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WO2017051319A1 - Aryl and heteroaryl ether compounds as ror gamma modulators - Google Patents

Aryl and heteroaryl ether compounds as ror gamma modulators Download PDF

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Publication number
WO2017051319A1
WO2017051319A1 PCT/IB2016/055620 IB2016055620W WO2017051319A1 WO 2017051319 A1 WO2017051319 A1 WO 2017051319A1 IB 2016055620 W IB2016055620 W IB 2016055620W WO 2017051319 A1 WO2017051319 A1 WO 2017051319A1
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chloro
phenyl
acetamide
fluorophenyl
oxy
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Inventor
Sachin Sundarlal Chaudhari
Sanjib Das
Laxmikant Atmaram Gharat
Sachin Vasantrao Dhone
Abraham Thomas
Neelima Khairatkar-Joshi
Daisy Manish Shah
Malini Bajpai
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present patent application is directed to aryl and heteroaryl ether 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 cell 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., 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 are modulators of the RORyt receptor.
  • the present invention relates to a compound of formula (I)
  • X 1 is selected from CR 3 and N;
  • Ring B is selected from phenyl, pyridyl and benzimidazolyl
  • R a and R b which may be same or different, are each independently selected from hydrogen and Ci_ 8 alkyl;
  • R 1 is selected from hydroxyl and Ci_ 8 alkyl
  • each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8 alkyl, Ci_ 8 alkoxy, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, hydroxyCi_ 8 alkyl, C3_ 6 cycloalkyl and 3 to 15 membered heterocyclyl;
  • R is selected from hydrogen and halogen
  • R 4 is selected from hydrogen and Ci_ 8 alkyl
  • R x and R y are each independently selected from Ci_ 8 alkyl and haloCi_ 8 alkyl; or R x and R y together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
  • 'n' is 0, 1, 2, 3 or 4;
  • 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 and 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 X 1 is N (according to an embodiment defined below), R 1 is hydroxyl or methyl (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
  • R a and R b are hydrogen and the other is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R a and R b are Ci_ 8 alkyl (e.g. methyl).
  • R 1 is hydroxyl or Ci_ 8 alkyl (e.g. methyl).
  • R is hydroxyl, halogen (e.g. fluoro or chloro), Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), C3_ 6 cycloalkyl (e.g. cyclopropyl) or 3 to 15 membered heterocyclyl (e.g. pyrrolidinyl).
  • halogen e.g. fluoro or chloro
  • Ci-galkyl e.g. methyl or ethyl
  • Ci-galkoxy e.g. methoxy
  • C3_ 6 cycloalkyl e.g. cyclopropyl
  • 3 to 15 membered heterocyclyl e.g. pyrrolidinyl
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl and 'n' is 1, 2 or 3.
  • R 4 is Ci-galkyl (e.g. ethyl).
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
  • Ring A is X 1 is CH, CF or N;
  • Ring B is phenyl, pyridyl or benzimidazolyl
  • R a is hydrogen or methyl
  • R b is hydrogen or methyl
  • R 1 is hydroxyl or methyl
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl;
  • R 4 is ethyl;
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
  • 'n' is 1, 2 or 3;
  • R a is hydrogen or methyl
  • R b is hydrogen or methyl
  • Ring A is H 3C-
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • X 1 is selected from CR 3 and N;
  • Ring B is selected from phenyl, pyridyl and benzimidazolyl
  • x, y and z represents point of attachment
  • each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ galkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl and C3_ 6 cycloalkyl; R is selected from hydrogen and halogen;
  • R 4 is selected from hydrogen and Ci_ 8 alkyl
  • R x and R y are each independently selected from Ci_ 8 alkyl and haloCi_ 8 alkyl; or R x and R y together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
  • 'n' is 0, 1, 2, 3 or 4;
  • 'q' is 1 or 2.
  • 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 and 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 is hydrogen or fluorine (according to an embodiment defined below), R 4 is ethyl (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
  • R 3 is hydrogen or fluorine.
  • R is halogen (e.g. fluoro or chloro), Ci_ 8 alkyl (e.g. methyl or ethyl) and Ci- 8 alkoxy (e.g. methoxy).
  • R is halogen (e.g. fluoro or chloro)
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci- 8 alkoxy e.g. methoxy
  • R 4 is Ci_ 8 alkyl (e.g. ethyl).
  • compounds of formula (II), in which R 4 is ethyl specifically provided are compounds of formula (II), in which R 4 is ethyl.
  • formula (II) in which is 5-chloro- l -ethyl- lH-benzimidazol-2-yl, 4-chloro-2- methoxyphenyl, 4-chloro-2-methylphenyl, 5-chloro-3-methylpyridin-2-yl, 2,4- dichlorophenyl, 3,5-dichloropyridin-2-yl or 2,4-difluorophenyl.
  • I Z y ' ⁇ is l Z 3 ⁇ 4 y i .
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
  • X 1 is CH or CF; 1 2 y ⁇ is I Z 4 J l or 1 2 4 y i , wherein x, y and z represents point of attachment;
  • Ring B is phenyl or benzimidazolyl
  • R is fluoro, chloro, methyl, ethyl or methoxy
  • R 4 is ethyl
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring;
  • 'n' is 2;
  • V ⁇ / ' * is 5-chloro-l -ethyl- lH-benzimidazol-2-yl, 4-chloro-2-methoxyphenyl,
  • compounds of formula (II) with an IC 50 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).
  • X 1 is selected from CR 3 and N;
  • Ring B is selected from phenyl, pyridyl and benzimidazolyl
  • each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8 alkyl, Ci_ 8 alkoxy, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, hydroxyCi_ 8 alkyl and C3_ 6 cycloalkyl;
  • R is selected from hydrogen and halogen
  • R 4 is selected from hydrogen and Ci_ 8 alkyl
  • R x and R y are each independently selected from Ci_ 8 alkyl and haloCi_ 8 alkyl; or R x and R y together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
  • 'n' is 0, 1, 2, 3 or 4;
  • 'q' is 1 or 2.
  • 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 and 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
  • X is CR (according to an embodiment defined below), R is hydrogen or fluorine (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
  • R is hydrogen or fluorine (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
  • X 1 is N.
  • R is hydroxyl, halogen (e.g. fluoro or chloro), Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), C3_ 6 cycloalkyl (e.g. cyclopropyl) or 3 to 15 membered heterocyclyl (e.g. pyrrolidinyl).
  • halogen e.g. fluoro or chloro
  • Ci-galkyl e.g. methyl or ethyl
  • Ci-galkoxy e.g. methoxy
  • C3_ 6 cycloalkyl e.g. cyclopropyl
  • 3 to 15 membered heterocyclyl e.g. pyrrolidinyl
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl and 'n' is 1, 2 or 3.
  • R 4 is Ci-galkyl (e.g. ethyl).
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
  • ⁇ '" 3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro-l-ethyl- lH-benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methylphenyl, 3-chloro-6-methylpyridin-2-yl, 4-chloro-6- methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro-2-methylpyridin-4-yl, 3-chloro- 6-(pyrrolidin-l-yl)pyridin-2-yl, 3-
  • I Z y ' ⁇ is l Z 3 ⁇ 4 y i .
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
  • X 1 is CH, CF or N
  • Ring B is phenyl, pyridyl or benzimidazolyl
  • R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl;
  • R 4 is ethyl
  • R x and R y are independently methyl; or R x and R y together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
  • 'n' is 1, 2 or 3;
  • compounds of formula (III) with an IC 50 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 1-57. 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 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 an 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 an autoimmune disease, inflammatory disease, respiratory disorder, 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 an autoimmune disease, inflammatory disease, respiratory disorder, 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 herein.
  • 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 (e.g. C 1-8 alkoxy). Representative examples of such groups are -OCH 3 and - OC 2 H 5 . 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_ 8 alkyl). Examples of such haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.
  • haloCi_ 8 alkyl refers to at least one halo group linked an alkyl chain having 1 to 8 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_ 8 alkoxy).
  • 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.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.Cs-ncycloalkyl).
  • 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_ 6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms.
  • Examples of “C 3 _ 6 cycloalkyl” 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 (e.g. C 3 _ 6 cycloalkylCi_ 8 alkyl).
  • 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, 6-oxo-l,6
  • 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. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • 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) or (III) 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) or (III) 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 the 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
  • converting e.g., hydrolysing
  • Enantiomers can also be separated by use of chiral HPLC column.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • 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.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of route of administration, such as orally or parenterally.
  • 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.
  • 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 beneficial.
  • the compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases or 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 - s
  • 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, post-operative 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, post-traumatic 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.
  • the starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein.
  • the intermediates and compounds of the present invention can be prepared through the reaction schemes as follows.
  • the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and cleavage of protecting groups etc., by following procedures known in the art of organic synthesis.
  • 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 (I).
  • the suitable coupling agent(s) may be 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).
  • 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 CH 2 C1 2 , CHC1 3 , DMF and THF or combination thereof.
  • a general approach for the preparation of compound of formula (la) and (lb) (wherein ring A, ring B, L, R 2 , R a , R b , ' ⁇ ', ' ⁇ ', 'z' and 'y' are defined as in general description) is depicted in synthetic scheme 2.
  • the coupling of amine compound of formula (1) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (3).
  • the suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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 CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the reaction of alkyl lithium of formula R b -Li (5) with the ester compound of formula (3) in the presence of suitable solvent gives the ketone compound of formula (4).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the coupling of amine compound of formula (1) with the keto-carboxylic acid compound of formula (2b) in the presence of a suitable coupling agent(s) and suitable base directly gives the amide compound of formula (4) using the same coupling reaction conditions as described above.
  • the reduction of the carbonyl group in compound of formula (4) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (la).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol.
  • the reaction of compound of formula (4) with alkyl magnesium bromide of formula R a MgX affords the tertiary alcohol compound of formula (lb).
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from diethyl ether, CH 2 CI 2 , CHCI 3 , DMF and THF or combination thereof.
  • the coupling of appropriately substituted 4-iodoaniline (6) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (7).
  • the suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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 CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the reaction of alkyl lithium of formula (5) with the ester compound of formula (7) in the presence of suitable solvent gives the ketone compound of formula (8).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the reduction of the carbonyl group in compound of formula (8) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (9).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol.
  • the chiral reduction of keto group of compound of formula (4) using suitable chiral reducing agent in a suitable solvent yields one enantiomer of hydroxyl compound of formula (Ib-i) as a major product.
  • the chiral reducing agent may be selected from (R or 5)-2-methyl- CBS-oxazaborolidine in the presence of borane dimethyl sulfide, hydrogenation using BINAP-Ru dihalide, H 2 / ruthenium (diphosphane) 2 (diamine) 2 complex, etc.
  • Suitable solvent for the reaction may be THF, DCM or DMF.
  • the compound of formula (Ib-i) can be further purified (to enhance the enantiomeric excess) through diastereomeric separation using N- benzyloxycarbonyl-L-phenylalanine, mandelic acid, or any other suitable agent to yield the diastereomeric ester of formula (11).
  • the esterification can be done in the presence of suitable coupling agent and a suitable base.
  • 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 Et 3 N, DIPEA, pyridine or DMAP.
  • the solvent used in the reaction may be selected from CH 2 C1 2 , CHC1 3 , DMF and THF or combination thereof. Saponification of the diastereomeric ester of formula (11) using lithium hydroxide in suitable solvent such as methanol, THF and water or combination thereof furnishes relatively pure form of compound of formula (R or S)-(Ib-i).
  • the coupling of amine compound of formula (12) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (13).
  • the suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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 CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the reaction of alkyl lithium of formula (5) with the ester compound of formula (13) in the presence of suitable solvent affords the ketone compound of formula (14).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • De-methylation of the methoxy group in compound of formula (14) using sodium iodide and trimethylsilyl chloride in appropriate solvent such as acetonitrile affords the hydroxypyridine compound of formula (15).
  • the reduction of the carbonyl group in compound of formula (15) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (Id).
  • the suitable solvent may be selected from CH 2 CI 2 , CHC1 3 , DMF and THF or combination thereof.
  • the suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol.
  • the copper mediated coupling reaction of halo substituted phenylacetic acid of formula (16) with ethyl bromo(difluoro)acetate (17) in a suitable aprotic polar solvent affords the mono ester derivative of dicarboxylic acid compound of formula (2a).
  • a suitable aprotic polar solvent e.g. DMSO
  • the suitable base may be selected from Ag 2 C0 3i Et 3 N, DIPEA and DMAP.
  • the selective deprotection of ethyl ester in compound of formula (18) using lithium hydroxide monohydrate in a suitable solvent or mixture thereof gives the carboxylic acid compound of formula (19).
  • the suitable solvent may be CH 2 CI 2 , CHC1 3 , DMF, THF, methanol, water mixtures thereof.
  • the reaction of compound of formula (19) with oxalyl chloride gives the corresponding acid chloride which on coupling with N,0-dimethylhydroxylamine hydrochloride in the presence of a suitable base (e.g. Et 3 N, DIPEA and DMAP) and in a suitable solvent (e.g. CH 2 C1 2 , CHC1 , DMF or THF) gives the Weinreb amide of formula (20).
  • a suitable base e.g. Et 3 N, DIPEA and DMAP
  • a suitable solvent e.g. CH 2 C1 2 , CHC1 , DMF or THF
  • halogen substituted phenyl ketone compound of formula (23) (wherein Hal is halogen) with ethane- 1,2-dithiol (to protect the carbonyl group) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (24).
  • the suitable Lewis acid may be boron trifluoride diethyletherate and suitable solvent may be selected from CH 2 CI 2 , CHCI 3 , DMF and THF.
  • the compound of formula (24) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives benzyl difluoro compound of formula (25).
  • the suitable solvent may be pyridine, CH 2 CI 2 , CHCI 3 , DMF or mixtures thereof.
  • Halogen substitution of compound of formula (25) on a reaction with ie/ -butyl acetate in the presence of palladium catalyst and suitable base gives compound of formula (26).
  • the suitable base for this substitution reaction may be lithium dicyclohexylamine.
  • the substitution reaction can be carried out in a suitable solvent such as toluene.
  • the compound of formula (26) on deprotection of ie/ -butyl group, using trifluoroacetic acid in a suitable solvent gives the compound of formula (2c).
  • the suitable solvent may be selected from CH 2 CI 2 , CHCI 3 , DMF and THF.
  • X 2 , X 3 and X 4 are CH or N, with a proviso that only one of X 2 , X 3 and X 4 is N; and R z is Ci_ 8 alkyl) is illustrated in synthetic scheme 8.
  • keto compound of formula (27) (wherein R' is Ci-galkoxy)
  • alkyl magnesium halide of formula (28) affords the tertiary alcohol compound of formula (29).
  • an appropriately substituted heterocyclic halide of formula (30) (wherein X is F, CI, Br or I)
  • a keto derivative of formula (31) in the presence of suitable base gives the tertiary alcohol (29).
  • the suitable base may be butyl lithium.
  • the nucleophilic substitution reaction of compound of formula (29) with compound of formula (32) (wherein X is F, CI, Br or I) in the presence of suitable base (e.g. sodium hydride) in a suitable solvent (e.g.
  • a suitable solvent e.g. CH 2 CI 2 , CHCI 3 , DMF, THF, methanol or water
  • the reduction of the nitro group can also be carried out by using sodium borohydride in the presence of nickel chloride.
  • amide coupling of phenyl acetic acid compound of the formula (40) with 4- nitrobenzene-l,2-diamine derivative of formula (41) using CDI or any other suitable coupling agent in a suitable solvent (e.g. CH 2 CI 2 , CHCI 3 , DMF or THF) followed by cyclization in the presence of acetic acid yields substituted 5-nitrobenzimidazole intermediate of formula (42).
  • a suitable solvent e.g. CH 2 CI 2 , CHCI 3 , DMF or THF
  • a suitable solvent e.g. CH 2 CI 2 , CHCI 3 , DMF, THF, methanol or water
  • the reduction of the nitro group can also be carried out by using sodium borohydride in the presence of nickel chloride.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • CDI ⁇ , ⁇ -carbonyldiimidazole
  • DCM dichloromethane
  • DMSO- 6 Hexadeuterodimethyl sulfoxide
  • DMSO dimethyl sulfoxide 1H NMR: Proton Nuclear Magnetic Resonance
  • DMF N,N-dimethyl formamide
  • EDCI.HC1 l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • Et 3 N triethylamine
  • HOBT 1- hydroxybenzotriazole
  • NaOH Sodium Hydroxide
  • KOH Potassium Hydroxide
  • LiOH Lithium Hydroxide
  • DIPEA N,N-diisopropylethylamine
  • THF Tetrahydofuran
  • HC1 hydrochloric acid
  • Na 2 S0 4 Sodium sulf
  • Step 1 intermediate (22.7 g, 0.11 mmol) in anhydrous diethyl ether (100 mL) was dropwise added methylmagnesium bromide (1.4 M in THF, 197 mL, 0.27 mmol) at -78 °C.
  • the resulting mixture was stirred at the RT for 18 h.
  • the mixture was quenched with aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL x 2).
  • the combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate.
  • the solution was filtered and concentrated under the reduced pressure.
  • Step 2 intermediate 11 g, 53.6 mmol
  • anhydrous DMF 100 mL
  • sodium hydride 60% w/w, 3.2 g, 80.5 mmol
  • 4- fluoronitrobenzene 7.5 g, 53.6 mmol
  • the reaction mixture was warmed to the RT and stirred for 18 h.
  • the reaction mixture was quenched with ice cold water (100 mL) and was extracted with ethyl acetate (150 mL x 2).
  • the combined organic layers were washed with water (200 mL) followed by brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 intermediate 750 mg, 2.29 mmol
  • iron powder 642 mg, 11.5 mmol
  • ammonium chloride 1.2 g, 23.0 mmol
  • 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 (20 mL) and extracted with ethyl acetate (50 mL x 2).
  • the combined organic layers were washed with water (100 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 2-(4-Bromophenyl)-2-ethyl- 1 ,3-dithiolane
  • Step 2 1 -Bromo-4-( 1 , 1 -difluoropropyl)benzene
  • the filtrate was concentrated and the residue was diluted with ethyl acetate (50 mL). The residue was washed with 10% sodium thiosulfate (20 mL), 2% potassium permanganate (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 203 mg of the titled product.
  • Step 3 ie/t-Butyl [4-(l, l-difluoropropyl)phenyl] acetate
  • Step 4 [4-(l,l-Difluoropropyl)phenyl] acetic acid
  • step 3 intermediate (1.42 g, 5.25 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (10 mL) and the reaction mixture was stirred at the RT for 1 h. The solvent in the reaction mixture was evaporated and the residue thus obtained was purified by silica gel column chromatography to yield 491 mg of the titled product.
  • Step 1 [4-(2-Ethoxy-l,l-difluoro-2-oxoethyl)phenyl] acetic acid
  • step 1 intermediate 3.3 g, 12.8 mmol
  • a mixture of dichloromethane and THF (2: 1, 90 mL) were added molecular sieves (3.3 g, 4 A) and silver carbonate (10.58 g, 38.3 mmol).
  • the reaction mixture was stirred, cooled to 0 °C and to it was drop-wise added ieri-butyl bromide (7.3 mL, 63.9 mmol).
  • the reaction mixture was allowed to attain room temperature and was stirred overnight.
  • the reaction mixture was filtered through celite bed and washed with dichloromethane (100 mL). The filtrate was concentrated under the reduced pressure and the residue obtained was purified by flash chromatography to yield 1.82 g of the titled product.
  • step 2 intermediate To a stirred solution of step 2 intermediate (915 mg, 2.91 mmol) in a solvent mixture of THF, methanol and water (3:2: 1, 30 mL) at 0 °C was added lithium hydroxide monohydrate (366 mg, 8.73 mmol) and the reaction mixture was stirred for 1 h.
  • the reaction mixture was acidified with IN HC1 till pH 2-3 and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure to afford 839 mg of the titled product.
  • Step 4 ie/t-Butyl (4- ⁇ l,l-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl ⁇ phenyl)acetate
  • dichloromethane 15 mL
  • oxalyl chloride 2.2 mL, 4.36 mmol
  • catalytic amount of DMF catalytic amount of DMF.
  • the reaction mixture was allowed to attain the RT and stirred for 3 h.
  • the reaction mixture was concentrated under the inert atmosphere to give an oily residue, which was diluted with dichloromethane (15 mL) and cooled to 0 °C.
  • N,Odimethyl hydroxylamine hydrochloride (425 mg, 4.36 mmol) was added followed by triethyl amine (1.6 mL, 11.63 mmol) and the reaction mixture was stirred overnight at RT.
  • the reaction mixture was diluted with dichloromethane (15 mL), washed with aqueous saturated sodium bicarbonate solution (20 mL) and brine (20 mL). The organic layer was concentrated and the crude obtained was purified by silica gel column chromatography to afford 581 mg of the product.
  • Step 5 ie/t-Butyl [4-(l, l-difluoro-2-oxopropyl)phenyl] acetate
  • step 4 intermediate To a stirred solution of step 4 intermediate (572 mg, 1.73 mmol) in THF (15 mL) at 0 °C was added methylmagnesium bromide (1.4 , 1.15 mL, 3.47 mmol) and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), concentrated and the crude obtained was purified by silica gel column chromatography to yield 369 mg of the desired product.
  • Step 6 4-(l,l-Difluoro-2-oxopropyl)phenyl] acetic acid
  • Step 5 intermediate 501 mg, 1.76 mmol
  • dichloromethane 10 mL
  • trifluoroacetic acid 10 mL
  • the solvent was evaporated under nitrogen blower to give an oily residue which was dried well under vacuum to yield 379 mg of the titled product.
  • Step 1 1 ,3-Dichloro-2-(2,4-dichlorophenyl)propan-2-ol
  • Step 1 intermediate (1.10 g, 4.01 mmol) in diethyl ether (20 mL) were simultaneously added ethylmagnesium bromide ( M in ether, 6.6 mL, 20.07 mmol) and a solution of ferric chloride (13 mg, 0.08 mmol) in diethyl ether (20 mL) over a period of 1 h.
  • the resultant mixture was stirred at the RT for 18 h.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL).
  • Step 3 l-(2,4-Dichlorophenyl)cyclopropyl 2-fluoro-4-nitrophenyl ether
  • Step 2 intermediate 350 mg, 1.72 mmol
  • sodium hydride 60% w/w, 69 mg, 1.72 mmol
  • 3,4-Difluoro- l -nitrobenzene 274 mg, 1.72 mmol
  • the reaction mixture was stirred further at RT for 2 h.
  • the reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Step 4 4- ⁇ [l-(2,4-Dichlorophenyl)cyclopropyl]oxy ⁇ -3-fluoroaniline
  • Step 3 intermediate 380 mg, 1.11 mmol
  • iron powder 310 mg, 5.55 mmol
  • ammonium chloride 594 mg, 11.10 mmol
  • the reaction mixture was heated to 80 °C and stirred for 2 h at the same temperature.
  • the reaction mixture was cooled to the RT and the suspended emulsion was filtered off.
  • the filtrate was concentrated under the reduced pressure and diluted with water (20 mL).
  • the aqueous mixture was extracted with ethyl acetate (2 x 20 mL).
  • Step 2 of Intermediate 1 To a stirred and cooled (0 °C) solution of 2-(2,4-dichlorophenyl)propan-2-ol (Step 2 of Intermediate 1) (500 mg, 2.43 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% w/w, 146 mg, 3.65 mmol) and the reaction mixture was stirred at RT for 30 min. 3,4- Difluoronitrobenzene (0.27 mL, 2.43 mmol) was added to the reaction mixture at 0 °C and the mixture was gradually warmed up to the RT. The reaction mixture was stirred at the RT for 18 h.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 561 mg of the titled product.
  • Step 1 intermediate 500 mg, 0.45 mmol
  • nickel chloride 691 mg, 2.90 mmol
  • sodium borohydride 220 mg, 5.812 mmol
  • the reaction mixture was stirred at the room temperature for 1 h.
  • the reaction mixture was concentrated under the reduced pressure to yield a viscous residue.
  • the residue was diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL).
  • reaction mixture was diluted with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 221 g of the titled product.
  • Step 1 intermediate 210 mg, 0.84 mmol
  • sodium hydride 60% w/w, 51 mg, 1.27 mmol
  • l-Fluoro-4-nitrobenzene (0.09 mL, 0.84 mmol) was added to the reaction mixture and stirred for 18 h at the RT.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL).
  • Step 3 4- ⁇ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl] oxy ⁇ aniline
  • Step 2 intermediate 260 mg, 0.70 mmol
  • nickel chloride 335 mg, 1.41 mmol
  • sodium borohydride 107 mg, 2.82 mmol
  • the reaction mixture was stirred at the room temperature for 1 h.
  • the reaction mixture was concentrated under the reduced pressure to yield a viscous residue.
  • the residue was diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL).
  • Step 1 5-Chloro- l-ethyl-2-[2-(4-nitrophenoxy)propan-2-yl]- lH-benzimidazole
  • Step 2 4- ⁇ [2-(5-Chloro- 1 -ethyl- lH-benzimidazol-2-yl)propan-2-yl]oxy janiline
  • the titled compound was prepared by the reduction of Step 1 intermediate (65 mg, 0.18 mmol) using iron powder (50.4 mg, 0.90 mmol) and ammonium chloride (96 mg, 1.80 mmol) in water (3 mL) and THF (5 mL) as per the process described in Step 4 of Intermediate 1 to yield 75 mg of the product.
  • the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 460 mg of the product.
  • Step 2 5-Chloro- l-ethyl-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-lH-benzo[ ]imidazole
  • Step 1 intermediate 450 mg, 1.13 mmol
  • acetic acid 5.0 mL
  • the solvent in the mixture was evaporated under the reduced pressure.
  • the residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (30 mL), followed by brine (30 mL), dried over anhydrous sodium sulfate and filtered.
  • Step 3 4- ⁇ [2-(5-Chloro- 1 -ethyl- lH-benzimidazol-2-yl)propan-2-yl]oxy ⁇ -3-fluoroaniline
  • the titled compound was prepared by the reduction of Step 2 intermediate (150 mg, 0.39 mmol) using iron powder (111 mg, 1.98 mmol) and ammonium chloride (212 mg, 3.97 mmol) in a mixture of water (5 mL) and THF (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 109 mg of the product.
  • Step 1 2-[2-(2,4-Difluorophenoxy)propan-2-yl]-l-ethyl-5-nitro-lH-benzimidazole
  • the combined organic layers were washed with water (2 x 100 mL) and dried over anhydrous sodium sulfate.
  • the filtered solvents were distilled off under the reduced pressure to yield a gummy residue.
  • the residue was dissolved in acetic acid and refluxed for 1.5 h.
  • the acetic acid was distilled out under the reduced pressure and the residue obtained was diluted with water (50 mL) and ethyl acetate (50 mL).
  • the aqueous layer was extracted with ethyl acetate (3 x 50 mL).
  • the combined organic layers were washed with water (2 x 100 mL), brine (50 mL), dried over sodium sulfate and filtered.
  • the titled compound was prepared by the reduction of Step 1 intermediate (150 mg, 0.41 mmol) using iron powder (106 mg, 2.08 mmol) and ammonium chloride (323 mg, 4.17 mmol) in a mixture of methanol (2 mL), THF (5 mL) and water (2 mL) as per the process described in Step 4 of Intermediate 1 to yield 126 mg of the product.
  • Step 1 4-(2,4-Dichlorophenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran
  • Step 1 of Intermediate 6 To a stirred and cooled (0 °C) solution of 4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-ol (Step 1 of Intermediate 6) (300 mg, 1.21 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% w/w, 58 mg, 1.45 mmol) and the reaction mixture was stirred at the RT for 30 min. 3, 4-Difluoro nitrobenzene (193 mg, 1.21 mmol) was added to the reaction mixture and stirred for 2 h at RT. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the titled compound was prepared by the reduction of Step 1 intermediate (280 mg, 0.72 mmol) using iron powder (202 mg, 3.62 mmol) and ammonium chloride (388 mg, 7.25 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 224 mg of the product.
  • Step 1 2-(2-Chloro-4-fluorophenyl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 2-chloro-4-fluorobenzoate (550 mg, 2.91 mmol) and methylmagnesium bromide (3 in diethyl ether, 2.4 mL) in diethyl ether
  • Step 2 2-(2-Chloro-4-fluorophenyl)propan-2-yl 4-nitrophenyl ether
  • the titled compound was synthesized by the reaction of Step 1 intermediate (500 mg, 2.65 mmol) with l-fluoro-4-nitrobenzene (374 mg, 2.65 mmol) using sodium hydride (60% w/w, 159 mg, 3.97 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 213 mg of the product.
  • the titled compound was synthesized by the nitro reduction of the Step 2 intermediate (200 mg, 0.64 mmol) using sodium borohydride (96 mg, 2.58 mmol) and nickel chloride (309 mg, 1.29 mmol) in methanol (10 mL) as per the process described in Step 2 of Intermediate 5 to yield 131 mg of the product.
  • Step 1 2-(2-Chloro-4-fluorophenyl)propan-2-yl 2-fluoro-4-nitrophenyl ether
  • the titled compound was synthesized by the reaction of 2-(2-chloro-4-fluorophenyl)propan- 2-ol (300 mg, 1.59 mmol) with 3,4-difluoronitrobenzene (253 mg, 1.59 mmol) using sodium hydride (60% w/w, 95 mg, 2.38 mmol) in DMF (5 mL) as per the process described in Step 3 of Intermediate 1 to yield 261 mg of the product.
  • the titled compound was synthesized by the nitro reduction of the Step 1 intermediate (250 mg, 0.76 mmol) using sodium borohydride (116 mg, 3.05 mmol) and nickel chloride (362 mg, 1.52 mmol) in methanol (5 mL) as per the process described in Step 2 of Intermediate 5 to yield 191 mg of the product.
  • Step 1 2-(4-Chloro-3-fluorophenoxy)-N-[2-(ethylamino)-5-nitroph( methylpropanamide
  • Step 2 2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-5-nitro- lH-benzimidazole
  • the step 1 intermediate (400 mg, 1.160 mmol) was refluxed in acetic acid (5 mL) for 16 h.
  • the reaction mixture was concentrated under the reduced pressure and the residue was diluted with ethyl acetate (20 mL) and water (15 mL).
  • the organic layer was separated and washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure.
  • the residue obtained was purified by silica gel column chromatography to yield 325 mg of the titled product.
  • Step 3 2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-lH-benzimidazol-5-amine
  • step 3 2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-lH-benzimidazol-5-amine
  • sodium borohydride 40 mg, 1.058 mmol
  • the reaction mixture was stirred at the room temperature for 30 min.
  • the reaction mixture was concentrated under the reduced pressure to yield a viscous residue.
  • the residue was diluted with water (10 mL) and ethyl acetate (10 mL).
  • Step 1 Ethyl difluoro(4- ⁇ 2-[(4-iodophenyl)amino]-2-oxoethyl ⁇ phenyl)acetate
  • Step 2 2-[4-( 1 , 1 -Difluoro-2-oxopropyl)phenyl] -N-(4-iodophenyl)acetamide
  • Step 1 intermediate 700 mg, 1.52 mmol
  • diethyl ether 10 mL
  • 3M methyl lithium 1.25 mL, 3.65 mmol
  • the reaction mixture was stirred at the same temperature for 30 min.
  • the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 50 mL).
  • the combined organic layers were washed with water (2 x 100 mL), brine (100 mL) and dried over anhydrous sodium sulfate.
  • the solution was filtered and concetrated under the reduced pressure.
  • Step 3 2-[4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl] - V-(4-iodophenyl)acetamide
  • Step 2 intermediate 180 mg, 0.41 mmol
  • methanol 5.0 mL
  • sodium borohydride 23 mg, 0.62 mmol
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL x 2).
  • the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure.
  • the residue obtained was purified by silica gel column chromatography to yield 170 mg of the desired product.
  • Step 1 4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-ol
  • the titled compound was prepared by the reaction of 2-bromo-5-chloroanisole (2.0 g, 9.02 mmol) with tetrahydro-4H-pyran-4-one (986 ⁇ , 10.83 mmol) and n-butyl lithium (1.6 M in THF, 6.2 mL, 9.93 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 617 mg of the product.
  • Step 2 4-(4-Chloro-2-methoxyphenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran
  • the titled compound was synthesized by the reaction of Step 1 intermediate (600 mg, 2.47 mmol) with 3,4-difluoronitrobenzene (432 mg, 2.71 mmol) using sodium hydride (60% w/w, 108 mg, 2.71 mmol) in DMSO (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 398 mg of the product.
  • Step 3 4- ⁇ [4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-yl]oxy ⁇ -3-fluoroaniline
  • the titled compound was prepared by the reduction of Step 2 intermediate (570 mg, 1.49 mmol) using iron powder (417 mg, 7.46 mmol) and ammonium chloride (798 mg, 14.93 mmol) in a mixture of methanol (20 mL) and water (20 mL) as per the process described in Step 4 of Intermediate 1 to yield 469 mg of the product.
  • Step 1 2-(3,5-Dichloropyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 3,5-dichloropyridine-2- carboxylate (1.0 g, 4.854 mmol) and methyl magnesium bromide (1.4 in THF, 10.4 mL) in THF (20 mL) as per the process described in step 2 of Intermediate 1 to yield 800 mg of the product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4 ⁇ 1.55 (s, 6H), 8.50 (br s, 1H), 8.53 (br s, 1H)
  • step 1 The titled compound was synthesized by the reaction of step 1 intermediate (200 mg, 0.970 mmol) with l-fluoro-4-nitrobenzene (150 mg, 1.060 mmol) using sodium hydride (60% w/w, 42 mg, 1.060 mmol) in DMF (5 mL) as per the process described in step 3 of Intermediate 1 to yield 150 mg of the product.
  • Step 3 4- ⁇ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy ⁇ aniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (150 mg, 0.458 mmol) using sodium borohydride (69 mg, 1.833 mmol) and nickel chloride (217 mg, 0.916 mmol) in methanol (5 mL) as per the process described in step 2 of Intermediate 5 to yield 77 mg of the product.
  • 1H NMR 300 MHz, DMSO-d 6 ) ⁇ 1.66 (s, 6H), 4.65 (s, 2H), 6.32 (s, 4H), 8.18 (s, 1H), 5.58 (s, 1H); APCI-MS (m/z) 297 (M) + .
  • Step 1 4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-ol
  • the titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (2.0 g, 8.81 mmol) with tetrahydro-4H-pyran-4-one (962 ⁇ , 10.57 mmol) and n-butyl lithium (1.6 M in THF, 6.0 mL, 9.69 mmol) in diethyl ether (50 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 1.1 g of the product.
  • the titled compound was synthesized by the reaction of Step 1 intermediate (600 mg, 2.41 mmol) with l-fluoro-4-nitrobenzene (341 mg, 2.41 mmol) using sodium hydride (60% w/w, 116 mg, 2.90 mmol) in DMF (5.0 mL) as per the process described in step 3 of Intermediate 1 to yield 880 mg of the product.
  • the titled compound was prepared by the reduction of Step 2 intermediate (850 mg, 2.30 mmol) using iron powder (640 mg, 11.51 mmol) and ammonium chloride (1.23 g, 23.02 mmol) in a mixture of methanol (10 mL), THF (25 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 750 mg of the product.
  • Step 1 2- ⁇ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl]oxy ⁇ -5-nitropyridine
  • the titled compound was prepared by the reaction of 4-(2,4-dichlorophenyl)tetrahydro-2H- pyran-4-ol (Step 1 of Intermediate 6) (500 mg, 2.03 mmol) with 2-chloro-5-nitropyridine (321 mg, 2.03 mmol) using sodium hydride (60% w/w, 122 mg, 3.04 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 290 mg of the product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4) ⁇ 2.19-2.25 (m, 2H), 2.74-2.82 (m, 2H), 3.73-3.82 (m, 4H),
  • the titled compound was synthesized by the nitro reduction of the step 1 intermediate (290 mg, 0.78 mmol) using iron powder (218 mg, 3.92 mmol) and ammonium chloride (420 mg, 7.85 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 210 mg of the product.
  • Step 1 3,5-Dichloro-2- ⁇ 4-[(5-nitropyridin-2-yl)oxy]tetrahydro-2H-pyran-4-yl ⁇ pyridine
  • the titled compound was prepared by the reaction of 4-(3,5-Dichloropyridin-2-yl)tetrahydro- 2H-pyran-4-ol (Step 1 of Intermediate 19) (500 mg, 2.01 mmol) with 2-chloro-5- nitropyridine (319 mg, 2.01 mmol) using sodium hydride (60% w/w, 121 mg, 3.02 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 518 mg of the product.
  • Step 2 6- ⁇ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy ⁇ pyridin-3-amine
  • the titled compound was synthesized by the nitro reduction of the step 1 intermediate (500 mg, 1.34 mmol) using iron powder (375 mg, 6.73 mmol) and ammonium chloride (720 mg, 13.47 mmol) in a mixture of methanol (5.0 mL), THF (15 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 1.06 g of the product.
  • Step 1 3,5-Dichloro-2-[2-(2-fluoro-4-nitrophenoxy)propan-2-yl]pyridine
  • the titled compound was prepared by the reaction of 2-(3,5-dichloropyridin-2-yl)propan-2-ol (Step 1 of Intermediate 17) (1.0 g, 4.85 mmol) with 3,4-difluoronitrobenzene (590 ⁇ , 5.33 mmol) using sodium hydride (60% w/w, 232 mg, 5.82 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 1.34 g of the product.
  • Step 2 4- ⁇ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy ⁇ -3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 1 intermediate (1.3 g, 3.76 mmol) using iron powder (1.1 g, 18.83 mmol) and ammonium chloride (2.0 g, 37.66 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 1.06 g of the product.
  • Step 1 3,5-Dichloro-2-[4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran-4-yl]pyridine
  • the titled compound was prepared by the reaction of 4-(3,5-dichloropyridin-2-yl)tetrahydro- 2H-pyran-4-ol (Step 1 of Intermediate 19) (500 mg, 2.01 mmol) with 3,4- difluoronitrobenzene (224 ⁇ , 2.01 mmol) using sodium hydride (60% w/w, 96 mg, 2.41 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 770 mg of the product.
  • Step 2 4- ⁇ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy ⁇ -3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 1 intermediate (750 mg, 1.93 mmol) using iron powder (539 mg, 9.68 mmol) and ammonium chloride (1.03 g, 19.36 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 522 mg of the product.
  • Step 1 3-(3,5-Dichloropyridin-2-yl)oxetan-3-ol
  • the titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (3.0 g, 13.22 mmol) with 3-oxitanone (840 ⁇ , 14.54 mmol) and n-butyl lithium (1.6 M in THF, 9.1 mL, 14.54 mmol) in diethyl ether (40 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 888 mg of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (435 mg, 1.97 mmol) with 3,4-difluoronitrobenzene (314 mg, 1.97 mmol) using sodium hydride (60% w/w, 118 mg, 2.96 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 574 mg of the product.
  • Step 3 4- ⁇ [3-(3 ,5-Dichloropyridin-2-yl)oxetan-3-yl]oxy ⁇ -3 -fluoro aniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (560 mg, 1.55 mmol) using iron powder (435 mg, 7.79 mmol) and ammonium chloride (834 mg, 15.59 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 497 mg of the product.
  • Step 1 4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-ol
  • Step 2 4-(4-Chloro-2-methylphenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran
  • the titled compound was prepared by the reaction of step 1 intermediate (320 mg, 1.41 mmol) with 3,4-difluoronitrobenzene (157 ⁇ , 1.41 mmol) using sodium hydride (60% w/w, 68 mg, 1.69 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 390 mg of the product.
  • Step 3 4- ⁇ [4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-yl] oxy ⁇ -3 -fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (375 mg, 1.02 mmol) using iron powder (286 mg, 5.12 mmol) and ammonium chloride (548 mg, 10.02 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 238 mg of the product.
  • Step 1 4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-ol
  • the titled compound was prepared by the reaction of 2-bromo-5-chloro-3-methylpyridine (1.0 g, 4.84 mmol) with tetrahydro-4H-pyran-4-one (536 ⁇ , 5.81 mmol) and n-butyllithium (1.6 M in THF, 3.1 mL, 4.84 mmol) in diethyl ether (10 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 333 mg of the product.
  • Step 2 5-Chloro-2-[4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran-4-yl]-3-methylpyridine
  • the titled compound was prepared by the reaction of step 1 intermediate (320 mg, 1.40 mmol) with 3,4-difluoronitrobenzene (246 ⁇ , 1.54 mmol) using sodium hydride (60% w/w, 62 mg, 1.54 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 403 mg of the product.
  • Step 3 4- ⁇ [4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy ⁇ -3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (390 mg, 1.06 mmol) using iron powder (297 mg, 5.31 mmol) and ammonium chloride (568 mg, 10.63 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 336 mg of the product.
  • Step 1 2-(5-Chloro-3-methylpyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of 2-bromo-5-chloro-3-picoline (1.2 g, 5.81 mmol) with acetone (579 ⁇ , 6.97 mmol) and n-butyl lithium (1.6 M in THF, 3.9 mL, 6.32 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 174 mg of the product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4: ⁇ 1.45 (s, 6H), 2.45-2.53 (m, 3H), 5.15 (s, 1H), 7.65 (s, 1H), 8.29 (s, 1H).
  • the titled compound was prepared by the reaction of step 1 intermediate (170 mg, 0.91 mmol) with 3,4-difluoronitrobenzene (102 ⁇ , 0.91 mmol) using sodium hydride (60% w/w, 44 mg, 1.09 mmol) in DMF (3.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 201 mg of the product.
  • Step 3 4- ⁇ r2-(5-Chloro-3-methvlpvridin-2-vl)propan-2-vlloxvl-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.92 mmol) using iron powder (257 mg, 4.61 mmol) and ammonium chloride (496 mg, 9.23 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 205 mg of the product.
  • Step 1 2-(5-Chloropyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 5-chloropicolinate (1.2 g, 6.99 mmol) and methyl magnesium bromide (3 in diethyl ether, 6.9 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 1.08 g of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (600 mg, 3.50 mmol) with 3,4-difluoronitrobenzene (428 ⁇ , 3.84 mmol) using sodium hydride (60% w/w, 167 mg, 4.19 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 1.04 g of the product.
  • Step 3 4-((2-(5-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (1.0 g, 3.22 mmol) using iron powder (896 mg, 16.1 mmol) and ammonium chloride (1.72 g, 32.2 mmol) in a mixture of methanol (10 mL), THF (20 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 560 mg of the product.
  • Step 1 2-(3-Chloropyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 3-chloropicolinate (1.5 g, 8.74 mmol) and methyl magnesium bromide (3 in diethyl ether, 8.7 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 1.21 g of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (600 mg, 3.50 mmol) with 3,4-difluoronitrobenzene (428 ⁇ , 3.84 mmol) using sodium hydride (60% w/w, 154 mg, 3.85 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 852 mg of the product.
  • Step 3 4-((2-(3-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (840 mg, 2.71 mmol) using iron powder (758 mg, 13.5 mmol) and ammonium chloride (1.45 g, 27.7 mmol) in a mixture of methanol (10 mL), THF (20 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 659 mg of the product.
  • Step 1 l-(3,5-Dichloropyridin-2-yl)cyclobutanol
  • the titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (2.0 g, 8.81 mmol) with cyclobutanone (790 ⁇ , 10.57 mmol) and n-butyl lithium (1.6 M in hexane, 5.5 mL, 8.81 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 248 mg of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (235 mg, 1.07 mmol) with 3, 4-difluoro- l -nitrobenzene (171 mg, 1.07 mmol) using sodium hydride (60% w/w, 47 mg, 1.18 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 322 mg of the product.
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (310 mg, 0.87 mmol) using iron powder (242 mg, 4.33 mmol) and ammonium chloride (463 mg, 8.66 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 248 mg of the product.
  • Step 1 l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutanol
  • the titled compound was prepared by the reaction of 2-bromo-5-chloro-3-fluoropyridine (1.0 g, 4.75 mmol) with cyclobutanone (408 ⁇ , 5.70 mmol) and n-butyl lithium (1.6 M in hexane, 3.2 mL, 5.22 mmol) in diethyl ether (15 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 220 mg of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (220 mg, 1.09 mmol) with 3, 4-difluoro-l -nitrobenzene (121 ⁇ L ⁇ , 1.09 mmol) using sodium hydride (60% w/w, 53 mg, 1.31 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 210 mg of the product.
  • Step 3 4-(l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutoxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (210 mg, 0.62 mmol) using iron powder (171 mg, 3.08 mmol) and ammonium chloride (330 mg, 6.16 mmol) in a mixture of THF (10 mL), methanol (3.0 mL) and water (3.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 155 mg of the product.
  • Step 1 2-(3-Chloro-6-methylpyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 3-chloro-6-methylpicolinate (550 mg, 2.97 mmol) and methyl magnesium bromide (3 in diethyl ether, 2.9 mL) in diethyl ether (15 mL) as per the process described in Step 2 of Intermediate 1 to yield 440 mg of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (500 mg, 2.69 mmol) with 3, 4-difluoro-l -nitrobenzene (300 ⁇ , 2.69 mmol) using sodium hydride (60% w/w, 130 mg, 3.23 mmol) in DMF (3.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 510 mg of the product.
  • Step 3 4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (500 mg, 1.53 mmol) using iron powder (428 mg, 7.69 mmol) and ammonium chloride (823 mg, 15.39 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 280 mg of the product.
  • Step 1 2-(4-Chloro-6-methylpyridin-3-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 4-chloro-6-methylnicotinate (350 mg, 1.89 mmol) and methyl magnesium bromide (3 in diethyl ether, 1.8 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 245 mg of the product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4 ⁇ 1.56 (s, 6H), 1.42 (s, 3H), 5.43 (s, 1H), 7.31 (s, 1H), 8.75 (s, 1H); APCI-MS (m/z) 186 (M) + .
  • the titled compound was prepared by the reaction of step 1 intermediate (240 mg, 1.29 mmol) with 3, 4-difluoro-l -nitrobenzene (143 ⁇ , 1.29 mmol) using sodium hydride (60% w/w, 62 mg, 1.55 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 320 mg of the product.
  • Step 3 4-((2-(4-Chloro-6-methylpyridin-3-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.92 mmol) using iron powder (257 mg, 4.62 mmol) and ammonium chloride (443 mg, 9.23 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 310 mg of the product.
  • Step 1 2-(5-chloro-2-methylpyridin-4-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 5-chloro-2-methylisonicotinate (800 mg, 4.32 mmol) and methyl magnesium bromide (3M in diethyl ether, 4.3 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 515 mg of the product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4: ⁇ 1.47 (s, 6H), 2.43 (s, 3H), 5.32 (s, 1H), 7.45 (s, 1H), 8.11 (s, 1H).
  • Step 2 5-Chloro-4-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-2-methylpyridine
  • the titled compound was prepared by the reaction of step 1 intermediate (500 mg, 2.69 mmol) with 3, 4-difluoro-l -nitrobenzene (299 ⁇ , 2.69 mmol) using sodium hydride (60% w/w, 129 mg, 3.23 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 780 mg of the product.
  • Step 3 4-((2-(5-Chloro-2-methylpyridin-4-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (780 mg, 2.48 mmol) using iron powder (668 mg, 12.0 mmol) and ammonium chloride (1.28 g,
  • Step 1 2-(3-Chloro-6-cyclopropylpyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 2-chloro-5-cyclopropylbenzoate (700 mg, 3.30 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 6.6 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 640 mg of the product.
  • Step 2 3-Chloro-6-cyclopropyl-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)pyridine
  • the titled compound was prepared by the reaction of step 1 intermediate (640 mg, 3.02 mmol) with l,2-difluoro-4-nitrobenzene (336 ⁇ , 3.02 mmol) using sodium hydride (60% w/w, 145 mg, 3.62 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 235 mg of the product.
  • Step 3 4-((2-(3-Chloro-6-cyclopropylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (220 mg, 0.627 mmol) using iron powder (174 mg, 3.15 mmol) and ammonium chloride (335 mg, 6.27 mmol) in a mixture of THF (10 mL), methanol (3.0 mL) and water (3.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 170 mg of the product.
  • Step 1 intermediate 250 mg, 1.15 mmol
  • dry DMF 5 mL
  • sodium hydride 60% w/w, 46 mg, 1.15 mmol
  • 4-Difluoro-l -nitrobenzene 183 mg, 1.151 mmol
  • the reaction mixture was diluted with saturated aqueous solution of ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Step 2 intermediate 270 mg, 0.76 mmol
  • methanol 5 mL
  • water 5 mL
  • iron powder 211 mg, 3.790 mmol
  • ammonium chloride 405 mg, 7.58 mmol
  • the reaction mixture was heated to 80 °C and stirred for 2 h at the same temperature.
  • the reaction mixture was cooled to the RT and the suspended emulsion was filtered off.
  • the filtrate was concentrated under the reduced pressure and diluted with water (20 mL).
  • the aqueous mixture was extracted with ethyl acetate (2 x 20 mL).
  • Step 2 2,4-Dichloro-l-(l-(2-fluoro-4-nitrophenoxy)cyclopentyl)benzene
  • sodium hydride 60% w/w, 77 mg, 1.947 mmol
  • 4-Difluoro-l -nitrobenzene 206 mg, 1.298 mmol
  • the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Step 2 intermediate 160 mg, 0.432 mmol
  • iron powder 120 mg, 2.160 mmol
  • ammonium chloride 231 mg, 4.321 mmol
  • the reaction mixture was heated to 90 °C and stirred for 3 h at the same temperature.
  • the reaction mixture cooled to RT and the suspended emulsion was filtered off.
  • the filtrate was concentrated under the reduced pressure and diluted with water (15 mL).
  • the aqueous mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered.
  • Step 1 2-(3,5-Dichloro-6-methylpyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of 2-bromo-3,5-dichloro-6-methylpyridine (2.0 g, 8.30 mmol) and acetone (827 ⁇ , 9.96 mmol) in the presence of n-butyl lithium (1.6 M in diethyl ether, 5.7 mL) in diethyl ether (10 mL) as per the process described in Step 1 of Intermediate 6 to yield 480 mg of the product.
  • 1H NMR 300 MHz, DMSO-d 6 ): ⁇ 1.54 (s, 6H), 2.52 (s, 3H), 5.37 (s, 1H), 8.06 (s, 1H).
  • the titled compound was prepared by the reaction of step 1 intermediate (460 mg, 2.08 mmol) with l,2-difluoro-4-nitrobenzene (232 ⁇ L ⁇ , 2.08 mmol) using sodium hydride (60% w/w, 100 mg, 2.50 mmol) in DMF (5.0 mL) as per the process described in Step 3 of
  • Step 3 4-((2-(3,5-Dichloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.83 mmol) using iron powder (232 mg, 4.17 mmol) and ammonium chloride (446 mg, 8.34 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 157 mg of the product.
  • the titled compound was prepared by the reaction of methyl 3-chloro-6-methoxypicolinate (900 mg, 4.46 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 8.9 mL) in diethyl ether (30 mL) as per the process described in Step 2 of Intermediate 1 to yield 541 mg of the product.
  • the titled compound was prepared by the reaction of step 1 intermediate (700 mg, 3.47 mmol) with l,2-difluoro-4-nitrobenzene (394 ⁇ L ⁇ , 3.47 mmol) using sodium hydride (60% w/w, 167 mg, 4.16 mmol) in DMF (15 mL) as per the process described in Step 3 of Intermediate 1 to yield 655 mg of the product.
  • Step 3 4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (600 mg, 1.76 mmol) using iron powder (489 mg, 8.80 mmol) and ammonium chloride (941 mg, 17.6 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 157 mg of the product.
  • Step 1 2-(3-chloro-6-(pyrrolidin-l-yl)pyridin-2-yl)propan-2-ol
  • the titled compound was prepared by the reaction of methyl 3-chloro-6-(pyrrolidin-l- yl)picolinate (700 mg, 2.90 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 5.8 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 315 mg of the product.
  • Step 2 3-chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-6-(pyrrolidin- l-yl)pyridine
  • the titled compound was prepared by the reaction of step 1 intermediate (300 mg, 1.24 mmol) with l,2-difluoro-4-nitrobenzene (198 ⁇ , 1.24 mmol) using sodium hydride (60% w/w, 59 mg, 1.49 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 100 mg of the product.
  • Step 3 4-((2-(3-Chloro-6-(pyrrolidin-l-yl)pyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
  • the titled compound was synthesized by the nitro reduction of the step 2 intermediate (120 mg, 0.32 mmol) using iron powder (87 mg, 1.57 mmol) and ammonium chloride (169 mg, 3.15 mmol) in a mixture of methanol (5.0 mL), THF (3.0 mL) and water (2.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 105 mg of the product.
  • the reaction mixture was quenched with water (20 mL) and the product was extracted in ethyl acetate (70 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to afford 56 mg of the titled product.
  • Step 1 N-(4-((2-(2,4-Dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l, l-difluoro-2- oxopropyl)phenyl) acetamide
  • the titled compound was prepared by the reaction of 4- ⁇ [2-(2,4-dichlorophenyl)propan-2- yl]oxy ⁇ aniline (Intermediate 1) (161 mg, 0.54 mmol) and 4-(l,l-difluoro-2- oxopropyl)phenyl] acetic acid (Intermediate 3) (116 mg, 0.54 mmol) using ⁇ , ⁇ '- diisopropylethylamine (232 ⁇ , 1.35 mmol) and propylphosphonic anhydride (50% in EtOAc, 326 ⁇ , 1.08 mmol) at the RT as per the procedure described in Example 1 to yield 175 mg of the product.
  • Step 2 N-(4-((2-(2,4-Dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l, l-difluoro-2- hydroxypropyl)phenyl)acetamide
  • Step 1 intermediate N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l,l- difluoro-2-oxopropyl)phenyl)acetamide
  • Step 1 intermediate 161 mg, 0.31 mmol
  • sodium borohydride 15 mg, 0.39 mmol
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL x 2).
  • Step 1 Ethyl 2-(4-(2-((4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate
  • the titled compound was prepared by the reaction of 4- ⁇ [4-(2,4-dichlorophenyl)tetrahydro- 2H-pyran-4-yl]oxy ⁇ -3-fluoroaniline (Intermediate 10) (500 mg, 1.40 mmol) and [4-(2- ethoxy- l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Step 1 compound of Intermediate 3) (398 mg, 1.54 mmol) using N,N'-diisopropylethylamine (604 ⁇ , 3.50 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.8 mL, 2.80 mmol) in DMF (10 mL) at 0 °C as per the procedure described in Method A to yield 584 mg of the product.
  • Step 2 N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
  • Step 1 intermediate ethyl 2-(4-(2-((4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4- yl)oxy)-3-fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate (Step 1 intermediate) (415 mg, 0.69 mmol) in anhydrous THF (10 mL) was added 3M methyl lithium (556 ⁇ , 1.66 mmol) dropwise at -78 °C. The reaction mixture was stirred at the same temperature for 30 min.
  • reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 203 mg of the titled product.
  • Step 3 N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
  • the titled compound was prepared by the reduction of N-(4-((4-(2,4- dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4-(l, l-difluoro-2- oxopropyl)phenyl)acetamide (Step 2 intermediate) (115 mg, 0.20 mmol) using sodium borohydride (12 mg, 0.30 mmol) in methanol (2.0 mL) as per the procedure described in Step 2 of Method B to yield 48 mg of the desired product.
  • Step 1 N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluo -2-oxopropyl)phenyl)acetamide
  • the titled compound was prepared by the reaction of 4- ⁇ [2-(5-chloro-l-ethyl-lH- benzimidazol-2-yl)propan-2-yl]oxy ⁇ -3-fluoroaniline (Intermediate 8) (95 mg, 0.27 mmol) and 4-(l,l-Difluoro-2-oxopropyl)phenyl] acetic acid (Intermediate 3) (62 mg, 0.27 mmol) using N,N'-diisopropylethylamine (117 ⁇ , 0.68 mmol) and propylphosphonic anhydride (50% in EtOAc, 304 ⁇ , 0.54 mmol) in DMF (3.0 mL) at 0 °C as per the procedure described in Method A to give 140 mg of the product.
  • Step 2 N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamide
  • Step 1 intermediate (50 mg, 0.08 mmol) in diethyl ether (5.0 mL) was added methylmagnesium bromide (3 , 89 ⁇ , 0.26 mmol) at 0 °C and the reaction mixture was stirred at the RT for 1 h.
  • the reaction mixture was quenched with aqueous saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 15 mg of the desired product.
  • the reaction mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 115 mg the titled product.
  • Step 1 N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-oxopropyl)phenyl)acetamide
  • the titled compound was prepared by the coupling reaction of 4- ⁇ [2-(3,5-dichloropyridin-2- yl)propan-2-yl]oxy ⁇ -3-fluoroaniline (Intermediate 22) (1.3 g.
  • Step 1 Intermediate (1.0 g, 1.90 mmol) in THF (10 mL) was drop wise added to the reaction mixture over a period of 10 min at 0 °C. The resultant mixture was stirred at the RT for 20 min. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under the reduced pressure. The residue obtained was purified by flash silica gel column chromatography to yield 950 mg of the titled product as solid.
  • Step 3 (5)-( ?)-l-(4-(2-((4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-l,l-difluoropropan-2-yl 2-(((benzyloxy)carbonyl) amino)-3-phenylpropanoate
  • Step 4 ( ?)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide
  • Step 3 intermediate (675 mg, 0.84 mmol) in a mixture of methanol (5.0 mL), water (5.0 mL) and THF (20 mL) was added lithium hydroxide monohydrate (70 mg, 1.67 mmol) and the reaction mixture was stirred at the RT for 1 h.
  • the reaction mixture was concentrated and the residue was diluted with water (20 mL).
  • the aqueous mixture was acidified with IN HCl and extracted with ethyl acetate (2 x 50 mL).
  • the combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and filtered.
  • the solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 405 mg of the titled product.
  • Step 1 (5)-N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide (Crude)
  • Step 2 (5)-(5)-l-(4-(2-((4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate
  • Step 3 (5)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide
  • Step 2 intermediate 750 mg, 0.92 mmol
  • methanol 5.0 mL
  • water 5.0 mL
  • THF 20 mL
  • lithium hydroxide monohydrate 78 mg, 1.85 mmol
  • the reaction mixture was concentrated and the residue was diluted with water (20 mL).
  • the aqueous mixture was acidified with IN HC1 and extracted with ethyl acetate (2 x 50 mL).
  • the combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered.
  • the solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 430 mg of the titled product.
  • Step 1 Ethyl 2-(4-(2-((4-((2-(3-chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate
  • the titled compound was prepared by the reaction of 4-((2-(3-chloro-6-methoxypyridin-2- yl)propan-2-yl)oxy)-3-fluoroaniline (Intermediate 39) (390 mg, 1.25 mmol) and [4-(2- ethoxy- l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Step 1 compound of Intermediate 3) (388 mg, 1.50 mmol) using N,N'-diisopropylethylamine (540 ⁇ , 3.13 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.6 mL, 2.51 mmol) in DMF (5.0 mL) as per the procedure described in Method A to yield 459 mg of the product.
  • Step 2 N-(4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
  • Step 3 N-(4-((2-(3-Chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
  • Step 2 intermediate N-(4-((2-(3-chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-(l,l-difluoro-2-oxopropyl)phenyl)acetamide (Step 2 intermediate) (50 mg, 0.09 mmol) in acetonitrile (10 mL) were added sodium iodide (42 mg, 0.29 mmol) and trimethylsilyl chloride (39 ⁇ , 0.29 mmol at the RT under the nitrogen atmosphere. The reaction mixture was stirred at 65 °C for 18 h.
  • the reaction mixture was quenched with aqueous sodium thiosulfate solution (1.0 mL) and further diluted with water (20 mL).
  • the aqueous mixture was extracted with ethyl acetate (50 mL x 2).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure.
  • the crude material obtained was purified by silica gel column chromatography to yield 25 mg of the titled product.
  • Step 4 N-(4-((2-(3-chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
  • the titled compound was prepared by the reduction of N-(4-((2-(3-Chloro-6-hydroxypyridin- 2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-oxopropyl)phenyl)acetamide (Step 3 intermediate) (20 mg, 0.04 mmol) using sodium borohydride (3.0 mg, 0.06 mmol) in methanol (5.0 mL) as per the procedure described in Step 2 of Method B to yield 11 mg of the desired product.
  • 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 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 10 nM 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 h.
  • the pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and 10 nM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 h 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. IC 50 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 IC 50 (nM) details for selected examples. The compounds were found to have IC 50 less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM.
  • IC 50 (nM) values are set forth in Table 2 wherein "A” refers to an IC 50 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.

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Abstract

Provided are compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring B, L, R 1, R 2, R a, R b, n, x, y and z are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORyt).

Description

ARYL AND HETEROARYL ETHER COMPOUNDS AS ROR GAMMA
MODULATORS
RELATED APPLICATIONS
This application claims the benefit of the Indian Provisional Application No. 3587/MUM/2015 filed on September 21, 2015; which is hereby incorporated by the reference in its entirety.
TECHNICAL FIELD
The present patent application is directed to aryl and heteroaryl ether 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 cell 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., 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.
PCT Publication Nos. WO 2012/139775, WO 2012/027965, WO 2012/028100, WO 2012/100732, WO 2012/100734, WO2012/064744, WO 2013/171729 and WO 2015/008234 disclose heterocyclic compounds which are modulators of retinoid-related orphan receptor gamma (RORy) receptor activity.
In view of the above, a need exists for new therapeutic agents that modulate the activity of RORyt and thus will provide new methods for treating diseases or conditions associated with the modulation of RORyt.
The present application is directed to compounds that are modulators of the RORyt receptor.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a compound of formula (I)
Figure imgf000004_0001
(I)
or a tautomer thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof,
wherein
Figure imgf000004_0002
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
Figure imgf000004_0003
'~ L~< is selected from 5 |~ 0(CR Ry)q- y i and !- 0(CRxRy)qC≡C^; . x, y and z represent point of attachment;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and Ci_8alkyl;
R1 is selected from hydroxyl and Ci_8alkyl;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl, C3_6cycloalkyl and 3 to 15 membered heterocyclyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurance of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2. 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 and 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 X1 is N (according to an embodiment defined below), R1 is hydroxyl or methyl (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which X1 is N.
According to another embodiment, specifically provided are compounds of formula (I), in which X is CR . In this embodiment, R is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (I), in which Ra and Rb are hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which one of Ra and Rb is hydrogen and the other is hydrogen or Ci_8alkyl (e.g. methyl).
According to yet another embodiment specifically provided are compounds of formula (I), in which one of Ra and Rb is hydrogen and the other is hydrogen or methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which Ra and Rb are Ci_8alkyl (e.g. methyl).
According to yet another embodiment specifically provided are compounds of formula (I), in which Ra and Rb are methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydroxyl or Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydroxyl or methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which R1 is methyl; Ra is hydrogen and Rb is hydrogen. According to yet another embodiment specifically provided are compounds of formula (I), in which R1 is hydroxyl; Ra is hydrogen and Rb is methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which R1 is hydroxyl; Ra is methyl and Rb is methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which R is hydroxyl, halogen (e.g. fluoro or chloro), Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), C3_6cycloalkyl (e.g. cyclopropyl) or 3 to 15 membered heterocyclyl (e.g. pyrrolidinyl).
According to yet another embodiment specifically provided are compounds of formula (I), in which R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl and 'n' is 1, 2 or 3.
According to yet another embodiment specifically provided are compounds of formula (I), in which R is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (I), in which R4 is Ci-galkyl (e.g. ethyl).
According to yet another embodiment specifically provided are compounds of formula (I), in which R4 is ethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
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 'q' is 1. According to yet another embodiment, specifically provided are compounds of
or
Figure imgf000007_0001
According to yet another embodiment, specifically provided are compounds of
(R2)n
formula (I), in which - —i) ¾ is 3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro- 1-ethyl- lH-benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methoxyphenyl, 4-chloro-2-methylphenyl, 3-chloro-6- methylpyridin-2-yl, 4-chloro-6-methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro- 2-methylpyridin-4-yl, 3-chloro-6-(pyrrolidin- l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5- chloropyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5- dichloro-6-methylpyridin-2-yl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which I Z y '< is l Z ¾ y i . In this embodiment, Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
According to yet another embodiment, specifically provided are compounds of
Figure imgf000007_0002
formula (I), in which
Figure imgf000007_0003
According to yet another embodiment, specifically provided are compounds of formula (I), in which
Ring A is
Figure imgf000007_0004
X1 is CH, CF or N;
:— L-j is 0(CRxRy)qC≡(
Figure imgf000008_0001
wherein x, y and z represents point of attachment;
Ring B is phenyl, pyridyl or benzimidazolyl;
Ra is hydrogen or methyl; Rb is hydrogen or methyl;
R1 is hydroxyl or methyl;
R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl; R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
'n' is 1, 2 or 3; and
'q' is 1.
According to yet another embodiment, specifically provided are compounds of formula (I), in which
Ra is hydrogen or methyl; Rb is hydrogen or methyl;
Figure imgf000008_0002
Ring A is H3C-
Figure imgf000008_0003
3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro-l-ethyl-lH- benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methoxyphenyl, 4-chloro-2-methylphenyl, 3-chloro-6- methylpyridin-2-yl, 4-chloro-6-methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro- 2-methylpyridin-4-yl, 3-chloro-6-(pyrrolidin-l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5- chloropyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5- dichloro-6-methylpyridin-2-yl. According to 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 ring A, ring B, L, R1, R2, Ra, Rb and n (and groups defined therein) are described hereinafter in relation to the compounds of formula (II) or Formula (III). It is to be understood that these embodiments are not limited to use in conjunction with formula (II) or Formula (III), 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) or Formula (III) in which R is hydrogen or fluorine and consequently there is also provided a compound of the formula (I) in which R is hydrogen or fluorine.
The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (II)
Figure imgf000009_0001
(II)
or a tautomer thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof,
wherein
Figure imgf000009_0002
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
Figure imgf000009_0003
'~ L~< is selected from ;
x, y and z represents point of attachment;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ galkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl and C3_6cycloalkyl; R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurance of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
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 and 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 R is hydrogen or fluorine (according to an embodiment defined below), R4 is ethyl (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below).
According to another embodiment, specifically provided are compounds of formula
(II), in which X 1 is CR3. In this embodiment, R 3 is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (II), in which R is halogen (e.g. fluoro or chloro), Ci_8alkyl (e.g. methyl or ethyl) and Ci-8alkoxy (e.g. methoxy).
According to yet another embodiment specifically provided are compounds of formula (II), in which R is fluoro, chloro, methyl, ethyl or methoxy.
According to yet another embodiment specifically provided are compounds of formula (II), in which R is fluoro, chloro, methyl, ethyl or methoxy and 'n' is 2.
According to yet another embodiment specifically provided are compounds of formula (II), in which R is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (II), in which R4 is Ci_8alkyl (e.g. ethyl).
According to yet another embodiment specifically provided are compounds of formula (II), in which R4 is ethyl. According to yet another embodiment, specifically provided are compounds of formula (II), in which Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
According to yet another embodiment, specifically provided are compounds of formula (II), in which 'n' is 2.
According to yet another embodiment specifically provided are compounds of formula (II), in which 'q' is 1.
According to yet another embodiment, specifically provided are compounds of
formula (II), in which ring A
Figure imgf000011_0001
According to yet another embodiment, specifically provided are compounds of
Figure imgf000011_0002
formula (II), in which is 5-chloro- l -ethyl- lH-benzimidazol-2-yl, 4-chloro-2- methoxyphenyl, 4-chloro-2-methylphenyl, 5-chloro-3-methylpyridin-2-yl, 2,4- dichlorophenyl, 3,5-dichloropyridin-2-yl or 2,4-difluorophenyl.
According to yet another embodiment, specifically provided are compounds of
I j ] ! (CRXR^) O '
formula (II), in which I Z y '< is l Z ¾ y i . In this embodiment, Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
According to yet another embodiment, specifically provided are comp f ■— OC(CH3)2— ;
Figure imgf000011_0003
According to yet another embodiment, specifically provided are compounds of formula (II), in which
Figure imgf000011_0004
X1 is CH or CF; 1 2 y < is I Z 4 J l or 1 2 4 y i , wherein x, y and z represents point of attachment;
Ring B is phenyl or benzimidazolyl;
R is fluoro, chloro, methyl, ethyl or methoxy;
R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring;
'n' is 2; and
'q' is 1.
According to yet another embodiment, specifically provided are compounds of formul
Figure imgf000012_0001
'" V ~^/ ' * is 5-chloro-l -ethyl- lH-benzimidazol-2-yl, 4-chloro-2-methoxyphenyl,
4-chloro-2-methylphenyl, 5-chloro-3-methylpyridin-2-yl, 2,4-dichlorophenyl, 3,5- dichloropyridin-2-yl or 2,4-difluorophenyl.
According to 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 provides a compound of formula (III)
Figure imgf000012_0002
(III)
or a tautomer thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof,
wherein
Figure imgf000013_0001
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
i— L— y ! :„
selected from — (CRxRy)Q0— ;
is y i and
0(CRxRy)q( x, y and z represents point of attachment;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl and C3_6cycloalkyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurance of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
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 and 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
1 3 3 defined above wherein X is CR (according to an embodiment defined below), R is hydrogen or fluorine (according to another embodiment defined below) and 'q' is 1 (according to yet another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (III), in which X1 is N.
According to another embodiment, specifically provided are compounds of formula
1 3 3
(III), in which X is CR . In this embodiment, R is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (III), in which R is hydroxyl, halogen (e.g. fluoro or chloro), Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), C3_6cycloalkyl (e.g. cyclopropyl) or 3 to 15 membered heterocyclyl (e.g. pyrrolidinyl).
According to yet another embodiment specifically provided are compounds of formula (III), in which R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
According to yet another embodiment specifically provided are compounds of formula (III), in which R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl and 'n' is 1, 2 or 3.
According to yet another embodiment specifically provided are compounds of formula (III), in which R is hydrogen or fluorine.
According to yet another embodiment specifically provided are compounds of formula (III), in which R4 is Ci-galkyl (e.g. ethyl).
According to yet another embodiment specifically provided are compounds of formula (III), in which R4 is ethyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
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 'q' is 1. According to yet another embodiment, specifically provided are compounds of
formula (III), in which ring A is
Figure imgf000015_0001
Figure imgf000015_0002
According to yet another embodiment, specifically provided are compounds of formula (III), in which ^ '" s 3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro-l-ethyl- lH-benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methylphenyl, 3-chloro-6-methylpyridin-2-yl, 4-chloro-6- methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro-2-methylpyridin-4-yl, 3-chloro- 6-(pyrrolidin-l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl, 2,4- dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5-dichloro-6- methylpyridin-2- yl .
According to yet another embodiment, specifically provided are compounds of
I j I ! (CRXR^) O '
formula (III), in which I Z y '< is l Z ¾ y i . In this embodiment, Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring and 'q' is 1.
According to yet another embodiment, specifically provided are compounds of formula III in hich '~ L~> !~C(CH3)20-^| ^ \~ OC(CH3)2— ^ z^ y
Figure imgf000015_0003
According to yet another embodiment, specifically provided are compounds of formula (III), in which
Figure imgf000015_0004
X1 is CH, CF or N;
- 0(CRxRy)qC≡( is I— (CRxRy)qO I— 0(CRxRy), q i or
wherein x, y and z represents point of attachment;
Ring B is phenyl, pyridyl or benzimidazolyl;
R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl;
R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
'n' is 1, 2 or 3; and
'q' is 1.
According to yet another embodiment, specifically provided are compounds of formula III , in which
Figure imgf000016_0001
(R^)
Ms 3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro-l-ethyl-lH- benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methylphenyl, 3-chloro-6-methylpyridin-2-yl, 4-chloro-6- methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro-2-methylpyridin-4-yl, 3-chloro- 6-(pyrrolidin-l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl, 2,4- dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5-dichloro-6- methylpyridin-2-yl.
According to 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 1-57. 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 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 an 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 an autoimmune disease, inflammatory disease, respiratory disorder, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
In another 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 herein.
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-8alkyl" refers to an alkyl chain having 1 to 8 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 (e.g. 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_8alkyl). Examples of such haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term "haloCi_8alkyl" refers to at least one halo group linked an alkyl chain having 1 to 8 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_8alkoxy). 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 "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.Cs-ncycloalkyl). 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 (e.g. C3_6cycloalkylCi_8alkyl). 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, 6-oxo-l,6-dihydropyridin-3-yl, 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. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
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) or (III) 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) or (III) 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 the 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 centers of the present invention can have the S or R configuration as defined by the IUPAC 1974.
Pharmaceutical Compositions
The compounds of the invention are typically administered in the form of a pharmaceutical composition. 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.
Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of route of administration, such as orally or parenterally. 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.
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 beneficial.
The compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases or 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, and 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, post-operative 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, post-traumatic 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), (la), (lb), (Ic), (Ib-i), (Id), intermediates and specific examples are prepared through the synthetic methods as depicted in Schemes 1 to 11. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The 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 using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention can be prepared through the reaction schemes as follows. In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and cleavage of protecting groups etc., by following procedures known in the art of organic synthesis.
A general approach for the preparation of compound of formula (I) (wherein ring A, ring B, L, R1, R2, Ra, Rb, 'η', 'χ' , 'z' and 'y' are defined as in general description) is depicted in synthetic scheme 1.
Synthetic scheme 1
Figure imgf000025_0001
(I)
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 (I). The suitable coupling agent(s) may be 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). 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. The suitable solvent may be selected from CH2C12, CHC13, DMF and THF or combination thereof. A general approach for the preparation of compound of formula (la) and (lb) (wherein ring A, ring B, L, R2, Ra, Rb, 'η', 'χ', 'z' and 'y' are defined as in general description) is depicted in synthetic scheme 2.
Synthetic scheme 2
Figure imgf000026_0001
The coupling of amine compound of formula (1) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (3). The suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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. The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The reaction of alkyl lithium of formula Rb-Li (5) with the ester compound of formula (3) in the presence of suitable solvent gives the ketone compound of formula (4). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. Alternatively, the coupling of amine compound of formula (1) with the keto-carboxylic acid compound of formula (2b) in the presence of a suitable coupling agent(s) and suitable base directly gives the amide compound of formula (4) using the same coupling reaction conditions as described above. The reduction of the carbonyl group in compound of formula (4) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (la). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol. The reaction of compound of formula (4) with alkyl magnesium bromide of formula RaMgX affords the tertiary alcohol compound of formula (lb). The reaction may be carried out in a suitable solvent or mixture thereof. The suitable solvent may be selected from diethyl ether, CH2CI2, CHCI3, DMF and THF or combination thereof.
A general approach for the preparation of the compounds of the formula (Ic), (wherein R2, Rb, Rx, Ry and 'n' are as defined in the general description) is illustrated in synthetic scheme 3.
Synthetic scheme 3
Figure imgf000027_0001
The coupling of appropriately substituted 4-iodoaniline (6) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (7). The suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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. The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The reaction of alkyl lithium of formula (5) with the ester compound of formula (7) in the presence of suitable solvent gives the ketone compound of formula (8). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The reduction of the carbonyl group in compound of formula (8) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (9). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol. The Sonogashira coupling reaction of the compound of formula (9) with acetylene derivative of formula (10) yields the final compound of formula (Ic). A general approach for the preparation of compounds of the formulae (Ib-i) (wherein R2, Rb, 'η' , 'χ', 'z' and 'y' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 4.
Synthetic scheme 4
Figure imgf000028_0001
The chiral reduction of keto group of compound of formula (4) using suitable chiral reducing agent in a suitable solvent yields one enantiomer of hydroxyl compound of formula (Ib-i) as a major product. The chiral reducing agent may be selected from (R or 5)-2-methyl- CBS-oxazaborolidine in the presence of borane dimethyl sulfide, hydrogenation using BINAP-Ru dihalide, H2/ ruthenium (diphosphane)2 (diamine)2 complex, etc. Suitable solvent for the reaction may be THF, DCM or DMF. The compound of formula (Ib-i) can be further purified (to enhance the enantiomeric excess) through diastereomeric separation using N- benzyloxycarbonyl-L-phenylalanine, mandelic acid, or any other suitable agent to yield the diastereomeric ester of formula (11). The esterification can be done in the presence of suitable coupling agent and a suitable base. 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 solvent used in the reaction may be selected from CH2C12, CHC13, DMF and THF or combination thereof. Saponification of the diastereomeric ester of formula (11) using lithium hydroxide in suitable solvent such as methanol, THF and water or combination thereof furnishes relatively pure form of compound of formula (R or S)-(Ib-i).
A general approach for the preparation of compounds of the formulae (Id) (wherein Rb is as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 5. Synthetic scheme 5
Figure imgf000029_0001
The coupling of amine compound of formula (12) with the mono ester derivative of dicarboxylic acid compound of formula (2a) in the presence of a suitable coupling agent(s) and suitable base gives the ester amide compound of formula (13). The suitable coupling agent(s) may be EDCI, DCC, T3P (50% in EtOAc) or 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. The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The reaction of alkyl lithium of formula (5) with the ester compound of formula (13) in the presence of suitable solvent affords the ketone compound of formula (14). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. De-methylation of the methoxy group in compound of formula (14) using sodium iodide and trimethylsilyl chloride in appropriate solvent such as acetonitrile affords the hydroxypyridine compound of formula (15). The reduction of the carbonyl group in compound of formula (15) using a suitable reducing agent in a suitable solvent gives the racemic hydroxyl compound of formula (Id). The suitable solvent may be selected from CH2CI2, CHC13, DMF and THF or combination thereof. The suitable reducing agent may be sodium borohydride and the suitable solvent may be methanol.
A general approach for the preparation of carboxylic acid of formula (2a) and (2b) (wherein Rb is as defined in the general description) are illustrated in synthetic scheme 6. Synthetic scheme 6
Figure imgf000030_0001
The copper mediated coupling reaction of halo substituted phenylacetic acid of formula (16) with ethyl bromo(difluoro)acetate (17) in a suitable aprotic polar solvent (e.g. DMSO) affords the mono ester derivative of dicarboxylic acid compound of formula (2a). The acid group in compound of formula (2a) on protection with iert-butyl bromide in the presence of a suitable base and a suitable solvent such as CH2CI2, CHCI3, DMF or THF or mixture thereof to affords heterogeneous di-ester compound of formula (18). The suitable base may be selected from Ag2C03i Et3N, DIPEA and DMAP. The selective deprotection of ethyl ester in compound of formula (18) using lithium hydroxide monohydrate in a suitable solvent or mixture thereof gives the carboxylic acid compound of formula (19). The suitable solvent may be CH2CI2, CHC13, DMF, THF, methanol, water mixtures thereof. The reaction of compound of formula (19) with oxalyl chloride gives the corresponding acid chloride which on coupling with N,0-dimethylhydroxylamine hydrochloride in the presence of a suitable base (e.g. Et3N, DIPEA and DMAP) and in a suitable solvent (e.g. CH2C12, CHC1 , DMF or THF) gives the Weinreb amide of formula (20). The reaction of compound (20) with suitable alkyl magnesium halide of formula RbMgX (21) in a suitable solvent (e.g. CH2CI2, CHC13, DMF or THF) furnishes the difluoro ketone compound of formula (22). The deprotection of ester group in compound of formula (22) using trifluoroacetic acid in a suitable solvent affords the carboxylic acid compound of formula (2b). 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 (2c) (wherein R1 is as defined in the general description) is illustrated in synthetic scheme 7.
Synthetic scheme 7
Figure imgf000031_0001
The reaction of halogen substituted phenyl ketone compound of formula (23) (wherein Hal is halogen) with ethane- 1,2-dithiol (to protect the carbonyl group) in the presence of a suitable Lewis acid in a suitable solvent gives the thioacetal compound of formula (24). The suitable Lewis acid may be boron trifluoride diethyletherate and suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF. The compound of formula (24) on reaction with HF-pyridine complex in the presence of N-iodosuccinimide in a suitable solvent gives benzyl difluoro compound of formula (25). The suitable solvent may be pyridine, CH2CI2, CHCI3, DMF or mixtures thereof. Halogen substitution of compound of formula (25) on a reaction with ie/ -butyl acetate in the presence of palladium catalyst and suitable base gives compound of formula (26). The suitable base for this substitution reaction may be lithium dicyclohexylamine. The substitution reaction can be carried out in a suitable solvent such as toluene. The compound of formula (26) on deprotection of ie/ -butyl group, using trifluoroacetic acid in a suitable solvent gives the compound of formula (2c). The suitable solvent may be selected from CH2CI2, CHCI3, DMF and THF.
A general approach for the preparation of amine of formula (la) (wherein X 1 , R 2 , and
'n' are as defined in the general description; X 2 , X 3 and X 4 are CH or N, with a proviso that only one of X2, X3 and X4 is N; and Rz is Ci_8alkyl) is illustrated in synthetic scheme 8.
Synthetic scheme 8
Figure imgf000031_0002
(3°) The reaction of keto compound of formula (27) (wherein R' is Ci-galkoxy) with alkyl magnesium halide of formula (28) affords the tertiary alcohol compound of formula (29). Alternatively, the reaction of an appropriately substituted heterocyclic halide of formula (30) (wherein X is F, CI, Br or I) with a keto derivative of formula (31) in the presence of suitable base gives the tertiary alcohol (29). The suitable base may be butyl lithium. The nucleophilic substitution reaction of compound of formula (29) with compound of formula (32) (wherein X is F, CI, Br or I) in the presence of suitable base (e.g. sodium hydride) in a suitable solvent (e.g. DMF) followed by reduction of the nitro group using iron powder in the presence of aqueous acetic acid or ammonium chloride furnishes the corresponding amine compound of formula (la). The reduction of the nitro group can also be carried out by using sodium borohydride in the presence of nickel chloride.
A general approach for the preparation of compound of formula (lb) (wherein R2, Rx, Ry and 'n' are as defined in the general description) is illustrated in synthetic scheme 9.
Synthetic scheme 9
Figure imgf000032_0001
The coupling reaction of appropriately substituted benzene- 1,2-diamne derivative compound of formula (33) with the phenoxy acetic acid compound of formula (34) using Ι,Γ-carbonyldiimidazole (CDI) or other suitable coupling agent in a suitable solvent (e.g. CH2CI2, CHCI3, DMF or THF) gives the an amide which in the presence of acetic acid cyclizes to yield benzimidazole compound of formula (35). The reduction of the nitro group of compound of formula (35) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent (e.g. CH2CI2, CHCI3, DMF, THF, methanol or water) or mixture thereof yields the corresponding amine compound of formula (lb). Alternately, reduction of the nitro group to give the corresponding amine can be carried out using sodium borohydride in the presence of nickel chloride.
A general approach for the preparation of the compound of formula (lc) (wherein X , R" and ' n' are as defined in the general description; Y is CH, O or N; V is 0, 1 or 2; 'w' is 1, 2 or 3; X 2 , X 3 and X 4 are CH or N, 2 3 4
with a proviso that only one of X , X and X is N) is illustrated in synthetic scheme 10.
Synthetic scheme 10
Figure imgf000033_0001
The metallation of the aryl halide compound of formula (36) with a suitable base (e.g. ft-butyl lithium) followed by reaction with an appropriate keto compound of formula (37) in a suitable solvent (e.g. diethyl ether or THF) affords the alcohol compound of formula (38). The nucleophilic substitution reaction of compound of formula (32) (wherein X is F, CI, Br or I) with compound of formula (38) in the presence of a suitable base (e.g. sodium hydride) in a suitable solvent (e.g. THF, DMF) yields the ether compound of formula (39). The reduction of the nitro group in compound of formula (39) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent (e.g. CH2CI2, CHCI3, DMF, THF, methanol or water) or mixture thereof gives the corresponding amine compound of formula (lc). The reduction of the nitro group can also be carried out by using sodium borohydride in the presence of nickel chloride.
A general approach for the preparation of compound of formula (Id) (wherein R 2 , R 4 , Rx, Ry and 'n' are as defined in the general description) is illustrated in synthetic scheme 11. Synthetic scheme 11
Figure imgf000033_0002
Thus, amide coupling of phenyl acetic acid compound of the formula (40) with 4- nitrobenzene-l,2-diamine derivative of formula (41) using CDI or any other suitable coupling agent in a suitable solvent (e.g. CH2CI2, CHCI3, DMF or THF) followed by cyclization in the presence of acetic acid yields substituted 5-nitrobenzimidazole intermediate of formula (42). The reduction of nitro group in compound of formula (42) using iron powder in the presence of aqueous acetic acid or ammonium chloride in a suitable solvent (e.g. CH2CI2, CHCI3, DMF, THF, methanol or water) or mixture thereof gives the corresponding amine compound of formula (Id). The reduction of the nitro group can also be carried out by using sodium borohydride in the presence of nickel chloride.
Experimental Section
Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
The abbreviations, symbols and terms used in the examples and assays have the following meanings throughout: CDI: Ι,Γ-carbonyldiimidazole; DCM: dichloromethane; DMSO- 6: Hexadeuterodimethyl sulfoxide; DMSO dimethyl sulfoxide; 1H NMR: Proton Nuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; EDCI.HC1: l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride; Et3N: triethylamine; HOBT: 1- hydroxybenzotriazole; NaOH: Sodium Hydroxide; KOH: Potassium Hydroxide; LiOH: Lithium Hydroxide; DIPEA: N,N-diisopropylethylamine; THF: Tetrahydofuran; HC1: hydrochloric acid; Na2S04: Sodium sulfate; NaHC03: Sodium bicarbonate; : Coupling constant in units of Hz; h: hour(s); mins: minutes; RT or rt: Room temperature (22-26°C); o: ortho; m: meta; p: para; APCI-MS: Atmospheric Pressure Chemical Ionization Mass Spectrometry; MHz: Megahertz; aq.: aqueous
Intermediates
Intermediate 1
4- { [2-(2,4-Dichlorophenyl)propan-2-yl]oxy } aniline
Figure imgf000034_0001
Step 1: Methyl 2,4-dichlorobenzoate
To a stirred solution of 2,4-dichlorobenzoic acid (20 g, 105 mmol) in methanol (200 mL) was drop-wise added concentrated sulfuric acid (2.0 mL) and the mixture was refluxed for 18 h. The solvent was evaporated under the reduced pressure. The residue was diluted with ice cold water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL), aqueous saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 22.7 g of the titled product. 1H NMR (300 MHz, DMSO-i¾ δ 3.32 (s, 3H), 8.10 (d, J = 7.8 Hz, 2H), 8.30 (s, 1H); APCI-MS (m/z) 205 (M+H)+.
Step 2: 2-(2,4-Dichlorophenyl)propan-2-ol
To a stirred solution of Step 1 intermediate (22.7 g, 0.11 mmol) in anhydrous diethyl ether (100 mL) was dropwise added methylmagnesium bromide (1.4 M in THF, 197 mL, 0.27 mmol) at -78 °C. The resulting mixture was stirred at the RT for 18 h. The mixture was quenched with aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 16.8 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 1.56 (s, 6H), 5.39 (s, 1H), 7.36-7.50 (m, 2H), 7.82 (d, = 7.5 Hz, 1H); APCI- MS (m/z) 205 (M+H)+.
Step 3: 2,4-Dichloro-l-[2-(4-nitrophenoxy)propan-2-yl]benzene
To a stirred solution of Step 2 intermediate (11 g, 53.6 mmol) in anhydrous DMF (100 mL) was added sodium hydride (60% w/w, 3.2 g, 80.5 mmol) at 0 °C followed by addition of 4- fluoronitrobenzene (7.5 g, 53.6 mmol). The reaction mixture was warmed to the RT and stirred for 18 h. The reaction mixture was quenched with ice cold water (100 mL) and was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with water (200 mL) followed by brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 14.96 g of the titled product H NMR (300 MHz, DMSO-ifc) δ 1.87 (s, 6H), 6.80 (d, = 7.8 Hz, 2H), 7.52-7.59 (m, 2H), 7.65 (d, = 8.2 Hz, 1H), 8.03 (d, = 8.2 Hz, 2H).
Step 4: 4-{ [2-(2,4-Dichlorophenyl)propan-2-yl]oxy}aniline
To a stirred solution of Step 3 intermediate (750 mg, 2.29 mmol) in a mixture of methanol and water (1 : 1, 20 mL) were added iron powder (642 mg, 11.5 mmol) followed by ammonium chloride (1.2 g, 23.0 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 (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (100 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 504 mg of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 1.64 (s, 6H), 4.69 (s, 2H), 6.39 (q, J = 7.5 Hz, 4H), 7.38-7.43 (m, 1H), 7.58 (d, 7 = 8.1 Hz, 2H).
Intermediate 2
[4-(l,l-Difluoropropyl)phenyl] acetic acid
Figure imgf000036_0001
Step 1 : 2-(4-Bromophenyl)-2-ethyl- 1 ,3-dithiolane
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 reaction mixture was stirred overnight at RT. The reaction mixture was diluted with dichloromethane (10 mL), washed with aqueous sodium hydroxide solution (10% w/v, 10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure to yield 2.21 g of the desired product. 1H NMR (300 MHz, CDC13) δ 0.89 (t, = 7.5 Hz, 3H), 2.33 (q, = 7.5 Hz, 2H), 3.19-3.32 (m, 2H), 3.34-3.41 (m, 2H), 7.41 (d, = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H); APCI-MS (m/z) 287.9 (M)+.
Step 2: 1 -Bromo-4-( 1 , 1 -difluoropropyl)benzene
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, 20.9 mmol). After being stirred for 2 min, was added a solution of 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 (5.0 mL), filtered through basic alumina and washed with n-hexane (30 mL). The filtrate was concentrated and the residue was diluted with ethyl acetate (50 mL). The residue was washed with 10% sodium thiosulfate (20 mL), 2% potassium permanganate (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 203 mg of the titled product. 1H NMR (300 MHz, CDCI3) δ 0.97 (t, = 7.5 Hz, 3H), 2.02-2.21 (m, 2H), 7.33 (d, = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H); APCI-MS (m/z) 231 (M-H)~.
Step 3: ie/t-Butyl [4-(l, l-difluoropropyl)phenyl] acetate
To a solution of dicyclohexylamine (1.8 g, 10.3 mmol) in anhydrous toluene (20 mL) at 0 °C was added n-butyl lithium (1.6 , 6.41 mL, 10.3 mmol) followed by ie/ -butyl acetate (1.15 niL, 8.55 mmol) and the reaction mixture was stirred for 15 min at 0 °C. In a separate flask, tri-ieri-butylphosphonium tetrafluoroborate (248 mg, 0.85 mmol) and bis(dibenzylideneacetone) palladium (0) (245 mg, 0.42 mmol), were taken together and was evacuated and refilled with nitrogen (3 times). The solid mixture was taken in toluene (10 mL) and to this suspension was added step 2 Intermediate (2.01 g, 8.55 mmol) followed by the first reaction mixture. The resulting mixture was stirred overnight at RT. The reaction mixture was diluted with diethyl ether (50 mL), filtered through celite and the bed was washed with diethyl ether (30 mL). The combined filtrates were concentrated and the residue obtained was purified by silica gel column chromatography to afford 1.43 g of the desired product. 1H NMR (300 MHz, CDC13) 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 step 3 intermediate (1.42 g, 5.25 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (10 mL) and the reaction mixture was stirred at the RT for 1 h. The solvent in the reaction mixture was evaporated and the residue thus obtained was purified by silica gel column chromatography to yield 491 mg of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, = 6.0 Hz, 3H), 2.11-2.28 (m, 2H), 3.63 (s, 2H), 7.33 (d, = 8.4 Hz, 2H), 7.42 (d, = 8.4 Hz, 2H), 12.42 (br s, 1H); APCI-MS im/z) 213 (M-H)~.
Intermediate 3
4-( 1 , 1 -Difluoro-2-oxopropyl)phenyl] acetic acid
Figure imgf000037_0001
Step 1: [4-(2-Ethoxy-l,l-difluoro-2-oxoethyl)phenyl] acetic acid
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 ethyl bromodifluoroacetate (196 mg, 1.52 mmol). The reaction mixture was stirred overnight at 60 °C in a sealed tube. The reaction mixture was cooled to the RT and quenched with aqueous ammonium chloride solution (30 mL). The aqueous mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 171 mg of the desired product. H NMR (300 MHz, DMSO-d6) δ 1.22 (t, = 6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, = 7.2 Hz, 2H), 7.44 (d, = 8.1 Hz, 2H), 7.53 (d, = 8.1 Hz, 2H), 12.45 (s, 1H). Step 2: Ethyl [4-(2-iert-butoxy-2-oxoethyl)phenyl](difluoro)acetate
To a stirred solution of step 1 intermediate (3.3 g, 12.8 mmol) in a mixture of dichloromethane and THF (2: 1, 90 mL) were added molecular sieves (3.3 g, 4 A) and silver carbonate (10.58 g, 38.3 mmol). The reaction mixture was stirred, cooled to 0 °C and to it was drop-wise added ieri-butyl bromide (7.3 mL, 63.9 mmol). The reaction mixture was allowed to attain room temperature and was stirred overnight. The reaction mixture was filtered through celite bed and washed with dichloromethane (100 mL). The filtrate was concentrated under the reduced pressure and the residue obtained was purified by flash chromatography to yield 1.82 g of the titled product.
Step 3: [4-(2-ieri-Butoxy-2-oxoethyl)phenyl](difluoro)acetic acid
To a stirred solution of step 2 intermediate (915 mg, 2.91 mmol) in a solvent mixture of THF, methanol and water (3:2: 1, 30 mL) at 0 °C was added lithium hydroxide monohydrate (366 mg, 8.73 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was acidified with IN HC1 till pH 2-3 and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure to afford 839 mg of the titled product. 1H NMR (300 MHz, DMSO- 6) δ 1.40 (s, 9H), 3.64 (s, 2H), 7.40 (d, / = 8.4 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H).
Step 4: ie/t-Butyl (4-{ l,l-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)acetate To a stirred solution of step 3 intermediate (833 mg, 2.90 mmol) in dichloromethane (15 mL) at 0 °C were added oxalyl chloride (2.2 mL, 4.36 mmol) and catalytic amount of DMF. The reaction mixture was allowed to attain the RT and stirred for 3 h. The reaction mixture was concentrated under the inert atmosphere to give an oily residue, which was diluted with dichloromethane (15 mL) and cooled to 0 °C. Thereafter, N,Odimethyl hydroxylamine hydrochloride (425 mg, 4.36 mmol) was added followed by triethyl amine (1.6 mL, 11.63 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with dichloromethane (15 mL), washed with aqueous saturated sodium bicarbonate solution (20 mL) and brine (20 mL). The organic layer was concentrated and the crude obtained was purified by silica gel column chromatography to afford 581 mg of the product. 1H NMR (300 MHz, CDC13) δ 1.43 (s, 9H), 3.21 (s, 3H), 3.56 (s, 5H), 7.34 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H).
Step 5: ie/t-Butyl [4-(l, l-difluoro-2-oxopropyl)phenyl] acetate
To a stirred solution of step 4 intermediate (572 mg, 1.73 mmol) in THF (15 mL) at 0 °C was added methylmagnesium bromide (1.4 , 1.15 mL, 3.47 mmol) and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), concentrated and the crude obtained was purified by silica gel column chromatography to yield 369 mg of the desired product. 1H NMR (300 MHz, CDC13) δ 1.43 (s, 9H), 2.31 (s, 3H), 3.56 (s, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), APCI-MS (m/z) 285 (M+H)+.
Step 6: 4-(l,l-Difluoro-2-oxopropyl)phenyl] acetic acid
To a stirred solution of Step 5 intermediate (501 mg, 1.76 mmol) in dichloromethane (10 mL) at 0 °C was added trifluoroacetic acid (10 mL) and the reaction mixture was allowed to attain RT. The solvent was evaporated under nitrogen blower to give an oily residue which was dried well under vacuum to yield 379 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 2.36 (s, 3H), 3.66 (s, 3H), 7.43 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 12.22 (br s, 1H).
Intermediate 4
4-{ [l-(2,4-Dichlorophenyl)cyclopropyl]oxy}-3-fluoroaniline
Figure imgf000039_0001
Step 1 : 1 ,3-Dichloro-2-(2,4-dichlorophenyl)propan-2-ol
To a cooled solution of 2,4-dichloro-l-bromobenzene (2.0 mL, 16.7 mmol) in anhydrous THF (20 mL) was slowly added 2M isopropylmagnesium bromide in THF (12.5 mL, 25.1 mmol) at the RT and it was stirred for 1 h. A solution of 1,3-dichloroacetone (3.1 g, 25.1 mmol) in THF (20 mL) was drop-wise added to the reaction mixture and allowed to stir at RT for 18 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 1.19 g of the titled compound. 1H NMR (300 MHz, DMSO-ifc) δ 4.00 (d, J = 11.7 Hz, 2H), 4.31 (d, J = 11.7 Hz, 2H), 6.36 (s, 1H), 7.44-7.49 (m, 1H), 7.58- 7.60 (m, 1H), 7.80 (d, = 8.7 Hz, 1H).
Step 2: l-(2,4-Dichlorophenyl)cyclopropanol
To a solution of Step 1 intermediate (1.10 g, 4.01 mmol) in diethyl ether (20 mL) were simultaneously added ethylmagnesium bromide ( M in ether, 6.6 mL, 20.07 mmol) and a solution of ferric chloride (13 mg, 0.08 mmol) in diethyl ether (20 mL) over a period of 1 h. The resultant mixture was stirred at the RT for 18 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 1.19 g of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 0.79-0.82 (m, 2H), 0.95-1.01 (m, 2H), 5.79 (br s, 1H), 7.35 (d, = 7.8 Hz, 1H), 7.44 (d, = 8.4 Hz, 1H), 7.54 (s, 1H).
Step 3: l-(2,4-Dichlorophenyl)cyclopropyl 2-fluoro-4-nitrophenyl ether
To a stirred and cooled (0 °C) solution of Step 2 intermediate (350 mg, 1.72 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% w/w, 69 mg, 1.72 mmol) and the reaction mixture was stirred for 30 min at the RT. 3,4-Difluoro- l -nitrobenzene (274 mg, 1.72 mmol) was added and the reaction mixture was stirred further at RT for 2 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 393 mg of the titled product. lH NMR (300 MHz, DMSO-d6) δ 1.40-1.43 (m, 2H), 1.49-1.52 (m, 2H), 7.43 (d, = 8.7 Hz, 1H), 7.65-7.72 (m, 2H), 7.86 (d, 7 = 8.4 Hz, 1H), 7.99 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H).
Step 4: 4-{ [l-(2,4-Dichlorophenyl)cyclopropyl]oxy}-3-fluoroaniline
To a stirred solution of Step 3 intermediate (380 mg, 1.11 mmol) in a mixture of methanol and water (1 : 1, 20 mL) were added iron powder (310 mg, 5.55 mmol) and ammonium chloride (594 mg, 11.10 mmol) at the RT. The reaction mixture was heated to 80 °C and stirred for 2 h at the same temperature. The reaction mixture was cooled to the RT and the suspended emulsion was filtered off. The filtrate was concentrated under the reduced pressure and diluted with water (20 mL). The aqueous mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (30 mL) followed by brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvents were recovered under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 283 mg of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (t, = 6.9 Hz, 2H), 1.39 (t, J = 6.9 Hz, 2H), 5.00 (br s, 2H), 6.13-6.25 (m, 2H), 6.71 (t, J = 8.7 Hz, 1H), 7.30 (d, = 8.4 Hz, 1H), 7.35 (d, = 8.4 Hz, 1H),7.61 (s, 1H); APCI-MS (m/z) 339 (M)+.
Intermediate 5 4-{ [2-(2,4-Dichlorophenyl)propan-2-yl]oxy}-3-fluoroaniline
Figure imgf000041_0001
Step 1 : 2,4-Dichloro-l-[2-(2-fluoro-4-nitrophenoxy)propan-2-yl]benzene
To a stirred and cooled (0 °C) solution of 2-(2,4-dichlorophenyl)propan-2-ol (Step 2 of Intermediate 1) (500 mg, 2.43 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% w/w, 146 mg, 3.65 mmol) and the reaction mixture was stirred at RT for 30 min. 3,4- Difluoronitrobenzene (0.27 mL, 2.43 mmol) was added to the reaction mixture at 0 °C and the mixture was gradually warmed up to the RT. The reaction mixture was stirred at the RT for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 561 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 1.90 (s, 6H), 6.65 (t, J = 9.3 Hz, 1H), 7.53-7.58 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.79-7.84 (m, 1H), 8.15 (d, 7 = 11.4 Hz, 1H).
Step 2: 4-{ [2-(2,4-Dichlorophenyl)propan-2-yl]oxy}-3-fluoroaniline
To a stirred solution of Step 1 intermediate (500 mg, 0.45 mmol) and nickel chloride (691 mg, 2.90 mmol) in methanol (10 mL) was added sodium borohydride (220 mg, 5.812 mmol) in small portions. The reaction mixture was stirred at the room temperature for 1 h. The reaction mixture was concentrated under the reduced pressure to yield a viscous residue. The residue was diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (50 mL), brine (25 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 403 mg of the titled product. 1H
NMR (300 MHz, DMSO-d6) δ 1.64 (s, 6H), 5.07 (br s, 2H), 6.13 (d, J = 9.0 Hz, 1H), 6.33- 6.44 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.62-6.67 (m, 2H); APCI-MS (m/z) 314 (M+H)+.
Intermediate 6
4-{ [4-(2,4-Dichlorophenyl)tetrahyd -2H-pyran-4-yl]oxy}aniline
Figure imgf000041_0002
Step 1 : 4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-ol
To a stirred solution of l-bromo-2,4-dichlorobenzene (500 mg, 2.21 mmol) in diethyl ether (10 mL) was added n-butyl lithium (1.6 M in THF, 1.6 mL) drop-wise at -78 °C under the nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 30 min. A solution of tetrahydro-4H-pyran-4-one (0.24 mL, 2.65 mmol) in diethyl ether (10 mL) was added to the reaction mixture at -78 °C. The cooling bath was removed and the reaction mixture was stirred at the room temperature for 18 h. The reaction mixture was diluted with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 221 g of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (d, = 13.2 Hz, 2H), 2.48- 2.57 (m, 2H), 3.71-3.79 (m, 4H), 5.35 (s, 1H), 7.41-7.51 (m, 2H), 7.78 (d, = 8.7 Hz, 1H). Step 2: 4-(2,4-Dichlorophenyl)-4-(4-nitrophenoxy)tetrahydro-2H-pyran
To a stirred and cooled (0 °C) solution of Step 1 intermediate (210 mg, 0.84 mmol) in anhydrous DMF (4 mL) was added sodium hydride (60% w/w, 51 mg, 1.27 mmol) and the reaction mixture was stirred at the RT for 30 min. l-Fluoro-4-nitrobenzene (0.09 mL, 0.84 mmol) was added to the reaction mixture and stirred for 18 h at the RT. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 274 mg of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (br s, 2H), 2.55 (br s, 2H), 3.76-3.79 (m, 4H), 6.82 (d, = 9.0 Hz, 2H), 7.58 (br s, 2H), 7.70-7.73 (m, 1H), 8.05 (d, = 9.3 Hz, 2H).
Step 3: 4- { [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl] oxy } aniline
To a stirred solution of Step 2 intermediate (260 mg, 0.70 mmol) and nickel chloride (335 mg, 1.41 mmol) in methanol (5 mL) was added sodium borohydride (107 mg, 2.82 mmol) in small portions. The reaction mixture was stirred at the room temperature for 1 h. The reaction mixture was concentrated under the reduced pressure to yield a viscous residue. The residue was diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (50 mL) followed by brine (25 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 204 mg of the titled product; 1H NMR (300 MHz, DMSO-d6) δ 2.12-2.16 (m, 2H), 2.33-2.37 (m, 2H), 3.72-3.84 (m, 4H), 4.62 (br s, 2H), 6.32 (s, 4H), 7.44-7.53 (m, 2H), 7.59 (s, 1H).
Intermediate 7
4- { [2-(5-Chloro- 1 -ethyl- lH-be ]oxy } aniline
Figure imgf000043_0001
Step 1 : 5-Chloro- l-ethyl-2-[2-(4-nitrophenoxy)propan-2-yl]- lH-benzimidazole
A solution of 2-methyl-2-(4-nitrophenoxy)propanoic acid (529 mg, 2.35 mmol) and CDI (381 mg, 2.35 mmol) in THF (5 mL) was stirred at 50 °C for 30 min. 4-Chloro-N1-ethylbenzene- 1,2-diamine (400 mg, 2.35 mmol) was added to the reaction mixture and stirred further for 2 h at 50 °C. To the mixture was added acetic acid (5 mL) and stirred at 130 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (50 mL), aqueous saturated sodium bicarbonate solution (30 mL) followed by brine (25 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 70 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 1.07 (t, = 7.2 Hz, 3H), 1.92 (s, 6H), 4.42 (q, = 7.2 Hz, 2H), 6.84 (d, = 9.3 Hz, 2H), 7.27-7.32 (m, 1H), 7.59 (d, = 8.7 Hz, 1H), 7.78 (s,lH), 8.08 (d, = 9.3 Hz, 2H).
Step 2: 4-{ [2-(5-Chloro- 1 -ethyl- lH-benzimidazol-2-yl)propan-2-yl]oxy janiline
The titled compound was prepared by the reduction of Step 1 intermediate (65 mg, 0.18 mmol) using iron powder (50.4 mg, 0.90 mmol) and ammonium chloride (96 mg, 1.80 mmol) in water (3 mL) and THF (5 mL) as per the process described in Step 4 of Intermediate 1 to yield 75 mg of the product. 1H NMR (300 MHz, DMSO- 6) δ 1.30 (t, = 6.9 Hz, 3H), 1.71 (s, 6H), 4.61 (d, = 7.2 Hz, 1H), 4.74 (br s, 2H), 6.33 (br s, IH), 7.29 (d, = 7.2 Hz, 1H), 7.62 (d, = 7.6 Hz, 1H), 7.70 (s, 1H).
Intermediate 8
4- { [2-(5-Chloro- 1 -ethyl- lH-be ]oxy } -3 -fluoro aniline
Figure imgf000043_0002
Step 1 : N-(5-Chloro-2-(ethylamino)phenyl)-2-(2-fluoro-4-nitrophenoxy)-2-methyl propanamide
To a stirred solution of 2-(2-fluoro-4-nitrophenoxy)-2-methylpropanoic acid (453 mg, 2.66 mmol) in dichloromethane (5.0 mL) was added catalytic amount of DMF followed by drop- wise addition of oxalyl chloride (900 μί, 11.09 mmol) at the RT and the reaction mixture was stirred for 2 h. To this mixture were added 4-chloro-N1-ethylbenzene- l,2-diamine (500 mg, 2.21 mmol) in dichloromethane (5.0 mL) and triethylamine (0.6 mL, 4.43 mmol). The reaction mixture was stirred at the RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 460 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (t, J = 7.2 Hz, 3H), 1.69 (s, 6H), 2.98 (q, J = 6.9 Hz, 2H), 4.46 (t, J = 6.3 Hz, 1H), 6.64 (d, J = 9.0 Hz, 1H), 7.07-7.18 (m, 2H), 7.24 (t, J = 9.0 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.20-8.26 (m, 1H), 9.57 (s, 1H) .
Step 2: 5-Chloro- l-ethyl-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-lH-benzo[ ]imidazole A mixture of Step 1 intermediate (450 mg, 1.13 mmol) and acetic acid (5.0 mL) was stirred at 100 °C for 3 h. The solvent in the mixture was evaporated under the reduced pressure. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (30 mL), followed by brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 360 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J = 6.9 Hz, 3H), 1.96 (s, 6H), 4.46 (q, J = 6.9 Hz, 2H), 6.70 (t, J = 9.3 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.90 (d, J = 11.1 Hz, 1H), 8.21 (d, 7 = 8.7 Hz, 1H).
Step 3: 4-{ [2-(5-Chloro- 1 -ethyl- lH-benzimidazol-2-yl)propan-2-yl]oxy }-3-fluoroaniline The titled compound was prepared by the reduction of Step 2 intermediate (150 mg, 0.39 mmol) using iron powder (111 mg, 1.98 mmol) and ammonium chloride (212 mg, 3.97 mmol) in a mixture of water (5 mL) and THF (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 109 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.16 (t, J = 7.2 Hz, 3H), 1.70 (s, 6H), 4.65 (q, = 7.2 Hz, 2H), 5.14 (br s, 2H), 6.13 (d, = 9.3 Hz, 1H), 6.25-6.37 (m, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7 '.62-7 '.69 (m, 2H); APCI-MS (m/z) 348 (M+H)+.
Intermediate 9 2-[2-(2,4-Difluorophenoxy)propan-2-yl]- l-ethyl- lH-benzimidazol-5-amine
Figure imgf000045_0001
Step 1 : 2-[2-(2,4-Difluorophenoxy)propan-2-yl]-l-ethyl-5-nitro-lH-benzimidazole
To a stirred solution of 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (500 mg, 2.32 mmol) in THF (10 mL) was added CDI (376 mg, 2.32 mmol) and the reaction mixture was stirred at 50 °C for 30 min. Thereafter, N;-ethyl-4-nitrobenzene-l,2-diamine (420 mg, 2.32 mmol) was added to the reaction mixture and further stirred for 2 h at the same temperature. The reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 100 mL) and dried over anhydrous sodium sulfate. The filtered solvents were distilled off under the reduced pressure to yield a gummy residue. The residue was dissolved in acetic acid and refluxed for 1.5 h. The acetic acid was distilled out under the reduced pressure and the residue obtained was diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), brine (50 mL), dried over sodium sulfate and filtered. The solvent was recovered under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 434 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾ δ 1.36 (t, = 6.9 Hz, 3H), 1.83 (s, 6H), 4.72 (q, J = 6.9 Hz, 2H), 6.64-6.70 (m, 1H), 6.85-6.90 (m, 1H), 7.31-7.35 (m, 1H), 7.90 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.56 (s, 1H); ESI-MS (m/z) 362 (M+H)+. Step 2: 2-[2-(2,4-Difluorophenoxy)propan-2-yl]-l-ethyl- lH-benzimidazol-5-amine
The titled compound was prepared by the reduction of Step 1 intermediate (150 mg, 0.41 mmol) using iron powder (106 mg, 2.08 mmol) and ammonium chloride (323 mg, 4.17 mmol) in a mixture of methanol (2 mL), THF (5 mL) and water (2 mL) as per the process described in Step 4 of Intermediate 1 to yield 126 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J = 6.9 Hz, 3H), 1.77 (s, 6H), 4.45 (q, J = 6.9 Hz, 2H), 4.78 (br s, 2H), 6.40-6.46 (m, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.75 (s, 1H), 6.76-6.84 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.29-7.31 (m, 1H); ESI-MS (m/z) 332 (M+H)+.
Intermediate 10
4-{ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline
Figure imgf000046_0001
Step 1 : 4-(2,4-Dichlorophenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran
To a stirred and cooled (0 °C) solution of 4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-ol (Step 1 of Intermediate 6) (300 mg, 1.21 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% w/w, 58 mg, 1.45 mmol) and the reaction mixture was stirred at the RT for 30 min. 3, 4-Difluoro nitrobenzene (193 mg, 1.21 mmol) was added to the reaction mixture and stirred for 2 h at RT. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 292 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 2.25-3.32 (m, 2H), 2.53-2.59 (m, 2H), 3.69-3.82 (m, 4H), 6.54 (t, J = 7.2 Hz, 1H), 7.60 (s, 2H), 7.72-7.82 (m, 2H), 8.17 (d, / = 8.7 Hz, 1H); APCI-MS (m/z) 389 (M+H)+.
Step 2: 4-{ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline
The titled compound was prepared by the reduction of Step 1 intermediate (280 mg, 0.72 mmol) using iron powder (202 mg, 3.62 mmol) and ammonium chloride (388 mg, 7.25 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 224 mg of the product. 1H NMR (300 MHz, DMSO- 6) δ 2.20-2.33 (m, 4H), 3.69-3.81 (m, 4H), 4.92 (s, 2H), 5.98 (q, J = 7.8 Hz, 2H), 6.33-6.39 (m, 1H), 7.46-7.61 (m, 3H); APCI-MS (m/z) 358 (M+H)+.
Intermediate 11
4- { [2-(2-Chloro-4-fluorophenyl)propan-2-yl] oxy } aniline
Figure imgf000046_0002
Step 1 : 2-(2-Chloro-4-fluorophenyl)propan-2-ol
The titled compound was prepared by the reaction of methyl 2-chloro-4-fluorobenzoate (550 mg, 2.91 mmol) and methylmagnesium bromide (3 in diethyl ether, 2.4 mL) in diethyl ether
(10 mL) as per the process described in Step 2 of Intermediate 1 to yield 513 g of the product.
1H NMR (300 MHz, DMSO-i¾): δ 1.57 (s, 6H), 5.37 (s, 2H), 7.16-7.22 (m, 1H), 7.30-7.38
(m, 1H), 7.81-7.86 (m, 1H).
Step 2: 2-(2-Chloro-4-fluorophenyl)propan-2-yl 4-nitrophenyl ether The titled compound was synthesized by the reaction of Step 1 intermediate (500 mg, 2.65 mmol) with l-fluoro-4-nitrobenzene (374 mg, 2.65 mmol) using sodium hydride (60% w/w, 159 mg, 3.97 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 213 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.88 (s, 6H), 6.80 (d, = 9.3 Hz, 2H), 7.14 (d, = 9.3 Hz, 1H), 7.30-7.41 (m, 2H), 7.66-7.71 (m, 1H), 8.04 (d, = 9.3 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H); APCI-MS (m/z) 309 (M+H)+.
Step 3: 4-{ [2-(2-Chloro-4-fluorophenyl)propan-2-yl]oxy} aniline
The titled compound was synthesized by the nitro reduction of the Step 2 intermediate (200 mg, 0.64 mmol) using sodium borohydride (96 mg, 2.58 mmol) and nickel chloride (309 mg, 1.29 mmol) in methanol (10 mL) as per the process described in Step 2 of Intermediate 5 to yield 131 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.65 (s, 6H), 4.69 (br s, 2H), 6.35 (d, = 8.4 Hz, 2H), 6.43 (d, = 9.0 Hz, 2H), 7.19 (t, = 8.4 Hz, 1H), 7.42 (d, = 8.7 Hz, 1H), 7.56-7.61 (m, 1H); APCI-MS (m/z) 279 (M)+.
Intermediate 12
4-{ [2-(2-Chloro-4-fluorophenyl)propan-2-yl]oxy}-3-fluoroaniline
Figure imgf000047_0001
Step 1 : 2-(2-Chloro-4-fluorophenyl)propan-2-yl 2-fluoro-4-nitrophenyl ether
The titled compound was synthesized by the reaction of 2-(2-chloro-4-fluorophenyl)propan- 2-ol (300 mg, 1.59 mmol) with 3,4-difluoronitrobenzene (253 mg, 1.59 mmol) using sodium hydride (60% w/w, 95 mg, 2.38 mmol) in DMF (5 mL) as per the process described in Step 3 of Intermediate 1 to yield 261 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 6H), 6.64 (t, = 9.3 Hz, 1H), 7.34-7.43 (m, 2H), 7.69-7.82 (m, 2H), 8.14 (d, J = 11.7 Hz, 1H).
Step 2: 4-{ [2-(2-Chloro-4-fluorophenyl)propan-2-yl]oxy}-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the Step 1 intermediate (250 mg, 0.76 mmol) using sodium borohydride (116 mg, 3.05 mmol) and nickel chloride (362 mg, 1.52 mmol) in methanol (5 mL) as per the process described in Step 2 of Intermediate 5 to yield 191 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.64 (s, 6H), 5.04 (br s, 2H), 6.12 (d, = 8.1 Hz, 1H), 6.32-6.41 (m, 2H), 7.16-7.23 (m, 1H), 7.42-7.45 (m, 1H), 7.64- 7.69 (m, 1H); APCI-MS (m/z) 298 (M+H)+.
Intermediate 13
2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-lH-benzimidazol-5-amine
Figure imgf000048_0001
Step 1 : 2-(4-Chloro-3-fluorophenoxy)-N-[2-(ethylamino)-5-nitroph( methylpropanamide
To a stirred solution of 2-(4-chloro-3-fluorophenoxy)-2-methylpropanoic acid (400 mg, 1.715 mmol) in dichloromethane (5 mL) were added catalytic amount of anhydrous DMF and oxalyl chloride (745 μί, 8.575 mmol). The reaction mixture was stirred at the room temperature for 2 h. The excess of the oxalyl chloride was distilled off under the reduced pressure and the residue was dissolved in DCM (5 mL). To that solution were added N1- ethyl-4-nitrobenzene- l,2-diamine (372 mg, 2.058 mmol) and triethylamine (482 μί, 3.430 mmol) at 0 °C. The mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 413 mg of the desired product. 1H NMR (300 MHz, DMSO-i¾) δ 1.08 (t, J = 6.9 Hz, 3H), 1.72 (s, 6H), 3.17 (q, J = 6.9 Hz, 2H), 5.67 (br s, 1H), 6.75 (d, J = 9.3 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 8.7 Hz, 1H), 7.92 (s, 1H), 8.00 (d, J = 6.9 Hz, 1H), 9.64 (s, 1H).
Step 2: 2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-5-nitro- lH-benzimidazole The step 1 intermediate (400 mg, 1.160 mmol) was refluxed in acetic acid (5 mL) for 16 h. The reaction mixture was concentrated under the reduced pressure and the residue was diluted with ethyl acetate (20 mL) and water (15 mL). The organic layer was separated and washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 325 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 1.22 (t, J = 6.3 Hz, 3H), 1.89 (s, 6H), 4.59 (q, J = 6.6 Hz, 2H), 6.49 (d, J = 9.3 Hz, 1H), 6.83 (d, J = 11.4 Hz, 1H), 7.38 (t, J = 9.3 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.60 (s, 1H); APCI-MS (m/z) 378 (M+H)+.
Step 3: 2-[2-(4-Chloro-3-fluorophenoxy)propan-2-yl]- l-ethyl-lH-benzimidazol-5-amine To a stirred solution of step 2 intermediate (100 mg, 0.264 mmol) and nickel chloride (125 mg, 0.528 mmol) in methanol (5 mL) was added sodium borohydride (40 mg, 1.058 mmol) in portions. The reaction mixture was stirred at the room temperature for 30 min. The reaction mixture was concentrated under the reduced pressure to yield a viscous residue. The residue was diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 84 mg of the titled product. 1H
NMR (300 MHz, DMSO-d6) δ 1.14 (t, J = 6.9 Hz, 3H), 1.83 (s, 6H), 4.33 (q, J = 6.9 Hz, 2H), 4.80 (br s, 2H), 6.47 (d, = 8.7 Hz, 1H), 6.60-6.69 (m, 2H), 6.79 (s, 1H), 7.19 (d, = 8.7 Hz, 1H), 7.35 (t, / = 9.0 Hz, 1H).
Intermediate 14
2-[4-(l, l-Difluoro-2-hydroxypropyl)phenyl]-N-(4-iodophenyl)acetamide
Figure imgf000049_0001
Step 1 : Ethyl difluoro(4-{2-[(4-iodophenyl)amino]-2-oxoethyl}phenyl)acetate
To a stirred solution of [4-(2-ethoxy-l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Step 1 of Intermediate 3) (1.5 g, 5.80 mmol) and 4-iodoaniline (1.27 g, 5.80 mmol) in DMF (15 mL) at 0 °C were added N,N'-diisopropylethylamine (2.5 mL, 14.52 mmol) and propylphosphonic anhydride (50% in EtOAc, 7.0 mL, 11.61 mmol). The reaction mixture was stirred overnight at the RT. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (750 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 1.7 g of the titled product. 1H NMR (300 MHz, DMSO-i¾ δ 1.22 (t, = 7.2 Hz, 3H), 3.72 (s, 2H), 4.29 (q, = 7.5 Hz, 2H), 7.41-7.64 (m, 8H), 10.32 (s, 1H).
Step 2: 2-[4-( 1 , 1 -Difluoro-2-oxopropyl)phenyl] -N-(4-iodophenyl)acetamide
To a stirred solution of Step 1 intermediate (700 mg, 1.52 mmol) in diethyl ether (10 mL) was added 3M methyl lithium (1.25 mL, 3.65 mmol) dropwise at -78 °C. The reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concetrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 185 mg of the titled product; 1H NMR (300 MHz, DMSO-i¾ δ 2.36 (s, 3H), 3.72 (s, 2H), 7.41-7.55 (m, 6H), 7.63 (d, / = 8.1 Hz, 2H) 10.32 (s, 1H).
Step 3: 2-[4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl] - V-(4-iodophenyl)acetamide
To a stirred solution of Step 2 intermediate (180 mg, 0.41 mmol) in methanol (5.0 mL) at 0 °C was added sodium borohydride (23 mg, 0.62 mmol) and the resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 170 mg of the desired product. 1H NMR (300 MHz, DMSO- d6) δ 1.06 (d, J = 6.3 Hz, 3H), 3.68 (s, 2H), 4.00-4.05 (m, 1H), 5.49 (d, = 5.3 Hz, 1H), 7.40- 7.46 (m, 6H), 7.62 (d, = 8.7 Hz, 2H), 10.30 (s, 1H).
Intermediate 15
l-Chloro-2-fluoro-4-[(2-methylbut-3-yn-2-yl)oxy]benzene
Figure imgf000050_0001
To a stirred solution of 4-chloro-3-fluorophenol (700 mg, 4.776 mmol) in DMF (10 mL) were added 3-chloro-3-methylbut- l-yne (0.78 mL, 7.164 mmol), potassium carbonate (1.32 g, 9.553 mmol), copper iodide (18 mg, 0.0955 mmol) and potassium iodide (1.34 g, 8.120 mmol). The reaction mixture was stirred at 65 °C for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The filtered solution was concentrated under the reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 538 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.58 (s, 6H), 3.75 (s, 1H), 7.02-7.05 (m, 1H), 7.15-7.21 (m, 1H), 7.49 (t, = 8.7 Hz, 1H); APCI-MS (m/z) 213 (M+H)+.
Intermediate 16
4-{ [4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline
Figure imgf000050_0002
Step 1 : 4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-ol The titled compound was prepared by the reaction of 2-bromo-5-chloroanisole (2.0 g, 9.02 mmol) with tetrahydro-4H-pyran-4-one (986 μί, 10.83 mmol) and n-butyl lithium (1.6 M in THF, 6.2 mL, 9.93 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 617 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (d, 7 = 13.2 Hz, 2H), 2.30-2.47 (m, 2H), 3.65-3.76 (m, 4H), 3.82 (s, 3H), 5.00 (s, 1H), 6.98-7.07 (m, 2H), 7.57 (d, 7 = 8.4 Hz, 1H); ESI-MS (m/z) 224 (M+H)+.
Step 2: 4-(4-Chloro-2-methoxyphenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran The titled compound was synthesized by the reaction of Step 1 intermediate (600 mg, 2.47 mmol) with 3,4-difluoronitrobenzene (432 mg, 2.71 mmol) using sodium hydride (60% w/w, 108 mg, 2.71 mmol) in DMSO (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 398 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 4H), 3.72 (br s, 7H), 6.67 (t, 7 = 8.7 Hz, 1H), 7.10 (s, 2H), 7.42 (d, 7 = 8.4 Hz, 1H), 7.80 (d, 7 = 9.9 Hz, 1H), 8.14 (d, 7 = 9.6 Hz, 1H).
Step 3: 4-{ [4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline The titled compound was prepared by the reduction of Step 2 intermediate (570 mg, 1.49 mmol) using iron powder (417 mg, 7.46 mmol) and ammonium chloride (798 mg, 14.93 mmol) in a mixture of methanol (20 mL) and water (20 mL) as per the process described in Step 4 of Intermediate 1 to yield 469 mg of the product. 1H NMR (300 MHz, DMSO- 6) δ 2.07-2.14 (m, 2H), 2.28-2.35 (m, 2H), 3.63-3.74 (m, 4H), 3.81 (s, 3H), 4.94 (s, 2H), 6.02 (d, 7 = 8.7 Hz, 1H), 6.16 (t, 7 = 9.6 Hz, 1H), 6.29-6.36 (m, 1H), 6.98 (d, 7 = 10.2 Hz, 1H), 7.11 (s, 1H), 7.32 (d, 7 = 8.4 Hz, 1H).
Intermediate 17
4-{ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy} aniline
Figure imgf000051_0001
Step 1 : 2-(3,5-Dichloropyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 3,5-dichloropyridine-2- carboxylate (1.0 g, 4.854 mmol) and methyl magnesium bromide (1.4 in THF, 10.4 mL) in THF (20 mL) as per the process described in step 2 of Intermediate 1 to yield 800 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.55 (s, 6H), 8.50 (br s, 1H), 8.53 (br s, 1H)
Step 2: 3,5-Dichloro-2-[2-(4-nitrophenoxy)propan-2-yl]pyridine
The titled compound was synthesized by the reaction of step 1 intermediate (200 mg, 0.970 mmol) with l-fluoro-4-nitrobenzene (150 mg, 1.060 mmol) using sodium hydride (60% w/w, 42 mg, 1.060 mmol) in DMF (5 mL) as per the process described in step 3 of Intermediate 1 to yield 150 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.88 (s, 6H), 6.70 (d, = 7.2 Hz, 2H), 8.05 (d, J = 7.2 Hz, 2H), 8.18 (s, 1H), 8.74 (s, 1H); APCI-MS (m/z) 327 (M)+. Step 3: 4-{ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy} aniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (150 mg, 0.458 mmol) using sodium borohydride (69 mg, 1.833 mmol) and nickel chloride (217 mg, 0.916 mmol) in methanol (5 mL) as per the process described in step 2 of Intermediate 5 to yield 77 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.66 (s, 6H), 4.65 (s, 2H), 6.32 (s, 4H), 8.18 (s, 1H), 5.58 (s, 1H); APCI-MS (m/z) 297 (M)+.
Intermediate 18
4-Chloro-2-fluoro- l-[(2-methylbut-3-yn-2-yl)oxy]benzene
Figure imgf000052_0001
To a stirred solution of 4-chloro-2-fluorophenol (500 mg, 3.411 mmol) in DMF (5 mL) were added 3-chloro-3-methylbut- l-yne (0.45 mL, 4.094 mmol), potassium carbonate (943 mg, 6.823 mmol), copper iodide (12 mg, 0.068 mmol) and potassium iodide (962 mg, 5.800 mmol). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvent was recovered under the reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 332 mg of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 1.59 (s, 6H), 3.69 (s, 1H), 7.22-7.25 (m, 1H), 7.41-7.49 (m, 2H); APCI-MS (m/z) 213 (M+H)+.
Intermediate 19
4-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy} aniline
Cl
Figure imgf000052_0002
Step 1 : 4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-ol
The titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (2.0 g, 8.81 mmol) with tetrahydro-4H-pyran-4-one (962 μί, 10.57 mmol) and n-butyl lithium (1.6 M in THF, 6.0 mL, 9.69 mmol) in diethyl ether (50 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 1.1 g of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.82- 1.89 (m, 2H), 2.13-2.23 (m, 2H), 3.66-3.83 (m, 4H), 5.35 (s, 1H), 8.15 (s, 1H), 8.56 (s, 1H); APCI-MS (m/z) 309 (M+H)+.
Step 2: 3,5-Dichloro-2-[4-(4-nitrophenoxy)tetrahydro-2H-pyran-4-yl]pyridine
The titled compound was synthesized by the reaction of Step 1 intermediate (600 mg, 2.41 mmol) with l-fluoro-4-nitrobenzene (341 mg, 2.41 mmol) using sodium hydride (60% w/w, 116 mg, 2.90 mmol) in DMF (5.0 mL) as per the process described in step 3 of Intermediate 1 to yield 880 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 2.39-2.43 (m, 4H), 3.78 (br s, 4H), 6.72 (d, = 9.9 Hz, 2H), 8.06 (d, = 9.3 Hz, 1H), 8.79 (s, 1H).
Step 3: 4-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy} aniline
The titled compound was prepared by the reduction of Step 2 intermediate (850 mg, 2.30 mmol) using iron powder (640 mg, 11.51 mmol) and ammonium chloride (1.23 g, 23.02 mmol) in a mixture of methanol (10 mL), THF (25 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 750 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 2.20-2.33 (m, 4H), 3.69-3.81 (m, 4H), 4.63 (s, 2H), 6.23 (d, = 8.4 Hz, 2H), 6.30 (d, = 9.0 Hz, 2H), 8.21 (s, 1H), 8.65 (s, 1H).
Intermediate 20
6-{ [4-(2,4-Dichlorophenyl)tetrahyd - -pyran-4-yl]oxy}pyridin-3-amine
Figure imgf000053_0001
Step 1 : 2-{ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl]oxy}-5-nitropyridine
The titled compound was prepared by the reaction of 4-(2,4-dichlorophenyl)tetrahydro-2H- pyran-4-ol (Step 1 of Intermediate 6) (500 mg, 2.03 mmol) with 2-chloro-5-nitropyridine (321 mg, 2.03 mmol) using sodium hydride (60% w/w, 122 mg, 3.04 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 290 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 2.19-2.25 (m, 2H), 2.74-2.82 (m, 2H), 3.73-3.82 (m, 4H),
7.14 (d, = 8.7 Hz, 1H), 7.43-7.52 (m, 2H), 7.64-7.71 (m, 1H), 8.45-8.48 (m, 1H), 8.63 (s 1H).
Step 2: 6-{ [4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl]oxy}pyridin-3-amine
The titled compound was synthesized by the nitro reduction of the step 1 intermediate (290 mg, 0.78 mmol) using iron powder (218 mg, 3.92 mmol) and ammonium chloride (420 mg, 7.85 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 210 mg of the product. 1H NMR (300
MHz, DMSO-i¾) δ 1.97-2.12 (m, 2H), 2.67 (d, = 12.6 Hz, 2H), 3.75 (d, = 8.4 Hz, 4H), 4.68 (br s, 2H), 6.59 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 7.10 (s, 1H), 7.40 (s, 2H), 7.55 (d, J = 9.3 Hz, 1H); APCI-MS (m/z) 339 (M+H)+.
Intermediate 21
6-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy}pyridin-3-amine
Figure imgf000054_0001
Step 1 : 3,5-Dichloro-2-{4-[(5-nitropyridin-2-yl)oxy]tetrahydro-2H-pyran-4-yl}pyridine The titled compound was prepared by the reaction of 4-(3,5-Dichloropyridin-2-yl)tetrahydro- 2H-pyran-4-ol (Step 1 of Intermediate 19) (500 mg, 2.01 mmol) with 2-chloro-5- nitropyridine (319 mg, 2.01 mmol) using sodium hydride (60% w/w, 121 mg, 3.02 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 518 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 2.34-2.53 (m, 4H), 3.72-3.79 (m, 4H), 7.18 (d, = 8.7 Hz, 1H), 8.04 (s, 1H), 8.45 (d, = 8.7 Hz, 1H), 8.58 (s, 1H), 8.66 (s, 1H).
Step 2: 6-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy}pyridin-3-amine The titled compound was synthesized by the nitro reduction of the step 1 intermediate (500 mg, 1.34 mmol) using iron powder (375 mg, 6.73 mmol) and ammonium chloride (720 mg, 13.47 mmol) in a mixture of methanol (5.0 mL), THF (15 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 1.06 g of the product. 1H NMR (300 MHz, DMSO-i¾ δ 2.25-2.44 (m, 4H), 3.74 (d, = 6.6 Hz, 4H), 4.66 (s, 2H), 6.64 (d, = 8.7 Hz, 1H), 6.92-7.01 (m, 2H), 7.98 (s, 1H), 8.60 (s, 1H); APCI-MS (m/z) 339.5 (M)+.
Intermediate 22
4-{ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy}-3-fluoroaniline
Figure imgf000054_0002
Step 1 : 3,5-Dichloro-2-[2-(2-fluoro-4-nitrophenoxy)propan-2-yl]pyridine
The titled compound was prepared by the reaction of 2-(3,5-dichloropyridin-2-yl)propan-2-ol (Step 1 of Intermediate 17) (1.0 g, 4.85 mmol) with 3,4-difluoronitrobenzene (590 μί, 5.33 mmol) using sodium hydride (60% w/w, 232 mg, 5.82 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 1.34 g of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.88 (s, 6H), 6.42 (t, = 7.2 Hz, 1H), 7.80 (d, = 7.2 Hz, 1H), 8.10-8.20 (m, 2H), 8.71 (s, 1H); APCI-MS (m/z) 344.6 (M+H)+.
Step 2: 4-{ [2-(3,5-Dichloropyridin-2-yl)propan-2-yl]oxy}-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 1 intermediate (1.3 g, 3.76 mmol) using iron powder (1.1 g, 18.83 mmol) and ammonium chloride (2.0 g, 37.66 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 1.06 g of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.65 (s, 6H), 5.02 (s, 2H), 6.07 (d, = 9.0 Hz, 1H), 6.16-6.24 (m, 1H), 6.28-6.35 (m, 1H), 8.23 (s, 1H), 8.56 (s, 1H).
Intermediate 23
4-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy} -3-fluoroaniline
Figure imgf000055_0001
Step 1 : 3,5-Dichloro-2-[4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran-4-yl]pyridine
The titled compound was prepared by the reaction of 4-(3,5-dichloropyridin-2-yl)tetrahydro- 2H-pyran-4-ol (Step 1 of Intermediate 19) (500 mg, 2.01 mmol) with 3,4- difluoronitrobenzene (224 μί, 2.01 mmol) using sodium hydride (60% w/w, 96 mg, 2.41 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 770 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 2.42-2.50 (m, 4H), 3.70-3.81 (m, 4H), 6.35 (t, = 9.0 Hz, 1H), 7.82 (d, = 7.2 Hz, 1H), 8.15-8.25 (m, 2H), 8.80 (s, 1H).
Step 2: 4-{ [4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 1 intermediate (750 mg, 1.93 mmol) using iron powder (539 mg, 9.68 mmol) and ammonium chloride (1.03 g, 19.36 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 522 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 2.21-2.29 (m, 4H), 3.62-3.68 (m, 2H), 3.74-3.79 (m, 2H), 4.98 (s, 2H), 5.88 (t, = 9.3 Hz, 1H), 5.99 (d, = 9.3 Hz, 1H), 6.34 (d, = 12.9 Hz, 1H), 8.25 (s, 1H), 8.65 (s, 1H).
Intermediate 24
4- { [3-(3 ,5-Dichloropyridin-2-yl)oxe aniline
Figure imgf000055_0002
Step 1 : 3-(3,5-Dichloropyridin-2-yl)oxetan-3-ol
The titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (3.0 g, 13.22 mmol) with 3-oxitanone (840 μί, 14.54 mmol) and n-butyl lithium (1.6 M in THF, 9.1 mL, 14.54 mmol) in diethyl ether (40 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 888 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 4.68 (d, = 6.9 Hz, 2H), 5.12 (d, J = 6.9 Hz, 2H); 6.60 (s, 1H), 8.26 (s, 1H), 8.60 (s, 1H); ESI-MS (m/z) 220.17 (M+H)+.
Step 2: 3,5-Dichloro-2-[3-(2-fluoro-4-nitrophenoxy)oxetan-3-yl]pyridine
The titled compound was prepared by the reaction of step 1 intermediate (435 mg, 1.97 mmol) with 3,4-difluoronitrobenzene (314 mg, 1.97 mmol) using sodium hydride (60% w/w, 118 mg, 2.96 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 574 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 5.09 (d, = 7.8 Hz, 2H), 5.38 (d, = 7.8 Hz, 2H), 6.80 (t, = 8.7 Hz, 1H), 7.90 (d, = 9.0 Hz, 1H), 8.15 (d, 7 = 11.1 Hz, 1H), 8.32 (s, 1H), 8.73 (s, 1H); APCI-MS (m/z) 358.8 (M+H)+.
Step 3: 4- { [3-(3 ,5-Dichloropyridin-2-yl)oxetan-3-yl]oxy } -3 -fluoro aniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (560 mg, 1.55 mmol) using iron powder (435 mg, 7.79 mmol) and ammonium chloride (834 mg, 15.59 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 497 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 4.92 (d, = 7.5 Hz, 2H), 5.05 (s, 2H), 5.15 (d, = 7.8 Hz, 2H), 6.06 (d, = 8.4 Hz, 1H), 6.20-6.26 (m, 1H), 6.35-6.40 (m, 1H), 8.28 (s, 1H), 8.57 (s, 1H).
Intermediate 25
4-{ [4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline
Figure imgf000056_0001
Step 1 : 4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-ol
To a stirred solution of activated magnesium turning (142 mg, 5.83 mmol) in diethyl ether (10 mL) was added catalytic amount of iodine followed by 2-bromo-5-chlorotoluene (1.0 g, 4.86 mmol) at the RT. The reaction mixture was stirred at 50 °C for 2 h and tetrahydropyrane- 4-one (531 μί, 5.83 mmol) was added to the reaction mixture. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with diethyl ether (30 mL x 2). The combined organic layers were washed with water (20 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure to obtain 631 mg of the desired product. 1H NMR (300 MHz, DMSO-i¾) δ 1.68-1.75 (m, 2H), 1.93-2.02 (m, 2H), 2.55 (s, 3H), 3.65-3.70 (m, 2H), 3.74-3.86 (m, 2H), 4.99 (s, 1H), 7.19 (d, = 7.8 Hz, 2H), 7.38 (d, = 7.8 Hz, 1H). Step 2: 4-(4-Chloro-2-methylphenyl)-4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran The titled compound was prepared by the reaction of step 1 intermediate (320 mg, 1.41 mmol) with 3,4-difluoronitrobenzene (157 μί, 1.41 mmol) using sodium hydride (60% w/w, 68 mg, 1.69 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 390 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 2.23-2.33 (m, 2H), 2.39- 2.50 (m, 5H), 3.66-3.79 (m, 4H), 6.52 (t, = 7.2 Hz, 1H), 7.28 (s, 1H), 7.40 (d, = 7.2 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 10.5 Hz, 1H); ESI-MS (m/z) 363 (M-H)~.
Step 3: 4- { [4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-yl] oxy } -3 -fluoroaniline The titled compound was synthesized by the nitro reduction of the step 2 intermediate (375 mg, 1.02 mmol) using iron powder (286 mg, 5.12 mmol) and ammonium chloride (548 mg, 10.02 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 238 mg of the product. 1H NMR (300 MHz, DMSO-i¾): δ 1.97-2.06 (m, 2H), 2.16-2.24 (m, 2H), 2.45-2.49 (m, 3H), 3.66-3.79 (m, 4H), 4.91 (s, 2H), 5.85-5.94 (m, 2H), 6.34-6.41 (m, 1H), 7.27-7.40 (m, 3H).
Intermediate 26
4-{ [4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline
Figure imgf000057_0001
Step 1 : 4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-ol
The titled compound was prepared by the reaction of 2-bromo-5-chloro-3-methylpyridine (1.0 g, 4.84 mmol) with tetrahydro-4H-pyran-4-one (536 μί, 5.81 mmol) and n-butyllithium (1.6 M in THF, 3.1 mL, 4.84 mmol) in diethyl ether (10 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 333 mg of the product. 1H NMR (300 MHz, DMSO-i¾): δ 1.67- 1.74 (m, 2H), 2.08-2.17 (m, 2H), 2.55 (s, 3H), 3.67-3.84 (m, 4H), 5.23 (s, 1H), 7.70 (s, 1H), 8.35 (s, 1H).
Step 2: 5-Chloro-2-[4-(2-fluoro-4-nitrophenoxy)tetrahydro-2H-pyran-4-yl]-3-methylpyridine The titled compound was prepared by the reaction of step 1 intermediate (320 mg, 1.40 mmol) with 3,4-difluoronitrobenzene (246 μί, 1.54 mmol) using sodium hydride (60% w/w, 62 mg, 1.54 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 403 mg of the product. 1H NMR (300 MHz, DMSO-i¾: δ 2.30-2.37 (m, 7H), 3.74- 3.79 (m, 4H), 6.39-6.41 (m, 1H), 7.81 (s, 2H), 8.24-8.27 (m, 1H), 8.60 (s, 1H).
Step 3: 4-{ [4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-yl]oxy}-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 2 intermediate (390 mg, 1.06 mmol) using iron powder (297 mg, 5.31 mmol) and ammonium chloride (568 mg, 10.63 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 336 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.97-2.09 (m, 3H), 3.62-3.80 (m, 8H), 4.94 (s, 2H), 5.82 (t, J = 9.3 Hz, 2H), 5.99 (d, J = 8.4 Hz, 2H), 6.37 (d, J = 13.8 Hz, 1H).
Intermediate 27
4-{ [2-(5-Chloro-3-methylpyridin-2-yl)propan-2-yl]oxy}-3-fluoroaniline
Figure imgf000058_0001
Step 1 : 2-(5-Chloro-3-methylpyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of 2-bromo-5-chloro-3-picoline (1.2 g, 5.81 mmol) with acetone (579 μί, 6.97 mmol) and n-butyl lithium (1.6 M in THF, 3.9 mL, 6.32 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 174 mg of the product. 1H NMR (300 MHz, DMSO-i¾: δ 1.45 (s, 6H), 2.45-2.53 (m, 3H), 5.15 (s, 1H), 7.65 (s, 1H), 8.29 (s, 1H).
Step 2: 5-Chloro-2-[2-(2-fluoro-4-nitrophenoxy)propan-2-yl]-3-methylpyridine
The titled compound was prepared by the reaction of step 1 intermediate (170 mg, 0.91 mmol) with 3,4-difluoronitrobenzene (102 μί, 0.91 mmol) using sodium hydride (60% w/w, 44 mg, 1.09 mmol) in DMF (3.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 201 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.85 (s, 6H), 2.32 (s, 3H), 6.43 (t, 7 = 7.2 Hz, 1H), 7.76-7.87 (m, 2H), 8.17 (d, / = 11.4 Hz, 1H), 8.55 (s, 1H).
Step 3: 4-{ r2-(5-Chloro-3-methvlpvridin-2-vl)propan-2-vlloxvl-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.92 mmol) using iron powder (257 mg, 4.61 mmol) and ammonium chloride (496 mg, 9.23 mmol) in a mixture of methanol (5.0 mL), THF (10 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 205 mg of the product. 1H NMR (300 MHz, DMSO-i¾: δ 1.58 (s, 6H), 2.59 (s, 3H), 5.02 (s, 2H), 6.05-6.09 (m, 1H), 6.14-6.19 (m, 1H), 6.31-6.37 (m, 1H), 7.82 (s, 1H), 8.37 (s, 1H).
Intermediate 28
4-((2-(5-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000059_0001
Step 1 : 2-(5-Chloropyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 5-chloropicolinate (1.2 g, 6.99 mmol) and methyl magnesium bromide (3 in diethyl ether, 6.9 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 1.08 g of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 6H), 5.31 (br s, 1H), 7.68 (d, 7 = 8.4 Hz, 1H), 7.87 (d, 7 = 8.4 Hz, 1H), 8.51 (s, 1H).
Step 2: 5-Chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)pyridine
The titled compound was prepared by the reaction of step 1 intermediate (600 mg, 3.50 mmol) with 3,4-difluoronitrobenzene (428 μί, 3.84 mmol) using sodium hydride (60% w/w, 167 mg, 4.19 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 1.04 g of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.76 (s, 6H), 6.62 (t, 7 = 8.7 Hz, 1H), 7.60 (d, 7 = 8.4 Hz, 1H), 7.85 (d, 7 = 9.0 Hz, 1H), 7.94 (d, 7 = 8.4 Hz, 1H), 8.14 (d, 7 = 11.4 Hz, 1H), 8.64 (s, 1H); APCI-MS im/z) 311 (M+H)+.
Step 3: 4-((2-(5-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (1.0 g, 3.22 mmol) using iron powder (896 mg, 16.1 mmol) and ammonium chloride (1.72 g, 32.2 mmol) in a mixture of methanol (10 mL), THF (20 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 560 mg of the product. 1H NMR (300 MHz, DMSO-i¾: δ 1.52 (s, 6H), 5.11 (s, 2H), 6.18 (d, 7 = 8.4 Hz, 1H), 6.34 (d, 7 = 13.2 Hz, 1H), 6.51 (t, 7 = 9.0 Hz, 1H), 7.78 (d, 7 = 8.7 Hz, 1H), 7.95 (d, 7 = 9.0 Hz, 1H), 8.58 (s, 1H); APCI-MS (m/z) 281 (M+H)+.
Intermediate 29
4-((2-(3-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000059_0002
Step 1 : 2-(3-Chloropyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 3-chloropicolinate (1.5 g, 8.74 mmol) and methyl magnesium bromide (3 in diethyl ether, 8.7 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 1.21 g of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.56 (s, 6H), 5.49 (s, 1H), 7.34-7.40 (m, 1H), 7.90 (d, J = 8.1
Hz, 1H), 8.48 (d, = 4.5 Hz, 1H); APCI-MS (m/z) 172 (M)+.
Step 2: 3-Chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)pyridine
The titled compound was prepared by the reaction of step 1 intermediate (600 mg, 3.50 mmol) with 3,4-difluoronitrobenzene (428 μί, 3.84 mmol) using sodium hydride (60% w/w, 154 mg, 3.85 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 852 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.93 (s, 6H), 6.38 (t, = 8.7 Hz, 1H), 7.45-7.48 (m, 1H), 7.80 (d, = 10.2 Hz, 1H), 7.90 (d, = 8.1 Hz, 1H), 8.14 (d, = 10.2 Hz, 1H), 8.65 (s, 1H).
Step 3: 4-((2-(3-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (840 mg, 2.71 mmol) using iron powder (758 mg, 13.5 mmol) and ammonium chloride (1.45 g, 27.7 mmol) in a mixture of methanol (10 mL), THF (20 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 659 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.64 (s, 6H), 4.96 (s, 2H), 6.01 (d, = 8.7 Hz, 1H), 6.10 (t, = 9.3 Hz, 1H), 6.30 (d, = 13.8 Hz, 1H), 7.37-7.41 (m, 1H), 7.90 (d, = 6.9 Hz, 1H), 8.45 (s, 1H); APCI-MS (m/z) 281 (M+H)+.
Intermediate 30
4-(l-(3 ,5 -Dichloropyridin-2-yl)cyclobutoxy)-3 -fluoroaniline
Figure imgf000060_0001
Step 1 : l-(3,5-Dichloropyridin-2-yl)cyclobutanol
The titled compound was prepared by the reaction of 2-bromo-3,5-dichloropyridine (2.0 g, 8.81 mmol) with cyclobutanone (790 μί, 10.57 mmol) and n-butyl lithium (1.6 M in hexane, 5.5 mL, 8.81 mmol) in diethyl ether (20 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 248 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.38- 1.42 (m, 1H), 1.86- 1.91 (m, 1H), 2.21-2.28 (m, 2H), 2.74-2.78 (m, 2H), 5.72 (s, 1H), 8.15 (s, 1H), 8.54 (s, 1H); APCI-MS (m/z) 218 (M)+.
Step 2: 3,5-Dichloro-2-(l-(2-fluoro-4-nitrophenoxy)cyclobutyl)pyridine
The titled compound was prepared by the reaction of step 1 intermediate (235 mg, 1.07 mmol) with 3, 4-difluoro- l -nitrobenzene (171 mg, 1.07 mmol) using sodium hydride (60% w/w, 47 mg, 1.18 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 322 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.65- 1.71 (m, 1H), 1.97-2.02 (m, 1H), 2.68-2.75 (m, 2H), 3.10-3.15 (m, 2H), 6.76 (t, / = 8.1 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 8.11 (d, = 10.5 Hz, 1H), 8.25 (s, 1H), 8.74 (s, 1H); APCI-MS (m/z) 356 (M)+.
Step 3: 4-(l-(3,5-Dichloropyridin-2-yl)cyclobutoxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (310 mg, 0.87 mmol) using iron powder (242 mg, 4.33 mmol) and ammonium chloride (463 mg, 8.66 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 248 mg of the product. 1H NMR (300 MHz, DMSO- 6) δ 1.15- 1.19 (m, 1H), 1.53- 1.57 (m, 1H), 1.95-2.03 (m, 2H), 2.82-2.87 (m, 2H), 4.97 (s, 2H), 6.01-6.08 (m, 1H), 6.24-6.32 (m, 2H), 8.23 (s, 1H), 8.59 (s, 1H); APCI-MS (m/z) 327 (M+H)+.
Intermediate 31
4-(l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutoxy)-3-fluoroaniline
Figure imgf000061_0001
Step 1 : l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutanol
The titled compound was prepared by the reaction of 2-bromo-5-chloro-3-fluoropyridine (1.0 g, 4.75 mmol) with cyclobutanone (408 μί, 5.70 mmol) and n-butyl lithium (1.6 M in hexane, 3.2 mL, 5.22 mmol) in diethyl ether (15 mL) as per the procedure described in Step 1 of Intermediate 6 to yield 220 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.36-1.45 (m, 1H), 1.76- 1.82 (m, 1H), 2.19-2.28 (m, 2H), 2.65-2.72 (m, 2H), 5.78 (s, 1H), 8.03 (d, = 10.2 Hz, 1H), 8.44 (s, 1H); APCI-MS (m/z) 202 (M+H)+.
Step 2: 5-Chloro-3-fluoro-2-(l-(2-fluoro-4-nitrophenoxy)cyclobutyl)pyridine
The titled compound was prepared by the reaction of step 1 intermediate (220 mg, 1.09 mmol) with 3, 4-difluoro-l -nitrobenzene (121 μL·, 1.09 mmol) using sodium hydride (60% w/w, 53 mg, 1.31 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 210 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.67- 1.77 (m, 1H), 1.96-2.02 (m, 1H), 2.64-2.73 (m, 2H), 3.01-3.07 (m, 2H), 6.80 (t, = 8.7 Hz, 1H), 7.91 (d, = 9.9 Hz, 1H), 8.13 (d, = 10.8 Hz, 2H), 8.62 (s, 1H).
Step 3: 4-(l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutoxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (210 mg, 0.62 mmol) using iron powder (171 mg, 3.08 mmol) and ammonium chloride (330 mg, 6.16 mmol) in a mixture of THF (10 mL), methanol (3.0 mL) and water (3.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 155 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.48- 1.55 (m, 1H), 1.85-2.02 (m, 1H), 2.45-2.52 (m, 2H), 2.73-2.79 (m, 2H), 5.00 (br s, 2H), 6.08 (d, = 7.5 Hz, 1H), 6.25 (d, = 13.2 Hz, 1H), 6.37 (t, = 8.7 Hz, 1H), 8.09 (d, J = 10.5 Hz, 1H), 8.48 (s, 1H); APCI-MS (m/z) 311 (M+H)+.
Intermediate 32
4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000062_0001
Step 1 : 2-(3-Chloro-6-methylpyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 3-chloro-6-methylpicolinate (550 mg, 2.97 mmol) and methyl magnesium bromide (3 in diethyl ether, 2.9 mL) in diethyl ether (15 mL) as per the process described in Step 2 of Intermediate 1 to yield 440 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.54 (s, 6H), 2.47 (s, 3H), 5.70 (s, 1H), 7.24 (d, = 8.1 Hz, 1H), 7.79 (d, = 7.8 Hz, 1H).
Step 2: 3-Chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-6-methylpyridine
The titled compound was prepared by the reaction of step 1 intermediate (500 mg, 2.69 mmol) with 3, 4-difluoro-l -nitrobenzene (300 μί, 2.69 mmol) using sodium hydride (60% w/w, 130 mg, 3.23 mmol) in DMF (3.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 510 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.90 (s, 6H), 2.53 (s, 3H), 6.38 (t, = 8.7 Hz, 1H), 7.32 (d, = 8.1 Hz, 1H), 7.73 (d, = 8.4 Hz, 1H), 7.81 (d, = 9.3 Hz, 1H), 8.13 (d, 7 = 11.1 Hz, 1H); APCI-MS (m/z) 325 (M+H)+.
Step 3: 4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (500 mg, 1.53 mmol) using iron powder (428 mg, 7.69 mmol) and ammonium chloride (823 mg, 15.39 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 280 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.65 (s, 6H), 2.43 (s, 3H), 4.99 (s, 2H), 6.03 (d, = 9.9 Hz, 1H), 6.15 (t, = 9.0 Hz, 1H), 6.33 (d, = 12.6 Hz, 1H), 7.25 (d, = 8.7 Hz, 1H), 7.79 (d, = 8.1Hz, 1H); APCI-MS (m/z) 295 (M+H)+.
Intermediate 33
4-((2-(4-Chloro-6-methylpyridin-3-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000063_0001
Step 1 : 2-(4-Chloro-6-methylpyridin-3-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 4-chloro-6-methylnicotinate (350 mg, 1.89 mmol) and methyl magnesium bromide (3 in diethyl ether, 1.8 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 245 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.56 (s, 6H), 1.42 (s, 3H), 5.43 (s, 1H), 7.31 (s, 1H), 8.75 (s, 1H); APCI-MS (m/z) 186 (M)+.
Step 2: 4-Chloro-5-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-2-methylpyridine
The titled compound was prepared by the reaction of step 1 intermediate (240 mg, 1.29 mmol) with 3, 4-difluoro-l -nitrobenzene (143 μί, 1.29 mmol) using sodium hydride (60% w/w, 62 mg, 1.55 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 320 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.91 (s, 6H), 2.44 (s, 3H), 6.73 (t, = 8.7 Hz, 1H), 7.37 (s, 1H), 7.79 (d, = 10.5 Hz, 1H), 8.12 (d, = 10.8 Hz, 1H), 8.65 (s, 1H); APCI-MS (m/z) 325 (M+H)+.
Step 3: 4-((2-(4-Chloro-6-methylpyridin-3-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.92 mmol) using iron powder (257 mg, 4.62 mmol) and ammonium chloride (443 mg, 9.23 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 310 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.64 (s, 6H), 2.44 (s, 3H), 5.07 (s, 2H), 6.11 (d, = 8.7 Hz, 1H), 6.29- 6.42 (m, 2H), 7.42 (s, 1H), 8.57 (s, 1H); APCI-MS (m/z) 295 (M+H)+.
Intermediate 34
4-((2-(5-Chloro-2-methylpyridin-4-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000063_0002
Step 1 : 2-(5-chloro-2-methylpyridin-4-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 5-chloro-2-methylisonicotinate (800 mg, 4.32 mmol) and methyl magnesium bromide (3M in diethyl ether, 4.3 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 515 mg of the product. 1H NMR (300 MHz, DMSO-i¾: δ 1.47 (s, 6H), 2.43 (s, 3H), 5.32 (s, 1H), 7.45 (s, 1H), 8.11 (s, 1H). Step 2: 5-Chloro-4-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-2-methylpyridine The titled compound was prepared by the reaction of step 1 intermediate (500 mg, 2.69 mmol) with 3, 4-difluoro-l -nitrobenzene (299 μί, 2.69 mmol) using sodium hydride (60% w/w, 129 mg, 3.23 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 780 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.84 (s, 6H), 2.26 (s, 3H), 6.70 (t, 7 = 8.7 Hz, 1H), 7.51 (s, 1H), 7.84 (d, 7 = 9.3 Hz, 1H), 8.16 (s, 1H), 8.20 (s, 1H).
Step 3: 4-((2-(5-Chloro-2-methylpyridin-4-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (780 mg, 2.48 mmol) using iron powder (668 mg, 12.0 mmol) and ammonium chloride (1.28 g,
240 mmol) in a mixture of THF (25 mL), methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 520 mg of the product. 1H NMR (300
MHz, DMSO-i¾ δ 1.56 (s, 6H), 2.52 (s, 3H), 5.08 (s, 2H), 6.09-6.16 (m, 1H), 6.29-6.38 (m,
2H), 7.36 (s, 1H), 8.23 (s, 1H); APCI-MS (m/z) 295 (M+H)+.
Intermediate 35
4-((2-(3-Chloro-6-cyclopropylpyrid -2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000064_0001
Step 1 : 2-(3-Chloro-6-cyclopropylpyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 2-chloro-5-cyclopropylbenzoate (700 mg, 3.30 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 6.6 mL) in diethyl ether (10 mL) as per the process described in Step 2 of Intermediate 1 to yield 640 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 0.85-0.99 (m, 4H), 1.51 (s, 6H), 2.09-2.15 (m, 1H), 5.45 (s, 1H), 7.23 (d, 7 = 8.4 Hz, 1H), 7.71 (d, 7 = 8.4 Hz, 1H).
Step 2: 3-Chloro-6-cyclopropyl-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)pyridine
The titled compound was prepared by the reaction of step 1 intermediate (640 mg, 3.02 mmol) with l,2-difluoro-4-nitrobenzene (336 μί, 3.02 mmol) using sodium hydride (60% w/w, 145 mg, 3.62 mmol) in DMF (5.0 mL) as per the process described in Step 3 of Intermediate 1 to yield 235 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 0.98- 1.04 (m, 4H), 1.86 (s, 6H), 2.15-2.19 (m, 1H), 6.35 (t, 7 = 8.7 Hz, 1H), 7.34 (d, 7 = 8.4 Hz, 1H), 7.68 (d, 7 = 7.8 Hz, 1H), 7.83 (d, 7 = 8.7 Hz, 1H), 8.13 (d, 7 = 8.7 Hz, 1H).
Step 3: 4-((2-(3-Chloro-6-cyclopropylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 2 intermediate (220 mg, 0.627 mmol) using iron powder (174 mg, 3.15 mmol) and ammonium chloride (335 mg, 6.27 mmol) in a mixture of THF (10 mL), methanol (3.0 mL) and water (3.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 170 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 0.80-0.85 (m, 2H), 0.91-0.96 (m, 2H), 1.61 (s, 6H), 2.05-2.10 (m, 1H), 4.97 (s, 2H), 6.03 (d, = 8.1 Hz, 1H), 6.10 (d, = 9.0 Hz, 1H), 6.32 (d, = 13.2 Hz, 1H), 7.27 (d, = 8.1 Hz, 1H), 7.72 (d, = 8.4 Hz, 1H).
Intermediate 36
4-(l-(2,4-Dichlorophenyl)cyclobuto -3-fluoroaniline
Figure imgf000065_0001
Step 1: 1 -(2,4-Dichlorophenyl)cyclobutanol
To a stirred solution of 2,4-dichloro-l-bromobenzene (2.0 g, 8.853 mmol) in anhydrous THF (10 mL) was drop-wise added isopropylmagnesium chloride (2 in THF, 6.6 mL, 13.320 mmol) at the RT and the reaction mixture was stirred 1 h. A solution of cyclobutanone (1.0 mL, 13.280 mmol) in THF (10 mL) was added to the reaction mixture and stirred at the RT for 18 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 625 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ: 1.58-1.62 (m, 1H), 1.99-2.06 (m, 1H), 2.28-2.32 (m, 2H), 2.51-2.58 (m, 2H), 5.46 (s, 1H), 7.38-7.45 (m, 2H), 7.51 (s, 1H).
Step 2: 2,4-Dichloro-l-(l-(2-fluoro-4-nitrophenoxy)cyclobutyl)benzene
To a stirred and cooled (0 °C) solution of Step 1 intermediate (250 mg, 1.15 mmol) in dry DMF (5 mL) was added sodium hydride (60% w/w, 46 mg, 1.15 mmol) and the reaction mixture was stirred for 30 min at the RT. 3, 4-Difluoro-l -nitrobenzene (183 mg, 1.151 mmol) was added to the reaction mixture and further stirred at the RT for 18 h. The reaction mixture was diluted with saturated aqueous solution of ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 283 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 1.70-1.78 (m, 1H), 1.98-2.05 (m, 1H), 2.73-2.82 (m, 2H), 2.90-2.95 (m, 2H), 6.88 (t, J = 8.7 Hz, 1H), 7.50 (d, = 8.4 Hz, 1H), 7.59-7.61 (m, 1H), 7.83 (d, = 8.7 Hz, 1H), 7.96 (d, = 8.7 Hz, 1H), 8.07-8.13 (m, 1H).
Step 3: 4-(l-(2,4-Dichlorophenyl)cyclobutoxy)-3-fluoroaniline
To a stirred solution of Step 2 intermediate (270 mg, 0.76 mmol) in a mixture of methanol (5 mL) and water (5 mL) were added iron powder (211 mg, 3.790 mmol) and ammonium chloride (405 mg, 7.58 mmol) at the RT. The reaction mixture was heated to 80 °C and stirred for 2 h at the same temperature. The reaction mixture was cooled to the RT and the suspended emulsion was filtered off. The filtrate was concentrated under the reduced pressure and diluted with water (20 mL). The aqueous mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (30 mL) followed by brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvents were recovered under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 198 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ
1.62-1.65 (m, 1H), 2.04-2.12 (m, 1H), 2.59 (t, J = 7.8 Hz, 4H), 5.00 (s, 2H), 6.05 (d, J = 8.7
Hz, 1H), 6.17-6.27 (m, 2H), 7.33 (s, 2H), 7.58 (s, 1H); ESI-MS (m/z) 326 (M+H)+.
Intermediate 37
4-((l-(2,4-Dichlorophenyl)cyclopentyl)oxy)-3-fluoroaniline
Figure imgf000066_0001
Step 1: l-(2,4-Dichlorophenyl)cyclopentanol
To a stirred solution of l-bromo-2,4-dichlorobenzene (1.0 g, 4.426 mmol) in dry THF (10 mL) was drop- wise added isopropylmagnessium chloride (2M in THF, 3.3 mL) at -10 °C and the reaction mixture was stirred at the same temperature for 1 h. A solution of cyclopentanone (0.58 mL, 6.640 mmol) in THF (10 mL) was added to the reaction mixture and stirred at the RT for 18 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 37 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾ δ 1.78-2.10 (m, 6H), 2.23 (br s, 2H), 5.07 (s, 1H), 7.40 (d, = 8.7 Hz, 1H), 7.51 (s, 1H), 7.79 (d, / = 8.1 Hz, 1H).
Step 2: 2,4-Dichloro-l-(l-(2-fluoro-4-nitrophenoxy)cyclopentyl)benzene To a stirred and cooled (0 °C) solution of Step 1 intermediate (300 mg, 1.298 mmol) in dry DMF (10 mL) was added sodium hydride (60% w/w, 77 mg, 1.947 mmol) and the reaction mixture was stirred for 30 min at the RT. 3, 4-Difluoro-l -nitrobenzene (206 mg, 1.298 mmol) was added to the reaction mixture and it was further stirred at the RT for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and the solvent was distilled off under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 171 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 1.81- 1.83 (m, 4H), 1.98 (s, 2H), 2.36-2.39 (m, 2H), 2.48-2.52 (m, 2H), 6.68 (t, J = 9.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H); APCI-MS (m/z) 339 (M)+.
Step 3: 4-((l-(2,4-Dichlorophenyl)cyclopentyl)oxy)-3-fluoroaniline
To a stirred solution of Step 2 intermediate (160 mg, 0.432 mmol) in a mixture of methanol (5 mL) and water (5 mL) were added iron powder (120 mg, 2.160 mmol) and ammonium chloride (231 mg, 4.321 mmol) at the RT. The reaction mixture was heated to 90 °C and stirred for 3 h at the same temperature. The reaction mixture cooled to RT and the suspended emulsion was filtered off. The filtrate was concentrated under the reduced pressure and diluted with water (15 mL). The aqueous mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvents were recovered under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 64 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 1.67- 1.70 (m, 2H), 1.88- 1.90 (m, 2H), 1.98-2.03 (m, 2H), 2.50 (s, 2H), 4.98 (s, 2H), 6.00 (s, 2H), 6.25 (s, 1H), 7.36 (q, J = 8.7 Hz, 2H), 7.62 (s, 1H); APCI-MS (m/z) 339 (M)+.
Intermediate 38
4-((2-(3,5-Dichloro-6-methylpyridin- -yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000067_0001
Step 1 : 2-(3,5-Dichloro-6-methylpyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of 2-bromo-3,5-dichloro-6-methylpyridine (2.0 g, 8.30 mmol) and acetone (827 μί, 9.96 mmol) in the presence of n-butyl lithium (1.6 M in diethyl ether, 5.7 mL) in diethyl ether (10 mL) as per the process described in Step 1 of Intermediate 6 to yield 480 mg of the product. 1H NMR (300 MHz, DMSO-d6): δ 1.54 (s, 6H), 2.52 (s, 3H), 5.37 (s, 1H), 8.06 (s, 1H).
Step 2: 3,5-Dichloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-6-methylpyridine
The titled compound was prepared by the reaction of step 1 intermediate (460 mg, 2.08 mmol) with l,2-difluoro-4-nitrobenzene (232 μL·, 2.08 mmol) using sodium hydride (60% w/w, 100 mg, 2.50 mmol) in DMF (5.0 mL) as per the process described in Step 3 of
Intermediate 1 to yield 310 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.88 (s, 6H),
2.59 (s, 3H), 6.44 (t, 7 = 8.7 Hz, 1H), 7.82 (d, 7 = 8.1 Hz, 1H), 8.08 (s, 1H), 8.09-8.21 (m,
1H).
Step 3: 4-((2-(3,5-Dichloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
The titled compound was synthesized by the nitro reduction of the step 2 intermediate (300 mg, 0.83 mmol) using iron powder (232 mg, 4.17 mmol) and ammonium chloride (446 mg, 8.34 mmol) in a mixture of THF (10 mL), methanol (5.0 mL) and water (5.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 157 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.64 (s, 6H), 2.51 (s, 3H), 5.02 (s, 2H), 6.04 (d, 7 = 8.1 Hz, 1H), 6.21 (t, 7 = 8.7 Hz, 1H), 6.32 (d, 7 = 13.2 Hz, 1H), 8.11 (s, 1H).
Intermediate 39
4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000068_0001
Step 1: 2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 3-chloro-6-methoxypicolinate (900 mg, 4.46 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 8.9 mL) in diethyl ether (30 mL) as per the process described in Step 2 of Intermediate 1 to yield 541 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.55 (s, 6H), 3.86 (s, 3H), 5.21 (s, 1H), 6.76 (d, 7 = 8.4 Hz, 1H), 7.74 (d, 7 = 8.4 Hz, 1H).
Step 2: 3-Chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-6-methoxypyridine
The titled compound was prepared by the reaction of step 1 intermediate (700 mg, 3.47 mmol) with l,2-difluoro-4-nitrobenzene (394 μL·, 3.47 mmol) using sodium hydride (60% w/w, 167 mg, 4.16 mmol) in DMF (15 mL) as per the process described in Step 3 of Intermediate 1 to yield 655 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 6H), 3.92 (s, 3H), 6.50 (t, 7 = 8.4 Hz, 1H), 6.87 (d, 7 = 8.7 Hz, 1H), 7.73 (d, 7 = 9.0 Hz, 1H), 7.83 (d, 7 = 8.7 Hz, 1H), 8.14 (d, 7 = 11.1 Hz, 1H). Step 3: 4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 2 intermediate (600 mg, 1.76 mmol) using iron powder (489 mg, 8.80 mmol) and ammonium chloride (941 mg, 17.6 mmol) in a mixture of methanol (10 mL) and water (10 mL) as per the process described in Step 4 of Intermediate 1 to yield 157 mg of the product. 1H NMR (300 MHz, DMSO- 6) δ 1.66 (s, 6H), 3.80 (s, 3H), 4.99 (s, 2H), 6.07 (d, 7 = 8.7 Hz, 1H), 6.21 (t, 7 = 8.7 Hz, 1H), 6.34 (d, 7 = 13.2 Hz, 1H), 6.82 (d, 7 = 8.4 Hz, 1H), 7.78 (d, 7 = 8.4 Hz, 1H); APCI-MS (m/z) 311 (M+H)+.
Intermediate 40
4-((2-(3-Chloro-6-(pyrrolidin- l-yl)pyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline
Figure imgf000069_0001
Step 1 : 2-(3-chloro-6-(pyrrolidin-l-yl)pyridin-2-yl)propan-2-ol
The titled compound was prepared by the reaction of methyl 3-chloro-6-(pyrrolidin-l- yl)picolinate (700 mg, 2.90 mmol) and methyl magnesium bromide (1.5 in diethyl ether, 5.8 mL) in diethyl ether (20 mL) as per the process described in Step 2 of Intermediate 1 to yield 315 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.51 (s, 6H), 1.92- 1.96 (m, 4H), 3.34-3.39 (m, 4H), 5.79 (s, 1H), 6.40 (d, 7 = 9.0 Hz, 1H), 7.52 (d, 7 = 8.4 Hz, 1H); ESI- MS (m/z) 241 (M+H)+.
Step 2: 3-chloro-2-(2-(2-fluoro-4-nitrophenoxy)propan-2-yl)-6-(pyrrolidin- l-yl)pyridine The titled compound was prepared by the reaction of step 1 intermediate (300 mg, 1.24 mmol) with l,2-difluoro-4-nitrobenzene (198 μί, 1.24 mmol) using sodium hydride (60% w/w, 59 mg, 1.49 mmol) in DMF (10 mL) as per the process described in Step 3 of Intermediate 1 to yield 100 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 6H), 1.94-2.04 (m, 4H), 3.38-3.43 (m, 4H), 6.43 (d, 7 = 9.0 Hz, 1H), 6.53 (t, 7 = 8.7 Hz, 1H), 7.43 (d, 7 = 8.7 Hz, 1H), 7.86 (d, 7 = 8.1 Hz, 1H), 8.12 (d, 7 = 11.7 Hz, 1H).
Step 3: 4-((2-(3-Chloro-6-(pyrrolidin-l-yl)pyridin-2-yl)propan-2-yl)oxy)-3-fluoroaniline The titled compound was synthesized by the nitro reduction of the step 2 intermediate (120 mg, 0.32 mmol) using iron powder (87 mg, 1.57 mmol) and ammonium chloride (169 mg, 3.15 mmol) in a mixture of methanol (5.0 mL), THF (3.0 mL) and water (2.0 mL) as per the process described in Step 4 of Intermediate 1 to yield 105 mg of the product. 1H NMR (300
MHz, DMSO-d6) δ 1.61 (s, 6H), 1.89-1.97 (m, 4H), 3.30-3.35 (m, 4H), 4.94 (s, 2H), 6.06 (d, / = 8.1 Hz, 1H), 6.23 (t, = 9.3 Hz, 1H), 6.28 (d, = 10.8 Hz, 1H), 6.34-6.41 (m, 1H), 7.50 (d, 7 = 8.7 Hz, 1H).
Examples
The general methods of preparation of the Examples 1-57 are given below as Method A to Method H.
Method A
Synthesis of N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-( 1,1- difluoropropyl)phenyl)acetamide (Example 1)
Figure imgf000070_0001
To a stirred solution of 4-{ [2-(2,4-dichlorophenyl)propan-2-yl]oxy}aniline (Intermediate 1) (98 mg, 0.33 mmol) and [4-(l,l-Difluoropropyl)phenyl] acetic acid (Intermediate 2) (71 mg, 0.33 mmol) in DMF (5.0 mL) at 0 °C were added N,N'-diisopropylethylamine (141 μί, 0.82 mmol) and propylphosphonic anhydride (50% in EtOAc, 398 μί, 0.66 mmol). The reaction mixture was stirred overnight at the RT. The reaction mixture was quenched with water (20 mL) and the product was extracted in ethyl acetate (70 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to afford 56 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 0.88 (t, J = 7.8 Hz, 3H), 1.73 (s, 6H), 2.11-2.25 (m, 2H), 3.63 (s, 2H), 6.60 (d, J = 8.7 Hz, 2H), 7.32-7.46 (m, 7H), 7.57 (d, = 9.0 Hz, 2H), 10.05 (s, 1H); APCI-MS im/z) 493 (M+H)+.
Method B
Synthesis of N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide (Example 2)
Figure imgf000070_0002
Step 1 : N-(4-((2-(2,4-Dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l, l-difluoro-2- oxopropyl)phenyl) acetamide
Figure imgf000070_0003
The titled compound was prepared by the reaction of 4-{ [2-(2,4-dichlorophenyl)propan-2- yl]oxy} aniline (Intermediate 1) (161 mg, 0.54 mmol) and 4-(l,l-difluoro-2- oxopropyl)phenyl] acetic acid (Intermediate 3) (116 mg, 0.54 mmol) using Ν,Ν'- diisopropylethylamine (232 μί, 1.35 mmol) and propylphosphonic anhydride (50% in EtOAc, 326 μί, 1.08 mmol) at the RT as per the procedure described in Example 1 to yield 175 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.73 (s, 6H), 2.35 (s, 3H), 3.66 (s, 2H), 6.60 (d, = 9.3 Hz, 2H), 7.34 (d, = 9.0 Hz, 2H), 7.42-7.57 (m, 7H), 10.06 (s, 1H); APCI-MS (m/z) 504 (M-H)~.
Step 2: N-(4-((2-(2,4-Dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l, l-difluoro-2- hydroxypropyl)phenyl)acetamide
To a stirred solution of N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l,l- difluoro-2-oxopropyl)phenyl)acetamide (Step 1 intermediate) (161 mg, 0.31 mmol) in methanol (5.0 mL) at 0 °C was added sodium borohydride (15 mg, 0.39 mmol) and the resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography to yield 61 mg of the desired product. 1H NMR (300 MHz, DMSO-i¾ δ 1.05 (d, = 5.4 Hz, 3H), 1.73 (s, 6H), 3.62 (s, 2H), 3.99-4.04 (m, 1H), 5.50 (d, = 8.1 Hz, 1H), 6.60 (d, = 8.1 Hz, 2H), 7.32-7.44 (m, 7H), 7.57 (s, 2H), 10.05 (s, 1H); APCI-MS (m/z) 506 (M-H)".
Method C
Synthesis of N-(4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluoroph( (4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide (Example 9)
Figure imgf000071_0001
Step 1 : Ethyl 2-(4-(2-((4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate
Figure imgf000071_0002
The titled compound was prepared by the reaction of 4-{ [4-(2,4-dichlorophenyl)tetrahydro- 2H-pyran-4-yl]oxy}-3-fluoroaniline (Intermediate 10) (500 mg, 1.40 mmol) and [4-(2- ethoxy- l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Step 1 compound of Intermediate 3) (398 mg, 1.54 mmol) using N,N'-diisopropylethylamine (604 μί, 3.50 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.8 mL, 2.80 mmol) in DMF (10 mL) at 0 °C as per the procedure described in Method A to yield 584 mg of the product. 1H NMR (300 MHz, DMSO-i¾ δ 1.20 (t, = 6.9 Hz, 3H), 2.20-2.26 (m, 2H), 2.48 (s, 2H), 3.62-3.73 (m, 6H), 4.27 (q, = 5.7 Hz, 2H), 6.20-6.24 (m, 1H), 6.83-6.87 (m, 1H), 7.44-7.61 (m, 8H), 10.21 (s, 1H); APCI-MS (m/z) 593 (M-H)~.
Step 2: N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
Figure imgf000072_0001
To a stirred solution of ethyl 2-(4-(2-((4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4- yl)oxy)-3-fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate (Step 1 intermediate) (415 mg, 0.69 mmol) in anhydrous THF (10 mL) was added 3M methyl lithium (556 μί, 1.66 mmol) dropwise at -78 °C. The reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 203 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 2.23-2.26 (m, 2H), 2.32-2.40 (m, 5H), 3.66 (s, 2H), 3.70-3.75 (m, 4H), 6.21-6.26 (m, 1H), 6.88-6.92 (m, 1H), 7.45-7.62 (m, 8H), 10.23 (s, 1H); APCI-MS (m/z) 563 (M-H)".
Step 3: N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
The titled compound was prepared by the reduction of N-(4-((4-(2,4- dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4-(l, l-difluoro-2- oxopropyl)phenyl)acetamide (Step 2 intermediate) (115 mg, 0.20 mmol) using sodium borohydride (12 mg, 0.30 mmol) in methanol (2.0 mL) as per the procedure described in Step 2 of Method B to yield 48 mg of the desired product. 1H NMR (300 MHz, DMSO-i¾) δ 1.05 (d, = 6.3 Hz, 3H), 2.21-2.25 (m, 2H), 2.38-2.49 (m, 2H), 3.62 (s, 2H), 3.71-3.75 (m, 4H), 4.00-4.04 (m, 1H), 5.50 (d, 7 = 5.7 Hz, 1H), 6.22-6.25 (m, 1H), 6.88-6.92 (m, 1H), 7.35-7.41 (m, 4H), 7.51-7.63 (m, 4H), 10.21 (s, 1H); APCI-MS (m/z) 570 (M+H)+.
Method D
Synthesis of N-(4-((2-(5-chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-(l,l-difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamide (Example 16)
Figure imgf000073_0001
Step 1 : N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluo -2-oxopropyl)phenyl)acetamide
Figure imgf000073_0002
The titled compound was prepared by the reaction of 4-{ [2-(5-chloro-l-ethyl-lH- benzimidazol-2-yl)propan-2-yl]oxy}-3-fluoroaniline (Intermediate 8) (95 mg, 0.27 mmol) and 4-(l,l-Difluoro-2-oxopropyl)phenyl] acetic acid (Intermediate 3) (62 mg, 0.27 mmol) using N,N'-diisopropylethylamine (117 μί, 0.68 mmol) and propylphosphonic anhydride (50% in EtOAc, 304 μί, 0.54 mmol) in DMF (3.0 mL) at 0 °C as per the procedure described in Method A to give 140 mg of the product. 1H NMR (300 MHz, DMSO-i¾) δ 1.30 (t, J = 6.9 Hz, 3H), 1.78 (s, 6H), 2.35 (s, 3H), 3.68 (s, 2H), 4.60 (q, 7 = 6.9 Hz, 2H), 6.53 (t, 7 = 8.7 Hz, 1H), 6.97-7.01 (m, 1H), 7.31 (d, 7 = 7.2 Hz, 1H), 7.49 (q, 7 = 9.6 Hz, 4H), 7.61- '.73 (m, 3H), 10.31 (s, 1H).
Step 2: N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamide
To a stirred solution of N-(4-((2-(5-chloro- l-ethyl-lH-benzo[d]imidazol-2-yl)propan-2- yl)oxy)-3-fluorophenyl)-2-(4-(l, l-difluoro-2-oxopropyl)phenyl)acetamide (Step 1 intermediate) (50 mg, 0.08 mmol) in diethyl ether (5.0 mL) was added methylmagnesium bromide (3 , 89 μί, 0.26 mmol) at 0 °C and the reaction mixture was stirred at the RT for 1 h. The reaction mixture was quenched with aqueous saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 15 mg of the desired product. 1H NMR (300 MHz, DMSO- e) δ 1.12 (s, 6H), 1.26 (t, J = 6.9 Hz, 3H), 1.76 (s, 6H), 3.62 (s, 2H), 4.57 (q, J = 7.8 Hz, 2H), 5.24 (br s, 1H), 6.50-6.55 (m, 1H), 6.99-7.02 (m, 1H), 7.26-7.39 (m, 5H), 7.60-7.72 (m, 3H), 10.29 (s, 1H); ESI-MS (mJz) 574 (M+H)+.
Method E
Synthesis of N-(4-(3-(4-chloro-3-fluorophenoxy)-3-methylbut- l-yn- l-yl)phenyl)-2-(4-(l, l- difluoro-2-hydroxypropyl)phenyl)acetamide (Example 20)
Figure imgf000074_0001
To a degassed solution of 2-[4-(l ,l-difluoro-2-hydroxypropyl)phenyl]- V-(4- iodophenyl)acetamide (Intermediate 14) (170 mg, 0.39 mmol) in diethylamine (5.0 ml) were added l-chloro-2-fluoro-4-[(2-methylbut-3-yn-2-yl)oxy]benzene (Intermediate 15) (251 mg, 1.18 mmol), copper iodide (30 mg, 0.15 mmol), triphenylphosphine (2.0 mg, 0.007 mmol) and bis(triphenylphosphine)palladium(II) dichloride (110 mg, 0.15 mmol) and the reaction mixture was stirred at the RT for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 115 mg the titled product. 1H NMR (300 MHz, DMSO-<¾ δ 1.06 (d, = 5.7 Hz, 3H), 1.68 (s, 6H), 3.70 (s, 2H), 4.00-4.08 (m, 1H), 5.50 (d, = 6.3 Hz, 1H), 7.12 (d, = 9.0 Hz, 1H), 7.24 (d, = 8.7 Hz, 1H), 7.35 (d, = 8.4 Hz, 2H), 7.42 (s, 4H), 7.49-7.57 (m, 1H), 7.62 (d, = 8.7 Hz, 2H), 10.39 (s, 1H); APCI-MS (m/z) 516 (M+H)+.
Method F
Synthesis of ( ?)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (l, l-difluoro-2-hydroxypropyl)phenyl)acetamide (Example 44)
Figure imgf000074_0002
Step 1 : N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-oxopropyl)phenyl)acetamide
Figure imgf000074_0003
The titled compound was prepared by the coupling reaction of 4-{ [2-(3,5-dichloropyridin-2- yl)propan-2-yl]oxy}-3-fluoroaniline (Intermediate 22) (1.3 g. 4.14 mmol) and [4-(2-ethoxy- l,l-difluoro-2-oxoethyl)phenyl] acetic acid (Step-1 of Intermediate 3) (1.28 g, 4.96 mmol) in the presence of N,N'-diisopropylethylamine (1.7 mL, 10.35 mmol) and propylphosphonic anhydride (50% in EtOAc, 4.9 mL, 8.28 mmol) in DMF (10 mL) followed by the reaction mixture with methyl lithium (3.0 , 2.0 mL, 6.04 mmol) in THF (10 mL) as per the procedures described in Step 1 and Step 2 of Method C to afford 1.43 g of the product. 1H NMR (300 MHz, OMSO-d6) δ 1.74 (s, 6H), 2.35 (s, 3H), 3.67 (s, 2H), 6.35 (t, = 9.0 Hz, 1H), 6.95 (d, = 6.9 Hz, 1H), 7.43-7.60 (m, 5H), 8.22 (s, 1H), 8.62 (s, 1H), 10.26 (s, 1H). Step 2: ( ?)-N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide (Crude)
Figure imgf000075_0001
To a stirred solution of (5)-(-)-2-methyl-CBS-oxaborolidine (1.1 mL, 1.14 mmol) [Ref. (i) Corey, E. J; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986-2012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109 (18), 5551-5553] in anhydrous THF (15 mL) was added borane dimethyl sulfide complex (216 μί, 2.28 mmol) at 0 °C and the reaction mixture was stirred for 30 min at the same temperature. A solution of Step 1 Intermediate (1.0 g, 1.90 mmol) in THF (10 mL) was drop wise added to the reaction mixture over a period of 10 min at 0 °C. The resultant mixture was stirred at the RT for 20 min. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under the reduced pressure. The residue obtained was purified by flash silica gel column chromatography to yield 950 mg of the titled product as solid. Chiral HPLC purity: 70.17%; 1H NMR (300 MHz, DMSO-i¾) δ 1.06 (d, = 6.3 Hz, 3H), 1.75 (s, 6H), 3.64 (s, 2H), 3.98-4.05 (m, 1H), 5.50 (d, = 6.3 Hz, 1H), 6.36 (t, = 9.0 Hz, 1H), 6.97-7.08 (m, 1H), 7.36-7.42 (m, 4H), 7.54-7.59 (m, 1H), 8.22 (s, 1H), 8.62 (s, 1H), 10.24 (s, 1H); ESI-MS (m/z) 527 (M)+.
Step 3: (5)-( ?)-l-(4-(2-((4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-l,l-difluoropropan-2-yl 2-(((benzyloxy)carbonyl) amino)-3-phenylpropanoate
Figure imgf000076_0001
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine (465 mg, 1.55 mmol), DMAP (104 mg, 0.85 mmol) and ( ?)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-(l,l-difluoro-2-hydroxypropyl)phenyl)acetamide (Step 2 product) (900 mg, 1.71 mmol) in dichloromethane (25 mL) was added EDCI. HCl (247 mg, 1.87 mmol) at 0 °C and the reaction mixture was stirred for 2 h at the same temperature before stirring overnight at the RT. The reaction mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was separated and washed with IN HCl (20 mL), saturated aqueous sodium bicarbonate solution (20 mL) followed by brine (20 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 705 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 1.03 (d, = 6.3 Hz, 3H), 1.74 (s, 6H), 2.80-2.87 (m, 2H), 3.65 (s, 2H), 4.23-4.27 (m, 1H), 4.99 (s, 2H), 5.29 (br s, 1H), 6.34 (t, = 9.9 Hz, 1H), 6.93 (d, = 7.2 Hz, 2H), 7.12-7.32 (m, 8H), 7.40-7.49 (m, 5H), 7.89-7.95 (m, 1H), 8.21 (s, 1H), 8.62 (s, 1H), 10.23 (s, 1H); ESI-MS (m/z) 808 (M+H)+.
Step 4: ( ?)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide
To a stirred solution of (5)-( ?)- l-(4-(2-((4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2-(((benzyloxy)carbonyl) amino)-3-phenylpropanoate (Step 3 intermediate) (675 mg, 0.84 mmol) in a mixture of methanol (5.0 mL), water (5.0 mL) and THF (20 mL) was added lithium hydroxide monohydrate (70 mg, 1.67 mmol) and the reaction mixture was stirred at the RT for 1 h. The reaction mixture was concentrated and the residue was diluted with water (20 mL). The aqueous mixture was acidified with IN HCl and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 405 mg of the titled product. Chiral HPLC purity 94.96% (Column: Chiralcel-OJ-H, 250 mm x 4.6 mm, 5μ, mobile phase (A : B): n-hexane : ethanol (90: 10:0.1% diethyl amine), run time: 40 min, RT: 31.38 min); 1H NMR (300 MHz, DMSO- 6) δ 1.06 (d, = 6.6 Hz, 3H), 1.74 (s, 6H), 3.64 (s, 2H), 3.98-4.02 (m, 1H), 5.49 (d, J = 6.6 Hz, 1H), 6.36 (t, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 7.37-7.42 (m, 4H), 7.58-7.63 (m, 1H), 8.22 (s, 1H), 8.63 (s, 1H), 10.23 (s, 1H); ESI-MS (m/z) 528 (M+H)+.
Method G
Synthesis of (5)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (l,l-difluoro-2-hydroxypropyl)phenyl)acetamide (Example 45)
Figure imgf000077_0001
Step 1: (5)-N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide (Crude)
Figure imgf000077_0002
To a stirred solution of ( ?)-(+)-2-methyl-CBS-oxaborolidine (1.2 mL, 1.25 mmol) [Ref: (i) Corey, E. J; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986-2012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109 (18), 5551-5553] in anhydrous THF (10 mL) was added borane dimethyl sulfide complex (239 μί, 2.51 mmol) at 0 °C and the reaction mixture was stirred for 30 min at the same temperature. A solution of N-(4-((2-(3,5- dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l-difluoro-2- oxopropyl)phenyl)acetamide (Method F-Step 1 Intermediate) (1.1 g, 2.09 mmol) in THF (15 mL) was drop wise added to the reaction mixture over a period of 10 min at 0 °C. The resultant mixture was stirred at the RT for 20 min. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under the reduced pressure. The residue obtained was purified by flash silica gel column chromatography to yield 1.02 g of the titled product as solid. Chiral HPLC purity: 92.62%; 1H NMR (300 MHz, DMSO-i¾) δ 1.03 (d, = 6.3 Hz, 3H), 1.72 (s, 6H), 3.61 (s, 2H), 3.97-4.02 (m, 1H), 5.48 (d, J = 6.3 Hz, 1H), 6.34 (t, J = 9.0 Hz, 1H), 6.94 (d, = 7.2 Hz, 1H), 7.36-7.42 (m, 4H), Ί .52-1.59 (m, 1H), 8.20 (s, 1H), 8.60 (s, 1H), 10.22 (s, 1H).
Step 2: (5)-(5)-l-(4-(2-((4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-l,l-difluoropropan-2-yl 2- (((benzyloxy)carbonyl)amino)-3-phenylpropanoate
Figure imgf000078_0001
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine (516 mg, 1.72 mmol), DMAP (105 mg, 0.86 mmol) and (5)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-(l,l-difluoro-2-hydroxypropyl)phenyl)acetamide (Step 1 product) (1.0 g, 1.89 mmol) in dichloromethane (25 mL) was added EDCI. HC1 (249 mg, 1.89 mmol) at 0 °C and the reaction mixture was stirred for 2 h at the same temperature before stirring overnight at RT. The mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was separated and washed with IN HC1 (20 mL), saturated aqueous sodium bicarbonate solution (20 mL) followed by brine (20 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 750 mg of the titled product. 1H NMR (300 MHz, DMSO-i¾) δ 1.21 (d, = 5.7 Hz, 3H), 1.74 (s, 6H), 2.62-2.74 (m, 2H), 3.63 (s, 2H), 4.20 (br s, 1H), 4.95 (s, 2H), 5.38 (br s, 1H), 6.33 (t, = 9.9 Hz, 1H), 6.93 (d, = 7.2 Hz, 2H), 7.15-7.30 (m, 8H), 7.38-7.47 (m, 4H), 7.52-7.58 (m, 1H), 7.81 (d, = 7.2 Hz, 1H), 8.22 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H); APCI-MS (m/z) 808 (M+H)+.
Step 3: (5)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide
To a stirred solution of (5)-l-(4-(2-((4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)- l,l-difluoropropan-2-yl 2-(2-(benzyloxy)-2- oxoacetamido)-3-phenylpropanoate (Step 2 intermediate) (750 mg, 0.92 mmol) in a mixture of methanol (5.0 mL), water (5.0 mL) and THF (20 mL) was added lithium hydroxide monohydrate (78 mg, 1.85 mmol) and the reaction mixture was stirred at the RT for 1 h. The reaction mixture was concentrated and the residue was diluted with water (20 mL). The aqueous mixture was acidified with IN HC1 and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was distilled out under the reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 430 mg of the titled product. Chiral HPLC purity 98.60% (Column: Chiralcel-OJ-H, 250 mm x 4.6 mm, 5μ, mobile phase (A : B): n-hexane : ethanol (90: 10: 0.1% diethyl amine), run time: 40 min, RT: 29.60 min); 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, = 6.3 Hz, 3H), 1.74 (s, 6H), 3.63 (s, 2H), 4.01-4.05 (m, 1H), 5.50 (d, J = 6.3 Hz, 1H), 6.36 (t, J = 8.7 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 7.37-7.42 (m, 4H), 7.54-7.63 (m, 1H), 8.22 (s, 1H), 8.62 (s, 1H), 10.25 (s, 1H); APCI-MS (m/z) 527 (M+H)+.
Method H
Synthesis of N-(4-((2-(3-chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2- (4-(l, l-difluoro-2-hydroxypropyl)phenyl)acetamide (Example 56)
Figure imgf000079_0001
Step 1 : Ethyl 2-(4-(2-((4-((2-(3-chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate
Figure imgf000079_0002
The titled compound was prepared by the reaction of 4-((2-(3-chloro-6-methoxypyridin-2- yl)propan-2-yl)oxy)-3-fluoroaniline (Intermediate 39) (390 mg, 1.25 mmol) and [4-(2- ethoxy- l, l-difluoro-2-oxoethyl)phenyl] acetic acid (Step 1 compound of Intermediate 3) (388 mg, 1.50 mmol) using N,N'-diisopropylethylamine (540 μί, 3.13 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.6 mL, 2.51 mmol) in DMF (5.0 mL) as per the procedure described in Method A to yield 459 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J = 7.5 Hz, 3H), 1.75 (s, 6H), 3.67 (s, 2H), 3.84 (s, 3H), 4.29 (q, J = 7.5 Hz, 2H), 6.37 (t, J = 9.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.91-6.95 (m, 1H), 7.45-7.51 (m, 3H), 7.52-7.61 (m, 2H), 7.75 (d, / = 8.4 Hz, 1H), 10.22 (s, 1H); APCI-MS (m/z) 551 (M+H)+. Step 2: N-(4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
Figure imgf000079_0003
The title compound was prepared by the reaction of ethyl 2-(4-(2-((4-((2-(3-chloro-6- methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)amino)-2-oxoethyl)phenyl)-2,2- difluoroacetate (Step 1 intermediate) (450 mg, 0.81 mmol) with 3M methyl lithium (680 μί, 2.04 mmol) in anhydrous THF (10 mL) as per the procedure described in Step 2 of Method C to yield 205 mg of the product. 1H NMR (300 MHz, DMSO-d6) δ 1.75 (s, 6H), 2.35 (s, 3H), 3.67 (s, 2H), 3.84 (s, 3H), 6.37 (t, J = 9.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 7.45-7.55 (m, 5H), 7.75 (d, J = 8.4 Hz, 1H), 10.22 (s, 1H).
Step 3: N-(4-((2-(3-Chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-oxopropyl)phenyl)acetamide
Figure imgf000080_0001
To a stirred solution of N-(4-((2-(3-chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-(l,l-difluoro-2-oxopropyl)phenyl)acetamide (Step 2 intermediate) (50 mg, 0.09 mmol) in acetonitrile (10 mL) were added sodium iodide (42 mg, 0.29 mmol) and trimethylsilyl chloride (39 μί, 0.29 mmol at the RT under the nitrogen atmosphere. The reaction mixture was stirred at 65 °C for 18 h. The reaction mixture was quenched with aqueous sodium thiosulfate solution (1.0 mL) and further diluted with water (20 mL). The aqueous mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 25 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 1.71 (s, 6H), 2.35 (s, 3H), 3.67 (s, 2H), 6.12-6.16 (m, 1H), 6.31-6.35 (m, 1H), 6.60-6.65 (m, 1H), 6.91-6.95 (m, 1H), 7.45-7.53 (m, 4H), 7.61-7.67 (m, 1H), 10.23 (s, 1H), 10.97 (s, 1H).
Step 4: N-(4-((2-(3-chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide
The titled compound was prepared by the reduction of N-(4-((2-(3-Chloro-6-hydroxypyridin- 2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-oxopropyl)phenyl)acetamide (Step 3 intermediate) (20 mg, 0.04 mmol) using sodium borohydride (3.0 mg, 0.06 mmol) in methanol (5.0 mL) as per the procedure described in Step 2 of Method B to yield 11 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 1.06 (d, = 6.0 Hz, 3H), 1.71 (s, 6H), 3.63 (s, 2H), 3.99-4.04 (m, 1H), 5.48 (d, J = 5.7 Hz, 1H), 6.30-6.35 (m, 1H), 6.62-6.66 (m, 1H), 6.92-6.96 (m, 1H), 7.37-7.44 (m, 4H), 7.54-7.58 (m, 2H), 10.21 (s, 1H), 10.97 (s, 1H); APCI-MS (m/z) 509 (M+H)+. The chemical name, structure Intermediate No., method of preparation, analytical data of Example 3-8, 10-15, 17-19, 21-43, 46-55 and 57 are given in the below table. Table 1 : Chemical name, structure Intermediate No., method of preparation and analytical data of Example 3-8, 10-15, 17-19, 21-43, 46-55 and 57
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_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 10 nM 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 h. The pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and 10 nM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 h 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 500 nM, preferably less than 100 nM, more preferably less than 50 nM.
The IC50 (nM) values are set forth in Table 2 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 2: In-vitro screening results
Figure imgf000093_0001
Figure imgf000094_0001
47. Example 47 58.78 70.82 C
Figure imgf000095_0001
(-): Not determined

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I)
Figure imgf000096_0001
(I)
or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000096_0002
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
Figure imgf000096_0003
; z 0(CRxRy)q y; and
:— 0(CRxRy)( yi - x, y and z represent point of attachment;
Ra and Rb, which may be same or different, are each independently selected from hydrogen and C1-8alkyl;
R1 is selected from hydroxyl and C1-8alkyl;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ galkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl, C3_6cycloalkyl and 3 to 15 membered heterocyclyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurrence of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
2. The compound according to claim 1, wherein X is N.
1 3
3. The compound according to claim 1, wherein X is CR .
4. The compound according to claim 3, wherein R is hydrogen or fluorine.
5. The compound according to claim 1, wherein R4 is ethyl.
6. The compound according to any one of claim 1 to 5, wherein R1 is hydroxyl or methyl.
7. The compound according to any one of claim 1 to 6, wherein R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
8. The compound according to any one of claim 1 to 7, wherein 'n' is 1, 2 or 3.
9. The compound according to any one of claim 1 to 8, wherein Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
10. The compound according to any one of claim 1 to 9, wherein 'q' is 1.
11. The compound according to any one of claim 1 to 10, wherein Ra and Rb are hydrogen.
12. The compound according to any one of claim 1 to 10, wherein one of Ra and Rb is hydrogen and the other is hydrogen or methyl.
13. The compound according to any one of claim 1 to 10, wherein Ra and Rb are methyl.
14. The compound according to any one of claim 1 to 10, wherein R1 is methyl; Ra is hydrogen and Rb is hydrogen.
15. The compound according to any one of claim 1 to 10, wherein R1 is hydroxyl; Ra is hydrogen and Rb is methyl.
16. The compound according to any one of claim 1 to 10, wherein R1 is hydroxyl; Ra is methyl and Rb is methyl.
wherein ring A
Figure imgf000097_0001
. The compound according to claim 1, wherein is 3-chloro-6- cyclopropylpyridin-2-yl, 5-chloro-l -ethyl- lH-benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4- chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6- hydroxypyridin-2-yl, 3-chloro-6-methoxypyridin-2-yl, 4-chloro-2-methoxyphenyl, 4-chloro- 2-methylphenyl, 3-chloro-6-methylpyridin-2-yl, 4-chloro-6-methylpyridin-3-yl, 5-chloro-3- methylpyridin-2-yl, 5-chloro-2-methylpyridin-4-yl, 3-chloro-6-(pyrrolidin- l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4- difluorophenyl or 3,5-dichloro-6-methylpyridin-2-yl.
Figure imgf000098_0001
;- OC(CH3)2C≡C-7;
or
20. The compound according to claim 1,
wherein
Figure imgf000098_0002
X1 is CH, CF or N;
■— L-j is — (CRxRy)qo^j — o(CRxRy)q— ; or i- 0(CR¾V wherein x, y and z represents point of attachment;
Ring B is phenyl, pyridyl or benzimidazolyl;
Ra is hydrogen or methyl; Rb is hydrogen or methyl;
R1 is hydroxyl or methyl;
R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl; R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
'n' is 1, 2 or 3; and
'q' is 1.
21. The compound according to claim 1,
wherein
Ra is hydrogen or methyl; Rb is hydrogen or methyl;
R1 is hydroxyl or methyl;
Figure imgf000099_0001
or l Z OC(CH3)2C≡C-7| . ; and
Figure imgf000099_0002
3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro- 1 -ethyl- 1H- benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methoxyphenyl, 4-chloro-2-methylphenyl, 3-chloro-6- methylpyridin-2-yl, 4-chloro-6-methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro- 2-methylpyridin-4-yl, 3-chloro-6-(pyrrolidin-l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5- chloropyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5- dichloro-6-methylpyridin-2-yl.
22. A compound of formula (II)
Figure imgf000099_0003
(II)
or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000099_0004
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
Figure imgf000099_0005
1 2 0(CRxRy)q— ; .
x, y and z represent point of attachment; 2
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ galkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl and C3_6cycloalkyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurrence of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
23. The compound according to claim 22, wherein R is fluoro, chloro, methyl, ethyl or methoxy.
24. The compound according to claim 22 or 23, wherein 'n' is 2.
25. The compound according to any one of claims 22 to 24, wherein Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
26. The compound according to claim 22, wherein ring A is
Figure imgf000100_0001
27. The compound according to claim 22, wherein is 5-chloro-l -ethyl- 1H- benzimidazol-2-yl, 4-chloro-2-methoxyphenyl, 4-chloro-2-methylphenyl, 5-chloro-3- methylpyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl or 2,4-difluorophenyl. 28. The compound according to claim 22, wherein
Figure imgf000100_0002
i— L-; is i—
29. The compound according to claim 22,
wherein
Ring A is
Figure imgf000101_0001
X1 is CH or CF;
— L— j . \— (CRxRy)qQ i— 0(CRxRy),
y i or q y i , wherein x, y and z represent point of attachment;
Ring B is phenyl or benzimidazolyl;
R is fluoro, chloro, methyl, ethyl or methoxy;
R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring;
'n' is 2; and
'q' is 1.
30. The compound according to claim 22,
wherein
Ring A is
Figure imgf000101_0002
and
Figure imgf000101_0003
is 5-chloro- 1 -ethyl- lH-benzimidazol-2-yl, 4-chloro-2-methoxyphenyl,
4-chloro-2-methylphenyl, 5-chloro-3-methylpyridin-2-yl, 2,4-dichlorophenyl, 3,5- dichloropyridin-2-yl or 2,4-difluorophenyl.
31. A compound of formula (III)
Figure imgf000101_0004
(III) or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Ring A is
Figure imgf000102_0001
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl; selected from l z (CRXRy)qO-^; ; z 0(CRxRy)q y; and
0(CRxRy)Q x, y and z represents point of attachment;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ galkyl, Ci-galkoxy, haloCi-galkyl, haloCi-galkoxy, hydroxyCi-galkyl and C3_6cycloalkyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and C1-8alkyl;
each occurrence of Rx and Ry, which may be same or different, are each independently selected from C1-8alkyl and haloC1-8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
32. The compound according to claim 31, wherein R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl.
33. The compound according to claim 31 or 32, wherein 'n' is 1, 2 or 3.
34. The compound according to any one of claims 31 to 33, wherein Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4-yl or oxetan-3-yl ring.
wherein ring A
Figure imgf000102_0002
36. The compound according to claim 31, wherein
Figure imgf000103_0001
3-chloro-6- cyclopropylpyridin-2-yl, 5-chloro- 1 -ethyl- lH-benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4- chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6- hydroxypyridin-2-yl, 3-chloro-6-methoxypyridin-2-yl, 4-chloro-2-methylphenyl, 3-chloro-6- methylpyridin-2-yl, 4-chloro-6-methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro- 2-methylpyridin-4-yl, 3-chloro-6-(pyrrolidin- l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5- chloropyridin-2-yl, 2,4-dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5- dichloro-6-methylpyridin-2-yl.
The compound according to claim 31, wherein L-; is I— C(CH3)20 yi
Figure imgf000103_0002
38. The compound according to claim 31
wherein
Figure imgf000103_0003
X1 is CH, CF or N;
:— L-; ;— (CRxRy)qO-^; ;— 0(CRxRy)q— ; |- 0(CRxRy)q(
is
wherein x, y and z represents point of attachment;
Ring B is phenyl, pyridyl or benzimidazolyl;
R is hydroxyl, fluoro, chloro, methyl, ethyl, methoxy, cyclopropyl or pyrrolidinyl; R4 is ethyl;
Rx and Ry are independently methyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydro-2H-pyran-4- yl or oxetan-3-yl ring;
'n' is 1, 2 or 3; and
'q' is 1.
39. The compound according to claim 31,
wherein
Figure imgf000104_0001
i— L-; :— C(CH3)20-^; ;— OC(CH3)2— ; ζ·· ο --| -y \ z—o-: ,y z ^ o-
Figure imgf000104_0002
Figure imgf000104_0003
3-chloro-6-cyclopropylpyridin-2-yl, 5-chloro- l -ethyl- 1H- benzimidazol-2-yl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3- fluorophenyl, 5-chloro-3-fluoropyridin-2-yl, 3-chloro-6-hydroxypyridin-2-yl, 3-chloro-6- methoxypyridin-2-yl, 4-chloro-2-methylphenyl, 3-chloro-6-methylpyridin-2-yl, 4-chloro-6- methylpyridin-3-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloro-2-methylpyridin-4-yl, 3-chloro- 6-(pyrrolidin-l-yl)pyridin-2-yl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl, 2,4- dichlorophenyl, 3,5-dichloropyridin-2-yl, 2,4-difluorophenyl or 3,5-dichloro-6- methylpyridin-2- yl .
40. A compound selected from
N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-( 1,1- difluoropropyl)phenyl) acetamide,
N-(4-((2-(2,4-dichlorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l,l-difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(5-chloro- l-ethyl- lH-benzo[d]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamide,
N-(4-(3-(4-chloro-3-fluorophenoxy)-3-methylbut- l-yn-l-yl)phenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
( ?)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
(5)-N-(4-((2-(3,5-dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l, l- difluoro-2-hydroxypropyl)phenyl)acetamide, N-(4-((2-(3-chloro-6-hydroxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-( 1 -(2,4-Dichlorophenyl)cyclopropoxy)-3-fluorophenyl)-2-(4-( 1,1- difluoropropyl)phenyl)acetamide,
N-(4-( 1 -(2,4-Dichlorophenyl)cyclopropoxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-((2-(2,4-Dichlorophenyl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-(4-(l,l- difluoropropyl)phenyl)acetamide,
N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoropropyl)phenyl)acetamide,
N-(4-((2-(2-Chloro-4-fluorophenyl)propan-2-yl)oxy)phenyl)-2-(4-(l, l-difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-((2-(2-Chloro-4-fluorophenyl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l, l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(5-Chloro- l-ethyl H-benzo[ ]imidazol-2-yl)propan-2-yl)oxy)phenyl)-2-(4- (1, 1 -difluoropropyl)phenyl)acetamide,
N-(4-((2-(5-Chloro- l-ethyl H-benzo[ ]imidazol-2-yl)propan-2-yl)oxy)phenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl) phenyl)acetamide,
N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[ ]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoropropyl)phenyl)acetamide,
N-(4-((2-(5-Chloro- l-ethyl-lH-benzo[ ]imidazol-2-yl)propan-2-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(2-(2-(2,4-Difluorophenoxy)propan-2-yl)- l-ethyl- lH-benzo[<i]imidazol-5-yl)-2-(4- (1, 1 -difluoropropyl)phenyl)acetamide,
2-(4-( 1 , 1 -Difluoro-2-hydroxypropyl)phenyl)-N-(2-(2-(2,4-difluorophenoxy) propan- 2-yl)-l-ethyl-lH-benzo[<i]imidazol-5-yl)acetamide,
N-(2-(2-(4-Chloro-3-fluorophenoxy)propan-2-yl)- l-ethyl-lH-benzo[d]imidazol-5-yl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(4-Chloro-2-methoxyphenyl)tetrahydro-2H-pyran-4-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoropropyl)phenyl)acetamide, N-(4-((2-(3 ,5-Dichloropyridin-2-yl)propan-2-yl)oxy)phenyl)-2-(4-( 1,1- difluoropropyl)phenyl)acetamide,
N-(4-((2-(3 ,5-Dichloropyridin-2-yl)propan-2-yl)oxy)phenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-(3-(4-Chloro-2-fluorophenoxy)-3 -methylbut- 1 -yn- 1 -yl)phenyl)-2-(4-( 1,1- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(6-((4-(2,4-Dichlorophenyl)tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(6-((4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2-(4- (1,1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2 (4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(3,5-Dichloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)-2 (4-( 1 , 1 -difluoropropyl)phenyl)acetamide,
N-(4-((2-(3,5-Dichloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoropropyl)phenyl)acetamide,
N-(4-((3-(3,5-Dichloropyridin-2-yl)oxetan-3-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoropropyl)phenyl)acetamide,
N-(4-((3-(3,5-Dichloropyridin-2-yl)oxetan-3-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((3-(3,5-Dichloropyridin-2-yl)oxetan-3-yl)oxy)-3-fluorophenyl)-2-(4-(l,l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(4-Chloro-2-methylphenyl)tetrahydro-2H-pyran-4-yl)oxy)-3-fluorophenyl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoropropyl)phenyl)acetamide,
N-(4-((4-(5-Chloro-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-yl)oxy)-3- fluorophenyl)-2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(5-Chloro-3-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l difluoro-2-hydroxypropyl)phenyl)acetamide, N-(4-((2-(5-Chloro-3-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l difluoropropyl)phenyl)acetamide,
N-(4-((2-(5-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l, l-difluoro- 2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3-Chloropyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l, l-difluoro- 2-hydroxypropyl)phenyl)acetamide,
N-(4-( 1 -(3 ,5-Dichloropyridin-2-yl)cyclobutoxy)-3 -fluorophenyl)-2-(4-( 1 , 1 -difluoro-2 hydroxypropyl)phenyl)acetamide,
N-(4-(l-(5-Chloro-3-fluoropyridin-2-yl)cyclobutoxy)-3-fluorophenyl)-2-(4-(l, l- difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(4-Chloro-6-methylpyridin-3-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(5-Chloro-2-methylpyridin-4-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4-(l,l difluoro-2-hydroxypropyl)phenyl)acetamide,
( ?)-N-(4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
(5)-N-(4-((2-(3-Chloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3-Chloro-6-cyclopropylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4 (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-( 1 -(2,4-Dichlorophenyl)cyclobutoxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-(( 1 -(2,4-Dichlorophenyl)cyclopentyl)oxy)-3-fluorophenyl)-2-(4-( 1 , 1 -difluoro-2- hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3,5-Dichloro-6-methylpyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide,
N-(4-((2-(3-Chloro-6-methoxypyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)-2-(4- (1, 1 -difluoro-2-hydroxypropyl)phenyl)acetamide, or
N-(4-((2-(3-Chloro-6-(pyrrolidin-l-yl)pyridin-2-yl)propan-2-yl)oxy)-3-fluorophenyl)- 2-(4-( 1 , 1 -difluoro-2-hydroxypropyl)phenyl)acetamide and
pharmaceutically acceptable salt thereof.
41. A compound of formula
Figure imgf000108_0001
or a pharmaceutically acceptable salt thereof.
42. A compound of formula
Figure imgf000108_0002
or a pharmaceutically acceptable salt thereof.
43. A compound of formula
Figure imgf000108_0003
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable excipient.
45. The pharmaceutical composition according to claim 44, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
46. 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 43.
47. The method according to claim 46, wherein the disease, disorder, syndrome or condition is an inflammatory or autoimmune disease.
48. The method according to claim 47, 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.
49. The method according to claim 46, wherein the disease, disorder, syndrome or condition is pain, chronic pain, acute pain, inflammatory pain, arthritic pain, neuropathic pain, post-operative 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, post-traumatic injury, or pain associated with irritable bowel syndrome.
50. The method according to claim 46, wherein the disease, disorder, syndrome or condition is chronic obstructive pulmonary disease (COPD), asthma, bronchospasm or cough.
51. 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 43.
52. A process for p
Figure imgf000109_0001
(I)
or a pharmaceutically acceptable salt thereof, the process comprising:
(i) reacting a compound of formula (1) with a compound of formula (2) to afford the compound of formula (I)
Figure imgf000109_0002
(I)
wherein
Ring A is
Figure imgf000109_0003
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
'~ L~' is selected from (CR RY)qO y and
0(CRxRy)qC≡C^; . x, y and z represent point of attachment; which may be same or different, are each independently selected from hydrogen and Ci_8alkyl;
R1 is selected from hydroxyl and Ci_8alkyl;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi_8alkyl, C3_6cycloalkyl and 3 to 15 membered heterocyclyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurrence of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl and haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
53. The process according to claim 52, wherein the compound of formula (1) is reacted with a compound of formula (2) in the presence of a coupling agent.
54. The process according to claim 53, wherein the coupling agent is selected from l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), propylphosphonic anhydride (T3P), N,N'-dicyclohexylcarbodiimide (DCC) and (l-[Bis(dimethylamino)methylene]- lH- l,2,3- triazolo[4,5- ]pyridinium 3-oxid hexafluorophosphate) (HATU) or combination thereof.
55. A process for preparing compound of formula (la)
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof, the process comprising:
(i) reacting a compound of formula (1) with a compound of formula (2a) to afford the compound of formula (3)
Figure imgf000110_0002
(ii) reacting compound of formula (3) with compound of formula (5) to afford the compound of formula 4 and
Figure imgf000111_0001
in the compound of formula (4) to afford the compound of
Figure imgf000111_0002
wherein,
Ring A is
Figure imgf000111_0003
X1 is selected from CR3 and N;
Ring B is selected from phenyl, pyridyl and benzimidazolyl;
— L— : · , . , r ;— (CRxRy)Q0— ; j— 0(CRxRy)Q— ; , 1 2 y - is selected from l Z /£1 y , l Z yq y and i- 0(CRxRy)qC≡C^; . x, y and z represent point of attachment;
Rb is selected from hydrogen and Ci_8alkyl;
each occurrence of R is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, hydroxyCi-galkyl, C3_6cycloalkyl and 3 to 15 membered heterocyclyl;
R is selected from hydrogen and halogen;
R4 is selected from hydrogen and Ci_8alkyl;
each occurance of Rx and Ry, which may be same or different, are each independently selected from Ci_8alkyl aed haloCi_8alkyl; or Rx and Ry together with the carbon atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'n' is 0, 1, 2, 3 or 4; and
'q' is 1 or 2.
56. The process according to claim 55, wherein in step (i) the compound of formula (1) is reacted with a compound of formula (3) in the presence of a coupling agent.
57. The process according to claim 56, wherein the coupling agent is selected from l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), propylphosphonic anhydride (T3P), N,N'-dicyclohexylcarbodiimide (DCC) and (l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5- ]pyridinium 3-oxid hexafluorophosphate) (HATU) or combination thereof.
58. The process according to claim 55, wherein in step (c), the reduction of keto group in compound of formula (4) is carried out using sodium borohydride.
Ill
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WO2018193297A1 (en) 2017-04-21 2018-10-25 Cadila Healthcare Limited Novel compounds as ror-gamma modulators
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
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WO2013171729A2 (en) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator
WO2015087234A1 (en) * 2013-12-10 2015-06-18 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl indole analogues useful as ror gamma modulators

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WO2018042342A1 (en) * 2016-08-30 2018-03-08 Glenmark Pharmaceuticals S.A. 1,2,3-benzotriazole derivatives as ror gamma t modulators
WO2018193297A1 (en) 2017-04-21 2018-10-25 Cadila Healthcare Limited Novel compounds as ror-gamma modulators
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US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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