-4-ylmethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((2-methylthiazol-4-yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-cyclopropylisoxazol-3- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisothiazol-4-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl) acetamide;
2-(4-((5-methyl- l,2,4-oxadiazol-3-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((5-ethyl- l,2,4-oxadiazol-3-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((3 -methyl- 1 ,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((5-methyl- l,3,4-oxadiazol-2-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-(hydroxymethyl)-5-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-methylisoxazol-3- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N- methylacetamide; 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(4- (trifluoromethyl)phenyl)methyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)propanamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(2-(3,5-dimethylisoxazol-4- yl)ethoxy)phenyl)acetamide;
2-(4-((3-ethyl-5-methylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
N-(di- /j-tolylmethyl)-2-(4-(l-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-ethyl-5-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(isoxazol-4-ylmethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-methylthiazol-4-yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(oxazol-5-ylmethoxy)phenyl)acetamide;
2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)amino)acetic acid;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2- methylpropanamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2- yl)acetamide; and
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methylthio)phenyl)acetamide;
and pharmaceutically acceptable salts thereof.
The meaning of any functional group or substituent thereon at any one occurrence in Formula (I), or any subformula thereof, is independent of its meaning, or any other functional group's or substituent's meaning, at any other occurrence, unless stated otherwise.
The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the
stereochemistry of a chiral center present in Formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
"Enantiomerically pure" means products whose enantiomeric excess is 99% ee or greater. When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as
"polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof.
Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
For solvates of the compounds of the invention, or salts thereof, that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
Because of their potential use in medicine, the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1- 19. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha- hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates,
phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthalene-2-sulfonates.
Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
dehydroabietylamine, N,N-Z?z'sdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.
Other non-pharmaceutically acceptable salts, e.g. trifluoroacetate, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula (I).
If a disclosed compound containing a basic amine or other basic functional group is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pKa than the free acid form of the compound.
The invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride or sodium borodeuteride).
Methods of Use The compounds of the invention are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases and cancer. The inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Behcets disease, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, dry eye and glomerulonephritis, myocarditis. The cancer diseases of the invention include lytic bone disease in multiple myeloma, acute
myelogenous leukemia (AML), head and neck squamous cell carcinoma, bladder carcinoma, gastric cancer, hepatocellular carcinoma, melanoma, medulloblastoma and colon cancer.
Accordingly, in another aspect the invention is directed to methods of treating such diseases.
The methods of treatment of the invention futher comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
As used herein, "treatment" in reference to a condition means: (1) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
An "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein, "patient" refers to a human or animal.
The compounds of the invention may be administered by any suitable route of
administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of Formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention.
Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as
"pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate
functionalities when such functionalities are present within compounds of the invention.
Preferred "pro-moieties" for compounds of the invention include: ester, carbonate ester, hemi-ester, phosphate ester, nitro ester, sulfate ester, sulfoxide, amide, carbamate, azo-, phosphamide, glycoside, ether, acetal, and ketal derivatives of the compounds of Formula (I).
Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
The invention includes the use of compounds of the invention for the preparation of a composition for treating or ameliorating diseases mediated by RORy in a subject in need thereof, wherein the composition comprises a mixture of one or more of the compounds of the invention and an optional pharmaceutically acceptable excipient.
The invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by RORy. In another embodiment, the invention relates to the use of compounds of the invention in the preparation of a medicament for the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, Dry Eye, glomerulonephritis, myocarditis and cancer diseases including lytic bone disease in multiple myeloma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, bladder carcinoma, gastric cancer, hepatocellular carcinoma, melanoma,
medulloblastoma and colon cancer.
Compositions
The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to methods of treatment of diseases mediated by RORy which comprise administering to a human in need thereof pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient(s).
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
The compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain
pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.
microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc. Compound Preparation
The compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The reaction sequences provided in these Schemes are applicable for producing compounds of the invention having a variety of different R1, R3, R3a, R4, R4a, R11, Κ Κ4, and A1 -A4 groups employing appropriate precursors. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de -protecting different substituents using such suitable protecting groups are well known to those skilled in the art;
examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
Scheme 1
Figure imgf000028_0001
Conditions: a) R MgBr or R^Li, THF, NaBH4, MeOH; b) NH2OH«HCl, pyridine; c) Zn, EtOH, NH4OH, NH4OAc.
Sch
Figure imgf000028_0002
Conditions: a) K2C03 or Cs2C03 or NaH, DMF or acetone or CH3CN; b) NaOH, MeOH, H20; c) (II), EDC, HOBt, Et3N or DIPEA, DMF or THF or CH2C12; or (II), HATU, NMM, CH2C12.
Figure imgf000029_0001
Conditions: a) (II), EDC, HOBt, Et3N or DIPEA, DMF or THF or CH2C12; or (II), HATU, NMM, CH2C12; b) K2C03 or Cs2C03 or NaH, DMF or acetone or CH3CN (X = CI or Br); or PPh3, DIAD, THF (X = OH).
Sc
Figure imgf000029_0002
Conditions: a) K2C03 or Cs2C03 or NaH, DMF or acetone or CH3CN; b) NaBH4, MeOH; c) SOC1; CH2C12; d) NaCN, KI, MeOH; e) NaOH, MeOH, H20. Scheme 5
Figure imgf000030_0001
Conditions: a) n-BuLi, R'CHO, THF, -78 °C-0 °C; b) SOCl2, CH2C12, 0 °C-rt; c) NaCN, K2C03, DMF, 60 °C; d) NaOH, EtOH, H20, reflux; e) H2S04, AcOH, H20, reflux; f) (III), EDC, HOBt, Et3N or DIPEA, DMF or THF or CH2C12 or (III), HATU, NMM, CH2C12; g) K2C03 or Cs2C03 or NaH, DMF or acetone or CH3CN.
Scheme 6
Figure imgf000030_0002
Conditions: a) KHC03, KI, CH3CN; b) HC1, Et20, MeOH; c) K2C03, BrCR3R3aC02CH3, DMF; d) LiOH, THF, H20; e) (II), EDC, HOBt, Et3N or DIPEA, DMF or THF or CH2C12.
Examples
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
Compounds names were generated using the software program ChemBioDraw Ultra VI 2.0 available from CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, MA 02140 USA (http:// www.cambridgesoft.com).
Abbreviations
AcOH acetic acid
aq. aqueous
Ar argon gas
CH2CI2 dichloromethane
CH3CN acetonitrile
CH3I methyl iodide
cone. concentrated
CS2CO3 cesium carbonate
DIAD diisopropyl azodicarboxylate
DIPEA NN-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
Et3N triethylamine
Et20 diethyl ether
EtOH ethanol
h hour(s)
HATU 0-(7-azabenzotriazol- 1 -yl)-NNN',N'-tetramethyluronium hexafluorophosphate
HC1 hydrochloric acid
H20 water
HOBt hydroxybenzotriazole
HPLC high-performance liquid chromatography
H2SO4 sulfuric acid
K2CO3 potassium carbonate
KI potassium iodide
KOH potassium hydroxide
KO?-Bu potassium tert-butoxide
LCMS liquid chromatography mass spectrometry
L1AIH4 lithium aluminum hydride
LiOH lithium hydroxide
MeOH methanol
min minute(s)
NaBH4 sodium borohydride
NaCN sodium cyanide
NaH sodium hydride
NaHC03 sodium bicarbonate
NaOH sodium hydroxide
Na2S04 sodium sulfate
n-BuLi «-butyllithium NH4CI ammonium chloride
NMM N-methylmorpholine
PPI13 triphenylphosphine
rt room temperature
Rt retention time
SOCl2 thionyl chloride
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
Zn zinc powder
LCMS Conditions
LCMS-P 1
Column: Waters Sunfire CI 8, 3.5 μηι, 50 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA) Gradient: 5% B for 0.2 min, increase to 95% B within 1.2 min, 95% B for 1.6 min, return to 5% B within 0.01 min.
Flow Rate: 1.8 mL/min
Detection: PDA 190-400 nm
LCMS-G7
Column: XBridge C 18, 3.6 μηι, 50 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.1% formic acid) B: methanol
Gradient: 10% B for 0.1 min, increase to 95% B within 2.5 min, 95% B for 2.5 min, return to 10% B within 0.1 min, 10% B for 2 min. Flow Rate: l .O mL/min
Detection: PDA 190-400 nm
LCMS-G9
Column: XBridge C 18, 3.6 μηι, 50 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.1% ammonium acetate) B: methanol Gradient: 10% B for 0.2 min, increase to 95% B within 5 min,
95% B for 2 min, return to 10% B within 0.1 min, 10% B for 2 min. Flow Rate: 0.8 mL/min
Detection: PDA 190-400 nm LCMS-G12
Column: Sunfire C I 8, 5 μηι, 50 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.1% formic acid) B: methanol
Gradient: 30% B for 0.1 min, increase to 90% B within 4 min,
99% B for 4 min, return to 30% B within 0.1 min, 10% B for 2 min.
Flow Rate: 0.8 mL/min
Detection: PDA 190-400 nm LCMS-G30
Column: Eclipse XDB C I 8, 5 μηι, 250 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA)
Gradient: 30% B for 0.2 min, increase to 95% B within 15 min,
95% B for 5 min, return to 30% B within 3 min 30% B for 5 min.
Flow Rate: 0.8 mL/min
Detection: PDA 190-400 nm
LCMS-X
Column: Eclipse XDB C 18, 5 μηι, 150 x 4.6 mm
Temperature: 50 °C
Mobile Phase: A: water (0.1% formic acid) B: acetonitrile (0.1% formic acid) Gradient: 10% B for 0.1 min, increase to 90% B within 5 min, 100% within 2 min 100% B for 4 min, return to 10% B within 0.01 min, 10% B for 1 min.
Flow Rate: 1.0 mL/min
Detection: PDA 190-400 nm
LCMS-T1
Column: Eclipse XDB C I 8, 5 μηι, 150 x 4.6 mm
Temperature: 50 °C
Mobile Phase: water (0.05% TFA) B: acetonitrile (0.05% TFA)
Gradient: 5% B for 0.1 min, increase to 95% B within 7 min, 100% within 2 min return to 5% B within 0.1 min, 5% B for 3 min.
Flow Rate: 1.0 mL/min
Detection: PDA 190-400 nm Example 1
N-(bis(4-methoxcyphenyl)methy ethoxy)phenyl)acetamide
Figure imgf000034_0001
(a) bis(4-methoxyphenyl)methanamine
To a solution of 4-methoxybenzonitrile (0.50 g, 3.70 mmol) in anhydrous THF (5 mL) at 0 °C was added 0.5 M solution of 4-methoxyphenyl magnesium bromide in THF (1 1.2 mL, 5.60 mmol) very slowly within 10 min and the resulted mixture was warmed to rt. The reaction mixture was stirred at rt for 5 h followed by heated to 60 °C and stirred at the same temperature for 2 h. After completion of the imine formation, the reaction mixture was cooled to 0 °C and 5 mL of methanol was added very slowly followed by NaBH4 (0.212 g, 5.60 mmol). The resulted mixture was warmed to rt and stirred overnight. After completion of the reaction, 10 mL of water was added into the reaction mixture and the mixture was extracted with EtOAc (2 x 40 mL), washed with brine (25 mL), dried over Na2S04 and evaporated to obtained a crude product which was purified using silica gel chromatography using 10% EtOAc in hexanes to obtain the title compound (0.815 g, 89.20%) as a light brown oil. lU NMR (400 MHz, DMSO-dg) δ 7.23-7.27 (m, 4 H), 6.81-6.87 (m, 4 H), 4.99 (s, 1 H), 3.70 (s, 6 H).
(b) N-(bis(4-methoxyphenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide.
To a solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetic acid (0.200 g, 0.76 mmol) in DMF (5 mL) at 25 °C was added HOBt (0.140 g, 0.91 mmol), EDC (0.175 g, 0.91 mmol), DMAP (0.186 g, 1.50 mmol) and the resulting mixture was stirred at rt for 10 min. After 10 min, bis (4-methoxyphenyl) methanamine 3 (0.204 g, 0.84 mmol) in DMF (1 mL) was added slowly and the stirring at rt was continued overnight. After completion of the reaction, 10 mL of water was added into the reaction mixture very slowly with cooling and the obtained white solid was filtered off and washed with water (20 mL) and hexanes (20 mL) and dried in vacuum to obtain the title compound (0.185 g, 45.34% ). 'HNMR (400 MHz, DMSO- dg) δ 8.83-8.85 (d,l H), 7.18-7.20 (d, 2 H), 7.13- 7.15 (d, 4 H), 6.91-6.93 (d, 2 H), 6.85-6.88 (d, 4 H), 5.96-5.98 (d, 1 H), 4.87 (s, 2 H), 3.72 (s, 6 H), 3.41-3.44 (s, 2 H), 2.38 (s, 3 H), 2.19 (s, 3 H). Following essentially the same procedures as described in Example 1, the following compounds in table 1 were prepared. Table 1
Figure imgf000035_0001
Figure imgf000036_0001
yl)methoxy)phenyl)acetamide
Example 7
N-(di-f>-tolylmethyl)-2-(4-((3,5- acetamide
Figure imgf000036_0002
(a) di-/ tolylmethanamine
The title compound was synthesized from 4-methylbenzonitrile and / tolylmagnesium bromide essentially as described in Example 1 (a). LCMS-P 1 : 195 [M-NH2] +; Rt: 1.217min. !H NMR (400 MHz, CDC13) δ ppm 7.24 (d, J= 7.6 Hz, 4H), 7.11 (d, J= 8 Hz, 4H), 5.15 (s, 1H), 2.31 (s, 6H), 1.82 (br, 2H).
(b) N-(di-f>-tolylmethyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide
To a stirred solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetic acid (261 mg, 1 mmol) in CH2CI2 (10 mL) was added di-p-tolylmethanamine (211 mg, 1 mmol), DIPEA (258 mg, 2 mmol), EDC (230 mg, 1.2 mmol) and HOBt (162 mg, 1.2 mmol) successively. The resulting mixture was stirred at rt overnight. Additional CH2CI2 (20 mL) was added, the resulting mixture was washed with 1 % HC1 (3 x 10 mL), and the organic layer was dried over Na2S04. After removal of the organic solvent, the crude product was purified by preparatory HPLC using 10- 100% water/CH3CN with 0.1% TFA to give the title compound (275 mg, 61%). LCMS-P1 : 455 [M+H]+; Rt: 1.753min. lU NMR (500MHz, CDC13) δ ppm 7.14 (d, J= 8.0 Hz, 2H), 7.02 (d, J= 8.0 Hz, 4H), 6.92 (d, J= 8.2 Hz, 4H), 6.85 (d, J= 8.5 Hz, 2H), 6.10 (d, J= 8.5 Hz, 1H), 5.90 (d, J= 8.5 Hz, 1H), 4.71 (s, 2H), 3.51 (s, 2H), 2.33 (s, 3H), 2.24 (s, 6H), 2.22 (s, 3H).
Following essentially the same procedures as described in Example 7, the following compounds in table 2 were prepared.
Table 2
Figure imgf000037_0001
Figure imgf000038_0001
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetic acid (60 mg, 0.2 mmol) and 1- phenyl- l-(/ tolyl)ethanamine (24 mg, 0.1 mmol) were dissolved in CH2CI2 (15 mL). HATU (349 mg, 0.9 mmol) was added followed by N-methyl morpholine (200 mg, 1.6 mmol) and the reaction was stirred overnight. Solvent was removed and title compound was purified by reverse phase chromatography using CH3CN/water with 0.05% TFA. (2 mg, 2%). LCMS-T1 : 454.5 [M+H]+; Rt = 5.74 min. lU NMR (400 MHz, CDC13) δ ppm 7.28 (m, 2H), 7.15 (d, 2H), 7.09 (d, 2H), 6.89 (t, 2H), 6.83 (d, 2H) 6.18 (d, 1H), 5.91 (d, 2H), 3.99 (s, 3H), 3.70 (s, 2H), 3.55 (s, 2H), 2.31 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H).
Example 12
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3- fluorophenyl)acetamide
Figure imgf000038_0002
(a) ethyl 2-(3-fluoro-4-hydroxyphenyl)acetate
To a solution of 2-(2-fluoro-4-hydroxyphenyl)acetic acid (0.500 g, 2.9 mmol) in EtOH (10.8 mL) and benzene (15 mL) was added cone. H2SO4 (1 mL) and refluxed for overnight. After completion of the reaction the reaction mixture was distilled off to remove EtOH. The residue obtained was neutralized with saturated NaHCC>3, extracted with EtOAc (250 mL) dried over Na2S04 and distilled out to provide title compound (0.500 g, 85.91%). lU NMR (400 MHz, DMSO- d6) δ 9.75 (s, 1H), 7.02-7.05 (s, 1 H), 6.85-6.90 (s, 2 H), 4.03-4.09 (q, 2 H), 3.54 (s, 2 H), 1.17 (t, 3 H). (b) ethyl 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3-fluorophenyl)acetate
To a solution of ethyl 2-(2-fluoro-4-hydroxyphenyl) acetate (0.500 g, 2.52 mmol) in dimethyl formamide (10 mL) was added 4-(chloromethyl)-3, 5-dimethylisoxazole (0.551 g, 3.78 mmol) and K2C03 (1.04 g, 7.57 mmol) and reaction mixture was refluxed overnight at 85 °C. After completion of the reaction, the reaction mixture was cooled to rt and crushed ice was added to the reaction mass and extracted with EtOAc (250 mL). The organic layer was dried over Na2S04 and evaporated to provide title compound (0.700 g, crude). The obtained crude was used in the next step without further purification. (c) 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3-fluorophenyl)acetic acid
A solution of ethyl 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-2-fluorophenyl)acetate (0.700 g, crude) in 5 N NaOH solution (5 mL) was stirred at rt for 1 h. After completion of the reaction, the reaction mass was extracted with EtOAc (100 mL) and it was discarded. The aqueous fraction was acidified with 1 N hydrochloride acid, extracted with CH2CI2 (200 mL) and the organic layer was dried over Na2S04 and evaporated to provide title compound (0.300 g, 47.16%). LCMS-X1 : 479.2
[M+H]+; Rt = 6.88 min ^ NMR (400 MHz, DMSO) δ 12.36 (b, 1H), 7.19-7.23 (t, 1 H), 7.1 1-7.14 (dd, 1 H), 7.02-7.04 (d, 1 H), 4.97 (s, 2 H), 3.53 (s, 2 H), 2.38(s, 3 H), 2.21 (s, 3 H).
(d) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3- fluorophenyl)acetamide
To a solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3-fluorophenyl)acetic acid (0.100 g, 0.35 mmol) in dimethyl formamide (5 mL), EDC (0.083 g, 0.43 mmol), HOBt (0.066 g, 0.43 mmol), DMAP(0.090 g, 0.73 mmol) and (4-chlorophenyl)(phenyl)methanamine 6 (0.109 g, 0.43 mmol) was added and reaction mixture was stirred for overnight at rt. After completion of the reaction, the reaction mass was cooled and water (10 mL) was added drop wise during which solid precipitate falls out. The solid precipitate was filtered, washed with hexanes (10 mL) and purified with preparative TLC using 30% EtOAc in hexanes as a mobile phase to provide title compound (0.032 g, 18.7%). LCMS-X1 : 479.2 [M+H]+; Rt = 6.88 min. ¾ NMR (400 MHz, DMSO- d6) δ 9.00-9.02 (d, 1H), 7.17-7.40 (m, 10 H), 7.09-7.12 (dd, 1 H), 7.02-7.04 (d, 1 H), 6.08-6.10 (d, 1 H), 4.96 (s, 2 H), 3.49 (s, 2 H), 2.36 (s, 3 H), 2.20 (s, 3H).
Following essentially the same procedures as described in Example 12, the following compound in table 3 was prepared.
Table 3
Figure imgf000040_0002
Example 14
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(((3,5-dimethylisoxazol-4- yl)methyl)(methyl)amino)
Figure imgf000040_0001
To a solution ofN-((4-chlorophenyl)(phenyl)methyl)-2-(4-(((3,5-dimethylisoxazol-4- yl)methyl)amino)phenyl)acetamide (0.200 g, 0.435 mmol) in acetone (10 mL) at 25 °C was added K2C03 (0.151 g, 1.08 mmol) followed by addition of CH3I (0.123 g, 0.87 mmol) at 0 °C and the reaction was allowed to stir for 24 h. Then the solvent was evaporated in vacuum and water (10 mL) was added. The solution was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with water (20 mL), brine (25 mL), dried over Na2S04; and evaporated in vacuum to obtain a crude product which was purified using preparative TLC on silica gel using 40% EtOAc in hexanes to provide title compound was isolated. (22 mg, 10.67%). LCMS-X1 : 474.6 [M+H]+; Rt = 6.78 min. lH NMR (400 MHz, DMSO-d6) δ ppm 8.92-8.94 (d, 1 H), 7.34-7.39 (d, 2 H), 7.24-7.32 (m, 7 H), 7.09-7.11 (d, 2 H), 6.76-6.79 (d, 2 H), 6.07-6.09 (d, 1 H), 4.19 (d, 2 H), 3.36 (s, 2 H), 2.69 (s, 3 H), 2.33 (s, 3H), 2.05 (s, 3 H). Example 15
N-(( -chlorophenyl)(phenyl)methyl)-2-(4-(thiazol-4-ylmethoxy)phenyl)acetamide
(a)
Figure imgf000041_0001
The title compound was synthesized from 2-(4-hydroxyphenyl)acetic acid and (4- chlorophenyl)(phenyl)methanamine essentially as Example 1 (b) and the product was purified by silica gel column chromatography (40% EtOAc/Hexane) to provide title compound (4.5 g, 65.2%) lH NMR (400 MHz, DMSO-dg) δ ppm 9.25 (s, 1 H), 8.94-8.96, (d, 1H), 3.37-3.39 (d, 2 H), 7.28-7.34 (m,3 H), 7.24-7.26 (m 3 H),7.04-7.06 (d, 2 H), 6.65-6.67 (d, 2 H), 6.07-6.09 (d, 1 H), 4.08 (s, 2 H).
(b) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(thiazol-4-ylmethoxy)phenyl)acetamide.
To a solution ofN-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetamide (0.300 g, 0.85 mmol) in DMF (4.0 mL) was added K2C03 (0.353 g, 0.2.55 mmol) and 4-(chloromethyl)thiazole (0.136 g, 1.02 mmol), and the reaction was stirred for 20 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na2S04 and concentrated. The compound was purified by silica gel column chromatography (32% EtOAc/Hexane) to provide title compound (0.185 g, 48.42%). LCMS-X1 : 449.1 [M+H]+; Rt = 5.58 min. ¾ NMR (400 MHz, DMSO-d6) δ ppm 9.120-125 (d, 1 H), 9.00-9.02 (d, 1 H), 7.77 (s, 1 H), 7.37-7.40 (d, 2 H ), 7.25-7.35 (m, 7 H), 6.95-6.97 (d, 2 H), 6.07-6.09 (s, 1 H), 5.18 (s, 2 H), 3.47 (s, 2 H);
Following essentially the same procedures as described in Example 9, the following compounds in table 4 were prepared.
Table 4
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Example 23
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-(hydroxymethyl)-5-methylisoxazol-4- yl)methoxy)phenyl)acetami
Figure imgf000044_0002
(a) ethyl 4-((4-(2-((4-chlorophenyl)(phenyl)methylamino)-2-oxoethyl)phenoxy)methyl)-5- methylisoxazole-3-carboxylate
To a solution ofN-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetamide (0.259 g, 0.73 mmol) in DMF (5 mL) was added ethyl 4-(chloromethyl)-5-methylisoxazole-3-carboxylate (0.150 g, 0.73 mmol) and anhydrous K2CO3 (0.304 g, 2.20 mmol), and the reaction was refluxed for 2 h. After completion of the reaction, water (30 mL) was added into the reaction mixture and the mixture was extracted with EtOAc (125 mL). The organic layer was washed with brine (25 mL), dried over Na2S04; and evaporated to obtain a crude product which was purified using silica gel column chromatography using 32% EtOAc: Hexanes to obtain the title compound (0.310 g, 81.3%) as a light yellow semi solid. MS (ESI+) 519.4 (M + H).
(b) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-(hydroxymethyl)-5-methylisoxazol-4- yl)methoxy)phenyl)acetamide
To a solution ethyl 4-((4-(2-((4-chlorophenyl)(phenyl)methylamino)-2- oxoethyl)phenoxy)methyl)-5-methylisoxazole-3-carboxylate (0.300 g, 0.579 mmol) in THF (5 mL) at 0 °C was added 1 M L1AIH4 solution in THF (0.57 mL, 0.579 mmol) and the reaction was stirred at 0 °C for 1 h. After completion of the reaction, crushed ice was added to the reaction mixture and extracted with EtOAc (300 mL). The combined organic layers were dried over Na2S04 and concentrated to obtain a crude product which was purified by preparative TLC on silica gel using (50% EtOAc /hexanes) as mobile phase to provide title compound (0.075 g, 51.7%). LCMS-X1 : 477.3 [M+H]+; Rt = 6.32 min. lH NMR (400 MHz, DMSO-dg) δ ppm 8.99-9.01 (d, 1H), 7.38-7.40 (d, 2 H), 7.24-7.35 (m, 7 H), 7.17-7.20 (m, 2 H), 6.91 -6.93 (d, 2 H), 6.07-6.10 (d, 1 H), 5.42-5.45 (t, 1 H), 4.93 (s, 2 H), 4.51 -4.52 (d, 2 H), 3.47 (s, 2 H), 2.40 (s, 3H).
Example 24
N-((4-chlorophenyl)(p acetamide
Figure imgf000045_0001
To a solution of N-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetamide (0.250 g,
0.710 mmol) in DMF (2.0 mL) was added 60% NaOH (0.034g, 0.85 mmol) at 0 °C and stirred for 20 min. 3-(chloromethyl)-5-methylisoxazole (0.1 12 g, 0.852 mmol) was added and the reaction was stirred for lh. After completion of the reaction, the reaction mixture was poured into crushed ice and extracted with EtOAc (100 mL). The organic layer was dried over Na2S04 and concentrated and product was purified by silica gel column chromatography (40% EtOAc/Hexane) to provide title compound (0.080 g, 25.23%). LCMS-X1 : 447.1 [M+H]+; Rt =5.60 min. lH NMR (400 MHz, DMSO-ds) δ ppm 9.00-9.02 (d, 1 H), 7.38-7.40 (d, 2 H), 7.33-7.34 (d, 2 H), 7.24-7.33 (m, 4 H), 7.18- 7.20 (d, 2 H), 6.92-6.94 (d, 2 H), 6.31 (s, 1 H), 6.07-6.09 (d, 1 H), 5.10 (s, 2 H), 3.47 (s, 2 H), 2.40 (s, 3 H).
Example 25
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N- methylacetamide
Figure imgf000045_0002
(a) l-(4-chlorophenyl)-N-methyl- l -phenylmethanamine
To a solution of (4-chlorophenyl)(phenyl)methanamine (0.3 g 1.181 mmol) in
dimethylformamide (15 mL), K2C03 (0.407 g, 2.95 mmol) was added and reaction was stirred at rt for 0.5 h. After 0.5 h, CH3I (0.073 mL, 1.181 mmol) was added and reaction mixture was stirred at rt for 16 h. After completion of the reaction, the reaction mixture was quenched by addition of water (50 mL) and extracted it with 2 x 50 mL EtOAc. The organic layer was dried (Na2S04) and concentrated to obtain a crude product which was purified by silica gel chromatography (10% EtOAc/hexane) to provide title compound (0.1 1 g, 40.44%). ¾ NMR (400 MHz, DMSO- d6) δ 7.39-7.43 (t, 3 H), 7.32-7.37 (t, 4 H), 7.26-7.30 (t, 2 H), 7.16-7.22 (t, 1 H), 4.65 (s, 1 H), 2.12 (s, 3 H).
(b) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N- methylacetamide
To a solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetic acid (0.20 g, 0.76 mmol) in THF (35 mL), EDC (0.21 g, 0.1 14 mmol) was added portion wise and reaction was stirred at rt for 2 h. After 2 h, 1 -(4-chlorophenyl)-N-methyl- 1 -phenylmethanamine (0.191 g, 0.826 mmol), HOBt (0.1 17 g, 0.766 mmol), Et3N (0.31mL, 2.298 mmol) was added to the reaction mixture and stirred for 24 h at rt. The completion of the reaction was monitored by TLC using (hexanes: EtOAc (5:5) system. After completion of the reaction, water (50 mL) was added to reaction mixture and extracted with EtOAc (2X50 mL). The organic layer was dried over Na2S04 and concentrated to obtain a crude product which was purified by silica gel chromatography (30% EtOAc/hexane) to provide title compound (0.184 g, 50.68%). MS 475.21 [M+H]+. ¾ NMR (400 MHz, DMSO-dg) δ 7.32-7.44 (m 6H), 7.04-7.17 (m, 6H), 6.91-6.96 (m, 3H), 4.89 (s 2H), 3.77 (s, 2H), 2.75 (s, 2H), 2.39 (s, 3H) 2.20 (s 3H).
Example 26
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(4- (trifluoromethyl)pheny
Figure imgf000046_0001
(a) phenyl(4-(trifluoromethyl)phenyl)methanamine
To a stirred solution of phenylmagnesium bromide (5.0 mL, 5.0 mmol, 1 N in THF) was added 4-(trifluoromethyl)benzonitrile (513 mg, 3 mmol) in 10 ml of THF under Ar. The resulting mixture was refluxed for 4h and then stirred at r.t overnight. 10 mL of MeOH was added to quench the reaction. Then NaBFL, (429 mg, 5.5mmol) was added to the reaction mixture under Ar and the mixture was stirred at r.t for additional 30 min. 50 mL of water was added and 100 mL DCM was used to extracted the organic compounds for 3 times. The organic phase was evaporated and the crude product was purified by silica gel column with EtO Ac/petroleum ether 1/1 to give the title compound as pale yellow oil (360 mg, yield: 47.8%). LC-MS-P1 : 235 [M-NH2] +; Rt: 2.136 min. lH NMR (CDC13, 500 MHz): δ 7.61 - 7.28 (m, 9H), 5.29 (s, 1H), 1.88 (s, 2H).
(b) 2-(4-hydroxyphenyl)-N-(phenyl(4-(trifluoromethyl)phenyl)methyl)acetamide
To a stirred solution of 2-(4-hydroxyphenyl)acetic acid (152 mg, 1.0 mmol) in 10 mL of CH2C12 was added phenyl(4-(trifluoromethyl)phenyl)methanamine (251 mg, 1.0 mmol), DIPEA (258 mg, 2.0 mmol), EDC (230 mg, 1.2 mmol) and HOBt (162 mg, 1.2 mmol) successively. The resulting mixture was stirred at rt for 2.5 h. Additional 20 mL of CH2CI2 was added and the resulting mixture was washed with water (10 mL*3), 1% HC1 (10 mL*3), and dried over Na2S04. After removal of the organic solvent, title compound was obtained (231 mg, 60%), and The title compound was used directly without further purification. LC-MS-P1 : 385 [M+H]+; R: 1.607min. (c) 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(4- (trifluoromethyl)phenyl)methyl)acetamide
To a stirred solution of 2-(4-hydroxyphenyl)-N-(phenyl(4- (trifluoromethyl)phenyl)methyl)acetamide (231mg, 0.6 mmol) in 10 mL of DMF was added 4- (chloromethyl)-3,5-dimethylisoxazole (87 mg, 0.6 mmol), K2CO3 (166 mg, 1.2 mmol), and tetrabutylammonium iodide ( 22mg, 0.06mmol) successively. The reaction mixture was stirred at rt overnight. 20 mL of water was added, and extracted with EtO Ac (3 x 30 mL), washed with brine, and dried over Na2S04. After removal of the organic solvent, the crude product was purified by flash chromatography (petroleum ether/EtOAc = 2/1) to and further purified prep-HPLC to obtain the title compound (156 mg, 53%). LC-MS-P1 : 495 [M+H]+; Rt: 1.735 min. 'H NMR (CDCI3, 500MHz): δ 7.56-6.92 (m, 13H), 6.27 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 4.79 (s, 2H), 3.61 (s, 2H), 2.40 (s, 3H), 2.29 (s, 3H).
Following essentially the same procedures as described in Example 26, the following compounds in table 5 were prepared. Table 5
Figure imgf000048_0001
Figure imgf000049_0001
yl)methoxy)phenyl)acetamide Example 35
N-((4-chlorophenyl)(ph e
Figure imgf000050_0001
To a solution ofN-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetamide (0.423 g, 1.20 mmol), in THF (1.0 mL) was added oxazol-5-ylmethanol (0.150 g, 1.50 mmol) and PPh3 (0.409 g, 1.56 mmol) and the reaction was sonicated in a 33-KHz sonicating bath at 0 °C until a clear solution was obtained. To the reaction mixture, DIAD (0.315 g, 1.56 mmol) was added drop wise over a period of 5 min at 0 °C and sonicated for 15 min. The THF was removed under vacumn and then remaining mixture was poured into water (20 mL) and extracted with CH2CI2 (100 mL). The organic layer was dried over Na2S04 and concentrated and the product was purified by silica gel column chromatography (40% EtOAc/Hexane) and again repurified by preparative TLC on silica gel (80% EtOAc/Hexane) to provide title compound. (0.128 g, 24.6%). LCMS-X1 : 433.1 [M+H]+; Rt = 5.01 min. !H NMR (400 MHz, DMSO-d6) δ ppm 8.99-9.02 (d, 1 H), 8.41 (s, 1 H), 7.38-7.40 (d, 2 H), 7.29-7.35 (m, 3 H), 7.24-7.27 (m, 5 H), 7.18-7.20 (d, 2 H), 6.94-6.96 (d, 2 H), 6.08-6.10 (d, 1 H), 5.14 (s, 2 H), 3.47 (s, 2 H).
Example 36
2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)
Figure imgf000050_0002
(a) 2-(4-(((3,5-dimethylisoxazol-4-yl)methyl)amino)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide
The title compound was synthesized from 2-(4-(((3,5-dimethylisoxazol-4- yl)methyl)amino)phenyl)acetic acid and phenyl(/ tolyl)methanamine essentially as Example 26 (c) and purified by silica gel column chromatography using 0- 100% EtOAc/hexane (1 18 mg, 12%). LCMS-T1 : 440.3 [M+H]+; Rt: 5.53 min.
(b) methyl 2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)amino)acetate
2-(4-(((3,5-dimethylisoxazol-4-yl)methyl)amino)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide (1 18 mg, 0.3 mmol), methyl 2-bromoacetate (41 mg, 0.3 mmol), tetrabutylammonium iodide (198 mg, 0.5 mmol), and Cs2C03 (174 mg, 0.5 mmol) in DMF (lmL) were stirred overnight. The reaction was filtered to remove solids. Water was added and the solution was purified by reverse phase using 10-90% CH3CN/water with 0.05% TFA to give the title compound (130 mg, 94%). LCMS-T1 : 512.2 [M+H]+; Rt: 6.30 min.
(c) 2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)amino)acetic acid
Methyl 2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)amino)acetate (130 mg, 0.3 mmol) was stirred for 3 h in 1 M aq. LiOH (1.5 mL) and dioxane (6 mL). The reaction was acidified and the solution was purified by reversed phase chromatography using 10-90% CH3CN/water with 0.05% TFA to give the title compound (130 mg, 94%). LCMS-T1 : 498.3 [M+H]+; Rt: 5.74 min. lH NMR (400 MHz, MeOH- d ) δ ppm 7.30-7.05 (m, 1 1H), 6.80 (d, 2H), 6.10 (t, 1H), 4.38 (s, 2H), 3.97 (s, 2H), 3.58 (s, 2H), 2.31 (s, 6H), 2.17 (s, 3H).
Example 37
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2- methylpropanamide
Figure imgf000051_0001
(a) methyl 2-(4-((3 ,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-methylpropanoate
To a solution of methyl 2-(4-((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetate (0.5 g, 1.818 mmol) in THF (25 mL) at -78 °C, CH3I (0.34 mL, 5.454 mmol) was added drop wise. To this solution, KO?-Bu (0.627 g, 5.454 mmol) was added portion wise over 30 min and the reaction was stirred at -78 °C for lh followed by room temperature for another one h. After completion of the reaction, the reaction mixture was quenched by addition of NH4CI in water (25 mL) and extracted with (2 X 50 mL) EtOAc. The organic layers were dried (Na2S04) and concentrated to obtain crude title compound (0.60 g, 91.66%). MS (ESI+) 304.2 (M + H). (b) 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-methylpropanoic acid
To a solution of methyl 2-(4-((3, 5-dimethylisoxazol-4-yl) methoxy)phenyl)-2- methylpropanoate (0.60 g, 1.980 mmol) in MeOH (50 mL), NaOH (0.16g, 3.96 mmol) (solution in water) was added drop wise and the reaction was stirred at rt for 2 h. After completion of the reaction, the MeOH was distilled off and the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was washed with EtOAc and aqueous layer was acidified with dilute HC1. The product was extracted with 2 x 50 mL EtOAc. The organic layer was dried (Na2SOzt) and concentrated to obtain crude title compound (0.350 g, 61.188%). ¾ NMR (400 MHz, DMSO- d6) δ 12.33 (s, 1H), 7.26-7.28 (d, 2H), 6.94-6.97 (d, 2H), 4.88 (s, 2H), 2.39 (s, 3 H), 2.20 (s, 3 H), 1.42 (s, 6 H).
(c) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2- methylpropanamide
To a solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-methylpropanoic acid (0.20 g, 0.692 mmol) in THF (35 mL), EDC (0.2 g, 1.41 mmol) was added portion wise and the reaction was stirred at rt for 2 h. (4-chlorophenyl) (phenyl) methanamine hydrochloride (0.21 g,
0.826 mmol), HOBt (0.105 g, 0.686 mmol), and Et3N (0.287 mL, 2.074 mmol) were then added, and the reaction mixture was stirred for 24 h at rt. After completion of the reaction, the reaction mixture was quenched by addition of water (50 mL) and extracted with 2 x 50 mL EtOAc. The organic layers were dried (Na2S04) and concentrated to obtain a crude product which was purified by silica gel column chromatography (35% EtOAc/hexane) to provide title compound (0.074 g, 21.95%). MS 489.3 [M + H]+. ¾ NMR (400 MHz, CDC13) δ ppm 7.25-7.31 (m, 8 H), 7.03-7.04 (m, 4 H), 6.92-6.99(m, 2 H), 6.16-6.18 (d, 1 H), 5.72-5.74 (d, 1 H), 4.80 (s, 2 H), 2.43 (s, 3 H), 2.31 (s, 3 H),1.59-1.63 (d 6H).
Example 38
N-((4-chlorophenyl)(phenyl)methyl)-2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2- yl)acetamide
Figure imgf000053_0001
(a) methyl 5-hydroxypicolinate
To a solution of 5-hydroxypicolinic acid (4.0 g, 28.77 mmol) in MeOH (75 mL), cone. H2SO4 (5 mL) was added drop wise at 0 °C and the reaction mixture was refluxed at 80 °C for 6 h. MeOH was removed under reduced pressure. The residue was dissolved in water and neutralized by NaHCC>3. Product was extracted with (3 X 50 mL) EtOAc. The combined organic layers were dried over Na2S04 and concentrated to provide title compound (2.10 g, 47.72%). MS 154.08 [M + H]+. lH NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1 H), 8.20 (s, 1 H), 7.93-7.98 (d, 1 H), 7.25- 7.28 (s, 1 H), 3.81 (s, 3 H).
(b) methyl 5-((3,5-dimethylisoxazol-4-yl)methoxy)picolinate
To a solution of methyl 5-hydroxypicolinate (3.0 g, 19.60 mmol) in dimethylformamide (35 mL) was added K2C03 (4.05 g, 29.41 mmol) and the reaction was stirred at rt for 30 min. 4- (chloromethyl)-3,5-dimethylisoxazole (3.41 g, 23.52 mmol) was added and the reaction mixture was stirred at 80 °C for 6 h. After completion of the reaction, the reaction mixture was quenched by addition of water (50 mL) and the mixture was extracted with 2 X 50 mL EtOAc. The organic layers were dried (Na2S04) and concentrated to obtain a crude product which was purified by silica gel column chromatography (30% EtOAc/Hexane) to provide the title compound (3.9 g, 76.47%). lH NMR (400 MHz, DMSO-dg) δ ppm 8.43 (s, 1 H), 8.07-8.09 (d, 1 H), 7.60-7.63 (d, 1 H), 5.1 1 (s, 2 H), 3.85 (s, 3 H), 2.43 (s, 3 H), 2.23 (s, 3 H). (c) (5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2-yl)methanol
To a solution of methyl 5-((3,5-dimethylisoxazol-4-yl)methoxy) picolinate (3.80 g, 14.50 mmol) in MeOH (150 mL), NaBH4 (10.74 g, 290.07 mmol) was added portion wise at 0 °C and stirred at rt for 3 h. After completion of the reaction, MeOH was evaporated and diluted with water. The product was extracted with 2 x 100 mL EtOAc. The combined organic layers were dried over Na2S04 and concentrated to obtain title compound (3.1 g, 91.44%). lH NMR (400 MHz, DMSO- ds) δ ppm 8.23 (s, 1 H), 7.46-7.48 (s, 1 H), 7.38-7.40 (s, 1 H), 5.31 -5.34 (t, 1 H), 4.99 (s, 2 H), 4.48 (s, 2 H), 2.40 (s 3H), 2.21 (s, 3H). (d) 4-(((6-(chloromethyl)pyridin-3 -yl)oxy)methyl)-3 ,5-dimethylisoxazole
The title compound was synthesized from (5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2- yl)methanol essentially as described in Example 10 (d). (3.5 g, 94.59%). lU NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 7.61-7.67 (m, 2 H), 5.06 (s, 2 H), 4.81 (s, 2 H), 2.42 (s, 3 H), 2.22 (s, 3 H).
(e) 2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2-yl)acetonitrile
To a solution of 4-(((6-(chloromethyl)pyridin-3-yl)oxy)methyl)-3,5-dimethylisoxazole (1.0 g, 3.968 mmol) in MeOH (35 mL) and water mixture was added KI (0.05 g, 0.30 mmol) and NaCN
(0.388 g, 7.936 mmol). The reaction mixture was refluxed at 80 °C for 4 h. After completion of the reaction, the MeOH was evaporated. The reaction mixture was quenched by addition of water (50 mL) and extracted it with EtOAc (2 X 25 mL). The combined organic layers were dried over Na2S04and concentrated to provide title compound which was used as crude in the next step, (0.90 g, 93.75%). MS 244.10 [M + H]+.
(f) 2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2-yl)acetic acid
To a solution of 2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2-yl)acetonitrile (0.90 g, 3.70 mmol) in MeOH (35 mL), NaOH (0.444 g, 11.1 mmol) in water (50 mL) was added dropwise and the reaction was refluxed at 80 °C for 6 h. After completion of the reaction, the MeOH was distilled off at reduced pressure and water (50 mL) was added to the reaction mixture. The aqueous layer was washed with EtOAc and then the aqueous layer was acidified to pH=3 using 10% HCl and extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to provide title compound (0.160 g, 16.49%) MS 263.1 [M + H]+
(g) N-((4-chlorophenyl)(phenyl)methyl)-2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2- yl)acetamide
To a solution of 2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2-yl)acetic acid (0.150 g 0.572 mmol) in THF (25 mL), EDC (0.164 g, 0.858 mmol) was added portion wise and the reaction was stirred at rt for 2 h. (4-chlorophenyl) (phenyl) methanamine hydrochloride (0.200 g, 0.858 mmol), HOBt (0.100 g, 0.572 mmol), and Et3N (0.237 mL, 1.751 mmol) were then added and the reaction mixture was stirred for 24 h at rt. After completion of the reaction, water (50 mL) was added to the reaction mixture and extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to obtain a crude product which was purified by silica gel column chromatography using (30% EtOAc/Hexane) as mobile phase to provide title compound (0.130 g, 49.24%). MS 462.34 [M + H]+ lH NMR (400 MHz, DMSO-dg) δ ppm 9.05 (d, 1 H), 8.24 (s, 1 H), 7.33-7.42 (m, 3 H), 7.24-7.32 (m, 7 H), 6.10-6.12 (d, 1 H), 4.98 (s, 2 H), 3.69 (s, 2 H), 2.40 (s, 3 H), 2.18 (s, 3 H). Example 39
N-((4-chlorophenyl)(phenyl) ethylthio)phenyl)acetamide
Figure imgf000055_0001
(a) 2-(4-((3,5-dimethylisoxazol-4-yl)methylthio)phenyl)acetic acid
To a solution of 2-(4-mercaptophenyl)acetic acid (0.25 g, 1.40 mmol) in DMF (3 mL) at 25 °C was added 4-(chlorophenyl)-3,5-dimethylisoxazole (0.227 g, 1.5 mmol) followed by addition of KOH (0.208 g, 3.7 mmol) in two drops of water. After completion of the addition, the reaction mixture was heated to 120 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to rt, water (10 mL) was added and the mixture was acidified to pH=2 using 10% aq. HC1. The aqueous layer then was extracted with EtOAc (2 x 25 mL). The combine organic layers were washed with brine (25 mL), dried over (Na2S04), and evaporated to obtain the title compound as a light yellow oil (0.46 g) which was used in the next step without further purification. H NMR (400 MHz, DMSO- ds) δ ppm 12.453 (br, 1 H), 7.19-7.29 (m, 4 H), 3.93 (s, 2 H), 3.55 (s, 2 H), 2.14 (s, 3 H), 2.04 (s, 3 H).
(b) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methylthio)phenyl)acetamide
To a solution of 2-(4-((3,5-dimethylisoxazol-4-yl)methylthio)phenyl)acetic acid (0.460 g, 1.6 mmol) in DMF (5 mL) at 25 °C was added HOBt (0.304 g, 1.8 mmol), EDC (0.382 g, 1.9 mmol), and DMAP (0.405 g, 3.2 mmol) and the resulting mixture was stirred at rt for 10 min. (4- chlorophenyl)(phenyl)methanamine hydrochloride (0.466 g, 1.8 mmol) in DMF (1 mL) was added slowly and the stirring at rt was continued overnight. After completion of the reaction, water (10 mL) was added into the reaction mixture and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (10 mL), dried over (Na2S04), and evaporated to obtain a crude product which was purified using silica gel column chromatography using 24% EtOAc:hexanes and then purified using prep TLC on silica gel (50% EtOAc in hexanes + 5 drops of AcOH) to obtain the title compound (66 mg, 16.68%). LCMS-X1 : 477.2 [M+H]+; Rt = 3.61 min. lH NMR (400 MHz, CDC13) δ ppm 7.28-7.35 (m, 6 H), 7.21 -7.23 (d, 2 H), 7.06-7.1 1 (m, 4 H), 6.21-6.23 (d, 1 H), 5.93-5.94 (d, 1 H), 3.76 (s, 2 H), 3.63 (s, 2 H), 2.24 (s, 3 H), 2.01 (s, 3 H). Biological Data
As stated above, the compounds according to Formula (I) are RORy modulators, and are useful in the treatment of diseases mediated by RORy. The biological activities of the compounds according to Formula (I) can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models.
Dual Fluorescence Energy Transfer (FRET) Assay
This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner. RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co-activators. The sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC 1(2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co- activator.
The assay measures ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) to indirectly assess ligand binding. RORy has a basal level of interaction with the co-activator SRC 1(2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRCl(2) interaction.
Materials
Generation of RORy-LBD bacterial expression plasmid
Human RORy Ligand Binding Domain (RORy-LBD) was expressed in E.coli strain
BL21(DE3) as an amino-terminal polyhistidine tagged fusion protein. DNA encoding this recombinant protein was sub-cloned into a modified pET21 a expression vector (Novagen). A modified polyhistidine tag (MKKHHHHHHLVPRGS) (SEQ ID No: 1) was fused in frame to residues 263-518 of the human RORy sequence.
Protein Purification
Approximately 50 g E.coli cell pellet was resuspended in 300 mL of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCl). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 min at 20,000 g at 4 °C. The cleared supernatant was filtered through a 0.45 μΜ cellulose acetate membrane filter. The clarified lysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (InVitrogen), pre-equilibrated with 30 mM imidazole pH 7.0 and 150 mM NaCl. After washing to baseline absorbance with the equilibration buffer, the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0. Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mL. The concentrated protein was loaded onto a Superdex 200 column pre- equilibrated with 20 mM Tris-Cl pH 7.2 and 200 mM NaCl. The fractions containing the desired RORy-LBD protein were pooled together.
Protein Biotinylation
Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [100 mM NaPhosphate, pH 8 and 150 mM NaCl]. The concentration of RORy-LBD was approximately 30 μΜ in PBS. Five-fold molar excess of NHS- LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 min at ambient rt. The modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5 mM DTT, 2 mM EDTA and 2% sucrose - each at least 20 times of the volume. The modified protein was distributed into aliquots, frozen on dry ice and stored at -80 °C. The biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent. In general, approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five.
A biotinylated peptide corresponding to amino acid 676 to 700
(CPS SHS SLTERHKILHRLLQEGSPS) (SEQ ID No: 2) of the co-activator steroid receptor coactivator SRC 1 (2) was generated using similar method.
Assay
Preparation of Europium labeled SRC 1(2) peptide: biotinylated SRC 1(2) solution was prepared by adding an appropriate amount of biotinylated SRC 1(2) from the 100 μΜ stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC 1(2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 min at rt. Twenty- fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 min at rt.
Preparation of APC labeled RORy-LBD: biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy-LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 min at rt. Twenty- fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 min at rt.
Equal volumes of the above-described Europium labeled SRC 1 (2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20 nM RORy-LBD, 10 nM APC- Strepavidin, 20 nM SRC 1(2) and 5 nM Europium- Streptavidin. The reaction mixtures were incubated for 5 min. Using a Thermo Combi Multidrop 384 stacker unit, 25 μΐ^ of the reaction mixtures per well was added to the 384-well assay plates containing 1 μΐ^ of test compound per well in 100% DMSO. The plates were incubated for 1 h and then read on ViewLux in Lance mode for EU/APC.
Results
The compounds of Examples 1 -33 and 35-39 were tested in the dual FRET assay described above. All tested compounds were found to have a p!C5o between 5 and 9.

Claims

1. A method of treatment of a disease mediated by RORy which comprises administering to a human in n thereof an effective amount of a compound according to Formula (I):
Figure imgf000059_0001
wherein:
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
one of Y1 and Y2 is O or NR8 and the other is a bond;
Cy is (C3-C8)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one to three times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy, -((C0-C3)alkyl)NHCO2R7, -((Co-C3)alkyl)N((Ci-C4)alkyl)C02R7,
-((C0-C3)alkyl)NHC(O)R7, -((Co-C3)alkyl)N((Ci-C4)alkyl)C(0)R7, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, -((C0-C3)alkyl)C(O)R7, (Ci-C4)alkoxy(Ci-C6)alkyl, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C )alkyl)((Ci-C )alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
Z is O, S, S02, C=0, NR6, or a bond;
A1, A2, A3, and A4 are each independently selected from N, NR6, O, S, CH, and CR10, wherein one of A1, A2, A3, and A4 is NR6, O, or S, 0-2 of A1, A2, A3, and A4 are CR10, and 0-3 of A1, A2, A3, and A4 are CH or N;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5;
R2 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, (d-C alkoxy, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino; each R is independently selected from hydrogen, halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -C02R7, -CONRV, -OR9, and -NR8R9, wherein said (C C6)alkyl or (C C6)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
(C C6)alkyl;
or R4 and R4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl,
(C3-C6)cycloalkyl, -C02R7, -CONR7R8, hydroxyl, hydroxy(C C6)alkyl, (C C4)alkoxy,
(Ci-C4)alkoxy(Ci-C6)alkyl, amino,
Figure imgf000060_0001
((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHCO2R7, -N((Ci-C4)alkyl)C02R7, -NHC(0)R7, or -N((Ci-C4)alkyl)C(0)R7;
each R5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(Ci-C6)alkyl, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl,
(Ci-C4)alkoxy(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(CrC4)alkyl, hydroxyl, hydroxy(C C6)alkyl, (C C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
R9 is -C(0)R7, -C02R7, -C(0)NR7R8, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl,
heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -C02R7, -CONH2, -CONH(Ci-C4)alkyl, -CON((Ci-C4)alkyl)((Ci-C4)alkyl), hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((Ci-C4)alkyl)C02R7, -NHC(0)R7, or -N((Ci-C4)alkyl)C(0)R7; or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(Ci-C4)alkyl, -CONR7R8, hydroxyl, hydroxy(C1-C6)alkyl,
(Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino,
((C1-C4)alkyl)((C1-C4)alkyl)amino, -NHC02R7, -N((C C4)alkyl)C02R7, -NHC(0)R7, or
-N((C C4)alkyl)C(0)R7;
R10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (C C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl,
(Ci-C4)alkylamino(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl; and
R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein m is 1 and n is 1 or 2.
3. The method according to claim 1 or claim 2, wherein Y1 is NH or NCH3 and Y2 is a bond.
4. The method according to any one of claims 1-3, wherein Cy is heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one or two times,
independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, cyano, (Ci-C4)alkoxy,
Figure imgf000061_0001
-((C0-C3)alkyl)CO2R7,
or -((C0-C3)alkyl)CONR7R8.
5. The method according to any one of claims 1-3, wherein Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one or two times, independently, by (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, cyano, (Ci-C4)alkoxy, (Ci-C4)alkyl)((Ci-C4)alkyl)amino, -((C0-C3)alkyl)CO2H,
-((C0-C3)alkyl)CO2(Ci-C6)alkyl, or -((C0-C3)alkyl)CONH(Ci-C6)alkyl.
6. The method according to any one of claims 1-3, wherein Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-Cz alkyl,
Figure imgf000062_0001
cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
7. The method according to any one of claims 1-6, wherein Z is a bond, O, or NH.
8. The method according to any one of claims 1-7, wherein R1 is (C3-C6)alkyl,
(C3-C6)cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one or two times, independently, by halogen,
Figure imgf000062_0002
or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
9. The method according to any one of claims 1-7, wherein R1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl,
(Ci-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
10. The method according to any one of claims 1-9, wherein R2 is hydrogen or methyl.
1 1. The method according to any one of claims 1-10, wherein R3 and R3a are each
independently hydrogen or methyl.
12. The method according to any one of claims 1-1 1, wherein each R4 is independently selected from hydrogen, (C C4)alkyl, (C C4)haloalkyl, -OR9, and -NR8R9, wherein said
(Ci-C4)alkyl or (Ci-C4)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7,
-CONR7R8, or -NR8R9.
13. The method according to any one of claims 1-1 1, wherein each R4 is independently selected from hydrogen, (Ci-C4)alkyl, (d-C4)alkoxy, hydroxy(C2-C4)alkoxy,
(Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, -0((Ci-C3)alkyl)C02H,
-0((Ci-C3)alkyl)C02(Ci-C4)alkyl, -0((C C3)alkyl)CONH2, -0((Ci-C3)alkyl)CONH(Ci-C4)alkyl, and -0((Ci-C3)alkyl)CON((Ci-C4)alkyl)((Ci-C4)alkyl).
14. The method according to any one of claims 1-13, wherein each R a is independently selected from hydrogen and methyl.
15. The method according to any one of claims 1-14, wherein A1 and A4 are each
independently selected from CH and CR10, and one of A2 and A3 is NR6, O, or S and the other is N or CH.
16. The method according to any one of claims 1-14, wherein A1 and A4 are each
independently selected from CH and C((Ci-C4)alkyl), and one of A2 and A3 is N((Ci-C4)alkyl), O, or S and the other is N or CH.
17. The method according to any one of claims 1-16, wherein R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or
((C1-C4)alkyl)((C1-C4)alkyl)amino.
18. The method according to any one of claims 1-16, wherein R11 is hydrogen, (Ci-C4)alkyl, -CF3, F, CI, Br, cyano, hydroxyl, or (Ci-C )alkoxy.
19. A method of treatment of a disease mediated by RORy which comprises administering to human in need thereof an effective amount of a com ound according to Formula (la):
Figure imgf000063_0001
wherein:
m is 1 ;
n is 1 or 2;
Y1 is NH or NCH3 and Y2 is a bond;
K1, K2, K3, and K4 are each independently selected from N, N+-0~, CH, and CR10, wherein 0-2 of K1, K2, K3, and K4 are N or N+-0" and 0-2 of K1, K2, K3, and K4 are CR10;
Z is O, NR6, or a bond; A1, A2, A3, and A4 are each independently selected from N, NR6, O, S, CH, and CR10, wherein one of A1, A2, A3, and A4 is NR6, O, or S, 0-2 of A1, A2, A3, and A4 are CR10, and 0-3 of A1, A2, A3, and A4 are CH or N;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy,
(Ci-C6)alkoxy(Ci-C2)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one to three times, independently, by R5;
R2 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one to three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl, halogen, (d-d)alkoxy, amino, (d -Chalky lamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
each R4 is independently selected from hydrogen, halogen, (d-d)alkyl, (d-d)haloalkyl, -OR9, and -NR8R9, wherein said (d-d)alkyl or (d-d)haloalkyl is optionally substituted by hydroxyl, -OR9, -C02R7, -CONR7R8, or -NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and
(Ci-C4)alkyl;
each R5 is independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(d-d)alkyl, (C1-C4)alkoxy(C1-C6)alkyl, -((C0-C3)alkyl)CO2R7, -((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C C6)alkyl, (C C6)haloalkyl, (C3-C6)cycloalkyl,
(Ci-C4)alkoxy(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C C6)alkyl, or (C C6)haloalkyl;
or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(C C4)alkyl, hydroxyl, hydroxy(Ci-C6)alkyl, (C C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
R9 is -C(0)R7, -C02R7, -C(0)NR7R8, (Ci-C6)alkyl, (d-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(d-d)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl,
heteroaryl(Ci-C6)alkyl, or heterocycloalkyl is optionally substituted by -CO2R7, -CONH2,
-CONH(Ci-C4)alkyl, -CON((Ci-C4)alkyl)((Ci-C4)alk l), hydroxy., (Ci-C4)alkoxy, amino,
(C1-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((C C4)alkyl)C02R7, -NHC(0)R7, or -N((C C4)alkyl)C(0)R7;
or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, -C02H, -C02(C C4)alkyl, -CONR7R8, hydroxyl, hydroxy(Ci-C6)alkyl,
(Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino, (Ci-C4)alkylamino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -NHC02R7, -N((C C4)alkyl)C02R7, -NHC(0)R7, or
-N((Ci-C4)alkyl)C(0)R7;
R10 is (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (C C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, -((C0-C3)alkyl)CO2R7,
-((C0-C3)alkyl)CONR7R8, amino(Ci-C6)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl, (Ci-C4)alkylamino(Ci-C6)alkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl; and
R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
20. The method according to claim 19, wherein:
Y1 is NH or NCH3 and Y2 is a bond;
K1, K2, K3, and K4 are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C4)alkyl, (C C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, wherein 2-4 of K1, K2, K3, and K4 are a carbon atom substituted by hydrogen;
Z is O, NH, -N(Ci-C4)alkyl, -N((C0-C3)alkyl)CO2R7, -N((C0-C3)alkyl)CONR7R8, or a bond; A1 and A4 are each independently selected from CH and CR10, and one of A2 and A3 is NR6,
O, or S and the other is N or CH;
R2 is hydrogen;
R3 and R3a are each independently hydrogen or methyl; each R is independently selected from hydrogen, (Ci-Cz alkyl,
Figure imgf000066_0001
hydroxy(C2-C4)alkoxy, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino,
(Ci-C4)alkoxy(Ci-C4)alkylamino, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
-0((CrC3)alkyl)C02H, -0((C1-C3)alkyl)C02(C1-C4)alkyl, -0((CrC3)alkyl)CONH2,
-0((C1-C3)alkyl)CONH(C1-C4)alkyl, and -0((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl); each R4a is independently selected from hydrogen, hydroxyl, amino, and (Ci-C4)alkyl; and
R11 is hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C6)alkyl, amino,
(Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino;
or a pharmaceutically acceptable salt thereof.
21. The method according to claim 20, wherein:
Y1 is NH and Y2 is a bond;
Z is O, NH, -N(C C4)alkyl, or a bond;
A1 and A4 are each independently selected from CH and C((Ci-C4)alkyl), and one of A and A3 is O or S and the other is N;
R1 is phenyl optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano, (d-C4)alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino; each R4 is independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, and (d-C4)alkoxy; and
R11 is hydrogen, (Ci-C4)alkyl, -CF3, F, CI, Br, cyano, hydroxyl, or (Ci-C4)alkoxy;
or a pharmaceutically acceptable salt thereof.
22. The method according to claim 1, wherein the compound according to Formula (I) is selected from the group consisting of:
N-(bis(4-methoxcyphenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- methoxyphenyl)(phenyl)methyl)acetamide;
N-((4-(dimethylamino)phenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl) methoxy)phenyl)acetamide;
N-((2,3-dihydrobenzo[Z7][l,4]dioxin-6-yl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- fluorophenyl)(phenyl)methyl)acetamide; N-(bis(4-fluorophenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide;
N-(di-/j-tolylmethyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-((4- isopropylphenyl)(phenyl)methyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -(p-tolyl)cyclohexyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -phenylcyclohexyl)acetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(l -phenyl- 1 -(p-tolyl)ethyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3- fluorophenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-2- fluorophenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(((3,5-dimethylisoxazol-4- yl)methyl)(methyl)amino)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(thiazol-4-ylmethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((2-methylthiazol-4-yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-cyclopropylisoxazol-3- yl)methoxy)phenyl)acetamide;
2-(4-((3,5-dimethylisothiazol-4-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl) acetamide;
2-(4-((5-methyl- l,2,4-oxadiazol-3-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((5-ethyl- l,2,4-oxadiazol-3-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((3 -methyl- 1 ,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
2-(4-((5-methyl- l,3,4-oxadiazol-2-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-(hydroxymethyl)-5-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-methylisoxazol-3- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N- methylacetamide;
2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(4- (trifluoromethyl)phenyl)methyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methoxy)phenyl)propanamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(2-(3,5-dimethylisoxazol-4- yl)ethoxy)phenyl)acetamide;
2-(4-((3-ethyl-5-methylisoxazol-4-yl)methoxy)phenyl)-N-(phenyl(p-tolyl)methyl)acetamide; N-(di- /j-tolylmethyl)-2-(4-(l-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-ethyl-5-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3-methylisoxazol-4- yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(isoxazol-4-ylmethoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((5-methylthiazol-4-yl)methoxy)phenyl)acetamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-(oxazol-5-ylmethoxy)phenyl)acetamide;
2-(((3,5-dimethylisoxazol-4-yl)methyl)(4-(2-oxo-2-((phenyl(p- tolyl)methyl)amino)ethyl)phenyl)amino)acetic acid;
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2- methylpropanamide;
N-((4-chlorophenyl)(phenyl)methyl)-2-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyridin-2- yl)acetamide; and
N-((4-chlorophenyl)(phenyl)methyl)-2-(4-((3,5-dimethylisoxazol-4- yl)methylthio)phenyl)acetamide;
or a pharmaceutically acceptable salt thereof.
23. The method according to any one of claims 1-22, wherein said disease is an inflammatory or autoimmune disease.
24. The method according to claim 23, wherein said inflammatory or autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriasis, uveitis, dry eye, glomerulonephritis, and Crohn's disease.
PCT/US2012/067735 2011-12-06 2012-12-04 Therapeutic methods WO2013085890A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161567300P 2011-12-06 2011-12-06
US61/567,300 2011-12-06

Publications (1)

Publication Number Publication Date
WO2013085890A1 true WO2013085890A1 (en) 2013-06-13

Family

ID=48574802

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/067735 WO2013085890A1 (en) 2011-12-06 2012-12-04 Therapeutic methods

Country Status (1)

Country Link
WO (1) WO2013085890A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015198232A1 (en) 2014-06-25 2015-12-30 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
WO2018149991A1 (en) 2017-02-17 2018-08-23 Galderma Research & Development Hydroxylated sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma, ror gamma (t)
WO2018185236A1 (en) 2017-04-06 2018-10-11 Galderma Research & Development Pzrayole derivatives used as inverse agonists of the ror gamma (t) retinoid-related orphan gamma receptor
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11072610B2 (en) 2018-09-12 2021-07-27 Novartis Ag Antiviral pyridopyrazinedione compounds
US11220492B2 (en) 2017-05-17 2022-01-11 Arcus Biosciences, Inc. Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders
US11377427B2 (en) 2016-05-24 2022-07-05 Universidad Del Pais Vasco Triazoles for regulating intracellular calcium homeostasis
US11667613B2 (en) 2019-09-26 2023-06-06 Novartis Ag Antiviral pyrazolopyridinone compounds
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265809A1 (en) * 2001-05-07 2004-12-30 Dino Moras Polypeptides derived from retinoic acid-related orphan receptor(ror) and their applications
WO2008057862A2 (en) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
WO2011115892A1 (en) * 2010-03-15 2011-09-22 Griffin Patrick R Modulators of the retinoic acid receptor-related orphan receptors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265809A1 (en) * 2001-05-07 2004-12-30 Dino Moras Polypeptides derived from retinoic acid-related orphan receptor(ror) and their applications
WO2008057862A2 (en) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
WO2011115892A1 (en) * 2010-03-15 2011-09-22 Griffin Patrick R Modulators of the retinoic acid receptor-related orphan receptors

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015198232A1 (en) 2014-06-25 2015-12-30 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
US10105373B2 (en) 2014-06-25 2018-10-23 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
US11377427B2 (en) 2016-05-24 2022-07-05 Universidad Del Pais Vasco Triazoles for regulating intracellular calcium homeostasis
WO2018149991A1 (en) 2017-02-17 2018-08-23 Galderma Research & Development Hydroxylated sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma, ror gamma (t)
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
WO2018185236A1 (en) 2017-04-06 2018-10-11 Galderma Research & Development Pzrayole derivatives used as inverse agonists of the ror gamma (t) retinoid-related orphan gamma receptor
US11220492B2 (en) 2017-05-17 2022-01-11 Arcus Biosciences, Inc. Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders
US11072610B2 (en) 2018-09-12 2021-07-27 Novartis Ag Antiviral pyridopyrazinedione compounds
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11667613B2 (en) 2019-09-26 2023-06-06 Novartis Ag Antiviral pyrazolopyridinone compounds

Similar Documents

Publication Publication Date Title
WO2013085890A1 (en) Therapeutic methods
US20140256740A1 (en) Compounds and methods
JP5411927B2 (en) Pyrazole compounds as CCR1 antagonists
EP2736332A1 (en) Compounds and methods
US11634395B2 (en) Sulfonamide compound or salt thereof
WO2013019682A1 (en) Compounds and methods
ES2367455T3 (en) ARILAMIDES REPLACED BY TIAZOL OR OXAZOL.
US20140155419A1 (en) Compounds and methods
US20230103791A1 (en) 2,3-dihydroquinazolin compounds as nav1.8 inhibitors
US9643927B1 (en) Process for the preparation of kinase inhibitors and intermediates thereof
EP2611772B1 (en) 2-(benzyloxy)benzamides as lrrk2 kinase inhibitors
BRPI0721163A2 (en) COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF CANABINOID RECEIVER ACTIVITY 1.
CN101712657A (en) heteroarylcarbamoylbenzene derivative
JP2014198738A (en) Triazine derivative and pharmaceutical compound that contains the same and exhibits analgesic activity
WO2012028100A1 (en) Novel compounds
WO2012027965A1 (en) Novel compounds
US10550087B2 (en) Process for the preparation of kinase inhibitors and intermediates thereof
KR20120047211A (en) Compounds which selectively modulate the cb2 receptor
US20100222396A1 (en) 4-aryl-butane-1,3-diamides
WO2019191327A1 (en) Ox2r compounds
US10889555B2 (en) Sulfonamide compound or salt thereof
CN100591671C (en) Heteroarylcarbamoylbenzene derivative
JP2018501282A (en) Method for producing thiazole derivative

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12855069

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12855069

Country of ref document: EP

Kind code of ref document: A1