WO2018042342A1 - 1,2,3-benzotriazole derivatives as ror gamma t modulators - Google Patents

1,2,3-benzotriazole derivatives as ror gamma t modulators Download PDF

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Publication number
WO2018042342A1
WO2018042342A1 PCT/IB2017/055205 IB2017055205W WO2018042342A1 WO 2018042342 A1 WO2018042342 A1 WO 2018042342A1 IB 2017055205 W IB2017055205 W IB 2017055205W WO 2018042342 A1 WO2018042342 A1 WO 2018042342A1
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benzo
phenyl
methylpropyl
difluoro
hydroxypropyl
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PCT/IB2017/055205
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French (fr)
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Sachin Sundarlal Chaudhari
Sanjib Das
Laxmikant Atmaram Gharat
Sachin Vasantrao Dhone
Neelima Khairatkar-Joshi
Daisy Manish Shah
Malini Bajpai
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Glenmark Pharmaceuticals S.A.
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Publication of WO2018042342A1 publication Critical patent/WO2018042342A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present patent application is directed to 1,2,3-benzotriazole compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (RORp) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and 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, RORyl and RORyt (also known as RORy2) have been identified.
  • RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).
  • Thl7 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines and 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 have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649).
  • Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman et al., J. Exp. Med., 2008, 205: 1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). 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., Annu. Rev.
  • RORyt is also shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340).
  • RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T-cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol, 2009, 123: 1004-1011), suggesting an important function for RORyt in these cells.
  • the present application is directed to compounds that may be modulators of the RORyt receptor.
  • RORyt plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORyt activity, which can be used in the treatment of diseases mediated by RORyt.
  • the present invention relates to compound of formula (I)
  • Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
  • G is selected from G 1 and G 2 ;
  • L is selected from L 1 , L 2 and L 3 ;
  • X 1 , X 2 , X 3 and X 4 which may be same or different, are each independently selected from N and CH; with a proviso that not more than two of X 1 , X 2 and X 3 are N simultaneously; each occurrence of R 1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C 3 - 6cycloalkylCi-salkyl;
  • R 2 is selected from Ci-galkyl and haloCi-galkyl
  • R 3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
  • R a and R b which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
  • R c is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
  • R x and R y which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
  • 'n' is 0, 1, 2 or 3;
  • 't' is 1, 2 or 3;
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (II) and formula (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein ring A is phenyl (according to an embodiment defined below), R 2 is ethyl (according to another embodiment defined below) and R 3 is hydroxyl, amine or methyl (according to yet another embodiment defined below).
  • ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl).
  • ring A is phenyl, pyridine or pyrimidinyl.
  • R 1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
  • R 1 is halogen (e.g. F or CI)
  • O-galkyl e.g. methyl
  • haloCi-galkyl e.g. trifluoromethyl
  • haloCi-galkoxy e.g. trifluoromethoxy
  • R 1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
  • R 2 is Ci-galkyl (e.g. methyl or ethyl).
  • R 3 is hydroxyl (-OH), amino (-NH 2 ) or Ci-galkyl (e.g. methyl).
  • R 3 is hydroxyl, amino or methyl.
  • R a and R b are independently hydrogen or methyl.
  • one of R a and R b is hydrogen and the other is methyl.
  • R c is -CH 2 OH.
  • X 1 and X 4 are independently CH or N and X 2 and X 3 are CH.
  • R x and R y are hydrogen or Ci-galkyl (e.g. methyl).
  • ring A is phenyl, pyridinyl, pyrimidinyl or chromanyl
  • each of R 1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy;
  • R 2 is ethyl
  • R 3 is hydroxyl, amino or methyl
  • R a and R b are independently hydrogen or methyl
  • R c is hydrogen and CH 2 OH
  • X 1 is CH or N;
  • X 2 , X 3 and X 4 are CH;
  • R x and R y are independently hydrogen or methyl
  • 'n' is 1, 2 or 3;
  • compounds of formula (I) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
  • the invention specifically provides compounds of formula (II) in which ring A is phenyl, pyridine or pyrimidinyl and consequently there is also provided a compound of formula (I) in which ring A is phenyl, pyridine or pyrimidinyl.
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
  • X 1 is N or CH
  • each occurrence of R 1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C 3 - 6cycloalkylCi-salkyl;
  • R 3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
  • R a and R b which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
  • R c is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
  • R x and R y which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
  • 'n' is 0, 1, 2 or 3;
  • 't' is 1, 2 or m 3;
  • the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (II) as defined above wherein R 3 is hydroxyl, amine or methyl (according to an embodiment defined below) and 'n' is 1, 2 or 3 (according to another embodiment defined below).
  • ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl).
  • ring A is phenyl, pyridinyl or pyrimidinyl.
  • R 1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
  • R 1 is halogen (e.g. F or CI)
  • O-galkyl e.g. methyl
  • haloCi-galkyl e.g. trifluoromethyl
  • haloCi-galkoxy e.g. trifluoromethoxy
  • R 1 is F, CI, trifluoromethoxy or trifluoromethyl.
  • R 3 is hydroxyl (-OH), amino (-NH2) or Ci-galkyl (e.g. methyl).
  • R x is Ci-galkyl (e.g. methyl) and R y is Ci-galkyl (e.g. methyl).
  • R x and R y are hydrogen or Ci-galkyl (e.g. methyl).
  • compounds of formula (II) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
  • the invention also provides a compound of formula (III), which is an embodiment of a compound of formula (I).
  • Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
  • L is selected from ⁇ wherein p and q represents point of attachment
  • X 1 and X 4 which may be same or different, are each independently selected from N and
  • each occurrence of R 1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
  • R 2 is selected from Ci-galkyl and haloCi-galkyl
  • R c is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
  • R x and R y which may be same or different, are each independently selected from hydrogen and Ci-galkylp and q represents point of attachment; 'n' is 0, 1, 2 or 3; and
  • 't' is 1, 2 or 3;
  • the compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (III) as defined above wherein R 2 is ethyl (according to an embodiment defined below) and 'n' is 1, 2 or 3 (according to another embodiment defined below).
  • ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl).
  • ring A is phenyl, pyridine or pyrimidinyl.
  • R 1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
  • R 1 is halogen (e.g. F or CI)
  • O-galkyl e.g. methyl
  • haloCi-galkyl e.g. trifluoromethyl
  • haloCi-galkoxy e.g. trifluoromethoxy
  • R 1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
  • R 2 is Ci-galkyl (e.g. methyl or ethyl).
  • R c is hydrogen.
  • R x and R y are hydrogen or Ci-galkyl (e.g. methyl).
  • compounds of formula (III) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
  • Compounds of the present invention include the compounds in Examples 1- 75. It should be understood that the formulas (I), (II) and (III) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
  • the present invention relates to com ound of formula (IV)
  • R 3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
  • R 4 is selected from hydrogen and Ci-galkyl
  • R a and R b which may be same or different, are each independently selected from rogen and Ci-galkyl; and R c is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl.
  • the compounds of formula (IV) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (IV) as defined above wherein R 3 is hydroxyl, amine or methyl (according to an embodiment defined below) and R c is hydrogen (according to another embodiment defined below).
  • R 4 is hydrogen or Ci-galkyl (e.g. methyl).
  • R 3 is hydroxyl (-OH), amino (-NH2) or Ci-galkyl (e.g. methyl).
  • R a and R b are independently hydrogen or Ci-galkyl (e.g. methyl).
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt.
  • the present invention further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
  • the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
  • a disease, disorder or condition modulated by RORyt such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer
  • the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described here.
  • COPD chronic obstructive pulmonary disease
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-galkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • Ci-galkyl carbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-galkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl,
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C 1-8 alkoxy).
  • Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi-galkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.
  • haloCi- 4 alkyl refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi-galkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched.
  • hydroxyCi-galkyl refers to an Ci-galkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi- 4 alkyl).
  • hydroxyCi- 4 alkyl moieties include, but are not limited to - CH2OH and -C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C3-6cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms.
  • Examples of “C3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkylCi-salkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6 - i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroind
  • heteroaryl refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of formula (I), (II), (III) or (IV) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I), (II), (III) or (IV) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of chiral HPLC column.
  • the chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974.
  • salt or “solvate”, and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of such compounds or pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, and topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions described herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the compounds of the present invention are particularly useful because they inhibit the activity of retinoid-related orphan receptor gamma, particularly retinoid-related orphan receptor gamma t (RORyt), i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit a RORyt modulating effect.
  • RORyt retinoid-related orphan receptor gamma
  • Compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of ROR gamma activity, and particularly RORyt, is required.
  • the compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.
  • autoimmune diseases will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
  • An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function.
  • An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin.
  • autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - spru
  • inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • arthritis including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • the compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • bronchospasm bronchospasm
  • cough cough
  • respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory
  • the compounds of the present invention may also be used for treatment of pain conditions.
  • the pain can be acute or chronic pain.
  • the compounds of the present invention may be used for treatment of e.g., inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, posttraumatic injury, or pain associated with irritable bowel syndrome.
  • the compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer.
  • cancers include, e.g., multiple myeloma and bone disease associated with multiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, bladder carcinoma and colon cancer.
  • the compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease.
  • COPD chronic obstructive pulmonary disease
  • Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula I, (II) or (III) or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.
  • the present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.
  • the compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.
  • the daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.
  • a suitable coupling agent(s) may be 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU).
  • EDCI 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide
  • DCC N,N'-dicyclohexylcarbodiimide
  • T 3 P propylphosphonic anhydride
  • the suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU).
  • suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • the ester compound of formula (5) on treating with methyllithium in suitable solvent such as THF affords the keto compound of formula (6) which on reduction in the presence of suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (lib).
  • suitable reducing agent used in the reaction may be selected from the sodium borohydride and the suitable solvent may be methanol, THF or combination thereof.
  • the ketone compound of formula (6) on reductive amination using sodium cyanoborohydride and ammonium acetate in a suitable solvent affords the amine derivative of general formula (lie).
  • the suitable solvent used in the reaction may be THF.
  • the mono-ester of di-carboxylic acid compound of formula (2b) on protection with a suitable protecting agent such as, triisopropylchlorosilane (Tips-Cl) affords the heteroester compound of formula (7).
  • the reaction may be carried out in the presence of suitable base and solvent.
  • the suitable base for the reaction may be imidazole and solvent can be selected from THF or DMF.
  • the ethyl ester group of compound (7) on reaction with methyllithium in a suitable solvent yields the methyl ketone of formula (8).
  • the suitable solvent for the reaction may be THF.
  • the keto reduction of compound of formula (8) using chiral reducing agent in a suitable solvent affords the corresponding chiral isomer of the hydroxyl derivative of formula (9).
  • the chiral reducing agent may be selected from (R or 5)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B-chlorodiisopinocampheylborane (DIP-Chloride), etc.
  • Suitable solvent may be THF, DCM or DMF.
  • suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU).
  • suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • compound of formula (2b) on coupling reaction with amine of formula (la) followed by reaction with methyllithium affords the keto compound (6a) as described in scheme 2.
  • Keto reduction of compound of formula (6a) using suitable chiral reducing agent yields the hydroxyl derivative (lid).
  • the chiral reducing agent may be selected from (R or S)- 2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B- chlorodiisopinocampheylborane (DIP-Chloride), etc.
  • Suitable solvent may be THF, DCM or DMF.
  • the hydroxyl derivative (lid) can be further purified by diastereomeric separation using a chiral amino acid, such as N-benzyloxycarbonyl-L-phenylalanine.
  • Lithium hydroxide mediated hydrolysis of the ester affords compound of general formula (lid) as a pure enantiomer.
  • the esterification can be done using suitable coupling agent in the presence of suitable base and solvent.
  • the suitable coupling agent(s) may be BOP, PyBOP, EDCI, DCC, T 3 P (50% in EtOAc) or HATU.
  • the suitable base used in the reaction may be Et 3 N, DIPEA, pyridine or DMAP.
  • the suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • Methylation of phenyl acetonitrile derivative (10) with methyl halide in the presence of suitable base and solvent affords the di-methylated phenyl acetonitrile derivative of formula (11).
  • the suitable base used in this reaction may be sodium or potassium ie/t-butoxide and the suitable solvent may be THF.
  • Reductive amination of the compound of formula (11) using lithium aluminium hydride in the presence of a Lewis acid such as aluminium chloride in a suitable solvent such as THF gives the corresponding primary amine derivative of formula (12).
  • Substitution reaction of the amino compound (12) with ester compound of formula (13) in the presence of suitable base and solvent yields the compound of formula (14).
  • the suitable base used in the reaction may be triethylamine, DIPEA, pyridine or DMAP, and the solvent used may be selected from DCM, THF or chloroform.
  • the suitable solvent may selected from CH2CI2, CHC1 3 , DMF, THF, methanol or water or mixture thereof affords the corresponding amine of formula (15).
  • the cyclization of amine of formula (15) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (16).
  • Ester hydrolysis of compound of formula (16) using sodium hydroxide or lithium hydroxide monohydrate in a suitable solvent or mixture thereof yields the corresponding carboxylic acid of formula (17).
  • the suitable solvent may selected from CH2CI2, CHCI3, DMF, THF, methanol, water or mixtures thereof.
  • the coupling reaction of carboxylic compound of formula (17) with the amine compound of formula (18) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (Ilia).
  • the suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU).
  • the suitable base used in the reaction may be Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • the mono-ester of di-carboxylic acid compound of formula (2b) on protection with a suitable protecting agent such as, triisopropylchlorosilane (Tips-Cl) affords the hetero-di-ester compound of formula (7).
  • the reaction may be carried out in the presence of suitable base and solvent.
  • the suitable base for the reaction may be imidazole and solvent can be selected from THF or DMF.
  • the compound (7) on reaction with Grignard reagent, methylmagnesium bromide affords the tertiary alcohol (19) which on deprotection yields 2-(4-(l,l-difluoro-2- hydroxy-2-methylpropyl)phenyl)acetic acid (2d).
  • the carboxylic acid (2d) on coupling reaction with the amine compound of formula (la) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (He).
  • the suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU).
  • the suitable base used in the reaction may be Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • Substitution reaction of the amino compound (12) with fluoro compound of formula (20) at elevated temperature yields the compound of formula (21).
  • the solvent used in the reaction may be selected from DMSO, toluene, DMF or 1,4-dioxane.
  • the cyclization of compound of formula (21) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (22).
  • the reduction of nitro group in compound of formula (22) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent, such as CH2CI2, CHC1 3 , DMF, THF, methanol or water or mixture thereof, furnishes the corresponding amine compound of formula (la).
  • Reduction of the nitro group to give the corresponding amine compound may also be carried out using sodium borohydride in the presence of nickel chloride.
  • the reaction of carboxylic acid compound of formula (17) with ethyl chioroformate followed by sodium azide in suitable solvent yields the corresponding azide compound of formula (23).
  • the suitable solvent for the reaction may be THF, water or mixture thereof.
  • the Curtius rearrangement by heating the azide (23) in the presence of water and a high boiling solvent such as 1,4-dioxane yields the desired amine of formula (la).
  • halogen substituted phenylketone of formula (24) (wherein Hal is halogen) with ethane 1, 2-dithiol (25) (to protect the carbonyl group) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (26).
  • the suitable Lewis acid may be boron trifluoride-diethyl etherate.
  • the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF.
  • the compound of formula (26) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives the difluoro compound of formula (27).
  • the suitable solvent may be pyridine, CH2CI2, CHCI3, DMF or mixtures thereof.
  • Halogen substitution of compound of formula (27) with ie/ -butyl acetate in the presence of palladium catalyst and suitable base gives compound of formula (28).
  • the suitable base may be lithium dicyclohexylamine.
  • the substitution reaction may be carried out in a suitable solvent.
  • the suitable solvent may be toluene.
  • the compound of formula (28) on deprotection of ie/ -butyl group, using trifluoroacetic acid in a suitable solvent gives the carboxylic acid of formula (2e).
  • the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF.
  • ethyl sulfane compound (30) S-alkylation of 4-methylbenzenethiol (29) with ethyl bromide in the presence of suitable base and solvent yields the ethyl sulfane compound (30).
  • suitable base used in the reaction may be selected from sodium carbonate or potassium carbonate.
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from acetone, CH2CI2, CHCI3, DMF and THF or combination thereof.
  • Oxidation of sulfane compound of formula (30) using m-CPBA in a suitable solvent such as CH2CI2 yields the corresponding ethanesulfonyl compound of formula (31).
  • Ethyl 2-hydroxyacetate (39) on reaction with ie/ -butyldimethylsilyl chloride in the presence of a suitable base and solvent yields the silyl ether of formula (40).
  • the suitable base for the reaction may be imidazole and solvent may be dichloromethane.
  • Compound (40) on reaction with N,0-dimethylhydroxylamine hydrochloride in the presence of ethylmagnesium bromide in a suitable solvent affords the Weinreb amide (41).
  • the suitable solvent for the reaction may be THF.
  • the Weinreb amide (41) reacts with (4-bromophenyl)(ethyl)sulfane (42) in the presence of magnesium metal in THF to give the bromo-substituted product (43).
  • Compound (43) on reaction with (R or 5)-(-)-2-methyl-2-propanesulfinamide in the presence of titanium isopropoxide in a suitable solvent such as THF affords the imine derivative (44) which on reduction using DIBAL-H in THF yields compound (45).
  • suitable coupling agent(s) may be selected from l-ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU).
  • suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • Substitution reaction of the iodo compound of formula (48) with ethyl 2-bromo-2,2- difluoroacetate (4) in the presence of copper powder and suitable solvent at elevated temperature yields the ester of formula (49).
  • the suitable solvent for the reaction may be DMSO.
  • the ester compound of formula (49) on treating with methyllithium in suitable solvent such as THF gives the corresponding keto compound which on reduction in the presence of suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (Ilf).
  • suitable reducing agent used in the reaction may be sodium borohydride and the suitable solvent may be methanol, THF or combination thereof.
  • the keto reduction of compound of formula (53) can also be done using chiral reducing agent in a suitable solvent to furnish the pure enantiomer of the hydroxyl derivative of general formula (3 ⁇ 4)).
  • the coupling reaction of 4-iodobenzoic acid (50) with ethyl 2-bromo-2, 2-difluoroacetate (4) in the presence of copper powder and suitable solvent at elevated temperature yields the ester of formula (51).
  • the suitable solvent for the reaction may be DMSO.
  • the ester compound of formula (51) on treating with methyllithium in suitable solvent such as THF gives the corresponding keto compound of formula (52).
  • the coupling reaction of compound of formula (52) with ammonia in the presence of 1, l'-carbonyldiimidazole in THF yields the amide of formula (53).
  • Compound of formula (53) on reaction with phosphorous oxychloride in DMF gives the nitrile derivative of formula (54).
  • amine hydrochloride of formula (55) Catalytic hydrogenation of compound of formula (54) in the presence of hydrochloric acid in suitable solvent affords amine hydrochloride of formula (55).
  • the suitable solvent for the reaction may be ethyl acetate, THF, methanol, ethanol Boc protection of the amine of formula (55) using Boc anhydride, a suitable base and solvent affords the protected amine of formula (56).
  • the suitable base for the reaction may be sodium hydroxide, and solvent may be 1, 4-dioxane, water or mixture thereof.
  • the keto compound of formula (56) on reduction using suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (57).
  • suitable reducing agent used in the reaction may be sodium borohydride and the suitable solvent may be methanol, THF or combination thereof.
  • suitable solvent may be ethyl acetate, ethanol, methanol, diethyl ether or combination thereof.
  • suitable coupling agent(s) may be selected from l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T 3 P) (50% in EtOAc) or (1- [bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid
  • hexafluorophosphate HATU
  • suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from CH2CI2, CHC1 3 , DMF and THF or combination thereof.
  • the compound of formula (56) on reduction by using appropriate chiral reducing agent, followed by Boc deprotection affords the chiral hydroxyl derivative of formula (59).
  • the chiral reducing agent may be selected from (R or 5)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B-chlorodiisopinocampheylborane (DIP-Chloride), etc. and the suitable solvent may be THF, DCM or DMF.
  • the reaction of keto compound (56) with excess of methyl magnesium bromide in a suitable solvent yields the tertiary alcohol (60).
  • the suitable solvent for the reaction may be THF or diethyl ether.
  • Deprotection of the amine group of formula (60) using hydrochloric acid in appropriate solvent yields the compound of formula (61) as a hydrochloride salt.
  • the suitable solvent for the reaction may be ethyl acetate, ethanol, methanol, diethyl ether or combination thereof.
  • the coupling reaction of compound of formula (61) with the acid of formula (17) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (Ilh) under the conditions described in above in the previous schemes.
  • Substitution reaction of the amino compound (62) with fluoro dinitro compound of formula (63) at elevated temperature yields the compound (64).
  • the solvent used in the reaction may be selected from DMSO, toluene, DMF or 1,4-dioxane.
  • Selective reduction of one of the nitro group yields the amine derivative of formula (65).
  • the selective reduction may be carried out using sodium sulfide, ammonium chloride and aqueous ammonia in an appropriate solvent such as ethanol.
  • the cyclization of compound of formula (65) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (66).
  • the reaction of l-(p-tolyl)propan-l-one (67) with ethane 1,2-dithiol (25) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (68).
  • the suitable Lewis acid may be boron trifluoride-diethyl etherate.
  • the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF.
  • the compound (68) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives the difluoro compound of formula (69).
  • the suitable solvent may be pyridine, CH2CI2, CHCI3, DMF or mixtures thereof.
  • the reaction of carboxylic compound of formula (17) with the amine compound of formula (59) in the presence of diphenylphosphoryl azide, a suitable base in a suitable solvent affords the urea derivative of formula (Hi).
  • the suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from CH2CI2, CHC1 3 , DMF, DMSO, THF or combination thereof.
  • the amine of formula (la) on reaction with phenyl chloroformate in the presence of suitable base and solvent yields the carbamate of formula (74).
  • the suitable base for the reaction may be pyridine and solvent may be THF.
  • the suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from DMF, DMSO, THF or combination thereof.
  • the carbamate (74) on reaction with amine compound of formula (18) in the presence of suitable base in a suitable solvent affords the urea derivative of formula (Illf).
  • suitable base used in the reaction may be selected from Et 3 N, DIPEA, pyridine or DMAP.
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • suitable solvent may be selected from DMF, DMSO, THF or combination thereof.
  • Step 2 1 -Bromo-4-( 1 , 1 -difluoropropyl)b
  • the reaction mixture was diluted with n-hexane, filtered through basic alumina and washed with n-hexane. The filtrate was concentrated and the residue was diluted with ethyl acetate. The organic solution was washed with 10% sodium thiosulfate, 2% potassium permanganate, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 203 mg of the titled product.
  • Step 3 ie/ -Butyl [4-(l, l-difluoropropyl)phenyl] acetate
  • Step 3 intermediate To a stirred solution of ieri-butyl [4-(l, l-difluoropropyl)phenyl] acetate (Step 3 intermediate) (1.42 g, 5.25 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (10 mL) and the mixture was stirred at RT for 1 h. The solvent in the reaction mixture was recovered under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 491 mg of the titled product.
  • step 1 intermediate To a solution of ethyl(p-tolyl)sulfane (step 1 intermediate) (12.9 g, 84.72 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (36.5 g, 212 mmol) at 0 °C. The reaction mixture was stirred at RT for 18 h. The mixture was filtered and the filtrated was washed with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford 15.5 g of the titled product.
  • Step 2 intermediate l-(ethylsulfonyl)-4-methylbenzene (Step 2 intermediate) (15.5 g, 0.08 mmol) in tetrachloromethane (100 mL) were added N-bromosuccinimide (17.9, 0.10 mmol) followed by azobisisobutyronitrile (AIBN) (1.38 g, 0.008 mmol) and the mixture was stirred at 80 °C for 18 h. The mixture was cooled to RT and filtered through celite. The filtrate was concentrated and dissolved in ethyl acetate. The solution was washed with water followed by brine and dried over anhydrous sodium sulfate.
  • AIBN azobisisobutyronitrile
  • Step 3 intermediate l-(bromomethyl)-4-(ethylsulfonyl)benzene (Step 3 intermediate) (2.0 g, 7.60 mmol) in methanol (10 mL) was added ammonium hydroxide (10 mL) and the mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The solid obtained was dissolved in saturated hydrochloric acid in ethyl acetate (10 mL) and stirred for 30 min. The solvent was removed under reduced pressure and the solid obtained was dried well to afford 894 mg of the titled product.
  • Step 1 N -(2,4-Dichlorophenethyl)-4-nitrobenzene- 1 ,2-diamine
  • Step 1 intermediate N 1 -(2,4-dichlorophenethyl)-4-nitrobenzene- l,2-diamine (Step 1 intermediate) (350 mg, 1.08 mmol) in acetic acid (5.0 mL) was added a solution of sodium nitrite (111 mg, 1.61 mmol) in water (1.5 mL) at 0 °C and the mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 310 mg of the titled product.
  • Step 3 l-(2,4-Dichlorophenethyl)- lH-benzo[ ⁇ i] [l,2,3]triazol-5-amine
  • Step 2 intermediate To a stirred solution of l-(2,4-dichlorophenethyl)-5-nitro- lH-benzo[ ⁇ i][l,2,3]triazole (Step 2 intermediate) (300 mg, 0.88 mmol) and nickel chloride (423 mg, 1.78 mmol) in methanol (10 mL) was added sodium borohydride (134 mg, 3.55 mmol) in small portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to yield a viscous residue. The residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate.
  • Step 1 N -(2-(2,4-Dichlorophenyl)- -methylpropyl)-4-nitrobenzene- 1 ,2-diamine
  • the titled compound was prepared by the reaction of 2-fluoro-5-nitroaniline (360 mg, 2.30 mmol) with 2-(2,4-dichlorophenyl)-2-methylpropan-l -amine (500 mg, 2.30 mmol) in DMSO (5.0 mL) as per the procedure described in step 1 of Intermediate 4 to yield 198 mg of the product.
  • Step 2 1 -(2-(2,4-Dichlorophenyl)-2-methylpropyl)-5-nitro- lH-benzo[ ⁇ i] [ 1 ,2,3] triazole
  • the titled compound was prepared by the reaction of N 1 -(2-(2,4-dichlorophenyl)-2- methylpropyl)-4-nitrobenzene-l,2-diamine (Step 1 intermediate) (180 mg, 0.51 mmol) with sodium nitrite (52 mg, 0.76 mmol) and acetic acid (4.0 mL) in water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 138 mg of the product.
  • Step 1 intermediate 180 mg, 0.51 mmol
  • sodium nitrite 52 mg, 0.76 mmol
  • acetic acid 4.0 mL
  • water 1.0 mL
  • Step 3 l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[ ⁇ i] [l,2,3]triazol-5-amine
  • Step 2 intermediate To a stirred solution of l-(2-(2,4-dichlorophenyl)-2-methylpropyl)-5-nitro- lH- benzo[ ⁇ J [ 1,2,3] triazole (Step 2 intermediate) (130 mg, 0.36 mmol) in a mixture of methanol and water (1 : 1, 10 niL) were added iron powder (100 mg, 1.78 mmol) and ammonium chloride (190 mg, 3.55 mmol) at RT. The reaction mixture was stirred at 80 °C for 2 h. The solvents were distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate.
  • Step 3 N 1 -(2-(2,4-Difluorophenyl)- -methylpropyl)-4-nitrobenzene- 1 ,2-diamine
  • the titled compound was prepared by the reaction of 2-fluoro-5-nitroaniline (750 mg, 4.80 mmol) with 2-(2,4-difluorophenyl)-2-methylpropan- l -amine (Step 2 intermediate) (890 mg, 4.80 mmol) in DMSO (10 mL) as per the procedure described in step 1 of Intermediate 4 to yield 289 mg of the product.
  • the titled compound was prepared by the reaction of N 1 -(2-(2,4-difluorophenyl)-2- methylpropyl)-4-nitrobenzene-l,2-diamine (Step 3 intermediate) (275 mg, 0.85 mmol) with sodium nitrite (89 mg, 1.28 mmol) and acetic acid (4.0 mL) in water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 238 mg of the product.
  • Step 5 l-(2-(2,4-Difluorophenyl)-2-methylpropyl)-lH-benzo[ ⁇ i][l,2,3]triazol-5-amine
  • the titled compound was synthesized by the nitro reduction of the l-(2-(2,4-difluorophenyl)- 2-methylpropyl)-5-nitro- lH-benzo[d][l,2,3]triazole (Step 4 intermediate) (225 mg, 0.68 mmol) by using iron powder (189 mg, 3.38 mmol) and ammonium chloride (362 mg, 6.77 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in step 3 of Intermediate 5 to yield 173 mg of the product.
  • the titled compound was synthesized by the nitro reduction of the ethyl 4-((2-(2,4- dichlorophenyl)-2-methylpropyl)amino)-3-nitrobenzoate (Step 3 intermediate) (900 mg, 2.18 mmol) by using iron powder (609 mg, 10.94 mmol) and ammonium chloride (1.17 g, 21.88 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in step 3 of Intermediate 5 to yield 700 mg of the product.
  • Step 5 Ethyl l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ⁇ i][l,2,3]triazole-5- carboxylate
  • the titled compound was prepared by the reaction of ethyl 3-amino-4-((2-(2,4-dichlorophenyl)- 2-methylpropyl)amino)benzoate (Step 4 intermediate) (650 mg, 1.70 mmol) with sodium nitrite (176 mg, 2.56 mmol) and acetic acid (5.0 mL) in water (3.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 570 mg of the product.
  • Step 6 l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[ ⁇ i] [l,2,3]triazole-5-carboxylic acid
  • Step 5 intermediate ethyl l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH- benzo[ ⁇ J [l,2,3]triazole-5-carboxylate (Step 5 intermediate) (550 mg, 1.40 mmol) in a mixture of THF, methanol and water (2: 1 : 1, 20 mL) was added lithium hydroxide monohydrate (117 mg, 2.80 mmol) at RT and the mixture was stirred for 1.5 h at RT. The reaction mixture was concentrated and added water. The aqueous mixture was acidified with IN HCl and extracted twice with ethyl acetate.
  • Step 1 ie/ -Butyl ((5-bromopyridin-2-yl)methyl)carbamate
  • Step 2 ie/ -Butyl ((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamate
  • Step 1 intermediate tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (Step 1 intermediate) (500 mg, 17.36 mmol), ethane sulfonic acid sodium salt (403 mg, 34.72 mmol), L-proline (39 mg, 3.47 mmol), copper (I) iodide (33 mg, 1.73 mmol) and sodium hydroxide (13 mg, 3.47 mmol) at RT.
  • the mixture was purged with nitrogen and then added DMSO (10 mL). The mixture was stirred at 110 °C for 15 h.
  • the reaction mixture was partitioned between ethyl acetate and saturated aqueous solution of ammonium chloride.
  • Step 2 intermediate To a stirred solution of tert-butyl ((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamate (Step 2 intermediate) (325 mg, 1.08 mmol) in methanol (15 mL) was drop wise added acetyl chloride (0.8 mL, 10.83 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to afford 258 mg of the titled product.
  • acetyl chloride 0.8 mL, 10.83 mmol
  • Step 1 intermediate 4-(ethylsulfonyl)benzaldehyde (Step 1 intermediate) (1.0 g, 5.04 mmol) in DMF (10 mL) was added trimethylsulfonium iodide (1.18 g, 5.80 mmol) followed by potassium hydroxide powder (560 mg, 10.08 mmol) at RT. The mixture was stirred at RT for 20 min. The mixture was quenched with water and carefully neutralized with IN HC1. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a quick filter column to yield 1.1 g of the titled product; APCI-MS (m/z) 211 (M+H)-.
  • Step 2 intermediate 2-(4-(ethylsulfonyl)phenyl)oxirane (Step 2 intermediate) (1.1 g, 5.18 mmol) in acetonitrile (20 mL) was slowly added concentrated sulfuric acid (0.55 mL, 10.19 mmol) and the mixture was stirred at RT for 1.5 h. Water (1.5 mL) was added to the mixture and continued to stirred at RT for another 8 h. The mixture was heated to 45 °C and stirred for 10 h. The mixture was cooled to RT and adjusted the pH to 3-4 using IN aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic layer was extracted back with water.
  • the combined aqueous layers were basified with IN sodium hydroxide solution till pH 9.
  • the aqueous layer was extracted with 1-butanol and the combined organic extracts were dried over anhydrous sodium sulfate.
  • the solvent was removed under reduced pressure and the solid obtained was stirred with methanol.
  • the solid was filtered, dried and further purified by silica gel column chromatography to yield 150 mg of the titled product.
  • Step 2 l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)- lH-benzo[ ⁇ i] [l,2,3]triazol-5-amine
  • Step 1 intermediate A suspension of l-(2-(2,6-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ⁇ i][l,2,3]triazole-5- carbonyl azide (Step 1 intermediate) (490 mg, 1.26 mmol) in 10% aqueous 1,4-dioxane was refluxed for 4 h. The mixture was allowed to cool at RT and stirred for 18 h at RT. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and filtered.
  • Step 1 Ethyl 2-((tert-butyldimethylsilyl)oxy)acetate
  • Step 1 intermediate ethyl 2-((ie/t-butyldimethylsilyl)oxy)acetate (Step 1 intermediate) (25.0 g, 144 mmol) and N,0-dimethylhydroxylamine hydrochloride (22.4 g, 228 mmol) in THF (400 mL) was added ethylmagnesium bromide (152 mL, 457 mmol) dropwise at - 10 °C in a duration of 1.5 h. The mixture was stirred at -10 to -5 °C for 1.5 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate.
  • Step 3 2-((ieri-Butyldimethylsilyl)o -l-(4-(ethylthio)phenyl)ethanone
  • Step 4 N-(2-((ieri-Butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethylidene)-2- methylpropane-2- sulfinamide
  • Step 3 intermediate 2-((ieri-butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethanone (Step 3 intermediate) (2.0 g, 6.44 mmol) and (S)-(-)-2-methyl-2-propanesulfinamide (936 mg, 7.72 mmol) in THF (25 mL) was added titanium isopropoxide (4.73 mL, 16.10 mmol) at RT. The mixture was heated to 80 °C and stirred for 6 h. The reaction was cooled to RT and quenched with brine. The mixture was diluted with ethyl acetate and stirred for 15 min.
  • Step 5 N-((R)-2-((tert-Butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethyl)-2- methylpropane-2- sulfinamide
  • Step 4 intermediate N-(2-((ieri-butyldimethylsilyl)oxy)- l-(4-(ethylthio)phenyl)ethylidene)- 2-methylpropane-2- sulfinamide (Step 4 intermediate) (1.6 g, 3.86 mmol) in THF (15 mL) was added DIBAL-H (1.2 , 9.66 mL, 11.6 mmol) at -78 °C and the mixture was stirred for 1 h at the same temperature. The mixture was quenched with water. The mixture was diluted with ethyl acetate and stirred for 15 min.
  • Step 6 ( ?)-2-Amino-2-(4-(ethylthio)phenyl)ethanol To a stirred solution of N-(( ?)-2-((ieri-butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethyl)- 2-methylpropane-2-sulfinamide (Step 5 intermediate) (1.0 g, 2.40 mmol) in methanol (10 mL) was added hydrochloric acid in ethyl acetate (10 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water.
  • the aqueous mixture was washed with ethyl acetate and basified with solid sodium carbonate till pH 8-9.
  • the solution was extracted twice with ethyl acetate and the combined organic extracts were dried over anhydrous sodium sulfate.
  • the solvent was removed under reduced pressure to yield 415 mg of the desired product.
  • Step 7 ( ?)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol
  • Step 1 Ethyl 2,2-difluoro-2-(4-(2 xy)ethyl)phenyl)acetate
  • Step 2 Triisopropylsilyl 2-(4-(l, l- yl)acetate
  • Step 1 intermediate ethyl 2,2-difluoro-2-(4-(2-oxo-2- ((triisopropylsilyl)oxy)ethyl)phenyl)acetate (Step 1 intermediate) (12.0 g, 28.94 mmol) in anhydrous THF (100 mL) was added 3.1 methyllithium (19.0 mL, 57.89 mmol) dropwise at -78 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted thrice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate.
  • Step 3 (S)-Triisopropylsilyl 2-(4-(l, -difluoro-2-hydroxypropyl)phenyl)acetate
  • Step 2 intermediate a solution of triisopropylsilyl 2-(4-(l, l-difluoro-2-oxopropyl)phenyl)acetate (Step 2 intermediate) (4.0 g, 10.42 mmol) in THF (5.0 mL) was added to the mixture.
  • the reaction mixture was stirred at -20 °C for 30 min before quenching with methanol.
  • the solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography to yield 1.8 g of the titled product.
  • Step 4 (5)-2-(4-(l, l-Difluoro-2-hydroxypropyl)phenyl)acetic acid
  • Step 3 intermediate 400 mg, 1.03 mmol
  • THF 5.0 mL
  • TBAF tetrabutylammonium fluoride
  • l .OM 2.0 mL, 2.08 mmol
  • the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 1 Triisopropylsilyl 2-(4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetate
  • step 1 of Intermediate 46 To a stirred solution of ethyl 2,2-difluoro-2-(4-(2-oxo-2- ((triisopropylsilyl)oxy)ethyl)phenyl)acetate (step 1 of Intermediate 46) (2.3 g, 5.54 mmol) in diethyl ether (20 mL) was added methylmagnesium bromide ( 1.5 , 18.4 mL, 27.7 mmol) at - 10 °C and the mixture was stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over anhydrous sodium sulfate.
  • Step 2 2-(4-(l, l-Difluoro-2-hydroxy-2-methylpropyl)phenyl)acetic acid
  • the titled compound was prepared by the deprotection reaction of triisopropylsilyl 2-(4-(l,l- difluoro-2-hydroxy-2-methylpropyl)phenyl)acetate (Step 1 intermediate) (260 mg, 0.68 mmol) using tetrabutylammonium fluoride (TBAF) (1 , 5.16 mL, 1.35 mmol) in THF (5.0 mL) as per the procedure described in step 4 of Intermediate 46 to yield 111 mg of the compound.
  • TBAF tetrabutylammonium fluoride
  • Step 1 4-(2-Ethoxy- l,l-difluoro-2-oxoethyl)benzoic acid
  • the titled compound was prepared by the reaction of 4-iodobenzoic acid (3.0 g, 12.1 mmol) with 2-bromo-2,2-difluoroacetate (4.9 g, 24.2 mmol) in the presence of copper powder (3.05 g, 48.4 mmol) in DMSO (15 mL) as per the procedure described in Intermediate 2 to yield 1.7 g of the compound.
  • Step 2 4-(l, l-Difluoro-2-oxopropyl)benzoic acid
  • the titled compound was prepared by the reaction of 4-(2-ethoxy- l,l-difluoro-2- oxoethyl)benzoic acid (stepl intermediate) (1.0 g, 4.09 mmol) with methyllithium (3.0 , 4.1 mL, 12.3 mmol) in THF (10 mL) as per the procedure described in Step 2 of Intermediate 46 to yield 570 mg of the compound.
  • Step 3 4-( 1 , 1 -Difluoro-2-oxopropyl)benzamide
  • Step 2 intermediate -(l, l-difluoro-2-oxopropyl)benzoic acid (Step 2 intermediate) (4.0 g, 18.7 mmol) in THF (200 mL) was added l, l '-carbonyldiimidazole (CDI) (4.52 g, 28.0 mmol) and the mixture was stirred at RT for 1 h. The mixture was cooled to 0 °C and aqueous ammonia (2.0 mL) was added drop-wise. The reaction mixture was stirred for 2 h at RT. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate.
  • CDI l, l '-carbonyldiimidazole
  • Step 4 4-( 1 , 1 -Difluoro-2-oxopropyl)be
  • Step 3 intermediate 4-(l, l-difluoro-2-oxopropyl)benzamide (Step 3 intermediate) (1.5 g, 7.04 mmol) in DMF (5.0 mL) at 0 °C and the mixture was stirred for 15 min.
  • the reaction mixture was poured into a mixture of ammonia, water and crushed ice.
  • the product was extracted twice in ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 905 mg of the titled product.
  • Step 5 1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-one hydrochloride
  • Step 4 intermediate A solution of 4-(l, l-difluoro-2-oxopropyl)benzonitrile (Step 4 intermediate) (895 mg, 4.56 mmol) in methanol (30 mL) with catalytic amount of cone, hydrochloric acid was purged with nitrogen gas for 10 min. Palladium on carbon (10%, 50% wet, 500 mg) was added to the solution and the mixture was hydrogenated (under hydrogen balloon) for 4 h at RT. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield 1.0 g of the titled product.
  • Step 6 ie/ -Butyl 4-(l, l-difluoro-2-oxopropyl)benzylcarbamate
  • Step 5 intermediate l-(4-(aminomethyl)phenyl)- l,l-difluoropropan-2-one hydrochloride (Step 5 intermediate) (1.5 g, 6.36 mmol) in a mixture of 1,4-dioxane (10 mL) and water (10 mL) were added Boc anhydride (1.53 g, 7.0 mmol) and sodium hydroxide (381 mg, 9.55 mmol) at RT. The mixture was stirred for 3 h at RT. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate.
  • Step 7 (S)-ie/t-Butyl 4-(l, l-difluoro-2-hydroxypropyl)benzylcarbamate
  • Step 8 (S)- 1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-ol hydrochloride
  • Step 7 intermediate a solution of ⁇ S)-tert-buty ⁇ 4-(l,l-difluoro-2-hydroxypropyl)benzylcarbamate (Step 7 intermediate) (190 mg, 0.63 mmol) in methanol (5.0 mL) was added hydrochloric acid in ethyl acetate (5.0 mL) and the mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the residue was triturated with hexane followed by diethyl ether. The solid was dried under reduced pressure to yield 110 mg of the desired product.
  • Step 1 tert-butyl 4-(l, l-difluoro-2-hydroxypropyl)benzylcarbamate
  • Step 2 l-(4-(Aminomethyl)phenyl)- l,l-difluoropropan-2-ol hydrochloride
  • the titled compound was prepared by the reaction of tert-butyl 4-(l, l-difluoro-2- hydroxypropyl)benzylcarbamate (Step 1 intermediate) (150 mg, 0.50 mmol) with hydrochloric acid in ethyl acetate (5.0 mL) in methanol (5.0 mL) as per the procedure described in step 8 of intermediate 49 to yield 100 mg of the product.
  • Step 1 ie/ -Butyl 4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)benzylcarbamate
  • the titled compound was prepared by the reaction of tert-butyl 4-(l, l-difluoro-2- oxopropyl)benzylcarbamate (Step 6 of Intermediate 49) (500 mg, 1.67 mmol) with methylmagnesium bromide (1.5 , 5.57 mL, 8.35 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 48 to yield 300 mg of the product.
  • Step 2 l-(4-(Aminomethyl)phenyl)- l,l-difluoro-2-methylpropan-2-ol hydrochloride
  • the titled compound was prepared by the reaction of ieri-Butyl 4-(l,l-difluoro-2-hydroxy-2- methylpropyl)benzylcarbamate (Step 1 intermediate) (300 mg, (0.95 mmol) with hydrochloric acid in ethyl acetate (5.0 mL) in methanol (5.0 mL) as per the procedure described in Step 8 of Intermediate 49 to yield 153 mg of the product.
  • Step 1 N-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-2,4-dinitroaniline
  • the titled compound was prepared by the reaction of l-fluoro-2,4-dinitrobenzene (660 mg, 3.54 mmol) with 2-methyl-2-(2,4,6-trifluorophenyl)propan- l -amine (550 mg, 3.19 mmol) in the presence of DIPEA (1.31 mL, 7.09 mmol) as per the procedure described in Step 3 of Intermediate 21 to yield 670 mg of the compound.
  • Step 2 N 1 -(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-4-nitrobenzene- 1 ,2-diamine
  • Step 1 intermediate N-(2-methyl-2-(2,4,6-trifluorophenyl)propyl)-2,4-dinitroaniline (Step 1 intermediate) (650 mg, 1.75 mmol) and ammonium chloride (936 mg, 1.75 mmol) in ethanol (15 mL) was heated to 60 °C. To that mixture, were added a solution of sodium sulfide in ethanol (15 mL) followed by aqueous ammonia (50 mL) drop-wise. The reaction mixture was stirred at 90 °C for 4 h. The mixture was diluted with saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate.
  • Step 3 l-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-5-nitro- lH-benzo[ ⁇ i] [l,2,3]triazole
  • the titled compound was prepared by the cyclization reaction of N 1 -(2-Methyl-2-(2,4,6- trifluorophenyl)propyl)-4-nitrobenzene- l,2-diamine (Step 2 intermediate) (250 mg, 7.36 mmol) in the presence of sodium nitrite (101 mg, 1.47 mmol) in acetic acid (10 mL) and water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 181 mg of the product.
  • Step 4 l-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)- lH-benzo[ ⁇ i] [l,2,3]triazol-5-arnine
  • the titled compound was synthesized by the nitro reduction of the l-(2-methyl-2-(2,4,6- trifluorophenyl)propyl)-5-nitro- lH-benzo[ ⁇ i] [l,2,3]triazole (Step 3 intermediate) (170 mg, 0.48 mmol) by using iron powder (134 mg, 2.42 mmol) and ammonium chloride (259 mg, 4.85 mmol) in a mixture of methanol (10 mL), THF (10 mL) and water (5.0 mL) as per the process described in step 3 of Intermediate 5 to yield 121 mg of the product.
  • Step 1 2-Ethyl-2-(p-tolyl)- 1 ,3-dithiolane
  • Step 2 1 -( 1 , 1 -Difluoropropyl)-4-methylb
  • N-iodosuccinimide (9.0 g, 10.11 mmol) and flushed twice with nitrogen.
  • Dichloromethane (30 mL) was added to the flask and the mixture was cooled to -78 °C.
  • Hydrogen fluoride pyridine (70%, 7.0 mL, 267 mmol) was added drop wise to the mixture.
  • a solution of 2-ethyl-2-(p-tolyl)- l,3- dithiolane (Step 1 intermediate) (3.0 g, 13.37 mmol) in dichloromethane (15 mL) was added drop wise.
  • Step 3 l-(Bromomethyl)-4-(l, l-difluoropropyl)benzene
  • Step 2 intermediate l-(l,l-difluoropropyl)-4-methylbenzene (Step 2 intermediate) (350 mg, 2.05 mmol) in carbon tetrachloride (10 mL) were added AIBN (33 mg, 0.21 mmol) followed by N-bromosuccinimide (430 mg, 2.41 mmol) at RT and the mixture was stirred overnight at 100 °C.
  • the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 50 mg of the desired compound.
  • Step 4 2-(4-( 1 , 1 -Difluoropropyl)benzyl)isoindoline- 1 ,3-dione
  • Step 3 intermediate l-(bromomethyl)-4-(l, l-difluoropropyl)benzene (Step 3 intermediate) (48 mg, 0.19 mmol) in DMF (5.0 mL) were added cesium carbonate (94 mg, 0.28 mmol) followed by phthalimide (34 mg, 0.23 mmol) and the mixture was stirred at RT for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 50 mg of the desired compound.
  • Step 4 intermediate 2-(4-(l, l-difluoropropyl)benzyl)isoindoline- l,3-dione (Step 4 intermediate) (47 mg, 0.15 mmol) in methanol (5.0 mL) was added hydrazine monohydrate (0.1 mL, 2.72 mmol) and the reaction mixture was stirred at 60 °C for 1.5 h. The mixture was cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and stirred for 15 min. The precipitated solid was filtered off. The filtrate was concentrated to yield 25 mg of the desired compound.
  • Examples 1-68 were synthesized by following methods (A-G) as described below:
  • Step 1 Ethyl 2-(4-(2-((l-(2,4-dichlorophenethyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)amino)-2- oxoethyl)phenyl)-2,2-difluoroacetate
  • Step 2 N- ⁇ 1 -(2,4-Dichlorophenethyl)- lH-benzo[d] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1 , 1 -difluoro-2- oxopropyl)phenyl)acetamide
  • step 1 intermediate ethyl 2-(4-(2-((l-(2,4-dichlorophenethyl)-lH-benzo[ ⁇ i][l,2,3]triazol-5- yl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate (step 1 intermediate) (1.1 g, 2.01 mmol) in anhydrous THF (10 mL) was added 3M methyllithium (1.6 mL, 5.02 mmol) dropwise at -78 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction was quenched with saturated ammonium chloride solution and extracted thrice with ethyl acetate.
  • Step 3 N-( 1 -(2,4-Dichlorophenethyl)- lH-benzo[d] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide
  • step 2 intermediate N-(l-(2,4-dichlorophenethyl)- lH-benzo[ ⁇ i] [l,2,3]triazol-5-yl)-2-(4- (l,l-difluoro-2-oxopropyl)phenyl)acetamide (step 2 intermediate) (100 mg, 0.19 mmol) in a mixture of THF (4.0 mL) and methanol (1.0 mL) at 0 °C was added sodium borohydride (11 mg, 0.28 mmol) and the resulting mixture was stirred for 1 h at same temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate.
  • the reaction was stirred overnight at RT.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the combined organic layers were washed with aqueous sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude material obtained was purified by silica gel column chromatography to obtain 46 mg of the desired product.
  • Step 1 Ethyl 2-(4-(2-((l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH-benzo[i/] [l,2,3]triazol- 5-yl)amino)-2-oxoethyl)phen -2,2-difluoroacetate
  • the titled compound was prepared by the reaction of l-(2-(2,5-dichlorophenyl)-2- methylpropyl)-lH-benzo[d] [l,2,3]triazol-5-amine (Intermediate 15) (1.2 g, 3.57 mmol) and [4- (2-ethoxy- l,l-difluoro-2-oxoethyl)phenyl] acetic acid (Intermediate 2) (1.10 g, 4.29 mmol) in the presence of propylphosphonic anhydride (50% in EtOAc, 2.28 mL, 7.15 mmol) and ⁇ , ⁇ '- diisopropylethylamine (2.12 mL, 8.94 mmol) in DMF (10 mL) as per the procedure described in Method D to yield 1.70 g of the product.
  • DMF 10 mL
  • Step 2 N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ][l,2,3]triazol-5-yl)-2-(4- (1,1 -difluoro-2-oxopropyl)phenyl)acetamide
  • the titled compound was prepared by the reaction of ethyl 2-(4-(2-((l-(2-(2,5-dichlorophenyl)- 2-methylpropyl)- lH-benzo[ ⁇ i] [ 1 ,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)-2,2- difluoroacetate (step 1 intermediate) (1.65 g, 2.86 mmol) with in 3 methyllithium (2.4 mL,
  • Step 3 (5)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)-2- (4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
  • step 2 intermediate N-(l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[ ⁇ J [l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro-2-oxopropyl)phenyl)acetamide (step 2 intermediate) (200 mg, 0.37 mmol) in THF (5.0 mL) was drop wise added to the mixture. The reaction mixture was stirred at -10 °C for 30 min before quenching with methanol. The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography to yield 95 mg of the titled product.
  • Step 4 ( ?)-(5)- l-(4-(2-((l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH- benzo[ ⁇ J [l,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate
  • step 3 intermediate (5)-N-(l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[ ⁇ J [l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide (step 3 intermediate) (95 mg, 0.17 mmol) in dichloromethane (4.0 mL) were added N- benzyloxycarbonyl-L-phenylalanine (52 mg, 0.17 mmol), EDCI.HCl (37 mg, 0.19 mmol) and DMAP (10 mg, 0.08 mmol) at RT. The reaction mixture was stirred overnight at RT.
  • reaction mixture was diluted with water and extracted twice with ethyl acetate.
  • the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution followed by brine.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified by silica gel column chromatography to isolate 62 mg of the desired diastereomer. APCI-MS imlz) 828 (M+H) + .
  • Step 5 (5)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)-2- (4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
  • step 3 To a stirred solution of ( ?)-(5)-l-(4-(2-((l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[ ⁇ J [l,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate (step 3 intermediate) (55 mg, 0.07 mmol) in a mixture of THF, methanol and water (4:4: 1, 4.5 mL) was added lithium hydroxide monohydrate (5.5 mg, 0.11 mmol) at RT and the mixture was stirred for 1.5 h at RT.
  • the reaction mixture was concentrated and added water.
  • the aqueous mixture was acidified with IN HC1 and extracted twice with ethyl acetate.
  • the combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate.
  • the solution was filtered and concentrated under reduced pressure.
  • the residue obtained was purified by silica gel column chromatography to afford 26 mg of the desired product.
  • Step 1 Phenyl (l-(2-(2,6-difluorophenyl)-2-methylpropyl)-lH-benzo[ ][l,2,3]triazol-5- yl)carbamate
  • Step 2 (5)- 1 -(4-( 1 , 1 -Difluoro-2-hydroxypropyl)benzyl)-3-( 1 -(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[ ⁇ i] [ 1 ,2,3]triazol-5-yl)urea
  • (5)- l-(4-(aminomethyl)phenyl)- l,l-difluoropropan-2-ol hydrochloride (Intermediate 49) (50 mg, 0.20 mmol) in DMSO (10 mL) were added triethylamine (83 ⁇ , 0.60 mmol) followed by phenyl (l-(2-(2,6-difluorophenyl)-2-methylpropyl)-lH- benzo[ ⁇ J [l,2,3]triazol-5-yl)carbamate (Step 1 Intermediate) (125 mg, 0.30 mmol
  • the reaction mixture was diluted with ethyl acetate and water. The layers were separated and aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 49 mg of the product.
  • Step 1 l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-iodobenzyl)- lH- benzo [d] [ 1 ,2,3 ] triazole-5-carboxamide
  • the titled compound was prepared by the reaction of l-(2-(2,4-dichlorophenyl)-2- methylpropyl)-lH-benzo[d] [l,2,3]triazole-5-carboxylic acid (Intermediate 21) (300 mg, 0.82 mmol) and (4-iodophenyl)methanamine (192 mg, 0.82 mmol) in the presence of EDCI HC1 (237 mg, 1.23 mmol), HOBt (133 mg, 0.99 mmol) and DMAP (150 mg, 1.23 mmol) in dichloromethane (10 mL) as per the procedure described in Method C to yield 410 mg of the product.
  • Step 2 Ethyl 2-(4-((l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ][l,2,3]triazole-5- carboxamido)methyl)phenyl)-2,2-difluoroacetate
  • Step 1 intermediate 400 mg, 0.69 mmol
  • copper powder 174 mg, 2.76 mmol
  • 2-bromo-2,2-difluoroacetate 279 mg, 1.38 mmol
  • the aqueous mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 35 mg of the desired product.
  • Step 3 l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2-oxopropyl)benzyl)- lH-benzo[ ⁇ i] [ 1 ,2,3]triazole-5-carboxamide
  • the titled compound was prepared by the reaction of ethyl 2-(4-((l-(2-(2,4-dichlorophenyl)-2- methylpropyl)- lH-benzo[ ⁇ i] [ 1 ,2,3]triazole-5-carboxamido)methyl)phenyl)-2,2-difluoroacetate (step 2 intermediate) (35 mg, 0.061 mmol) with in 3M methyllithium (50 ⁇ , 0.15 mmol) in THF (5.0 mL) as per the process described in step 2 of Method A to yield 30 mg of the product.
  • Step 4 1 -(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-( 1 , 1 -difluoro-2- hydroxypropyl)benzyl)- lH-benzo[ ⁇ i] [ 1 ,2,3]triazole-5-carboxamide
  • the titled compound was prepared by the reaction of l-(2-(2,4-dichlorophenyl)-2- methylpropyl)- V-(4-( 1 , 1 -difluoro-2-oxopropyl)benzyl)- lH-benzo[ ⁇ i] [ 1 ,2,3] triazole-5- carboxamide (step 3 intermediate) (30 mg, 0.06 mmol) with in sodium borohydride (4.1 mg, 0.11 mmol) in a mixture of THF (2.0 mL) and methanol (3.0 mL) as per the process described in step 3 of Method A to yield 10 mg of the product.
  • Example 1 4-16, 18-23, 25-46, 48-71 and 73-75 are given below in Table 9.
  • Table 9 Structure, chemical name, intermediate used, method of preparation and analytical data of Example 1, 4-16, 18-23, 25-46, 48-71 and 73-75.
  • BIOLOGICAL ASSAY The compounds described herein were screened for ROR gamma modulator activity using the TR-FRET assay by Lantha Screen as described in JBC 2011, 286, 26: 22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.
  • the assay is based on the principle that binding of the agonist to the ROR gamma causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide.
  • ROR gamma being constitutively active, the Fluorescein- D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an antagonist decreases the recruitment of the co-activator peptide, causing a decrease in the TR- FRET signal compared to control with no compound.
  • the assay was performed using a two- step procedure, pre-incubation step with the compound followed by the detection step on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.
  • Test compounds or reference compounds such as T0901317 were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration.
  • DMSO dimethylsulfoxide
  • the final concentration of DMSO in the reaction was 4% (v/v).
  • the assay mixture was prepared by mixing lOnM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01% BSA with or without the desired concentration of the compound. The reaction was incubated at 22°C for 1 hour.
  • the pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and lOnM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 hour at room temperature and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound was calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.
  • the compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 ⁇ and 10.0 ⁇ are given in the table along with IC50 (nM) details for selected examples. The compounds were found to have IC50 less than 500nM, preferably less than ⁇ , more preferably less than 50nM.
  • the IC50 (nM) values are set forth in Table 10 wherein "A” refers to an IC50 value of less than 50 nM, "B” refers to IC50 value in range of 50.01 to 100.0 nM and "C” refers to IC50 values more than 100 nM.
  • Example 9 81.63 73.95 A
  • Example 10 80.30 84.22 A
  • Example 11 80.67 61.60 A
  • Example 12 71.80 66.98 A
  • Example 13 70.03 59.29 A
  • Example 17 77.84 80.98 A
  • Example 21 77.39 81.58 A
  • Example 28 84.9 88.6 A Sr.
  • Example 41 80.81 84.69 A
  • Example 60 79.52 80.69 A Sr.
  • Example 70 34.03 43.28 -

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Abstract

The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, G, L, R1, Rx, Ry, X1, X2, X3, X4, n, p, q and t are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORyt). These compounds prevent, inhibit, or suppress the action of RORyt and are therefore useful in the treatment of RORyt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer (I).

Description

1 ,2,3-BENZOTRIAZOLE DERIVATIVES AS ROR GAMMA T MODULATORS
RELATED APPLICATIONS
This application claims the benefit of the Indian Provisional Application No. 201621029489 filed on August 30, 2016 and 201721012965 filed on April 11, 2017; each of which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present patent application is directed to 1,2,3-benzotriazole compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.
BACKGROUND OF THE INVENTION
Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor super family. The ROR family consists of three members, ROR alpha (RORa), ROR beta (RORp) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and 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, RORyl and RORyt (also known as RORy2) have been identified.
RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).
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 and 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 have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol., 2008, 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 et al., J. Exp. Med., 2008, 205: 1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). 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., Annu. Rev. Immunol., 2009, 27:485-517) and RORyt has been shown to play a critical role in the pathogenic responses of Thl7 cells (Ivanov et al., Cell, 2006 126: 1121-1133). RORyt deficient mice have shown no Thl7 cells and also resulted in amelioration of EAE. The genetic disruption of RORy in a mouse colitis model also prevented colitis development (Buonocore et al., Nature, 2010, 464: 1371-1375). The role of RORyt in the pathogenesis of autoimmune or inflammatory diseases has been well documented in the literature. ( Jetten et al., Adv. Dev. Biol., 2006, 16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat. Rev. Immunol, 2006, 6:205-217; Jager et al., J. Immunol, 2009, 183:7169-7177; Serafmi et al., Brain Pathol, 2004, 14: 164-174; Magliozzi et al., Brain, 2007, 130: 1089-1104; Barnes et al., Nat. Rev. Immunol, 2008, 8: 183-192).
In addition, RORyt is also shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340). RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T-cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol, 2009, 123: 1004-1011), suggesting an important function for RORyt in these cells.
In view of the above, a need exists for therapeutic agents that could modulate the activity of RORyt and thus will open new methods for treating diseases or condition associated with the modulation of RORyt.
PCT publication numbers WO2012/139775, WO2012/027965, WO2012/028100, WO2012/100732, WO2012/100734, and WO2012/064744 disclose numerous heterocyclic compounds which are shown to be modulators of retinoid-related orphan receptor gamma (RORy) receptor activity.
The present application is directed to compounds that may be modulators of the RORyt receptor. Thus in light of the role RORyt plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORyt activity, which can be used in the treatment of diseases mediated by RORyt.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to compound of formula (I)
Figure imgf000004_0001
(I)
or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
G is selected from G1 and G2;
Figure imgf000004_0002
L is selected from L1, L2 and L3;
Figure imgf000004_0003
proviso that when G is G , then L is not L ; wherein p and q represents point of attachment;
X1, X2, X3 and X4 which may be same or different, are each independently selected from N and CH; with a proviso that not more than two of X1, X2 and X3 are N simultaneously; each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R2 is selected from Ci-galkyl and haloCi-galkyl;
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
'n' is 0, 1, 2 or 3; and
't' is 1, 2 or 3; The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II) and formula (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein ring A is phenyl (according to an embodiment defined below), R2 is ethyl (according to another embodiment defined below) and R3 is hydroxyl, amine or methyl (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl).
According to another embodiment, specifically provided are compounds of formula (I), in which ring A is phenyl, pyridine or pyrimidinyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is Ci-galkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is ethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydroxyl (-OH), amino (-NH2) or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydroxyl, amino or methyl.
According to yet another embodiment, specifically provided are compounds of formula
which G is
Figure imgf000005_0001
R3 is hydroxyl, amino or methyl. In another embodiment, Ra and Rb are independently hydrogen or methyl. In yet another embodiment, one of Ra and Rb is hydrogen and the other is methyl.
According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000006_0001
(I), in which G is . In this embodiment R2 is ethyl.
According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000006_0002
(I), in which L is O in this embodiment Rc is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula
O Rc
(I), in which L is H . in this embodiment Rc is hydrogen or. -CH2OH.
According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000006_0003
this embodiment Rc is -CH2OH.
According to yet another embodiment, specifically provided are compounds of formula
(I), in which L is
Figure imgf000006_0004
. In this embodiment Rc is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1, X2, X3 and X4 are CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 and X4 are independently CH or N and X2 and X3 are CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is N and X2, X3 and X4 are CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rx and Ry are hydrogen or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rx and Ry are hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rx and Ry are methyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which 'n' is 1, 2 or 3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which 't' is 1.
According to yet another embodiment, specifically provided are compounds of formula (I), in which
ring A is phenyl, pyridinyl, pyrimidinyl or chromanyl;
each of R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy;
R2 is ethyl;
R3 is hydroxyl, amino or methyl
Ra and Rb are independently hydrogen or methyl;
Rc is hydrogen and CH2OH;
X1 is CH or N; X2, X3 and X4 are CH;
Rx and Ry are independently hydrogen or methyl;
'n' is 1, 2 or 3; and
't' is 1.
According to yet an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
Further embodiments relating to groups R1, R2, R3, Rx, Ry, X1, X2, X3, X4, G, L, p, q, 'n' and 't' (and groups defined therein) are described hereinafter in relation to the compounds of formula (II). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II) in which ring A is phenyl, pyridine or pyrimidinyl and consequently there is also provided a compound of formula (I) in which ring A is phenyl, pyridine or pyrimidinyl.
The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
Accordingly the in ention provides a compound of formula (II)
Figure imgf000007_0001
(II) or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
Figure imgf000008_0001
; wherein p and q represents point of attachment;
X1 is N or CH;
each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
'n' is 0, 1, 2 or 3; and
't' is 1, 2 or m 3;
The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein R3 is hydroxyl, amine or methyl (according to an embodiment defined below) and 'n' is 1, 2 or 3 (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (II), in which ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl). According to another embodiment, specifically provided are compounds of formula (II), in which ring A is phenyl, pyridinyl or pyrimidinyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is F, CI, trifluoromethoxy or trifluoromethyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R3 is hydroxyl (-OH), amino (-NH2) or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R3 is hydroxyl, amino or methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Ra and Rb are independently hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which one of Ra and Rb is hydrogen and the other is methyl.
According to yet another embodiment, specifically provided are compounds of formula
H
(II), in which L is O jn m^s embodiment Rc is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula
(II), in which L is
Figure imgf000009_0001
in this embodiment Rc is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula
O Rc
' N N - q
(II), in which L is H H . In this embodiment Rc is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (II), in which Rx is Ci-galkyl (e.g. methyl) and Ryis Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which Rx and Ry are hydrogen or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which Rx and Ry are hydrogen. According to yet another embodiment, specifically provided are compounds of formula (II), in which Rx and Ry are methyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which 'n' is 1, 2 or 3.
According to yet another embodiment, specifically provided are compounds of formula (II), in which 't' is 1.
According to yet an embodiment, specifically provided are compounds of formula (II) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
The invention also provides a compound of formula (III), which is an embodiment of a compound of formula (I).
Accordingly the invention rovides a compound of formula (III)
Figure imgf000010_0001
(III)
or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
L is selected from
Figure imgf000010_0002
· wherein p and q represents point of attachment;
X1 and X4 which may be same or different, are each independently selected from N and
CH;
each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R2 is selected from Ci-galkyl and haloCi-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkylp and q represents point of attachment; 'n' is 0, 1, 2 or 3; and
't' is 1, 2 or 3;
The compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (III) as defined above wherein R2 is ethyl (according to an embodiment defined below) and 'n' is 1, 2 or 3 (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (III), in which ring A is C6-i4aryl (e.g. phenyl) or 5-14 membered heteroaryl (e.g. pyridyl or pyrimidinyl).
According to another embodiment, specifically provided are compounds of formula (III), in which ring A is phenyl, pyridine or pyrimidinyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which R1 is halogen (e.g. F or CI), O-galkyl (e.g. methyl) haloCi-galkyl (e.g. trifluoromethyl) or haloCi-galkoxy (e.g. trifluoromethoxy).
According to another embodiment, specifically provided are compounds of formula (III), in which R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
According to yet another embodiment, specifically provided are compounds of formula (III), in which R2 is Ci-galkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which R2 is ethyl.
According to yet another embodiment, specifically provided are compounds of formula
O Rc
p' \ ,' - q
(III), in which L is H in this embodiment Rc is hydrogen or CH2OH.
According to yet another embodiment, specifically provided are compounds of formula
O Rc
' N N q
(III), in which L is H H . In this embodiment Rc is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (III), in which Rx and Ry are hydrogen or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which Rx and Ry are hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (III), in which Rx and Ry are methyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which 'n' is 1, 2 or 3.
According to yet another embodiment, specifically provided are compounds of formula (III), in which 't' is 1.
According to yet an embodiment, specifically provided are compounds of formula (III) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
Compounds of the present invention include the compounds in Examples 1- 75. It should be understood that the formulas (I), (II) and (III) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
In one aspect, the present invention relates to com ound of formula (IV)
Figure imgf000012_0001
(IV)
or a stereoisomer thereof, diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Q is selected from
Figure imgf000012_0002
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
R4 is selected from hydrogen and Ci-galkyl;
Ra and Rb, which may be same or different, are each independently selected from rogen and Ci-galkyl; and Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl.
The compounds of formula (IV) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (IV) as defined above wherein R3 is hydroxyl, amine or methyl (according to an embodiment defined below) and Rc is hydrogen (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (IV),
-;— COR4
in which Q is o . In this embodiment R4 is hydrogen or Ci-galkyl (e.g. methyl).
According to another embodiment, specifically provided are compounds of formula
-;— COR4
(IV), in which Q is o . In this embodiment R4 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula
-|— COR4
(IV), in which Q is o . In this embodiment R4 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (IV), in which R3 is hydroxyl (-OH), amino (-NH2) or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (IV), in which R3 is hydroxyl, amino or methyl.
According to yet another embodiment, specifically provided are compounds of formula (IV), in which R3 is hydroxyl.
According to yet another embodiment, specifically provided are compounds of formula (IV), in which Ra and Rb are independently hydrogen or Ci-galkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of (IV), in which one of Ra and Rb is hydrogen and the other is methyl.
According to yet another embodiment, specifically provided are compounds of formula (IV), in which Rc is hydrogen.
It should be understood that the formule (IV) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt. Thus, the present invention further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
In a further aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
In another further aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described here.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-galkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "Ci-6alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "Ci-4alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8 alkoxy). Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi-galkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term "haloCi-4alkyl" refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi-galkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched.
The term "hydroxyCi-galkyl" refers to an Ci-galkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi-4alkyl). Examples of hydroxyCi-4alkyl moieties include, but are not limited to - CH2OH and -C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C3-6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms. Examples of "C3- 6cycloalkyl" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkylCi-salkyl). The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- i4aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroaryl" unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
The compounds of formula (I), (II), (III) or (IV) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I), (II), (III) or (IV) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC column. The chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974.
The terms "salt" or "solvate", and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.
PHARMACEUTICAL COMPOSITIONS
The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
The pharmaceutical compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of such compounds or pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, and topical.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
The pharmaceutical compositions described herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
METHODS OF TREATMENT
The compounds of the present invention are particularly useful because they inhibit the activity of retinoid-related orphan receptor gamma, particularly retinoid-related orphan receptor gamma t (RORyt), i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit a RORyt modulating effect. Compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of ROR gamma activity, and particularly RORyt, is required.
The compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.
The term "autoimmune diseases" will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function. An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin. Examples of autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - sprue (gluten-sensitive enteropathy), Graves's disease, thymopoiesis and Lupus.
Compounds of the present patent application may also be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.
The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever.
The compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
The compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
Other respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy, idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS, acute respiratory failure, mediastinitis.
The compounds of the present invention may also be used for treatment of pain conditions. The pain can be acute or chronic pain. Thus, the compounds of the present invention may be used for treatment of e.g., inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, posttraumatic injury, or pain associated with irritable bowel syndrome.
The compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
In addition, the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer. Such cancers include, e.g., multiple myeloma and bone disease associated with multiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, bladder carcinoma and colon cancer.
The compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease.
Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula I, (II) or (III) or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.
The present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.
The compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.
The daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.
GENERAL METHODS OF PREPARATION
The compounds, described herein, including those of general formula (I), (II), (III), (IV) and specific examples are prepared through the synthetic methods as depicted in Schemes 1 to 19. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of this invention.
A general approach for the preparation of compound of formula (Ha) (wherein R1, R3, X1, X2, X3, X4, Rx, Ry, Ra, Rb, Rc and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 1. Synthetic Scheme 1
Figure imgf000023_0001
The coupling reaction of amine compound of formula (1) with carboxylic acid compound of formula (2) in the presence of a suitable coupling agent(s) and suitable base yields the amide compound of formula (Ila). In an embodiment the suitable coupling agent(s) may be 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU). In an embodiment the suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
A general approach for the preparation of compound of formula (lib) and (lie) (wherein R1, X1, Rc and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 2.
Synthetic Scheme 2
Figure imgf000023_0002
Substitution reaction on 4-halo phenyl acetic acid compound of formula (3) with ethyl 2-bromo- 2,2-difluoroacetate (4) in the presence of copper powder and suitable solvent at elevated temperature yields the mono-ester of di-carboxylic acid compound of formula (2a). In an embodiment the suitable solvent for the reaction may be DMSO. The coupling reaction of amine compound of formula (la) with the carboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (5). In an embodiment suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). In an embodiment suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The ester compound of formula (5) on treating with methyllithium in suitable solvent such as THF affords the keto compound of formula (6) which on reduction in the presence of suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (lib). In an embodiment suitable reducing agent used in the reaction may be selected from the sodium borohydride and the suitable solvent may be methanol, THF or combination thereof. Alternatively, the ketone compound of formula (6) on reductive amination using sodium cyanoborohydride and ammonium acetate in a suitable solvent affords the amine derivative of general formula (lie). The suitable solvent used in the reaction may be THF.
A general approach for the preparation of compound of formula (lid) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 3.
Synthetic Scheme 3
Figure imgf000024_0001
The mono-ester of di-carboxylic acid compound of formula (2b) on protection with a suitable protecting agent such as, triisopropylchlorosilane (Tips-Cl) affords the heteroester compound of formula (7). The reaction may be carried out in the presence of suitable base and solvent. The suitable base for the reaction may be imidazole and solvent can be selected from THF or DMF. The ethyl ester group of compound (7) on reaction with methyllithium in a suitable solvent yields the methyl ketone of formula (8). The suitable solvent for the reaction may be THF. The keto reduction of compound of formula (8) using chiral reducing agent in a suitable solvent affords the corresponding chiral isomer of the hydroxyl derivative of formula (9). The chiral reducing agent may be selected from (R or 5)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B-chlorodiisopinocampheylborane (DIP-Chloride), etc. Suitable solvent may be THF, DCM or DMF. Deprotection of compound of formula (9) using TBAF in a suitable solvent such as THF affords (R or 5)-2-(4-(l, l-difluoro-2- hydroxypropyl)phenyl)acetic acid (2c) The coupling reaction of the carboxylic acid compound of formula (2c) with amine compound of formula (la) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (lid). In an embodiment suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU). In an embodiment suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
Alternatively, compound of formula (2b) on coupling reaction with amine of formula (la) followed by reaction with methyllithium affords the keto compound (6a) as described in scheme 2. Keto reduction of compound of formula (6a) using suitable chiral reducing agent yields the hydroxyl derivative (lid). The chiral reducing agent may be selected from (R or S)- 2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B- chlorodiisopinocampheylborane (DIP-Chloride), etc. Suitable solvent may be THF, DCM or DMF. The hydroxyl derivative (lid) can be further purified by diastereomeric separation using a chiral amino acid, such as N-benzyloxycarbonyl-L-phenylalanine. Lithium hydroxide mediated hydrolysis of the ester affords compound of general formula (lid) as a pure enantiomer. The esterification can be done using suitable coupling agent in the presence of suitable base and solvent. The suitable coupling agent(s) may be BOP, PyBOP, EDCI, DCC, T3P (50% in EtOAc) or HATU. The suitable base used in the reaction may be Et3N, DIPEA, pyridine or DMAP. The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
A general approach for the preparation of compound of formula (Ilia) (wherein R1, X1, X4, Rc and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 4.
Synthetic Scheme 4
Figure imgf000026_0001
Methylation of phenyl acetonitrile derivative (10) with methyl halide in the presence of suitable base and solvent affords the di-methylated phenyl acetonitrile derivative of formula (11). In an embodiment the suitable base used in this reaction may be sodium or potassium ie/t-butoxide and the suitable solvent may be THF. Reductive amination of the compound of formula (11) using lithium aluminium hydride in the presence of a Lewis acid such as aluminium chloride in a suitable solvent such as THF gives the corresponding primary amine derivative of formula (12). Substitution reaction of the amino compound (12) with ester compound of formula (13) in the presence of suitable base and solvent yields the compound of formula (14). In an embodiment the suitable base used in the reaction may be triethylamine, DIPEA, pyridine or DMAP, and the solvent used may be selected from DCM, THF or chloroform. The reduction of nitro group in compound of formula (14) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent. In an embodiment the suitable solvent may selected from CH2CI2, CHC13, DMF, THF, methanol or water or mixture thereof affords the corresponding amine of formula (15). The cyclization of amine of formula (15) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (16). Ester hydrolysis of compound of formula (16) using sodium hydroxide or lithium hydroxide monohydrate in a suitable solvent or mixture thereof yields the corresponding carboxylic acid of formula (17). In an embodiment the suitable solvent may selected from CH2CI2, CHCI3, DMF, THF, methanol, water or mixtures thereof. The coupling reaction of carboxylic compound of formula (17) with the amine compound of formula (18) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (Ilia). In an embodiment the suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in the reaction may be Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
A general approach for the preparation of compound of formula (He) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 5.
Synthetic Scheme 5
Figure imgf000027_0001
The mono-ester of di-carboxylic acid compound of formula (2b) on protection with a suitable protecting agent such as, triisopropylchlorosilane (Tips-Cl) affords the hetero-di-ester compound of formula (7). The reaction may be carried out in the presence of suitable base and solvent. The suitable base for the reaction may be imidazole and solvent can be selected from THF or DMF. The compound (7) on reaction with Grignard reagent, methylmagnesium bromide affords the tertiary alcohol (19) which on deprotection yields 2-(4-(l,l-difluoro-2- hydroxy-2-methylpropyl)phenyl)acetic acid (2d). The carboxylic acid (2d) on coupling reaction with the amine compound of formula (la) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (He). In an embodiment the suitable coupling agent(s) may be selected from l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in the reaction may be Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
A general approach for the preparation of compound of formula (la) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 6.
Synthetic Scheme 6
Figure imgf000028_0001
Substitution reaction of the amino compound (12) with fluoro compound of formula (20) at elevated temperature yields the compound of formula (21). The solvent used in the reaction may be selected from DMSO, toluene, DMF or 1,4-dioxane. The cyclization of compound of formula (21) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (22). The reduction of nitro group in compound of formula (22) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent, such as CH2CI2, CHC13, DMF, THF, methanol or water or mixture thereof, furnishes the corresponding amine compound of formula (la). Reduction of the nitro group to give the corresponding amine compound may also be carried out using sodium borohydride in the presence of nickel chloride.
Another approach for the preparation compound of formula (la) is depicted in Synthetic scheme 7.
Synthetic scheme 7
Figure imgf000028_0002
The reaction of carboxylic acid compound of formula (17) with ethyl chioroformate followed by sodium azide in suitable solvent yields the corresponding azide compound of formula (23). The suitable solvent for the reaction may be THF, water or mixture thereof. The Curtius rearrangement by heating the azide (23) in the presence of water and a high boiling solvent such as 1,4-dioxane yields the desired amine of formula (la).
An approach for the preparation of compound of formula (2e) (wherein R3 is as defined in the general description) is illustrated in synthetic scheme 8.
Synthetic Scheme 8
Figure imgf000029_0001
The reaction of halogen substituted phenylketone of formula (24) (wherein Hal is halogen) with ethane 1, 2-dithiol (25) (to protect the carbonyl group) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (26). The suitable Lewis acid may be boron trifluoride-diethyl etherate. In an embodiment the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF. The compound of formula (26) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives the difluoro compound of formula (27). In an embodiment the suitable solvent may be pyridine, CH2CI2, CHCI3, DMF or mixtures thereof. Halogen substitution of compound of formula (27) with ie/ -butyl acetate in the presence of palladium catalyst and suitable base gives compound of formula (28). In an embodiment the suitable base may be lithium dicyclohexylamine. The substitution reaction may be carried out in a suitable solvent. The suitable solvent may be toluene. The compound of formula (28) on deprotection of ie/ -butyl group, using trifluoroacetic acid in a suitable solvent gives the carboxylic acid of formula (2e). In an embodiment the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF.
An approach for the preparation of compound of general formula (Illb) (wherein R1, X1, X4 and 'n' are defined as in general description and X5 is N or CH) is illustrated in synthetic scheme 9.
Synthetic Scheme 9
Figure imgf000029_0002
S-alkylation of 4-methylbenzenethiol (29) with ethyl bromide in the presence of suitable base and solvent yields the ethyl sulfane compound (30). In an embodiment the suitable base used in the reaction may be selected from sodium carbonate or potassium carbonate. The reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from acetone, CH2CI2, CHCI3, DMF and THF or combination thereof. Oxidation of sulfane compound of formula (30) using m-CPBA in a suitable solvent such as CH2CI2 yields the corresponding ethanesulfonyl compound of formula (31). Bromination of compound (31) using N-bromosuccinimide in the presence of azobisisobutyronitrile (AIBN) in a suitable solvent such as tetrachloromethane affords the bromo compound of formula (32). The reaction of compound (32) with aqueous ammonia yields the corresponding amine derivative which on reaction with hydrochloric acid furnishes (4- (ethylsulfonyl)phenyl)methanamine hydrochloride (18a). The amine compound of formula (18a) on coupling reaction with the carboxylic acid (17) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (Illb). The coupling reaction condition may be the same as described in synthetic scheme 1.
An approach for the preparation of compound of general formula (IIIc) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 10.
Synthetic Scheme 10
Figure imgf000030_0001
Reduction of the nitrile group of 5-bromopicolinonitrile (33) using sodium borohydride in the presence of a Lewis acid such as nickel chloride in a suitable solvent such as THF affords the corresponding amine derivative which on in situ reaction with Boc anhydride gives the protected amino compound (34). Substitution of bromine in compound (34) with ethane sulfonic acid (sodium salt) in the presence of L-proline, copper (I) iodide, sodium hydroxide in a suitable solvent such as DMSO yields the ie/ -butyl ((5-(ethylsulfonyl)pyridin-2- yl)methyl)carbamate (35). Deprotection of the amino group of compound (35) using acetyl chloride affords (5-(ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (18b). The amine compound of formula (18b) on coupling reaction with the carboxylic acid (17) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (IIIc). The coupling reaction conditions may be the same as described in synthetic scheme 1.
An approach for the preparation of compound of general formula (Hid) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH)is depicted in synthetic scheme 11.
Synthetic Sche
Figure imgf000031_0001
The fluoro displacement of 4-fluorobenzaldehyde (36) with sodium ethanesulfinate in a suitable solvent such as DMSO yields 4-(ethylsulfonyl) benzaldehyde (37). Epoxidation of compound
(37) using trimethylsulfonium iodide in the presence of suitable base and solvent yields 2-(4- (ethylsulfonyl) phenyl) oxirane (38). In an embodiment the suitable base may be potassium hydroxide powder and DMF may be used as the suitable solvent for the reaction. The epoxide
(38) on hydrolysis in acidic medium in the presence of acetonitrile furnishes 2-amino-2-(4- (ethylsulfonyl) phenyl) ethanol (18c). The amine compound of formula (18c) on coupling reaction with the carboxylic acid (17) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (Hid). The coupling reaction conditions may be the same as described in synthetic scheme 1.
An approach for the preparation of compound of general formula (Hie) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 12.
Synthetic Scheme 12
Figure imgf000032_0001
Ethyl 2-hydroxyacetate (39) on reaction with ie/ -butyldimethylsilyl chloride in the presence of a suitable base and solvent yields the silyl ether of formula (40). The suitable base for the reaction may be imidazole and solvent may be dichloromethane. Compound (40) on reaction with N,0-dimethylhydroxylamine hydrochloride in the presence of ethylmagnesium bromide in a suitable solvent affords the Weinreb amide (41). The suitable solvent for the reaction may be THF. The Weinreb amide (41) reacts with (4-bromophenyl)(ethyl)sulfane (42) in the presence of magnesium metal in THF to give the bromo-substituted product (43). Compound (43) on reaction with (R or 5)-(-)-2-methyl-2-propanesulfinamide in the presence of titanium isopropoxide in a suitable solvent such as THF affords the imine derivative (44) which on reduction using DIBAL-H in THF yields compound (45). Deprotection of compound (45) in acidic medium furnishes the (R or 5)-2-amino-2-(4-(ethylthio)phenyl)ethanol (46) which on sulfur oxidation using a suitable oxidizing agent such as oxone in appropriate solvent such as methanol, ethanol, water or combination thereof, affords the desired (R or 5)-2-amino-2-(4- (ethylsulfonyl)phenyl)ethanol (18d). The amine compound of formula (18d) on coupling reaction with the carboxylic acid (17) in the presence of a suitable coupling agent(s) and suitable base in an appropriate solvent yields the amide compound of formula (Me). The coupling reaction conditions may be the same as described in synthetic scheme 1.
A general approach for the preparation of compound of formula (Ilf) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 13.
Synthetic Scheme 13
Figure imgf000033_0001
The coupling reaction of the acid compound of formula (17) with 4-iodobenzylamine (47) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (48). In an embodiment suitable coupling agent(s) may be selected from l-ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). In an embodiment suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may carried out in a suitable solvent or mixture thereof. In an embodiment suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. Substitution reaction of the iodo compound of formula (48) with ethyl 2-bromo-2,2- difluoroacetate (4) in the presence of copper powder and suitable solvent at elevated temperature yields the ester of formula (49). In an embodiment the suitable solvent for the reaction may be DMSO. The ester compound of formula (49) on treating with methyllithium in suitable solvent such as THF gives the corresponding keto compound which on reduction in the presence of suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (Ilf). In an embodiment suitable reducing agent used in the reaction may be sodium borohydride and the suitable solvent may be methanol, THF or combination thereof. (The keto reduction of compound of formula (53) can also be done using chiral reducing agent in a suitable solvent to furnish the pure enantiomer of the hydroxyl derivative of general formula (¾)).
A general approach for the preparation of compound of formula (Ilg (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 14.
Synthetic Scheme 14
Figure imgf000034_0001
Figure imgf000034_0002
The coupling reaction of 4-iodobenzoic acid (50) with ethyl 2-bromo-2, 2-difluoroacetate (4) in the presence of copper powder and suitable solvent at elevated temperature yields the ester of formula (51). In an embodiment the suitable solvent for the reaction may be DMSO. The ester compound of formula (51) on treating with methyllithium in suitable solvent such as THF gives the corresponding keto compound of formula (52). The coupling reaction of compound of formula (52) with ammonia in the presence of 1, l'-carbonyldiimidazole in THF yields the amide of formula (53). Compound of formula (53) on reaction with phosphorous oxychloride in DMF gives the nitrile derivative of formula (54). Catalytic hydrogenation of compound of formula (54) in the presence of hydrochloric acid in suitable solvent affords amine hydrochloride of formula (55). The suitable solvent for the reaction may be ethyl acetate, THF, methanol, ethanol Boc protection of the amine of formula (55) using Boc anhydride, a suitable base and solvent affords the protected amine of formula (56). The suitable base for the reaction may be sodium hydroxide, and solvent may be 1, 4-dioxane, water or mixture thereof. The keto compound of formula (56) on reduction using suitable reducing agent in a suitable solvent yields the racemic hydroxyl compound of general formula (57). In an embodiment suitable reducing agent used in the reaction may be sodium borohydride and the suitable solvent may be methanol, THF or combination thereof. Deprotection of the amine group of formula (57) using hydrochloric acid in appropriate solvent yields the compound of formula (58). The suitable solvent for the reaction may be ethyl acetate, ethanol, methanol, diethyl ether or combination thereof. The coupling reaction of compound of formula (58) with the acid of formula (17) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (Ilf). In an embodiment suitable coupling agent(s) may be selected from l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) (50% in EtOAc) or (1- [bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium3-oxid
hexafluorophosphate) (HATU). In an embodiment suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may carried out in a suitable solvent or mixture thereof. In an embodiment suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof.
Alternatively, the compound of formula (56) on reduction by using appropriate chiral reducing agent, followed by Boc deprotection affords the chiral hydroxyl derivative of formula (59). The chiral reducing agent may be selected from (R or 5)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethyl sulfide, transfer hydrogenation using appropriate chiral ruthenium complexes/IPA, (+) or (-)-B-chlorodiisopinocampheylborane (DIP-Chloride), etc. and the suitable solvent may be THF, DCM or DMF. The amine compound with chiral hydroxyl group (59) on coupling reaction with the acid of formula (17) in the presence of a suitable coupling agent(s) and suitable base, as described above, gives the amide compound of formula
(iig).
A general approach for the preparation of compound of formula (Ilh) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 15.
Synthetic Scheme 15
Figure imgf000035_0001
The reaction of keto compound (56) with excess of methyl magnesium bromide in a suitable solvent yields the tertiary alcohol (60). The suitable solvent for the reaction may be THF or diethyl ether. Deprotection of the amine group of formula (60) using hydrochloric acid in appropriate solvent yields the compound of formula (61) as a hydrochloride salt. The suitable solvent for the reaction may be ethyl acetate, ethanol, methanol, diethyl ether or combination thereof. The coupling reaction of compound of formula (61) with the acid of formula (17) in the presence of a suitable coupling agent(s) and suitable base forms the amide compound of formula (Ilh) under the conditions described in above in the previous schemes.
A general approach for the preparation of compound of formula (lb) (wherein R1, and 'n' are defined as in general description) is depicted in synthetic scheme 16.
Synthetic Scheme 16
Figure imgf000036_0001
Substitution reaction of the amino compound (62) with fluoro dinitro compound of formula (63) at elevated temperature yields the compound (64). The solvent used in the reaction may be selected from DMSO, toluene, DMF or 1,4-dioxane. Selective reduction of one of the nitro group yields the amine derivative of formula (65). The selective reduction may be carried out using sodium sulfide, ammonium chloride and aqueous ammonia in an appropriate solvent such as ethanol. The cyclization of compound of formula (65) using sodium nitrite and acetic acid affords the benzotriazole compound of formula (66). The reduction of nitro group in compound of formula (66) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent, such as CH2CI2, CHCI3, DMF, THF, methanol or water or mixture thereof, furnishes the corresponding amine compound of formula (lb). Reduction of the nitro group to give the corresponding amine compound may also be carried out using sodium borohydride in the presence of nickel chloride.
A general approach for the preparation of (4-(l,l-difluoropropyl)phenyl)methanamine (73) is depicted in synthetic scheme 17.
Synthetic Scheme 17
Figure imgf000036_0002
The reaction of l-(p-tolyl)propan-l-one (67) with ethane 1,2-dithiol (25) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (68). The suitable Lewis acid may be boron trifluoride-diethyl etherate. In an embodiment the suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF. The compound (68) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives the difluoro compound of formula (69). In an embodiment the suitable solvent may be pyridine, CH2CI2, CHCI3, DMF or mixtures thereof. Bromination of compound (69) using N- bromosuccinimide in the presence of azobisisobutyronitrile (AIBN) in a suitable solvent such as tetrachloromethane affords the bromo compound of formula (70). Compound (70) on reaction with phthalimide (71) in the presence of suitable base and solvent affords the protected amine (72). Deprotection of amine (72) using hydrazine hydrate in methanol yields (4-(l,l- difluoropropyl)phenyl)methanamine (73).
A general approach for the preparation of compound of formula (Hi) (wherein R1, X1 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 18.
Synthetic Scheme 18
Figure imgf000037_0001
(1 a) (74)
The reaction of carboxylic compound of formula (17) with the amine compound of formula (59) in the presence of diphenylphosphoryl azide, a suitable base in a suitable solvent affords the urea derivative of formula (Hi). In an embodiment the suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The coupling reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from CH2CI2, CHC13, DMF, DMSO, THF or combination thereof. Alternatively, the amine of formula (la) on reaction with phenyl chloroformate in the presence of suitable base and solvent yields the carbamate of formula (74). The suitable base for the reaction may be pyridine and solvent may be THF. The carbamate (74) on reaction with amine compound of formula (59) in the presence of suitable base in a suitable solvent affords the urea derivative of formula (Hi). In an embodiment the suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from DMF, DMSO, THF or combination thereof.
A general approach for the preparation of compound of formula (Illf) (wherein R1, Rc, X1, X4 and 'n' are defined as in general description and X5 is N or CH) is depicted in synthetic scheme 19.
Synthetic Scheme 19
Figure imgf000038_0001
The carbamate (74) on reaction with amine compound of formula (18) in the presence of suitable base in a suitable solvent affords the urea derivative of formula (Illf). In an embodiment the suitable base used in the reaction may be selected from Et3N, DIPEA, pyridine or DMAP. The reaction may be carried out in a suitable solvent or mixture thereof. In an embodiment the suitable solvent may be selected from DMF, DMSO, THF or combination thereof.
PREPARATION OF INTERMEDIATES
Intermediate 1
[4-( 1 , 1 -Difluoropropyl)phenyl] acetic acid
Figure imgf000038_0002
Step 1: 2-(4-Bromophenyl)-2-ethyl-l,3-dithiolane
Figure imgf000038_0003
To a stirred solution of 4-bromopropiophenone (2.01 g, 9.43 mmol) in anhydrous dichloromethane (20 mL) were added boron trifluoride diethyl etherate (0.49 mL, 4.71 mmol) and ethane 1,2-dithiol (1.57 mL, 18.8 mmol). The mixture was stirred overnight at RT. The mixture was diluted with dichloromethane, washed with aqueous sodium hydroxide solution (10% w/v), water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 2.21 g of the desired product. lH NMR (300 MHz, CDCb) δ 0.89 (t, J = 7.5 Hz, 3H), 2.33 (q, J = 7.5 Hz, 2H), 3.19-3.32 (m, 2H), 3.34-3.41 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H); APCI-MS (m/z) 290 (M)+.
Step 2: 1 -Bromo-4-( 1 , 1 -difluoropropyl)b
Figure imgf000039_0001
To a stirred solution of N-iodosuccinimide (704 mg, 3.13 mmol) in dichloromethane (5.0 mL) at -20 °C was added hydrogen fluoride in pyridine (70%, 0.52 mL, 20.88 mmol). After being stirred for 2 min, was added a solution of 2-(4-bromophenyl)-2-ethyl-l,3-dithiolane (Step 1 intermediate) (302 mg, 1.04 mmol) in dichloromethane (5.0 mL). The resulting mixture was stirred at -20 °C for 30 min. The reaction mixture was diluted with n-hexane, filtered through basic alumina and washed with n-hexane. The filtrate was concentrated and the residue was diluted with ethyl acetate. The organic solution was washed with 10% sodium thiosulfate, 2% potassium permanganate, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 203 mg of the titled product. lU NMR (300 MHz, CDCb) δ 0.97 (t, = 7.5 Hz, 3H), 2.02-2.21 (m, 2H), 7.33 (d, = 8.1 Hz, 2H), 7.56 (d, = 8.1 Hz, 2H); APCI- MS (m/z) 231 (M-H)-.
Step 3: ie/ -Butyl [4-(l, l-difluoropropyl)phenyl] acetate
Figure imgf000039_0002
To a stirred solution of dicyclohexylamine (1.8 g, 10.25 mmol) in anhydrous toluene (20 mL) at 0 °C were added n-butyl lithium (6.41 mL, 10.26 mmol) followed by ie/ -butyl acetate (1.15 mL, 8.55 mmol) and the mixture was stirred for 15 min at 0 °C. In a separate flask, tri-tert- butylphosphonium tetrafluoroborate (248 mg, 0.85 mmol) and bis(dibenzylideneacetone)palladium (0) (245 mg, 0.42 mmol), were stirred together and the mixture was evacuated and replenished with nitrogen (3 times). To that solid mixture were added toluene (10 mL), l-bromo-4-(l,l-difluoropropyl)benzene (Step 2 intermediate) (2.01 g, 8.55 mmol) and the first reaction mixture. The resulting mixture was stirred overnight at RT. The mixture was diluted with diethyl ether, filtered the solution through celite and washed the celite bed twice with diethyl ether. The combined filtrates were concentrated and the residue obtained was purified by silica gel column chromatography to yield 1.43 g of the desired product. lH NMR (300 MHz, CDCb) δ 0.98 (t, = 7.5 Hz, 3H), 1.44 (s, 9H), 2.04-2.22 (m, 2H), 3.55 (s, 2H), 7.31 (d, = 8.1 Hz, 2H), 7.41 (d, = 8.1 Hz, 2H). Step 4: [4-(l, l-Difluoropropyl)phenyl] acetic acid
To a stirred solution of ieri-butyl [4-(l, l-difluoropropyl)phenyl] acetate (Step 3 intermediate) (1.42 g, 5.25 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (10 mL) and the mixture was stirred at RT for 1 h. The solvent in the reaction mixture was recovered under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 491 mg of the titled product. lU NMR (300 MHz, DMSO- 6) δ 0.90 (t, J = 6.0 Hz, 3H), 2.11-2.28 (m, 2H), 3.63 (s, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 12.42 (br s, 1H); APCI-MS (m/z) 213 (M-H)\
Intermediate 2
[4-(2-Ethoxy- 1 , 1 -difluoro-2-oxoethyl)phenyl] acetic acid
Figure imgf000040_0001
To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol) and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) was added 2-bromo-2,2-difluoroacetate (196 mg, 1.52 mmol). The mixture was stirred overnight at 60 °C in a sealed tube. The reaction mixture was cooled to RT and quenched with aqueous ammonium chloride solution (30 mL). The aqueous mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 171 mg of the desired product. lH NMR (300 MHz, DMSO-d6) δ 1.22 (t, J = 6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 12.45 (s, 1H).
Intermediate 3
(4-(Ethylsulfonyl)phenyl)methanamine hydrochloride
Figure imgf000040_0002
Step 1 : Ethyl( ?-tolyl)sulfane
Figure imgf000040_0003
To a stirred solution of /?-thiocresol (10 g, 80.51 mmol) in acetone (100 mL) were added potassium carbonate (22.2 g, 161 mmol) and ethyl bromide (10.5 g, 96.6 mmol) at RT. The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was filtered and the filtrated was concentrated to afford 12.9 g of the titled product. lH NMR (300 MHz, DMSO- 6): 6 1.19 (t, = 7.2 Hz, 3H), 2.25 (s, 3H), 2.90 (q, = 7.2 Hz, 2H), 7.12 (d, = 8.4 Hz, 2H), 7.21 (d, = 7.8 Hz, 2H). Step 2: l-(Ethylsulfonyl)-4-methylbenzen
Figure imgf000041_0001
To a solution of ethyl(p-tolyl)sulfane (step 1 intermediate) (12.9 g, 84.72 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (36.5 g, 212 mmol) at 0 °C. The reaction mixture was stirred at RT for 18 h. The mixture was filtered and the filtrated was washed with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford 15.5 g of the titled product. lH NMR (300 MHz, DMSO-d6): δ 1.07 (t, = 7.5 Hz, 3H), 2.41 (s, 3H), 3.24 (q, = 7.5 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H); APCI-MS (m/z) 185 (M-+H)+. Step 3: l-(Bromomethyl)-4-(ethylsulfonyl)benzene
Figure imgf000041_0002
To a stirred solution of l-(ethylsulfonyl)-4-methylbenzene (Step 2 intermediate) (15.5 g, 0.08 mmol) in tetrachloromethane (100 mL) were added N-bromosuccinimide (17.9, 0.10 mmol) followed by azobisisobutyronitrile (AIBN) (1.38 g, 0.008 mmol) and the mixture was stirred at 80 °C for 18 h. The mixture was cooled to RT and filtered through celite. The filtrate was concentrated and dissolved in ethyl acetate. The solution was washed with water followed by brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 25.6 g of the titled product. XH NMR (300 MHz, DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H), 3.27 (q, J = 7.2 Hz, 2H), 4.79 (s, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H).
Step 4: (4-(Ethylsulfonyl)phenyl)methanamine hydrochloride
To a stirred solution of l-(bromomethyl)-4-(ethylsulfonyl)benzene (Step 3 intermediate) (2.0 g, 7.60 mmol) in methanol (10 mL) was added ammonium hydroxide (10 mL) and the mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The solid obtained was dissolved in saturated hydrochloric acid in ethyl acetate (10 mL) and stirred for 30 min. The solvent was removed under reduced pressure and the solid obtained was dried well to afford 894 mg of the titled product. lH NMR (300 MHz, DMSO-d6): δ 1.06 (t, = 7.2 Hz, 3H), 3.25-3.32 (m, 4H), 4.12 (s, 2H), 7.77 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 7.8 Hz, 2H), 8.64 (s, 1H); ESI-MS (m/z) 200 (M+H-HC1)+.
Intermediate 4 l-(2,4-Dichlorophenethyl)- lH-benzo[<i] [ 1 ,2,3]triazol-5-amine
Figure imgf000042_0001
Step 1 : N -(2,4-Dichlorophenethyl)-4-nitrobenzene- 1 ,2-diamine
Figure imgf000042_0002
To a solution of 2-fluoro-5-nitroaniline (2.0 g, 12.8 mmol) in DMSO (10 niL) was added 2,4- dichlorophenethylamine (2.03 niL, 12.8 mmol) and the reaction mixture was stirred at 120 °C for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 1.7 g of the titled product. lH NMR (300 MHz, DMSO-d6): δ 3.01 (t, = 6.6 Hz, 2H), 3.35-3.45 (m, 2H), 5.14 (s, 2H), 6.08 (s, 1H), 6.58 (d, J = 8.7 Hz, 1H), 7.39-7.43 (m, 3H), 7.52 (d, J = 7.5 Hz, 1H), 7.61 (s, 1H). Step 2: 1 -(2,4-Dichlorophenethyl)-5 ,3] triazole
Figure imgf000042_0003
To a solution of N1-(2,4-dichlorophenethyl)-4-nitrobenzene- l,2-diamine (Step 1 intermediate) (350 mg, 1.08 mmol) in acetic acid (5.0 mL) was added a solution of sodium nitrite (111 mg, 1.61 mmol) in water (1.5 mL) at 0 °C and the mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 310 mg of the titled product. lH NMR (300 MHz, DMSO-d6) δ 3.34-3.34 (m, 2H), 5.08 (t, J = 6.9 Hz, 2H), 7.28 (s, 2H), 7.53 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 9.01 (s, 1H).
Step 3: l-(2,4-Dichlorophenethyl)- lH-benzo[<i] [l,2,3]triazol-5-amine
To a stirred solution of l-(2,4-dichlorophenethyl)-5-nitro- lH-benzo[<i][l,2,3]triazole (Step 2 intermediate) (300 mg, 0.88 mmol) and nickel chloride (423 mg, 1.78 mmol) in methanol (10 mL) was added sodium borohydride (134 mg, 3.55 mmol) in small portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to yield a viscous residue. The residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 210 mg of the titled product. lH NMR (300 MHz, DMSO-d6): δ 3.29 (t, = 6.6 Hz, 2H), 4.81 (t, = 6.6 Hz, 2H), 5.45 (br s, 2H), 6.88 (s, 1H), 6.91 (s, 1H), 7.21 (d, = 8.4 Hz, 1H), 7.29 (d, = 8.4 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.56 (s, 1H).
Intermediate 5
l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[<i] [ 1 ,2,3]triazol-5-amine
Figure imgf000043_0001
Step 1 : N -(2-(2,4-Dichlorophenyl)- -methylpropyl)-4-nitrobenzene- 1 ,2-diamine
Figure imgf000043_0002
The titled compound was prepared by the reaction of 2-fluoro-5-nitroaniline (360 mg, 2.30 mmol) with 2-(2,4-dichlorophenyl)-2-methylpropan-l -amine (500 mg, 2.30 mmol) in DMSO (5.0 mL) as per the procedure described in step 1 of Intermediate 4 to yield 198 mg of the product. lH NMR (300 MHz, DMSO-d6): δ 1.50 (s, 6H), 3.70 (d, J = 6.0 Hz, 2H), 5.15 (s, 2H), 5.31 (br s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 7.35-7.42 (m, 2H), 7.43-7.46 (m, 2H), 7.54 (s, 1H); ESI-MS (m/z) 354 (M)+.
Step 2: 1 -(2-(2,4-Dichlorophenyl)-2-methylpropyl)-5-nitro- lH-benzo[<i] [ 1 ,2,3] triazole
Figure imgf000043_0003
The titled compound was prepared by the reaction of N1-(2-(2,4-dichlorophenyl)-2- methylpropyl)-4-nitrobenzene-l,2-diamine (Step 1 intermediate) (180 mg, 0.51 mmol) with sodium nitrite (52 mg, 0.76 mmol) and acetic acid (4.0 mL) in water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 138 mg of the product. lH NMR (300
MHz, DMSO-d6) 6 1.51 (s, 6H), 5.32 (s, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.24 (d, 7 = 7.2 Hz, 1H),
7.64 (s, 1H), 8.02 (d, J = 9.3 Hz, 1H), 8.35 (d, J = 9.3 Hz, 1H), 8.95 (s, 1H).
Step 3: l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[<i] [l,2,3]triazol-5-amine
To a stirred solution of l-(2-(2,4-dichlorophenyl)-2-methylpropyl)-5-nitro- lH- benzo[< J [ 1,2,3] triazole (Step 2 intermediate) (130 mg, 0.36 mmol) in a mixture of methanol and water (1 : 1, 10 niL) were added iron powder (100 mg, 1.78 mmol) and ammonium chloride (190 mg, 3.55 mmol) at RT. The reaction mixture was stirred at 80 °C for 2 h. The solvents were distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 111 mg of the titled product. ESI-MS im/z) 335 (M+H)+.
Structure, chemical name and characterization data of the intermediates prepared by using appropriate starting materials as per the method described in the case of Intermediate 5 are given in Table 1.
Table 1 : Structure, chemical name and characterization data of Intermediate 6-7
Figure imgf000044_0002
Intermediate 8
l-(2-(2,4-Difluorophenyl)-2-methylpropyl)- lH-benzo[< J [l,2,3]triazol-5-amine
FOC €rNHz
Step 1 : 2-(2,4-Difluorophenyl)-2-methylpropanenitrile
Figure imgf000044_0001
To a stirred solution of 2,4-fluororophenylacetonitrile (5.0 g, 32.66 mmol) in THF (50 mL) was added potassium-ie/ -butoxide (10.9 g, 97.97 mmol) followed by methyl iodide (6.3 mL, 97.97 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to afford 4.92 g of the desired product. lH NMR (300 MHz, DMSO-d6): δ 1.79 (s, 6H), 6.82-6.92 (m, 2H), 7.43-7.49 (m, 1H). Step 2: 2-(2,4-Difluorophenyl)-2-methylpropan- 1 -amine
Figure imgf000045_0001
To a suspension of lithium aluminium hydride (2.0 g, 54.08 mmol) in THF (200 mL) was added aluminium chloride (7.2 g, 54.08 mmol) in small portions followed by a solution of 2-(2,4- difluorophenyl)-2-methylpropanenitrile (Step 1 intermediate) (4.9 g, 27.04 mmol) in THF (50 mL) at 0 °C. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with ice-cold water and the layers were separated. The aqueous layer was basified with ammonia and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to afford 2.1 g of the desired product. lH NMR (300 MHz, DMSO-d6) δ 1.24 (s, 6H), 2.73 (s, 2H), 3.34 (br s, 2H), 6.99 (t, = 8.1 Hz, 1H), 7.10 (t, = 9.0 Hz, 1H), 7.27-7.37 (m, 1H).
Step 3: N1-(2-(2,4-Difluorophenyl)- -methylpropyl)-4-nitrobenzene- 1 ,2-diamine
Figure imgf000045_0002
The titled compound was prepared by the reaction of 2-fluoro-5-nitroaniline (750 mg, 4.80 mmol) with 2-(2,4-difluorophenyl)-2-methylpropan- l -amine (Step 2 intermediate) (890 mg, 4.80 mmol) in DMSO (10 mL) as per the procedure described in step 1 of Intermediate 4 to yield 289 mg of the product. lH NMR (300 MHz, DMSO-d6): δ 1.39 (s, 6H), 3.51 (d, = 5.1 Hz, 2H), 5.15 (s, 2H), 5.43 (br s, 1H), 6.56 (d, = 9.3 Hz, 1H), 7.02 (t, = 8.4 Hz, 1H), 7.17 (t, = 9.6 Hz, 1H), 7.35-7.39 (m, 2H), 7.46 (d, = 8.7 Hz, 1H); APCI-MS im/z) 322 (M+H)+. Step 4: l-(2-(2,4-Difluorophenyl)-2-methylpropyl)-5-nitro- lH-benzo[<i] [l,2,3]triazole
Figure imgf000045_0003
The titled compound was prepared by the reaction of N1-(2-(2,4-difluorophenyl)-2- methylpropyl)-4-nitrobenzene-l,2-diamine (Step 3 intermediate) (275 mg, 0.85 mmol) with sodium nitrite (89 mg, 1.28 mmol) and acetic acid (4.0 mL) in water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 238 mg of the product. lH NMR (300 MHz, DMSO- ) δ 1.44 (s, 6H), 5.07 (s, 2H), 6.89 (t, J = 8.7 Hz, 1H), 7.09-7.26 (m, 2H), 7.93 (d, = 9.3 Hz, 1H), 8.34 (d, = 8.7 Hz, 1H), 8.95 (s, 1H); APCI-MS (m/z) 333 (M+H)+.
Step 5: l-(2-(2,4-Difluorophenyl)-2-methylpropyl)-lH-benzo[<i][l,2,3]triazol-5-amine The titled compound was synthesized by the nitro reduction of the l-(2-(2,4-difluorophenyl)- 2-methylpropyl)-5-nitro- lH-benzo[d][l,2,3]triazole (Step 4 intermediate) (225 mg, 0.68 mmol) by using iron powder (189 mg, 3.38 mmol) and ammonium chloride (362 mg, 6.77 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in step 3 of Intermediate 5 to yield 173 mg of the product. Ή NMR (300 MHz, DMSO-d6): δ 1.39 (s, 6H), 4.79 (s, 2H), 5.15 (s, 2H), 6.79-6.92 (m, 3H), 7.09 (t, = 8.7 Hz, 1H), 7.17-7.25 (m, 2H); APCI- MS (m/z) 303 (M+H)+.
Structure, chemical name and characterization data of the intermediates prepared by using appropriate starting materials as per the method described in the case of Intermediate 8 are given in Table 2.
Table 2: Structure, chemical name and characterization data of Intermediate 9-20
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Intermediate 21
l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-lH-benzo[<i][l,2,3]triazole-5-carboxylic acid
Figure imgf000048_0002
Step 1 : 2-(2,4-Dichlorophenyl)-2-methylpropanenitrile
Figure imgf000048_0003
To a stirred solution of 2,4-dichlorophenylacetonitrile (2.0 g, 10.07 mmol) in THF (25 mL) was added potassium-ie/ -butoxide (3.6 g, 32.25 mmol) followed by methyl iodide (2.0 mL, 32.25 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to afford 4.49 g of the desired product. lH NMR (300 MHz, DMSO-d6): δ 1.78 (s, 6H), 7.49-7.57 (m, 2H), 7.73 (s, 1H). Step 2: 2-(2,4-Dichlorophenyl)-2-methylpropan- 1-amine
Figure imgf000048_0004
To a suspension of lithium aluminium hydride (1.56 g, 41.31 mmol) in THF (100 mL) was added aluminium chloride (5.5 g, 41.31 mmol) in small portions followed by a solution of 2- (2,4-dichlorophenyl)-2-methylpropanenitrile (Step 1 intermediate) (4.49 g, 20.65 mmol) in THF (50 mL) at 0 °C. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with ice-cold water and layers were separated. The aqueous layer was basified with ammonia and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to afford 3.6 g of the desired product. lH NMR (300 MHz, CDC13): δ 1.43 (s, 6H), 3.15 (s, 2H), 3.86 (s, 2H), 7.18-7.39 (m, 3H).
Step 3: Ethyl 4-((2-(2,4-dichlorophenyl)-2-methylpropyl)amino)-3-nitrobenzoate
Figure imgf000049_0001
To a stirred solution of ethyl 4-fluoro-3-nitrobenzoate (750 mg, 3.51 mmol) in THF (10 mL) was added 2-(2,4-dichlorophenyl)-2-methylpropan-l -amine (Step 2 intermediate) (916 mg, 4.22 mmol) flowed by dropwise addition of DIPEA (667 μί, 3.86 mmol) at RT. The reaction mixture was stirred at RT for 4 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 910 mg of the desired product. lH NMR (300 MHz, DMSO- ) δ 1.29 (t, = 7.2 Hz, 3H), 1.54 (s, 6H), 3.94 (d, = 5.4 Hz, 2H), 4.27 (q, = 7.2 Hz, 2H), 7.21 (d, = 9.3 Hz, 1H), 7.45 (d, = 8.7 Hz, 1H), 7.53 (d, = 8.7 Hz, 1H), 7.59 (s, 1H), 7.92-7.99 (m, 2H), 8.54 (s, 1H).
Step 4: Ethyl 3-amino-4-((2-(2,4-dichlorophenyl)-2-methylpropyl)amino)benzoate
Figure imgf000049_0002
The titled compound was synthesized by the nitro reduction of the ethyl 4-((2-(2,4- dichlorophenyl)-2-methylpropyl)amino)-3-nitrobenzoate (Step 3 intermediate) (900 mg, 2.18 mmol) by using iron powder (609 mg, 10.94 mmol) and ammonium chloride (1.17 g, 21.88 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in step 3 of Intermediate 5 to yield 700 mg of the product. lH NMR (300 MHz, DMSO- ) δ 1.25 (t, = 6.9 Hz, 3H), 1.50 (s, 6H), 3.60 (d, = 6.0 Hz, 2H), 4.17 (q, = 6.9 Hz, 2H), 4.60 (t, = 5.7 Hz, 1H), 4.72 (s, 2H), 6.55 (d, = 8.4 Hz, 1H), 7.13-7.20 (m, 2H), 7.38 (d, = 8.7 Hz, 1H), 7.46 (d, = 8.7 Hz, 1H), 7.53 (s, 1H).
Step 5: Ethyl l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH-benzo[<i][l,2,3]triazole-5- carboxylate
Figure imgf000049_0003
The titled compound was prepared by the reaction of ethyl 3-amino-4-((2-(2,4-dichlorophenyl)- 2-methylpropyl)amino)benzoate (Step 4 intermediate) (650 mg, 1.70 mmol) with sodium nitrite (176 mg, 2.56 mmol) and acetic acid (5.0 mL) in water (3.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 570 mg of the product. lU NMR (300 MHz, DMSO- 6) δ 1.32 (t, J = 7.5 Hz, 3H), 1.49 (s, 6H), 4.33 (q, J = 7.5 Hz, 2H), 5.24 (s, 2H), 7.13 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.61 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 8.53 (s, 1H).
Step 6: l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[<i] [l,2,3]triazole-5-carboxylic acid
To a stirred solution of ethyl l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH- benzo[< J [l,2,3]triazole-5-carboxylate (Step 5 intermediate) (550 mg, 1.40 mmol) in a mixture of THF, methanol and water (2: 1 : 1, 20 mL) was added lithium hydroxide monohydrate (117 mg, 2.80 mmol) at RT and the mixture was stirred for 1.5 h at RT. The reaction mixture was concentrated and added water. The aqueous mixture was acidified with IN HCl and extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford 525 mg of the desired product. lH NMR (300 MHz, DMSO- de) δ 1.50 (s, 6H), 5.25 (s, 2H), 7.13 (d, J = 9.0 Hz, 1H), 7.22 (d, = 8.1 Hz, 1H), 7.64 (s, 1H), 7.82 (d, = 9.0 Hz, 1H), 8.03 (d, = 7.8 Hz, 1H), 8.51 (s, 1H), 13.16 (s, 1H).
Structure, chemical name and characterization data of the intermediates prepared by using appropriate starting materials as per the method described in the case of Intermediate 21 are given in Table 3.
Table 3: Structure, chemical name and characterization data of Intermediate 22-39
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Intermediate 40 (5-(Ethylsulfonyl)pyridin-2-yl)methanamine hydrochloride
Figure imgf000054_0001
Step 1 : ie/ -Butyl ((5-bromopyridin-2-yl)methyl)carbamate
BOCHN'
To a solution of 5-bromo-2-cyanopyridine (5.0 g, 27.32 mmol) in methanol (50 mL) at 0 °C were added nickel (II) chloride hexahydrate (649 mg, 27.32 mmol), di-ie/ -butyl dicarbonate (11.9 g, 54.64 mmol) and sodium borohydride (2.06 g, 54.64 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to afford 1.0 g of the titled product. XH NMR (300 MHz, CDCb) δ 1.45 (s, 9H), 4.39 (d, = 5.4 Hz, 2H), 5.47 (br s, 1H), 7.21 (d, = 8.1 Hz, 1H), 7.79 (d, = 8.1 Hz, 1H), 8.59 (s, 1H); APCI-MS (m/z) 289 (M+H)+.
Step 2: ie/ -Butyl ((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamate
Figure imgf000054_0002
To a flame dried flask were added tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (Step 1 intermediate) (500 mg, 17.36 mmol), ethane sulfonic acid sodium salt (403 mg, 34.72 mmol), L-proline (39 mg, 3.47 mmol), copper (I) iodide (33 mg, 1.73 mmol) and sodium hydroxide (13 mg, 3.47 mmol) at RT. The mixture was purged with nitrogen and then added DMSO (10 mL). The mixture was stirred at 110 °C for 15 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous solution of ammonium chloride. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to afford 257 mg of the titled product. lH NMR (300 MHz, CDCb) δ 1.31 (t, = 7.2 Hz, 3H), 1.47 (s, 9H), 3.15 (q, = 7.2 Hz, 2H), 4.55 (d, = 5.4 Hz, 2H), 5.50 (br s, 1H), 7.50 (d, = 7.8 Hz, 1H), 8.15 (d, = 7.8 Hz, 1H), 9.02 (s, 1H).
Step 3: (5-(Ethylsulfonyl)pyridin-2-yl)methanamine hydrochloride
To a stirred solution of tert-butyl ((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamate (Step 2 intermediate) (325 mg, 1.08 mmol) in methanol (15 mL) was drop wise added acetyl chloride (0.8 mL, 10.83 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to afford 258 mg of the titled product. 1H NMR (300 MHz, CD3OD) δ 1.24 (t, J = 6.9 Hz, 3H), 3.30 (s, 2H), 4.44 (s, 2H), 7.70-7.74 (m, 1H), 8.30-8.34 (m, 1H), 9.08 (s, 1H); APCI-MS (m/z) 201 (M+H)+ (free base).
Intermediate 41
2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol
Figure imgf000055_0001
Step 1 : 4-(Ethylsulfonyl)benzaldehyde
Figure imgf000055_0002
To a solution of 4-fluorobenzaldehyde (1.3 g, 10.47 mmol) in DMSO (10 mL) was added sodium ethanesulfinate (2.43 g, 20.94 mmol) and the resulting mixture was stirred at 125 °C for 20 h. The mixture was cooled to RT and partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane and the solid was collected through filtration to yield 1.0 g of the titled product. lU NMR (300 MHz, DMSO- 6) δ 1.11 (t, = 7.2 Hz, 3H), 3.38 (q, = 7.2 Hz, 2H), 8.10 (d, = 8.1 Hz, 2H), 8.16 (d, = 8.1 Hz, 2H), 10.14 (s, 1H).
Step 2: 2-(4-(Ethylsulfonyl)phenyl)oxirane
Figure imgf000055_0003
To a solution of 4-(ethylsulfonyl)benzaldehyde (Step 1 intermediate) (1.0 g, 5.04 mmol) in DMF (10 mL) was added trimethylsulfonium iodide (1.18 g, 5.80 mmol) followed by potassium hydroxide powder (560 mg, 10.08 mmol) at RT. The mixture was stirred at RT for 20 min. The mixture was quenched with water and carefully neutralized with IN HC1. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a quick filter column to yield 1.1 g of the titled product; APCI-MS (m/z) 211 (M+H)-.
Step 3: 2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol
To a stirred solution of 2-(4-(ethylsulfonyl)phenyl)oxirane (Step 2 intermediate) (1.1 g, 5.18 mmol) in acetonitrile (20 mL) was slowly added concentrated sulfuric acid (0.55 mL, 10.19 mmol) and the mixture was stirred at RT for 1.5 h. Water (1.5 mL) was added to the mixture and continued to stirred at RT for another 8 h. The mixture was heated to 45 °C and stirred for 10 h. The mixture was cooled to RT and adjusted the pH to 3-4 using IN aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic layer was extracted back with water. The combined aqueous layers were basified with IN sodium hydroxide solution till pH 9. The aqueous layer was extracted with 1-butanol and the combined organic extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the solid obtained was stirred with methanol. The solid was filtered, dried and further purified by silica gel column chromatography to yield 150 mg of the titled product. lH NMR (300 MHz, CD3OD) δ 1.20 (t, J = 7.2 Hz, 3H), 3.19 (q, J = 7.2 Hz, 2H), 3.61-3.67 (m, 2H), 4.05-4.09 (m, 1H), 7 '.65-7 '.69 (m, 2H), 7.87 (d, J = 8.4 Hz, 2H); APCI-MS (m/z) 230
(M+H)+.
Intermediate 42
l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)-lH-benzo[<i][l,2,3]triazol-5-
Figure imgf000056_0001
l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)- lH-benzo[<i] [l,2,3]triazole-5-carbonyl azide
Figure imgf000056_0002
To a stirred solution of l-(2-(2,6-dichlorophenyl)-2-methylpropyl)- lH-benzo[< J[l,2,3]triazole- 5-carboxylic acid (Intermediate 23) (500 mg, 1.37 mmol) in THF (10 mL) was dropwise added ethyl chloroformate (262 μί, 2.75 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. A solution of sodium azide (223 mg, 3.43 mmol) in water (2.0 mL) was added to the reaction mixture at 0 °C and stirred for 2 h at RT. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to yield 496 mg of the desired product. The compound was as such used in the next step without characterization.
Step 2: l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)- lH-benzo[<i] [l,2,3]triazol-5-amine
A suspension of l-(2-(2,6-dichlorophenyl)-2-methylpropyl)- lH-benzo[<i][l,2,3]triazole-5- carbonyl azide (Step 1 intermediate) (490 mg, 1.26 mmol) in 10% aqueous 1,4-dioxane was refluxed for 4 h. The mixture was allowed to cool at RT and stirred for 18 h at RT. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 56 mg of the titled product. lH NMR (300 MHz, DMSO-ifc) δ 1.76 (s, 6H), 5.15 (s, 2H), 5.19 (br s, 2H), 6.78 (d, = 10.2 Hz, 1H), 6.83 (s, 1H), 7.14-7.25 (m, 2H), 7.38 (d, J = 7.8 Hz, 2H); APCI-MS (m/z) 335 (M+H)+.
Intermediate 43 was prepared from Intermediate 31 by following the procedure described in the case of Intermediate 42. Structure, chemical name and characterization data of Intermediate 36 are given in Table 4.
Table 4: Structure, chemical name and characterization data of Intermediate 43
Figure imgf000057_0002
Intermediate 44
( ?)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol
Figure imgf000057_0001
Step 1 : Ethyl 2-((tert-butyldimethylsilyl)oxy)acetate
O
>r "
To a stirred solution of ethyl 2-hydroxyacetate (25.0 g, 240 mmol) in dichloromethane (100 mL) was added imidazole (17.98 g, 264 mmol) at 0 °C. ie/t-Butyldimethylsilyl chloride (39.8 g, 264 mmol) was added to the mixture at 0 °C and stirred for 2 h at the same temperature. The reaction mixture was diluted with water and extracted twice with ethyl acetate for 20 h. The combined organic layers were washed with aqueous sodium bicarbonate solution followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 30.5 g of the titled product. XH NMR (400 MHz, DMSO- ) δ 0.06 (s, 6H), 0.87 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H), 4.11 (q, J = 7.2 Hz, 2H), 4.23 (s, 2H). Step 2: 2-((ieri-Butyldimethylsilyl)oxy)-N-methoxy-N-methylacetamide
Figure imgf000058_0001
To a stirred mixture of ethyl 2-((ie/t-butyldimethylsilyl)oxy)acetate (Step 1 intermediate) (25.0 g, 144 mmol) and N,0-dimethylhydroxylamine hydrochloride (22.4 g, 228 mmol) in THF (400 mL) was added ethylmagnesium bromide (152 mL, 457 mmol) dropwise at - 10 °C in a duration of 1.5 h. The mixture was stirred at -10 to -5 °C for 1.5 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 18.01 g of the desired compound. lH NMR (300 MHz, DMSO- ) δ 0.03 (s, 6H), 0.85 (s, 9H), 3.05 (s, 3H), 3.62 (s, 3H), 4.36 (s, 2H); ESI-MS (m/z) 234 (M+H)+.
Step 3: 2-((ieri-Butyldimethylsilyl)o -l-(4-(ethylthio)phenyl)ethanone
Figure imgf000058_0002
In a dry flask with magnesium turnings (525 mg, 21.59 mmol) were added THF (5.0 mL) and five drops of 1,2-dichlororethane and the mixture was slowly heated to 40 °C. To that mixture, (4-bromophenyl)(ethyl)sulfane (3.0 g, 10.81 mmol) dropwise was added and stirred for 30 min at 40 °C. The reaction mixture was cooled down to 0 °C and 2-((tert-butyldimethylsilyl)oxy)- N-methoxy-N-methylacetamide (Step 2 intermediate) (3.78 g, 16.21 mmol) was added to the mixture and stirred for 3 h at the same temperature. The mixture was quenched with saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 2.02 g of the desired compound. XH NMR (300 MHz, CDC13) δ 0.11 (s, 6H), 0.92 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H), 3.02 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H); ESI-MS (m/z) 311 (M+H)+.
Step 4: N-(2-((ieri-Butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethylidene)-2- methylpropane-2- sulfinamide
Figure imgf000059_0001
To a mixture of 2-((ieri-butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethanone (Step 3 intermediate) (2.0 g, 6.44 mmol) and (S)-(-)-2-methyl-2-propanesulfinamide (936 mg, 7.72 mmol) in THF (25 mL) was added titanium isopropoxide (4.73 mL, 16.10 mmol) at RT. The mixture was heated to 80 °C and stirred for 6 h. The reaction was cooled to RT and quenched with brine. The mixture was diluted with ethyl acetate and stirred for 15 min. The solution was filtered through celite bed and the filtrate was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 1.61 g of the desired compound. lU NMR (300 MHz, CDC13) δ 0.08 (s, 6H), 0.82 (s, 9H), 1.29 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H), 3.00 (q, J = 7.2 Hz, 2H), 4.98-5.02 (m, 1H), 5.21-5.25 (m, 1H), 7.27 (d, = 8.4 Hz, 2H), 7.78 (d, = 8.4 Hz, 2H); APCI-MS (m/z) 414 (M+H)+.
Step 5: N-((R)-2-((tert-Butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethyl)-2- methylpropane-2- sulfinamide
Figure imgf000059_0002
To a stirred solution of N-(2-((ieri-butyldimethylsilyl)oxy)- l-(4-(ethylthio)phenyl)ethylidene)- 2-methylpropane-2- sulfinamide (Step 4 intermediate) (1.6 g, 3.86 mmol) in THF (15 mL) was added DIBAL-H (1.2 , 9.66 mL, 11.6 mmol) at -78 °C and the mixture was stirred for 1 h at the same temperature. The mixture was quenched with water. The mixture was diluted with ethyl acetate and stirred for 15 min. The solution was filtered through celite bed and the filtrate was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 1.05 g of the desired compound. lH NMR (300 MHz, CDCI3) δ 0.01 (s, 6H), 0.89 (s, 9H), 1.31 (s, 9H), 1.36 (t, = 7.2 Hz, 3H), 2.98(q, = 7.2 Hz, 2H), 3.85 (d, = 5.4 Hz, 2H), 4.43-4.47 (m, 1H), 7.31- 7.37 (m, 4H); APCI-MS (m/z) 416 (M+H)+.
Step 6: ( ?)-2-Amino-2-(4-(ethylthio)phenyl)ethanol
Figure imgf000059_0003
To a stirred solution of N-(( ?)-2-((ieri-butyldimethylsilyl)oxy)-l-(4-(ethylthio)phenyl)ethyl)- 2-methylpropane-2-sulfinamide (Step 5 intermediate) (1.0 g, 2.40 mmol) in methanol (10 mL) was added hydrochloric acid in ethyl acetate (10 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The aqueous mixture was washed with ethyl acetate and basified with solid sodium carbonate till pH 8-9. The solution was extracted twice with ethyl acetate and the combined organic extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 415 mg of the desired product. XH NMR (300 MHz, DMSO-ifc) δ 1.20 (t, J = 6.6 Hz, 3H), 1.83 (br s, 2H), 2.93 (q, J = 6.6 Hz, 2H), 3.24-3.40 (m, 2H), 3.82 (br s, 1H), 4.75 (br s, 1H), 7.24 (d, = 7.2 Hz, 2H), 7.30 (d, = 7.8 Hz, 2H); APCI-MS (m/z) 181 (M- OH+H)+.
Step 7: ( ?)-2-Amino-2-(4-(ethylsulfonyl)phenyl)ethanol
To a stirred solution of ( ?)-2-amino-2-(4-(ethylthio)phenyl)ethanol (Step 6 intermediate) (400 mg, 2.02 mmol) in methanol (15 mL) was added a solution of oxone (2.49 g, 4.05 mmol) in water (15 mL) at 0 °C. The mixture was stirred at RT for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water and the aqueous mixture was washed with ethyl acetate. The aqueous layer was basified with solid sodium carbonate till pH 8-9. The aqueous mixture was extracted twice with 10% methanol in chloroform. The aqueous layer was concentrated and the solid obtained was dissolved in 10% methanol in chloroform. The solution was stirred for 30 min and filtered. The filtrate was combined with organic extracts and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 210 mg of the desired compound. lH NMR (300 MHz, DMSO-d6) δ 1.07 (t, = 7.5 Hz, 3H), 2.48 (br s, 2H), 3.21-3.44 (m, 4H), 3.94-3.98 (m, 1H), 4.84-4.88 (m, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H); Chiral HPLC: Mobile phase A: 0.1% TFA in n-hexane, Mobile phase B: 0.1 % TFA in IPA, A: B 50 : 50, Flow rate: 1.2 mL/min, Column: Phenomenax Cellulose-4-250 * 4.6 ιηιη-5μ, sample diluent: IPA, Temperature: 40 °C, Run time: 25 min, purity: 99.85% (7.76 min).
Structure, chemical name and characterization data of the intermediate prepared by using appropriate reagent as per the method described in the case of Intermediate 44 are given in Table 5.
Table 5: Structure, chemical name and characterization data of Intermediate 45 Intermediate Structure and Analytical data No. Chemical name
.OH lH NMR (300 MHz, DMSO-d6) δ
Intermediate 1.07 (t, = 7.2 Hz, 3H), 2.29 (s, 45 H2N iso 2H), 3.24 (q, J = 7.2 Hz, 2H), 3.26- 3.45 (m, 2H), 3.94-3.98 (m, 1H),
(5)-2-Amino-2-(4- 4.85 (br s, 1H), 7.62 (d, = 7.8 Hz, (ethylsulfonyl)phenyl)ethanol 2H), 7.79 (d, = 7.2 Hz, 2H); ESI- MS (m/z) 230 (M+H)+, Chiral purity: 100% (14.35 min).
Intermediate 46
(S)-2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetic acid
Step 1 : Ethyl 2,2-difluoro-2-(4-(2 xy)ethyl)phenyl)acetate
Figure imgf000061_0001
To a stirred solution of [4-(2-ethoxy-l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Intermediate 2) (10 g, 38.72 mmol) in THF (50 mL) was added imidazole (3.4 g, 50.34 mmol) at 0 °C. Triisopropylchlorosilane (Tips-Cl) (10.8 mL, 50.34 mmol) was drop wise added at 0 °C and the resultant mixture was stirred overnight at RT. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water followed by brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to afford 12 g of the desired product. lH NMR (400 MHz, CDC13) δ 1.04 (d, J = 2.8 Hz, 18H), 1.22-1.33 (m, 6H), 3.71 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H).
Step 2: Triisopropylsilyl 2-(4-(l, l- yl)acetate
Figure imgf000061_0002
To a stirred solution of ethyl 2,2-difluoro-2-(4-(2-oxo-2- ((triisopropylsilyl)oxy)ethyl)phenyl)acetate (Step 1 intermediate) (12.0 g, 28.94 mmol) in anhydrous THF (100 mL) was added 3.1 methyllithium (19.0 mL, 57.89 mmol) dropwise at -78 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted thrice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 6.3 g of the titled product. lH NMR (400 MHz, CDCb) δ 1.02 (d, J = 7.6 Hz, 18H), 1.06-1.09 (m, 3H), 2.31 (m, 3H), 3.71 (s, 2H), 7.40 (d, = 8.4 Hz, 2H), 7.52 (d, = 8.4 Hz, 2H).
Step 3: (S)-Triisopropylsilyl 2-(4-(l, -difluoro-2-hydroxypropyl)phenyl)acetate
Figure imgf000062_0001
To a solution of borane dimethyl sulfide complex (1.18 mL, 12.49 mmol) in THF (15 mL) was added a solution of (tf)-(+)-2-methyl-CBS-oxazaborolidine (1.82 mL, 6.25 mmol) in THF (5.0 mL) at -20 °C and the mixture was stirred at RT for 1 h. The mixture was again cooled to -20 °C and a solution of triisopropylsilyl 2-(4-(l, l-difluoro-2-oxopropyl)phenyl)acetate (Step 2 intermediate) (4.0 g, 10.42 mmol) in THF (5.0 mL) was added to the mixture. The reaction mixture was stirred at -20 °C for 30 min before quenching with methanol. The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography to yield 1.8 g of the titled product. XH NMR (400 MHz, DMSO-d6) δ 0.98-1.06 (m, 21H), 1.15- 1.23 (m, 3H), 3.77 (s, 2H), 4.01-4.08 (m, 1H), 5.53 (d, = 6.0 Hz, 1H), 7.37 (d, = 8.4 Hz, 2H), 7.43 (d, = 8.4 Hz, 1H).
Step 4: (5)-2-(4-(l, l-Difluoro-2-hydroxypropyl)phenyl)acetic acid
To a stirred solution of (K)-triisopropylsilyl 2-(4-(l ,l-difluoro-2-hydroxypropyl)phenyl)acetate (Step 3 intermediate) (400 mg, 1.03 mmol) in THF (5.0 mL) was added tetrabutylammonium fluoride (TBAF) (l .OM, 2.0 mL, 2.08 mmol) at -20 °C and the mixture was stirred for 1 h at the same temperature. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to yield 145 mg of the titled product. lH NMR (400 MHz, DMSC fc) δ 1.21-1.31 (m, 3H), 3.63 (s, 2H), 4.01-4.07 (m, 1H), 5.52 (d, = 5.2 Hz, 1H), 7.35 (d, = 8.4 Hz, 2H), 7.42 (d, = 8.4 Hz, 2H), 12.38 (br s, 1H); Chiral HPLC: Mobile phase A: 0.1% trifluoroacetic acid in n-Hexane, Mobile phase B: 0.1% trifluoroacetic acid in ethanol, A: B 85: 15, Column: Phenomenax-Amylose-2-250*4.6 ιηιη-5μ, Temperature: 40 °C, Flow rate: 1.0 mL/min, Sample concentration: 250 ppm in IPA, Purity: 99.92%, RT:
10.98 min. Structure, chemical name and characterization data of the intermediate prepared by using appropriate reagent as per the method described in the case of Intermediate 46 are given in Table 6.
Table 6: Structure, chemical name and characterization data of Intermediate 47
Figure imgf000063_0003
Intermediate 48
2-(4-(l, l-Difluoro-2-hydroxy-2-methylpropyl)phenyl)acetic acid
Figure imgf000063_0001
Step 1 : Triisopropylsilyl 2-(4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetate
Figure imgf000063_0002
To a stirred solution of ethyl 2,2-difluoro-2-(4-(2-oxo-2- ((triisopropylsilyl)oxy)ethyl)phenyl)acetate (step 1 of Intermediate 46) (2.3 g, 5.54 mmol) in diethyl ether (20 mL) was added methylmagnesium bromide ( 1.5 , 18.4 mL, 27.7 mmol) at - 10 °C and the mixture was stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated. The residue was purified by silica gel column chromatography to yield 276 mg of the titled product. XH NMR (400 MHz, DMSO- 6) δ 0.97 (d, 7 = 6.3 Hz, 18H), 1.14 (s, 6H), 1.15-1.22 (m, 3H), 3.76 (s, 2H), 5.27 (s. 1H), 7.34 (d, 7 = 8.0 Hz, 2H), 7.43 (d, 7 = 8.4 Hz, 1H).
Step 2: 2-(4-(l, l-Difluoro-2-hydroxy-2-methylpropyl)phenyl)acetic acid
The titled compound was prepared by the deprotection reaction of triisopropylsilyl 2-(4-(l,l- difluoro-2-hydroxy-2-methylpropyl)phenyl)acetate (Step 1 intermediate) (260 mg, 0.68 mmol) using tetrabutylammonium fluoride (TBAF) (1 , 5.16 mL, 1.35 mmol) in THF (5.0 mL) as per the procedure described in step 4 of Intermediate 46 to yield 111 mg of the compound. Ή NMR (400 MHz, DMSO- ) δ 1.16 (s, 6H), 3.62 (s, 2H), 5.28 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.42 (d, 7 = 8.4 Hz, 2H).
Intermediate 49
(S)- 1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-ol hydrochloride
Figure imgf000064_0001
Step 1 : 4-(2-Ethoxy- l,l-difluoro-2-oxoethyl)benzoic acid
Figure imgf000064_0002
The titled compound was prepared by the reaction of 4-iodobenzoic acid (3.0 g, 12.1 mmol) with 2-bromo-2,2-difluoroacetate (4.9 g, 24.2 mmol) in the presence of copper powder (3.05 g, 48.4 mmol) in DMSO (15 mL) as per the procedure described in Intermediate 2 to yield 1.7 g of the compound. lH NMR (400 MHz, DMSO-d6) δ 1.22 (t, = 6.8 Hz, 3H), 4.32 (q, = 6.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 13.36 (br s, 1H); ESI-MS (m/z) 243 (M-H)-.
Step 2: 4-(l, l-Difluoro-2-oxopropyl)benzoic acid
Figure imgf000064_0003
The titled compound was prepared by the reaction of 4-(2-ethoxy- l,l-difluoro-2- oxoethyl)benzoic acid (stepl intermediate) (1.0 g, 4.09 mmol) with methyllithium (3.0 , 4.1 mL, 12.3 mmol) in THF (10 mL) as per the procedure described in Step 2 of Intermediate 46 to yield 570 mg of the compound. lH NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.72 (d, = 8.4 Hz, 2H), 8.09 (d, / = 8.4 Hz, 2H), 13.35 (br s, 1H); APCI-MS (m/z) 213 (M-H)".
Step 3: 4-( 1 , 1 -Difluoro-2-oxopropyl)benzamide
O
H2NAT A
To a stirred solution of -(l, l-difluoro-2-oxopropyl)benzoic acid (Step 2 intermediate) (4.0 g, 18.7 mmol) in THF (200 mL) was added l, l '-carbonyldiimidazole (CDI) (4.52 g, 28.0 mmol) and the mixture was stirred at RT for 1 h. The mixture was cooled to 0 °C and aqueous ammonia (2.0 mL) was added drop-wise. The reaction mixture was stirred for 2 h at RT. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 3.5 g of the titled product. ESI-MS (m/z) 243 (M-H)-.
Step 4: 4-( 1 , 1 -Difluoro-2-oxopropyl)be
Figure imgf000065_0001
To a stirred solution of phosphorous oxychloride (1.36 mL, 14.08 mmol) in DMF (5.0 mL) was slowly added a solution of 4-(l, l-difluoro-2-oxopropyl)benzamide (Step 3 intermediate) (1.5 g, 7.04 mmol) in DMF (5.0 mL) at 0 °C and the mixture was stirred for 15 min. The reaction mixture was poured into a mixture of ammonia, water and crushed ice. The product was extracted twice in ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 905 mg of the titled product. lH NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.80 (d, = 8.8 Hz, 2H), 8.04 (d, = 8.8 Hz, 2H).
Step 5: 1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-one hydrochloride
Figure imgf000065_0002
A solution of 4-(l, l-difluoro-2-oxopropyl)benzonitrile (Step 4 intermediate) (895 mg, 4.56 mmol) in methanol (30 mL) with catalytic amount of cone, hydrochloric acid was purged with nitrogen gas for 10 min. Palladium on carbon (10%, 50% wet, 500 mg) was added to the solution and the mixture was hydrogenated (under hydrogen balloon) for 4 h at RT. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield 1.0 g of the titled product. ¾ NMR (400 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.07-4.11 (m, 2H), 7.63 (d, = 8.4 Hz, 2H), 7.68 (d, = 8.4 Hz, 2H), 8.53 (br s, 2H); ESI-MS (m/z) 200 (M+H-HC1)+.
Step 6: ie/ -Butyl 4-(l, l-difluoro-2-oxopropyl)benzylcarbamate
Figure imgf000065_0003
To a stirred solution of l-(4-(aminomethyl)phenyl)- l,l-difluoropropan-2-one hydrochloride (Step 5 intermediate) (1.5 g, 6.36 mmol) in a mixture of 1,4-dioxane (10 mL) and water (10 mL) were added Boc anhydride (1.53 g, 7.0 mmol) and sodium hydroxide (381 mg, 9.55 mmol) at RT. The mixture was stirred for 3 h at RT. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to yield 850 mg of the desired product. lH NMR (400 MHz, DMSC fc) δ 1.39 (s, 9H), 2.36 (s, 3H), 4.18 (d, J = 6.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.53 (d, = 8.0 Hz, 2H).
Step 7: (S)-ie/t-Butyl 4-(l, l-difluoro-2-hydroxypropyl)benzylcarbamate
Figure imgf000066_0001
An oven-dried flask was charged with dichloro(p-cymene)ruthenium(II) dimer (25 mg, 0.041 mmol), (15,25)-(+)-N-(4-toluenesulfonyl)- l,2-diphenylethylenediamine (30 mg, 0.083 mmol) and powdered molecular sieves (4 A, 300 mg) at ambient temperature. To that mixture, degassed IPA (10 mL) was added and the resultant suspension was evacuated and flushed with nitrogen. The mixture was heated to 90 °C for 30 min followed by 15 min at 50 °C. A solution of ieri-butyl 4-(l,l-difluoro-2-oxopropyl)benzylcarbamate (Step 6 intermediate) (250 mg, 0.83 mmol) in degassed IPA (15 mL) was dropwise added to the reaction mixture over a period of 10 min. After 5 min, a solution of potassium ie/t-butoxide (23 mg, 0.21 mmol) in IPA (5.0 mL) was slowly added to the mixture and the mixture was stirred for 2 h at 50 °C. The mixture was cooled to RT and diluted with ethyl acetate (20 mL). The suspension was filtered through silica gel bed and the bed was rinsed thoroughly with ethyl acetate. The combined filtrate and washings were concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatography to yield 198 mg of the desired product. lH NMR (400 MHz,
DMSO- ) δ 1.06 (d, = 8.0 Hz, 3H), 1.40 (s, 9H), 3.99-4.07 (m, 1H), 4.16 (d, = 8.0 Hz, 2H), 5.50 (d, = 8.0 Hz, 1H), 7.31 (d, = 8.0 Hz, 2H), 7.41 (d, = 8.0 Hz, 2H), 7.46 (t, = 8.0 Hz,
1H).
Step 8: (S)- 1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-ol hydrochloride
To a solution of {S)-tert-buty\ 4-(l,l-difluoro-2-hydroxypropyl)benzylcarbamate (Step 7 intermediate) (190 mg, 0.63 mmol) in methanol (5.0 mL) was added hydrochloric acid in ethyl acetate (5.0 mL) and the mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the residue was triturated with hexane followed by diethyl ether. The solid was dried under reduced pressure to yield 110 mg of the desired product. lH NMR (400 MHz, DMSO- ) δ 1.07 (d, = 8.0 Hz, 3H), 4.04-4.09 (m, 3H), 5.58 (d, = 8.0 Hz, 1H), 7.52 (d, = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 8.54 (br s, 3H); ESI-MS (m/z) 202 (M+H-HC1)+; Chiral HPLC: Mobile phase A: 0.1% diethylamine in n-Hexane, Mobile phase B: 0.1% diethylamine in IPA, (A:B 80:20), Flow rate: 1.0 niL/min, Column: Chiralpak-ADH- 250 mm * 4.6 ιηιη-5μ, Sample diluent: IPA: methanol (90: 10), Run time: 30 min, Purity: 99.09%, RT: 8.44 min. Structure, chemical name and characterization data of the intermediate prepared by using appropriate reagent as per the method described in the case of Intermediate 49 is given in Table 7.
Table 7: Structure, chemical name and characterization data of Intermediate 50
Figure imgf000067_0003
Intermediate 51
1 -(4-(Aminomethyl)phenyl)- 1 , 1 -difluoropropan-2-ol hydrochloride
Figure imgf000067_0001
Step 1 : tert-butyl 4-(l, l-difluoro-2-hydroxypropyl)benzylcarbamate
Figure imgf000067_0002
To a stirred solution of tert-butyl 4-(l, l-difluoro-2-oxopropyl)benzylcarbamate (Step 6 of Intermediate 49) (250 mg, 0.84 mmol) in a mixture of THF (5.0 mL) and methanol (5.0 mL) at 0 °C was added sodium borohydride (126 mg, 3.34 mmol) and the resulting mixture was stirred for 1 h at same temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 150 mg of the desired product. lH NMR (400 MHz, DMSO-d6) δ 1.07 (d, J = 6.4 Hz, 3H), 1.40 (s, 9H), 4.00- 4.08 (m, 1H), 4.17 (d, = 6.0 Hz, 2H), 5.50 (d, = 6.0 Hz, 1H), 7.31 (d, = 8.0 Hz, 2H), 7.43- 7.48 (m, 3H).
Step 2: l-(4-(Aminomethyl)phenyl)- l,l-difluoropropan-2-ol hydrochloride The titled compound was prepared by the reaction of tert-butyl 4-(l, l-difluoro-2- hydroxypropyl)benzylcarbamate (Step 1 intermediate) (150 mg, 0.50 mmol) with hydrochloric acid in ethyl acetate (5.0 mL) in methanol (5.0 mL) as per the procedure described in step 8 of intermediate 49 to yield 100 mg of the product. ¾ NMR (400 MHz, DMSO-d6) δ 1.08 (d, = 6.4 Hz, 3H), 3.41-3.07 (m, 1H), 4.01-4.12 (m, 2H), 5.59 (br s, 1H), 7.52 (d, = 8.0 Hz, 2H), 7.59 (d, / = 8.4 Hz, 2H), 8.52 (br s, 3H).
Intermediate 52
1 -(4-(Aminomethyl)phenyl)- 1 , 1 - -2-ol hydrochloride
Figure imgf000068_0001
Step 1 : ie/ -Butyl 4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)benzylcarbamate
Figure imgf000068_0002
The titled compound was prepared by the reaction of tert-butyl 4-(l, l-difluoro-2- oxopropyl)benzylcarbamate (Step 6 of Intermediate 49) (500 mg, 1.67 mmol) with methylmagnesium bromide (1.5 , 5.57 mL, 8.35 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 48 to yield 300 mg of the product. lH NMR (400 MHz, DMSC fc) δ 1.15 (s, 6H), 1.40 (s, 9H), 4.17 (d, J = 6.0 Hz, 2H), 5.27 (br s, 1H), 7.29 (d, = 8.0 Hz, 2H), 7.42 (d, = 8.0 Hz, 2H), 7.45 (t, = 6.0 Hz, 1H).
Step 2: l-(4-(Aminomethyl)phenyl)- l,l-difluoro-2-methylpropan-2-ol hydrochloride
The titled compound was prepared by the reaction of ieri-Butyl 4-(l,l-difluoro-2-hydroxy-2- methylpropyl)benzylcarbamate (Step 1 intermediate) (300 mg, (0.95 mmol) with hydrochloric acid in ethyl acetate (5.0 mL) in methanol (5.0 mL) as per the procedure described in Step 8 of Intermediate 49 to yield 153 mg of the product. XH NMR (400 MHz, DMSO-d6) δ 1.16 (s, 6H), 4.06 (d, J = 6.0 Hz, 2H), 5.37 (br s, 1H), 7.51 (d, = 8.4 Hz, 2H), 7.57 (d, = 8.4 Hz, 2H), 8.51 (br s, 3H).
Intermediate 53
l-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)- lH-benzo[<i] [l,2,3]triazol-5-amine
Figure imgf000068_0003
Step 1 : N-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-2,4-dinitroaniline
Figure imgf000069_0001
The titled compound was prepared by the reaction of l-fluoro-2,4-dinitrobenzene (660 mg, 3.54 mmol) with 2-methyl-2-(2,4,6-trifluorophenyl)propan- l -amine (550 mg, 3.19 mmol) in the presence of DIPEA (1.31 mL, 7.09 mmol) as per the procedure described in Step 3 of Intermediate 21 to yield 670 mg of the compound. lU NMR (400 MHz, DMSO- 6) δ 1.55 (s, 6H), 3.82 (d, = 5.6 Hz, 2H), 7.16 (t, = 9.6 Hz, 1H), 7.32 (d, = 9.6 Hz, 1H), 7.91 (t, = 9.2 Hz, 1H), 8.24 (d, = 7.6 Hz, 1H), 8.63-8.71 (m, 1H), 8.79-8.90 (m, 1H).
Step 2: N1-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-4-nitrobenzene- 1 ,2-diamine
Figure imgf000069_0002
To a stirred mixture of N-(2-methyl-2-(2,4,6-trifluorophenyl)propyl)-2,4-dinitroaniline (Step 1 intermediate) (650 mg, 1.75 mmol) and ammonium chloride (936 mg, 1.75 mmol) in ethanol (15 mL) was heated to 60 °C. To that mixture, were added a solution of sodium sulfide in ethanol (15 mL) followed by aqueous ammonia (50 mL) drop-wise. The reaction mixture was stirred at 90 °C for 4 h. The mixture was diluted with saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 271 mg of the desired compound. lH NMR (400 MHz, DMSO-d6) δ 1.49 (s, 6H), 3.56 (d, = 6.0 Hz, 2H), 5.18 (s, 2H), 5.58 (t, = 6.4 Hz, 1H), 6.56 (d, = 8.8 Hz, 1H), 7.05-7.12 (m, 2H), 7.37 (d, = 2.8 Hz, 1H), 7.42-7.47 (m, 1H).
Step 3: l-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)-5-nitro- lH-benzo[<i] [l,2,3]triazole
Figure imgf000069_0003
The titled compound was prepared by the cyclization reaction of N1-(2-Methyl-2-(2,4,6- trifluorophenyl)propyl)-4-nitrobenzene- l,2-diamine (Step 2 intermediate) (250 mg, 7.36 mmol) in the presence of sodium nitrite (101 mg, 1.47 mmol) in acetic acid (10 mL) and water (1.0 mL) as per the procedure described in step 2 of Intermediate 4 to yield 181 mg of the product. lH NMR (400 MHz, DMSO-d6) δ 1.54 (s, 6H), 5.10 (s, 2H), 7.09 (t, = 9.2 Hz, 2H), 8.02 (d, J = 9.2 Hz, 1H), 8.38 (dd, = 9.2, 2.0 Hz, 1H), 8.99 (d, = 2.0 Hz, 1H); ESI-MS (m/z) 351 (M+H)+.
Step 4: l-(2-Methyl-2-(2,4,6-trifluorophenyl)propyl)- lH-benzo[<i] [l,2,3]triazol-5-arnine The titled compound was synthesized by the nitro reduction of the l-(2-methyl-2-(2,4,6- trifluorophenyl)propyl)-5-nitro- lH-benzo[<i] [l,2,3]triazole (Step 3 intermediate) (170 mg, 0.48 mmol) by using iron powder (134 mg, 2.42 mmol) and ammonium chloride (259 mg, 4.85 mmol) in a mixture of methanol (10 mL), THF (10 mL) and water (5.0 mL) as per the process described in step 3 of Intermediate 5 to yield 121 mg of the product. lH NMR (300 MHz, DMSO-ifc): δ 1.51 (s, 6H), 4.82 (s, 2H), 5.20 (s, 2H), 6.82-6.88 (m, 2H), 7.00-7.10 (m, 2H), 7.29 (d, = 8.0 Hz, 1H).
Structure, chemical name and characterization data of the intermediate prepared by using appropriate reagent as per the method described in the case of Intermediate 53 is given in Table
8.
Table 8: Structure, chemical name and characterization data of Intermediate 54-55
Figure imgf000070_0002
Intermediate 56
(4-( 1 , 1 -Difluoropropyl)phenyl)methanamine
Figure imgf000070_0001
Step 1 : 2-Ethyl-2-(p-tolyl)- 1 ,3-dithiolane
Figure imgf000071_0001
To a stirred solution of l-(/?-tolyl)propan- l-one (2.0 g, 13.49 mmol) in dichloromethane (20 mL) were added 1,2-ethanedithiol (1.69 mL, 20.17 mmol) and BF3-etherate (3.33 mL) and the mixture was stirred overnight at RT. The mixture was poured into 1 N sodium hydroxide solution the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.0 g of the crude compound. The crude compound was as such used in the next step without any characterization.
Step 2: 1 -( 1 , 1 -Difluoropropyl)-4-methylb
Figure imgf000071_0002
To an oven-dried flask was charged N-iodosuccinimide (9.0 g, 10.11 mmol) and flushed twice with nitrogen. Dichloromethane (30 mL) was added to the flask and the mixture was cooled to -78 °C. Hydrogen fluoride pyridine (70%, 7.0 mL, 267 mmol) was added drop wise to the mixture. After being agitated for 30 min at -78 °C, a solution of 2-ethyl-2-(p-tolyl)- l,3- dithiolane (Step 1 intermediate) (3.0 g, 13.37 mmol) in dichloromethane (15 mL) was added drop wise. The mixture was stirred at -78°C for 2 h and then at -10 °C for 30 min. The mixture was diluted with n-hexane, filtered through basic alumina and the bed was washed with n- hexane. The combined filtrates were concentrated and the residue was diluted with ethyl acetate. The solution was washed with 10% sodium thiosulfate, 2% potassium permanganate, water and brine. The solvent was removed under reduced pressure and the residue thus obtained was purified by flash column chromatography to yield 350 mg of the desired compound. lH
NMR (400 MHz, CDC13) δ 1.00 (t, = 7.2 Hz, 3H), 2.10-2.22 (m, 2H), 2.40 (s, 3H), 7.24 (d,
= 8.0 Hz, 2H), 7.37 (d, = 8.0 Hz, 2H).
Step 3: l-(Bromomethyl)-4-(l, l-difluoropropyl)benzene
Figure imgf000071_0003
To a stirred solution of l-(l,l-difluoropropyl)-4-methylbenzene (Step 2 intermediate) (350 mg, 2.05 mmol) in carbon tetrachloride (10 mL) were added AIBN (33 mg, 0.21 mmol) followed by N-bromosuccinimide (430 mg, 2.41 mmol) at RT and the mixture was stirred overnight at 100 °C. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 50 mg of the desired compound. lH NMR (400 MHz, CDCb) δ 1.01 (t, J = 7.2 Hz, 3H), 2.10-2.22 (m, 2H), 4.52 (s, 2H), 7.47 (s, 4H).
Step 4: 2-(4-( 1 , 1 -Difluoropropyl)benzyl)isoindoline- 1 ,3-dione
Figure imgf000072_0001
To a stirred solution of l-(bromomethyl)-4-(l, l-difluoropropyl)benzene (Step 3 intermediate) (48 mg, 0.19 mmol) in DMF (5.0 mL) were added cesium carbonate (94 mg, 0.28 mmol) followed by phthalimide (34 mg, 0.23 mmol) and the mixture was stirred at RT for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 50 mg of the desired compound. lH NMR (400 MHz, CDCb) δ 0.97 (t, J = 7.6 Hz, 3H), 2.05-2.19 (m, 2H), 4.89 (s, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.50 (d, = 8.4 Hz, 2H), 7.74 (dd, = 5.6, 3.2 Hz, 2H), 7.88 (dd, = 5.6, 3.2 Hz, 2H). Step 5: (4-( 1 , 1 -Difluoropropyl)phenyl)methanamine
To a stirred mixture of 2-(4-(l, l-difluoropropyl)benzyl)isoindoline- l,3-dione (Step 4 intermediate) (47 mg, 0.15 mmol) in methanol (5.0 mL) was added hydrazine monohydrate (0.1 mL, 2.72 mmol) and the reaction mixture was stirred at 60 °C for 1.5 h. The mixture was cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and stirred for 15 min. The precipitated solid was filtered off. The filtrate was concentrated to yield 25 mg of the desired compound. lH NMR (400 MHz, DMSO-d6) δ 0.89 (t, J = 1.2 Hz, 3H), 2.12-2.26 (m, 2H), 3.71 (br s, 2H), 3.77 (s, 2H), 7.44 (s, 4H); ESI-MS (m/z) 186 (M+H)+.
EXAMPLES
Examples 1-68 were synthesized by following methods (A-G) as described below:
Method A
Synthesis of N-(l-(2,4-dichlorophenethyl)-lH-benzo[ ][l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro- 2-hydroxypropyl)phenyl)acetamide (Example 2)
Figure imgf000072_0002
Step 1 : Ethyl 2-(4-(2-((l-(2,4-dichlorophenethyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)amino)-2- oxoethyl)phenyl)-2,2-difluoroacetate
Figure imgf000073_0001
To a stirred solution of l-(2,4-dichlorophenethyl)-lH-benzo[<i][l,2,3]triazol-5-amine (Intermediate 4) (675 mg, 2.19 mmol) and [4-(2-ethoxy- l,l-difluoro-2-oxoethyl)phenyl] acetic acid (Intermediate 2) (518 mg, 2.42 mmol) in DMF (10 mL) at 0 °C were added Ν,Ν'- diisopropylethylamine (946 μί, 5.49 mmol) and propylphosphonic anhydride (50% in EtOAc, 2.8 mL, 4.39 mmol). The mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 1.11 g of the titled product. lH NMR (300 MHz, DMSO-d6) δ 1.22 (t, J = 6.9 Hz, 3H),
3.28-3.32 (m, 2H), 3.78 (s, 2H), 4.30 (q, J = 6.9 Hz, 2H), 4.93 (t, J = 6.9 Hz, 2H), 7.20 (d, J =
7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), Ί .50-1.61 (m, 7H), 8.36 (s, 1H), 10.47 (s, 1H).
Step 2: N-{ 1 -(2,4-Dichlorophenethyl)- lH-benzo[d] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1 , 1 -difluoro-2- oxopropyl)phenyl)acetamide
Figure imgf000073_0002
To a stirred solution of ethyl 2-(4-(2-((l-(2,4-dichlorophenethyl)-lH-benzo[<i][l,2,3]triazol-5- yl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate (step 1 intermediate) (1.1 g, 2.01 mmol) in anhydrous THF (10 mL) was added 3M methyllithium (1.6 mL, 5.02 mmol) dropwise at -78 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction was quenched with saturated ammonium chloride solution and extracted thrice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was distilled out under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 274 mg of the titled product. lH NMR (300 MHz, DMSO- ) δ 2.37 (s, 3H), 3.28-3.32 (m, 2H), 3.77 (s, 2H), 4.93 (t, J = 6.9 Hz, 2H), 7.20 (d, = 8.1 Hz, 1H), 7.28 (d, = 8.1 Hz, 1H), 7.54 (s, 6H), 7.64 (d, = 8.7 Hz, 1H), 8.36 (s, 1H), 10.45 (s, 1H).
Step 3: N-( 1 -(2,4-Dichlorophenethyl)- lH-benzo[d] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide
To a stirred solution of N-(l-(2,4-dichlorophenethyl)- lH-benzo[<i] [l,2,3]triazol-5-yl)-2-(4- (l,l-difluoro-2-oxopropyl)phenyl)acetamide (step 2 intermediate) (100 mg, 0.19 mmol) in a mixture of THF (4.0 mL) and methanol (1.0 mL) at 0 °C was added sodium borohydride (11 mg, 0.28 mmol) and the resulting mixture was stirred for 1 h at same temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 92 mg of the desired product. XH NMR (300 MHz, DMSO-ifc) δ 1.07 (d, J = 6.3 Hz, 3H), 3.30-3.34 (m, 2H), 3.74 (s, 2H), 4.02-4.06 (m, 1H), 4.92 (t, J = 7.2 Hz, 2H), 5.52 (d, = 6.0 Hz, 1H), 7.20 (d, = 8.1 Hz, 1H), 7.28 (d, = 8.1 Hz, 1H), 7.44 (s, 4H), 7.52- 7.56 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 8.37 (s, 1H), 10.45 (s, 1H); ESI-MS (m/z) 519 (M)+.
Method B
Synthesis of 2-(4-(2-amino-l,l-difluoropropyl)phenyl)-N-(l-(2,4-dichlorophenethyl)- lH- benzo[< J [l,2,3]triazol-5-yl)acetamide (Example 3)
Figure imgf000074_0001
To a solution of N-(l-(2,4-dichlorophenethyl)- lH-benzo[ ] [l,2,3]triazol-5-yl)-2-(4-(l, l- difluoro-2-oxopropyl)phenyl)acetamide (Method A, step 2 intermediate) (50 mg, 0.096 mmol) in a mixture of methanol (4.0 mL) and THF (4.0 mL) was added ammonium acetate (75 mg, 0.96 mmol) followed by molecular sieves (250 mg) at RT. The mixture was stirred at RT for 4 h. Sodium cyanoborohydride (5.7 mg, 0.09 mmol) was added to the reaction mixture and allowed to stir for 2 days at RT. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography to afford 22 mg of the titled product. lU NMR (300 MHz, DMSO- 6) δ 0.95
(d, = 6.3 Hz, 3H), 2.10-2.14 (m, 2H), 3.32-3.34 (m, 2H), 3.74 (s, 2H), 4.92 (t, = 7.2 Hz, 2H), 7.20 (d, = 7.8 Hz, 1H), 7.28 (d, = 8.1 Hz, 1H), 7.45 (s, 4H), 7.51-7.55 (m, 2H), 7.64 (d, = 8.4 Hz, 1H), 8.37 (s, 1H), 10.44 (s, 1H); ESI-MS (m/z) 518 (M)+.
Method C
Synthesis of l-(2-(3,4-dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[< J [l,2,3]triazole-5-carboxamide (Example 17)
Figure imgf000075_0001
To a stirred solution of l-(2-(3,4-dichlorophenyl)-2-methylpropyl)- lH-benzo[<i][l,2,3]triazole- 5-carboxylic acid (Intermediate 24) (50 mg, 0.14 mmol) and (4- (ethylsulfonyl)phenyl)methanamine (Intermediate 3) (38 mg, 0.16 mmol) in dichloromethane (5.0 mL) were added EDCI. HC1 (39 mg, 0.21 mmol), HOBt (22 mg, 0.16 mmol) and DMAP (25 mg, 0.21 mmol) at RT. The reaction was stirred overnight at RT. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material obtained was purified by silica gel column chromatography to obtain 60 mg of the product. lH NMR
(300 MHz, DMSO- ) δ 1.08 (t, J = 7.5 Hz, 3H), 1.40 (s, 6H), 3.26 (q, J = 7.5 Hz, 2H), 4.61- 4.65 (m, 2H), 4.94 (s, 2H), 7.32-7.37 (m, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.68 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 8.7 Hz, 1H), 8.57 (s, 1H), 9.31 (s, 1H); APCI-MS (m/z) 545 (M+H)+.
Method D
Synthesis of (5)-N-(l-(2-(2,6-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ][l,2,3]triazol-5- yl)-2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide (Example 47)
Figure imgf000075_0002
To a stirred solution of l-(2-(2,6-dichlorophenyl)-2-methylpropyl)-lH-benzo[< J [l,2,3]triazol- 5-amine (Intermediate 42) (73 mg, 0.22 mmol) and (5)-2-(4-(l,l-difluoro-2- hydroxypropyl)phenyl)acetic acid (Intermediate 46) (50 mg, 0.22 mmol) in DMF (4.0 mL) were added propylphosphonic anhydride (T3P) (50% solution in ethyl acetate, 0.28 mL, 0.43 mmol) and N,N'-diisopropylethylamine (DIPEA) (93 μί, 0.54 mmol) at RT. The reaction was stirred overnight at RT. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material obtained was purified by silica gel column chromatography to obtain 46 mg of the desired product. lH NMR (400 MHz, DMSO-d6) δ 1.08 (d, = 6.4 Hz, 3H), 1.78 (s, 6H), 3.73 (s, 2H), 4.01-4.05 (m, IH), 5.27 (s, 2H), 5.51 (d, J = 6.0 Hz, IH), 7.19-7.25 (m, IH), 7.38 (d, J = 8.0 Hz, 2H), 7.45 (s, 4H), 7.50 (s, 2H), 8.32 (s, IH), 10.41 (s, IH); APCI-MS (m/z) 547 (M+H)+; Chiral HPLC: Mobile phase A: 0.1% diethylamine in n-hexane, Mobile phase B: 0.1% diethylamine in IPA: MEOH (90: 10), A: B 70: 30, Flow rate: 0.8 mL/min, Column: Chiralcel ΟΙ-Η-250Μ-4.6-5μ, Sample preparation: 200 ppm in IPA, Temperature: 40 °C, Run time: 30 min, Purity: 98.93%, RT: 18.56 min.
Method E
Synthesis of (5)-N-(l-(2-(2,5-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ][l,2,3]triazol-5- yl)-2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide (Example 35)
Figure imgf000076_0001
Method E-l
Step 1 : Ethyl 2-(4-(2-((l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH-benzo[i/] [l,2,3]triazol- 5-yl)amino)-2-oxoethyl)phen -2,2-difluoroacetate
Figure imgf000076_0002
The titled compound was prepared by the reaction of l-(2-(2,5-dichlorophenyl)-2- methylpropyl)-lH-benzo[d] [l,2,3]triazol-5-amine (Intermediate 15) (1.2 g, 3.57 mmol) and [4- (2-ethoxy- l,l-difluoro-2-oxoethyl)phenyl] acetic acid (Intermediate 2) (1.10 g, 4.29 mmol) in the presence of propylphosphonic anhydride (50% in EtOAc, 2.28 mL, 7.15 mmol) and Ν,Ν'- diisopropylethylamine (2.12 mL, 8.94 mmol) in DMF (10 mL) as per the procedure described in Method D to yield 1.70 g of the product. lH NMR (400 MHz, DMSO-ifc) δ 1.23 (t, = 7.2 Hz, 3H), 1.49 (s, 6H), 3.78 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 5.18 (s, 2H), 7.16 (s, IH), 7.36 (dd, = 8.4, 2.4 Hz, IH), 7.51-7.60 (m, 6H), 7.66 (d, = 8.8 Hz, IH), 8.31 (s, IH), 10.46 (s,
1Η).
Step 2: N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ][l,2,3]triazol-5-yl)-2-(4- (1,1 -difluoro-2-oxopropyl)phenyl)acetamide
Figure imgf000076_0003
The titled compound was prepared by the reaction of ethyl 2-(4-(2-((l-(2-(2,5-dichlorophenyl)- 2-methylpropyl)- lH-benzo[<i] [ 1 ,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)-2,2- difluoroacetate (step 1 intermediate) (1.65 g, 2.86 mmol) with in 3 methyllithium (2.4 mL,
7.17 mmol) in THF (10 mL) as per the process described in step 2 of Method A to yield 830 mg of the product. lH NMR (400 MHz, DMSO-d6) δ 1.49 (s, 6H), 2.49 (s, 3H), 3.77 (s, 2H),
5.18 (s, 2H), 7.16 (s, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.51-7.56 (m, 6H), 7.66 (d, J = 8.8 Hz, 1H), 8.31 (s, 1H), 10.44 (s, 1H).
Step 3: (5)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)-2- (4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
Figure imgf000077_0001
To a solution of borane dimethyl sulfide complex (0.22 mL, 0.44 mmol) in THF (5.0 mL) was added a solution of (tf)-(+)-2-methyl-CBS-oxazaborolidine (0.22 mL, 0.22 mmol) in THF (5.0 mL) at -30 °C and the mixture was stirred at the same temperature for 1 h. The mixture was cooled to - 10 °C and a solution of N-(l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[< J [l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro-2-oxopropyl)phenyl)acetamide (step 2 intermediate) (200 mg, 0.37 mmol) in THF (5.0 mL) was drop wise added to the mixture. The reaction mixture was stirred at -10 °C for 30 min before quenching with methanol. The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography to yield 95 mg of the titled product. lU NMR (400 MHz, DMSO- 6) δ 1.08 (d, J = 6.4 Hz, 3H), 1.49 (s, 6H), 3.74 (s, 2H), 4.01-4.09 (m, 1H), 5.18 (s, 2H), 5.51 (d, J = 6.0 Hz, 1H), 7.16 (s, 1H), 7.37 (dd, = 8.4, 2.4 Hz, 1H), 7.45 (s, 4H), 7.51-7.56 (m, 2H), 7.66 (d, = 8.8 Hz, 1H), 8.32 (s, 1H), 10.43 (s, 1H); APCI-MS {mlz) 547 (M+H)+; Chiral HPLC: Mobile phase A: 0.1% diethylamine in n-hexane, Mobile phase B: 0.1% diethylamine in IPA: MEOH (90: 10), A:B 70: 30, Flow: 0.8 mL/min, Column: Chiralcel ΟΙ-Η-250Μ-4.6-5μ, Sample preparation: 200 ppm in IPA, Temperature: 40 °C, Run time: 40 min, Purity: 75.70%, RT: 19.30 min.
Step 4: ( ?)-(5)- l-(4-(2-((l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH- benzo[< J [l,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate
Figure imgf000078_0001
To a stirred solution of (5)-N-(l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[< J [l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide (step 3 intermediate) (95 mg, 0.17 mmol) in dichloromethane (4.0 mL) were added N- benzyloxycarbonyl-L-phenylalanine (52 mg, 0.17 mmol), EDCI.HCl (37 mg, 0.19 mmol) and DMAP (10 mg, 0.08 mmol) at RT. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to isolate 62 mg of the desired diastereomer. APCI-MS imlz) 828 (M+H)+.
Step 5: (5)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ] [l,2,3]triazol-5-yl)-2- (4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
To a stirred solution of ( ?)-(5)-l-(4-(2-((l-(2-(2,5-dichlorophenyl)-2-methylpropyl)-lH- benzo[< J [l,2,3]triazol-5-yl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate (step 3 intermediate) (55 mg, 0.07 mmol) in a mixture of THF, methanol and water (4:4: 1, 4.5 mL) was added lithium hydroxide monohydrate (5.5 mg, 0.11 mmol) at RT and the mixture was stirred for 1.5 h at RT. The reaction mixture was concentrated and added water. The aqueous mixture was acidified with IN HC1 and extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to afford 26 mg of the desired product. lH NMR (400 MHz, DMSO- de) δ 1.08 (d, = 6.4 Hz, 3H), 1.49 (s, 6H), 3.74 (s, 2H), 4.02-4.07 (m, 1H), 5.18 (s, 2H), 5.51 (d, = 6.0 Hz, 1H), 7.16 (s, 1H), 7.37 (dd, = 8.4, 2.4 Hz, 1H), 7.45 (s, 4H), 7.51-7.56 (m, 2H), 7.66 (d, = 9.2 Hz, lH), 8.32 (s, 1H), 10.43 (s, 1H); APCI-MS imlz) 547 (M+H)+; Chiral HPLC: Mobile phase A: 0.1% diethylamine in n-hexane, Mobile phase B: 0.1% diethylamine in IPA: MEOH (90: 10), A:B 70: 30, Flow: 0.8 mL/min, Column: Chiralcel ΟΙ-Η-250Μ-4.6-5μ, Sample preparation: 200 ppm in IPA, Temperature: 40 °C, Run time: 40 min, Purity: 93.49%, RT: 19.30 min.
Method E-2 (S)-N-(l-(2-(2,5-dichlorophenyl)-2-methy^
difluoro-2-hydroxypropyl)phenyl)acetamide (Example 35)
Figure imgf000079_0001
An oven-dried flask was charged with dichloro(p-cymene)ruthenium(II) dimer (11 mg, 0.018 mmol), (15,25)-(+)-N-(4-toluenesulfonyl)- l,2-diphenylethylenediamine (13 mg, 0.036 mmol) and powdered molecular sieves (4 A, 240 mg) at ambient temperature. To that mixture, degassed IPA (10 mL) was added and the resultant suspension was evacuated and flushed with nitrogen. The mixture was heated to 90 °C for 30 min followed by 15 min at 50 °C. A solution of N-( 1 -(2-(2,5-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1,1- difluoro-2-oxopropyl)phenyl)acetamide (Step 2 of Method E- l) (200 mg, 0.36 mmol) in degassed IPA (10 mL) was dropwise added to the reaction mixture over a period of 10 min. After 5 min, a solution of potassium ie/t-butoxide (23 mg, 0.21 mmol) in IPA (5.0 mL) was slowly added to the mixture and the mixture was stirred for 2 h at 50 °C. The mixture was cooled to RT and diluted with ethyl acetate. The suspension was filtered through silica gel bed and the bed was rinsed thoroughly with ethyl acetate. The combined filtrate and washings were concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatography to yield 90 mg of the desired product. The product was confirmed by comparing the analytical data with the product obtained by Method E-2. Chiral purity: 97.02% (19.30 min).
Method F
Method F-l
Synthesis of (5)-l-(l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-lH-benzo[ ][l,2,3]triazol-5- yl)-3-(4-(l,l-difluoro-2-hydroxypropyl)benzyl)urea (Example 24)
Figure imgf000079_0002
To a stirred solution of l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH- benzo[< J [l,2,3]triazole-5-carboxylic acid (Intermediate 21) (150 mg, 0.41 mmol) and triethylamine (57 μί, 0.41 mmol) in dichloromethane (10 mL) was drop wise added diphenylphosphoryl azide (88 μί, 0.41 mmol) at RT and the mixture was stirred at RT for 2 h before heated to reflux for another 2 h. (S)-l-(4-(Aminomethyl)phenyl)- l, l-difluoropropan-2- ol hydrochloride (Intermediate 49) 904-BA-033 (48 mg, 0.20 mmol) was added to the reaction mixture and continued to reflux for 2 h. The mixture was cooled to RT and quenched with ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 10 mg of the product. XH NMR (400 MHz, DMSO-ifc) δ 1.06 (d, = 6.4 Hz, 3H), 1.49 (s, 6H), 399-4.06 (m, 1H), 4.36 (d, J = 6.0 Hz, 2H), 5.15 (s, 2H), 5.51 (d, J = 6.0 Hz, 1H), 6.73-6.78 (m, 1H), 7.16 (d, = 8.8 Hz, 1H), 7.24 (dd, = 8.4, 2.0 Hz, 1H), 7.33- 7.41 (m, 4H), 7.45 (d, = 8.4 Hz, 1H), 7.53 (d, = 8.8 Hz, 1H), 7.64 (d, = 2.4 Hz, 1H), 8.07 (s, 1H), 8.81 (s, 1H); ESI-MS (mlz) 562 (M)+.
Method F-2
Synthesis of (5)- 1 -(4-( 1 , 1 -difluoro-2-hydroxypropyl)benzyl)-3-( 1 -(2-(2,6-difluorophenyl)-2- methylpropyl)-lH-benzo[d] [l,2,3]triazol-5-yl)urea (Example 72)
Figure imgf000080_0001
Step 1 : Phenyl (l-(2-(2,6-difluorophenyl)-2-methylpropyl)-lH-benzo[ ][l,2,3]triazol-5- yl)carbamate
Figure imgf000080_0002
To a stirred solution of l-(2-(2,6-difluorophenyl)-2-methylpropyl)-lH-benzo[< J [l,2,3]triazol- 5-amine (Intermediate 54) (500 mg, 1.65 mmol) in THF (10 mL) was added and pyridine (0.26 mL, 3.31 mmol) followed by phenyl chloroformate (0.31 mL, 2.48 mmol) slowly at 0 °C. The reaction was stirred at RT for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 510 mg of the product. lH NMR (400 MHz, DMSO- ) δ 1.55 (s, 6H), 4.97 (s, 2H), 6.93-7.01 (m, 2H), 7.23-7.35 (m, 4H), 7.42-7.48 (m, 2H), 7.52 (dd, = 9.2, 2.0 Hz, 1H), 7.59 (d, = 8.8 Hz, 1H), 8.12 (s, 1H), 10.44 (s, 1H).
Step 2: (5)- 1 -(4-( 1 , 1 -Difluoro-2-hydroxypropyl)benzyl)-3-( 1 -(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[<i] [ 1 ,2,3]triazol-5-yl)urea To a stirred solution of (5)- l-(4-(aminomethyl)phenyl)- l,l-difluoropropan-2-ol hydrochloride (Intermediate 49) (50 mg, 0.20 mmol) in DMSO (10 mL) were added triethylamine (83 μί, 0.60 mmol) followed by phenyl (l-(2-(2,6-difluorophenyl)-2-methylpropyl)-lH- benzo[< J [l,2,3]triazol-5-yl)carbamate (Step 1 Intermediate) (125 mg, 0.30 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 49 mg of the product. *H NMR (400 MHz, DMSO-ifc) δ 1.06 (d, = 6.4 Hz, 3H), 1.53 (s, 6H), 3.99-4.09 (m, 1H), 4.37 (d, J = 6.0 Hz, 2H), 4.94 (s, 2H), 5.51 (d, J = 6.0 Hz, 1H), 6.75 (t, J = 6.0 Hz, 1H), 6.93-7.01 (m, 2H), 7.25-7.51 (m, 7H), 8.07 (d, J = 1.6 Hz, 1H), 8.81 (s, 1H); ESI-MS (mlz) 530 (M+H)+.
Method G
Synthesis of l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2- hydroxypropyl)benzyl)- lH-benzo[<i] [ 1 ,2,3]triazole-5-carboxamide (Example 54)
Figure imgf000081_0001
Step 1 : l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-iodobenzyl)- lH- benzo [d] [ 1 ,2,3 ] triazole-5-carboxamide
Figure imgf000081_0002
The titled compound was prepared by the reaction of l-(2-(2,4-dichlorophenyl)-2- methylpropyl)-lH-benzo[d] [l,2,3]triazole-5-carboxylic acid (Intermediate 21) (300 mg, 0.82 mmol) and (4-iodophenyl)methanamine (192 mg, 0.82 mmol) in the presence of EDCI HC1 (237 mg, 1.23 mmol), HOBt (133 mg, 0.99 mmol) and DMAP (150 mg, 1.23 mmol) in dichloromethane (10 mL) as per the procedure described in Method C to yield 410 mg of the product. lH NMR (400 MHz, DMSO-d6) δ 1.17 (s, 6H), 4.46 (d, = 6.0 Hz, 2H), 5.25 (s, 2H), 7.12-7.26 (m, 4H), 7.64 (s, 1H), 7.65-7.71 (m, 2H), 7.78-7.83 (m, 1H), 7.79-8.02 (m, 1H), 8.53 (s, 1H), 9.19 (s, 1H).
Step 2: Ethyl 2-(4-((l-(2-(2,4-dichlorophenyl)-2-methylpropyl)- lH-benzo[ ][l,2,3]triazole-5- carboxamido)methyl)phenyl)-2,2-difluoroacetate
Figure imgf000082_0001
To a stirred suspension of l-(2-(2,4-dichlorophenyl)-2-methylpropyl)-N-(4-iodobenzyl)-lH- benzo[< J [l,2,3]triazole-5-carboxamide (Step 1 intermediate) (400 mg, 0.69 mmol) and copper powder (174 mg, 2.76 mmol) in DMSO (8.0 mL) was added 2-bromo-2,2-difluoroacetate (279 mg, 1.38 mmol). The mixture was stirred overnight at 60 °C in a sealed tube. The reaction mixture was cooled to RT and quenched with aqueous ammonium chloride solution. The aqueous mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 35 mg of the desired product. lH NMR (300 MHz, DMSO-d6) δ 1.24 (t, J = 6.8 Hz, 3H), 1.51 (s, 6H), 4.30 (q, J = 6.8 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 8.8, 1.6 Hz, 1H), 8.55 (s, 1H), 9.27 (s, 1H).
Step 3: l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2-oxopropyl)benzyl)- lH-benzo[<i] [ 1 ,2,3]triazole-5-carboxamide
Figure imgf000082_0002
The titled compound was prepared by the reaction of ethyl 2-(4-((l-(2-(2,4-dichlorophenyl)-2- methylpropyl)- lH-benzo[<i] [ 1 ,2,3]triazole-5-carboxamido)methyl)phenyl)-2,2-difluoroacetate (step 2 intermediate) (35 mg, 0.061 mmol) with in 3M methyllithium (50 μί, 0.15 mmol) in THF (5.0 mL) as per the process described in step 2 of Method A to yield 30 mg of the product. lH NMR (400 MHz, DMSO-d6) δ 1.23 (s, 6H), 2.36 (s, 3H), 4.57 (d, J = 6.0 Hz, 2H), 5.26 (s, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.4, 2.0 Hz, 1H), 7.49-7.57 (m, 4H), 7.65 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.8, 1.6 Hz, 1H), 8.55 (s, 1H), 9.26 (d, J = 6.0 Hz, 1H); ESI-MS (mlz) 545 (M+H)+.
Step 4: 1 -(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-( 1 , 1 -difluoro-2- hydroxypropyl)benzyl)- lH-benzo[<i] [ 1 ,2,3]triazole-5-carboxamide
The titled compound was prepared by the reaction of l-(2-(2,4-dichlorophenyl)-2- methylpropyl)- V-(4-( 1 , 1 -difluoro-2-oxopropyl)benzyl)- lH-benzo[<i] [ 1 ,2,3] triazole-5- carboxamide (step 3 intermediate) (30 mg, 0.06 mmol) with in sodium borohydride (4.1 mg, 0.11 mmol) in a mixture of THF (2.0 mL) and methanol (3.0 mL) as per the process described in step 3 of Method A to yield 10 mg of the product. XH NMR (400 MHz, DMSO-d6) δ 1.07 (s, 3H), 1.51 (s, 6H), 4.01-4.05 (m, 1H), 4.56 (d, 7 = 6.0 Hz, 2H), 5.26 (s, 2H), 5.51 (d, 7 = 6.0 Hz, 1H), 7.15 (d, 7 = 8.4 Hz, 1H), 7.24 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.40-7.47 (m, 4H), 7.65 (s, 1H), 7.82 (d, 7 = 8.8 Hz, 1H), 8.02 (dd, 7 = 8.8, 1.6 Hz, 1H), 8.55 (s, 1H), 9.25 (d, 7 = 6.0 Hz, 1H).
Structure, chemical name, intermediates used, method of preparation and analytical data of
Example 1, 4-16, 18-23, 25-46, 48-71 and 73-75 are given below in Table 9.
Table 9: Structure, chemical name, intermediate used, method of preparation and analytical data of Example 1, 4-16, 18-23, 25-46, 48-71 and 73-75.
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
Hz, 1H); APCI-MS (m/z) 575 (M)+. lH NMR (300 MHz, DMSO- 6) 6 1.08 (t, J = 7.2 Hz, 3H), 1.51 (s, 6H), 3.25 (q, J = 6.9 Hz, 2H), 4.59-4.63 (m, 2H),
Intermediate 3
Example 15 5.27 (s, 2H), 7.61 (d, and
l-(2-(3,5-Dichloropyridin-2-yl)-2- J = 8.1 Hz, 2H),
Intermediate 22
methylpropyl)-N-(4- 7.82-7.93 (m, 3H),
Method C
(ethylsulfonyl)benzyl)- 1H- 8.02 (d, J = 8.7 Hz, benzo[JJ [l,2,3]triazole-5- 1H), 8.22 (s, 1H), carboxamide 8.41 (s, 1H), 8.56 (s,
1H), 9.31 (s, 1H); APCI-MS (m/z) 546 (M)+.
lH NMR (300 MHz, DMSO-d6) 6 1.08 (t, J = 7.2 Hz, 3H), -N o 1.80 (s, 6H), 3.26 (q,
J = 7.2 Hz, 2H),
1 -(2-(2,6-Dichlorophenyl)-2- 4.60-4.65 (m, 2H), methylpropyl)-N-(4- 5.35 (s, 2H), 7.21- (ethylsulfonyl)benzyl)- 1H- Intermediate 3
Example 16 7.25 (m, 1H), 7.39 benzo [d] [ 1 ,2, 3 ] triazole-5 - and
(d, = 7.8 Hz, 2H), carboxamide Intermediate 23
7.61 (d, = 6.6 Hz, Method C
2H), 7.69 (d, = 7.8 Hz, 1H), 7.85 (d, = 8.4 Hz, 2H), 7.98 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 9.31 (s, 1H); ESI-MS (m/z) 545 (M+H)+.
lU NMR (300 MHz, DMSO-d6) 6 1.08 (t, / = 7.5 Hz, 3H), 1.44 (s, 6H), 3.26 (q,
Intermediate 3 / = 7.5 Hz, 2H),
Example 18
and 4.59-4.64 (m, 2H),
N-(4-(Ethylsulfonyl)benzyl)- 1 -(2- Intermediate 25 4.96 (s, 2H), 7.58- methyl-2-(4- Method C 7.64 (m, 7H), 7.85 (trifluoromethyl)phenyl)propyl)- (d, = 8.1 Hz, 2H), 1 H-benzo [d] [ 1 ,2,3 ] triazole-5- 7.93 (d, = 8.7 Hz, carboxamide 1H), 7.56 (s, 1H),
9.27-9.31 (m, 1H).
Figure imgf000088_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
7.44 (s, 4H), 7.53 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H), 10.42 (s, 1H); APCI-MS (m/z) 547 (M+H)+.
!H NMR (300 MHz, DMSO-d6) 5 1.08 (t, = 7.2 Hz, 3H), 1.51 (s, 6H), 3.26 (q,
CI
= 7.2 Hz, 2H), 4.60-4.64 (m, 2H), 5.27 (s, 2H), 7.16
Intermediate 3
Example 23 N--N o 1 (s, 1H), 7.36-7.41 and
l-(2-(2,5-Dichlorophenyl)-2- (m, 1H), 7.51 (d, / =
Intermediate 27
methylpropyl)-/V-(4- 7.8 Hz, 1H), 7.61 (d,
Method C
(ethylsulfonyl)benzyl)- 1H- J = 8.1 Hz, 2H), benzo[JJ [ 1 ,2,3]triazole-5- 7.84 (d, J = 7.8 Hz, carboxamide 3H), 8.03 (d, 7 = 8.7
Hz, 1H), 8.58 (s, 1H), 9.31 (s, 1H); APCI-MS (m/z) 545 (M+H)+.
XH NMR (300 MHz,
Figure imgf000089_0001
J = 7.5 Hz, 3H),
CI
1.40 (s, 6H), 3.26 (q, = 7.5 Hz, 2H), 4.59-4.63 (m, 2H),
N--N o Intermediate 3 4.95 (s, 2H), 7.42
Example 25 and (s, 3H), 7.61 (d, J =
1 - (2-(3 ,5 -Dichlorophenyl)-2- Intermediate 28 8.4 Hz, 2H), 7.77 (d, methylpropyl)- V-(4- Method C = 8.4 Hz, 1H), (ethylsulfonyl)benzyl)- 1H- 7.85 (d, = 8.1 Hz, benzo[i/] [ 1 ,2,3] triazole-5- 2H), 7.98 (d, = 8.7 carboxamide Hz, 1H), 8.57 (s,
1H), 9.31 (s, 1H); ESI-MS (m/z) 545 (M)+. Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
lH NMR (300 MHz,
Figure imgf000090_0001
(d, = 5.7 Hz, 3H), 1.77 (s, 6H), 3.72 (s, 2H), 4.01-4.05 (m,
Intermediate 2
Example 26 N-N F F 1H), 5.26 (s, 2H), and
N-(l-(2-(2,6-Dichlorophenyl)-2- 5.51 (d, = 6.3 Hz,
Intermediate 42
methylpropyl)- 1H- 1H), 7.22 (t, = 8.4
Method A
benzo[i/] [l,2,3]triazol-5-yl)-2-(4- Hz, 2H), 7.37 (d, =
(l,l-difluoro-2- 7.2 Hz, 2H), 7.37- hydroxypropyl)phenyl)acetamide 7.49 (m, 5H), 8.31
(s, 1H), 10.41 (s, 1H).
XH NMR (300 MHz,
Figure imgf000090_0002
(d, = 6.3 Hz, 3H), 1.53 (s, 6H), 3.72 (s, 2H), 4.02-4.06 (m,
3 N--N F f Intermediate 2 1H), 4.90 (s, 2H),
Example 27 2-(4-(l,l-Difluoro-2- and 5.50 (d, = 5.1 Hz, hydroxypropyl)phenyl) -N- ( 1 - (2- Intermediate 16 1H), 7.34 (d, = 7.2 methyl-2-(2- Method A Hz, 2H), 7.42-7.46 (trifluoromethyl)phenyl)propyl)- (m, 7H), 7.76-7.79 lH-benzo[< J [l,2,3]triazol-5- (m, 1H), 8.31 (s, yl)acetamide 1H), 10.38 (s, 1H);
ESI-MS (m/z) 547 (M+H)+.
XH NMR (300 MHz,
Figure imgf000090_0003
F (d, = 6.3 Hz, 3H),
1.40 (s, 6H), 3.73 (s, 2H), 4.03-4.07 (m, 1H), 4.94 (s, 2H),
N--N F*F Intermediate 2
Example 28 5.50 (d, = 5.4 Hz,
2-(4-(l,l-Difluoro-2- and
1H), 6.88-6.92 (m, hydroxypropyl)phenyl) -N- ( 1 - (2- Intermediate 17
1H), 7.11-7.24 (m, (2,5-difluorophenyl)-2- Method A
2H), 7.42-7.46 (m, methylpropyl)- 1H- 4H), 7.54 (d, = 7.2 benzo[< J [l,2,3]triazol-5- Hz, 2H), 8.31 (s, yl)acetamide 1H), 10.40 (s, 1H);
ESI-MS (m/z) 515 (M+H)+.
XH NMR (300 MHz,
Intermediate 2
Example 29 and
Figure imgf000090_0004
(d, = 5.7 Hz, 3H),
Intermediate 18
3 N-- F*F 1.43 (s, 6H), 3.72 (s,
Method A
2H), 4.01-4.05 (m,
Figure imgf000091_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
Hz, 1H), 8.32 (s, 1H), 10.41 (s, 1H); Chiral HPLC: Mobile phase A: 0.1% diethylamine in n-hexane, Mobile phase B: 0.1% diethylamine in IPA: methanol, A: B 70: 30, Flow rate: 0.8 mL/min, Column: Chiralcel- OJH- 250 mm *4.6 ιηιη-5μ, sample diluent: IPA, Temperature: 40 °C, Run time: 30 min, chiral purity: 97.83% (15.47 min).
XH NMR (500 MHz,
Figure imgf000092_0001
(d, J = 6.5 Hz, 3H),
I .53 (s, 6H), 3.73 (s, 2H), 4.02-4.06 (m,
Intermediate 54 1H), 4.95 (s, 2H), and 5.50 (d, J = 6.0 Hz,
Intermediate 47 1H), 6.97 (dd, J =
Example 33 Method D I I .0, 8.0 Hz, 2H),
(R)-2-(4-(l, l-Difluoro-2- or 7.27-7.33 (m, 1H), hydroxypropyl)phenyl) -N- ( 1 - (2-
Intermediate 2 7.50 (s, 4H), 7.52 (d, (2,6-difluorophenyl)-2- and J = 9.0 Hz, 1H), methylpropyl)- 1H-
Intermediate 54 7.57 (d, J = 9.0 Hz, benzo[< J [l,2,3]triazol-5- Method E 1H), 8.31 (s, 1H), yl)acetamide
10.40 (s, 1H); ESI- MS (m/z) 515 (M+H)+; chiral purity: 97.70% (16.99 min). Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
lH NMR (500 MHz,
Figure imgf000093_0001
(d, = 6.5 Hz, 3H),
Intermediate 15 1.49 (s, 6H), 3.73 (s, and 2H), 4.00-4.09 (m,
Intermediate 47 1H), 5.18 (s, 2H),
Example 34 N.N F*F Method D 5.50 (d, = 6.0 Hz,
(R)-N-(l-(2-(2,5-Dichlorophenyl)- or 1H), 7.15 (s, 1H),
2-methylpropyl)- 1H- Intermediate 2 7.16-7.20 (m, 1H), benzo[i/] [l,2,3]triazol-5-yl)-2-(4- and 7.51-7.56 (m, 6H),
(l,l-difluoro-2- Intermediate 15 7.66 (d, = 9.0 Hz, hydroxypropyl)phenyl)acetamide Method E 1H), 8.32 (s, 1H),
10.42 (s, 1H); chiral purity: 98.00% (22.17 min).
XH NMR (400 MHz,
Figure imgf000093_0002
(d, = 6.4 Hz, 3H), 1.49 (s, 6H), 3.74 (s, 2H), 4.02-4.07 (m,
Intermediate 15
1H), 5.18 (s, 2H), and
5.51 (d, = 6.0 Hz,
Intermediate 46
1H), 7.16 (s, 1H),
Example 35 Method D
7.37 (dd, = 8.4, 2.4
(S)-N-(l-(2-(2,5-Dichlorophenyl)- Or
Hz, 1H), 7.45 (s,
2-methylpropyl)- 1H- Intermediate 2
4H), 7.51-7.56 (m, benzo[d] [l,2,3]triazol-5-yl)-2-(4- and
2H), 7.66 (d, = 9.2
(l,l-difluoro-2- Intermediate 15
Hz, 1H), 8.32 (s, hydroxypropyl)phenyl)acetamide Method E
1H), 10.43 (s, 1H); APCI-MS (m/z) 547 (M+H)+; chiral purity: 98.42% (19.35 min).
lH NMR (300 MHz, DMSO-d6) 6 1.11 (t,
0 -0H = 7.2 Hz, 3H),
1.51 (s, 6H), 3.26 (q,
Intermediate 21 = 7.2 Hz, 2H), and 3.71-3.75 (m, 2H),
Example 36
(S)- l-(2-(2,4-Dichlorophenyl)-2- Intermediate 5.08 (t, = 6.3 Hz, methylpropyl)-N-( 1 -(4- 45 1H), 5.14-5.17 (m, (ethylsulfonyl)phenyl)-2- 1H), 5.26 (s, 2H), hydroxyethyl)- 1H- Method C 7.14 (d, = 8.7 Hz, benzo[d] [l,2,3]triazole-5- 1H), 7.23 (d, = 8.7 carboxamide Hz, 1H), 7.66 (d, =
9.3 Hz, 2H), 7.69 (s, 1H), 7.77-7.86 (m,
Figure imgf000094_0001
Figure imgf000095_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
lH NMR (400 MHz, DMSO-rf6) 6 1.10 (t, J = 7.4 Hz, 3H), 1.52 (s, 6H), 3.27 (q, = 7.4 Hz, 2H), 3.69-3.79 (m, 2H), 5.09 (t, J = 5.8 Hz,
CI o ^ 0H 1H), 5.16-5.21 (m,
1H), 5.27 (s, 2H), 7.15 (d, J = 2.4 Hz,
Intermediate 27
1H), 7.37 (dd, = and
Example 40 8.4, 2.4 Hz, 1H),
(S)- l-(2-(2,5-Dichlorophenyl)-2- Intermediate
7.54 (d, = 8.4 Hz, methylpropyl)-/V-(l-(4- 45
1H), 7.69 (d, = 8.4 (ethylsulfonyl)phenyl)-2- Hz, 2H), 7.82 (s, hydroxyethyl)-lH- Method C
1H), 7.85 (d, 7 = 8.2 benzo [d] [ 1 ,2 , 3 ] triazole-5 - Hz, 2H), 7.99 (dd, J carboxamide = 8.8, 1.2 Hz, 1H),
8.64 (s, 1H), 8.98 (d, = 7.7 Hz, 1H); APCI-MS (m/z) 575, 577 (M+H)+; chiral purity: 98.28% (16.06 min).
XH NMR (400 MHz, DMSO-d6) 6 1.10 (t, / = 7.4 Hz, 3H), 1.52 (s, 6H), 3.27 (q, J = 7.4 Hz, 2H), 3.69-3.79 (m, 2H),
Cl o ί-ΟΗ 5.09 (t, = 5.8 Hz,
1H), 5.16-5.21 (m,
Intermediate 27 1H), 5.27 (s, 2H),
N--N O and 7.15 (d, = 2.4 Hz,
Example 41
(R)- l-(2-(2,5-Dichlorophenyl)-2- Intermediate 1H), 7.37 (dd, = methylpropyl)-N-( 1 -(4- 44 8.4, 2.4 Hz, 1H), (ethylsulfonyl)phenyl)-2- 7.54 (d, J = 8.4 Hz, hydroxyethyl)- 1H- Method C 1H), 7.69 (d, = 8.4 benzo[d] [l,2,3]triazole-5- Hz, 2H), 7.82 (s, carboxamide 1H), 7.85 (d, = 8.2
Hz, 2H), 7.99 (dd, = 8.8, 1.2 Hz, 1H), 8.64 (s, 1H), 8.98 (d, J = 7.7 Hz, 1H); APCI-MS (m/z) 575, 577 (M+H)+;
Figure imgf000097_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
lH NMR (500 MHz, DMSO-d6) 6 1.08 (t, = 7.2 Hz, 3H), 1.28 (s, 6H), 3.26 (q,
CI = 7.2 Hz, 2H),
3.70-3.73 (m, IH), 3.75-3.79 (m, IH), 5.08 (s, 2H), 5.15- 5.21 (m, IH), 7.28
Intermediate 30
(d, = 6.3 Hz, IH),
Example 44 N'-N 0 " and
7.54 (d, = 8.4 Hz, l-(2-(2,4-Dichlorophenoxy)-2- Intermediate 41
2H), 7.69 (s, IH), methylpropyl)-N-(l-(4- Method C
7.70 (d, = 8.5 Hz, (ethylsulfonyl)phenyl)-2- 2H), 7.85 (d, = 8.4 hydroxyethyl)- 1H- Hz, 2H), 7.98 (d, 7 = benzo[d] [ 1 ,2,3] triazole-5- 2.5 Hz, IH), 8.02 (d, carboxamide
= 2.5 Hz, IH), 8.70 (s, lH), 8.99 (d, = 8.0 Hz, IH); ESI-MS (m/z) 591 (M)+.
XH NMR (300 MHz, DMSO-d6) 6 1.08 (t, = 7.5 Hz, 3H), 1.52 (s, 6H), 3.26 (q, = 7.5 Hz, 2H), 4.66 (d, = 6.3 Hz,
Intermediate 3
Example 45 N-.N O 2H), 5.27 (s, 2H), and
3-(2-(2,4-Dichlorophenyl)-2- 7.17-7.24 (m, 2H),
Intermediate 31
methylpropyl)- V-(4- 7.63 (d, = 6.9 Hz,
Method C
(ethylsulfonyl)benzyl)-3H- 3H), 7.85 (d, y = 7.8 [ 1 ,2,3]triazolo[4,5- ]pyridine-6- Hz, 2H), 8.98 (s, carboxamide IH), 9.16 (s, IH),
9.46 (s, IH); ESI- MS (m/z) 546, 548 (M+H)+.
XH NMR (300 MHz, DMSO- e) δ 1.07 (d, = 6.3 Hz, 3H), 1.49 (s, 6H), 3.77 (s,
N--N F F Intermediate 2
Example 46 2H), 4.02-4.06 (m,
N-(3-(2-(2,4-Dichlorophenyl)-2- and
IH), 5.19 (s, 2H), methylpropyl)-3H- Intermediate 43
5.52 (d, = 6.3 Hz, [ 1 ,2,3]triazolo[4,5- ]pyridin-6-yl)- Method A
IH), 7.15-7.19 (m,
2-(4-(l, l-dilluoro-2- 3H), 7.42-7.46 (m, hydroxypropyl)phenyl)acetamide 4H), 7.61 (s, IH),
8.70 (s, IH), 10.72 Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
(s, 1H); ESI-MS (m/z) 548 (M)+.
lH NMR (400 MHz,
Figure imgf000099_0001
(d, J = 6.4 Hz, 3H), 1.41 (s, 6H), 3.72 (s, 2H), 4.02-4.06 (m, 1H), 4.94 (s, 2H), 5.51 (d, J = 6.0 Hz, 1H), 6.90-6.93 (m, 1H), 7.10-7.15 (m, 1H), 7.21-7.26 (m, 1H), 7.44 (s, 4H),
F 7.49-7.59 (m, 2H),
Intermediate 17
8.31 (s, 1H), 10.41 and
(s, 1H); ESI-MS
Intermediate 46
Example 48 N--N FT (m/z) 513 (M-H)-;
Method D
(S)-2-(4-(l,l-Difluoro-2- Chiral HPLC:
Or
hydroxypropyl)phenyl) -N- ( 1 - (2- Mobile phase A:
Intermediate 2
(2,5-difluorophenyl)-2- 0.1% diethylamine and
methylpropyl)- 1H- in ft-hexane, Mobile
Intermediate 17
benzo[< J [l,2,3]triazol-5- phase B: 0.1%
Method E
yl)acetamide diethylamine in
IPA, A: B 70: 30, Flow rate: 0.8 mL/min, Column: Chiralcel-OJH- 250
Figure imgf000099_0002
sample diluent: IPA, Temperature: 40 °C, Run time: 30 min, chiral purity: 96.19% (20.75 min).
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Chemical Name
Example Intermediate/
and Analytical Data No. Method
Structure
(S)-N-(4-(l, l-Difluoro-2- Method C (d, J = 6.0 Hz, 2H), hydroxypropyl)benzyl)- 1 -(2- 5.00 (s, 2H), 5.51 (d, methyl-2-(2- = 6.0 Hz, 1H), (trifluoromethyl )phenyl)propyl) - 7.40-7.79 (m, 6H), lH-benzo[d][ l,2,3]triazole-5- 7.52 (d, = 7.8 Hz, carboxamide 1H), 7.78-7.85 (m,
2H), 7.94-7.98 (m, 1H), 8.56 (s, 1H), 9.25 (s, 1H); ESI- MS (m/z) 548 (M+H)+.
XH NMR (400 MHz,
Figure imgf000106_0001
(d, J = 6.0 Hz, 3H),
F 1.35 (s, 6H), 4.00- 4.12 (m, 1H), 4.56
Intermediate 35
(d, J = 6.0 Hz, 2H), and
4.94 (s, 2H), 5.51 (d,
Example 66 Intermediate 49
= 6.0 Hz, 1H),
(S)-N-(4-(l, l-Difluoro-2- 7.02-7.17 (m, 3H), hydroxypropyl)benzyl)- 1 -(2-(3 ,5- 7.40-7.49 (m, 4H), difluorophenyl)-2-methylpropyl)- Method C
7.71 (d, J = 7.8 Hz, lH-benzo[<i][l,2,3]triazole-5- 1H), 7.94-7.99 (m, carboxamide 1H), 8.57 (s, 1H),
7.22-9.29 (m, 1H); ESI-MS (m/z) 515 (M+H)+.
'H NMR (400 MHz,
Figure imgf000106_0002
(d, = 7.2 Hz, 3H), 1.67 (s, 6H), 3.99- 4.09 (m, 1H), 4.56
Intermediate 36 (d, J = 6.0 Hz, 2H), and 5.24 (s, 2H), 5.51 (d,
Example 67 Intermediate 49 = 6.0 Hz, 1H),
(S)-l-(2-(2-Chloro-6- 7.02-7.12 (m, 1H), fluorophenyl)-2-methylpropyl)- V- 7.25-7.35 (m, 2H), (4-( l, l-difluoro-2- Method C 7.40-7.49 (m, 4H), hydroxypropyl)benzyl)-lH- 7.73 (d, J = 9.0 Hz, benzo[JJ [ 1 ,2,3]triazole-5- 1H), 7.77-8.03 (m, carboxamide
1H), 8.57 (s, 1H), 9.23-9.29 (m, 1H); ESI-MS (m/z) 532 (M+H)+.
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
PHARMACOLOGICAL ACTIVITY
BIOLOGICAL ASSAY The compounds described herein were screened for ROR gamma modulator activity using the TR-FRET assay by Lantha Screen as described in JBC 2011, 286, 26: 22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.
TR-FRET ASSAY FOR ROR GAMMA:
The assay is based on the principle that binding of the agonist to the ROR gamma causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide. ROR gamma being constitutively active, the Fluorescein- D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an antagonist decreases the recruitment of the co-activator peptide, causing a decrease in the TR- FRET signal compared to control with no compound. The assay was performed using a two- step procedure, pre-incubation step with the compound followed by the detection step on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.
Test compounds or reference compounds such as T0901317 (Calbiochem) were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration. The final concentration of DMSO in the reaction was 4% (v/v). The assay mixture was prepared by mixing lOnM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01% BSA with or without the desired concentration of the compound. The reaction was incubated at 22°C for 1 hour. The pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and lOnM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 hour at room temperature and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound was calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.
The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 μΜ and 10.0 μΜ are given in the table along with IC50 (nM) details for selected examples. The compounds were found to have IC50 less than 500nM, preferably less than ΙΟΟηΜ, more preferably less than 50nM. The IC50 (nM) values are set forth in Table 10 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100.0 nM and "C" refers to IC50 values more than 100 nM.
Table 10:
Sr. Example No. % Inhibition at IC50 value
No 1 μΜ (range)
10 μΜ
1. Example 1 69.41 73.68 A
2. Example 2 69.07 79.14 B
3. Example 3 47.04 58.97 -
4. Example 4 78.52 71.28 A
5. Example 5 78.42 75.05 A
6. Example 6 28.42 56.73 -
7. Example 7 78.63 82.68 A
8. Example 8 81.13 82.19 A
9. Example 9 81.63 73.95 A
10. Example 10 80.30 84.22 A
11. Example 11 80.67 61.60 A
12. Example 12 71.80 66.98 A
13. Example 13 70.03 59.29 A
14. Example 14 77.45 79.52 B
15. Example 15 72.77 80.21 B
16. Example 16 48.43 49.40 -
17. Example 17 77.84 80.98 A
18. Example 18 75.36 80.00 A
19. Example 19 78.06 82.48 B
20. Example 20 78.62 85.57 A
21. Example 21 77.39 81.58 A
22. Example 22 81.46 85.66 A
23. Example 23 76.54 79.51 A
24. Example 24 69.06 72.10 -
25. Example 25 71.18 76.44 A
26. Example 26 77.45 79.54 A
27. Example 27 79.3 86.2 A
28. Example 28 84.9 88.6 A Sr. Example No. % Inhibition at IC50 value
No (range)
1 μΜ 10 μΜ
29. Example 29 64.96 72 B
30. Example 30 85 88.68 A
31. Example 31 79.67 82.35 A
32. Ex ample 32 80.44 81.92 A
33. Example 33 74.96 76.71 A
34. Example 34 85.9 88.5 A
35. Example 35 86.29 89.43 A
36. Example 36 72.43 80.54 B
37. Example 37 79.86 80.44 A
38. Example 38 73.17 77.83 A
39. Ex ample 39 67.27 68.64 -
40. Example 40 78.73 88.76 C
41. Example 41 80.81 84.69 A
42. Example 42 58.11 63.75 -
43. Example 43 51.15 55.25 -
44. Example 44 63.84 71.86 -
45. Example 45 53.97 26.38 -
46. Example 46 51.02 19.52 -
47. Example 47 69.42 71.67 A
48. Example 48 79.01 85.6 A
49. Example 49 76.32 78.69 A
50. Example 50 64.48 72.61 A
51. Example 1 76.58 81.88 B
52. Example 52 68.43 76.51 C
53. Example 53 46.81 52.01 -
54. Example 54 70.76 69.26 A
55. Example 55 76.85 82.31 A
56. Example 56 80.02 86.24 A
57. Example 57 74.7 80.39 A
58. Example 58 79.17 83.87 A
59. Example 59 76.69 74.77 A
60. Example 60 79.52 80.69 A Sr. Example No. % Inhibition at IC50 value
No 1 μΜ 10 μΜ (range)
61. Example 61 77.13 72.11 A
62. Example 62 67.05 70.9 -
63. Example 63 52.85 49.43 -
64. Example 64 67.05 70.9 -
65. Example 65 59.91 65.03 -
66. Example 66 64.84 75.2 -
67. Example 67 64 65.04 -
68. Example 68 52.85 49.43 -
69. Example 69 58.93 54.17 -
70. Example 70 34.03 43.28 -
71. Example 71 29.38 50.16 -
72. Example 72 67.78 75.5 C
73. Example 73 45.05 56.83 -
74. Example 74 1.59 0 -
75. Example 75 68.26 67.93 -
(-): Not determined.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I)
Figure imgf000114_0001
(I)
or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
G is selected from G1 and G2;
Figure imgf000114_0002
L is selected from L1, L2 and L3;
Figure imgf000114_0003
proviso that when G is G , then L is not L ; wherein p and q represents point of attachment;
X1, X2, X3 and X4 which may be same or different, are each independently selected from N and CH; with a proviso that not more than two of X1, X2 and X3 are N simultaneously; each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R2 is selected from Ci-galkyl and haloCi-galkyl;
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
'n' is 0, 1, 2 or 3; and 't' is 1, 2 or 3;
2. The compound according to claim 1 , wherein ring A is phenyl, pyridinyl or pyrimidinyl.
3. The compound according to claim 1 or 2, wherein R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
4. The compound according to any one of claims 1 to 3, wherein 'n' is 1, 2 or 3.
5. The compound according to any one of claims 1 to 4, wherein G is
Figure imgf000115_0001
6. The compound according to claim 5, wherein R2 is ethyl.
7. The compound according to any one of claims 1 to 4, wherein G is
Figure imgf000115_0002
8. The compound according to claim 7, wherein R3 is hydroxyl, amino or methyl.
9. The compound according to claim 7, wherein Ra and Rb are independently hydrogen or methyl.
10. The compound according to claim 7, wherein one of Ra and Rb is hydrogen and the other is methyl.
11. The compound according to any one of claims 1 to 10, wherein L is
Figure imgf000115_0003
and Rc is hydrogen.
o R°
p \ " q
12. The compound according to any one of claims 1 to 10, wherein L is H and R is hydrogen or CH2OH.
13. The compound according to any one of claims 1 to 10, wherein L is
Figure imgf000115_0004
and Rc is hydrogen.
14. The compound according to any one of claims 1 to 13, wherein X1, X2, X3 and X4 are CH.
15. The compound according to any one of claims 1 to 13, wherein X1 is N and X2, X3 and X4 are CH.
16. The compound according to any one of claims 1 to 15, wherein Rx and Ryare hydrogen.
17. The compound according to any one of claims 1 to 15, wherein Rx and Ry are methyl.
18. The compound according to any one of claims 1 to 15, wherein 't' is 1.
19. The compound according to claim 1, wherein ring A is phenyl, pyridinyl, pyrimidinyl or chromanyl;
each of R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy;
R2 is ethyl;
R3 is hydroxyl, amino or methyl
Ra and Rb are independently hydrogen or methyl;
Rc is hydrogen and CH2OH;
X1 is CH or N; X2, X3 and X4 are CH;
Rx and Ry are independently hydrogen or methyl;
'n' is 1, 2 or 3; and
't' is 1.
A compound of formula (II)
Figure imgf000116_0001
(II)
or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
Figure imgf000116_0002
; wherein p and q represents point of attachment;
X1 is N or CH;
each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl; Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkyl;
'n' is 0, 1, 2 or 3; and
't' is 1, 2 or m 3;
21. The compound according to claim 20, wherein ring A is phenyl, pyridinyl or pyrimidinyl.
22. The compound according to claim 20 or 21, wherein R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
23. The compound according to any one of claims 20 to 22, wherein 'n' is 1, 2 or 3.
24. The compound according to any one of claims 20 to 23, wherein R3 is hydroxyl, amino or methyl.
25. The compound according to any one of claims 20 to 24, wherein Ra and Rb are independently hydrogen or methyl.
26. The compound according to any one of claims 20 to 24, wherein one of Ra and Rb is hydrogen and the other is methyl.
27. The compound according to any one of claims 20 to 26, wherein L
Figure imgf000117_0001
and Rc is hydrogen.
O R° p \ ~ q
28. The compound according to any one of claims 20 to 26, wherein L is H and Rc is hydrogen.
O R° ' N N ,' ^ q
29. The compound according to any one of claims 20 to 26, wherein L is H H and Rc is hydrogen.
30. The compound according to any one of claims 20 to 29, wherein Rx and Ry are hydrogen.
31. The compound according to any one of claims 20 to 29, wherein Rx and Ry are methyl.
32. The compound according to any one of claims 20 to 31, wherein 't' is 1.
33. A compound of formula III)
Figure imgf000117_0002
(III) or a stereoisomer thereof, a diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
Ring A is selected from C6-i4aryl, C6-i4aryloxy, 5-14 membered heteroaryl and 3-15 membered heterocyclyl;
L is selected from
Figure imgf000118_0001
; wherein p and q represents point of attachment;
X1 and X4 which may be same or different, are each independently selected from N and
CH;
each occurrence of R1 is independently selected from halogen, cyano, hydroxyl, Ci- salkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3-6cycloalkyl and C3- 6cycloalkylCi-salkyl;
R2 is selected from Ci-galkyl and haloCi-galkyl;
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl;
Rx and Ry, which may be same or different, are each independently selected from hydrogen and Ci-galkylp and q represents point of attachment;
'n' is 0, 1, 2 or 3; and
't' is 1, 2 or 3;
34. The compound according to claim 33, wherein ring A is phenyl, pyridinyl or pyrimidinyl.
35. The compound according to claim 33 or 34, wherein R1 is F, CI, methyl, trifluoromethyl or trifluoromethoxy.
36. The compound according to any one of claims 33 to 35, wherein 'n' is 1, 2 or 3.
37. The compound according to claim 33, wherein R2 is ethyl.
O Rc
38. The compound according to any one of claims 33 to 37, wherein L is H and Rc is hydrogen or CH2OH.
O Rc ' N N q
39. The compound according to any one of claims 33 to 37, wherein L is H H and Rc is hydrogen.
40. The compound according to any one of claims 33 to 39, wherein Rx and Ry are hydrogen.
41. The compound according to any one of claims 33 to 39, wherein Rx and Ry are methyl. 42. The compound according to any one of claims 33 to 41, wherein 't' is 1.
43. A compound of formula (IV
Figure imgf000119_0001
(IV)
or a stereoisomer thereof, diastereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
-j— COR4 -|— c NH2
Q is selected from 0 , and o ;
R3 is selected from hydroxyl, amino, Ci-galkyl and Ci-galkoxy;
R4 is selected from hydrogen and Ci-galkyl;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci-galkyl; and
Rc is selected from hydrogen, hydroxyCi-galkyl and Ci-galkyl.
—COR4
44. The compound according to claim 43, wherein Q is 0
45. The compound according to claim 44, wherein R4 is hydrogen.
46. The compound according to any one of claims 43 to 45, wherein one of Ra and Rb is hydrogen and the other is methyl.
47. A compound selected from
N-( 1 -(2,4-Dichlorophenethyl)- lH-benzo[d] [ 1 ,2,3] triazol-5-yl)-2-(4-( 1 , 1 - difluoropropyl)phenyl)acetamide;
N-(l-(2,4-dichlorophenethyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4-(l, l-difluoro-2- hydroxypropyl)phenyl)acetamide;
2-(4-(2-amino-l, l-difluoropropyl)phenyl)-N-(l-(2,4-dichlorophenethyl)-lH- benzo [d] [ 1 ,2, 3 ] triazol-5 -yl) acetamide ;
N-(l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide; N-(l-(2-(3,5-Dichloropyridin-2-yl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol -5- yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(4-fluorophenethyl)- 1 H- benzo [d] [ 1 ,2, 3 ] triazol-5 -yl) acetamide ;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-(2,4-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-methyl-2-(4- (trifluoromethoxy)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-methyl-2-(4- (trifluoromethyl)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
N-(l-(2-(2-Chloro-4-fluorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5- yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide;
N-(l-(2-(4-Chloro-2-fluorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5- yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-((5-(ethylsulfonyl)pyridin-2- yl)methyl)- 1 H-benzo [d] [ 1 ,2,3 ] triazole-5-carboxamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- 1 H-benzo [d] [ 1 ,2,3] triazole-5-carboxamide; l-(2-(3,5-Dichloropyridin-2-yl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide; l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide; l-(2-(3,4-dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide;
N-(4-(Ethylsulfonyl)benzyl)- l-(2-methyl-2-(4-(trifluoromethyl)phenyl)propyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide;
N-(4-(Ethylsulfonyl)benzyl)- l-(2-methyl-2-(4-trifluoromethoxy)phenyl)propyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide; N-(l-(2-(3,5-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide;
N-(l-(2-(2-Chlorophenyl)-2-methylpropyl)-lH-benzo[d][l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide;
N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide; l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide;
(S)-l-(l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-lH-benzo[d] [l,2,3]triazol-5-yl)- 3-(4-( 1 , 1 -difluoro-2-hydroxypropyl)benzyl)urea;
1- (2-(3,5-Dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-lH- benzo[d] [l,2,3]triazole-5-carboxamide;
N-(l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide;
2- (4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-methyl-2-(2- (trifluoromethyl)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-(2,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-methyl-2-(2- (trifluoromethoxy)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-(3 ,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-( 1 -(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(R)-2-(4-(l, l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(R)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-lH-benzo[d][l,2,3]triazol-5-yl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide; (S)-N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide;
(S)-l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(R)- l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(R)- l-(2-(4-Chloro-2-fluorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl) phenyl)-2-hydroxyethyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide;
(R)- l-(2-(3,5-Dichloropyridin-2-yl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl) phenyl)-2-hydroxyethyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide;
(S)-l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(R)- l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(S)-l-(2-(2,6-Difluorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(R)- l-(2-(2,6-Difluorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
3-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(ethylsulfonyl)benzyl)-3H- [l,2,3]triazolo[4,5-b]pyridine-6-carboxamide;
N-(3-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-3H-[l,2,3]triazolo[4,5-b]pyridin-6- yl)-2-(4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide;
(S)-N-(l-(2-(2,6-dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-(2,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(R)-2-(4-(l, l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-(2,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(R)-N-(l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)-lH-benzo[d][l,2,3]triazol-5-yl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide; N-(l-(2-(2,5-Dichlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2-(4- (1, 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamide;
2-(4-(l,l-Difluoro-2-hydroxy-2-methylpropyl)phenyl)-N-(l-(2-(2,6-difluorophenyl)- 2-methylpropyl)- lH-benzo[d][l,2,3]triazol-5-yl)acetamide;
(R)- l-(2-(2,6-Dichlorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2- hydroxypropyl)benzyl)- lH-benzo[d][l,2,3]triazole-5-carboxamide;
(S)-N-(l-(2-(2-Chlorophenyl)-2-methylpropyl)- lH-benzo[d] [l,2,3]triazol-5-yl)-2- (4- ( 1 , 1 -difluoro -2-hydroxypropyl)phenyl) acetamide ;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-(3,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-methyl-2-(2- (trifluoromethyl)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-methyl-2-(3,4,5- trifluorophenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-methyl-2-(2,4,6- trifluorophenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(R)- l-(2-(2,5-Difluorophenyl)-2-methylpropyl)-N-(l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl)- lH-benzo[d] [ 1 ,2,3] triazole-5-carboxamide;
(S)-2-(4-(l,l-Difluoro-2-hydroxypropyl)phenyl)-N-(l-(2-methyl-2-(4- (trifluoromethyl)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)acetamide;
(S)- 1 -(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-( 1 , 1 -difluoro-2- hydroxypropyl)benzyl)- lH-benzo[d][l,2,3]triazole-5-carboxamide;
(R)- l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2- hydroxypropyl)benzyl)- lH-benzo[d][l,2,3]triazole-5-carboxamide;
(S)- 1 -(2-(2-Chlorophenyl)-2-methylpropyl)-N-(4-( 1 , 1 -difluoro-2- hydroxypropyl)benzyl)- lH-benzo[d][l,2,3]triazole-5-carboxamide;
(S)-N-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)benzyl)- 1 -(2-methyl-2-(2- (trifluoromethyl)phenyl)propyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide; (S)-N-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)benzyl)- l-(2-(3,5-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide;
(S)- 1 -(2-(2-Chloro-6-fluorophenyl)-2-methylpropyl)-N-(4-( 1 , 1 -difluoro-2- hydroxypropyl)benzyl)- lH-benzo[d][l,2,3]triazole-5-carboxamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoro-2-hydroxy-2- methylpropyl)benzyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide; l-(2-(2,4-Dichlorophenyl)-2-methylpropyl)-N-(4-(l, l-difluoropropyl)benzyl)- lH- benzo[d] [l,2,3]triazole-5-carboxamide;
(R)- l-(2-(2,6-Dimethylpyrimidin-4-yl)-2-methylpropyl)-N-(l-(4- (ethylsulfonyl)phenyl)-2-hydroxyethyl)- lH-benzo[d] [ 1 ,2,3]triazole-5-carboxamide;
(S)-N-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)benzyl)- 1 -(2-(2,6-dimethylpyrimidin-4-yl)-
2- methylpropyl)- 1 H-benzo [d] [ 1 ,2,3 ] triazole-5-carboxamide;
(S)- 1 -(4-( 1 , 1 -difluoro-2-hydroxypropyl)benzyl)-3 -( 1 -(2-(2,6-difluorophenyl)-2- methylpropyl)- lH-benzo[d] [ 1 ,2,3]triazol-5-yl)urea;
(R)- l-(l-(2-(2,6-Difluorophenyl)-2-methylpropyl)-lH-benzo[d] [l,2,3]triazol-5-yl)-
3- (l-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)urea; l-(6-Chloro-2,2-dimethylchroman-4-yl)-N-((R)- l-(4-(ethylsulfonyl)phenyl)-2- hydroxyethyl) - 1 H-benzo [d] [ 1 ,2, 3 ] triazole- 5 -carboxamide ; and
N-(l-(6-Chloro-2,2-dimethylchroman-4-yl)-lH-benzo[d][l,2,3]triazol-5-yl)-2-(4- ((S)- l,l-difluoro-2-hydroxypropyl)phenyl)acetamide; or a pharmaceutically acceptable salt thereof.
48. A compound of formul
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof.
49. A compound of formul
Figure imgf000124_0002
or a pharmaceutically acceptable salt thereof.
50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or claims 47 to 49 and a pharmaceutically acceptable excipient.
51. The pharmaceutical composition according to claim 50, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
52. A method of treating a RORyt mediated disease, disorder, syndrome, or condition in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 42 or claims 47 to 49.
53. The method according to claim 52, wherein the disease, disorder, syndrome or condition is an inflammatory or autoimmune disease.
54. The method according to claim 53, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease (COPD), asthma, multiple sclerosis, colitis, ulcerative colitis and inflammatory bowel disease.
55. The method according to claim 52, wherein the disease, disorder, syndrome or condition is pain, chronic pain, acute pain, inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, posttraumatic injury, or pain associated with irritable bowel syndrome.
56. The method according to claim 52, wherein the disease, disorder, syndrome or condition is chronic obstructive pulmonary disease (COPD), asthma, bronchospasm or cough.
57. A method of treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis, psoriasis and inflammatory bowel disease comprising administering to a subject in need thereof a compound according to any one of claims 1 to 42 or claims 47 to 49.
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