WO2015008234A1 - Bicyclic heterocyclic compounds as ror gamma modulators - Google Patents

Bicyclic heterocyclic compounds as ror gamma modulators Download PDF

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WO2015008234A1
WO2015008234A1 PCT/IB2014/063148 IB2014063148W WO2015008234A1 WO 2015008234 A1 WO2015008234 A1 WO 2015008234A1 IB 2014063148 W IB2014063148 W IB 2014063148W WO 2015008234 A1 WO2015008234 A1 WO 2015008234A1
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trifluoromethyl
thieno
mmol
chloro
methyl
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PCT/IB2014/063148
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French (fr)
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Sachin Sundarlal Chaudhari
Abraham Thomas
Sachin Vasantrao Dhone
Neelima Khairatkar-Joshi
Malini Bajpai
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Glenmark Pharmaceuticals S.A.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as modulator of retinoid-related orphan receptor gamma t (RORγt). These compounds prevent, inhibit, or suppress the action of RORγt and are therefore useful in the treatment of RORγt mediated disease, disorder, syndrome or condition such as pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, neurodegenerative diseases or cancer.

Description

BICYCLIC HETEROCYCLIC COMPOUNDS AS ROR GAMMA MODULATORS
Related Applications
This application claims the benefit of Indian Provisional Application No.
2395/MUM/2013 filed on Julyl7, 2013; which is hereby incorporated by reference in its entirety.
Technical Field
The present patent application is directed to bicyclic heterocyclic compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.
Background of the invention
Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor super family. The ROR family consists of three members, ROR alpha (RORa), ROR beta (RORP) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and each encoded by a separate gene RORA, RORB and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy, RORyl and RORyt (also known as RORy2) have been identified.
RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).
RORyt has been identified as a key regulator of Thl7 cell differentiation. Thl7 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines and have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl7 cells have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol, 2008, 9, 641-649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman et al., J. Exp. Med., 2008, 205: 1517-1522; Leung et al., Cell. Mol. Immunol, 2010 7: 182-189). Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al., Annu. Rev. Immunol, 2009, 27:485-517) and RORyt has been shown to play a critical role in the pathogenic responses of Thl7 cells (Ivanov et al., Cell, 2006 126: 1121-1133). RORyt deficient mice have shown no TM7 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-T 7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340). RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T- cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 31_: 331-341; Louten et al., J Allergy Clin. Immunol, 2009, 123 : 1004-1011), suggesting an important function for RORyt in these cells.
In view of the above, a need exists for therapeutic agents that could modulate the activity of RORyt and thus will open new methods for treating diseases or condition associated with the modulation of RORyt.
PCT publication numbers WO2012/139775, WO2012/027965, WO2012/028100, WO2012/100732, WO2012/100734, WO2012/064744 and WO2013/171729 disclose numerous heterocyclic compounds which are shown to be modulators of retinoid-related orphan receptor gamma (RORy) receptor activity. The present application is directed to compounds that may be modulators of the RORyt receptor. Thus in light of the role RORyt plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORyt activity, which can be used in the treatment of diseases mediated by RORyt.
Summary of the Invention
In one aspect, the present invention relates to compound of formula (I)
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof,
wherein,
Rin
Figure imgf000005_0002
Figure imgf000005_0003
Z is selected from CR1 and N;
X2 is selected from CH, CR4 and N;
Xx and X3 are each independently selected from CH, CR5 and N; M is C6-i4 aryl or 5- to 14- membered heteroaryl, each being optionally substituted with one or more R6;
L is selected from -C(O)-, -S(0)2- and -S(O)-; R1 is selected from hydrogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi-8alkyl, - C(0)OR9, -C(0) R7R8, -S(0)2 R7R8 and -C(0) HS(0)2R7;
R2 is selected from hydrogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi-8alkyl, - C(0)OR9, -C(0) R7R8, -S(0)2 R7R8 and -C(0) HS(0)2R7;
R3 is selected from hydrogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi-8alkyl, -
C(0)OR9, -C(0) R7R8, -S(0)2 R7R8 and -C(0) HS(0)2R7;
R4 is selected from cyano, halogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi. 8alkyl, haloCi-8alkoxy, hydroxyCi-8alkyl, -C(0)ORz, - RxRy, -C(0) RxRy, - S(0)2 RxRy, - HC(0)Rx and -C(0) HS(0)2Rx;
each occurrence of R5 is independently selected from cyano, halogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi-8alkyl, haloCi-8alkoxy, hydroxyCi-8alkyl, - C(0)ORz, - RxRy, -C(0) RxRy, -S(0)2 RxRy, - HC(0)Rx and -C(0) HS(0)2Rx; each occurrence of R6 is independently selected from cyano, halogen, hydroxy, Ci-8alkyl, Ci-8alkoxy, haloCi-8alkyl, haloCi-8alkoxy, hydroxyCi-8alkyl, - C(0)ORz, - RxRy, -C(0) RxRy, -S(0)2 RxRy, - HC(0)Rx and -C(0) HS(0)2Rx; each occurrence of R7 and R8 are independently selected from hydrogen, hydroxy, Ci-8alkyl, haloCi-8alkyl, hydroxyCi-8alkyl , C3-i2cycloalkyl and C6-i4 ryl; or R7 and R8 together with the common 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;
R9 is independently selected from hydrogen and Ci-8alkyl;
each occurrence of Rx and Ry are independently selected from hydrogen, hydroxy, Ci-8alkyl, haloCi-8alkyl, C3-i2cycloalkyl and C6-i4 ryl; or Rx and Ry together with the common 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; and
Rz is independently selected from hydrogen and Ci-8alkyl.
The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (la) and formula (lb), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein Z is CH or N (according to an embodiment defined below), L is -C(O)-
(according to another embodiment defined below) and R3 is hydrogen (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which Z is N.
According to another embodiment, specifically provided are compounds of formula (I), in which Z is CR1.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Z is CH or N.
According to yet another embodiment, specifically provided are compounds of
Figure imgf000007_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is hydrogen, Ci-salkyl (e.g. methyl or ethyl), -C(0)OR9 or - C(0) R7R8. In this embodiment R7 and R8 are independently selected from hydrogen, Ci-4alkyl (e.g. methyl or ethyl), hydroxyCi-salkyl (e.g. 2-hydroxy-ethyl) and C3- ocycloalkyl (e.g. cyclopropyl); or R7 and R8 together with the nitrogen atom to which they are attached, form a morpholine ring; and R9 is hydrogen or Ci-4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is -C(0)OR9. In this embodiment R9 is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R 2 is -C(0) R 7 R 8. In this embodiment R 7 and R 8 are each independently selected from hydrogen, methyl, cyclopropyl and 2-hydroxy-ethyl; or R7 and R8 together with the nitrogen atom to which they are attached, form a morpholine ring. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is methyl, methoxycarbonyl, dimethylcarbamoyl, 2-hydroxy- ethylcarbamoyl, cyclopropyl carbamoyl or morpholin-4-ylcarbonyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is CH3, -C(0)OCH3, -C(0)N(CH3)2, " or
Figure imgf000008_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 and X3 are independently selected from CH and CR5 and X2 is CR4.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 and X3 are independently selected from CH and CR5. In this embodiment R5 is halogen (e.g. fluoro, chloro or bromo).
According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 and X3 are independently selected from CH and CF.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is -C(0)ORz, -C(0) RxRy or -C(0) HS(0)2Rx In this embodiment, Rx and Ry are independently selected from hydrogen, hydroxyl, Ci-8alkyl (e.g. methyl or ethyl) and haloCi-8alkyl (e.g. trifluoromethyl); and Rz is hydrogen or Ci-4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is -C(0)ORz, -C(0) RxRy or -C(0) HS(0)2Rx. In this embodiment, Rx and Ry are independently selected from hydrogen, hydroxyl, methyl, ethyl and trifluoromethyl; and Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is -C(0)ORz. In this embodiment, Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, - C(0) HOH or -C(0) HS(0)2CF3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X2 is CR4. In this embodiment, R4 is -C(0)OH, -C(0)OCH3, - C(0)OCH2CH3; -C(0) H2, -C(0) HOH or -C(0) HS(0)2CF3. According to yet another embodiment, specifically provided are compounds of formula (I), in which L is -C(O)-.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is C6.14 aryl (e.g. phenyl), optionally substituted with one or more R6.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is phenyl optionally substituted with one or more R6.
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R6 is independently selected from halogen (e.g. fluoro, chloro or bromo), Ci-salkyl (e.g. methyl or ethyl) and haloCi-salkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R6 is independently selected from F, CI, Br, CH3 or CF3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is phenyl substituted with one or more R6. In this embodiment R6 is F, CI, Br, CH3 or CF3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is 2,6-dichlorophenyl, 2-chloro-6-trifluoromethylphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2- (trifluorom ethyl )phenyl, 2,3-dichlorophenyl, 2-chloro-3-(trifluoromethyl)phenyl, 3- fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 5-fluoro-2- (trifluorom ethyl )phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2-bromo-6-chlorophenyl or 2,6- bis-trifluoromethyl-phenyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which L-M is 2,6-dichlorobenzoyl, 2-chloro-6-trifluoromethyl- benzoyl, 2-chloro-6-fluorobenzoyl, 2-fluoro-6-(trifluoromethyl)benzoyl, 2,6- difluorobenzoyl, 2-(trifluorom ethyl )benzoyl, 2,3-dichlorobenzoyl, 2-chloro-3- (trifluoromethyl)benzoyl, 3-fluoro-5-(trifluoromethyl)benzoyl, 4-fluoro-2- (trifluorom ethyl )benzoyl, 5-fluoro-2-(trifluoromethyl)benzoyl, 4-Chloro-2- (trifluoromethyl)benzoyl, 5-chloro-2-(trifluoromethyl)benzoyl, 2-chloro-6- methylbenzoyl, 2-bromo-6-chlorobenzoyl or 2,6-bis-trifluoromethyl -benzoyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which
Figure imgf000010_0001
R2 is -CH3, -C(0)OCH3, -C(0)N(CH3)2, -CO HCH2CH2OH,
H or ^ ;
R3 is hydrogen;
R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, -C(0) HOH or - C(0) HS(0)2CF3.;
R5 is F; 'm' is 0 or 1 ; and
L-M is 2,6-dichlorobenzoyl, 2-chloro-6-trifluoromethyl-benzoyl, 2-chloro-6- fluorobenzoyl, 2-fluoro-6-(trifluoromethyl)benzoyl, 2,6-difluorobenzoyl, 2- (trifluorom ethyl )benzoyl, 2,3-dichlorobenzoyl, 2-chloro-3-(trifluoromethyl)benzoyl, 3-fluoro-5-(trifluoromethyl)benzoyl, 4-fluoro-2-(trifluoromethyl)benzoyl, 5-fluoro-2- (trifluoromethyl)benzoyl, 4-Chloro-2-(trifluoromethyl)benzoyl, 5-chloro-2- (trifluoromethyl)benzoyl, 2-chloro-6-methylbenzoyl, 2-bromo-6-chlorobenzoyl or 2,6-bis-trifluoromethyl -benzoyl.
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, Z, X1, X2, X3, L and M, (and groups defined therein) are described hereinafter in relation to the compounds of formula (la) and formula (lb). It is to be understood that these embodiments are not limited to use in conjunction with formula (la) or formula (lb), 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 (la) or formula (lb) in which R5 is F and consequently there is also provided a compound of formula (I) in which R5 is F.
The invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I). Accordingly the invention provides compound of formula (la)
Figure imgf000011_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
Z is selected from CR1 and N;
R1 is selected from hydrogen and Ci-8alkyl;
R2 is selected from hydrogen, Ci-8alkyl, -C(0)OR9, -C(0)N(CH3)2,
-CO HCH2CH2OH, H or ^0;
R3 is selected from hydrogen and Ci-8alkyl;
R4 is selected from -C(0)ORz, -C(0) RxRy and -C(0) HS(0)2Rx;
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
R9 is independently selected from hydrogen and Ci-8alkyl;
each occurrence of Rx and Ry are independently selected from hydrogen, hydroxy, Ci-8alkyl and haloCi-8alkyl;
Rz is independently selected from hydrogen and Ci-4alkyl;
'm' is an integer ranging from 0 to 2, both inclusive; and
'n' is an integer ranging from 0 to 5, both inclusive.
The compounds of formula (la) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (la) as defined above wherein, Z is CH or N (according to an embodiment defined below), R3 is hydrogen (according to another embodiment defined below), R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, - C(0) HOH or -C(0)NHS(0)2CF3 (according to yet another embodiment defined below) and 'n' is 1 or 2 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (la), in which Z is N.
According to another embodiment, specifically provided are compounds of formula (la), in which Z is CR1.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R1 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (la), in which Z is CH or N.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R2 is hydrogen, Ci-4alkyl (e.g. methyl or ethyl), -C(0)OR9, -
C(0)N(CH3)2, -CO HCH2CH2OH, H or
Figure imgf000012_0001
this embodiment R9 is hydrogen or Ci-4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which R2 is -C(0)OR9. In this embodiment R9 is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R2 is methyl, methoxycarbonyl, dimethylcarbamoyl, 2- hydroxy-ethylcarbamoyl, cyclopropylcarbamoyl or morpholin-4-ylcarbonyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in whi 2 is -CH3, -C(0)OCH3, -C(0)N(CH3)2, -CO HCH2CH2OH,
H or
Figure imgf000012_0002
and R3 is hydri
According to yet another embodiment, specifically provided are compounds of formula (la), in which R3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R4 is -C(0)ORz, -C(0) RxRy or -C(0) HS(0)2Rx. In this embodiment, Rx and Ry are independently selected from hydrogen, hydroxyl, Ci-8alkyl (e.g. methyl or ethyl) and haloCi-8alkyl (e.g. trifluoromethyl); and Rz is hydrogen or Ci-4alkyl (e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which R4 is -C(0)ORz, -C(0) RxRy or -C(0) HS(0)2Rx In this embodiment, Rx and Ry are independently selected from hydrogen, hydroxyl, methyl, ethyl and trifluoromethyl; and Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R4 is -C(0)ORz. In this embodiment Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, - C(0) HOH or -C(0) HS(0)2CF3.
According to yet another embodiment, specifically provided are compounds of formula (la), in which each occurrence of R5 is halogen (e.g. fluoro, chloro or bromo).
According to yet another embodiment, specifically provided are compounds of formula (la), in which R5 is F.
According to yet another embodiment, specifically provided are compounds of formula (la), in which 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R5 is F and 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (la), in which each occurrence of R6 is independently selected from halogen (e.g. fluoro, chloro or bromo), Ci-8alkyl (e.g. methyl or ethyl) and haloCi-8alkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which each occurrence of R6 is independently selected from F, CI, Br, CH3 or CF3.
According to yet another embodiment, specifically provided are compounds of formula (la), in which 'n' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which R6 is F, CI, Br, CH3 or CF3; and 'n' is 1 or 2. According to yet another embodiment, specifically provided are compounds of formula (la), in which
Figure imgf000014_0001
is 2,6-dichlorophenyl, 2-chloro-6- trifluoromethylphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2-(trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2-chloro-3- (trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-
(trifluoromethyl)phenyl, 5-fluoro-2-(trifluoromethyl)phenyl, 4-chloro-2-
(trifluorom ethyl )phenyl, 5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-6- methylphenyl, 2-bromo-6-chlorophenyl or 2, 6-bis-trifluorom ethyl -phenyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which
2 is -CH3, -C(0)OCH3, -C(0)N(CH3)2, -CO HCH2CH2OH,
Figure imgf000014_0002
; R is hydrogen;
R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, -C(0) HOH or - C(0) HS(0)2CF3; R5 is F;
each occurrence of R6 is independently selected from F, CI, Br, CH3 or CF3; 'm' is 0 or 1; and 'n' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which
Z is CH or N;
R2 is -CH3 or -C(0)N(CH3)2;
R3 is hydrogen;
R4 is -C(0)OH;
R5 is F;
' ' is 0 or 1; and
Figure imgf000014_0003
is 2,6-dichlorophenyl, 2-chloro-6-trifluoromethylphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2- (trifluorom ethyl )phenyl, 2,3-dichlorophenyl, 2-chloro-3-(trifluoromethyl)phenyl, 3- fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 5-fluoro-2- (trifluorom ethyl )phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2-bromo-6-chlorophenyl or 2,6- bis-trifluorom ethyl -phenyl. According to an embodiment, specifically provided are compounds of formula (la) 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 (lb), which is an embodiment of a compound of formula (I).
Accordingly the invention provides compound of formula (lb)
n
Figure imgf000015_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
R2 is selected from hydrogen and Ci-4alkyl;
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl, Ci-salkyl and haloCi-salkyl;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl, Ci-salkyl and haloCi-salkyl;
Rz is independently selected from hydrogen and Ci-4alkyl;
'm' is an integer ranging from 0 to 2, both inclusive; and
'n' is an integer ranging from 0 to 5, both inclusive.
The compounds of formula (lb) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (lb) as defined above wherein, R2 is methyl (according to an embodiment defined below), 'm' is 0 or 1 (according to another embodiment defined below) and 'n' is 1 or 2 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (lb), in which R2 is hydrogen or
Figure imgf000016_0001
(e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R2 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which each occurrence of R5 is halogen (e.g. fluoro, chloro or bromo).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R5 is F.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R5 is F and 'm' is 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R2 is CH3; R5 is F; and 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which each occurrence of R6 is independently selected from halogen (e.g. fluoro, chloro or bromo), Ci-8alkyl (e.g. methyl or ethyl) and haloCi-8alkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which each occurrence of R6 is independently selected from F, CI, Br, CH3 or CF3.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which 'n' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is F, CI, Br, CH3 or CF3; and 'n' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which
Figure imgf000016_0002
is 2,6-dichlorophenyl, 2-chloro-6- trifluoromethylphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2-(trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2-chloro-3- (trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-
(trifluoromethyl)phenyl, 5-fluoro-2-(trifluoromethyl)phenyl, 4-chloro-2- (trifluorom ethyl )phenyl, 5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-6- methylphenyl, 2-bromo-6-chlorophenyl or 2,6-bis-trifluoromethyl-phenyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Rz is hydrogen or
Figure imgf000017_0001
(e.g. methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which, Rz is hydrogen, methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which
R2 is methyl; R5 is F;
each occurrence of R6 is independently selected from F, CI, Br, CH3 or CF3; Rz is hydrogen, methyl or ethyl;
'm' is 0 or 1; and
'n' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which
2 is CH3; R5 is F; Rz is hydrogen; 'm' is 0 or 1; and
Figure imgf000017_0002
is 2,6-dichlorophenyl, 2-chloro-6-trifluoromethylphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2- (trifluorom ethyl )phenyl, 2,3-dichlorophenyl, 2-chloro-3 -(trifluorom ethyl)phenyl, 3- fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 5-fluoro-2- (trifluorom ethyl )phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2-bromo-6-chlorophenyl or 2,6- bis-trifluoromethyl-phenyl.
According to an embodiment, specifically provided are compounds of formula (lb) 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-
33.
It should be understood that the formulas (I), (la), and (lb), 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. As disclosed herein, esters of the compounds of present invention refer to a modified version or a precursor of a parent compound, designed to enhance the delivery properties and be converted to the parent compound in the body.
Ester of the compounds of present invention are entities structurally related to parent acidic drug compound (-COOH), which, after administration, release the parent drug in vivo as the result of some metabolic process, such as enzymatic or chemical hydrolysis of a susceptible functionality.
R4 is -COORz Ester (wherein Rz is Ci-4alkyl) of the compounds of present invention are entities structurally related to parent acidic drug compound (R4 is - COOH), which, after administration, release the parent drug in vivo as the result of some metabolic process, such as enzymatic or chemical hydrolysis of a susceptible functionality.
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 in the present patent application 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 capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt, which is believed to be related to a variety of disease states.
The present patent application further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
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-8alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n- butyl, n-pentyl, and 1,1 -dimethyl ethyl (t-butyl). The term "Ci-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term
Figure imgf000019_0001
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, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-ioalkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z'so-propenyl, 2-m ethyl- 1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C2-i0alkynyl). Non -limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci-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, substituted or unsubstituted.
The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci. 8alkoxyCi-8alkyl or Ci-8alkyloxyCi-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3 and -CH2OC2H5. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
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 moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted. 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, substituted or unsubstituted.
The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi-8alkyl). Examples of hydroxyalkyl moieties include, but are not limited to -CH2OH, -C2H4OH and -CH(OH)C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C3-6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group (i.e. C3-8cycloalkylCi. 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, cyclobutyl ethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, (i.e. C3- 8cycloalkenyl). Examples of "cycloalkenyl" include but are not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkenylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, (i.e. C3-8cycloalkenylCi-8alkyl). The cycloalkenylalkyl 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. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
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. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C6-i4aryloxy). Examples of aryloxy moieties include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i4arylCi-8alkyl, such as -CH2C6H5 and - C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamo holinyl 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 "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi-8alkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted 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. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. 5 to 14 membered heterarylCi-8alkyl). The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted. Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl alkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORx, - C(0)Rx', -C(S)RX', -C(0) RxRy', -C(0)ONRxRy', - RxCO RyRz, -N(Rx)SORy', - N(Rx,)S02Ry', -(=N-N(Rx)Ry), - RxC(0)ORy', -NRxRy, - RxC(0)Ry', - RxC(S)Ry', - Rx'C(S) Ry'Rz', -SONRxRy, -S02 Rx'Ry', -ORx', -OC(0) RyRz', -OC(0)ORy', - OC(0)Rx', -OC(0) RxRy', -SRX', -SORx', -S02Rx', and -ON02, wherein each occurrence of Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclyl alkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" can be unsubstituted alkenyl but cannot be "substituted alkenyl".
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, methyl sulfate, 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.
Pharmaceutical Compositions
The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises 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 composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration. The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
Methods of Treatment
Compounds of the present invention are particularly useful because they may inhibit the activity of Retinoid-related orphan receptor gamma {and particularly Retinoid-related orphan receptor gamma t (RORyt)}, i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit RORyt modulating effect. Compounds of the invention are thus useful in the treatment of those conditions in which inhibition of a ROR gamma activity, and particularly RORyt, is required.
The compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.
The term "autoimmune diseases" will be understood by those skilled in the art 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 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 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 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 such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
Other respiratory disorders include bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy, idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS, acute respiratory failure, mediastinitis.
The compounds of the present invention may 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 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 be used for treatment of gastrointestinal disorder such as 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 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 methods of treatment of the present patent application comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient (particularly a human) in need thereof.
The present patent application relates to the use of the compounds in the preparation of a medicament for the treatment of diseases mediated by RORyt. Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
Compounds of the present invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above- mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
General Methods of Preparation
The compounds, described herein, according to general formula (I), (la) and (lb) are prepared using techniques known to one skilled in the art of organic synthesis. Suitable synthetic methods are depicted in schemes 1 to 7. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, 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.
A general approach for the synthesis of compound of general formula (la) (wherein R2, R3, R4, R5, R6, 'm' and ' n' as defined with respect to a compound of formula (la)) is shown in scheme 1. Thus, heterocyclic derivative (1) on coupling with acid chloride of formula (2) in presence of a base such as triethylamine (TEA) or N,N- diisopropylethylamine (DIPEA) yields the iodo intermediate (3). The Suzuki coupling reaction of boronic acid of general formula (4) with Intermediate (3) affords the desired compound of general formula (la).
Synthetic scheme 1
Figure imgf000030_0001
A general approach for the synthesis of compound of general formula (Ic) and (Id) (wherein R5, R6, R7, R8, 'm' and ' n' as defined with respect to a compound of formula (la)) is depicted in scheme 2.
Synthetic scheme 2
Figure imgf000030_0002
Thus, methyl 5-methyl-4-nitrothiophene-2-carboxylate (5) is treated with N,N- dimethylformamide dimethyl acetal (DMF-DMA) followed by reduction to yield the cyclized thieno-pyrrole intermediate (6). Iodination (using N-iodosuccinimide) and hydrolysis (using lithium hydroxide) of Intermediate (6) gives acid (7). The coupling of amine of general formula (8) with acid (7) using suitable coupling reagent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1 -hydroxy benzotriazole (HOBt) in presence of a suitable base such as 4-dimethylaminopyridine (DMAP) yields Intermediate (9). Acid chloride of formula (2) is coupled with Intermediate (9) in presence of suitable base such as triethylamine (TEA) and DMAP to yield iodo intermediate (10) which on further Suzuki couplig reaction with boronic acid of general formula (4') (wherein Rz is
Figure imgf000031_0001
such as methyl or ethyl) affords the ester derivative (11). The ester hydrolysis of Intermediate (11) using base such as lithium hydroxide gives the final compound of general formula (Ic). The acid derivative of general formula (Ic) on treatment with hydroxylamine hydrochloride yields compound of general formula (Id).
A general approach for the synthesis of Intermediate (17) required for the synthesis of compounds of the present invention of general formula (Ie) is depicted in synthetic scheme 3. Thus, the nitration of 5-methylthiophene-2-carbaldehyde (12) using nitrating agent such as potassium nitrate gives Intermediate (13). Formyl group of Intermediate (13) is converted to methyl group using triethylsilane in presence of trifluoroacetic acid followed by reduction of nitro group to yield amino intermediate (14). Acetyl pyrazole intermediate (15) is obtained by treating Intermediate (14) with isobutyl nitrite and acetic anhydride in presence of a base such as potassium acetate. Deacetylation of Intermediate (15) followed by iodination using iodine in presence of methanol affords Intermediate (16). Acid chloride of general formula (2) is then coupled with pyrazole derivative (16) in presence of base such as triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) and DMAP to yield the amide compound (17).
Synthetic scheme 3 l nitrite, Ac20
Ac
Figure imgf000032_0001
A general approach for the synthesis of compound of general formula (Ie) and (If) (wherein R5, R6, Rx, 'm' and ' n' as defined with respect to compound of formula (la)) is depicted in scheme 4. Thus, Intermediate (17) is coupled with boronic acid of general formula (4') (wherein Rz is
Figure imgf000032_0002
under the Suzuki reaction conditions to yield Intermediate (18). Lithium hydroxide mediated hydrolysis of the ester group of Intermediate (18) gives final compound of general formula (Ie). Alternatively, compound of the general formula (Ie) can also be prepared by the Suzuki coupling reaction of iodo Intermediate (17) with boronic acid of general formula (19) followed by oxidation of the formyl group of Intermediate (20) using reagent such as sodium chlorite and sulfamic acid. The compound (Ie) is coupled with sulfonamide derivative (21) using activating agent such as N,N-dicyclohexylcarbodiimide (DCC) and a base such as DMAP to yield compound of general formula (If).
Synthetic scheme 4
Figure imgf000032_0003
(If)
A general approach for the synthesis of compound of general formula (Ig) (wherein R5, R6, R7, R8, 'm' and ' n' as defined with respect to a compound of formula (la)) is depicted in scheme 5. Thus, thiophene ester (22) is subjected to reduction followed by reaction with isobutyl nitrite and acetic anhydride in the presence of a base such as potassium acetate to yield thieno-pyrazole derivative (23). Deacetylation and iodination of Intermediate (23) yields iodo compound of formula (24). The ester hydrolysis followed by coupling of the acid thus obtained with amine of general formula (8) affords Intermediate of formula (25). Pyrazole of intermediate (25) is coupled with acid chloride of general formula (2) in the presence of a base to give Intermediate (26). The Suzuki coupling reaction of Intermediate (26) with boronic acid of general formula (4') (wherein Rz is
Figure imgf000033_0001
followed by lithium hydroxide mediated ester hydrolysis yields the desired compound of general formula (lg).
Synthetic scheme 5
Figure imgf000033_0002
A general approach for the synthesis of compound of general formula (I) (wherein Ring A, Z, X1, X2, X3, L and M as defined with respect to a compound of formula (I)) is shown in scheme 6.
Synthetic scheme 6
Figure imgf000033_0003
(28)
A heterocyclic compound of formula (28) on reaction with an acid chloride compound of formula (29) (wherein Lg is CI) in a suitable solvent such as dimethylformamide (DMF) or dichloromethane (DCM) in the presence of a suitable base such as N,N- diisoporpylethylamine (DIPEA) or triethylamine (TEA) and optionally in the presence of DMAP can provide the compound of formula (I).
A general approach for the synthesis of compound of general formula (la) (wherein R2, R3, R4, R5, R6, 'm' and ' n' as defined with respect to a compound of formula (la)) is shown in scheme 7.
Synthetic scheme 7
Figure imgf000034_0001
The process for the preparation of compound of formula (la) or a pharmaceutically acceptable salt thereof which comprises:
reacting a compound of formula (1) with a compound of formula (2) to obtain a compound of formula (3); reacting the compound of formula (3) with compound of formula (4); and optionally converting the compound of formula (la) to a pharmaceutically acceptable salt thereof.
The compound of formula (1) is reacted with compound of formula (2) in the presence of a suitable base. The suitable base may be selected from Et3N and DIPEA. The reaction may also optionally carried out in the presence of DMAP. The reaction may be carried out in a suitable solvent or mixture thereof. The suitable solvent may be selected from DCM and DMF or combination thereof. The compound of formula (3) is reacted with the compound formula (4) in the presence of suitable catalyst for example a suitable palladium catalyst such as [1, 1 - bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl2). The reaction may be carried out in the presence of a suitable base such as potassium acetate in a suitable solvent such as dioxane.
Experimental
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 sulphate, 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 application have the following meanings: DCC: N,N-dicyclohexylcarbodiimide; MDC or DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMSO-i¾:
Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethyl formamide; EDCI: l-ethyl-3-(3- dimethylaminopropyl)carbodiimide; EDCI.HC1: l-ethyl-3-(3- dimethylaminopropyl)carbodiimide.Hydrochloride; HOBt: hydroxybenzotriazole; BOP: benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate; Pd(dppf)Cl2: [l, l '-bis(diphenylphosphino)ferrocene]dichloropalladium (II); HC1: Hydrochloric acid; H2S04: Sulfuric acid; DIPEA: Diisopropyl ethyl amine; Et3N or TEA: Triethylamine; THF: Tetrahydofuran; TFA: Trifluoroacetic acid; LiOH. H20: Lithium hydroxide monohydrate; Na2S04: Sodium sulfate; 1H MR: Proton Nuclear Magnetic Resonance; J: Coupling constant in units of Hz; RT or rt: Room temperature (22-26°C); e.g. : for example; min/mins: minute(s); h: hour(s); APCI-MS: Atmospheric Pressure Chemical Ionization Mass Spectrometry; Pd: Palladium; MHz: Megahertz.
Preparation of Intermediates
Intermediate 1
Methyl 4-[(2,6-dichlorophenyl)carbonyl]-6-iodo-4H-thieno[3,2-^]pyrrole-2- carboxylate
Figure imgf000035_0001
Step 1 : Methyl 5-methyl-4-nitrothiophene-2-carboxylate:
To a stirred and cooled (0 °C) solution of methyl 5-methylthiophene-2-carboxylate (5.0 g, 32.010 mmol) in cone. H2S04 (30 ml) was added fuming nitric acid (1.41 ml, 33.616 mmol) and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured slowly on crushed ice and precipitate thus obtained was filtered and washed with water. The compound obtained after drying was purified by silica gel column chromatography to yield 2.90 g of the title product as white solid. ESI-MS (m/z) 200 (M-H)+.
Step 2: Methyl 5-[(£)-2-(dimethylamino)ethenyl]-4-nitrothiophene-2-carboxylate: The Step 1 intermediate (2.90 g, 14.427 mmol) was treated with N,N- dimethylformamide dimethyl acetal (15 ml) at 1 10 °C for lh. After the completion of the reaction, the reaction mixture was distilled under reduced pressure to result a viscous residue. The residue obtained was diluted with ethyl acetate (300 ml) and water (100 ml). The organic layer was separated, washed with water (2 x 100 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 3.50 g of the title product as yellow solid. The obtained product was as such carried forward to the next step. APCI-MS (m/z) 257 (M+H)+.
Step 3 : Methyl 4H-thieno[3,2-£]pyrrole-2-carboxylate:
To a stirred solution of Step 2 intermediate (3.40 g, 1.328 mmol) in a mixture of THF (25 ml) and acetic acid (4 ml) was added catalytic amount of palladium on carbon and the reaction mixture was stirred under hydrogen atmosphere (50 psi) for 3 h. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 1.50 g of the title product as pale yellow liquid. 1H MR (300 MHz, DMSO-i¾) δ 3.79 (s, 3H), 6.43 (s, 1H), 7.34 (s, 1H), 7.69 (s, 1H), 1 1.49 (br s, 1H); ESI-MS (m/z) 182 (M+H)+.
Step 4: Methyl 6-iodo-4H-thieno[3,2-£]pyrrole-2-carboxylate:
To a stirred solution of Step 3 intermediate (1.50 g, 8.274 mmol) in THF (25 ml) was added N-iodosuccinimide (2.0 g, 9.101 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (100 ml) followed by brine (50 ml). The solution was dried over sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 2.1 g of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.81 (s, 3H), 7.48 (s, 1H), 7.82 (s, 1H), 1 1.88 (br s, 1H); APCI-MS (m/z) 305 (M-H)+.
Step 5 : Methyl 4-[(2,6-dichlorophenyl)carbonyl]-6-iodo-4H-thieno[3,2-^]pyrrole-2- carboxylate: To a stirred and cooled (0 °C) solution of step 4 intermediate (500 mg, 1.628 mmol) in THF (5 ml) were added DMAP (199 mg, 1.628 mmol) and TEA (0.45 ml, 3.256 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride in THF (5 mL). [The required 2,6-Dichlorobenzoyl chloride was prepared separately by refluxing 2,6- dichlorobenzoic acid (622 mg, 3.256 mmol) with excess thionyl chloride in THF (5 mL) for 2h]. The reaction mixture was stirred at room temperature for 16 h. The reaction mass was diluted with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (100 ml) and brine (50 ml). The solution was dried over anhydrous Na2S04 and filtered. The solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to afford 700 mg of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.88 (s, 3H), 7.71 (s, 3H), 7.84 (s, 1H), 8.29 (s, 1H); APCI- MS (m/z) 480 (M)+.
Intermediate 2
4-[(2,6-Dichlorophenyl)carbonyl]-6-iodo-N,N-dimethyl-4H-thieno[3,2-^]pyrrole-2- carboxamide:
Figure imgf000037_0001
Step 1 : 6-Iodo-4H-thieno[3,2-£]pyrrole-2-carboxylic acid:
To a stirred solution of methyl 6-iodo-4H-thieno[3,2-£]pyrrole-2-carboxylate (500 mg, 1.628 mmol) in THF (15 ml) was added a solution of lithium hydroxide monohydrate (203 mg, 4.884 mmol) in a mixture of methanol (3 ml) and water (3 ml) and refluxed for 2h. The solvent was distilled off under reduced pressure and the residue obtained was diluted with water (50 ml). The solid was precipitated out after acidification with IN HCl, which was filtered, washed with water and dried to afford 200 mg of the title product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 7.43 (s, 1H), 7.74 (s, 1H), 11.96 (br s, 1H), 12.85 (br s, 1H); APCI-MS (m/z) 291 (M-H)+. Step 2: 6-Iodo-N,N-dimethyl-4H-thieno[3,2-^]pyrrole-2-carboxamide:
To a stirred solution of Step 1 intermediate (175 mg, 0.599 mmol) in dichloromethane (5 ml) were added EDC.HC1 (137 mg, 0.716 mmol), HOBt (97 mg, 0.716 mmol) and DMAP (110 mg, 0.895 mmol). After 30 minutes, N,N- dimethylamine (59 mg, 0.716 mmol) was added to the reaction mixture and further stirred at RT for 16 h. The reaction mass was diluted with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (100 ml), brine (50 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and the residue obtained was purified by column chromatography to afford 80 mg of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.11 (s, 6H), 7.33 (s, 1H), 7.51 (s, 1H), 11.65 (s, 1H); APCI-MS (m/z) 321 (M+H)+.
Step 3 : 4-[(2,6-Dichlorophenyl)carbonyl]-6-iodo-N,N-dimethyl-4H-thieno[3,2- £]pyrrole-2-carboxamide:
The title compound was synthesized by reacting the Step 2 intermediate (80 mg, 0.249 mmol) with 2,6-dichlorobenzoyl chloride (prepared from 2,6-dichlorobenzoic acid (95 mg, 0.499 mmol) and thionyl chloride) in presence of DMAP (31 mg, 0.249 mmol) and TEA (0.70 mL, 0.798 mmol) in THF (5 ml) as per the process described in step 5 of Intermediate 1 to yield 80 mg of the product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.18 (br s, 6H), 7.49 (s, 1H), 7.70-7.80 (m, 3H), 8.087 (s, 1H); APCI-MS (m/z) 493 (M+H)+.
Intermediate 3
4-{ [2-Chloro-6-(trifluoromethyl)phenyl]carbonyl } -6-iodo-N,N-dimethyl-4H- thieno[3,2-b]pyrrole-2-carboxamide
Figure imgf000038_0001
The title compound was synthesized by reacting 6-iodo-N,N-dimethyl-4H-thieno[3,2- ]pyrrole-2-carboxamide (300 mg, 0.937 mmol) with 2-chloro-6- (trifluoromethyl)benzoyl chloride (prepared from 2-chloro-6-(trifluoromethyl)benzoic acid (421 mg, 1.874 mmol) and thionyl chloride) in presence of DMAP (114 mg, 0.937 mmol) and TEA (0.26 ml, 1.87 mmol) in THF (10 ml) as per the process described in step 5 of Intermediate 1 to yield 340 mg of the product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.18 (br s, 6H), 7.51 (s, 1H), 7.85-7.91 (m, 1H), 7.98-8.15 (m, 3H); APCI-MS (m/z) 527 (M+H)+.
Intermediate 4
l-[(2,6-Dichlorophenyl)carbonyl]-3-iodo-N,N-dimethyl-lH-thieno[3,2-c]pyrazole-5- carboxamide
Figure imgf000039_0001
Step 1 : Methyl -4-amino-5-methylthiophene-2-carboxylate:
The title compound was prepared by hydrogenation of methyl 5-methyl-4- nitrothiophene-2-carboxylate (8 g, 39.80 mmol) in ethyl acetate (150 ml) in the presence of catalytic amount of palladium on carbon under 50 psi of hydrogen pressure at room temperature. The reaction mixture was filtered and removed the solvent under reduced pressure to yield 6.7 g of the product as off-white solid. 1H NMR (300 MHz, CDC13) δ 2.25 (s, 3H), 3.00 (s, 2H), 3.83 (s, 3H), APCI-MS (m/z) 172 (M+H)+.
Step 2: Methyl l-acetyl-lH-thieno[3,2-c]pyrazole-5-carboxylate:
To a stirred solution of Step 1 intermediate (1.0 g, 5.847 mmol) in toluene (15 ml) was added acetic anhydride (2.3 ml, 23.338 mmol) followed by potassium acetate (287 mg, 2.923 mmol) and the reaction mixture was heated at 100 °C for 3h. The reaction mixture was cooled to room temperature and isobutyl nitrite (2 ml, 17.541 mmol) was added. The reaction mixture was slowly heated to 100 °C and further stirred for 16 h at the same temperature. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 150 ml) and the combined organic layer was washed with water (2 x 100 ml) followed by brine (100 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 710 mg of the title product as white solid. 1H NMR (300 MHz, CDC13) δ 2.75 (s, 3H), 3.95 (s, 3H), 7.94 (s, 1H), 8.22 (s, 1H) .
Step 3 : Methyl 3-iodo-lH-thieno[3,2-c]pyrazole-5-carboxylate:
The deacetylation of Step 2 intermediate (700 mg, 3.121 mmol) was carried out using 25% solution of sodium methoxide in methanol (15 ml) followed by iodination using iodine (950 mg, 3.745 mmol) in DMF (2 mL) and methanol (20 mL) at 60 °C. The solvent was removed under reduced pressure and diluted the residue with ethyl acetate (50 mL). The organic mixture was washed with water (25 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography to afford 800 mg of the title compound as light yellow solid. 1H NMR (300 MHz, CDC13) δ 3.94 (s, 3H), 7.83 (s, 1H), 11.45 (br s, 1H); APCI-MS (m/z) 309 (M+H)+.
Step 4: Methyl l-[(2,6-dichlorophenyl)carbonyl]-3-iodo-lH-thieno[3,2-c]pyrazole-5- carboxylate
The title compound was synthesized by reacting the Step 3 intermediate (300 mg, 0.973 mmol) with 2,6-dichlorobenzoyl chloride (prepared from 2,6-dichlorobenzoic acid (372 mg, 1.947 mmol) and thionyl chloride) in presence of DMAP (119 mg, 0.973 mmol) and TEA (0.27 ml, 1.94 mmol) in THF (10 ml) as per the process described in step 5 of Intermediate 1 to yield 425 mg of the product as off white solid. 1H NMR (300 MHz, CDC13) δ 3.98 (s, 3H), 7.41 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H); APCI-MS (m/z) 481 (M+H)+.
Step 5: l-[(2,6-Dichlorophenyl)carbonyl]-3-iodo-N,N-dimethyl-lH-thieno[3,2- c] pyrazol e- 5 -carb oxami de
The title compound was synthesized by ester hydrolysis of Step 4 intermediate (400 mg, 0.831 mmol) with lithium hydroxide (138 mg, 3.325 mmol) in water (3 mL) and THF (10 mL) to yield the corresponding carboxylic acid (350 mg, 0.749 mmol) which was reacted with N,N-dimethylamine hydrochloride (73 mg, 0.899 mmol) in presence of EDC.HC1 (172 mg, 0.898 mmol), HOBt (121 mg, 0.898 mmol) and DMAP (183 mg, 1.498 mmol) in DCM (15 mL) as per the process described in step 2 of Intermediate 2 to yield 250 mg of the product as off white solid. 1H NMR (300 MHz, CDCI3) δ 3.26 (br s, 6H), 7.41 (s, 3H), 7.96 (s, 1H); APCI-MS (m/z) 494 (M+H)+.
Intermediate 5
l-{[2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-3-iodo-lH-thieno[3,2-c]pyrazole- 5-carboxylic acid
Figure imgf000040_0001
The title compound was synthesized by reacting methyl 3-iodo-lH-thieno[3,2- c]pyrazole-5-carboxylate (1.0 g, 3.246 mmol) with 2-chloro-6- (trifluoromethyl)benzoyl chloride (799 iL, 4.220 mmol) in presence of DMAP (396 mg, 3.246 mmol) and TEA (0.91 mL, 6.492 mmol) in THF (20 ml) to get the corresponding methyl ester of N-benzoyl derivative (300 mg, 0.583 mmol) which on hydrolysis with lithium hydroxide (97 mg, 2.33 mmol) in THF (10 mL) and water (10 mL) yielded 310 mg of the product as off white solid. APCI-MS (m/z) 501 (M+H)+.
Intermediate 6
(2,6-Dichlorophenyl)(3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000041_0001
Step 1 : 5-Methyl-4-nitrothiophene-2-carbaldehyde:
To a stirred and cooled (0 °C) solution of 5-methyl-2-thiophene carboxaldehyde (8.5 ml, 79.251 mmol) in cone. H2SO4 (50 ml) was added potassium nitrate (16 g, 158.50 mmol) and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with ice water and precipitate thus obtained was filtered and washed with water. The compound was purified with silica gel column chromatography to yield 12 g of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.84 (s, 3H), 8.52 (s, 1H), 9.88 (s, 1H), APCI-MS (m/z) 186 (M+H)+.
Step 2: 2,5-Dimethyl-3-nitrothiophene:
To a stirred and cooled (-10 °C) mixture of TFA (50 ml) and triethylsilane (19 ml, 122.80 mmol) was added 5-methyl-4-nitrothiophene-2-carbaldehyde (6.0 g, 35.087 mmol) portion wise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (250 ml) and extracted with ethyl acetate (3 x 250 ml). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution (400 ml) followed by brine (250 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to yield 3.60 g of the title product as off-white solid. 1H NMR (300 MHz, CDC13) δ 2.40 (s, 3H), 2.71 (s, 3H), 7.23 (s, 1H)
Step 3 : 2,5-Dimethylthiophen-3-amine:
The title compound was synthesized form catalytic hydrogenation of 2,5-dimethyl-3- nitrothiophene (1 g, 6.361 mmol) in ethyl acetate (50 mL) as per the process discussed in Step 1 of Intermediate 4 to yield 375 mg of the product as colorless oil. 1H NMR (300 MHz, DMSO-i¾) δ 2.02 (s, 3H), 2.23 (s, 3H), 4.34 (br s, 2H), 6.19 (s, 1H); APCI-MS (m/z) 128 (M+H)+. Step 4: l-(5-Methyl-lH-thieno[3,2-c]pyrazol-l-yl)ethanone:
The title compound was prepared by diazotization, acetylation followed by cyclization of Step 3 intermediate (350 mg, 2.75 mmol) with acetic anhydride (1.1 ml, 1 1.023 mmol), potassium acetate (133 mg, 1.377 mmol) and isobutyl nitrite (0.97 ml, 8.26 mmol) in toluene (10 ml) as described in the process of Step 2 of Intermediate 4 to yield 60 mg of the product as viscous liquid. 1H NMR (300 MHz, DMSO-<f6) δ 2.57 (s, 3H), 2.65 (s, 3H), 7.28 (s, 1H), 8.09 (s, 1H), APCI-MS (m/z) 180 (M+H)+. Step 5 : 3-Iodo-5-methyl-lH-thieno[3,2-c]pyrazole:
To a stirred solution of Step 4 intermediate (60 mg, 0.332 mmol) in methanol (5 ml) was added 25% solution of sodium methoxide in methanol (5 ml) and the reaction mixture was heated at 60 °C. After 20 minutes, the reaction mixture was cooled to room temperature followed by addition of iodine (1.65 g, 6.252 mmol) solution in methanol (2 mL) and it was further stirred at 60 °C for lh. The solvent was distilled off under reduced pressure and the residue obtained was diluted with ethyl acetate (250 ml) and water (100 ml). The organic layer was separated and washed with water (2 x 50 ml) followed by brine (50 ml). The solution was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 65 mg of the title product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.50 (s, 3H), 6.98 (s, 1H), 13.21 (br s, 1H); APCI-MS (m/z) 264 (M+H)+.
Step 6 : (2,6-Dichlorophenyl)(3 -iodo-5-m ethyl- lH-thieno[3 ,2-c]pyrazol- 1 - yl)methanone:
The title compound was prepared by reacting the Step 5 intermediate (60 mg, 0.227 mmol) with 2,6-dichlorobenzoyl chloride (prepared from 2,6-dichlorobenzoic acid (87 mg, 0.454 mmol) and thionyl chloride) in presence of DMAP (28 mg, 0.227 mmol) and TEA (0.06 ml, 0.454 mmol) in THF (5 ml) as per the process described in step 5 of Intermediate 1 to yield 100 mg of the product as off-white solid. 1H NMR (300 MHz, CDC13) δ 2.64 (s, 3H), 7.34-7.39 (m, 4H); APCI-MS (m/z) 438 (M+H)+.
Intermediate 7
(2-Chloro-6-fluorophenyl)(3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000043_0001
The title compound was prepared by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (125 mg, 0.473 mmol) with 2-chloro-6-fluoro-benzoyl chloride (prepared from 2-chloro-6-fluoro benzoic acid (165 mg, 0.946 mmol) and thionyl chloride) in presence of DMAP (58 mg, 0.473 mmol) and TEA (0.09 mL, 0.946 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 150 mg of the product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.65 (s, 3H), 7.46-7.56 (m, 3H), 7.66-7.71 (m, 1H); APCI-MS (m/z) 420 (M+H)+.
Intermediate 8
[2-Chloro-6-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000043_0002
To a stirred and cooled (0 °C) solution of 3-iodo-5-methyl-lH-thieno[3,2-c]pyrazole (125 mg, 0.473 mmol) in THF (5 ml) were added DMAP (58 mg, 0.473 mmol) and TEA (0.14 ml, 0.946 mmol) followed by a solution of 2-chloro-(6-trifluoromethyl)- benzoyl chloride in THF (5 mL). [The required 2-chloro-(6-trifluoromethyl)-benzoyl chloride was prepared separately by refluxing 2-chloro-(6-trifluoromethyl)-benzoic acid (622 mg, 3.256 mmol) with excess thionyl chloride in THF (5 mL) for 2h] . The reaction mixture was stirred at room temperature for 16 h. The reaction mass was diluted with water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic layer was washed with water (20 ml) and brine (20 ml). The solution was dried over anhydrous Na2S04 and filtered. The solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to yield
135 mg of the title product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.65 (s, 3H), 7.59 (s, 1H), 7.83-7.88 (m, 1H), 7.96-8.03 (m, 2H); APCI-MS (m/z) 470 (M+H)+.
Intermediate 9 [2-Fluoro-6-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000044_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (125 mg, 0.473 mmol) with 2-fluoro-6-(trifluoromethyl) benzoyl chloride (prepared from 2-fluoro-6-(trifluoromethyl) benzoic acid (198 mg, 0.946 mmol) and thionyl chloride) in presence of DMAP (58 mg, 0.473 mmol) and TEA (0.13 mL, 0.946 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 180 mg of the product as white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.65 (s 3H), 7.58 (s, 1H), 7.81 -7.87 (m, 2H), 7.89-7.95 (m, 1H); APCI-MS (m/z) 454 (M)+.
Intermediate 10
(2,6-Difluorophenyl)(3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000044_0002
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 2,6-difluorophenyl benzoyl chloride (prepared from 2,6-difluorophenyl benzoic acid (120 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.578 mmol) and TEA (106 μί, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 170 mg of the product as off white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.64 (s, 3H), 7.36 (t, J = 8.4 Hz, 2H), 7.45-7.55 (m, 1H), 7.73-7.77 (m, 1H); APCI-MS (m/z) 436 (M+H)+.
Intermediate 1 1
(3-Iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)[2-(trifluoromethyl) phenyl] methanone
Figure imgf000044_0003
The title compound was synthesized by coupling 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazol (100 mg, 0.378 mmol) with 2-(trifluoromethyl) benzoyl chloride (prepared from 2-(trifluoromethyl) benzoic acid (144 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μί, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 160 mg of product as white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.64 (s, 3H), 7.50 (s, 1 7.84-7.87 (m, 3H), 7.90-7.95 (m, 1H); APCI-MS (m/z) 404 (M+H)+.
Intermediate 12
(2,3-Dichlorophenyl)(3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000045_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 2,3-dichlorobenzoyl chloride (prepared from 2,3-dichlorobenzoic acid (145 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μί, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 140 mg of the product as off white solid; 1H NMR (300 MHz, DMSO-i¾) δ 2.64 (s, 3H), 7.53-7.58 (m, 2H), 7.73- 7.75 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H); APCI-MS (m/z) 437 (M+H)+.
Intermediate 13
[2-Chloro-3-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000045_0002
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 2-chloro-3-(trifluoromethyl)benzoyl chloride (prepared from 2-chloro-3-(trifluoromethyl)benzoic acid (170 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ^, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 140 mg of the product as off white solid; 1H NMR (300 MHz, DMSO-i¾) δ 2.64 (s, 3H), 7.55 (br s, 1H), 7.76-7.78 (m, 1H), 8.08-8.10 (m, 2H); APCI-MS (m/z) 470 (M+H)+.
Intermediate 14
[3-Fluoro-5-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000046_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1 15.4 mg, 0.757 mmol) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ., 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 150 mg of the product as off white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.64 (s, 3H), 7.51 (s, 1H), 8.07-8.09 (m, 1H), 8.16-8.20 (m, 2H); APCI-MS (m/z) 454 (M)+.
Intermediate 15
[4-Fluoro-2-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000046_0002
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 4-fluoro-2-(trifluoromethyl)benzoyl chloride (prepared from 4-fluoro-2-(trifluoromethyl)benzoic acid (157 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ^, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 165 mg of the product as off white solid; 1H NMR (300 MHz, DMSO-i¾) δ 2.63 (s, 3H), 7.50 (br s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.90-7.97 (m, 2H); APCI-MS (m/z) 454 (M)+.
Intermediate 16
[5-Fluoro-2-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000047_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 5-fluoro-2-(trifluoromethyl)benzoyl chloride (prepared from 5-fluoro-2-(trifluoromethyl)benzoic acid (158 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ^, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 140 mg of the product as off white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.64 (s, 3H), 7.54 (br s, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 8.01 - 8.06 (m, 1H); APCI-MS (m/z) 454 (M)+.
Intermediate 17
[4-Chloro-2-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000047_0002
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 4-chloro-2-(trifluoromethyl)benzoyl chloride (prepared from 4-chloro-2-(trifluoromethyl)benzoic acid (170 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ^, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 160 mg of the product as off white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.63 (s, 3H), 7.51 (br s, 1H), 7.91-7.99 (m, 2H), 8.09 (s, 1H); APCI-MS (m/z) 471 (M+H)+.
Intermediate 18
[5-Chloro-2-(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000047_0003
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 5-chloro-2-(trifluoromethyl)benzoyl chloride (prepared from 5-chloro-2-(trifluoromethyl)benzoic acid (170 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μΐ^, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 110 mg of the product as white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.64 (s, 3H), 7.54 (br s, 1H), 7.93-7.99 (m, 2H), 8.11 (s, 1H); APCI-MS (m/z) 470 (M+H)+.
Intermediate 19
(2-Chloro-6-methylphenyl)(3-iod -5-methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000048_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 2-chloro-6-methylbenzoyl chloride (prepared from 2-chloro-6-methylbenzoic acid (129 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μί, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 100 mg of the product as off white solid; 1H NMR (300 MHz, CDC13) δ 2.25 (s, 3H), 2.64 (s, 3H), 7.16 (d, J = 6.6 Hz, 1H), 7.27-7.32 (m, 2H), 7.51 (s, 1H); APCI-MS (m/z) All (M+H)+.
Intermediate 20
(2-Bromo-6-chlorophenyl)(3-iodo- -methyl-lH-thieno[3,2-c]pyrazol-l-yl)methanone
Figure imgf000048_0002
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (100 mg, 0.378 mmol) with 2-bromo-6-chlorolbenzoyl chloride (prepared from 2-bromo-6-chlorolbenzoic acid (178 mg, 0.757 mmol) and thionyl chloride) in presence of DMAP (46 mg, 0.378 mmol) and TEA (106 μί, 0.756 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 100 mg of the product as off white solid; 1H NMR (300 MHz, CDC13) δ 2.64 (s, 3H), 7.27-7.42 (m, 1H), 7.42-7.44 (m, 1H), 7.51-7.56 (m, 2H); APCI-MS (m/z) 482 (M+H)+. Intermediate 21
[2,6-Bis(trifluoromethyl)phenyl](3-iodo-5-methyl-lH-thieno[3,2-c]pyrazol-l- yl)methanone
Figure imgf000049_0001
The title compound was synthesized by reacting 3-iodo-5-methyl-lH-thieno[3,2- cjpyrazole (200 mg, 0.757 mmol) with 2,6-bis(trifluoromethyl)benzoyl chloride (prepared from 2,6-bis(trifluoromethyl)benzoic acid (293 mg, 1.136 mmol) and thionyl chloride) in presence of DMAP (93 mg, 0.757 mmol) and TEA (213 μΐ^, 1.514 mmol) in THF (5 mL) as per the process described in step 5 of Intermediate 1 to yield 225 mg of the product as white solid; 1H MR (300 MHz, CDC13) δ 2.64 (s, 3H), 7.48 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.96-7.99 (m, 2H); APCI-MS (m/z) 505 (M)+.
Examples
The following examples illustrate the present invention. However, these examples are not intended to limit the scope of the present invention. The person skilled in the art can readily recognize a variety of non-critical parameters which can be modified or altered to yield similar results.
Example 1
Methyl 6-(4-carbamoylphenyl)-4-[(2,6-dichlorophenyl)carbonyl]-4H-thieno[3,2- £]pyrrole-2-carboxylate
Figure imgf000049_0002
To a stirred and degassed solution of the Intermediate 1 (160 mg, 0.208 mmol) in dioxane (5 ml) were added 4-carbamoyl phenyl boronic acid (52 mg, 0.312 mmol), [l,l '-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl2) (17 mg, 0.020 mmol) and aqueous potassium acetate solution (61 mg, 0.624 mmol). The dark brown suspension was heated at 90-100 °C under nitrogen atmosphere for 3 h. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (100 ml), brine (50 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and the residue obtained was purified by column chromatography to afford 65 mg of the title product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 3.92 (s, 3H), 7.44 (br s, 1H), 7.75 (s, 2H), 7.85 (t, J= 7.2 Hz, 3H), 7.94-8.01 (m, 3H), 8.06- 8.1 1 (m, 1H), 8.13 (s, 1H); APCI-MS (m/z) 473 (M+H)+.
Example 2
4-{4-[(2,6-Dichlorophenyl)carbonyl]-2-(dimethylcarbamoyl)-4H-thieno[3,2-^] pyrrol - 6-yl}benzoic acid
Figure imgf000050_0001
Step 1 : Methyl 4-[4-(2,6-dichloro-benzoyl)-2-dimethylcarbamoyl-4H-thieno[3,2- b]pyrrol-6-yl]-benzoate
The title compound was prepared by the Suzuki coupling of Intermediate 2 (90 mg, 0.182 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (49 mg, 0.273 mmol) in presence of Pd(dppf)Cl2 (15 mg, 0.018 mmol) and potassium acetate (54 mg, 0.546 mmol) in dioxane (5 mL) and water (1 mL) as per the process described for the synthesis of Example 1 to yield 65 mg of the title compound as white solid. 1H NMR (300 MHz, CDC13) δ 3.32 (br s, 6H), 3.93 (s, 3H), 7.09 (s, 1H), 7.50 (s, 3H), 7.66 (d, J = 8.7 Hz, 2H), 8.06-8.12 (m, 3H); APCI-MS (m/z) 501 (M)+.
Ste^_4-{4-[(2,6-Dichlorophenyl)carbonyl]-2-(dimethylcarbamoyl)-4H-thieno[3,2- b] pyrrol-6-yl}benzoic acid
To a solution of the step 1 intermediate (60 mg, 0.1 19 mmol) in THF (2 mL) were added lithium hydroxide monohydrate (20 mg, 0.479 mmol) and water (2 mL). The reaction mixture was stirred at RT for 16 hours. The solvents were removed under reduced pressure and the residue was diluted with water (5 mL). The aqueous mixture was acidified with IN HCl to obtain a thick precipitate. The solid was filtered and dried to yield 45 mg of the titled product as white solid. 1H NMR (300 MHz, DMSO- d6) δ 3.33 (s, 6H), 7.09 (s, 1H), 7.50 (s, 3H), 7.68 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.4 Hz, 1H), 8.12-8.17 (m, 2H), 8.22 (d, J= 8.7 Hz, 1H); APCI-MS (m/z) 487 (M+H)+.
Example 3
6-(4-Carbamoylphenyl)-4-[(2,6-dichlorophenyl)carbonyl]-N,N-dimethyl-4H- thieno[3,2-£]pyrrole-2-carboxamide
Figure imgf000051_0001
The title compound was prepared by the Suzuki coupling of Intermediate 2 (45 mg, 0.0912 mmol) with 4-carbamoyl phenyl boronic acid (21 mg, 0.127 mmol) in presence of Pd(dppf)Cl2 (5.2 mg, 0.004 mmol) and potassium carbonate (19 mg,
0.136 mmol) in toluene (5 mL) and ethanol (1 mL) as per the method described for the synthesis of Example 1 to yield 35 mg of the title compound as off white solid. 1H MR (300 MHz, DMSO-i¾) δ 3.24 (br s, 6H), 7.43 (br s, 1H), 7.75 (s, 3H), 7.82 (d, J = 7.8 Hz, 3H), 7.93-7.98 (m, 3H), 8.04-8.10 (m, 1H); APCI-MS (m/z) 486 (M+H)+.
Example 4
4-[(2,6-Dichlorophenyl)carbonyl]-6-[4-(hydroxycarbamoyl)phenyl]-N,N-dimethyl- 4H-thieno[3,2-£]pyirole-2-carboxamide
Figure imgf000051_0002
To a stirred solution of the Example 2 (25 mg, 0.051 mmol) in DMSO (2 ml) were added (benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (BOP) (34 mg, 0.076 mmol), hydroxylamine hydrochloride (10 mg, 0.154 mmol) and diisopropylethylamine (DIPEA) (0.026 ml, 0.153 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic layer was washed with water (20 ml), brine (20 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to afford 13 mg of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.23 (br s, 6H), 7.74 (s, 2H), 7.83 (s, 4H), 7.91 (s, 1H), 7.96 (s, 1H), 8.09 (s, 1H), 9.07 (s, 1H), 1 1.29 (s, 1H); APCI-MS (m/z) 502 (M+H)+.
Example 5
4-[4-(2,6-Dichlorobenzoyl)-2-(mo holin-4-ylcarbonyl)-4H-thieno[3,2-^]pyrrol-6- yljbenzoic acid
Figure imgf000052_0001
Step 1 : 4-[(2,6-Dichlorophenyl)carbonyl]-6-iodo-4H-thieno[3,2-^]pyrrole-2- carboxylic acid:
The ester hydrolysis of the Intermediate 1 (300 mg, 0.625 mmol) using lithium hydroxide monohydrate (104 mg, 2.50 mmol) in water (5 mL) and THF (5 mL) was carried out as per the process described in step 2 of Example 2 to obtain 240 mg of the title compound as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 7.62 (s, 1H), 7.68-7.74 (m, 3H), 8.22 (s, 1H), 13.51 (s, 1H); ESI-MS (m/z) 481 (M+H)+.
Step 2: (2,6-Dichlorophenyl)[6-iodo-2-(mo holin-4-ylcarbonyl)-4H-thieno[3,2- ]pyrrol-4-yl]methanone:
To a solution of the Step 1 intermediate (240 mg, 0.819 mmol) in DCM (10 mL) were added EDCI (188 mg, 0.982 mmol), HOBt (132 mg, 0.982 mmol) and DMAP (150 mg, 1.22 mmol). To that mixture was added morpholine (0.08 ml, 0.982 mmol) and stirred for 48 hours at RT. The reaction mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The layers were separated and aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 260 mg of the title product as off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.79 (br s, 4H), 3.86 (br s, 4H), 6.80 (s, 1H), 7.47 (s, 3H), 8.02 (s, 1H); APCI-MS (m/z) 535 (M+H)+.
Step 3 : 4-[4-(2,6-Dichlorobenzoyl)-2-( ο ηο1ΐη6-4-ν1οαΛοην1)-4#-ίηΪ6ηο[3,2- b]pyrrol-6-yl]benzoic acid: The title compound was prepared by the Suzuki coupling of Step 2 intermediate (100 mg, 0.186 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (50 mg, 0.280 mmol) in presence of Pd(dppf)Cl2 (15 mg, 0.018 mmol) and potassium acetate (54 mg, 0.546 mmol) in dioxane (5 mL) and water (1 mL) followed by hydrolysis of the ester (70 mg, 0.128 mmol) with lithium hydroxide (21 mg, 0.515 mmol) in water (2 mL) and THF (2 mL) as per the process described for the synthesis of Example 2 to afford 25 mg of the compound as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 3.46 (br s, 1H), 3.56 (br s, 1H), 3.68 (br s, 3H), 3.78 (br s, 3H), 7.74 (s, 2H), 7.87 (d, J = 9.0 Hz, 3H), 7.99-8.04 (s, 4H); APCI-MS (m/z) 529 (M+H)+.
Example 6
4-[4-(2-Chloro-6-trifluoromethyl-benzoyl)-2-dimethylcarbamoyl-4H-thieno[3,2- b]pyrrol-6-yl]-3-fluoro-benzoic acid
Figure imgf000053_0001
Step 1 : 4-(2-Chloro-6-trifluoromethyl-benzoyl)-6-(2-fluoro-4-formyl-phenyl)-4H -thieno[3,2-b]pyrrole-2-dimethylamide
The title compound was prepared by the Suzuki coupling of Intermediate 3 (100 mg, 0.189 mmol) with 2-fluoro-4-formyl phenyl boronic acid (48 mg, 0.284 mmol) in presence of Pd(dppf)Cl2 (16 mg, 0.018 mmol) and potassium acetate (56 mg, 0.567 mmol) in dioxane (5 mL) and water (2 mL) as per the process described for the synthesis of Example 1 to yield 90 mg of the product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.21 (br s, 6H), 7.75 (s, 1H), 7.81-7.86 (m, 2H), 7.94-7.97 (m, 2H), 8.05-8.08 (m, 3H), 10.0 (s, 1H), APCI-MS (m/z) 523 (M+H)+.
Step 2: 4-[4-(2-Chloro-6-trifluoromethyl-benzoyl)-2-dimethylcarbamoyl-4H- thieno[3,2-b]pyrrol-6-yl]-3-fluoro-benzoic acid:
To a stirred and cooled (0 °C) solution of the step 1 intermediate (80 mg, 0.157 mmol) in acetone (5 ml) was added sodium chlorite (17 mg, 0.190 mmol) and sulphamic acid (23 mg, 0.235 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (50 ml), brine (25 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography to afford 50 mg of the title product as white solid. 1H NMR (300 MHz, CD3OD) δ 4.27 (br s, 6H), 7.34 (s, 1H), 7.76-7.79 (m, 2H), 7.86-8.00 (m, 4H), 8.52 (s, 1H), APCI-MS (m/z) 539 (M+H)+.
Example 7
4-[4-(2-Chloro-6-trifluoromethyl-benzoyl)-2-dimethylcarbamoyl-4H-thieno[3,2- b]pyrrol-6-yl]-benzoic acid
Figure imgf000054_0001
The title compound was prepared by the Suzuki coupling of Intermediate 3 (100 mg, 0.189 mmol) with 4-formyl phenyl boronic acid (42 mg, 0.284 mmol) in presence of Pd(dppf)Cl2 (15 mg, 0.018 mmol) and potassium acetate (56 mg, 0.567 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (50 mg, 0.099 mmol) by using sodium chlorite (1 1 mg, 0.123 mmol) and sulphamic acid (15 mg, 0.148 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to afford 15 mg of the product as off white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.90 (br s, 6H), 7.83-8.03 (m, 9H); APCI-MS (m/z) 521 (M+H)+.
Example 8
4-[l-(2,6-Dichlorobenzoyl)-5-(dimethylcarbamoyl)-lH-thieno[3,2-c]pyrazol-3-yl] benzoic acid
Figure imgf000054_0002
The title compound was prepared by the Suzuki coupling of Intermediate 4 (150 mg, 0.303 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (82 mg, 0.455 mmol) in presence of Pd(dppf)Cl2 (25 mg, 0.030 mmol) and potassium acetate (89 mg, 0.909 mmol) in dioxane (7 mL) and water (2 mL) followed by hydrolysis of the ester derivative (120 mg, 0.238 mmol) with lithium hydroxide (40 mg, 0.955 mmol) in THF (5 mL) and water (2 mL) as per the process described for the synthesis of Example 2 afforded 60 mg of the product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.31 (br s, 6H), 7.69-7.74 (m, 3H), 7.86 (d, J= 8.4 Hz, 2H), 8.10 (d, J = 7.5 Hz, 3H), 13.24 (s, 1H); APCI-MS (m/z) 488 (M+H)+.
Example 9
4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-dimethylcarbamoyl-lH-thieno[3,2- c]pyrazol-3-yl]-benzoic acid
Figure imgf000055_0001
Step 1 : l-{[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}-3-iodo-N,N-dimethyl-lH- thieno[3,2-c]pyrazole-5-carboxamide
To a stirred solution of Intermediate 5 (250 mg, 0.506 mmol) in DCM (5 mL) were added N,N-dimethylamine (49 mg, 0.600 mmol), EDCI.HC1 (115 mg, 0.600 mmol), HOBt (81 mg, 0.600 mmol) and DMAP (92 mg, 0.750 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (15 mL) and dried over anhydrous sodium sulphate. The solvents were removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to afford 200 mg of the title product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.08 (br s, 6H), 7.88-7.98 (m, 1H), 7.99-8.06 (m, 3H); APCI-MS (m/z) 528 (M+H)+.
Step 2: 4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-dimethylcarbamoyl-lH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid
The title compound was synthesized by Suzuki coupling of step 1 intermediate (90 mg, 0.170 mmol) with 4-formyl-phenyl boronic acid (39 mg, 0.256 mmol) in presence of Pd(dppf)Cl2 (14 mg, 0.017 mmol) and potassium acetate (50 mg, 0.510 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (60 mg, 0.1 18 mmol) by using sodium chlorite (13 mg, 0.148 mmol) and sulphamic acid (18 mg, 0.177 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to afford 51 mg of the product as off white solid. . 1H NMR (300 MHz, OMSO-d6) δ 3.15 (br s, 6H), 7.82-7.86 (m, 2H), 7.90-8.09 (m, 6H); APCI-MS (m/z) 522 (M+H)+.
Example 10
4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-dimethylcarbamoyl-lH-thieno[3,2- c] pyrazol -3 -yl ] -3 -fluoro-b enz
Figure imgf000056_0001
The title compound was prepared by the Suzuki coupling of l-{ [2-chloro-6- (trifluoromethyl)phenyl]carbonyl}-3-iodo-N,N-dimethyl-lH-thieno[3,2-c]pyrazole-5- carboxamide (Step 1 product of Example 9) (90 mg, 0.170 mmol) with 2-fluoro-4- formyl phenyl boronic acid (43 mg, 0.256 mmol) in presence of Pd(dppf)Cl2 (14 mg, 0.017 mmol) and potassium acetate (50 mg, 0.510 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (60 mg, 0.1 14 mmol) by using sodium chlorite (13 mg, 0.142 mmol) and sulphamic acid (17 mg, 0.171 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to afford 50 mg of the product as off white solid. 1H NMR (300 MHz, CDC13) δ 3.49 (br s, 6H), 7.25 (d, J = 7.8 Hz, 1H), 7.62-7.66 (m, 2H), 7.76-7.79 (m, 3H), 7.89 (s, 1H); APCI-MS (m/z) 542 (M+H)+.
Example 1 1
4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-cyclopropylcarbamoyl-lH-thieno[3,2- c]pyrazol-3-yl]-benzoic acid
Figure imgf000056_0002
Step 1 : 1 - { [2-chloro-6-(trifluorom ethyl )phenyl]carbonyl } -3 -[4-
(methoxycarbonyl)phenyl]-lH-thieno[3,2-c]pyrazole-5-carboxylic acid
The title compound was prepared by the Suzuki coupling of Intermediate 5 (300 mg, 0.600 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (162 mg, 0.900 mmol) in presence of Pd(dppf)Cl2 (49 mg, 0.060 mmol) and potassium acetate (177 mg, 1.80 mmol) in dioxane (10 mL) and water (3 mL) as per the process described for the synthesis of Example 1 to yield 150 mg of the product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 3.87 (s, 3H), 7.86-7.91 (m, 3H), 8.02-8.10 (m, 5H), APCI- MS (m/z) 509 (M+H)+.
Step 2: 4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-cyclopropylcarbamoyl-lH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid
The Step 1 intermediate (60 mg, 0.1 18 mmol) was coupled with cyclopropylamine (8.0 mg, 0.141 mmol) in presence of EDCI.HC1 (27 mg, 0.141 mmol), HOBt (19 mg, 0.141 mmol) and DMAP (14 mg, 0.1 18 mmol) in DMF (2 mL) as described in step 1 of Example 9 to give corresponding benzoic acid ester. The benzoic acid ester (40 mg, 0.073 mmol) which on hydrolysis with lithium hydroxide (9.2 mg, 0.219 mmol) in THF (5 mL), water (1 mL) and methanol (1 mL) as described the process in step 2 of Example 2 yielded 25 mg of the title product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 0.64-0.66 (m, 2H), 0.74-0.76 (m, 2H), 2.90-2.92 (m, 1H), 7.84-7.91 (m, 3H), 7.93-8.10 (m, 4H), 8.57 (s, 1H), 9.04 (s, 1H); APCI-MS (m/z) 534.2 (M+H)+.
Example 12
4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-(2-hydroxy-ethylcarbamoyl)-lH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid
Figure imgf000057_0001
l-{ [2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-3-[4-(methoxycarbonyl)phenyl]- lH-thieno[3,2-c]pyrazole-5-carboxylic acid (step 1 product of Example 1 1) (60 mg, 0.1 18 mmol) was coupled with ethanolamine (8.6 μΕ, 0.141 mmol) in presence of EDCI.HC1 (27 mg, 0.141 mmol), HOBt (19 mg, 0.141 mmol) and DMAP (14 mg, 0.1 18 mmol) in DMF (4 mL) as per the process described in step 1 of Example 9 to give the corresponding benzoic acid ester. The benzoic acid ester (30 mg, 0.054 mmol) on hydrolysis with lithium hydroxide (6.8 mg, 0.162 mmol) in THF (5 mL), methanol (1 mL) and water (1 mL) as per the process described in step 2 of Example 2 afforded 15 mg of the title product as off white solid. 1H NMR (300 MHz, DMSO- d6) δ 3.34-3.51 (m, 2H), 3.54-3.56 (m, 2H), 4.83 (s, 1H), 7.85-7.91 (m, 3H), 8.02-8.09 (m, 3H), 8.64 (s, 1H), 9.10 (br s, 1H); APCI-MS (m/z) 538 (M+H)+.
Example 13
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000058_0001
The title compound was prepared by the Suzuki coupling of Intermediate 6 (100 mg, 0.228 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (62 mg, 0.343 mmol) in presence of Pd(dppf)Cl2 (19 mg, 0.022 mmol) and potassium acetate (67 mg, 0.684 mmol) in dioxane (7 mL) and water (2 mL) followed by hydrolysis of the ester derivative (60 mg, 0.134 mmol) with lithium hydroxide (22 mg, 0.538 mmol) in water (2 mL) and THF (5 mL) as per the process described for the synthesis of Example 2 to afford 50 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.61 (s, 1H), 7.66-7.72 (m, 3H), 7.80 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 7.8 Hz, 2H), 13.20 (s, 1H); APCI-MS (m/z) 431 (M+H)+.
Example 14
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]-N- [(trifluoromethyl)sulfonyl]benzamide
Figure imgf000058_0002
To a well stirred solution of the Example 13 (30 mg, 0.069 mmol) in dichloromethane (5 ml) were added DCC (21 mg, 0.103 mmol), DMAP (10 mg, 0.075 mmol), trifluoromethanesulfonamide (13 mg, 0.083 mmol) and stirred at room temperature for 16 h. The reaction mass was diluted with water (25 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (50 ml), brine (25 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography to afford 35 mg of the title product as off-white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.71 (s, 3H), 7.59 (s, 1H), 7.66-7.71 (m, 5H), 8.04 (d, J = 7.8 Hz, 2H); APCI-MS (m/z) 559 (M-H)+.
Example 15
4-[l-(2-Chloro-6-fluorobenzoyl)- -methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000059_0001
The title compound was prepared by the Suzuki coupling of Intermediate 7 (150 mg, 0.357 mmol) with 4-(methoxycarbonyl) phenyl boronic acid (96 mg, 0.535 mmol) in presence of Pd(dppf)Cl2 (29 mg, 0.035 mmol) and potassium acetate (105 mg, 1.07 mmol) in dioxane (5 mL) and water (2 mL) followed by hydrolysis of the ester derivative (50 mg, 0.1 18 mmol) with lithium hydroxide (7.2 mg, 0.175 mmol) in THF (4 mL) and water (1 mL) as per the process described for the synthesis of Example 2 to yield 30 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.50-7.57 (m, 2H), 7.60 (s, 1H), 7.70-7.74 (m, 1H), 7.81 (d, J = 9.0 Hz, 2H), 8.09 (d, J = 7.8 Hz, 2H), 13.20 (br s, 1H); APCI-MS (m/z) 415 (M+H)+.
Example 16
4-{ l-[2-Chloro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000059_0002
Step 1 : Methyl 4-(l-{ [2-chloro-6-(trifluoromethyl)phenyl]carbonyl }-5-methyl-lH- thieno[3,2-c]pyrazol-3-yl)benzoate
To a stirred and degassed solution of the Intermediate 8 (125 mg, 0.265 mmol) in dioxane (5 ml) were added 4-(methoxycarbonyl) phenyl boronic acid (72 mg, 0.398 mmol), Pd(dppf)Cl2 (22 mg, 0.026 mmol) and aqueous potassium acetate solution (78 mg, 0.795 mmol). The resulting dark brown suspension was heated at 90-100 °C under nitrogen atmosphere for 3 h. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (50 ml), brine (50 ml) and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and the residue obtained was purified by column chromatography to afford 85 mg of the title product as off -white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.71 (s, 3H), 3.86 (s, 3H), 7.61 (s, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.89-7.91 (m, 1H), 7.99-8.10 (m, 4H), 13.19 (br s, 1H); APCI-MS (m/z) 479 (M+H)+.
Step 2: 4-{ l-[2-Chloro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid
To a solution of the step 1 intermediate (80 mg, 0.166 mmol) in THF (4 mL) were added lithium hydroxide monohydrate (10 mg, 0.250 mmol) and water (1 mL). The reaction mixture was stirred at RT for 16 hours. The solvents were recovered under reduced pressure and the residue was diluted with water (6 mL). The aqueous mixture was acidified with IN HCl and filtered the thick precipitate obtained. The solid was filtered and dried to yield 65 mg of the title product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.61 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.86-7.91 (m, 1H), 8.00 (d, J = 7.8 Hz, 1H), 8.03-8.09 (m, 3H), 13.19 (br s, 1H); APCI-MS (m/z) 465 (M+H)+.
Example 17
4-{ l-[2-Fluoro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000060_0001
The title compound was prepared by the Suzuki coupling of Intermediate 9 (100 mg, 0.219 mmol) with 4-formyl phenyl boronic acid (50 mg, 0.328 mmol) in presence of Pd(dppf)Cl2 (18 mg, 0.021 mmol) and potassium acetate (65 mg, 0.657 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (70 mg, 0.161 mmol) by using sodium chlorite (18 mg, 0.202 mmol) and sulphamic acid (24 mg, 0.241 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 50 mg of the product as white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.71 (s, 3H), 7.60 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.90-7.95 (m, 1H), 8.07 (d, J = 7.8 Hz, 2H), 13.19 (br s, 1H); APCI-MS (m/z) 449 (M+H)+.
Example 18
4-[l-(2,6-Difluorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000061_0001
The title compound was prepared by the Suzuki coupling of Intermediate 10 (100 mg, 0.247 mmol) with 4-formyl phenyl boronic acid (56 mg, 0.371 mmol) in presence of Pd(dppf)Cl2 (20 mg, 0.024 mmol) and potassium acetate (73 mg, 0.741 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (70 mg, 0.183 mmol) by using sodium chlorite (21 mg, 0.228 mmol) and sulphamic acid (27 mg, 0.274 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 50 mg of the product as white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.70 (s, 3H), 7.39 (t, J = 7.8 Hz, 2H), 7.55 (s, 1H), 7.74-7.80 (m, 1H), 7.83 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 13.20 (s, 1H); APCI-MS (m/z) 399 (M+H)+.
Example 19
4-{5-Methyl-l-[2-(trifluoromethyl)benzoyl]-lH-thieno[3,2-c]pyrazol-3-yl} benzoic acid
Figure imgf000062_0001
The title compound was prepared by the Suzuki coupling of Intermediate 1 1 (1 10 mg, 0.252 mmol) with 4-formyl phenyl boronic acid (57 mg, 0.378 mmol) in presence of Pd(dppf)Cl2 (21 mg, 0.025 mmol) and potassium acetate (75 mg, 0.756 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (70 mg, 0.169 mmol) by using sodium chlorite (19 mg, 0.21 1 mmol) and sulphamic acid (25 mg, 0.253 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 60 mg of the desired product as white solid. 1H MR (300 MHz, OMSO-d6) δ 2.69 (s, 3H), 7.53 (br s, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.86-7.91 (m, 3H), 7.96-8.01 (m, 1H), 8.07 (d, J = 7.8 Hz, 2H), 13.18 (s, 1H); APCI-MS (m/z) 431 (M+H)+.
Example 20
4-(l-{ [2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-5-methyl-lH-thieno[3,2-c] pyrazol -3 -yl )-3 -fluorob enzoi c aci d
Figure imgf000062_0002
The title compound was prepared by the Suzuki coupling of Intermediate 8 (100 mg, 0.212 mmol) with 2-fluoro-4-(methoxycarbonyl) phenyl boronic acid (63 mg, 0.319 mmol) in presence of Pd(dppf)Cl2 (17 mg, 0.021 mmol) and potassium acetate (62 mg, 0.637 mmol) in dioxane (5 mL) and water (2 mL) followed by hydrolysis of the ester derivative (80 mg, 0.161 mmol) with lithium hydroxide (10 mg, 0.241 mmol) in water (1 mL) and THF (4 mL) as per the process described for the synthesis of Example 2 to afford 50 mg of the desired product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.50 (s, 3H), 7.58 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.83-8.91 (m, 3H), 7.99-8.06 (m, 2H), 13.50 (s, 1H); APCI-MS (m/z) 483 (M+H)+.
Example 21 4-(l-{ [2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-5-methyl-lH-thieno[3,2-c] pyrazol -3 -yl )-2-fluorob enzoi c aci d
Figure imgf000063_0001
The title compound was prepared by the Suzuki coupling of Intermediate 8 (100 mg, 0.212 mmol) with 3-fluoro-4-(methoxycarbonyl) phenyl boronic acid (63 mg, 0.319 mmol) in presence of Pd(dppf)Cl2 (17 mg, 0.021 mmol) and potassium acetate (62 mg, 0.636 mmol) in dioxane (5 mL) and water (2 mL) followed by hydrolysis of the ester derivative (80 mg, 0.161 mmol) with lithium hydroxide (10 mg, 0.241 mmol) in water (1 mL) and THF (4 mL) as per the process described for the synthesis of Example 2 to afford 60 mg of the desired product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.38-7.44 (m, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 8.00-8.07 (m, 4H); APCI-MS (m/z) 483 (M+H)+.
Example 22
4-[l-(2,3-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000063_0002
The title compound was prepared by the Suzuki coupling of Intermediate 12 (125 mg, 0.285 mmol) with 4-formyl phenyl boronic acid (64 mg, 0.428 mmol) in presence of Pd(dppf)Cl2 (23 mg, 0.028 mmol) and potassium acetate (84 mg, 0.855 mmol) in dioxane (10 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (40 mg, 0.096 mmol) by using sodium chlorite (1 1 mg, 0.120 mmol) and sulphamic acid (14 mg, 0.144 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to afford 50 mg of the product as off white solid . 1H NMR (300 MHz, OMSO-d6) δ 2.70 (s, 3H), 7.53-7.62 (m, 2H), 7.82 (d, J = 7.8 Hz, 3H), 7.91 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 2H), 13.16 (s, 1H); APCI-MS (m/z) 431 (M+H)+. Example 23
4-{ l-[2-Chloro-3-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000064_0001
The title compound was prepared by the Suzuki coupling of Intermediate 13 (125 mg, 0.265 mmol) with 4-formyl phenyl boronic acid (60 mg, 0.398 mmol) in presence of Pd(dppf)Cl2 (22 mg, 0.026 mmol) and potassium acetate (78 mg, 0.795 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (80 mg, 0.178 mmol) by using sodium chlorite (20 mg, 0.223 mmol) and sulphamic acid (26 mg, 0.267 mmol) in water (2 mL) and acetone (4 mL) as per the process described for the synthesis of Example 6 to yield 8 mg of the product as off white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.58 (br s, 1H), 7.80 (d, J = 7.8 Hz, 3H), 8.08 (d, J= 8.4 Hz, 2H), 8.15 (t, J = 8.7 Hz, 2H), 13.18 (s, 1H); APCI- MS (m/z) 465 (M+H)+.
Example 24
4-{ l-[3-Fluoro-5-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000064_0002
The title compound was prepared by the Suzuki coupling of Intermediate 14 (140 mg, 0.311 mmol) with 4-formyl phenyl boronic acid (64 mg, 0.466 mmol) in presence of Pd(dppf)Cl2 (25 mg, 0.031 mmol) and potassium acetate (92 mg, 0.933 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (70 mg, 0.161 mmol) by using sodium chlorite (18.3 mg, 0.202 mmol) and sulphamic acid (23.4 mg, 0.241 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 8 mg of the product as white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.70 (s, 3H), 7.53 (s, 1H), 7.91 (d, J= 8.1 Hz, 2H), 8.1 1 (d, J = 7.5 Hz, 3H), 8.29 (d, J = 7.8 Hz, 1H), 8.34 (s, 1H), 13.22 (s, 1H); APCI-MS (m/z) 447 (M-H)+.
Example 25
4-{ l-[4-Fluoro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000065_0001
The title compound was prepared by the Suzuki coupling of Intermediate 15 (140 mg, 0.308 mmol) with 4-formyl phenyl boronic acid (64 mg, 0.462 mmol) in presence of Pd(dppf)Cl2 (25 mg, 0.031 mmol) and potassium acetate (90 mg, 0.924 mmol) in dioxane (10 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (60 mg, 0.138 mmol) by using sodium chlorite (16 mg, 0.173 mmol) and sulphamic acid (20 mg, 0.207 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 60 mg of the product as white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.69 (s, 3H), 7.53 (br s, 1H), 7.81 (d, J = 7.8 Hz, 3H), 7.96 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 7.8 Hz, 3H), 13.17 (s, 1H); APCI- MS (m/z) 449 (M+H)+.
Example 26
4-{ l-[5-Fluoro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000065_0002
The title compound was prepared by the Suzuki coupling of Intermediate 16 (1 10 mg, 0.242 mmol) with 4-formyl phenyl boronic acid (54 mg, 0.363 mmol) in presence of Pd(dppf)Cl2 (20 mg, 0.024 mmol) and potassium acetate (71 mg, 0.726 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (50 mg, 0.115 mmol) by using sodium chlorite (13 mg, 0.144 mmol) and sulphamic acid (17 mg, 0.172 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to obtain 45 mg of the product as white solid. 1H NMR (300 MHz, OMSO-d6) δ 2.70 (s, 3H), 7.56 (br s, 1H), 7.73 (t, J = 8.7Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.1 Hz, 3H), 13.17 (s, 1H); APCI-MS (m/z) 449 (M+H)+.
Example 27
4-{ l-[4-Chloro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
Figure imgf000066_0001
The title compound was prepared by the Suzuki coupling of Intermediate 17 (150 mg, 0.319 mmol) with 4-formyl phenyl boronic acid (71 mg, 0.478 mmol) in presence of Pd(dppf)Cl2 (26 mg, 0.031 mmol) and potassium acetate (94 mg, 0.957 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (80 mg, 0.178 mmol) by using sodium chlorite (20 mg, 0.223 mmol) and sulphamic acid (26 mg, 0.267 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 70 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.70 (s, 3H), 7.57 (br s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 7.8 Hz, 2H), 8.17 (s, 1H), 13.32 (s, 1H); APCI-MS (m/z) 465 (M+H)+.
Example 28
4-{ l-[5-Chloro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl}benzoic acid
The title compound was prepared by the Suzuki coupling of Intermediate 18 (100 mg, 0.212 mmol) with 4-formyl phenyl boronic acid (48 mg, 0.319 mmol) in presence of Pd(dppf)Cl2 (17 mg, 0.021 mmol) and potassium acetate (62 mg, 0.636 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (50 mg, 0.1 1 1 mmol) by using sodium chlorite (13 mg, 0.139 mmol) and sulphamic acid (16 mg, 0.166 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 20 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.70 (s, 3H), 7.57 (br s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 7.8 Hz, 2H), 8.17 (s, 1H), 13.21 (s, 1H); APCI-MS (m/z) 465 (M+H)+.
Example 29
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]-3-fluorobenzoic acid
Figure imgf000067_0001
The title compound was prepared by the Suzuki coupling of Intermediate 6 (150 mg, 0.343 mmol) with 2-fluoro-4-formyl phenyl boronic acid (87 mg, 0.515 mmol) in presence of Pd(dppf)Cl2 (28 mg, 0.034 mmol) and potassium acetate (101 mg, 1.02 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (100 mg, 0.230 mmol) by using sodium chlorite (26 mg, 0.288 mmol) and sulphamic acid (34 mg, 0.345 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 75 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.67 (s, 3H), 7.58 (s, 1H), 7.70 (br s, 3H), 7.78-7.85 (m, 3H), 13.52 (s, 1H); APCI-MS (m/z) 449 (M+H)+.
Example 30
4-[l-(2-Chloro-6-methylbenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000068_0001
The title compound was prepared by the Suzuki coupling of Intermediate 19 (100 mg, 0.239 mmol) with 4-formyl phenyl boronic acid (54 mg, 0.359 mmol) in presence of Pd(dppf)Cl2 (20 mg, 0.023 mmol) and potassium acetate (70 mg, 0.717 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (65 mg, 0.164 mmol) by using sodium chlorite (19 mg, 0.205 mmol) and sulphamic acid (24 mg, 0.246 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 45 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.23 (s, 3H), 2.70 (s, 3H), 7.40 (d, J =
6.9 Hz, 1H), 7.45-7.51 (m, 2H), 7.60 (s, 1H), 7.79 (d, J
Hz, 2H), 13.17 (s, 1H); APCI-MS (m/z) 41 1 (M+H)+.
Example 31
4-[l-(2-Bromo-6-chlorobenzoyl)- -methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid
Figure imgf000068_0002
The title compound was prepared by the Suzuki coupling of Intermediate 20 (100 mg, 0.207 mmol) with 4-formyl phenyl boronic acid (47 mg, 0.3 1 1 mmol) in presence of Pd(dppf)Cl2 (17 mg, 0.020 mmol) and potassium acetate (61 mg, 0.621 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (80 mg, 0.160 mmol) by using sodium chlorite (18 mg, 0.201 mmol) and sulphamic acid (24 mg, 0.240 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 40 mg of the product as white solid. 1H NMR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.55-7.61 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.79-7.84 (m, 3H), 8.08 (d, J = 8.4 Hz, 2H), 13.15 (s, 1H); APCI- MS (m/z) 476 (M+H)+.
Example 32 3-Fluoro-4-{ l-[2-fluoro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl} benzoic acid
Figure imgf000069_0001
The title compound was prepared by the Suzuki coupling of Intermediate 9 (100 mg, 0.239 mmol) with 2-fluoro-4-formyl phenyl boronic acid (60 mg, 0.359 mmol) in presence of Pd(dppf)Cl2 (20 mg, 0.023 mmol) and potassium acetate (70 mg, 0.717 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (70 mg, 0.167 mmol) by using sodium chlorite (19 mg, 0.209 mmol) and sulphamic acid (25 mg, 0.250 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 40 mg of the product as off white solid. 1H MR (300 MHz, OMSO-d6) δ 2.67 (s, 3H), 7.57 (s, 1H), 7.83-7.94 (m, 6H), 13.46 (s, 1H); APCI-MS (m/z) 467 (M+H)+.
Example 33
4-[l-(2,6-Bis-trifluoromethyl-benzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]- benzoic acid
The title compound was prepared by the Suzuki coupling of Intermediate 21 (100 mg, 0.198 mmol) with 4-formyl phenyl boronic acid (45 mg, 0.297 mmol) in presence of Pd(dppf)Cl2 (16 mg, 0.019 mmol) and potassium acetate (58 mg, 0.594 mmol) in dioxane (5 mL) and water (2 mL) followed by oxidation of the benzaldehyde derivative (60 mg, 0.124 mmol) by using sodium chlorite (14 mg, 0.155 mmol) and sulphamic acid (18 mg, 0.180 mmol) in water (2 mL) and acetone (5 mL) as per the process described for the synthesis of Example 6 to yield 45 mg of the product as off white solid. 1H MR (300 MHz, DMSO-i¾) δ 2.71 (s, 3H), 7.60 (s, 1H), 7.73 (d, J = 7.8 Hz, 2H), 8.05-8.12 (m, 3H), 8.35 (d, J = 8.4 Hz, 2H), 13.18 (s, 1H); APCI-MS (m/z) 499 (M+H)+.
Pharmacological Activity
Biological Assay
The illustrative examples of the present patent application were screened for ROR gamma modulator activity using the TR-FRET assay by Lantha Screen as described in JBC 2011, 286, 26: 22707-10; 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 dimethyl sulfoxide (DMSO) to prepare 10.0 mM stock solution and diluted suitably to get the desired concentration. Final concentration of DMSO in the reaction was 4% (v/v). Assay mixture was prepared by mixing ΙΟηΜ 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 lhr. The preincubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and ΙΟηΜ lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 minutes the reaction was further incubated for 2 hr at room temperature and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound is 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 prepared were tested using the above assay procedure. The preferred compounds were found to have IC50 less than ΙΟΟΟηΜ, preferably less than 500nM, more preferably less than lOOnM or most preferably less than 50nM.
The IC50 (nM) values of the compounds are set forth in Table 1 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. "C" refers to IC50 value in range of 100.01 to 500.0 nM.
Table 1 : In-vitro screening results of compounds of present invention
Sr. no. Example No. % inhibition at IC50 (nM)
1 iiM 10 μΜ
1. Example 1 24.63 29.88 -
2. Example 2 41.80 86.82 -
3. Example 3 20.80 29.38 -
4. Example 4 38.58 71.30 -
5. Example 5 28.55 53.23 -
6. Example 6 87.1 1 95.81 C
7. Example 7 65.43 91.53 C
8. Example 8 49.45 86.94 -
9. Example 9 80.31 92.71 C
10. Example 10 92.02 99.21 A
1 1. Example 1 1 6.74 50.18 -
12. Example 12 2.04 26.81 -
13. Example 13 97.07 98.17 A
14. Example 14 2.09 76.44 -
15. Example 15 76.73 94.50 C
16. Example 16 100.0 100.0 A
17. Example 17 96.69 100.0 B
18. Example 18 42.45 87.93 - Sr. no. Example No. % inhibition at IC50 (nM)
1 iiM 10 μΜ
19. Example 19 48.90 90.68 -
20. Example 20 98.29 97.56 A
21. Example 21 95.64 97.09 A
22. Example 22 12.49 67.41 -
23. Example 23 0.0 34.16 -
24. Example 24 13.35 34.72 -
25. Example 25 21.77 71.52 -
26. Example 26 17.72 71.28 -
27. Example 27 1.21 59.53 -
28. Example 28 17.93 67.94 -
29. Example 29 92.28 88.21 A
30. Example 30 93.03 92.39 A
31. Example 31 92.12 81.94 A
32. Example 32 95.87 95.01 A
33. Example 33 85.33 94.19 B
(-): Not determined

Claims

WHAT IS CLAIMED IS:
1. A compound of formu
Figure imgf000073_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
Z is selected from CR1 and N;
R1 is selected from hydrogen and Ci-8alkyl;
R2 is selected from h dro en Ci-8alkyl, -C(0)OR9, -C(0)N(CH3)2, -
CO HCH2
Figure imgf000073_0002
R3 is selected from hydrogen and Ci-8alkyl;
R4 is selected from -C(0)ORz, -C(0) RxRy and -C(0) HS(0)2Rx;
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
R9 is independently selected from hydrogen and Ci-8alkyl;
each occurrence of Rx and Ry are independently selected from hydrogen, hydroxy, Ci-8alkyl and haloCi-8alkyl;
Rz is independently selected from hydrogen and Ci-4alkyl;
'm' is an integer ranging from 0 to 2, both inclusive; and
'n' is an integer ranging from 0 to 5, both inclusive.
2. The compound according to claim 1, wherein Z is CH or N.
3. The compound according to claim 1 or 2 wherein R2 is -CH3, -C(0)OCH3, -
C(0)N(CH3)2, -CO HCH2CH2OH,
Figure imgf000073_0003
; and R3 is hydrogen.
4. The compound according to any one of claims 1 to 3, wherein R4 is -C(0)OH, -C(0)OCH3, -C(0)OCH2CH3; -C(0) H2, -C(0) HOH or -C(0) HS(0)2CF3.
5. The compound according to any one of claims 1 to 4, wherein R5 is F and 'm' is 0 or 1.
6. The compound according to any one of claims 1 to 5, wherein R6 is F, CI, Br, CH3 or CF3; and 'n' is 1 or 2.
7. The compound according to claim 1, wherein
Z is CH or N;
R2 is -CH3 or -C(0)N(CH3)2;
R3 is hydrogen;
R4 is -C(0)OH;
R5 is F;
' ' is 0 or 1 ; and
Figure imgf000074_0001
is 2,6-dichlorophenyl, 2-chloro-6-trifluoromethylphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2- (trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2-chloro-3-(trifluoromethyl)phenyl, 3- fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 5-fluoro-2- (trifluoromethyl)phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2-bromo-6-chlorophenyl or 2,6- bis-trifluorom ethyl -phenyl.
8. A compound of formula (lb)
)n
Figure imgf000074_0002
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
R2 is selected from hydrogen and Ci^alkyl; each occurrence of R5 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
Rz is independently selected from hydrogen and
Figure imgf000075_0001
'm' is an integer ranging from 0 to 2, both inclusive; and
'n' is an integer ranging from 0 to 5, both inclusive.
9. The compound according to claim 8, wherein R2 is CH3; R5 is F; and 'm' is 0 or 1.
10. The compound according to claim 8 or 9, wherein Rz is hydrogen, methyl or ethyl.
11. The compound according to any one of claims 8 to 10, wherein R6 is F, CI, Br, CH3 or CF3; and 'n' is 1 or 2.
12. The compound according to claim 8, wherein
2 is CH3; R5 is F; Rz is hydrogen; 'm' is 0 or 1; and
Figure imgf000075_0002
is 2,6-dichlorophenyl, 2-chloro-6-trifluoromethylphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 2- (trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2-chloro-3-(trifluoromethyl)phenyl, 3- fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 5-fluoro-2- (trifluorom ethyl )phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2-bromo-6-chlorophenyl or 2,6- bis-trifluorom ethyl -phenyl.
13. A compound selected from
Methyl 6-(4-carbamoylphenyl)-4-[(2,6-dichlorophenyl)carbonyl]-4H- thieno[3,2-£]pyrrole-2-carboxylate;
4-{4-[(2,6-Dichlorophenyl)carbonyl]-2-(dimethylcarbamoyl)-4H-thieno[3,2-^] pyrrol-6-yl}benzoic acid;
6-(4-Carbamoylphenyl)-4-[(2,6-dichlorophenyl)carbonyl]-N,N-dimethyl-4H- thieno[3,2-£]pyrrole-2-carboxamide;
4-[(2,6-Dichlorophenyl)carbonyl]-6-[4-(hydroxycarbamoyl)phenyl]-N,N- dimethyl-4H-thieno[3,2-£]pyrrole-2-carboxamide;
4-[4-(2,6-Dichlorobenzoyl)-2-(morpholin-4-ylcarbonyl)-4H-thieno[3,2- £]pyrrol-6-yl]benzoic acid; 4-[4-(2-Chloro-6-trifluoromethyl-benzoyl)-2-dimethylcarbamoyl-4H- thieno[3,2-b]pyrrol-6-yl]-3-fluoro-benzoic acid;
4-[4-(2-Chloro-6-trifluoromethyl-benzoyl)-2-dimethylcarbamoyl-4H- thieno[3,2-b]pyrrol-6-yl]-benzoic acid;
4-[l-(2,6-Dichlorobenzoyl)-5-(dimethylcarbamoyl)-lH-thieno[3,2-c]pyrazol- 3-yl] benzoic acid;
4-[ 1 -(2-Chloro-6-trifluoromethyl-benzoyl)-5 -dimethylcarbamoyl- IH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid;
4-[ 1 -(2-Chloro-6-trifluoromethyl-benzoyl)-5 -dimethylcarbamoyl- IH- thieno[3,2-c]pyrazol-3-yl]-3-fluoro-benzoic acid;
4-[ 1 -(2-Chloro-6-trifluoromethyl-benzoyl)-5 -cyclopropylcarbamoyl- IH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid;
4-[l-(2-Chloro-6-trifluoromethyl-benzoyl)-5-(2-hydroxy-ethylcarbamoyl)-lH- thieno[3,2-c]pyrazol-3-yl]-benzoic acid;
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid;
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]-N- [(trifluoromethyl)sulfonyl]benzamide;
4-[l-(2-Chloro-6-fluorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3- yljbenzoic acid;
4-{ l-[2-Chloro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[2-Fluoro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-[l-(2,6-Difluorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid;
4-{5-Methyl-l-[2-(trifluoromethyl)benzoyl]-lH-thieno[3,2-c]pyrazol-3-yl} benzoic acid;
4-(l-{[2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-5-methyl-lH- thieno[3,2-c] pyrazol-3-yl)-3-fluorobenzoic acid;
4-(l-{[2-Chloro-6-(trifluoromethyl)phenyl]carbonyl}-5-methyl-lH- thieno[3,2-c] pyrazol-3-yl)-2-fluorobenzoic acid;
4-[l-(2,3-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]benzoic acid; 4-{ l-[2-Chloro-3-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[3-Fluoro-5-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[4-Fluoro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[5-Fluoro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[4-Chloro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-{ l-[5-Chloro-2-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl}benzoic acid;
4-[l-(2,6-Dichlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3-yl]-3- fluorobenzoic acid;
4-[l-(2-Chloro-6-methylbenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3- yljbenzoic acid;
4-[l-(2-Bromo-6-chlorobenzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3- yljbenzoic acid;
3- Fluoro-4-{ l-[2-fluoro-6-(trifluoromethyl)benzoyl]-5-methyl-lH-thieno[3,2- c]pyrazol-3-yl} benzoic acid;
4- [l-(2,6-Bis-trifluoromethyl-benzoyl)-5-methyl-lH-thieno[3,2-c]pyrazol-3- yl] -benzoic acid;
and pharmaceutically acceptable salts thereof.
14. A compound of formula
Figure imgf000077_0001
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.
16. A method of treating a RORyt mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 14.
17. The method according to claim 16, 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.
18. The method according to claim 16, wherein the disease, disorder, syndrome or condition is chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, or cough.
19. 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 and inflammatory bowel disease comprising administering a compound according to any one of claims 1 to 14.
20. A process for preparing compound of formula (la)
)n
Figure imgf000078_0001
(la)
or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of formula (1) with a compound of formula (2) to obtain a compound of formula (3); reacting the compound of formula (3) with compound of formula (4); and optionally converting the compound of formula (la) to a pharmaceutically acceptable salt thereof:
Figure imgf000079_0001
wherein,
Z is selected from CR1 and N;
R1 is selected from hydrogen and Ci-8alkyl;
R2 is selected from hydrogen, Ci-8alkyl, -C(0)OR9, -C(0)N(CH3)2, -
CO HCH2CH2OH, H
Figure imgf000079_0002
R3 is selected from hydrogen and Ci-8alkyl;
R4 is selected from -C(0)ORz, -C(0) RxRy and -C(0) HS(0)2Rx;
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl, Ci-8alkyl and haloCi-8alkyl;
R9 is independently selected from hydrogen and Ci-8alkyl;
each occurrence of Rx and Ry are independently selected from hydrogen, hydroxy, Ci-8alkyl and haloCi-8alkyl;
Rz is independently selected from hydrogen and
Figure imgf000079_0003
'm' is an integer ranging from 0 to 2, both inclusive; and
'n' is an integer ranging from 0 to 5, both inclusive.
21. The process according to claim 20, wherein the compound of formula (1) is reacted with a compound of formula (2) in the presence of base selected from Et3N and DIPEA.
22. The process according to claim 20, wherein the compound of formula (3) is reacted with the compound formula (4) in the presence of [1,1 '- bi s(diphenylphosphino)ferrocene] dichloropall adium (II) (Pd(dppf)Cl2) .
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