WO2015129926A1 - Pyrazole amide derivative - Google Patents

Pyrazole amide derivative Download PDF

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Publication number
WO2015129926A1
WO2015129926A1 PCT/JP2015/056584 JP2015056584W WO2015129926A1 WO 2015129926 A1 WO2015129926 A1 WO 2015129926A1 JP 2015056584 W JP2015056584 W JP 2015056584W WO 2015129926 A1 WO2015129926 A1 WO 2015129926A1
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WO
WIPO (PCT)
Prior art keywords
group
groups
group substituted
alkyl
mmol
Prior art date
Application number
PCT/JP2015/056584
Other languages
French (fr)
Inventor
Hilary Plake Beck
Shon Keith BOOKER
Howard Bregman
Victor J. Cee
Nagasree Chakka
Timothy D. Cushing
Oleg Epstein
Brian M. Fox
Stephanie Geuns-Meyer
Xiaolin Hao
Kenta HIBIYA
Jun Hirata
Zihao Hua
Jason Human
Shinji KAKUDA
Patricia Lopez
Ryota Nakajima
Kazuhisa Okada
Steven H. Olson
Hiroyuki Oono
Lewis D. Pennington
Kosuke Sasaki
Keiko Shimada
Youngsook Shin
Ryan D. WHITE
Ryan P. WURZ
Shuyan Yi
Xiao Mei Zheng
Original Assignee
Teijin Pharma Limited
Amgen Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SG11201607045SA priority Critical patent/SG11201607045SA/en
Priority to MX2016011072A priority patent/MX2016011072A/en
Application filed by Teijin Pharma Limited, Amgen Inc. filed Critical Teijin Pharma Limited
Priority to BR112016019592-2A priority patent/BR112016019592B1/en
Priority to EP15713244.0A priority patent/EP3110810B1/en
Priority to SI201530248T priority patent/SI3110810T1/en
Priority to RU2016138364A priority patent/RU2658827C2/en
Priority to LTEP15713244.0T priority patent/LT3110810T/en
Priority to CA2940696A priority patent/CA2940696C/en
Priority to ES15713244.0T priority patent/ES2673279T3/en
Priority to AU2015223742A priority patent/AU2015223742C1/en
Priority to NZ723766A priority patent/NZ723766B2/en
Priority to PL15713244T priority patent/PL3110810T3/en
Priority to DK15713244.0T priority patent/DK3110810T3/en
Priority to KR1020167026800A priority patent/KR102309352B1/en
Priority to JP2016553682A priority patent/JP6211207B2/en
Priority to CN201580010967.0A priority patent/CN106459003B/en
Priority to RS20180871A priority patent/RS57575B1/en
Publication of WO2015129926A1 publication Critical patent/WO2015129926A1/en
Priority to IL247426A priority patent/IL247426B/en
Priority to PH12016501702A priority patent/PH12016501702A1/en
Priority to HRP20180750TT priority patent/HRP20180750T1/en
Priority to CY20181100769T priority patent/CY1120452T1/en

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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Definitions

  • the present invention relates to novel compounds that modulate RORy activity, pharmaceutical composition, and use in treatment or prevention of autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer diseases.
  • Retinoid-related orphan receptor gamma is a nuclear receptor that binds to DNA and regulates transcription (NPL 1). Two isoforms of RORy that differ only in the N- terminus are generated from the RORC gene; RORyl and RORyt (also referred to as RORy2) (NPL 2). RORy is used as a term to describe both isoforms of RORy 1 and RORyt.
  • RORyl is expressed in a variety of tissues including muscle, kidney, liver, and lung and is known to regulate adipogenesis (NPL 3). Loss of the RORC gene in mice accelerates preadipocyte differentiation to small adipocytes and protects against high fat diet induced insulin resistance. Consequently, by inhibiting the function of RORyl, insulin resistance could be improved.
  • RORyt is expressed exclusively in cells of the immune system (NPLs 4 and 5) and is a master regulator of a Thl 7 cell-related transcriptional network associated with
  • Thl 7 cells are a subset of CD4+ helper T cells implicated as key drivers of the inflammatory process in autoimmunity and characterized by production of the pro-inflammatory cytokine IL-17A. Thl 7 cells also express CCR6, which mediates migration to sites of inflammation, are maintained and expanded by IL-23, through the IL-23 receptor (IL23R), and express other pro-inflammatory cytokines and chemokines, including IL-17F, IL-21, IL-22, CCL20 and GM-CSF, which together promote recruitment of other inflammatory cell types, especially neutrophils, to mediate pathology at the target tissue. RORyt is required for the differentiation of Thl7 cells and directly and indirectly regulates expression of many of these pro-inflammatory mediators (NPL 6).
  • NPL 6 pro-inflammatory mediators
  • RORy-deficient mice have significantly reduced numbers of Thl7 cells in vivo, lack the ability to produce IL-17A and other Thl7-related cytokines ex vivo, and show resistance to induction of various disease models such as EAE, dermatitis, enteritis and nephritis (NPLs 6, and 12 to 14). Therefore, by inhibiting the function of RORy, development of various autoimmune diseases and inflammatory diseases, in which the Thl7 cell-related cytokines are involved, could be suppressed.
  • Thl7 cell-related transcriptional network has been observed in other immune cell types that may also be important in disease pathogenesis, namely CD8+ T cells, so called Tel 7s, ⁇ T cells, natural killer T cells, innate lymphoid cells, natural killer cells, and mast cells (NPLs 7 and 8).
  • Thl7 cell-related cytokines and chemokines have been implicated in the pathogenesis of various human autoimmune and inflammatory diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease, emphysema, lung fibrosis, systemic erythematodes, vasculitis, Wegener granuloma, polymyalgia rheumatica, giant cell arteritis, arteriosclerosis, autoimmune myositis, uveitis, dry eye, inflammatory bowel disease, alcohol-induced hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, viral hepatitis and type 1 diabetes. (NPLs 9 to 11).
  • RORyt is known to possess an inhibitory effect on the anti-tumorigenic activity of Th9 cells ⁇ a subtype of helper T cells (NPL 15).
  • NPL 15 helper T cells
  • a RORy modulator can be expected to show therapeutic or preventive benefit in treatment of; metabolic diseases such as diabetes; for autoimmune diseases or inflammatory diseases and; for melanoma and other cancer diseases.
  • NPL 1 Gigure, Endocrine. Reviews. 20: 689-725, 1999
  • NPL 2 Jetten, Nucl. Recept. Signal. 7: e003, 2009
  • NPL 3 Meissburger et al., EMBO Mol. Med. 3: 637-651, 2011
  • NPL 4 Hirose et al, Biochem. Biophys. Res. Commun. 30: 1976-1983, 1994
  • NPL 5 Eberl and Liftman., Science. 9: 248-251 , 2004
  • NPL 6 Ivanov et al., Cell 126: 1121-1133, 2006
  • NPL 7 Sutton et al., Eur. J. Immunol. 42: 2221-2231, 2012
  • NPL 8 Hueber et al., J. Immunol., 184: 3336-3340, 2010
  • NPL 9 Miossec et al., Nature Reviews Drug Discovery 11 : 763-776,2012
  • NPL 10 Hammerich et al., Clin. Dev. Immunol. 2011 : Article ID 345803, 2011
  • NPL 11 Ferraro et al., Diabetes 60: 2903-2913, 2011
  • NPL 12 Pantelyushin et al., J Clin Invest. 122: 2252-2256, 2012
  • NPL 13 Buonocore et al., Nature 464: 1371-1375, 2010
  • NPL 14 Steinmetz et al., J. Am. Soc. Nephrol. 22: 472-483, 201 1
  • NPL 15 Purwar et ' al., Nat. Med. 18: 1248-1254, 2012
  • the object of the present invention is to provide a compound having a function of inhibiting RORy activity.
  • R 1 is selected from F, CI, Br, a C t to C 6 alkyl group substituted by 0, 1, 2 or 3 R a groups and a C 3 to C 8 cycloalkyl group substituted by 0, 1 , 2 or 3 R a groups;
  • Y is selected from a C 4 to C 6 cycloalkyl group, a C 6 to C 9 bicycloalkyl group and a C 6 to C 9 spiroalkyl group, all of which are substituted by a R 2 group, 0 or 1 R 6 group and 0, 1, 2 or 3 R 7 groups;
  • R 2 is selected from -OH, -C0 2 H, -S0 3 H, -CONH 2 , -S0 2 NH 2 , a (Q to C 6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 R c groups, a (Ci to C alkyl)aminocarbonyl group substituted by 0, 1 , 2 or 3 R° groups, a Cj to C alkylsulfonyl group substituted by 0, 1 , 2 or 3 R c groups, a C ⁇ to C 6 alkylaminosulfonyl group substituted by 0, 1 , 2 or 3 R c groups, a (hydroxycarbonyl)(C 1 to C 3 alkyl) group substituted by 0, 1 , 2 or 3 R c groups, a (C ⁇ to C 6 alkoxy)carbonyl(Ci to C 3 alkyl) group substituted by 0, 1, 2 or 3 R° groups, a (Ci to C 6 to C 3 alkyl) group
  • R° and R' are independently selected from H, F, -OH, - H 2 , -CN, a C ⁇ to C 6 alkyl group substituted by 0, 1 , 2 or 3 R b groups and a Ci to C 6 alkoxy group substituted by 0, 1 , 2 or 3 R b groups;
  • R 3 is selected from H, F, CI, -CH 3 and -CF 3 ;
  • R 4 is selected from a C 1 to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (C 2 to C 6 alkenyl)(Ci to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (C 2 to C alkynyl)(C! to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (C ⁇ to C 6 alkoxy)(C 2 to C 4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (C to C 10
  • R 5 is selected from a C 6 to Cio aryl group substituted by 0, 1 , 2, 3, 4 or 5 R 1 groups, a 5- to 10-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R 1 groups, a C 3 to C 8
  • cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R J groups a C 3 to C 8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 R J groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R J groups;
  • R 8 and R 9 are independently selected from H, F, -OH, -NH 2 , a Q to C 3 alkyl group substituted by 0, 1 , 2 or 3 R groups, and a Q to C 6 alkoxy group substituted by 0, 1 , 2 or 3 R h groups; or R 8 and R 9 together form an oxo group or a thioxo group;
  • R 12 is H; or R 4 and R 12 together are -CR m R m -CR 13 R 14 -CR m R m - or -CR 13 R 14 -CR m R m - CR m R m - to form a pyrrolidine ring;
  • R 13 is selected from H, a Ci to C alkyl group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a
  • R 14 is independently selected from H and a d to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 R e groups; or R 13 and R 14 together form a C 3 to Cg cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 R s groups, C 3 to C 8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 R g groups; R m is independently selected from H, F, CI, -CH 3 and -CF 3 ;
  • R 8 and R J are , independently selected from F, CI, a C.i to C 6 alkyl group, -OH, -CN, -NH 2 , -N0 2 , -C0 2 H, a Ci to C 6 alkoxy group, a monoid to C 6 alkyl)amino group, a di(d to C 6 alkyl)amino group, -CF 3 , a d to C 6 alkylene group substituted by 0, 1, 2 or 3 R 1 , groups, a C 2 to C 6 alkenylene group substituted by 0, 1, 2 or 3 R 1 groups and an oxo group;
  • R f and R' are are independently selected from F, CI, Br, -OH, -CN, -N0 2, -C0 2 H, a d to C 6 alkyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkenyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkynyl group substituted by 0, 1, 2 or 3 R k groups, a C 3 to Cg cycloalkyl group substituted by 0, 1, 2 or 3 R k groups, a d to C 6 alkoxy group substituted by 0, 1, 2 or 3 R k groups, a C 3 to C 8 cycloalkyloxy group substituted by 0, 1, 2 or i R k groups, -SH, a C 1 to C 6 alkylthio group substituted by 0, 1, 2 or 3 R groups, a C 3 to Cg cycloalkylthio group substituted by 0, 1, 2 or 3 R k groups, a (C
  • R a , R b , R c , R 6 , R h , R k and R 1 are independently selected from F, a d to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Cj to C 6 alkoxy group, a mono(C! to C 6 alkyl)amino group, a di(C ! to C 6 alkyl)amino group, -CF 3 and an oxo group. :
  • k 0, 1 or 2;
  • n 1 , 2 or 3.
  • R 4 is a C to C 6 alkyl group substituted by 0, 1, 2 or 3 R e groups, a (C 6 to Cio aryl)(Ct to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups, a (C 3 to C 8
  • a pharmaceutical composition comprising a compound according to any one of sections 1 to 11 or pharmaceutically acceptable salt thereof.
  • the present invention provides a novel compound having excellent activity of inhibiting RORy and a method for producing the same.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent or a preventive agent for autoimmune diseases, inflammatory diseases (for example, multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease, and asthma), metabolic diseases (especially diabetes), cancer diseases (especially malignant melanoma), or the like.
  • inflammatory diseases for example, multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease, and asthma
  • metabolic diseases especially diabetes
  • cancer diseases especially malignant melanoma
  • each group of the compounds represented by formula (I) of the present invention is defined as described below.
  • the writing order in each group indicates the order of the bonds in formula (I).
  • a (C 3 to C 8 cycloalkylXd to C 3 alkyl) group in R 4 is represented by group wherein "a Ci to C 3 alkyl group” is bonded to nitrogen in formula (I) and "a C 3 to C 8 cycloalkyl group” and "a C ⁇ to C 3 alkyl group” are bonded.
  • the number situated to the right of carbon indicates the number of the carbon.
  • “Ci to C 6” means a group having "1 to 6 carbons”. It is a matter of course that, in the present invention, different number of carbons means a group having that number of carbons.
  • "a Ci to C 4 alkyl group” means alkyl groups having 1 to 4 carbon among those defined by "Ci to C 4 alkyl group”. Treatment of the number of carbons in other groups is the same.
  • a Ci to C 6 alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbons.
  • a methyl group an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2 -methyl butyl group, a 3-methylbutyl group, an 1 -ethylpropyl group, an 1,1-dimethypropyl group, an 1 ,2-dimethylpropyl group, a neopentyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, an 1-methylpentyl group,
  • a Ci to C 4 alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 1 to 4 carbons.
  • a methyl group an ethyl group, a n-propyl group, an isopropyl group a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like.
  • a C 2 to C 4 alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 2 to 4 carbons.
  • a C 2 to C 4 alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 2 to 4 carbons.
  • an ethyl group a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like.
  • a Ci to C 3 alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 1 to 3 carbons.
  • a methyl group an ethyl group, a n-propyl group, an isopropyl group, and the like.
  • a C 2 to C 6 alkenyl group means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbons with an unsaturated double bond.
  • a vinyl group an 1 -propenyl group, a 2-propenyl group, a 2 -methyl- 1 -propenyl group, a 2-methyl-2 -propenyl group, a 2-buten-l-yl group, a 3-buten-l-yl group, a 2-penten-l-yl group, a 3-penten-l-yl group, a 4-penten-l-yl group, a 5-hexen-l-yl group, a 4-hexen-l-yl group, a 3-hexen-l-yl group, a 2-hexen-l-yl group, a 3-methyl-2-buten-l-yl group, a 3-methyl-3-penten-l-yl group, a 3-methyl-2-buten-l-yl group, a
  • a C 2 to C 6 alkynyl group means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbons with an unsaturated triple bond.
  • a C 2 to C 6 alkynyl group means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbons with an unsaturated triple bond.
  • an ethynyl group an 1-propyn-l-yl group, a
  • a Cj to C 6 alkylene group means a bivalent group formed by removing hydrogen from "a d to C 6 alkyl group".
  • a d to C 6 alkyl group For example, there may be mentioned methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.
  • the C ⁇ to C 6 alkylene group can be bonded to one carbon atom or two different carbon atoms to form a ring.
  • a C 2 to C 6 alkenylene group means a bivalent group having a double bond at arbitrary position of "a C 2 to C 6 alkylene group”.
  • vinyl ene propenylene, 1-butenylene, 2-butenylene, 1-pentenyene, 2-pentenyene, 1-hexenyene, 2-hexenyene, 3-hexenyene, and the like.
  • a C 3 to C 8 cycloalkyl group means a cyclic alkyl group having 3 to 8 carbons.
  • a cyclopropyl group a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • a C 4 to C 6 cycloalkyl group means a cyclic alkyl group having 4 to 6 carbons.
  • a cyclobutyl group a cyclopentyl group, a cyclohexyl group, and the like.
  • a C 6 to C 9 bicycloalkyl group means a bicyclic alkyl group having 6 to 9 carbons.
  • a bicyclic alkyl group having 6 to 9 carbons for example, there may be mentioned a
  • bicyclo[3.1.0]hexanyl group a bicyclo[2.2.0]hexanyl group, a bicyclo[2.1.1]hexanyl group, bicyclo[3.2.0]heptanyl group, a bicyclo[2.2.1]heptanyl group, a bicyclo[3.1.1]heptanyl group, a bicyclo[4.1.OJheptanyl group, an octahydropentalenyl group, a
  • bicyclo[2.2.2]octanyl group a bicyclo[3.2.1]octanyl group, a bicyclo[4.2.0]octanyl group, a bicyclo[4.1.1]octanyl group, a bicyclo[5.1.0]octanyl group, an octahydro-lH-indenyl group, a bicyclo[3.2.2]nonanyl group, a bicyclo[3.3.1]nonanyl group, a
  • bicyclo[4.2.1]nonanyl group a bicyclo[5.2.0]nonanyl group, and the like.
  • a C 5 to C 9 bicycloalkyl group means a bicyclic alkyl group having 5 to 9 carbons!
  • a bicyclic alkyl group having 5 to 9 carbons for example, there may be mentioned a
  • bicyclo[l . l. l]pentanyl group bicyclo[3.1.0]hexanyl group, a bicyclo[2.2.0]hexanyl group, a bicyclo[2.1.1]hexanyl group, bicyclo[3.2.0]heptanyl group, a bicyclo[2.2.1]heptanyl group, a bicyclo[3.1.1]heptanyl group, a bicyclo[4.1.0]heptanyl group, an
  • octahydropentalenyl group a bicyclo[2.2.2]octanyl group, a bicyclo[3.2.1]octanyl group, a bicyclo[4.2.0]octanyl group, a bicyclo[4.1.1]octanyl group, a bicyclo[5.1.0]octanyl group, an octahydro-lH-indenyl group, a bicyclo[3.2.2]nonanyl group, a bicyclo[3.3.1]nonanyl 1 group, a bicyclo[4.2.1]nonanyl group, a bicyclo[5.2.0]nonanyl group, and the like.
  • spiroalkyl group means a group consisting of two cycloalkyl moieties that have exactly one atom in common.
  • a C 6 to C 9 spiroalkyl group means a spiroalkyl group having 6 to 9 carbons.
  • a spiro[2.3]hexanyl group a spiro[2.4]heptanyl group, a spiro[3.3]heptanyl group, a spiro[2.5]octanyl groiip, a spiro[3.4]octanyl group, a spiro[2.6]nonanyl group, a
  • a (C 6 to C 9 spiroalkyl)(Ci to C 3 alkyl) group means a group obtained by substituting "a d to C 3 alkyl group” with "a (C 6 to C 9 spiroalkyl) group” at arbitrary position.
  • a spiro[2.3]hexanyl methyl group a spiro[2.4]heptanyl methyl group, a spiro[3.3]heptanyl methyl group, a
  • spiro[2.5]octanyl methyl group a spiro[3.4]octanyl methyl group, a spiro[2.6]nonanyl methyl group, a spiro[3.5]nonanyl methyl group, a spiro[4.4]nonanyl methyl group, and the like.
  • a C 3 to C 8 cycloalkenyl group means a group having a double bond at arbitrary position of "a C 3 to C 8 cycloalkyl group” having 3 to 8 carbons.
  • a cyclopropenyl group a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, and the like.
  • a (C 3 to C 8 cycloalkylXQ to C 3 alkyl) group means a group obtained by substituting "a d to C 3 alkyl group” with "a C 3 to C 8 cycloalkyl group” at arbitrary position.
  • a cyclopropylmethyl group a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a
  • cyclohexylmethyl group a cyclohexylethyl group, a cycloheptylmethyl group, a cycloheptylethyl group, a cyclooctylmethyl group, and the like.
  • a (C 3 to C 8 cycloalkenylXQ to C 3 alkyl) group means a group obtained by substituting "a Q to C 3 alkyl group” with "a C 3 to C 8 cycloalkenyl group” at arbitrary position. For example, there may be mentioned a
  • cyclopropenylmethyl group a cyclopropenyl ethyl group, a cyclopropenylpropyl group, a cyclobutenylmethyl group, a cyclobutenylethyl group, a cyclopentenylmethyl group, a cyclopentenylethyl group, a cyclohexenylmethyl group, a cyclohexenylethyl group, a cycloheptenylmethyl group, a cycloheptenylethyl group, a cyclooctenylmethyl group, and the like.
  • a (C 2 to C 6 alkenyl)(Ci to C 3 alkyl) group means a group obtained by substituting "a C ⁇ to C 3 alkyl group” with "a C 2 to C 6 alkeriyl group” at arbitrary position.
  • a 2-propenyl group an l-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 2-buten-l-yl group, a
  • a (C 2 to C 6 alkynyl)(d to C 3 alkyl) group means a group obtained by substituting "a Ci to C 3 alkyl group” with "a C 2 to C 6 alkynyl group” at arbitrary position.
  • a 2-propyn-l-yl group an l-methyl-2-propyn-l-yl group, an l-ethyl-2-propyn-l-yl group, a 2-butyn-l-yl group, an l-methyl-2-butyn-l-yl group, an l-ethyl-2-butyn-l-yl group, a 3-butyn-l-yl group, an l-methyl-3-butyn-l-yl group, an l-ethyl-3-butyn-l-yl group, a 2-pentyn-l-yl group, an l-methyl-2-propyn-l-yl group, an l-ethyl-2-propyn-l-yl group, a 2-butyn-l-yl group, an l-methyl-2-butyn-l-yl group, an l-ethyl-2-butyn-l-yl group, a 3-but
  • a Ci to C 6 alkoxy group means a group obtained by substituting an oxy group with "a Ci to C 6 alkyl group".
  • a (Q to C 6 alkoxy)(C 2 to C 4 alkyl) means a group obtained by substituting "a C 2 to C 4 alkyl group” with "a C t to C 6 alkoxy group” or, in other words, a group obtained by replacing one carbon of a C 4 to Cn alkyl group with one oxygen at arbitrary chemically possible position.
  • a methoxyethyl group for example, there may be mentioned a methoxyethyl group, an ethoxyethyl group, a propyloxyethyl group, an isopropyloxyethyl group, a butyloxyethyl group, an isobutyloxyethyl group, a sec-butyloxyethyl group, a tert-butyloxyethyl group, an isopentyloxyethyl group, a 2-methylbutyloxyethyl group, a 3-methylbutyloxyethyl group, an 1 -ethylpropyloxy ethyl group, an
  • neopentyloxyethyl group a hexyloxyethyl group, a 4-methylpentyloxyethyl group, a 3-methylpentyloxyethyl group, a 2-methylpentyloxyethyl group, an
  • 2.3- dimethylbutyloxyethyl group an 1-ethylbutyloxyethyl group, a 2-ethylbutyloxyethyl group, a methoxypropyl group, an ethoxypropyl group, a propyloxypropyl group, an isopropyloxypropyl group, a butyloxypropyl group, an isobutyloxypropyl group, a sec-butyloxypropyl group, a tert-butyloxypropyl group, an isopentyloxypropyl group, a
  • a C ⁇ to C 6 alkylthio group means a group obtained by substituting a thio group with "a Ci to C 6 alkyl group”.
  • a methylthio group an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, a pentylthio group, a neopentylthio group, a tert-pentylthio group, a
  • a C 3 to C 8 cycloalkylthio group means a group obtained by substituting a thio group with "a C 3 to C 8 cycloalkyl group”.
  • a cyclopropylthio group a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, a cyclooctylthio group, and the like.
  • a (Ci to C 6 alkyl)carbonyl group means a group obtained by substituting a carbonyl group with "a C ⁇ to C 6 alkyl group”.
  • a (Cj to C 6 alkoxy)carbonyl group means a group obtained by substituting a carbonyl group with "a C] to C 6 alkoxy group".
  • a methoxycarbonyl group an ethoxycarbonyl group
  • a ethoxycarbonyl group an ethoxycarbonyl group
  • n-propoxycarbonyl group an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a n-pentoxycarbonyl group, an isopentoxycarbonyl group, a 2-methylbutoxycarbonyl group, a 3 -methylbutoxy carbonyl group, an 1 -ethylpropoxycarbonyl group, an
  • neopentoxycarbonyl group a 4-rhethylpentoxycarbonyl group, a 3-methylpentoxycarbonyl, a 2-methylpentoxycarbonyl group, an 1-methylpentoxycarbonyl group, a
  • a C 3 to C 8 cycloalkyloxy group means a group obtained by substituting an oxy group with "a C 3 to C 8 cycloalkyl group”.
  • a cyclopropyloxy group a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, and the like.
  • a mono(Ci to C 6 alkyl)amino group means a group obtained by substituting an amino group with "a C ⁇ to C 6 alkyl group”.
  • a methylamino group an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group, a pentylamino group, a hexylamino group, and the like.
  • a di(Ci to C 6 alkyl)amino group means a group obtained by substituting an amino group with two of the same or different "a Q to C 6 alkyl group".
  • a dimethylamino group a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, a di(sec-butyl)amino group, a di(tert-butyl)amino group, a dipentylamino group, a dihexylamino group, and the like.
  • a (Ci to C 6 alkyl)aminocarbonyl group means a group obtained by substituting a carbonyl group with "a (Cj to C 6 alkyl)amino group".
  • a methylaminocarbonyl group an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a
  • butylaminocarbonyl group an isobutylaminocarbonyl group, a sec-butylaminocarbonyl group, a tert-butylaminocarbonyl group, a pentylaminocarbonyl group, a
  • a Ci to C 6 alkylsulfonyl group means a group obtained by substituting a sulfonyl group with "a C ⁇ to C 6 alkyl group”.
  • a methylsulfonyl group an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a
  • a C ' i to C 6 alkylaminosulfonyl group means a group obtained by substituting a sulfonyl group with "a monoCCi to C 6 alkyl)amino group".
  • a methylaminosulfonyl group an ethylaminosulfonyl group, a propylaminosulfonyl group, an isopropylaminosulfonyl group, a
  • butylaminosulfonyl group an isobutylaminosulfonyl group, a sec-butylaminosulfonyl group, a tert-butylaminosulfonyl group, a pentylaminosulfonyl group, a
  • a (hydroxycarbonyl)(C] to C 3 alkyl) group means a group obtained by substituting "a Q to C 3 alkyl group” with "a (hydroxycarbonyl) group” at arbitrary position.
  • a hydroxycarbonylmethyl group a (l-hydroxycarbonyl)ethyl group, a (2-hydroxycarbonyl)ethyl group, a
  • a (Ci to C 6 alkoxy)carbonyl(C 1 to C 3 alkyl) group means a group obtained by substituting "a C ⁇ to C 3 alkyl group” with "a (C ⁇ to C 6 alkoxy)carbonyl group” at arbitrary position. For example, there may be mentioned a
  • methoxycarbonylmethyl group a methoxycarbonylethyl group, a
  • a (Ci to C to C 3 alkyl) group means a group obtained by substituting "a Q to C 3 alkyl group” with "a (Ci to C 6 alkyl)sulfonyl group” at arbitrary position.
  • a Q to C 3 alkyl group with "a (Ci to C 6 alkyl)sulfonyl group” at arbitrary position.
  • a methlsulfonyl methyl group a methylsulfonylethyl group
  • a (3-methylsulfonyl)propyl group a
  • ethylsulfonylethyl group an (3-ethylsulfonyl)propyl group, an (2-ethylsulfonyl)propyl group, an (l-ethylsulfonyl)propyl group, an (l-ethylsulfonyl)(l-methyl)ethyl group , and the like.
  • a C 6 to C 10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbons.
  • a phenyl group a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, an azulenyl group, and the like.
  • a C 6 to C 10 aryloxy group means a group obtained by
  • a (C to C 10 aryl)(C] to C 3 alkyl) group means a group obtained by substituting "a Ci to C 3 alkyl group” with "a C 6 to C] 0 aryl group”.
  • a benzyl group a phenethyl group, a phenylpropyl group, a naphthylmethyl group, and the like.
  • a 5- to 10-membered heteroaryl group means a 5- to 10-membered monocyclic or bicyclic heterocyclic group having aromaticity, wherein the heterocyclic group contains 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen.
  • the other ring may be non-aromatic ring.
  • the number of respective heteroatoms and combinations thereof are not particularly limited as long as ring having prescribed number of members carl be formed and can exist chemically stably.
  • a 5- to 10-membered heteroaryl group for example, there may be mentioned a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyridazinyl group, a furyl group, a thienyl group, a pyrrole group, a pyrazolyl group, an 1,3-dioxaindanyl group, an isoxazolyl group, an isothiazolyl group, a benzoiuranyl group, an isobenzofuryl group, a benzothienyl group, an indolyl group, an isoindolyl group, a chromanyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, a pyranyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triaziny
  • a (5- to 10-membered heteroarylXQ to C 3 alkyl) group means a group obtained by substituting "a Ci to C 3 alkyl group” with "a 5- to 10-membered heteroaryl group”.
  • a pyridylmethyl group for example, there may be mentioned a pyridylmethyl group, a thienylmethyl group, a thiazolylmethyl group, a benzothiazolylmethyl group, a
  • a 3- to 8-membered heterocycloalkyl group means a 3- to 8-membered aliphatic heterocyclic group which may be saturated or partially unsaturated, wherein the ring contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • a piperidyl group a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a morpholyl group, and the like.
  • a (3- to 8-membered heterocycloalkyl)(Ci to C 3 alkyl) group means a group obtained by substituting "a d to C 3 alkyl group” with "a 3- to 8-membered heterocycloalkyl group”. For example, there may be mentioned a
  • piperidylmethyl group a tetrahydrofuranylmethyl group, a tetrahydropyranylmethyl group, a tetrahydrothienylmethyl group, a morpholinoethyl group, a oxetan-3-ylmethyl group, and the like.
  • spiroheteroalkyl group means a spiroalkyl group in which 1 to 4 carbon atoms replaced with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • a C 6 to C 9 spiroheteroalkyl group means a spiroalkyl group having 6 to 9 carbons. For example, there may be mentioned a 4-oxaspiro[2.4]heptanyl group, a 4-oxaspiro[2.5]octaneyl group, and the like.
  • a (C 5 to C 9 bicycloalkylXCi to C 3 alkyl) group means a group obtained by substituting "a Q to C 3 alkyl group” with "a C 5 to C 9 bicycloalkyl group” at arbitrary position.
  • a bicyclo [1.1.1 Jpentanyl methyl group a bicyclo[3.1.0]hexanyl methyl group
  • a bicyclo [3. l .OJhexanyl ethyl group a bicyclo[2.2.0]hexanyl methyl group
  • a bicyclo[2.2.0]hexanyl ethyl group a bicyclo [2.2.0]hexanyl ethyl group
  • bicyclo[3.2.0]heptanyl methyl group a bicyclo[3.2.0]heptanyl ethyl group, a
  • bicyclo[2.2.1]heptanyl methyl group a bicyclo[2.2.1]heptanyl ethyl group, a
  • octahydropentalenyl methyl group a bicyclo[2.2.2]octanyl methyl group, a
  • heterocycloalkyl group means a bicycloalkyl group in which 1 to 4 carbon atoms replaced with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • a C 6 to C 9 heterobicycloalkyl group means a heterobicycloalkyl group having 6 to 9 carbons. For example, there may be mentioned a
  • a (C 6 to C 9 heterobicycloalkyl)(Ci to C 3 alkyl) group means a group obtained by substituting "a C] to C 3 alkyl group” with "a C 6 to C 9 heterobicycloalkyl group” at arbitrary position.
  • a 7-oxabicyclo[2.2.1]heptanyl methyl group there may be mentioned a 7-oxabicyclo[2.2.1]heptanyl ethyl group, and the like.
  • each R a group can be selected independently and the Q to C 6 alkyl group can be substituted by the same R a groups or by different R a groups.
  • meaning of other expressions such as "a Ci to C alkyl group substituted by 0, 1, 2 or 3 R b groups” and the like mean similar situations.
  • the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from F, CI, Br, a Ci to C 6 alkyl group substituted by 0, 1, 2 or 3 R a groups and a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2 or 3 R a groups; wherein R a is, independently selected from F, Ci to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono(C 1 to C 6 alkyl)amino group, a di(Ci to C 6 alkyl)amino group, -CF 3 and an oxo group.
  • the "a Ci to C 6 alkyl group substituted by 0, 1, 2 or 3 R a groups" in R 1 is preferably Ci to C 3 alkyl group substituted by 0, 1, 2 or 3 R a groups, and more preferable is a trifluoromethyl group or a difluoromethyl group.
  • the "a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2 or 3 R a groups" in R 1 is preferably C 3 to C 4 cycloalkyl group substituted by 0, 1, 2 or 3 R a groups, more preferable is a cyclopropyl group substituted by 0, 1, 2 or 3 R a groups.
  • R 1 is preferably CI, a Ci to C 4 alkyl group substituted by 0, 1, 2 or 3 R a groups or a cyclopropyl group substituted by 0, 1 , 2 or 3 R a groups, and more preferable is a trifluoromethyl group, a difluoromethyl group or CI.
  • Y is a C 4 to C cycloalkyl group, a C 6 to C 9 bicycloalkyl group or a C 6 to C 9 spiroalkyl group, all of which are substituted by a R group, 0 or 1 R group and 0, 1, 2 or 3 R groups;
  • R 2 is selected from -OH, -C0 2 H, -S0 3 H, -CONH 2 , -S0 2 NH 2 , a (d to C 6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 R c groups, a (Ci to C 6
  • alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 R c groups a d to C 6 alkylsulfonyl group substituted by 0, 1, 2 or 3 R c groups, a d to C 6 alkylaminosulfonyl group substituted by 0, 1, 2 or 3 R° groups, a (hydroxycarbonyl)(Ci to C 3 alkyl) group substituted by 0, 1, 2 or 3 R° groups, a (d to C 6 alkoxy)carbonyl(C 1 to C 3 alkyl) group substituted by 0, 1, 2 or 3 R c groups, a (Ci to C 6 alkyl)sulfqnyl(d to C 3 alkyl) group substituted by 0, 1 , 2 or 3 R c groups and a (C 2 to C 6 alkenyl)(C ! to C 3 alkyl) group substituted by 0, 1, 2 or 3 R c groups;
  • R 6 and R 7 are independently selected from H, F, -OH, -NH 2 , -CN, a d to C 6 alkyl group substituted by 0, 1, 2 or 3 R b groups and a d to C 6 alkoxy group substituted by 0, 1, 2 or 3 b
  • R b and R c are , independently selected from F, a C] to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Q to C 6 alkoxy group, a monoid to C 6 alkyl)amino group, a di(Ci to C 6 alkyl)amino group, -CF 3 and an oxo group;
  • 2 6 7 group all of which are substituted by a R group, 0 or 1 R group and 0, 1, 2 or 3 R groups" in Y is preferably a group represented by formula (Il-a), formula (Il-b), formula (II-c) or
  • k 0, 1 or 2;
  • n 1, 2 or 3.
  • Y is preferably a group represented by formula (Il-a), formula (II-c) or formula (Il-d); and more preferably a group represented by formula (Il-a) or formula (Il-d).
  • variable, n is preferably 2 in a group represented by formula (Il-d).
  • R 2 in Y is preferably -C0 2 H, -S0 3 H, -CONH 2 , -S0 2 NH 2 , a (C, to C 2
  • R 6 in Y is preferably H or a Q to C 4 alkyl group without R b group, and more preferable is H, a methyl group or an ethyl group.
  • R in Y is preferably H or a Cj to C 2 alkyl group without R group, and more preferable is H or a methyl group.
  • R 3 is selected from H, F, CI, -CH 3 and -CF 3 .
  • R 3 is preferably H.
  • R 4 is selected from a Q to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (C 2 to C 6 alkenyl)(d to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (C 2 to C 6 alkynyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (d to C 6 alko ⁇ y)(C 2 to C 4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups,
  • cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5R 8 groups a (C 3 to C 8 cycloalkyl)(C 1 to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, a (C 3 to C 8 cycloalkenyl)(C 1 to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, a 3- to 8-membered
  • heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R s groups a (3- to 8-membered heterocycloalkyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups, a C 6 to C 9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups, a (C 6 to C 9 spiroalkyl)(Ci to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, a C 6 to C 9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, a C 5 to C 9 bicycloalkyl group substituted by 0, 1,
  • R 8 groups a C 6 to C 9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups and a (C 6 to C 9 heterobicycloalkyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups;
  • R e isindependently selected from F, a d to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono ⁇ to C 6 alkyl)amino group, a di(C ! to C 6 alkyl)amino group, -CF 3 and an oxo group;
  • R f is independently selected from F, CI, Br, -OH, -CN, -N0 2j -C0 2 H, a Ci to C 6 alkyl group substituted by 0, 1 , 2 or 3 R k groups, a C 2 to C 6 alkenyl group substituted by 0, 1 , 2 or 3 R k groups, a C 2 to C 6 alkynyl group substituted by 0, 1 , 2 or 3 R k groups, a C 3 to Cg cycloalkyl group substituted by 0, 1, 2 or 3 R k groups, a Q to C 6 alkoxy group substituted by 0, 1 , 2 or 3 R k groups, a C 3 to Cg cycloalkyloxy group substituted by 0, 1 , 2 or 3 R k groups, -SH, a Ci to C 6 alkylthio group substituted by 0, 1 , 2 or 3 R k groups, a C 3 to Cg cycloalkylthio group substituted by 0, 1 , 2 or 3
  • R k is independently selected from F, a Q to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono ⁇ to C 6 alkyl)amino group, a di(Cj to C 6 alkyl)amino group, -CF 3 and an oxo group;
  • R g is is independently selected from F, CI, a d to C alkyl group, -OH, -CN, -NH 2 , -N0 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono(d to C 6 alkyl)amino group, a di(C 1 to C 6 alkyl)amino group, -CF 3 , a Ci to C 6 alkyl ene group substituted by 0, 1 , 2 or 3 R 1 groups, a C 2 to C 6 alkenylene group substituted by 0, 1 , 2 or 3 R 1 groups and an oxo group; wherein R 1 is independently selected from F, a Q to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono(C! to C 6 alkyl)amino group, a di(Ci to C 6 alkyl
  • the "a d to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5R e groups" in R 4 is preferably C 2 to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5R e and more preferably a tert-butylmethyl group or a 3,3,3-trifluoro-2,2-dimethylpropyl group.
  • the "a (C 2 to C 6 alkenylXd to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups" in R 4 is preferably one having 3 to 6 carbons in (C 2 to C 6 alkenyl)(Ci to C 3 alkyl) and more preferably a 3 -methyl-2-buten-l-yl group.
  • the "a (C 2 to C 6 alkynyl)(d to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5R e groups" in R 4 is preferably one having 4 to 8 carbons in (C 2 to C 6 alkynyl)(d to C 3 alkyl) and more preferably a 4,4-dimethyl-2-pentyn-l-yl group.
  • the "a (d to C 6 alkoxy)(C 2 to C 4 alkyl) group substituted by 0, 1,, 2, 3, 4 or 5R e groups" in R 4 is preferably one having 3 to 7 carbons in (d to C 6 alkoxy)(C 2 to C 4 alkyl), more preferably a d to C 4 alkoxyethyl group substituted by 0, 1, 2 or 3 alkyl groups, and even more preferably a 2,2-dimethyl-2-methoxyethyl group or a 2-(tert-butoxy)ethyl group.
  • the "a (C 6 to C 10 arylXd to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R f groups" in R 4 is preferably a benzyl group substituted by 0, 1, 2, 3, 4 or 5 R f 's; more preferably a benzyl group substituted by 1 , 2 or 3 groups selected from F and CI, or a unsubstituted benzyl group; and even more preferable is a 4-fluorobenzyl group, a
  • the "a (5- to 10-membered heteroaryl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R f groups" in R 4 is preferably a pyridylmethyl group, a thienylmethyl group, a thiazolylmethyl group or a furanylmethyl group.
  • the "a C 3 to C 8 cycloalkyl group substituted by 0, 1 , 2, 3 , 4 or 5 R 8 groups" in R 4 is preferably C 3 to C 6 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups and more preferably a 2,2-dimethylcyclobutyl group or a 4,4-dimethylcyclohexyl group.
  • the "a (C 3 to C 8 cycloalkylXQ to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups" in R 4 is preferably a C 3 to C 6 cycloalkyl methyl group substituted by 0, 1, 2, 3 or 4 R g groups; and more preferable is a (l-fluorocyclopentyl)methyl group, a
  • the "a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R s groups" in R 4 is preferably a 3- to 6-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups.
  • the "a (3- to 8-membered heterocycloalkylXQ to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups" in R 4 is preferably a 3- to 6-membered heterocycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups; more preferably a
  • the "a C 6 to C 9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups" in R 4 is preferably a C 7 to C 8 spiroalkyl ring substituted by 0, 1, 2, 3, 4 or 5 R g groups; more preferably a spiro[2.5]octan-l-yl group, a spiro[3.5]nonan-l-yl group, a
  • the "a (C 6 to C 9 spiroalkyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups" in R 4 is preferably a C 6 to C 8 spiroalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups; more preferably a spiro[2.5]octan-6-ylmethyl group substituted by 0, 1, 2 or 3 R g groups or a spiro[2.3]hexan-5-ylmethyl group substituted by 0, 1, 2 or 3 R g groups; and even more preferable is a spiro[2.5]octan-6-ylmethyl group,
  • R 4 is preferably a C 7 to C 8 spiroheteralkyl ring substituted by 0, 1, 2, 3, 4 or 5 R 8 groups.
  • the "a C 5 to C 9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R s groups" in R 4 is preferably a C to C 8 bicycloalkyl ring substituted by 0, 1, 2, 3, 4 or 5 R g groups; more preferably a bicyclo[3.1.0]hexan-3-yl group substituted by 0, 1, 2 or 3 R 8 groups; and even more preferable is a 6,6-dimethylbicyclo[3.1.0]hexan-3-yl group.
  • the "a (C 5 to C 9 bicycloalkylXd to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R s groups" in R 4 is preferably a C 5 to C 7 bicycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups; more preferably a (bicyclo[l . l . l]pentan-l-yl)methyl group substituted by 0, 1, 2 or 3 R g groups or a (bicyclo[2.2.1]heptan-l-yl)methyl group substituted by 0, 1, 2 or
  • the "a (C 6 to C heterobicycloalkyl)(C ! to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups" in R 4 is preferably a C 6 to C 7 heterobicycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups; more preferably (7-oxabicyclo[2.2.1]heptan-l-yl)methyl group substituted by 0, T, 2 or 3 R 8 groups; and, even more preferable is
  • R 5 is selected from a C to C 10 aryl group substituted by 0, 1, 2, 3,
  • R' groups a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R 1 groups, a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R J groups, a C 3 to C 8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 R J groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R J groups;
  • R' is independently selected from F, CI, Br, -OH, -CN,- -N0 2, -C0 2 H, a d to C 6 alkyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkenyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkynyl group substituted by 0, 1, 2 or 3 R k groups, a C 3 to Cg cycloalkyl group substituted by 0, 1 , 2 or 3 R k groups, a d to C 6 alkoxy group substituted by 0, 1, 2 or 3 R k groups, a C 3 to C cycloalkyloxy group substituted by 0, 1 , 2 or 3 R k groups, -SH, a Ci to C 6 alkylthio group substituted by 0, 1 , 2 or 3 R k groups, a C 3 to C 8 cycloalkylthio group substituted by 0, 1, 2 or 3 R k groups, a
  • R j isindependently selected from F, CI, a C] to C 6 alkyl group, -OH, -CN, -NH 2 , -N0 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono ⁇ to C 6 alkyl)amino group, a di(C ! to C 6 alkyl)amino group, -CF 3 , a Ci to C 6 alkyl ene group substituted by 0, 1, 2 or 3 R 1 groups, a C 2 to C 6 alkenylene group substituted by 0, 1, 2 or 3 R 1 groups and an oxo group;
  • R J is a divalent group of a Ci to C 6 alkylene group or a C 2 to C 6 alkenylene group
  • each group forms bonds with atoms in R 5 ; in this case, two bonds of each of these divalent groups are formed with the same atom or two different atoms in R 5
  • R k and R 1 are independently selected from F, a C] to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a C ⁇ to C 6 alkoxy group, a mono(d to C 6 alkyl)amino group, a di(C 1 to C 6 alkyl)amino group, -CF 3 and an oxo group.
  • the "a C 6 to Cio aryl group substituted by 0, 1, 2, 3, or 4 R 1 groups" in R 5 is preferably a phenyl group substituted by 2 to 4 groups selected from -OH, -NH 2 , CI, F, -CN, -CF 3 , -OCF3, -OCF2H, a methyl group, a cyclopropyl group and a methoxy group; and more preferable is a 2,6-dichlorophenyl group, a 2,6-dichloro-4-fluorophenyl group, a 2,6-dichloro-4-methylphenyl group, a 2,4,6-trichlorophenyl group, a
  • the "a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R 1 groups" in R 5 is preferably a pyridyl group substituted by 2 to 3 groups selected from -OH, -NH 2 , CI, F, -CN, -CF 3 , a methyl group, and a methoxy group; and more preferable is a
  • R 5 is preferably a phenyl group optionally substituted by 2, 3 or 4 R 1 groups or a 6-membered heteroaryl group optionally substituted by 2 or 3 R' groups.
  • R and R are independently selected from H, F, -OH, -NH 2 , a Ci to C 3 alkyl group substituted by 0, 1 , 2 or 3 R h groups, and a C ⁇ to C 6 . alkoxy group substituted by 0, 1, 2 or 3 R h groups; or R 8 and R 9 together form an oxo group or a thioxo group;
  • R h is, independently selected from F, a C ⁇ to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C alkoxy group, a mono(Cj to C 6 alkyl)amino group, a di(Ci to C 6 alkyl)amino group, -CF 3 and an oxo group.
  • Ci to C 3 alkyl group substituted by 0, 1 , 2 or 3 R h groups is preferably methyl group substituted by 0, 1 , 2 or 3 R groups.
  • the "a C ! to C 6 alkoxy group substituted by 0, 1 , 2 or 3 R h groups" in R 8 and R 9 is preferably methoxy group substituted by 0, 1 , 2 or 3 R groups.
  • R 8 and R 9 are preferably H, F, -OH or an oxo group, andmore preferable are H or an oxo group.
  • R 12 is H; or R 4 and R 12 together are -CR m R m -CR 13 R 14 -CR m R m - or -CR I3 R 14 -CR m R m -CR m R m - to form a pyrrolidine ring.
  • R 13 is selected from H, a Cy to C 6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a C 6 to Cio aryl group substituted by 0, 1 , 2, 3, 4 or 5 R f groups, a C 6 to C 10 aryloxy group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (C 2 to C 6 alkenyl)(Ci to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (C 2 to C 6 alkynylXQ to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (Q to C alkoxy)(C 2 to C 4 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R e groups, a (C 6 to C 10 aryl)(Ci to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (5- to 10-membere
  • R 14 is selected from H and a Q to C 6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 R e groups; or R 13 and R 14 together form a C 3 to C 8 cycloalkane ring substituted by 0, 1 , 2, 3, 4 or 5 R 8 groups, C 3 to C 8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 R s groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1 , 2, 3, 4 or 5 R 8 groups;
  • R m is independently selected from H, F, CI, -CH 3 and -CF 3 ; wherein R g is selected from F, CI, a Ci to C 6 alkyl group, -OH, -CN, -NH 2 , -N0 2 , -C0 2 H, a C ⁇ to C 6 alkoxy group, a mono(C ! to C 6 alkyl)amino group, a di(C ! to C 6 alkyl)amino group, -CF 3 , a Ci to C 6 alkylene group substituted by 0, 1 , 2 or 3 R 1 groups, a C 2 to C 6 alkenylene group substituted by 0, 1, 2 or 3 R 1 groups and an oxo group;
  • R f is independently selected from F, CI, Br, -OH, -CN, -N0 2, -C0 2 H, a d to C 6 alkyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkenyl group substituted by 0, 1, 2 or 3 R k groups, a C 2 to C 6 alkynyl group substituted by 0, 1 , 2 or 3 R k groups, a C 3 to C 8 cycloalkyl group substituted by 0, 1 , 2 or 3 R k groups, a Cj to C 6 alkoxy group substituted by 0, 1 , 2 or J R k groups, a C 3 to C 8 cycloalkyloxy group substituted by 0, 1, 2 or 3 R k groups, -SH, a Ci to C 6 alkylthio group substituted by 0, 1, 2 or 3 R k groups, a C 3 to C 8 cycloalkylthio group substituted by 0, 1, 2 or 3 R k groups, a
  • R e and R k are, independently selected from F, a d to C 4 alkyl group, -OH, -CN, -N0 2 , -NH 2 , -C0 2 H, a Ci to C 6 alkoxy group, a mono(d to C 6 alkyl)amino group, a di(Ci to C 6 alkyl)amino group, -CF 3 and an oxo group.
  • R 12 is H; or R 4 and R 12 together are -CH 2 -CR 13 R 14 -CH 2 - to form a
  • R is H
  • R 13 is preferably a C ⁇ to C 6 alkyl group, a C 6 to C 10 aryl group, a C 6 to C 10 aryloxy group, a (C6 to CIO aryl)(Cl to C3 alkyl) group, or a C 3 to Cg cycloalkenyl group.
  • R 14 is preferably H or CH 3 ; or R 13 and R 14 together form a C 3 to C 8 cycloalkane ring or a C 3 to C 8 cycloalkene ring.
  • a combination of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 Y, n, k, R a , R b , R c , R e , R f , R 8 , R h , R R j , R k , R 1 , R m is preferably one where respective preferable components described above are combined; and more preferably one where components described above as more preferable are combined.
  • R 1 is a Ci to C 6 alkyl group substituted by 0, 1, 2 or 3 R a groups.
  • R 1 is a Ci alkyl group substituted by 0, 1, 2 or 3 R a groups.
  • R 1 is
  • R 2 is C0 2 H.
  • Y is selected from formula (Il-a), formula (Il-b), formula (II-c) and formula (Il . -d):
  • Y is selected from formula Il-a) and formula (Il-d);
  • Y is selected from formula (Il-a) and formula (Il-d);
  • R 6 is selected from F, -OH, -NH 2 , -CN, a C t to C 6 alkyl group substituted by 0, 1, 2 or 3 R b groups and a Ci to C alkoxy group substituted by 0, 1, 2 or 3 R b groups.
  • R 6 is a Ci to C 6 alkyl group substituted by 0, 1 , 2 or 3 R b .
  • R 6 is CH 3 .
  • R 7 is independently selected from H, F and a Ci to C 6 alkyl group substituted by 0, 1, 2 or 3 R b groups.
  • R 7 is H.
  • R 2 is selected from -OH, -C0 2 H, -S0 3 H, -CONH 2 and -S0 2 NH 2 .
  • R 3 is H.
  • R 4 is selected from a Ci to C 6 'alkyl group substituted by 0, 1 , 2 or 3 R e groups, a (C 6 to C 10 arylXQ to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, a (C 3 to C 8 cycloalkyl)(C 1 to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups, a C 6 to C 9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups, a (C 6 to C 9 spiroalkylXCi to C 3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R s groups, a C 5 to C 9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R g groups,
  • R 4 is a d to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 R e groups.
  • R 4 is a (C 6 to C 10 arylXQ to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R f groups.
  • R 4 is a C 3 to C 8 cycloalkyl group substituted by 0, 1, 2 or 3 R g groups.
  • R 4 is a (C 5 to C 9 bicycloalkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups.
  • R 4 is a (C 3 to C 8 cycloalkyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R 8 groups.
  • R 4 is a C 6 to C 9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R g groups. In another embodiment, in conjunction with any above or below embodiments, R 4 is a (C 6 to C 9 spiroalkyl)(d to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups.
  • R 4 is a (C 5 to C 9 bicycloalkyl)(Ci to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups.
  • R 4 is a (C 6 to C 9 heterobicycloalkyl)(Ci to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R g groups.
  • R 8 and R 9 are independently selected from H and F.
  • R and R 9 together form an oxo group.
  • R 5 is a C 6 to C 10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R' groups.
  • R 5 is a phenyl group substituted by 0, 1, 2, 3, 4 or 5 R 1 groups.
  • R 5 is a 5- to 10-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R 1 groups.
  • R 5 is a 6-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R 1 groups.
  • R 5 is pyridyl substituted by 0, 1, 2, 3, or 4 R 1 groups.
  • R 12 is H.
  • R 4 and R 12 together are -CH 2 -CR 13 R I4 -CH 2 - to form a pyrrolidine ring.
  • R 14 is selected from H and CH 3 .
  • R 13 and R 14 together form a C 3 to C 8 cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 R groups, C 3 to C 8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 R 8 groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, ,3, 4 or 5 R g groups.
  • R is selected from a Q to C 6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a C 6 to C 10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C 6 to C 10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 R f groups, a (C 2 to C 6 alkenylXd to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (C 2 to C 6 alkynyl)(C 1 to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (Ci ' to C 6 alkoxy)(C 2 to C 4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R e groups, a (C 6 to C 10 arylX to C 3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a
  • R m is
  • the present invention also relates to a pharmaceutically acceptable salt of a compound represented by formula (I).
  • a compound represented by formula (I) forms acid addition salts.
  • the pyrazole amide derivative forms salts with bases. These salts are not particularly limited as long as they are pharmaceutically acceptable ones.
  • the acid addition salts include mineral acid salts such as a hydrofluoride, a hydrochloride, a hydrobromide, a hydroiodide, a phosphate, a nitrate, a sulfate, and the like; organic sulfonate such as a methanesulfonate, an ethanesulfonate, a 2-hydroxyethanesulfonate, a p-toluenesufonate, a benzenesulfonate, an ethane- 1 ,2-disulfonate ion, a 1,5-naphthalenedisulfonate ion, a naphthalene-2-sulfonate ion, and the like; and organic carboxylate such as an acetate, a trifluoroacetate, a
  • salts with bases there are mentioned salts with inorganic bases such as a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an aluminum salt, and the like; and salts with organic bases such as a methylamine salt, an ethylamine salt, a lysine salt, an ornithine salt, and the like.
  • a compound represented by formula (I) of the present invention contains isomers in some cases. Such isomers are included in a compound represented by formula (I) of the present invention.
  • isomers in the ring and condensed ring systems E-, Z-, cis-, and trans-forms
  • isomers due to the presence of chiral carbons R- and S-forms, a- and ⁇ -configurations, enantiomers, and diastereomers
  • optically active substances with optical rotation D-, L-, d-, and 1-forms
  • tautomers polar compounds obtained by chromatographic separation (a highly-polar compound and a lowly-polar compound), equilibrium compounds, rotamers, mixtures of these compounds in an arbitrary ratio, racemic mixtures, and the like.
  • the present invention also includes various deuterated forms of the compounds represented by formula (I). Each hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • the compound represented by formula (I) in the present invention can be produced by applying publicly known various synthesis methods with the use of characteristics based on types of basic structures or substituents.
  • the functional group may be protected with an appropriate protecting group or a group that can be easily converted to a functional group in the process of using a raw material and an intermediate depending on functional groups.
  • a functional group includes, for example, an amino group, a hydroxyl group, a carboxyl group, and the like.
  • the protecting groups thereof include, for example, protecting groups described in the "Protecting Groups in Organic Synthesis (the third edition, 1999)" written by T. W. Greene and P. G. M. Wuts. They may be suitably chosen and used depending on the reaction conditions. In these methods, the reaction is carried out by introducing the protecting group followed by eliminating the protecting group as necessary, or converting to an intended group to obtain ah intended compound.
  • a compound I- 1) can be prepared, for example, by the following method:
  • R 8 and R 9 are independently H; F; a hydroxyl group; an amino group; a Ci to C 3 alkyl group substituted by 0, 1, 2 or 3 R groups; a d to C 6 alkoxy group substituted by 0, 1 , 2 or 3 R h groups; or R 8 and R 9 together form oxo group or thioxo group.
  • Other symbols have the same meanings as described above.
  • the present step is a method for producing a compound (I- 1) by reacting a compound (1) or a reactive derivative thereof with a compound (2).
  • the reactive derivative of the compound (1) means a reactive derivative of a carboxyl group, and for example, acid chloride, acyl azide, mixed acid anhydride, symmetric acid anhydride, activated amide, activated ester, and the like are cited. These reactive derivatives can be optionally chosen depending on types of carboxylic acids used.
  • the present reaction may be carried out according to a general amide-forming reaction by methods described in the literature (e.g., Pepuchido Gousei no Kiso to Jikken by Nobuo Izumiya, etc., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6., Pergamon Press, 1991, etc.), equivalent methods thereto or a combination of these methods and the conventional method.
  • the present reaction can be carried out by using a condensation agent that is well known to a person skilled in the art, or an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method and the like that are well known in the art.
  • the reagents used in such an amide-forming reaction include, for example, thionyl chloride, oxalyl chloride,
  • bromo-tris(pyrrolidino)phosphonium hexafluorophosphate ethyl chloroformate, isobutyl chloroformate, or 2-(7-aza-iH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium
  • hexafluorophosphate and the like.
  • thionyl chloride for example, oxalyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or
  • a base and/or a condensation agent may be used along with the above-mentioned amide-forming agent.
  • the amount of the condensation agent that is consumed is not strictly limited, and is generally 0.1 equivalents to 100 equivalents with respect to 1 equivalent of the compound (1), and preferably 0.1 equivalents to 10 equivalents.
  • a base used includes, for example, tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, NN-dimethylaniline, l,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- azabicyclo[4.3.0]non-5-ene, and the like; aromatic amines such as pyridine, 4- dimethylaminopyridine, picoline, lutidine, quinoline, or isoquinoline, and the like. Above all, tertiary aliphatic amine and the like are preferable, and triethylamine orN,N- diisopropylethylamine and the like are in particular preferable.
  • the amount of the base used varies depending on the compound used, types of solvents and other reaction conditions, however, it is generally 0.1 equivalents to 100 equivalents with respect to 1 equivalent of the compound (1), preferably 1 equivalent to 5 equivalents.
  • the condensation agent used includes, for example, N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, and the like.
  • the amount of the compound (2) used varies depending on the compound used, types of solvents and other reaction conditions, however, it is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (1) or a reactive derivative thereof, and preferably 1 equivalent to 3 equivalents.
  • the reaction is generally carried out in an inactive solvent, and examples of the inactive solvent include tetrahydroiuran, acetonitrile, NN-dimethylformamide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, pyridine, and the like, or mixtures thereof.
  • the reaction time is generally 0.5 hours to 96 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 80°C.
  • a base, an amide-forming reagent, and a condensation agent used in the present reaction can be used as a combination of one or more types thereof.
  • the compound (1-1) obtained in such a manner can be isolated and purified by an isolation and purification method that is well known to a person skilled in the art (e.g., concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like; in the category of "general synthesis method", the term “isolation and purification method that is well known to a person skilled in the art” has the same meaning unless otherwise particularly specified).
  • an isolation and purification method that is well known to a person skilled in the art (e.g., concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like; in the category of "general synthesis method", the term “isolation and purification method that is well known to a person skilled in the art” has the same meaning unless otherwise particularly specified).
  • compounds (1-2) and (1-3) can be produced, for example, by the following method:
  • the present step is a method for producing a compound (1-2) by reacting the compound (1) or a reactive derivative thereof with a compound (3).
  • the reaction in the present step can be carried out by the same method as in the step 1 , an equivalent method thereto, or a combination- of these methods and a conventional method.
  • the compound (1-2) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (1-3) by subjecting the compound (1-2) to an oxidation reaction.
  • the present step can be carried out according to a method well known to a person skilled in the art.
  • the PCC oxidation, the Swern oxidation, the Mn0 2 oxidation, and the Dess-Martin oxidation, and the like are cited.
  • the Dess-Martin oxidation can be carried out by using the Dess-Martin reagent without solvent or in a solvent inert to the reaction.
  • the amount of the Dess-Martin reagent used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (1-2), preferably 1 equivalent to 4 equivalents.
  • the reaction in the present step is generally carried out in an inactive solvent.
  • the inactive solvent for example, tetrahydrofuran, acetonitrile, N.N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1 , 2-dichloroethane, and the like; or mixtures thereof are cited.
  • the reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
  • the reaction temperature is generally -78°C to the boiling point temperature of the solvent, and preferably -20°C to room temperature.
  • the compound (1-3) obtained in such a manner can be isolated and purified by an isolation and purification method that is well known to a person skilled in the art.
  • the carboxyl group is preferably protected iii advance by a protecting group and then the protecting group is eliminated after completion of the reaction. Selection of such a protecting group and eliminating conditions can be conducted by referring to the method in previously mentioned
  • a compound (1-3) can be prepared, for example, by the following method:
  • a compound (1) wherein R 3 is H can be prepared, for example, by the following method:
  • a compound represented by formula (a) can be synthesized according to a method well known to a person skilled in the art.
  • a compound represented by formula (c) can be synthesized according to a method well known to a person skilled in the art.
  • the present step is a method for producing a compound (b) by reacting a compound (a) with N,N-dimethylformamide dimethyl acetal in the presence or absence of a solvent.
  • N,jV-dimethylformamide diethyl acetal, NN-dimethylformamide diisopropyl acetal, or the like can be used instead of NN-dimethylformamide dimethyl acetal.
  • the amount of N,N-dimethylformamide dimethyl acetal used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (a).
  • the reaction solvent used is not in particular limited as far as it is inert to the reaction, and specifically includes, for example, methanol, ethanol, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, NN-dimethylformamide, or mixtures thereof.
  • the reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 160°C.
  • the compound (b) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification means well known to a person skilled in the art.
  • the present step is a method for producing a compound (d) by reacting the compound (b) with a compound having a hydrazine group represented by formula (c).
  • the amount of the compound (c) used is generally 0.5 equivalents to 10 equivalents with respect to 1 equivalent of the compound (b), and preferably 0.7 equivalents to 3 equivalents.
  • a base for neutralization.
  • a base include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine,
  • N,N-diisopropylethylamine, pyridine, and the like The amount of the base used is generally 1 equivalent to 3 equivalents with respect to 1 equivalent of the compound (c).
  • the reaction solvent used is not in particular limited as far as it is inert to the reaction. Specifically, examples include, methanol, ethanol, /?-propanol, «-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1 ,4rdioxane,
  • reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 100°C.
  • the compound (d) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (1 -a) by eliminating the protecting group R pro of the compound (d).
  • the elimination of the protecting group can be carried out by a method described in previously mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto or a combination of these methods and the conventional method.
  • the protecting group is a benzyl group
  • the benzyl grou can be eliminated by a catalytic reduction method with the use of hydrogen and palladium catalytic agent and the like.
  • the compound (1 -a) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • a compound (2-a) wherein both R 8 and R 9 are H can be synthesized, for example, by the following method:
  • the compound represented by formula (f) can be synthesized according to a method well known to a person skilled in the art.
  • the present step is a method for producing a compound (g) by reacting an organic lithium compound (e) with ethylene oxide (f).
  • the amount of ethylene oxide (f) used is generally 0.1 equivalents to 10 equivalents with respect to 1 equivalent of the compound (e), and preferably 0.5 equivalents to 3 equivalents.
  • the reaction solvent is not in particular limited as far as it is inert to the reaction, and examples include, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, 1 ,2-dimethoxyethane, w-hexane, «-heptane, dichloromethane, chloroform, carbon tetrachloride,
  • the reaction time is generally 0.5 hour to 48 hours, and preferably 1 hour to 24 hours.
  • the reaction temperature is generally -78°C to the boiling point temperature of the solvent, and preferably -78°C to room temperature.
  • the compound (g) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (h) by reacting the compound (g) with diphenylphosphoryl azide.
  • the reaction in the present step can be carried out by the same method as in the step 16, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (h) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (i) by subjecting the compound (h) to a reduction reaction of the azide group.
  • the present step can be carried out according to methods well known to a person skilled in the art. These methods include, for example, a reduction method using phosphine; a catalytic reduction method using H and a palladium catalyst and the like; a reduction method using sodium borohydride; and the like.
  • the reduction method using phosphine can be carried out using triphenylphosphine and water in a solvent inert to the reaction.
  • examples include tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, water, and the like; or mixtures thereof.
  • triphenylphosphine used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (15), and preferably 1 to 4 equivalents.
  • the reaction time is generally 0.5 hours to 96 hours, and preferably 2 hours to 48 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to the boiling point temperature of the solvent.
  • the compound (i) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (2-a) by reacting the compound (i) with a compound (j) in the presence of a reducing agent.
  • the amount of the compound (i) used in the present step is generally 0.5 equivalents to 10 equivalents with respect to 1 equivalent of the compound (j), and preferably, 0.8 equivalents to 4 equivalents.
  • the reducing agents used include, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.
  • the amount of the reducing agent used is generally 0.1 equivalents to 10 equivalents with respect to 1 equivalent of the compound (i), and preferably 0.3 equivalents to 5 equivalents. . ⁇ ' " ⁇ .
  • the reaction solvent used is not in particular limited as far as it is inert to the reaction, and examples include methanol, ethanol, acetic acid, tetrahydrofuran, 1 ,4-dioxane, dichloromethane, chloroform, 1 ,2-dichloroethane, benzene, toluene, xylene, and the like.
  • the reaction time is generally 0.5 hours to 48 hours, and preferably, 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent.
  • the compound (2-a) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • a compound (2-b) wherein either R or R is F and the other is H can be synthesized, for example, by the following method:
  • a compound represented by formula (k) can be synthesized according to a method well known to a person skilled in the art.
  • the present step is a method for producing a compound (1) by reacting the compound (k) with trimethylsilyl cyanide in the presence of a zinc catalyst and
  • the amount of trimethylsilyl cyanide used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (k), and preferably, 1 equivalent to 5 equivalents.
  • the zinc catalyst used includes, for example, zinc iodide, zinc bromide, and the like.
  • the fluorinating agent used includes, for example, (N, N-diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, l ,l ,2,2-tetrafluoroethyl-iV,N- dimethylamine, and the like.
  • the amount of fluorinating agent used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (k), and preferably, 1 equivalent to 5 equivalents.
  • the reaction solvent that used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, acetonitrile, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1 ,2-dichloroethane, carbon tetrachloride, benzene, toluene, N,N-dimethylformamide, and the like.
  • the reaction time is generally 30 minutes to 48 hours, and preferably, 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent.
  • the compound (1) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (m) by subjecting the compound (1) to a reduction reaction of the cyano group.
  • the reducing agents used include, for example, lithium aluminium hydride, sodium bis(2-methpxyethoxy)aluminumhydride, a borane-tetrahydrofuran complex, and the like.
  • the amount of the reducing agent used is generally 1 to 10 equivalents with respect to 1 equivalent of the compound (1).
  • reaction solvent that used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, 1 ,4-dioxane, dichloromethane, benzene, toluene, diethyl ether, and the like.
  • the reaction time is generally 1 hour to 24 hours.
  • the reaction temperature is generally 0°C to the boiling point temperature of the solvent.
  • the compound (m) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (2-b) by reacting the compound (m) with a compound (j) in the presence of a reducing agent.
  • the reaction in the present step can be carried out by the same method as in the step G, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (2-b) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • a compound (3-P) wherein either R 8 or R 9 is a hydroxyl group which is protected by a protecting group and the other is H can be synthesized, for example, by the following method:
  • R pr0 is a protecting group.
  • Other symbols have the same meanings as described above.
  • a compound represented by formula (n) can be synthesized according to a method well known to a person skilled in the art.
  • the present step is a method for producing a compound (o) by reacting an organic lithium compound (m) with (tert-butyldimethylsilyloxy)acetaldehyde (n).
  • the reaction in the present step can be carried out by the same method as in the step D, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (o) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for introducing a protecting group to the hydroxyl group of the compound (o).
  • the introduction of the protecting group can be carried out by a method described in the previously mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (p) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification rhethod that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (q) by eliminating the tert-butyldimethylsilyl group of the compound (p).
  • the elimination of the protecting group can be carried out by a method described in the previously-mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto, or a combination of these methods and the conventional method, and for example, tetrabutylammonium fluoride can be used.
  • the compound (q) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (r) by subjecting the compound (q) to an oxidation reaction.
  • the reaction in the present step can be carried out by the same method as in the step 3, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (r) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing the compound (3-P) by reacting the compound (r) with a compound (s) in the presence of a reducing agent.
  • the reaction in the present step can be carried out by the same method as in the step G, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (3-P) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • a compound represented by formula (u) can be synthesized according to a method well known to a person skilled in the art.
  • the present step is a method for producing a compound (v) by reacting the compound (t) with a compound (u) in the presence of copper to prepare.
  • the amount of the compound (t) used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (u), and preferably 1 equivalent to 3 equivalents.
  • the amount of copper used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (t), and preferably 1 equivalent to 5 equivalents.
  • the reaction solvent used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, acetonitrile, 1 ,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, and the like.
  • the reaction time is generally 30 minutes to 48 hours.
  • the reaction temperature is generally room temperature to the boiling point temperature of the solvent.
  • the compound (v) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (w) by eliminating the protecting group R pro of the compound (v).
  • the reaction in the present step can be carried out by the same method as in the step C, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (w) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification means well known to a person skilled in the art.
  • the present step is a method for producing a compound (x) by reacting the compound (w) or a reactive derivative thereof with a compound (s).
  • the reaction in the present step can be carried out by the same method as in the step 1 , an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (x) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the present step is a method for producing a compound (2-c) by reducing the amide group of the compound (x).
  • the reaction in the present step can be carried out by the same method as in the step I, an equivalent method thereto, or a combination of these methods and the conventional method.
  • the compound (2-c) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
  • the compound represented by formula (I) in the present invention may have a tautomer and/or optical isomer in some cases depending on types of substituents.
  • the present invention includes a mixture of these tautomers and isomers, and isolated ones.
  • the present invention relates to a pharmaceutically acceptable prodrug of the compound represented by formula (I).
  • pharmaceutically acceptable prodrug means a compound producing a compound represented by formula (I) by solvolysis or conversion to C0 2 H, NH 2 , OH, etc. under physiological conditions.
  • An example of the group that produces prodrug is found, for example, in Prog. Med., 5, 2157-2161 (1985), "lyakuhin no Kaihatsu” (Hirokawa Shoten, 1990) Vol.7., Bunshi Sekkei 163-198.
  • some of the compounds within the scope of formula (I) which have the group that produces a prodrug can serve as a prodrug of the
  • the present invention also relates to a pharmaceutically acceptable salt of the compound represented by formula (I) and a pharmaceutically acceptable prodrug thereof.
  • a salt includes, for example, hydrogen halides such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydriodic acid, and the like; inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like; lower alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and the like; arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, and the like; and acid addition salts with amino acids including aspartic
  • the salt in the present invention may form a salt with a base.
  • examples include inorganic bases including metals such as sodium, potassium, magnesium, calcium, aluminum, lithium, and the like; salts with an organic base such as methyl amine, ethylamine, ethanolamine, guanidine, lysine, ornithine, and the like; and an ammonium salt, and the like.
  • the compound represented by formula (I) and the pharmaceutically acceptable salt thereof in the present invention (hereinafter, general term for these is referred to as the compound of the present invention) has an excellent RORy inhibitory activity and can be used as a RORy inhibitor that is clinically applicable to treat or prevent RORy associated diseases and symptoms.
  • the compound of the present invention is useful as a therapeutic agent or preventive agent for, in particular, diseases selected from auto immune disease and inflammatory disease (e.g., multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease), and asthma), metabolic disease (especially, diabetes), and cancer (especially, malignant melanoma).
  • auto immune disease and inflammatory disease e.g., multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease), and asthma
  • metabolic disease especially, diabetes
  • cancer especially, malignant melanoma
  • prevention in the present invention means a procedure of administration of a pharmaceutical composition including the compound of the present invention or administration this to individuals who have not developed diseases or symptoms.
  • treatment means a procedure of administration of a pharmaceutical composition including the compound of the present invention or administration this to individuals who have already developed diseases or symptoms.
  • the compound of the present invention can be mixed with a pharmaceutically acceptable carrier (diluting agent, bonding agent, disintegrant, flavoring substance, odor improving agent, emulsifying agent, diluent, solubilizing agent, and the like) and can be administered in the form of a pharmaceutical composition or drug formulation (oral preparation, injections, and the like) orally or parenterally.
  • a pharmaceutically acceptable carrier for example, a pharmaceutically acceptable carrier
  • the pharmaceutical composition can be formulated according to an ordinal method.
  • parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion technique, and local administration (percutaneous administration, ophthalmic administration, pulmonary/bronchial administration, nasal administration, rectal administration, and the like), and the like.
  • the dosage form of oral administration includes, for example, tablets, pills, granules, powders, solvent, suspensions, syrups, capsules, and the like.
  • the amount of the compound of the present invention that can be combined with a carrier can be changed depending on a specific individual who receives treatment and on specific dosage forms.
  • the specific dosage for the specific patient is determined depending on various factors including age, body weight, overall health conditions, gender, diet, administration time, administration method, excretion rate, and the degree of the specified disease during treatment.
  • the dosage amount of the compound of the present invention is determined depending on age, body weight, general health conditions, gender, diet, administration time, administration method, excretion speed, the degree of a disease in a patient who is being treated, or in view of other factors.
  • the compound of the present invention can be administered in single or multiple times daily for adult in a range of 0.01 mg to 1000 mg, although the dosage is different depending on the conditions of the patient, body weight, types of the compound, administration route, and the like.
  • reagents, starting materials, and solvents were purchased from vendors (for example, Aldrich, Wako Junyaku, Tokyo Kasei, Fluka, Sigma, and the like) and used without further purification.
  • Solvent B 10% to 100%
  • Solvent A 90% to 0% 1.5 to 3.5 min
  • Solvent B 100%
  • Solvent A 0%
  • Step 1 l-(3,5-dichloropyridin-4-yl)-2-nitroethanol (Al-1)
  • Step 2 3,5-dichloro-4-(2-nitro-l-((triethylsilyl)oxy)ethyl)pyridine (Al-2)
  • Step 4 2-(3,5-dichloropyridin-4-yl)-N-(4-fluorobenzyl)-2-((triethylsilyl)oxy)ethanamine
  • Step 1 4-(methoxymethylene)-l,l-dimethylcyclohexane (A12-1)
  • n-BuLi (2.6 M in hexane, 2.3 mL, 5.94 mmol) was added dropwisely to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.04 g, 5.94 mmol) in THF (20 mL) at -78 °C and stirred for 10 min at the same temperature and then stirred for 2.5 h at room temperature.
  • the reaction mixture was cooled down to -78 °C, a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at - 78 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for overnight.
  • reaction mixture was quenched with sat. NaHC0 3 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil. The crude product was used for next step without purification.
  • Step 1 1 -(2,6-dichloro-4-fluorophenyl)-2-nitroethanol (A31 - 1 )
  • Step 2 (l-(2,6-dichloro-4-fluorophenyl)-2-nitroethoxy)triethylsilane (A31-2)
  • Step 3 2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (A31-3)
  • Step 1 2,6-dichloro-4-iodobenzaldehyde (A35-1)
  • Step 2 l-(2,6-dichloro-4-iodophenyl)-2-nitroethanol (A35-2)
  • Step 4 2-(2,6-dichloro-4-iodophenyl)-2-((triethylsilyl)oxy)ethanamine (A35-4)
  • Step 1 4-methylthiophene-3-carboxylic acid (A56-1)
  • the aqueous layer was acidified to pH ⁇ 5 and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8% MeOH/DCM as eluent) to provide compound A56-1 (1.5 g ⁇ 70%) as a white solid.
  • reaction mixture was quenched with saturated aqueous NH 4 C1 and extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% MeOH/DCM as eluent) to provide compound A56-2 (246 mg, 57%) as a white solid.
  • Step 5 l-(2,4-dimethylthiophen-3-yl)-2-nitroethanol (A56-5)
  • Step 6 (l-(2,4-dimethylthiophen-3-yl)-2-nitroethoxy)triethylsilane (A56-6)
  • Step 7 2-(2,4-dimethylthiophen-3-yl)-2-((triethylsilyl)oxy)ethanamine (A56-7)
  • Step 2 l -(2,6-dichloro-4-(methylthio)phenyl)-2-nitroethanol (A57-2)
  • Step 3 (l-(2,6-dichloro-4-(methylthio)phenyl)-2-nitroethoxy)triethylsilane (A57-3)
  • Step 4 2-(2,6-dichloro-4-(methylthio)phenyl)-2-((triethylsilyl)oxy)ethanamine (A57-4)
  • Step 1 4,4-dimethylpent-2-ynal (A66-1)
  • Step 1 l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3-carbaldehyde (A75-1)
  • Step 1 2 ⁇ (2-chloro-6-nitrophenyl)-2-((trimethylsilyl)oxy)acetonitrile (A84-1)
  • Step 3 1 -(2-chloro-6-nitrophenyl)-2-((3,5-difluorobenzyl)amino)ethanol (A84)
  • Step 1 (5S)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)dihydrofuran-2(3H)-one (A92-1)
  • Step 4 (S)-(5,5-dimethyltetrahydrofuran-2-yl)methyl methanesulfonate (A92-4)
  • Step 1 l-(2-chloro-6-methoxyphenyl)-2-nitroethanol (A93-1)
  • Step 3 2-(2-chloro-6-methoxyphenyl)-2-((triethylsilyl)oxy)ethanamine (A93-3)
  • Compound A93 -3 (1.6 g, 84%) was obtained as a colorless oil from the reaction of compound A93-2 (2.14 g, 6.2 mmol), Fe (3.48 g, 62.0 mmol) and NH 4 C1 (3.3 g, 62.0 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A 1, step 3.
  • Step 1 (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (A94-1)
  • Step 1 N-methoxy-N-methyl-l-(trifluoromethyl)cyclopropanecarboxamide (A103-1) To a mixture of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (150 mg, 0.974 mmol), 1 -hydroxybenzotrizole monohydrate (224 mg, 1.46 mmol),
  • Step 2 l-(trifluoromethyl)cyclopropanecarbaldehyde (A103-2)
  • Step 1 2,6-dichloro-4-methylbenzoic acid (Al l 1-1)
  • Step 4 methyl 2,6-dichloro-4-(difluoromethyl)benzoate (Al 11 -4)
  • Step 5 (2,6-dichloro-4-(difluoromethyl)phenyl)methanol (Al l 1 -5)
  • Step 7 2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((trimethylsilyl)oxy)acetonitrile (Al l 1 -7)
  • Step 8 2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((trimethylsilyl)oxy)ethanamine , (Al l 1 -8)
  • Step 9 l-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((3,5-difluorobenzyl)amino)ethanol ( ⁇ 1 1 1) .
  • Step 1 l,3-dibromo-2,2-dimethylpropane (Al 19-1)
  • Step 2 dipentyl 3,3-dimethylcyclobutane-l,l-dicarboxylate (A119-2)
  • the sodium (0.98 g, 43.0 mmol) was added in portion to pentanol (25 mL) and the mixture was stirred at 50 °C to get a clear solution.
  • the reaction mixture was heated to 70 °C, and then diethyl malonate (3.50 g, 26.0 mmol) was added over a period of 5 min.
  • the reaction mixture was heated to 130 °C and compound Al l 9-1 (5.0 g, 21 mmol) was added dropwise over a period of 10 min.
  • the reaction mixture was heated at 130 °C for 4 h.
  • the solvent was removed under vacuum at 100 °C.
  • the residue was quenched with water (100 mL) and extracted with EtOAc (2 x 50 mL).
  • Step 5 (3,3-dimethylcyclobutyl)methanol (Al l 9-5)
  • Step 1 ethyl 4-methylenecyclohexanecarboxylate (A 122-1) Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a stirred solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0 °C and stirred for 40 min at the same temperature. A solution of ethyl 4-oxocyclohexanecarboxylate (2.04 g, 12 mmol) in THF (20 mL) was added slowly at 0 °C and stirred for 2 h from 0 °C to room temperature.
  • Step 2 ethyl l-(bromomethyl)-4-methylenecyclohexanecarboxylate (A 122-2)
  • n-BuLi (2.6 M in hexane, 2.5 mL, 6.6 mmoL) was added dropwisely to a solution of diisopropylamine (0.93 mL, 6.6 mmol) in THF (20 mL) at -78 °C and stirred for 30 min at the same temperature.
  • Hexamethylphosphoramide (4 mL) was added to the reaction mixture and stirred for 20 min at the same temperature.
  • a solution of compound A 122-1 (1.01 g, 6 mmol) in THF (5 mL) was added and stirred for 1 h at the same temperature.
  • Step 3 ethyl 4-methylbicyclo[2.2.1]heptane-l-carboxylate (A122-3)
  • Step 1 ethyl cyclopentanecarboxylate (A124-1) To a solution of cyclopentanecarboxylate (1.14 g, 10 mmol) in EtOH (5mL) was added H 2 S0 4 (0.1 mL) at room temperature. The mixture was allowed to warm to 80 °C and stirred at the same temperature for 3.5 h. The reaction mixture was cooled down to room temperature and poured into saturated NaHC0 3 aq. (40 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure to provide compound A 124-1 (1.01 g, 71 %) as a pale yellow oil. The crude product was used for next step without purification.
  • Step 2 ethyl 1 -fluorocyclopentanecarboxylate (A 124-2)
  • n-BuLi (2.6 M in hexane, 4.0 mL, 10.5 mmoL) was added dropwisely to a solution of diisopropylamine (1.55 mL, 11 mmol) in THF (40 mL) at -78 °C and stirred for 30 min at the same temperature.
  • a solution of compound A 124-1 (1.00 g, 7 mmol) in THF (10 mL) was added to the mixture and the mixture was stirred for 50 min at the same temperature. The reaction mixture was allowed to warm to 0 °C for 1 h.
  • Step 4 1-fluoro-N-methoxy-N-methylcyclopentanecarboxamide (A 124-4)
  • Step 1 3-methylenecyclobutanecarboxylic acid (A141-1)
  • Trimethylsilyldiazomethane (2.0 M in hexane, 25 mL, 50 mmol) was added to a stirred solution of compound A141-1 (4.64 g, 41.4 mmol) in DCM (25 mL) and MeOH (5 mL) dropwise at 0 °C for 5 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 30 min. The reaction mixture was quenched with AcOH (0.45 mL) and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% DCM/hexane as eluent) to provide compound A141 -2 (3.8 g, 73%) as a colorless oil.
  • reaction mixture was quenched with saturated NH 4 C1 aq. (200 mL) and extracted with DCM. The collected organic layer was dried over MgS0 4 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% EtOAc/hexane as eluent) to provide compound Al 41-3 (1.77 g, 63%) as a colorless oil.
  • Step 4 spiro[2.3]hexane-5-carboxylic acid (A141-4)
  • Step 5 N-methoxy-N-methylspifo[2.3]hexane-5-carboxamide (A141-5) To a mixture of compound A l 41 -4 (1.51 mg, 12.0 mmol), 1 -hydroxybenzotrizole monohydrate (2.30 g, 15 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.33 g, 15 mmol) and ⁇ , ⁇ -dimethylhydroxylamine hydrochloride (1.46 g, 15 mmol) in DMF (20 mL) was added DIPEA (3.43 mL, 20 mmol) and the mixture was stirred at room temperature for overnight.
  • DIPEA 3.43 mL, 20 mmol
  • Step 6 spiro[2.3]hexane-5-carbaldehyde (A141-6)
  • Step 1 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile
  • Step 1 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)0xy)acetonitrile
  • a 100 ml RBF was charged with solution of 2,6-dichlorobenzaldehyde (5.08 g, 29.0 mmol) and TMSCN (4.64 ml, 34.8 mmol) in DCM (60 ml).
  • Zinc iodide (0.926 g, 2.90 mmol) was added and the mixture was stirred at ambient temperature for 3 h.
  • Reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), organic layer was filtered through celite and concentrated. The residue was purified by flash chromatography on 100 g Biotage SNAP cartridge using 0-40% EtO Ac in heptane to afford
  • Step 2 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde.
  • N-ethyl-N-isopropylpropan-2-amine (546 ⁇ , 3.13 mmol) were combined in MeCN (5 mL) and trimethylsilyl trifluoromethanesulfonate (517 ⁇ , 2.86 mmol) was added dropwise. The solution was stirred for 30 min and selectfluor (1061 mg, 3.00 mmol) in MeCN (5 mL) was added. The solution was stirred and sonicated for an additional 30 min.
  • Step 1 3-chloroquinolin-4(lH)-one (A275-1)
  • Steps 4 1 -(3 -chloroquinolin-4-yl)-2-nitroethanol (A275 -4)
  • Step 5 3-chloro-4-(2-nitro-l-((triethylsilyl)Oxy)ethyl)quinoline (A275-5)
  • A275-4 l-(3-chloroquinolin-4-yl)-2-nitroethanol
  • imidazole 0.342 g, 5.03 mmol
  • triethylsilyl chloride 0.341 mL, 2.01 mmol
  • the organic extract was washed with 1 M LiCl (1 x 50 mL) and brine (1 x 50 mL), and dried over Na 2 S0 4 .
  • the solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup.
  • the crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEPTM pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, and dried under high vacuum to give 3-chloro-4-(2-nitro-l-((triethylsilyl)oxy)ethyl)quinoline (A275-5).
  • Step 6 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6)
  • Step 1 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (A294-1)
  • the solution was filtered and concentrated in vacuo to give the crude material as orange syrup.
  • the crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to provide

Abstract

The present invention relates to a novel compound having a function of inhibiting RORγ activity. The present invention also relates to pharmaceutical composition comprising the compound, a use of the compound in treating or preventing autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer diseases.

Description

DESCRIPTION
PYRAZOLE AMIDE DERIVATIVE
Technical Field
The present invention relates to novel compounds that modulate RORy activity, pharmaceutical composition, and use in treatment or prevention of autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer diseases.
Background Art
Retinoid-related orphan receptor gamma (RORy) is a nuclear receptor that binds to DNA and regulates transcription (NPL 1). Two isoforms of RORy that differ only in the N- terminus are generated from the RORC gene; RORyl and RORyt (also referred to as RORy2) (NPL 2). RORy is used as a term to describe both isoforms of RORy 1 and RORyt.
RORyl is expressed in a variety of tissues including muscle, kidney, liver, and lung and is known to regulate adipogenesis (NPL 3). Loss of the RORC gene in mice accelerates preadipocyte differentiation to small adipocytes and protects against high fat diet induced insulin resistance. Consequently, by inhibiting the function of RORyl, insulin resistance could be improved.
RORyt is expressed exclusively in cells of the immune system (NPLs 4 and 5) and is a master regulator of a Thl 7 cell-related transcriptional network associated with
autoimmune pathology. Thl 7 cells are a subset of CD4+ helper T cells implicated as key drivers of the inflammatory process in autoimmunity and characterized by production of the pro-inflammatory cytokine IL-17A. Thl 7 cells also express CCR6, which mediates migration to sites of inflammation, are maintained and expanded by IL-23, through the IL-23 receptor (IL23R), and express other pro-inflammatory cytokines and chemokines, including IL-17F, IL-21, IL-22, CCL20 and GM-CSF, which together promote recruitment of other inflammatory cell types, especially neutrophils, to mediate pathology at the target tissue. RORyt is required for the differentiation of Thl7 cells and directly and indirectly regulates expression of many of these pro-inflammatory mediators (NPL 6).
RORy-deficient mice have significantly reduced numbers of Thl7 cells in vivo, lack the ability to produce IL-17A and other Thl7-related cytokines ex vivo, and show resistance to induction of various disease models such as EAE, dermatitis, enteritis and nephritis (NPLs 6, and 12 to 14). Therefore, by inhibiting the function of RORy, development of various autoimmune diseases and inflammatory diseases, in which the Thl7 cell-related cytokines are involved, could be suppressed. Furthermore, expression of RORyt and the consequent expression of the Thl7 cell-related transcriptional network has been observed in other immune cell types that may also be important in disease pathogenesis, namely CD8+ T cells, so called Tel 7s, γδ T cells, natural killer T cells, innate lymphoid cells, natural killer cells, and mast cells (NPLs 7 and 8).
Thl7 cell-related cytokines and chemokines have been implicated in the pathogenesis of various human autoimmune and inflammatory diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease, emphysema, lung fibrosis, systemic erythematodes, vasculitis, Wegener granuloma, polymyalgia rheumatica, giant cell arteritis, arteriosclerosis, autoimmune myositis, uveitis, dry eye, inflammatory bowel disease, alcohol-induced hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, viral hepatitis and type 1 diabetes. (NPLs 9 to 11).
RORyt is known to possess an inhibitory effect on the anti-tumorigenic activity of Th9 cells^ a subtype of helper T cells (NPL 15). In the RORy-deficient mice, production of IL-9 from Th9 cells is enhanced and tumor formation is delayed in mice injected with melanoma cells. Therefore, it is thought that, by inhibiting the function of RORy, the function of Th9 cells is activated and formation of melanoma and other malignant tumors can be suppressed.
From the evidence described above, a RORy modulator can be expected to show therapeutic or preventive benefit in treatment of; metabolic diseases such as diabetes; for autoimmune diseases or inflammatory diseases and; for melanoma and other cancer diseases.
Citation List
Non Patent Literature
NPL 1 : Gigure, Endocrine. Reviews. 20: 689-725, 1999
NPL 2: Jetten, Nucl. Recept. Signal. 7: e003, 2009
NPL 3: Meissburger et al., EMBO Mol. Med. 3: 637-651, 2011
NPL 4: Hirose et al, Biochem. Biophys. Res. Commun. 30: 1976-1983, 1994 NPL 5 : Eberl and Liftman., Science. 9: 248-251 , 2004
NPL 6: Ivanov et al., Cell 126: 1121-1133, 2006
NPL 7: Sutton et al., Eur. J. Immunol. 42: 2221-2231, 2012
NPL 8: Hueber et al., J. Immunol., 184: 3336-3340, 2010
NPL 9: Miossec et al., Nature Reviews Drug Discovery 11 : 763-776,2012
NPL 10: Hammerich et al., Clin. Dev. Immunol. 2011 : Article ID 345803, 2011 NPL 11 : Ferraro et al., Diabetes 60: 2903-2913, 2011
NPL 12: Pantelyushin et al., J Clin Invest. 122: 2252-2256, 2012
NPL 13: Buonocore et al., Nature 464: 1371-1375, 2010
NPL 14: Steinmetz et al., J. Am. Soc. Nephrol. 22: 472-483, 201 1 NPL 15: Purwar et'al., Nat. Med. 18: 1248-1254, 2012
Summary of Invention
Technical Problem
The object of the present invention is to provide a compound having a function of inhibiting RORy activity.
Solution to Problem
The present inventors conducted diligent research in order to achieve the
above-described object and, as a result, found a novel compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof having a function of inhibiting RORy activity. That is, the present invention is as follows.
(1) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
wherein: ,
R1 is selected from F, CI, Br, a Ct to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups and a C3 to C8 cycloalkyl group substituted by 0, 1 , 2 or 3 Ra groups;
Y is selected from a C4 to C6 cycloalkyl group, a C6 to C9 bicycloalkyl group and a C6 to C9 spiroalkyl group, all of which are substituted by a R2 group, 0 or 1 R6 group and 0, 1, 2 or 3 R7 groups;
R2 is selected from -OH, -C02H, -S03H, -CONH2, -S02NH2, a (Q to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rc groups, a (Ci to C alkyl)aminocarbonyl group substituted by 0, 1 , 2 or 3 R° groups, a Cj to C alkylsulfonyl group substituted by 0, 1 , 2 or 3 Rc groups, a C\ to C6 alkylaminosulfonyl group substituted by 0, 1 , 2 or 3 Rc groups, a (hydroxycarbonyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups, a (C\ to C6 alkoxy)carbonyl(Ci to C3 alkyl) group substituted by 0, 1, 2 or 3 R° groups, a (Ci to C6
Figure imgf000006_0001
to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups and a (C2 to C6 alkenyl)(Cl to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups;
R° and R' are independently selected from H, F, -OH, - H2, -CN, a C\ to C6 alkyl group substituted by 0, 1 , 2 or 3 Rb groups and a Ci to C6 alkoxy group substituted by 0, 1 , 2 or 3 Rb groups;
R3 is selected from H, F, CI, -CH3 and -CF3;
R4 is selected from a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkenyl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C2 to C alkynyl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C\ to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C to C10
f
aryl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (5- to 10-membered
f
heteroarylXCi to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkenyl) (C\ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (3- to 8:membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C to C9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl) (d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C5 to C9 bicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkylXd to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups;
R5 is selected from a C6 to Cio aryl group substituted by 0, 1 , 2, 3, 4 or 5 R1 groups, a 5- to 10-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R1 groups, a C3 to C8
cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 RJ groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 RJ groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 RJ groups;
R8 and R9 are independently selected from H, F, -OH, -NH2, a Q to C3 alkyl group substituted by 0, 1 , 2 or 3 R groups, and a Q to C6 alkoxy group substituted by 0, 1 , 2 or 3 Rh groups; or R8 and R9 together form an oxo group or a thioxo group;
R12 is H; or R4 and R12 together are -CRmRm-CR13R14-CRmRm- or -CR13R14-CRmRm- CRmRm- to form a pyrrolidine ring;
R13 is selected from H, a Ci to C alkyl group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a
C6 to C10 aryl group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C6 to C10 aryloxy group substituted by 0, 1 , 2, 3, 4 or 5 Rf groups,a (C2 to C6 alkenylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (Ci to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rf groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a (C3 to C8 cycloalkenyl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C6 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, and a (C6 to C9 heterobicycloalkyl) (d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups;
R14 is independently selected from H and a d to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups; or R13 and R14 together form a C3 to Cg cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rs groups, C3 to C8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 R8 groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups; Rm is independently selected from H, F, CI, -CH3 and -CF3;
R8 and RJ are , independently selected from F, CI, a C.i to C6 alkyl group, -OH, -CN, -NH2, -N02, -C02H, a Ci to C6 alkoxy group, a monoid to C6 alkyl)amino group, a di(d to C6 alkyl)amino group, -CF3, a d to C6 alkylene group substituted by 0, 1, 2 or 3 R1, groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 R1 groups and an oxo group;
Rf and R' are are independently selected from F, CI, Br, -OH, -CN, -N02, -C02H, a d to C6 alkyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1, 2 or 3 Rk groups, a C3 to Cg cycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a d to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkyloxy group substituted by 0, 1, 2 or i Rk groups, -SH, a C1 to C6 alkylthio group substituted by 0, 1, 2 or 3 R groups, a C3 to Cg cycloalkylthio group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkyl)carbonyl group substituted by 0, 1 , 2 or 3 Rk groups, a (Q to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkyl)aminocarbonyl group substituted by 0, 1 , 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2 or 3 Rk groups, a Ci to C6 alkylsulfonyl group substituted by 0, 1 , 2 or 3 Rk groups, -NH2, a mono(C1 to C6 alkyl)amino group substituted by 0, 1 , 2 or 3 Rk groups and a di(Ci to C6 alkyl)amino group substituted by 0, 1 , 2 or 3 Rk groups; and
Ra, Rb, Rc, R6, Rh, Rk and R1 are independently selected from F, a d to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Cj to C6 alkoxy group, a mono(C! to C6 alkyl)amino group, a di(C! to C6 alkyl)amino group, -CF3 and an oxo group. :
Figure imgf000009_0001
wherein:
k is 0, 1 or 2;
and n is 1 , 2 or 3.
(3) The compound according to section 2 or pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula (Il-a):
Figure imgf000009_0002
(4) The compound according to section 2 or pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula (Il-d):
Figure imgf000010_0001
(Π-d)
and n is 2.
(5) The compound according to any one of sections 1 to 4 or pharmaceutically acceptable salt thereof, wherein R3 is H.
(6) The compound according to any one of sections 1 to 5 or pharmaceutically acceptable salt thereof, wherein R is -C02H or a hydroxycarbonylmethyl group substituted by 0, 1 or 2 Rc groups.
(7) The compound according to any one of sections 1 to 6 or pharmaceutically acceptable salt thereof, wherein R is H.
(8) The compound according to any one of sections 1 to 7 or pharmaceutically acceptable salt thereof, wherein R8 and R9 together form an oxo group or both R8 and R9 are H.
(9) The compound according to any one of sections 1 to 8 or pharmaceutically acceptable salt thereof, wherein Rl is -CF3, -CF2H or CI.
(10) The compound according to any one of sections 1 to 9 or pharmaceutically acceptable salt thereof, wherein R5 is a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R1 groups or a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R1 groups.
(11) The compound according to any one of sections 1 to 10 or pharmaceutically acceptable salt thereof, wherein R4 is a C to C6 alkyl group substituted by 0, 1, 2 or 3 Re groups, a (C6 to Cio aryl)(Ct to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8
cycloalkylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups or a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups.
(12) A method of treating or preventing a disease using a compound according to any one of sections 1 to 11 or pharmaceutically acceptable salt thereof, wherein the disease is multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease or asthma. ,
(13) A pharmaceutical composition comprising a compound according to any one of sections 1 to 11 or pharmaceutically acceptable salt thereof.
Advantageous Effects of Invention
The present invention provides a novel compound having excellent activity of inhibiting RORy and a method for producing the same. Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent or a preventive agent for autoimmune diseases, inflammatory diseases (for example, multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease, and asthma), metabolic diseases (especially diabetes), cancer diseases (especially malignant melanoma), or the like.
Description of Embodiments
In the following, terms used either independently or in combination in the present description will be explained. Unless particularly described, explanation of each substituent shall be common to each position. In addition, when any variable substituent (for example, RJ and the like) is present in respective arbitrary constituent elements (for example, Rf, R1, and the like), its definition is independent in the respective constituent elements. Further, combination of substituents and variable substituents is allowed only when such combination provides a chemically stable compound. When a substituent itself is substituted by two or more groups, these plural groups can exist on the same carbon or different carbons as long as a, stable structure is formed.
Each group of the compounds represented by formula (I) of the present invention is defined as described below. The writing order in each group indicates the order of the bonds in formula (I). For example, "a (C3 to C8 cycloalkylXd to C3 alkyl) group" in R4 is represented by group wherein "a Ci to C3 alkyl group" is bonded to nitrogen in formula (I) and "a C3 to C8 cycloalkyl group" and "a C\ to C3 alkyl group" are bonded.
Additionally, the number situated to the right of carbon indicates the number of the carbon. For example^ "Ci to C6" means a group having "1 to 6 carbons". It is a matter of course that, in the present invention, different number of carbons means a group having that number of carbons. For example, "a Ci to C4 alkyl group" means alkyl groups having 1 to 4 carbon among those defined by "Ci to C4 alkyl group". Treatment of the number of carbons in other groups is the same.
In the present invention, "a Ci to C6 alkyl group" means a saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbons. For example, there may be mentioned a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2 -methyl butyl group, a 3-methylbutyl group, an 1 -ethylpropyl group, an 1,1-dimethypropyl group, an 1 ,2-dimethylpropyl group, a neopentyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, an 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, an 1 , 1 -dimethylbutyl group, an 1 ,2-dimethylbutyl group, an 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, an 1-ethylbutyl group, a 2-ethylbutyl group, and the like. In the present invention, "a Ci to C4 alkyl group" means a saturated linear or branched aliphatic hydrocarbon group having 1 to 4 carbons. For example, there may be mentioned a methyl group, an ethyl group, a n-propyl group, an isopropyl group a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like.
In the present invention, "a C2 to C4 alkyl group" means a saturated linear or branched aliphatic hydrocarbon group having 2 to 4 carbons. For example, there may be mentioned an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like.
In the present invention, "a Ci to C3 alkyl group" means a saturated linear or branched aliphatic hydrocarbon group having 1 to 3 carbons. For example, there may be mentioned a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and the like.
In the present invention, "a C2 to C6 alkenyl group" means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbons with an unsaturated double bond. For example, there may be mentioned a vinyl group, an 1 -propenyl group, a 2-propenyl group, a 2 -methyl- 1 -propenyl group, a 2-methyl-2 -propenyl group, a 2-buten-l-yl group, a 3-buten-l-yl group, a 2-penten-l-yl group, a 3-penten-l-yl group, a 4-penten-l-yl group, a 5-hexen-l-yl group, a 4-hexen-l-yl group, a 3-hexen-l-yl group, a 2-hexen-l-yl group, a 3-methyl-2-buten-l-yl group, a 3-methyl-3-penten-l-yl group, a 3-methyl-2-penten-l-yl group, a 4-methyl-3-penten-l-yl group, a 4-methyl-2-penten-l-yl group, a
2-methyl-2-penten-l-yl group, and the like.
In the present invention, "a C2 to C6 alkynyl group" means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbons with an unsaturated triple bond. For example, there may be mentioned an ethynyl group, an 1-propyn-l-yl group, a
2-propyn-l-yl group, a 2-butyn-l-yl group, a 3-butyn-l-yl group, a 2-pentyn-l-yl group, a 3-pentyn-l-yl group, a 4-pentyn-l-yl group, a 5-hexyn-l-yl group, a 4-hexyn-l-yl group, a 3-hexyn-l-yl group, a 2-hexyn-l-yl group, and the like.
In the present invention, "a Cj to C6 alkylene group" means a bivalent group formed by removing hydrogen from "a d to C6 alkyl group". For example, there may be mentioned methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like. The C\ to C6 alkylene group can be bonded to one carbon atom or two different carbon atoms to form a ring.
In the present invention, "a C2 to C6 alkenylene group" means a bivalent group having a double bond at arbitrary position of "a C2 to C6 alkylene group". There may be mentioned vinyl ene, propenylene, 1-butenylene, 2-butenylene, 1-pentenyene, 2-pentenyene, 1-hexenyene, 2-hexenyene, 3-hexenyene, and the like.
In the present invention, "a C3 to C8 cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbons. For example, there may be mentioned a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
In the present invention, "a C4 to C6 cycloalkyl group" means a cyclic alkyl group having 4 to 6 carbons. For example, there may be mentioned a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
In the present invention, "a C6 to C9 bicycloalkyl group" means a bicyclic alkyl group having 6 to 9 carbons. For example, there may be mentioned a
bicyclo[3.1.0]hexanyl group, a bicyclo[2.2.0]hexanyl group, a bicyclo[2.1.1]hexanyl group, bicyclo[3.2.0]heptanyl group, a bicyclo[2.2.1]heptanyl group, a bicyclo[3.1.1]heptanyl group, a bicyclo[4.1.OJheptanyl group, an octahydropentalenyl group, a
bicyclo[2.2.2]octanyl group, a bicyclo[3.2.1]octanyl group, a bicyclo[4.2.0]octanyl group, a bicyclo[4.1.1]octanyl group, a bicyclo[5.1.0]octanyl group, an octahydro-lH-indenyl group, a bicyclo[3.2.2]nonanyl group, a bicyclo[3.3.1]nonanyl group, a
bicyclo[4.2.1]nonanyl group, a bicyclo[5.2.0]nonanyl group, and the like.
In the present invention, "a C5 to C9 bicycloalkyl group" means a bicyclic alkyl group having 5 to 9 carbons! For example, there may be mentioned a
bicyclo[l . l. l]pentanyl group, bicyclo[3.1.0]hexanyl group, a bicyclo[2.2.0]hexanyl group, a bicyclo[2.1.1]hexanyl group, bicyclo[3.2.0]heptanyl group, a bicyclo[2.2.1]heptanyl group, a bicyclo[3.1.1]heptanyl group, a bicyclo[4.1.0]heptanyl group, an
octahydropentalenyl group, a bicyclo[2.2.2]octanyl group, a bicyclo[3.2.1]octanyl group, a bicyclo[4.2.0]octanyl group, a bicyclo[4.1.1]octanyl group, a bicyclo[5.1.0]octanyl group, an octahydro-lH-indenyl group, a bicyclo[3.2.2]nonanyl group, a bicyclo[3.3.1]nonanyl 1 group, a bicyclo[4.2.1]nonanyl group, a bicyclo[5.2.0]nonanyl group, and the like.
In the present invention, "spiroalkyl group" means a group consisting of two cycloalkyl moieties that have exactly one atom in common. "A C6 to C9 spiroalkyl group" means a spiroalkyl group having 6 to 9 carbons. For example, there may be mentioned a spiro[2.3]hexanyl group, a spiro[2.4]heptanyl group, a spiro[3.3]heptanyl group, a spiro[2.5]octanyl groiip, a spiro[3.4]octanyl group, a spiro[2.6]nonanyl group, a
spiro[3.5]nonanyl group, a spiro[4.4]nonanyl group, and the like.
In the present invention, "a (C6 to C9 spiroalkyl)(Ci to C3 alkyl) group" means a group obtained by substituting "a d to C3 alkyl group" with "a (C6 to C9 spiroalkyl) group" at arbitrary position. For example, there may be mentioned a spiro[2.3]hexanyl methyl group, a spiro[2.4]heptanyl methyl group, a spiro[3.3]heptanyl methyl group, a
spiro[2.5]octanyl methyl group, a spiro[3.4]octanyl methyl group, a spiro[2.6]nonanyl methyl group, a spiro[3.5]nonanyl methyl group, a spiro[4.4]nonanyl methyl group, and the like.
In the present invention, "a C3 to C8 cycloalkenyl group" means a group having a double bond at arbitrary position of "a C3 to C8 cycloalkyl group" having 3 to 8 carbons. For example, there may be mentioned a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, and the like.
In the present invention, "a (C3 to C8 cycloalkylXQ to C3 alkyl) group" means a group obtained by substituting "a d to C3 alkyl group" with "a C3 to C8 cycloalkyl group" at arbitrary position. For example, there may be mentioned a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a
cyclohexylmethyl group, a cyclohexylethyl group, a cycloheptylmethyl group, a cycloheptylethyl group, a cyclooctylmethyl group, and the like.
In the present invention, "a (C3 to C8 cycloalkenylXQ to C3 alkyl) group" means a group obtained by substituting "a Q to C3 alkyl group" with "a C3 to C8 cycloalkenyl group" at arbitrary position. For example, there may be mentioned a
cyclopropenylmethyl group, a cyclopropenyl ethyl group, a cyclopropenylpropyl group, a cyclobutenylmethyl group, a cyclobutenylethyl group, a cyclopentenylmethyl group, a cyclopentenylethyl group, a cyclohexenylmethyl group, a cyclohexenylethyl group, a cycloheptenylmethyl group, a cycloheptenylethyl group, a cyclooctenylmethyl group, and the like.
In the present invention, "a (C2 to C6 alkenyl)(Ci to C3 alkyl) group" means a group obtained by substituting "a C\ to C3 alkyl group" with "a C2 to C6 alkeriyl group" at arbitrary position. For example, there may be mentioned a 2-propenyl group, an l-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 2-buten-l-yl group, a
3-buten-l-yl group, a 2-penten-l-yl group, a 3-penten-l-yl group, a 4-penyten-l-yl group, a 5-hexen-l-yl group, a 4-hexen-l-yl group, a 3-hexen-l-yl group, a 2-hexen-l-yl group, an l-methyl-2-buten-l-yl group, an l -ethyl-2-buten-l-yl group, a 2-methyl-2-buten-l-yl group, a 3-methyl-2-buten-l-yl group, a 3-methyl-3-penten-l-yl group, a
3- methyl-2-penten-l-yl group, a 3-ethyl-2-penten-l-yl group, a 4-methyl-3-penten-l-yl group, a 4-methyl-2-penten-l-yl group, a 2-methyl-2-penten-l -yl group, and the like.
In the present invention, "a (C2 to C6 alkynyl)(d to C3 alkyl) group" means a group obtained by substituting "a Ci to C3 alkyl group" with "a C2 to C6 alkynyl group" at arbitrary position. For example, there may be mentioned a 2-propyn-l-yl group, an l-methyl-2-propyn-l-yl group, an l-ethyl-2-propyn-l-yl group, a 2-butyn-l-yl group, an l-methyl-2-butyn-l-yl group, an l-ethyl-2-butyn-l-yl group, a 3-butyn-l-yl group, an l-methyl-3-butyn-l-yl group, an l-ethyl-3-butyn-l-yl group, a 2-pentyn-l-yl group, an
1 - methyl -2 -pentyn-l-yl group, a 3-pentyn-l-yl group, an l-methyl-3-pentyn-l -yl group, a
4- pentyn-l-yl group, a 5-hexyn-l-yl group, a 4-hexyn-l-yl group, a 3-hexyn-l-yl group, a
2- hexyn-l-yl group, and the like.
In the present invention, "a Ci to C6 alkoxy group" means a group obtained by substituting an oxy group with "a Ci to C6 alkyl group". For example, there may be mentioned a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, a 2-methylpropoxy group, a n-pentyloxy group, an isopentyloxy group, a 2-methylbutoxy group, an 1 -ethylpropoxy group, a
2,2-dimethylpropoxy group, a n-hexyloxy group, a 4-methylpentoxy group, a
3- methylpentoxy group, a 2-methylpentoxy group, a 3,3-dimethylbutoxy group, a
2,2-dimethylbutoxy group, an 1,1-dimethylbutoxy group, a tert-butoxy group, and the like.
In the present invention, "a (Q to C6 alkoxy)(C2 to C4 alkyl)" means a group obtained by substituting "a C2 to C4 alkyl group" with "a Ct to C6 alkoxy group" or, in other words, a group obtained by replacing one carbon of a C4 to Cn alkyl group with one oxygen at arbitrary chemically possible position. For example, there may be mentioned a methoxyethyl group, an ethoxyethyl group, a propyloxyethyl group, an isopropyloxyethyl group, a butyloxyethyl group, an isobutyloxyethyl group, a sec-butyloxyethyl group, a tert-butyloxyethyl group, an isopentyloxyethyl group, a 2-methylbutyloxyethyl group, a 3-methylbutyloxyethyl group, an 1 -ethylpropyloxy ethyl group, an
1.1- dimethylpropyloxyethyl group, an 1 ,2-dimethylpropyloxy ethyl group, a
neopentyloxyethyl group, a hexyloxyethyl group, a 4-methylpentyloxyethyl group, a 3-methylpentyloxyethyl group, a 2-methylpentyloxyethyl group, an
1- methylpentyloxyethyl group, a 3,3-dimethylbutyloxyethyl group, a
2.2- dimethylbutyloxyethyl group, an 1,1-dimethylbutyloxy ethyl group, an
1.2- dimethylbutyloxyethyl group, an 1 ,3-dimethylbutyloxyethyl group, a
2.3- dimethylbutyloxyethyl group, an 1-ethylbutyloxyethyl group, a 2-ethylbutyloxyethyl group, a methoxypropyl group, an ethoxypropyl group, a propyloxypropyl group, an isopropyloxypropyl group, a butyloxypropyl group, an isobutyloxypropyl group, a sec-butyloxypropyl group, a tert-butyloxypropyl group, an isopentyloxypropyl group, a
2- methylbutyloxypropyl group, a 3-methylbutyloxypropyl group, an
1- ethylpropyloxypropyl group, an 1,1-dimethylpropyloxypropyl group, an
1.2- dimethylpropyloxypropyl group, a neopentyloxypropyl group, a hexyloxypropyl group, a 4-methylpentyloxypropyl group, a 3-methylpentyloxypropyl group, a
2- methylpentyloxypropyl group, an 1 -methylpentyloxypropyl group, a
3.3- dimethylbutyloxypropyl group, a 2,2-dimethylbutyloxypropyl group, an
1,1-dimethylbutyloxypropyl group, an 1 ,2-dimethylbutyloxypropyl group, an
1,3-dimethylbutyloxypropyl group, a 2,3-dimethylbutyloxypropyl group, an
1-ethylbutyloxypropyl group, a 2-ethylbutyloxypropyl group, a methoxybutyl group, an ethoxybutyl group, a propyloxybutyl group, an isopropyloxybutyl group, a butyloxybutyl group, an isobutyloxybutyl group, a sec-butyloxybutyl group, a tert-butyloxybutyl group, an isopentyloxybutyl group, a 2-methylbutyloxybutyl group, a 3-methylbutyloxybutyl group, an 1-ethylpropyloxybutyl group, an 1,1-dimethylpropyloxybutyl group, an
1 ,2-dimethylpropyloxybutyl group, a neopentyloxybutyl group, a hexyloxybutyl group, a 4-methylpentyloxybutyl group, a 3-methylpentyloxybutyl group, a 2-methylpentyloxybutyl group, an 1-methylpentyloxybutyl group, a 3,3-dimethylbutyloxybutyl group, a
2,2-dimethylbutyloxybutyl group, an 1,1-dimethylbutyloxybutyl group, an
1.2- dimethylbutyloxybutyl group, an 1,3-dimethylbutyloxybutyl group, a
2.3- dimethylbutyloxybutyl group, an 1-ethylbutyloxybutyl group, a 2-ethylbutyloxybutyl group, and the like.
In the present invention, "a C\ to C6 alkylthio group" means a group obtained by substituting a thio group with "a Ci to C6 alkyl group". For example, there may be mentioned a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, a pentylthio group, a neopentylthio group, a tert-pentylthio group, a
2-methylbutylthio group, a hexylthio group, an isohexylthio group, and the like.
In the present invention, "a C3 to C8 cycloalkylthio group" means a group obtained by substituting a thio group with "a C3 to C8 cycloalkyl group". For example, there may be mentioned a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, a cyclooctylthio group, and the like.
In the present invention, "a (Ci to C6 alkyl)carbonyl group" means a group obtained by substituting a carbonyl group with "a C\ to C6 alkyl group". For example, there may be mentioned an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a n-pentylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group, an isopentylcarbonyl group, a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, an 1-ethylpropylcarbonyl group, an 1,1-dimethylpropylcarbonyl group, an 1 ,2-dimethylpropylcarbonyl group, a neopentylcarbonyl group, a 4-methylpentylcarbonyl group, a 3-methylpentylcarbonyl, a 2-methylpentylcarbonyl group, an
1-methylpentylcarbonyl group, a 3,3-dimethylbutylcarbonyl group, a
2,2-dimethylbutylcarbonyl group, an 1 , 1 -dimethylbutylcarbonyl group, an
1.2- dimethylbutylcarbonyl group, an 1,3 -dimethylbutylcarbonyl group, a
2.3 - dimethylbutylcarbonyl group, an 1-ethylbutylcarbonyl group, a 2-ethylbutylcarbonyl group, a n-hexylcarbonyl group, and the like.
In the present invention, "a (Cj to C6 alkoxy)carbonyl group" means a group obtained by substituting a carbonyl group with "a C] to C6 alkoxy group". For example, there may be mentioned a methoxycarbonyl group, an ethoxycarbonyl group, a
n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a n-pentoxycarbonyl group, an isopentoxycarbonyl group, a 2-methylbutoxycarbonyl group, a 3 -methylbutoxy carbonyl group, an 1 -ethylpropoxycarbonyl group, an
1,1-dimethylpropoxycarbonyl group, an 1 ,2-dimethylpropoxycarbonyl group, a
neopentoxycarbonyl group, a 4-rhethylpentoxycarbonyl group, a 3-methylpentoxycarbonyl, a 2-methylpentoxycarbonyl group, an 1-methylpentoxycarbonyl group, a
3,3-dimethylbutoxycarbonyl group, a 2,2-dimethylbutoxycarbonyl group, an
1,1-dimethylbutoxycarbonyl group, an 1 ,2-dimethylbutoxycarbonyl group, an
1,3-dimethylbutoxycarbonyl group, a 2,3-dimethylbutoxycarbonyl group, an
1-ethylbutoxycarbonyl group, a 2-ethylbutoxycarbonyl group, a n-hexoxycarbonyl group, and the like. ^
In the present invention, "a C3 to C8 cycloalkyloxy group" means a group obtained by substituting an oxy group with "a C3 to C8 cycloalkyl group". For example, there may be mentioned a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, and the like.
In the present invention, "a mono(Ci to C6 alkyl)amino group" means a group obtained by substituting an amino group with "a C\ to C6 alkyl group". For example, there may be mentioned a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group, a pentylamino group, a hexylamino group, and the like.
In the present invention, "a di(Ci to C6 alkyl)amino group" means a group obtained by substituting an amino group with two of the same or different "a Q to C6 alkyl group". For example, there may be mentioned a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, a di(sec-butyl)amino group, a di(tert-butyl)amino group, a dipentylamino group, a dihexylamino group, and the like.
In the present invention, "a (Ci to C6 alkyl)aminocarbonyl group" means a group obtained by substituting a carbonyl group with "a (Cj to C6 alkyl)amino group". For example, there may be mentioned a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a
butylaminocarbonyl group, an isobutylaminocarbonyl group, a sec-butylaminocarbonyl group, a tert-butylaminocarbonyl group, a pentylaminocarbonyl group, a
hexylaminocarbonyl group, and the like.
In the present invention, "a Ci to C6 alkylsulfonyl group" means a group obtained by substituting a sulfonyl group with "a C\ to C6 alkyl group". For example, there may be mentioned a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a
sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group, and the like. In the present invention, "a C'i to C6 alkylaminosulfonyl group" means a group obtained by substituting a sulfonyl group with "a monoCCi to C6 alkyl)amino group". For example, there may be mentioned a methylaminosulfonyl group, an ethylaminosulfonyl group, a propylaminosulfonyl group, an isopropylaminosulfonyl group, a
butylaminosulfonyl group, an isobutylaminosulfonyl group, a sec-butylaminosulfonyl group, a tert-butylaminosulfonyl group, a pentylaminosulfonyl group, a
hexylaminosulfonyl group, and the like.
In the present invention, "a (hydroxycarbonyl)(C] to C3 alkyl) group" means a group obtained by substituting "a Q to C3 alkyl group" with "a (hydroxycarbonyl) group" at arbitrary position. For example, there may be mentioned a hydroxycarbonylmethyl group, a (l-hydroxycarbonyl)ethyl group, a (2-hydroxycarbonyl)ethyl group, a
(3-hydroxycarbonyl)propyl group, an a (2-hydroxycarbonyl)propyl group, a
(l -hydroxycarbonyl)propyl group, a (l-hydroxycarbonyl)(l-methyl)ethyl group, and the like.
In the present invention, "a (Ci to C6 alkoxy)carbonyl(C1 to C3 alkyl) group" means a group obtained by substituting "a C\ to C3 alkyl group" with "a (C\ to C6 alkoxy)carbonyl group" at arbitrary position. For example, there may be mentioned a
methoxycarbonylmethyl group, a methoxycarbonylethyl group, a
(3-methoxycarbonyl)propyl group, a (2-methoxycarbonyl)propyl group, a
(l-methoxycarbonyl)propyl group, a (l-methoxycarbonyl)(l-methyl)ethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonyl ethyl group, an (3-ethoxycarbonyl)propyl group, an (2-ethoxycarbonyl)propyl group, an (l-ethoxycarbonyl)propyl group, an
(l-ethoxycarbonyl)(l-methyl)ethyl group , and the like.
In the present invention, "a (Ci to C
Figure imgf000022_0001
to C3 alkyl) group" means a group obtained by substituting "a Q to C3 alkyl group" with "a (Ci to C6 alkyl)sulfonyl group" at arbitrary position. For example, there may be mentioned a methlsulfonyl methyl group, a methylsulfonylethyl group, a (3-methylsulfonyl)propyl group, a
(2-methylsulfonyl)propyl group, a (l-methylsulfonyl)propyl group, a
(l-methylsulfonyl)(l-methyl)ethyl group, an ethyl sulfonylmethyl group, an
ethylsulfonylethyl group, an (3-ethylsulfonyl)propyl group, an (2-ethylsulfonyl)propyl group, an (l-ethylsulfonyl)propyl group, an (l-ethylsulfonyl)(l-methyl)ethyl group , and the like.
In the present invention, "a C6to C10 aryl group" means an aromatic hydrocarbon group having 6 to 10 carbons. For example, there may be mentioned a phenyl group, a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, an azulenyl group, and the like.
In the present invention, "a C6 to C10 aryloxy group" means a group obtained by
substituting an oxy group with "a C6to C10 aryl group". For example, there may be mentioned a phenyloxy group, a naphthyloxy group, an indenyloxy group, a
tetrahydronaphthyloxy group, an indanyloxy group, an azulenyloxy group, and the like.
In the present invention, "a (C to C10 aryl)(C] to C3 alkyl) group" means a group obtained by substituting "a Ci to C3 alkyl group" with "a C6 to C]0 aryl group". For example, there may be mentioned a benzyl group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group, and the like.
In the present invention, "a 5- to 10-membered heteroaryl group" means a 5- to 10-membered monocyclic or bicyclic heterocyclic group having aromaticity, wherein the heterocyclic group contains 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen. Further, in the case of a bicyclic aromatic heterocyclic group, if one ring is aromatic ring or aromatic heterocyclic ring, the other ring may be non-aromatic ring. In such aromatic heterocyclic group, the number of respective heteroatoms and combinations thereof are not particularly limited as long as ring having prescribed number of members carl be formed and can exist chemically stably. As such "a 5- to 10-membered heteroaryl group", for example, there may be mentioned a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyridazinyl group, a furyl group, a thienyl group, a pyrrole group, a pyrazolyl group, an 1,3-dioxaindanyl group, an isoxazolyl group, an isothiazolyl group, a benzoiuranyl group, an isobenzofuryl group, a benzothienyl group, an indolyl group, an isoindolyl group, a chromanyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, a pyranyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazinyl group, a triazolyl group, a furazanyl group, a thiadiazolyl, a dihydrobenzofuryl group, a dihydroisobenzofuryl group, a dihydroquinolyl group, a dihydroisoquinolyl group, a dihydrobenzoxazolyl group, a dihydropteridinyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzodioxazolyl group, a quinolyl group, an isoquinolyl group, a benzotriazolyl group, a pteridinyl group, a purinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a tetrazolyl group, and the like.
In the present invention, "a (5- to 10-membered heteroarylXQ to C3 alkyl) group" means a group obtained by substituting "a Ci to C3 alkyl group" with "a 5- to 10-membered heteroaryl group". For example, there may be mentioned a pyridylmethyl group, a thienylmethyl group, a thiazolylmethyl group, a benzothiazolylmethyl group, a
benzothiophenylmethyl group, and the like.
In the present invention, "a 3- to 8-membered heterocycloalkyl group" means a 3- to 8-membered aliphatic heterocyclic group which may be saturated or partially unsaturated, wherein the ring contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. For example, there may be mentioned a piperidyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a morpholyl group, and the like.
In the present invention, "a (3- to 8-membered heterocycloalkyl)(Ci to C3 alkyl) group" means a group obtained by substituting "a d to C3 alkyl group" with "a 3- to 8-membered heterocycloalkyl group". For example, there may be mentioned a
piperidylmethyl group, a tetrahydrofuranylmethyl group, a tetrahydropyranylmethyl group, a tetrahydrothienylmethyl group, a morpholinoethyl group, a oxetan-3-ylmethyl group, and the like.
In the present invention, "spiroheteroalkyl group" means a spiroalkyl group in which 1 to 4 carbon atoms replaced with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. "A C6 to C9 spiroheteroalkyl group" means a spiroalkyl group having 6 to 9 carbons. For example, there may be mentioned a 4-oxaspiro[2.4]heptanyl group, a 4-oxaspiro[2.5]octaneyl group, and the like.
In the present invention, "a (C5 to C9 bicycloalkylXCi to C3 alkyl) group" means a group obtained by substituting "a Q to C3 alkyl group" with "a C5 to C9 bicycloalkyl group" at arbitrary position. For example, there may be mentioned a bicyclo [1.1.1 Jpentanyl methyl group, a bicyclo[3.1.0]hexanyl methyl group, a bicyclo [3. l .OJhexanyl ethyl group, a bicyclo[2.2.0]hexanyl methyl group, a bicyclo[2.2.0]hexanyl ethyl group, a
bicyclo[2.1. ljhexanyl methyl group, a bicyclo[2.1.ljhexanyl ethyl group, a
bicyclo[3.2.0]heptanyl methyl group, a bicyclo[3.2.0]heptanyl ethyl group, a
bicyclo[2.2.1]heptanyl methyl group, a bicyclo[2.2.1]heptanyl ethyl group, a
bicyclo [3. l .l]heptanyl methyl group, a bicyclo[4.1.0]heptanyl methyl group, an
octahydropentalenyl methyl group, a bicyclo[2.2.2]octanyl methyl group, a
bicyclo[3.2.1]octanyl methyl group, a bicyclo[4.2.0]octanyl methyl group, a
bicyclo [4. l .ljoctanyl methyl group, a bicyclo[5.1.0]octanyl methyl group, an
octahydro-lH-indenyl methyl group, a bicyclo[3.2.2]nonanyl methyl group, a
bicyclo[3.3.1 Jnonanyl methyl group, a bicyclo[4.2.1 Jnonanyl methyl group, a
bicyclo[5.2.0]nonanyl methyl group, and the like. In the present invention, "heterobicycloalkyl group" means a bicycloalkyl group in which 1 to 4 carbon atoms replaced with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. "A C6 to C9 heterobicycloalkyl group" means a heterobicycloalkyl group having 6 to 9 carbons. For example, there may be mentioned a
7-oxabicyclo[2.2.1]heptanyl group and the like.
In the present invention, "a (C6 to C9 heterobicycloalkyl)(Ci to C3 alkyl) group" means a group obtained by substituting "a C] to C3 alkyl group" with "a C6to C9 heterobicycloalkyl group" at arbitrary position. For example, there may be mentioned a 7-oxabicyclo[2.2.1]heptanyl methyl group, a 7-oxabicyclo[2.2.1]heptanyl ethyl group, and the like.
In the present invention, in "a Ci to C6 alkyl group substituted by 0, 1 , 2 or 3 Ra groups", when the C\ to C6 alkyl group is substituted by a plurality of Ra groups, each Ra group can be selected independently and the Q to C6 alkyl group can be substituted by the same Ra groups or by different Ra groups. In addition, meaning of other expressions such as "a Ci to C alkyl group substituted by 0, 1, 2 or 3 Rb groups" and the like mean similar situations.
The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000026_0001
In the formula (I), R1 is selected from F, CI, Br, a Ci to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups and a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Ra groups; wherein Ra is, independently selected from F, Ci to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(Ci to C6 alkyl)amino group, -CF3 and an oxo group.
The "a Ci to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups" in R1 is preferably Ci to C3 alkyl group substituted by 0, 1, 2 or 3 Ra groups, and more preferable is a trifluoromethyl group or a difluoromethyl group.
The "a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Ra groups" in R1 is preferably C3 to C4 cycloalkyl group substituted by 0, 1, 2 or 3 Ra groups, more preferable is a cyclopropyl group substituted by 0, 1, 2 or 3 Ra groups.
On the whole, R1 is preferably CI, a Ci to C4 alkyl group substituted by 0, 1, 2 or 3 Ra groups or a cyclopropyl group substituted by 0, 1 , 2 or 3 Ra groups, and more preferable is a trifluoromethyl group, a difluoromethyl group or CI.
In the formula (I), Y is a C4 to C cycloalkyl group, a C6 to C9 bicycloalkyl group or a C6 to C9 spiroalkyl group, all of which are substituted by a R group, 0 or 1 R group and 0, 1, 2 or 3 R groups;
wherein R2 is selected from -OH, -C02H, -S03H, -CONH2, -S02NH2, a (d to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rc groups, a (Ci to C6
alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rc groups, a d to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a d to C6 alkylaminosulfonyl group substituted by 0, 1, 2 or 3 R° groups, a (hydroxycarbonyl)(Ci to C3 alkyl) group substituted by 0, 1, 2 or 3 R° groups, a (d to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (Ci to C6 alkyl)sulfqnyl(d to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C! to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups;
R6 and R7 are independently selected from H, F, -OH, -NH2, -CN, a d to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups and a d to C6 alkoxy group substituted by 0, 1, 2 or 3 b
R groups;
wherein Rband Rc are , independently selected from F, a C] to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Q to C6 alkoxy group, a monoid to C6 alkyl)amino group, a di(Ci to C6 alkyl)amino group, -CF3 and an oxo group;
The "a C4 to C6 cycloalkyl group, a C6 to C9 bicycloalkyl group or a C6 to C9 spiroalkyl
2 6 7 group, all of which are substituted by a R group, 0 or 1 R group and 0, 1, 2 or 3 R groups" in Y is preferably a group represented by formula (Il-a), formula (Il-b), formula (II-c) or
Figure imgf000028_0001
wherein:
k is 0, 1 or 2;
and n is 1, 2 or 3.
In the case of the group represented by formula (Il-a), formula (Il-b), formula (II-c) or formula (Il-d), Y is preferably a group represented by formula (Il-a), formula (II-c) or formula (Il-d); and more preferably a group represented by formula (Il-a) or formula (Il-d).
The variable, n, is preferably 2 in a group represented by formula (Il-d).
R2 in Y is preferably -C02H, -S03H, -CONH2, -S02NH2, a (C, to C2
alkyl)aminocarbonyl group substituted by 0 or 1 Rc groups, a Ci to C2 alkylsulfonyl group substituted by 0 or 1 Rc groups, a Ci to C2 alkylaminosulfonyl group substituted by 0 or 1 Rc groups or a (hydroxycarbonyl)(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, and more preferable is -C02H or a hydroxycarbonylmethyl group substituted by 0, 1 or 2 Rc groups. R6 in Y is preferably H or a Q to C4 alkyl group without Rb group, and more preferable is H, a methyl group or an ethyl group.
R in Y is preferably H or a Cj to C2 alkyl group without R group, and more preferable is H or a methyl group.
In the formula (I), R3 is selected from H, F, CI, -CH3 and -CF3. R3 is preferably H.
In the formula (I), R4 is selected from a Q to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkenyl)(d to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (d to C6 alko^ y)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups,
f
a (C6 to C10 aryl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a (5- to 10-membered heteroaryl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C3 to Cg cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C3 to C8
cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5R8 groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a (C3 to C8 cycloalkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a 3- to 8-membered
heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rs groups, a (3- to 8-membered heterocycloalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C5 to C9 bicycloalkyl group substituted by 0, 1,
2, 3, 4 or 5 R8 groups, a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2,
3, 4 or 5 R8 groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (C6 to C9 heterobicycloalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups;
wherein Re isindependently selected from F, a d to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C6 alkoxy group, a mono^ to C6 alkyl)amino group, a di(C! to C6 alkyl)amino group, -CF3 and an oxo group;
Rf is independently selected from F, CI, Br, -OH, -CN, -N02j -C02H, a Ci to C6 alkyl group substituted by 0, 1 , 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1 , 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1 , 2 or 3 Rk groups, a C3 to Cg cycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a Q to C6 alkoxy group substituted by 0, 1 , 2 or 3 Rk groups, a C3 to Cg cycloalkyloxy group substituted by 0, 1 , 2 or 3 Rk groups, -SH, a Ci to C6 alkylthio group substituted by 0, 1 , 2 or 3 Rk groups, a C3 to Cg cycloalkylthio group substituted by 0, 1 , 2 or 3 Rk groups, a (Ci to C6 alkyl)carbonyl group substituted by 0, 1 , 2 or 3 Rk groups, a (Ci to C6 alkoxy)carbonyl group substituted by 0, 1 , 2 or 3 R groups, a (Ci to C6 alkyl)aminocarbonyl group substituted by 0, 1 , 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2 or 3 Rk groups, a Ci to C6 alkylsulfonyl group substituted by 0, 1 , 2 or 3 Rk groups, -NH2, a mono(Ci to C6
alkyl)amino group substituted by 0, 1 , 2 or 3 Rk groups and a di(Q to C6 alkyl)amino group substituted by 0, 1, 2 or 3 R groups;
wherein, Rk is independently selected from F, a Q to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C6 alkoxy group, a mono^ to C6 alkyl)amino group, a di(Cj to C6 alkyl)amino group, -CF3 and an oxo group;
Rg is is independently selected from F, CI, a d to C alkyl group, -OH, -CN, -NH2, -N02, -C02H, a Ci to C6 alkoxy group, a mono(d to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3, a Ci to C6 alkyl ene group substituted by 0, 1 , 2 or 3 R1 groups, a C2 to C6 alkenylene group substituted by 0, 1 , 2 or 3 R1 groups and an oxo group; wherein R1 is independently selected from F, a Q to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C6 alkoxy group, a mono(C! to C6 alkyl)amino group, a di(Ci to C6 alkyl)amino group, -CF3 and an oxo group.
The "a d to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5Re groups" in R4 is preferably C2 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5Re and more preferably a tert-butylmethyl group or a 3,3,3-trifluoro-2,2-dimethylpropyl group.
The "a (C2 to C6 alkenylXd to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups" in R4 is preferably one having 3 to 6 carbons in (C2 to C6 alkenyl)(Ci to C3 alkyl) and more preferably a 3 -methyl-2-buten-l-yl group. ,
The "a (C2 to C6 alkynyl)(d to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5Re groups" in R4 is preferably one having 4 to 8 carbons in (C2 to C6 alkynyl)(d to C3 alkyl) and more preferably a 4,4-dimethyl-2-pentyn-l-yl group.
The "a (d to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1,, 2, 3, 4 or 5Re groups" in R4 is preferably one having 3 to 7 carbons in (d to C6 alkoxy)(C2 to C4 alkyl), more preferably a d to C4 alkoxyethyl group substituted by 0, 1, 2 or 3 alkyl groups, and even more preferably a 2,2-dimethyl-2-methoxyethyl group or a 2-(tert-butoxy)ethyl group.
The "a (C6 to C10 arylXd to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups" in R4 is preferably a benzyl group substituted by 0, 1, 2, 3, 4 or 5 Rf's; more preferably a benzyl group substituted by 1 , 2 or 3 groups selected from F and CI, or a unsubstituted benzyl group; and even more preferable is a 4-fluorobenzyl group, a
3,5-difluorobenzyl group or a 4-(trifluoromethyl)benzyl group.
The "a (5- to 10-membered heteroaryl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups" in R4 is preferably a pyridylmethyl group, a thienylmethyl group, a thiazolylmethyl group or a furanylmethyl group.
The "a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3 , 4 or 5 R8 groups" in R4 is preferably C3 to C6 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and more preferably a 2,2-dimethylcyclobutyl group or a 4,4-dimethylcyclohexyl group.
The "a (C3 to C8 cycloalkylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups" in R4 is preferably a C3 to C6 cycloalkyl methyl group substituted by 0, 1, 2, 3 or 4 Rg groups; and more preferable is a (l-fluorocyclopentyl)methyl group, a
(3,3-dimethylcyclobutyl)methyl group, a (l-methylcyclobutyl)methyl group, a
(l-(trifluoromethyl)cyclobutyl)methyl group, a (l-(trifluoromethyl)cyclopropyl)methyl group or a (l-methylcyclopropyl)methyl group.
The "a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rs groups" in R4 is preferably a 3- to 6-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
The "a (3- to 8-membered heterocycloalkylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups" in R4 is preferably a 3- to 6-membered heterocycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a
s ■
tetrahydrofuranylmethyl group substituted by 1, 2 or 3 groups selected from F, a C\ to C4 alkyl group and a Ci to C6 alkyl ene group substituted by 0, 1, 2 or 3 R1 groups.
The "a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups" in R4 is preferably a C7 to C8 spiroalkyl ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a spiro[2.5]octan-l-yl group, a spiro[3.5]nonan-l-yl group, a
spiro[3.3]heptan-l-yl group or a spiro[3.3]heptan-2-yl group.
The "a (C6 to C9 spiroalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups" in R4 is preferably a C6 to C8 spiroalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a spiro[2.5]octan-6-ylmethyl group substituted by 0, 1, 2 or 3 Rg groups or a spiro[2.3]hexan-5-ylmethyl group substituted by 0, 1, 2 or 3 Rg groups; and even more preferable is a spiro[2.5]octan-6-ylmethyl group,
(5-fluoro-spiro[2.3]hexan)-5-ylmethyl group or spiro[2.3]hexan-5-ylmethyl group. The "a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups" in R4 is preferably a C7 to C8 spiroheteralkyl ring substituted by 0, 1, 2, 3, 4 or 5 R8 groups.
The "a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rs groups" in R4 is preferably a C to C8 bicycloalkyl ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a bicyclo[3.1.0]hexan-3-yl group substituted by 0, 1, 2 or 3 R8 groups; and even more preferable is a 6,6-dimethylbicyclo[3.1.0]hexan-3-yl group.
The "a (C5 to C9 bicycloalkylXd to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rs groups" in R4 is preferably a C5 to C7 bicycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups; more preferably a (bicyclo[l . l . l]pentan-l-yl)methyl group substituted by 0, 1, 2 or 3 Rg groups or a (bicyclo[2.2.1]heptan-l-yl)methyl group substituted by 0, 1, 2 or
3 Rg groups; and even more preferable is a (4-methylbicyclo[2.2.1]heptan-l-yl)methyl group or (bicyclo[l . l.l]pentan-l-yl)methyl group.
The "a (C6to C heterobicycloalkyl)(C! to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups" in R4 is preferably a C6 to C7 heterobicycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably (7-oxabicyclo[2.2.1]heptan-l-yl)methyl group substituted by 0, T, 2 or 3 R8 groups; and, even more preferable is
(4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl)methyl group or
(7-oxabicyclo[2.2.1]heptan-l-yl)methyl group.
In the formula (I), R5 is selected from a C to C10 aryl group substituted by 0, 1, 2, 3,
4 or 5 R' groups, a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R1 groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 RJ groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 RJ groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 RJ groups;
wherein R' is independently selected from F, CI, Br, -OH, -CN,- -N02, -C02H, a d to C6 alkyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1, 2 or 3 Rk groups, a C3 to Cg cycloalkyl group substituted by 0, 1 , 2 or 3 Rk groups, a d to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C cycloalkyloxy group substituted by 0, 1 , 2 or 3 Rk groups, -SH, a Ci to C6 alkylthio group substituted by 0, 1 , 2 or 3 Rk groups, a C3 to C8 cycloalkylthio group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Cj to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a C] to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rk groups, -NH2,.a mono^ to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups and a di(Ci to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups;
Rj isindependently selected from F, CI, a C] to C6 alkyl group, -OH, -CN, -NH2, -N02, -C02H, a Ci to C6 alkoxy group, a mono^ to C6 alkyl)amino group, a di(C! to C6 alkyl)amino group, -CF3, a Ci to C6 alkyl ene group substituted by 0, 1, 2 or 3 R1 groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 R1 groups and an oxo group;
wherein, when RJ is a divalent group of a Ci to C6 alkylene group or a C2 to C6 alkenylene group, it is meant that each group forms bonds with atoms in R5; in this case, two bonds of each of these divalent groups are formed with the same atom or two different atoms in R5; wherein Rk and R1 are independently selected from F, a C] to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a C\ to C6 alkoxy group, a mono(d to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
The "a C6 to Cio aryl group substituted by 0, 1, 2, 3, or 4 R1 groups" in R5 is preferably a phenyl group substituted by 2 to 4 groups selected from -OH, -NH2, CI, F, -CN, -CF3, -OCF3, -OCF2H, a methyl group, a cyclopropyl group and a methoxy group; and more preferable is a 2,6-dichlorophenyl group, a 2,6-dichloro-4-fluorophenyl group, a 2,6-dichloro-4-methylphenyl group, a 2,4,6-trichlorophenyl group, a
2- chloro-6-fluorophenyl group or a 2,6-dichloro-3 -fluorophenyl group.
The "a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R1 groups" in R5 is preferably a pyridyl group substituted by 2 to 3 groups selected from -OH, -NH2, CI, F, -CN, -CF3, a methyl group, and a methoxy group; and more preferable is a
3,5-dichloropyridin-4-yl group, a 3-chloro-5-methoxypyridin-4-yl group, a
3- chloro-5-fluoropyridin-4-yl group or a 2,4-dichloro-6-methylpyridin-3-yl group.
On the whole, R5 is preferably a phenyl group optionally substituted by 2, 3 or 4 R1 groups or a 6-membered heteroaryl group optionally substituted by 2 or 3 R' groups.
In the formula (I), R and R are independently selected from H, F, -OH, -NH2, a Ci to C3 alkyl group substituted by 0, 1 , 2 or 3 Rh groups, and a C \ to C6. alkoxy group substituted by 0, 1, 2 or 3 Rh groups; or R8 and R9 together form an oxo group or a thioxo group;
wherein Rh is, independently selected from F, a C\ to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C alkoxy group, a mono(Cj to C6 alkyl)amino group, a di(Ci to C6 alkyl)amino group, -CF3 and an oxo group.
The "a Ci to C3 alkyl group substituted by 0, 1 , 2 or 3 Rh groups" in R8 and R9 is preferably methyl group substituted by 0, 1 , 2 or 3 R groups.
The "a C ! to C6 alkoxy group substituted by 0, 1 , 2 or 3 Rh groups" in R8 and R9 is preferably methoxy group substituted by 0, 1 , 2 or 3 R groups.
On the whole, R8 and R9 are preferably H, F, -OH or an oxo group, andmore preferable are H or an oxo group.
In the formula (I), R12 is H; or R4 and R12 together are -CRmRm-CR13R14-CRmRm- or -CRI3R14-CRmRm-CRmRm- to form a pyrrolidine ring. R13 is selected from H, a Cy to C6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a C6 to Cio aryl group substituted by 0, 1 , 2, 3, 4 or 5 Rf groups, a C6 to C10 aryloxy group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (C2 to C6 alkenyl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (Q to C alkoxy)(C2 to C4 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (5- to 10-membered heteroaryl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 groups, a (C3 to C8 cycloalkylXCi to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkenylXCj to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups and a (3- to 8-membered heterocycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a (C6 to C9 spiroalkylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C6 to C9 bicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, (C6 to C9 heterobicycloalkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups;
R14 is selected from H and a Q to C6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 Re groups; or R13 and R14 together form a C3 to C8 cycloalkane ring substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, C3 to C8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 Rs groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1 , 2, 3, 4 or 5 R8 groups;
Rm is independently selected from H, F, CI, -CH3 and -CF3; wherein Rg is selected from F, CI, a Ci to C6 alkyl group, -OH, -CN, -NH2, -N02, -C02H, a C\ to C6 alkoxy group, a mono(C! to C6 alkyl)amino group, a di(C! to C6 alkyl)amino group, -CF3, a Ci to C6 alkylene group substituted by 0, 1 , 2 or 3 R1 groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 R1 groups and an oxo group;
Rf is independently selected from F, CI, Br, -OH, -CN, -N02, -C02H, a d to C6 alkyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1 , 2 or 3 Rk groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2 or 3 Rk groups, a Cj to C6 alkoxy group substituted by 0, 1 , 2 or J Rk groups, a C3 to C8 cycloalkyloxy group substituted by 0, 1, 2 or 3 Rk groups, -SH, a Ci to C6 alkylthio group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkylthio group substituted by 0, 1, 2 or 3 Rk groups, a (d to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkoxy)carbonyl group substituted by 0, 1 , 2 or 3 Rk groups, a (d to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a d to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rk groups, -NH2, a mono(Cj to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups and a di(d to C6 alkyl)amino group substituted by 0, 1, 2 or 3 R groups; and
Re and Rk are, independently selected from F, a d to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a Ci to C6 alkoxy group, a mono(d to C6 alkyl)amino group, a di(Ci to C6 alkyl)amino group, -CF3 and an oxo group.
Preferably R12 is H; or R4 and R12 together are -CH2-CR13R14-CH2- to form a
12
pyrrolidine ring, more preferably R is H.
R13 is preferably a C\ to C6 alkyl group, a C6 to C10 aryl group, a C6 to C10 aryloxy group, a (C6 to CIO aryl)(Cl to C3 alkyl) group, or a C3 to Cg cycloalkenyl group.
R14 is preferably H or CH3; or R13 and R14 together form a C3 to C8 cycloalkane ring or a C3 to C8 cycloalkene ring. In the formula (I), a combination of R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, R14 Y, n, k, Ra, Rb, Rc, Re, Rf, R8, Rh, R Rj, Rk, R1, Rm is preferably one where respective preferable components described above are combined; and more preferably one where components described above as more preferable are combined.
In another embodiment, in conjunction with any above or below embodiments, R1 is a Ci to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups.
In another embodiment, in conjunction with any above or below embodiments, R1 is a Ci alkyl group substituted by 0, 1, 2 or 3 Ra groups.
In another embodiment, in conjunction with any above or below embodiments, R1 is
CF3.
In another embodiment, in conjunction with any above or below embodiments, R2 is C02H.
In another embodiment, in conjunction with any above or below embodiments, Y is selected from formula (Il-a), formula (Il-b), formula (II-c) and formula (Il.-d):
Figure imgf000038_0001
In another embodiment, in conjunction with any above or below embodiments, Y is selected from formula Il-a) and formula (Il-d);
Figure imgf000038_0002
wherein in k is 0, 1 or 2; and n is 1, 2 or 3.
In another embodiment, in conjunction with any above or below embodiments, Y is selected from formula (Il-a) and formula (Il-d);
Figure imgf000039_0001
wherein in k is 0; and n 2.
In another embodiment, in conjunction with any above or below embodiments, Y is
Figure imgf000039_0002
In another embodiment, in conjunction with any above or below embodiments, Y is
Figure imgf000039_0003
In another embodiment, in conjunction with any above or below embodiments,
R6 is selected from F, -OH, -NH2, -CN, a Ct to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups and a Ci to C alkoxy group substituted by 0, 1, 2 or 3 Rb groups.
In another embodiment, in conjunction with any above or below embodiments, R6 is a Ci to C6 alkyl group substituted by 0, 1 , 2 or 3 Rb.
In another embodiment, in conjunction with any above or below embodiments, R6 is CH3.
In another embodiment, in conjunction with any above or below embodiments, R7 is independently selected from H, F and a Ci to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups.
In another embodiment, in conjunction with any above or below embodiments, R7 is H.
In another embodiment, in conjunction with any above or below embodiments, R2 is selected from -OH, -C02H, -S03H, -CONH2 and -S02NH2. In another embodiment, in conjunction with any above or below embodiments, R3 is H.
In another embodiment, in conjunction with any, above or below embodiments, R4 is selected from a Ci to C6 'alkyl group substituted by 0, 1 , 2 or 3 Re groups, a (C6 to C10 arylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkylXCi to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rs groups, a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups or a (C6 to C9 heterobicycloalkyl)(C! to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rs groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a d to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a (C6 to C10 arylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a (C5 to C9 bicycloalkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a (C3 to C8 cycloalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a C6 to C9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups. In another embodiment, in conjunction with any above or below embodiments, R4 is a (C6 to C9 spiroalkyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R4 is a (C6 to C9 heterobicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R8 and R9 are independently selected from H and F.
In another embodiment, in conjunction with any above or below embodiments, R and R9 together form an oxo group.
In another embodiment, in conjunction with any above or below embodiments, R5 is a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R' groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is a phenyl group substituted by 0, 1, 2, 3, 4 or 5 R1 groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is a 5- to 10-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R1 groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is a 6-membered heteroaryl group substituted by 0, 1 , 2, 3, or 4 R1 groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is pyridyl substituted by 0, 1, 2, 3, or 4 R1 groups.
In another embodiment, in conjunction with any above or below embodiments, R12 is H.
In another embodiment, in conjunction with any above or below embodiments, R4 and R12 together are -CH2-CR13RI4-CH2- to form a pyrrolidine ring.
In another embodiment, in conjunction with any above or below embodiments, R14 is selected from H and CH3.In another embodiment, in conjunction with any above or below embodiments, R13 and R14 together form a C3 to C8 cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 R groups, C3 to C8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 R8 groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, ,3, 4 or 5 Rg groups.
In another embodiment, in conjunction with any above or below embodiments, R is selected from a Q to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C6 to C10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (C2 to C6 alkenylXd to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (Ci'to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C6 to C10 arylX to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a
f
(5- to 10-membered heteroaryl)(C! to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rs groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkenylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a 3- to 8-membered
heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2,
3, 4 or 5 Rg groups, a C to C9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups;
In another embodiment, in conjunction with any above or below embodiments, Rm is
H;
The present invention also relates to a pharmaceutically acceptable salt of a compound represented by formula (I). For example, in the present invention, there are cases where a compound represented by formula (I) forms acid addition salts. Further, depending on the kind of substituent, there are cases where the pyrazole amide derivative forms salts with bases. These salts are not particularly limited as long as they are pharmaceutically acceptable ones. Specifically, the acid addition salts include mineral acid salts such as a hydrofluoride, a hydrochloride, a hydrobromide, a hydroiodide, a phosphate, a nitrate, a sulfate, and the like; organic sulfonate such as a methanesulfonate, an ethanesulfonate, a 2-hydroxyethanesulfonate, a p-toluenesufonate, a benzenesulfonate, an ethane- 1 ,2-disulfonate ion, a 1,5-naphthalenedisulfonate ion, a naphthalene-2-sulfonate ion, and the like; and organic carboxylate such as an acetate, a trifluoroacetate, a
propionate, an oxalate, a fumarate, a phthalate, a malonate, a succinate, a glutarate, an adipate, a tartrate, a maleate, a malate, a mandelate, a 1 -hydroxy-2-naphthoate, and the like. As the salts with bases, there are mentioned salts with inorganic bases such as a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an aluminum salt, and the like; and salts with organic bases such as a methylamine salt, an ethylamine salt, a lysine salt, an ornithine salt, and the like.
The various pharmaceutically acceptable salts of a compound represented by formula (I) can be produced suitably based on common knowledge in the present technical field. .
A compound represented by formula (I) of the present invention contains isomers in some cases. Such isomers are included in a compound represented by formula (I) of the present invention. For example, there may be mentioned isomers in the ring and condensed ring systems (E-, Z-, cis-, and trans-forms), isomers due to the presence of chiral carbons (R- and S-forms, a- and β-configurations, enantiomers, and diastereomers), optically active substances with optical rotation (D-, L-, d-, and 1-forms), tautomers, polar compounds obtained by chromatographic separation (a highly-polar compound and a lowly-polar compound), equilibrium compounds, rotamers, mixtures of these compounds in an arbitrary ratio, racemic mixtures, and the like.
The present invention also includes various deuterated forms of the compounds represented by formula (I). Each hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
Although the present invention has been described with respect to specific aspects or embodiments thereof, the invention can be understood by existing technology in the relevant field, and various modifications and substitutions of equivalents are possible without deviation from the true spirit and scope of the invention. Further, to the extent allowed by patent laws and rules, all publications, patents, and patent applications cited in the present description are herein incorporated by reference in their entirety to the same extent as if each individual document were individually indicated to be incorporated herein by reference in its entirety.
General synthesis method
The compound represented by formula (I) in the present invention can be produced by applying publicly known various synthesis methods with the use of characteristics based on types of basic structures or substituents. In this case, it may be effective in terms of manufacturing technology that the functional group may be protected with an appropriate protecting group or a group that can be easily converted to a functional group in the process of using a raw material and an intermediate depending on functional groups. Such a functional group includes, for example, an amino group, a hydroxyl group, a carboxyl group, and the like. The protecting groups thereof include, for example, protecting groups described in the "Protecting Groups in Organic Synthesis (the third edition, 1999)" written by T. W. Greene and P. G. M. Wuts. They may be suitably chosen and used depending on the reaction conditions. In these methods, the reaction is carried out by introducing the protecting group followed by eliminating the protecting group as necessary, or converting to an intended group to obtain ah intended compound.
Among compound represented by formula (I) in the present invention, a compound I- 1) can be prepared, for example, by the following method:
Figure imgf000045_0001
(1) (2) (1-1)
(wherein, R8 and R9 are independently H; F; a hydroxyl group; an amino group; a Ci to C3 alkyl group substituted by 0, 1, 2 or 3 R groups; a d to C6 alkoxy group substituted by 0, 1 , 2 or 3 Rh groups; or R8 and R9 together form oxo group or thioxo group. Other symbols have the same meanings as described above.)
(Step 1)
The present step is a method for producing a compound (I- 1) by reacting a compound (1) or a reactive derivative thereof with a compound (2).
The reactive derivative of the compound (1) means a reactive derivative of a carboxyl group, and for example, acid chloride, acyl azide, mixed acid anhydride, symmetric acid anhydride, activated amide, activated ester, and the like are cited. These reactive derivatives can be optionally chosen depending on types of carboxylic acids used.
The present reaction may be carried out according to a general amide-forming reaction by methods described in the literature (e.g., Pepuchido Gousei no Kiso to Jikken by Nobuo Izumiya, etc., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6., Pergamon Press, 1991, etc.), equivalent methods thereto or a combination of these methods and the conventional method. Namely, the present reaction can be carried out by using a condensation agent that is well known to a person skilled in the art, or an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method and the like that are well known in the art. The reagents used in such an amide-forming reaction include, for example, thionyl chloride, oxalyl chloride,
N,N-dicyclohexylcarbodiimide, l-methyl-2-bromopyridinium iodide,
N.iV'-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N,N'-disuccinimidyl carbonate, NN'-disuccinimidyl oxalate, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride,
benzotriazol-l-yl-oxy-tris(pyrrolidinol)phosphonium hexafluorophosphate,
2-(7H-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate,
2-(5-norbornene-2,3-dicarboximido)-l,l,3,3-tetramethyluronium tetrafluoroborate, O-(N-succinimidyl)-l,l,3,3-tetramethyluronium tetrafluoroborate,
bromo-tris(pyrrolidino)phosphonium hexafluorophosphate, ethyl chloroformate, isobutyl chloroformate, or 2-(7-aza-iH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate, and the like. Above all, for example, thionyl chloride, oxalyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or
2-(7-aza-7H-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate, and the like are preferable. In the amide-forming reaction, a base and/or a condensation agent may be used along with the above-mentioned amide-forming agent.
The amount of the condensation agent that is consumed is not strictly limited, and is generally 0.1 equivalents to 100 equivalents with respect to 1 equivalent of the compound (1), and preferably 0.1 equivalents to 10 equivalents.
A base used includes, for example, tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, NN-dimethylaniline, l,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- azabicyclo[4.3.0]non-5-ene, and the like; aromatic amines such as pyridine, 4- dimethylaminopyridine, picoline, lutidine, quinoline, or isoquinoline, and the like. Above all, tertiary aliphatic amine and the like are preferable, and triethylamine orN,N- diisopropylethylamine and the like are in particular preferable.
The amount of the base used varies depending on the compound used, types of solvents and other reaction conditions, however, it is generally 0.1 equivalents to 100 equivalents with respect to 1 equivalent of the compound (1), preferably 1 equivalent to 5 equivalents.
The condensation agent used includes, for example, N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, and the like. ,
The amount of the compound (2) used varies depending on the compound used, types of solvents and other reaction conditions, however, it is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (1) or a reactive derivative thereof, and preferably 1 equivalent to 3 equivalents.
The reaction is generally carried out in an inactive solvent, and examples of the inactive solvent include tetrahydroiuran, acetonitrile, NN-dimethylformamide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, pyridine, and the like, or mixtures thereof. The reaction time is generally 0.5 hours to 96 hours, preferably 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 80°C.
A base, an amide-forming reagent, and a condensation agent used in the present reaction can be used as a combination of one or more types thereof.
The compound (1-1) obtained in such a manner can be isolated and purified by an isolation and purification method that is well known to a person skilled in the art (e.g., concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like; in the category of "general synthesis method", the term "isolation and purification method that is well known to a person skilled in the art" has the same meaning unless otherwise particularly specified).
Moreover, among all the compounds represented formula (I) in the present invention, compounds (1-2) and (1-3) can be produced, for example, by the following method:
Figure imgf000048_0001
(1) (3) (I-2) (I-3)
(wherein, other symbols have the same meanings as described above.)
(Step 2)
The present step is a method for producing a compound (1-2) by reacting the compound (1) or a reactive derivative thereof with a compound (3).
The reaction in the present step can be carried out by the same method as in the step 1 , an equivalent method thereto, or a combination- of these methods and a conventional method.
The compound (1-2) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step 3)
The present step is a method for producing a compound (1-3) by subjecting the compound (1-2) to an oxidation reaction.
The present step can be carried out according to a method well known to a person skilled in the art. For example, the PCC oxidation, the Swern oxidation, the Mn02 oxidation, and the Dess-Martin oxidation, and the like are cited.
For example, the Dess-Martin oxidation can be carried out by using the Dess-Martin reagent without solvent or in a solvent inert to the reaction.
The amount of the Dess-Martin reagent used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (1-2), preferably 1 equivalent to 4 equivalents.
The reaction in the present step is generally carried out in an inactive solvent. As the inactive solvent, for example, tetrahydrofuran, acetonitrile, N.N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1 , 2-dichloroethane, and the like; or mixtures thereof are cited.
The reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
The reaction temperature is generally -78°C to the boiling point temperature of the solvent, and preferably -20°C to room temperature.
The compound (1-3) obtained in such a manner can be isolated and purified by an isolation and purification method that is well known to a person skilled in the art.
Also, when the reactive substance has a carboxyl group that is not involved in the reaction in the first step, the second step and the third step, the carboxyl group is preferably protected iii advance by a protecting group and then the protecting group is eliminated after completion of the reaction. Selection of such a protecting group and eliminating conditions can be conducted by referring to the method in previously mentioned
"Protecting Groups in Organic Synthesis (the third edition, 1999)".
Moreover, among compounds represented by formula (I) in the present invention, a compound (1-3) can be prepared, for example, by the following method:
Also, among the compounds (1) used to prepare the compounds in the present invention, a compound (1) wherein R3 is H can be prepared, for example, by the following method:
Figure imgf000050_0001
(wherein, Rpro is a protecting group. Other symbols have the same meanings as described above.)
A compound represented by formula (a) can be synthesized according to a method well known to a person skilled in the art.
A compound represented by formula (c) can be synthesized according to a method well known to a person skilled in the art.
(Step A)
The present step is a method for producing a compound (b) by reacting a compound (a) with N,N-dimethylformamide dimethyl acetal in the presence or absence of a solvent.
Also, N,jV-dimethylformamide diethyl acetal, NN-dimethylformamide diisopropyl acetal, or the like can be used instead of NN-dimethylformamide dimethyl acetal.
The amount of N,N-dimethylformamide dimethyl acetal used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (a).
The reaction solvent used is not in particular limited as far as it is inert to the reaction, and specifically includes, for example, methanol, ethanol, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, NN-dimethylformamide, or mixtures thereof.
The reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 160°C.
The compound (b) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification means well known to a person skilled in the art.
(Step B)
The present step is a method for producing a compound (d) by reacting the compound (b) with a compound having a hydrazine group represented by formula (c).
The amount of the compound (c) used is generally 0.5 equivalents to 10 equivalents with respect to 1 equivalent of the compound (b), and preferably 0.7 equivalents to 3 equivalents.
In the present step, when the compound (c) is a salt, it is necessary to use a base for neutralization. Examples of such a base include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine,
N,N-diisopropylethylamine, pyridine, and the like. The amount of the base used is generally 1 equivalent to 3 equivalents with respect to 1 equivalent of the compound (c).
The reaction solvent used is not in particular limited as far as it is inert to the reaction. Specifically, examples include, methanol, ethanol, /?-propanol, «-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1 ,4rdioxane,
N,N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, xylene or mixtures thereof. The reaction time is generally 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to 100°C.
The compound (d) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step C)
The present step is a method for producing a compound (1 -a) by eliminating the protecting group Rpro of the compound (d).
The elimination of the protecting group can be carried out by a method described in previously mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto or a combination of these methods and the conventional method. For example, when the protecting group is a benzyl group, the benzyl grou can be eliminated by a catalytic reduction method with the use of hydrogen and palladium catalytic agent and the like.
The compound (1 -a) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
Moreover, among the compounds (2) used to prepare the compounds of the present invention, a compound (2-a) wherein both R8and R9 are H can be synthesized, for example, by the following method:
O R1^0 R1O R11
LUR5 → HO^ R5 * N3^R5 ^ H2N^ R5 HN^ R5
Step D Step E Step F Step G
(e) (9) ( ) (i) (2-a) (wherein, R10 and R11 each independently are H, a group having one less carbon atoms than the hydrocarbon chain of R4, or R10 and R11 are together form a lower cycloalkyl or cycloalkenyl group. Other symbols have the same meanings as described above.)
The compound represented by formula (f) can be synthesized according to a method well known to a person skilled in the art.
(Step D)
The present step is a method for producing a compound (g) by reacting an organic lithium compound (e) with ethylene oxide (f).
The amount of ethylene oxide (f) used is generally 0.1 equivalents to 10 equivalents with respect to 1 equivalent of the compound (e), and preferably 0.5 equivalents to 3 equivalents.
The reaction solvent is not in particular limited as far as it is inert to the reaction, and examples include, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, 1 ,2-dimethoxyethane, w-hexane, «-heptane, dichloromethane, chloroform, carbon tetrachloride,
1 ,2-dichloroethane, benzene, toluene, xylene, and the like.
The reaction time is generally 0.5 hour to 48 hours, and preferably 1 hour to 24 hours.
The reaction temperature is generally -78°C to the boiling point temperature of the solvent, and preferably -78°C to room temperature.
The compound (g) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step E)
The present step is a method for producing a compound (h) by reacting the compound (g) with diphenylphosphoryl azide. The reaction in the present step can be carried out by the same method as in the step 16, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (h) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step F)
The present step is a method for producing a compound (i) by subjecting the compound (h) to a reduction reaction of the azide group.
The present step can be carried out according to methods well known to a person skilled in the art. These methods include, for example, a reduction method using phosphine; a catalytic reduction method using H and a palladium catalyst and the like; a reduction method using sodium borohydride; and the like.
For example, the reduction method using phosphine can be carried out using triphenylphosphine and water in a solvent inert to the reaction. Specifically, examples include tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, water, and the like; or mixtures thereof.
The amount of triphenylphosphine used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (15), and preferably 1 to 4 equivalents.
The reaction time is generally 0.5 hours to 96 hours, and preferably 2 hours to 48 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent, and preferably room temperature to the boiling point temperature of the solvent.
The compound (i) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step G)
The present step is a method for producing a compound (2-a) by reacting the compound (i) with a compound (j) in the presence of a reducing agent.
The amount of the compound (i) used in the present step is generally 0.5 equivalents to 10 equivalents with respect to 1 equivalent of the compound (j), and preferably, 0.8 equivalents to 4 equivalents.
The reducing agents used include, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.
The amount of the reducing agent used is generally 0.1 equivalents to 10 equivalents with respect to 1 equivalent of the compound (i), and preferably 0.3 equivalents to 5 equivalents. .■' " · .
The reaction solvent used is not in particular limited as far as it is inert to the reaction, and examples include methanol, ethanol, acetic acid, tetrahydrofuran, 1 ,4-dioxane, dichloromethane, chloroform, 1 ,2-dichloroethane, benzene, toluene, xylene, and the like.
The reaction time is generally 0.5 hours to 48 hours, and preferably, 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent.
The compound (2-a) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
A group represented by formula:
Figure imgf000056_0001
(wherein, each symbol has the same meanings as described above) corresponds to the R .
Moreover, among the compounds (2) used to prepare the compounds in the present invention, a compound (2-b) wherein either R or R is F and the other is H can be synthesized, for example, by the following method:
Figure imgf000056_0002
(wherein, each symbol has the same meanings as described above.)
A compound represented by formula (k) can be synthesized according to a method well known to a person skilled in the art.
(Step H)
The present step is a method for producing a compound (1) by reacting the compound (k) with trimethylsilyl cyanide in the presence of a zinc catalyst and
subsequently reacting with a fluorinating agent.
The amount of trimethylsilyl cyanide used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (k), and preferably, 1 equivalent to 5 equivalents.
The zinc catalyst used includes, for example, zinc iodide, zinc bromide, and the like.
The fluorinating agent used includes, for example, (N, N-diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, l ,l ,2,2-tetrafluoroethyl-iV,N- dimethylamine, and the like.
The amount of fluorinating agent used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (k), and preferably, 1 equivalent to 5 equivalents.
The reaction solvent that used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, acetonitrile, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1 ,2-dichloroethane, carbon tetrachloride, benzene, toluene, N,N-dimethylformamide, and the like.
The reaction time is generally 30 minutes to 48 hours, and preferably, 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent.
The compound (1) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step I)
The present step is a method for producing a compound (m) by subjecting the compound (1) to a reduction reaction of the cyano group.
The reducing agents used include, for example, lithium aluminium hydride, sodium bis(2-methpxyethoxy)aluminumhydride, a borane-tetrahydrofuran complex, and the like.
The amount of the reducing agent used is generally 1 to 10 equivalents with respect to 1 equivalent of the compound (1).
The reaction solvent that used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, 1 ,4-dioxane, dichloromethane, benzene, toluene, diethyl ether, and the like.
The reaction time is generally 1 hour to 24 hours.
The reaction temperature is generally 0°C to the boiling point temperature of the solvent. The compound (m) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step J)
The present step is a method for producing a compound (2-b) by reacting the compound (m) with a compound (j) in the presence of a reducing agent.
The reaction in the present step can be carried out by the same method as in the step G, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (2-b) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
Moreover, among the compounds (3) used to prepare the compounds of the present invention, a compound (3-P) wherein either R8 or R9 is a hydroxyl group which is protected by a protecting group and the other is H can be synthesized, for example, by the following method:
o
Figure imgf000058_0001
(wherein, Rpr0 is a protecting group. Other symbols have the same meanings as described above.)
A compound represented by formula (n) can be synthesized according to a method well known to a person skilled in the art.
(Step K)
The present step is a method for producing a compound (o) by reacting an organic lithium compound (m) with (tert-butyldimethylsilyloxy)acetaldehyde (n).
The reaction in the present step can be carried out by the same method as in the step D, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (o) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step L)
The present step is a method for introducing a protecting group to the hydroxyl group of the compound (o). The introduction of the protecting group can be carried out by a method described in the previously mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (p) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification rhethod that is well known to a person skilled in the art.
(Step M)
The present step is a method for producing a compound (q) by eliminating the tert-butyldimethylsilyl group of the compound (p).
The elimination of the protecting group can be carried out by a method described in the previously-mentioned "Protecting Groups in Organic Synthesis (the third edition, 1999)", an equivalent method thereto, or a combination of these methods and the conventional method, and for example, tetrabutylammonium fluoride can be used.
The compound (q) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step N)
The present step is a method for producing a compound (r) by subjecting the compound (q) to an oxidation reaction.
The reaction in the present step can be carried out by the same method as in the step 3, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (r) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step O)
The present step is a method for producing the compound (3-P) by reacting the compound (r) with a compound (s) in the presence of a reducing agent.
The reaction in the present step can be carried out by the same method as in the step G, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (3-P) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
Moreover, among the compounds (2) used to prepare the compounds in the present e,
Figure imgf000061_0001
_( wherein, Xa and Xb each independently are Br or I. Other symbols have the same meanings as described above.)
A compound represented by formula (u) can be synthesized according to a method well known to a person skilled in the art.
(Step P)
The present step is a method for producing a compound (v) by reacting the compound (t) with a compound (u) in the presence of copper to prepare.
The amount of the compound (t) used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (u), and preferably 1 equivalent to 3 equivalents.
The amount of copper used is generally 1 equivalent to 10 equivalents with respect to 1 equivalent of the compound (t), and preferably 1 equivalent to 5 equivalents.
The reaction solvent used is not in particular limited as far as it is inert to the reaction, and examples include tetrahydrofuran, acetonitrile, 1 ,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, and the like.
The reaction time is generally 30 minutes to 48 hours.
The reaction temperature is generally room temperature to the boiling point temperature of the solvent.
The compound (v) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step Q)
The present step is a method for producing a compound (w) by eliminating the protecting group Rpro of the compound (v).
The reaction in the present step can be carried out by the same method as in the step C, an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (w) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification means well known to a person skilled in the art.
(Step R)
The present step is a method for producing a compound (x) by reacting the compound (w) or a reactive derivative thereof with a compound (s).
The reaction in the present step can be carried out by the same method as in the step 1 , an equivalent method thereto, or a combination of these methods and the conventional method.
The compound (x) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
(Step S)
The present step is a method for producing a compound (2-c) by reducing the amide group of the compound (x).
The reaction in the present step can be carried out by the same method as in the step I, an equivalent method thereto, or a combination of these methods and the conventional method. The compound (2-c) obtained in such a manner can be subjected to a next step with or without isolation and purification by an isolation and purification method that is well known to a person skilled in the art.
Moreover, the compound represented by formula (I) in the present invention may have a tautomer and/or optical isomer in some cases depending on types of substituents. However, the present invention includes a mixture of these tautomers and isomers, and isolated ones.
Furthermore, the present invention relates to a pharmaceutically acceptable prodrug of the compound represented by formula (I). The term "pharmaceutically acceptable prodrug" means a compound producing a compound represented by formula (I) by solvolysis or conversion to C02H, NH2, OH, etc. under physiological conditions. An example of the group that produces prodrug is found, for example, in Prog. Med., 5, 2157-2161 (1985), "lyakuhin no Kaihatsu" (Hirokawa Shoten, 1990) Vol.7., Bunshi Sekkei 163-198. In the present invention, some of the compounds within the scope of formula (I) which have the group that produces a prodrug can serve as a prodrug of the
corresponding compound of formula (I) which has C02H, NH2, OH, etc. For example, a compound within the scope of formula (I) which has an alkoxycarbonyl group can be converted into a corresponding carboxyl acid derivative.
The present invention also relates to a pharmaceutically acceptable salt of the compound represented by formula (I) and a pharmaceutically acceptable prodrug thereof. Such a salt includes, for example, hydrogen halides such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydriodic acid, and the like; inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like; lower alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and the like; arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, and the like; and acid addition salts with amino acids including aspartic acid, glutamic acid, and the like. Moreover, depending on types of substituents, the salt in the present invention may form a salt with a base. Examples include inorganic bases including metals such as sodium, potassium, magnesium, calcium, aluminum, lithium, and the like; salts with an organic base such as methyl amine, ethylamine, ethanolamine, guanidine, lysine, ornithine, and the like; and an ammonium salt, and the like.
The various pharmaceutically acceptable salts of compound represented by formula (I) can be synthesized based on general knowledge in the technical field in the art.
The compound represented by formula (I) and the pharmaceutically acceptable salt thereof in the present invention (hereinafter, general term for these is referred to as the compound of the present invention) has an excellent RORy inhibitory activity and can be used as a RORy inhibitor that is clinically applicable to treat or prevent RORy associated diseases and symptoms. Among RORy related diseases, the compound of the present invention is useful as a therapeutic agent or preventive agent for, in particular, diseases selected from auto immune disease and inflammatory disease (e.g., multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease), and asthma), metabolic disease (especially, diabetes), and cancer (especially, malignant melanoma).
Moreover, the term "prevention" in the present invention means a procedure of administration of a pharmaceutical composition including the compound of the present invention or administration this to individuals who have not developed diseases or symptoms. Moreover, the term "treatment" means a procedure of administration of a pharmaceutical composition including the compound of the present invention or administration this to individuals who have already developed diseases or symptoms.
Accordingly, a procedure of administration to individuals who have already developed diseases or symptoms in order to prevent aggravation or attacks is one aspect of the
"treatment".
When the compound of the present invention is used as medicine, the compound of the present invention can be mixed with a pharmaceutically acceptable carrier (diluting agent, bonding agent, disintegrant, flavoring substance, odor improving agent, emulsifying agent, diluent, solubilizing agent, and the like) and can be administered in the form of a pharmaceutical composition or drug formulation (oral preparation, injections, and the like) orally or parenterally. The pharmaceutical composition can be formulated according to an ordinal method.
In the present description, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion technique, and local administration (percutaneous administration, ophthalmic administration, pulmonary/bronchial administration, nasal administration, rectal administration, and the like), and the like. The dosage form of oral administration includes, for example, tablets, pills, granules, powders, solvent, suspensions, syrups, capsules, and the like.
The amount of the compound of the present invention that can be combined with a carrier can be changed depending on a specific individual who receives treatment and on specific dosage forms. In this regard, the specific dosage for the specific patient is determined depending on various factors including age, body weight, overall health conditions, gender, diet, administration time, administration method, excretion rate, and the degree of the specified disease during treatment.
The dosage amount of the compound of the present invention is determined depending on age, body weight, general health conditions, gender, diet, administration time, administration method, excretion speed, the degree of a disease in a patient who is being treated, or in view of other factors. The compound of the present invention can be administered in single or multiple times daily for adult in a range of 0.01 mg to 1000 mg, although the dosage is different depending on the conditions of the patient, body weight, types of the compound, administration route, and the like.
Abbreviations
Ac acetyl
aq. aqueous
Bn benzyl
Boc tert-butoxycarbonyl
BuOH butanol
Bzl benzyl
cat. catalytic
cone. concentrated
DAST Ν,Ν-diethylaminosulfur trifluoride
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIPEA N,N-diisopropylethylamine
DMA N,N-dimethylacetoamide
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide Et20 dietylether
EtOAc ethyl acetate
EtOH ethanol
HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate
LDA litium diisopropylamide
MeOH methanol
Ms methanesulfonyl (rriesyl)
MTBE methyl tert-butyl ether
NBS N-Bromosuccinimide
NMO N-methylmorpholine N-oxide
quant. quantitative
sat. saturated
SEM 2-(trimethylsilyl)ethoxymethyl group
TBAF tetrabutylammonium fluoride
tert tertiary
TES triethylsilyl group
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl group
TMSCN trimethylsilyl cyanide
TsOH toluenesulfonic acid Examples
Hereinafter, the present invention will be explained based on specific examples. However, the present invention is not limited to these examples.
Unless noted otherwise, reagents, starting materials, and solvents were purchased from vendors (for example, Aldrich, Wako Junyaku, Tokyo Kasei, Fluka, Sigma, and the like) and used without further purification.
The structure of the novel compound isolated was confirmed by and/or mass spectrometry using single quadrupole instrumentation equipped with an electron spray source and other appropriate analytical methods.
As for the compounds for which spectrum (300 MHz, 400 MHz or 500 MHz, MeOH-d4, DMSO-d6, CD3CN or CDC13) was measured, the chemical shift (δ: ppm) and coupling constant (J: Hz) are shown. In addition, the following abbreviations represent the followings, respectively: s=singlet, d=doublet, t=triplet, q=quartet, brs=broad singlet, m=multiplet.
The compounds synthesized according to the following methods of examples were further analyzed by high performance liquid chromatography mass spectroscopy (LC/MS) analysis. As for the result of mass spectroscopy, the observed value of [M+H]+, that is, the observed value is shown as the value of the molecular mass of the compound (M) with a proton (H+).
LCMS Measurement Condition: (UPLC/MS)
LC Mass spectrometer: Waters Corporation AcquityUPLC™-SQD
Column: Acquity UPLC™ BEH C 18 1.7 μιη 2.1 mm χ 50 mm
UV: PDA detection (254 nm)
CAD:CORONA™ ULTRA detector Column temperature: 40 °C
ES voltage: 3.0 kV(capillary)
Cone voltage: 30 V
Gradient conditions:
Solvents: A: H20/MeCN = 95/5
0.05% TFA
B: H20/MeCN = 5/95
0.05% TFA
Flow rate: 0.6 mL/min
Gradients: 0.01 to 0.20 min, Solvent B: 2%, Solvent A: 98%
0.20 to 3.0 min, Solvent B : 2% to 100%, Solvent A: 98% to 0%
3.0 to 4.2 min, Solvent B: 100%, Solvent A: 0%
4.2 to 4.21 min, Solvent B: 100% to 2%, Solvent A: 0% to 98%
4.21 to 5.2 min, Solvent B: 2%, Solvent A: 98%
5.2 to 5.5 min, Solvent B: 2%, Solvent A: 98%, Flow rate: 0.2 mL/min
LCMS Measurement Condition (LC/MS method A):
LC Mass spectrometer: Agilent Technologies Corporation 1260 INFINITY™ HPLC-6130MSD
Column: Phenomenex Gemini™ C18 A110 3 μπι 4.6 mm x 30 mm
UV: PDA detection (254 nm)
Column temperature: 40 °C
Capillary voltage: 3.5 kV
Frag mentor voltage: 70 V
Gradient conditions: Solvents: A: H20/MeCN = 95/5
0.05% TFA
B: H20/MeCN = 5/95
0.05% TFA
Flow rate: 1.0 mL/min
Gradients: 0.01 to 0.30 min, Solvent B: 2% to 10%, Solvent A: 98% to 90%
0.30 to 1.5 min, Solvent B: 10% to 100%, Solvent A: 90% to 0% 1.5 to 3.5 min, Solvent B: 100%, Solvent A: 0%
3.5 to 3.51 min, Solvent B: 100% to 2%, Solvent A: 0% to 98% 3.51 to 4.5 min, Solvent B: 2%, Solvent A: 98%
LCMS Measurement Condition(LC/MS method B):
LC Mass spectrometer: Shimadzu Corporation LCMS-2010 EV
Column: Shim-pack™ XR-ODII 2.0 mm 75 mm
UV: PDA detection (254 nm)
Flow rate: 0.4 mL/min
Column temperature: 40 °C
Detection voltage: 1.20 kV
Gradient conditions:
Solvents: A: H20/MeCN = 90/5
0.1% HCO2H
B: H20/MeCN = 10/95
0.1% HCO2H
Flow rate: 0.4 mL/min
Gradients: 0.01 to 0.50 min, Solvent B: 10%, Solvent A: 90% 0.50 to 2.0 min, Solvent B: 10% to 95%, Solvent A: 90% to 5% 2.0 to 3.8 min, Solvent B: 95%, Solvent A: 5%
3.8 to 4.0 min, Solvent B: 95% to 10%, Solvent A: 5% to 90%
4.0 to 5.0 min, Solvent B: 10%, Solvent A: 90%
[Reference example Al]
Figure imgf000071_0001
A1-1 A1-2 A1-3 A1
Step 1 : l-(3,5-dichloropyridin-4-yl)-2-nitroethanol (Al-1)
To a solution of 3,5-dichloro-4-pyridinecarboxyaldehyde (2.3 g, 13.3 mmol) in MeOH (25 mL) were added nitromethane (2.2 mL, 39.9 mmol) and sodium methoxide (861 mg, 15.9 mmol). After addition, the mixture was stirred for 1 h. The reaction mixture was quenched by adding 2 M aqueous HC1 (7 mL) and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgS04. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound Al-1 (2.8 g, 90%) as a white solid.
Step 2: 3,5-dichloro-4-(2-nitro-l-((triethylsilyl)oxy)ethyl)pyridine (Al-2)
To a solution of compound Al-1 (2.8 g, 11.9 mmol) in DMF (15 mL) were added imidazole (973 mg, 14.3 mmol) and triethylchlorosilane (2.2 mL, 13.1 mmol). After addition, the mixture was stirred for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgS04. After the solvent was removed, the residue was purified by column
chromatography on silica gel to give compound Al-2 (4.1 g, 98%) as a colorless oil. Step 3: 2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (Al-3) Compound Al-2 (4.1 g, 11.6 mmol) and Raney nickel 2800 (690 mg, in water) in MeOH (50 mL) was hydrogenated in H2 atmosphere (1 atm) at room temperature for 8 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound Al-3 (1.9 g, 50%) as a white solid.
Step 4: 2-(3,5-dichloropyridin-4-yl)-N-(4-fluorobenzyl)-2-((triethylsilyl)oxy)ethanamine
(Al)
To a solution of compound Al-3 (2.8 g, 11.9 mmol) in toluene (6 mL) and MeOH (6 mL) was added 4-fluorobenzaldehyde (360 μί, 3.4 mmol), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to 0 °C, and NaBH4 was added gradually. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine x 2 and anhydrous Na2S04. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound Al (1.2 g, 88%) as a colorless oil.
Figure imgf000072_0001
Step 1 : 4-(methoxymethylene)-l,l-dimethylcyclohexane (A12-1)
n-BuLi (2.6 M in hexane, 2.3 mL, 5.94 mmol) was added dropwisely to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.04 g, 5.94 mmol) in THF (20 mL) at -78 °C and stirred for 10 min at the same temperature and then stirred for 2.5 h at room temperature. The reaction mixture was cooled down to -78 °C, a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at - 78 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for overnight. The reaction mixture was quenched with sat. NaHC03 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil. The crude product was used for next step without purification.
Step 2: 4,4-dimethylcyclohexanecarbaldehyde (A 12-2)
TFA (2 mL) was added to a stirred solution of compound A12-1 (512.2 mg, crude) in DCM (1 mL) at room temperature and stirred for 1.5 h at the same temperature. The reaction mixture was quenched with sat. NaHC03 aq. (10 mL) and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2S04, and concentrated under reduced pressure to provide crude compound A 12-2 as pale yellow oil. The crude product was used for next step without purification.
Step 3:
2-(3,5-dichloropyridin-4-yl)-N-((4,4-dimethylcyclohexyl)methyl)-2-((triethylsilyl)oxy)etha namine (A 12)
Crude A12-2 (52 mg) and amine Al-3 (100 mg, 311.2 mmol) was added to a solution of MeOH (1 mL) and toluene (1 mL) and stirred at 80 °C for 4 h. The reaction mixture was cooled down to room temperature. MeOH (2 mL) was added to the reaction mixture and NaBH4 (100 mg) was added to reaction mixture at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with sat. NaHC03 aq. (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with sat. NaHC03 aq. and brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck KGaA, PLC Silicagel 60 F254, 1 mm, 20 x 20 cm with
concentrating zone 20 x 4 cm, 20% EtOAc/hexane as eluent) to provide compound A12 (58.6 mg, 42%) as pale yellow oil. Ή NMR (CDC13, 400 MHz): δ 8.42 (s, 2H), 5.49 (dd, J = 8.8, J = 4.4 Hz, 1H), 3.21 (dd, J = 12.5, J = 8.8 Hz, lH), 2.77 (dd, J = 12.5, J = 4.4 Hz, 1H), 2.54-2.47 (m, 2H), 1.54-1.04 (m, 9H), 0.90-0.86 (m, 15H), 0.62-0.49 (m, 6H).
Figure imgf000074_0001
Step 1 : 1 -(2,6-dichloro-4-fluorophenyl)-2-nitroethanol (A31 - 1 )
A mixture of 2,6-dichloro-4-fluorobenzaldehyde ( 10.0 g, 51.8 mmol), nitromethane (2 mL) and K2C03 (3.57 g, 25.9 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2.x 100 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (20 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure to provide compound A31-1 (26.0 g, crude) as yellow gum. The crude product was used in the next step without purification.
Step 2: (l-(2,6-dichloro-4-fluorophenyl)-2-nitroethoxy)triethylsilane (A31-2)
To a stirred solution of compound A31-1 (26.0 g, 102.3 mmol) in DMF (100 mL) was added imidazole (20.9 g, 307.0 mmol) and TES-Cl (25.7 mL, 153.5 mmol) and the mixture was stirred at room temperature for 1 h. Upon reaction completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-10% EtOAc/hexane as eluent) to provide compound A31-2 (32.8 g, 74%) as colorless gum. 1H NMR (CDC13, 400 MHz): δ 7.12 (s, 1H), 7.10 (s, 1H), 6.22 (dd, J = 9.2, J = 3.2 Hz, 1H), 5.22-5.11 (m, 1H), 4.42 (dd, J = 12.2, J = 3.6 Hz, 1H), 0.84 (t, J = 8.0 Hz,.9H), 0.55-0.50 (m, 6H).
Step 3: 2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (A31-3)
To a stirred solution of compound A31-2 (15.0 g, 40.7 mmol) in EtOH/water (60 mL, 4:1) was added Fe powder (22.7 g, 407.6 mmol) and solid NH4C1 (21.8 g, 407.6 mmol). The mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered through a pad of celite, washed with EtOAc (3 x 150 mL) and solvent was removed under reduced pressure. The residue was suspended in water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 5% MeOH/DCM as eluent) to provide compound A31-3 (13.0 g, 94%) as colorless oil. 1H NMR (CDC13, 400 MHz): δ 7.06 (s, 1H), 7.04 (s, 1H), 5.29 (dd, J = 8.4, J = 5.0 Hz, 1H), 3.25 (dd, J = 13.2, J = 8.8 Hz, 1H), 2.89 (dd, J = 13.2, J = 5.0 Hz, 1H), 0.88 (t, J = 8.0 Hz, 9H), 0.57-0.52 (m, 6H).
Step
4:2-(2,6-dichloro-4-fluorophenyl)-N-(3,5-difluorobenzyl)-2-((triethylsilyl)oxy)ethanamine (A31)
To a stirred solution of compound A31 -3 (30.0 g, 88.7 mmol) in MeOH (200 mL) was added 3,5-difluorbenzaldehyde (12.6 g, 88.7 mmol) and the mixture was stirred at room temperature for 2 h. Upon completion of imine formation (monitored by TLC), solid NaBH4 (4.9 g, 133.1 mmol) was added in portions at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 75 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A31 (30.0 g, 70%) as colorless gum.
Figure imgf000076_0001
Step 1 : 2,6-dichloro-4-iodobenzaldehyde (A35-1)
To a stirred solution of l,3-dichloro-5-iodobenzene (4.0 g, 14.6 mmol) in THF (30 mL), LDA (2.0 M in THF/heptane/ethylbenzene, 9.6 mL, 16.9 mmol) was added dropwise at -78 °C and stirred for 1 h at the same temperature. A solution of DMF (1.7 mL, 22.0 mmol) in THF (5 mL) was added slowly at -78 °C and stirred for 3 h. The reaction mixture was quenched with saturated NH4C1 (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A35-1 (1.4 g, 32%) as colorless oil.
Step 2: l-(2,6-dichloro-4-iodophenyl)-2-nitroethanol (A35-2)
Compound A35 -2 (1.84 g, crude) was obtained as a colorless gum from the reaction of compound A35-1 (1.4 g, 4.8 mmol) and K2C03 (0.23 g, 2.0 mmol) in CH3N02 (10 mL) using a similar procedure to that described in reference example Al, step 1. Step 3: (l^(2,6-dichloro-4-iodophenyl)-2-nitroethoxy)triethylsilane (A35-3)
Compound A35-3 (2.4 g, crude) was obtained as colorless gum from the reaction of compound A35-2 (1.84 g, 5.08 mmol), TES-Cl (1.02 mL, 6.12 mmol) and imidazole (1.03 g, 15.2 mmol) in DMF (10 mL) using a similar procedure to that described in reference example A 1, step 2.
Step 4: 2-(2,6-dichloro-4-iodophenyl)-2-((triethylsilyl)oxy)ethanamine (A35-4)
Compound A35-4 (2.2 g, crude) was obtained as a brown oil from the reaction of compound A35-3 (2.4 g, 5.0 mmol), Fe (2.83 g, 50.0 mmol) and NH4C1 (2.68 g, 50.0 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A31 , step 3.
Step 5:
2-(2,6-dichloro-4-iodophenyl)-N-((3,5-difluorophenyl)((triethylsilyl)oxy)methyl)ethanami nc (A35-5)
Compound A35-5 (1.87 g, 67%) was obtained as a colorless gum from the reaction of compound A35-4 (2.2 g, 5.0 mmol), 3,5-difluorobenzaldehyde (0.55 mL, 5.0 mmol) and NaBH4 (0.38 g, 10.0 mmol) in MeOH (15 mL) using a similar procedure to that described in example A31 , step4.
Step 6: tert-butyl
(2-(2,6-dichloro-4-iodophenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl)carbamate (A35-6)
To a stirred solution of compound A35 -5 (1.87 g, 3.26 mmol) in DCM/water (4: 1, 20 mL) was added NaHC03 (0.55 g, 6.5 mmol) and (Boc)20 (1.07 g, 4.9 mmol) in DCM (8 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched in water (100 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound A35-6 (2.47 g, crude) as a colorless gum. r
Step 7: tert-butyl
(2-(2,6-dichloro-4-cyanophenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl)carbamate (A35-7) '
To a solution of compound A35-6 (2.0 g, 2.9 mmol) in DMA (10 mL) in sealed tube, Zn(CN) 2 (0.7 g, 5.9 mmol) and Pd(PPh3) 4 were added and stirred for 2 h at 80 °C. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A35-7 (1.1 g, 61%) as colorless oil.
Steo 8: 3,5-dichloro-4-(2-((3,5-difluorobenzyl)amino)-l-hydroxyethyl)benzonitrile (A35)
To a stirred solution of compound A35-7 (0.2 g, 0.3 mmol) in EtOH (10 mL) was added 4 M HC1 (5 mL) and the mixture was stirred at 80 °C for overnight. The reaction mixture was quenched with water (50 mL) and basified with 10%) NaOH solution up to pH 9 and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to afford compound A35 (0.12 g, 99%) as colorless oil.
[Reference example A56]
Figure imgf000079_0001
Step 1 : 4-methylthiophene-3-carboxylic acid (A56-1)
To a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in THF (35 mL) was added n-BuLi (1.6 M in hexane, 14.6 mL, 23.3 mmol) at -78 °C dropwise over a period of 15 min and the mixture was stirred at -78 °C for 30 min. The C02 (gaseous) was passed through the reaction mixture for 10 min and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was warmed to 0 °C, quenched with aqueous 1 M NaOH (60 mL) and washed with EtOAc (2 x 50 mL). The aqueous layer was acidified to pH ~ 5 and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8% MeOH/DCM as eluent) to provide compound A56-1 (1.5 g^ 70%) as a white solid.
Step 2: 2,4-dimethylthiophene-3-carboxylic acid (A56-2)
To a stirred solution of compound A56-1 (390 mg, 2.7 mmol) in THF (4 mL) was added n-BuLi (1.6 M in hexane, 3.8 mL, 6.0 mmol) dropwise at -78 °C for 10 min. The mixture was stirred at -78 °C for 5 min. A solution of iodomethane (0.4 mL, 6.8 mmol) in THF (1 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 30 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% MeOH/DCM as eluent) to provide compound A56-2 (246 mg, 57%) as a white solid.
Step 3: (2,4-dimethylthiophen-3-yl)methanol (A56-3)
To a stirred solution of compound A56-2 (246 mg, 1.5 mmol) in THF (3 mL) was added BH3 THF (1 M in THF, 5.5 mL, 5.5 mmol) dropwise at 0 °C for 15 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with saturated aqueous NaHC03 and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 25% EtOAc/hexane as eluent) to provide compound A56-3 (201 mg, 90%) as a colorless gum.
Step 4: 2,4-dimethylthiophene-3-carbaldehyde (A56-4)
To a stirred solution of compound A56-3 (740 mg, 5.2 mmol) in DCM (18 mL) was added Dess-Martin periodinane (4.6 g, 10.9 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous Na2S203 and NaHC03, and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A56-4 (275 mg, 38%) as a yellow solid.
Step 5: l-(2,4-dimethylthiophen-3-yl)-2-nitroethanol (A56-5)
A mixture of compound A56-4 (133 mg, 0.95 mmol), nitromethane (2 mL) and K2C03 (50 mg, 0.36 mmol) was stirred at room temperature for 60 h. The reaction mixture was quenched with water, and extracted with EtOAc (3x20 mL). The combined organic layers were washed with water (2x100 mL), and brine (100 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 40% EtOAc/hexane as eluent) to provide compound A56-5 (80 mg, 42%) as a yellow gum.
Step 6: (l-(2,4-dimethylthiophen-3-yl)-2-nitroethoxy)triethylsilane (A56-6)
To a stirred solution of compound A56-5 (235 mg, 1.17 mmol) in DMF (4 mL) were added imidazole (238 mg, 3.5 mmol) and TES-C1 (0.23 mL, 1.4 mmol) and the mixture was stirred at room temperature for 4 h. Upon completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 5% EtOAc/hexane as eluent) to provide compound A56-6 (240 mg, 65%) as a colorless gum.
Step 7: 2-(2,4-dimethylthiophen-3-yl)-2-((triethylsilyl)oxy)ethanamine (A56-7)
To a stirred solution of compound A56-6 (240 mg, 0.76 mmol) in EtOH/water (10 mL, 4:1) were added powdered Fe (425 mg, 7.6 mmol) and solid NH4C1 (407 mg, 7.6 mmol). The mixture was stirred at 70 °C for 45 min. Upon completion, the reaction mixture was filtered through a pad of celite and washed with MeOH (3x15 mL). The solvent was removed under reduced pressure. The residue was suspended in EtOAc (100 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 5% MeOH/DCM as eluent) to provide compound A56-7 (192 mg, 88%) as a yellow gum.
Step 8:
N-(3,5-difluorobenzyl)-2-(2,4-dimethylthiophen-3-yl)-2-((triethylsilyl)oxy)ethanamine (A56)
To a stirred solution of compound A56-7 (192 mg, 0.67 mmol) in MeOH (5 mL) was added 3,5-difluorbenzaldehyde (95 mg, 0.67 mmol) and the mixture was stirred at room temperature for 2 h. Upon completion of imine formation (monitored by TLC), solid NaBH4 (51 mg, 1.3 mmol) was added in portions at 0 °C. The mixture was warmed to room temperature and stirred at the same temperature for 4 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A56 (200 mg, 72%) as a colorless gum. 1H NMR (CDC13, 300 MHz): δ 6.90-6.77 (m, 3H), 6.71-6-60 (m, 1H), 5.09 (dd, J = 7.8, 4.2 Hz, 1H), 3.78 (s, 2H), 2.87 (dd, J = 12.0, 7.8 Hz, 1H), 2.71 (dd, J = 12.0, 4.5 Hz, 1H), 2.11 (d, J = 0.6, 3H), 2.06 (s, 3H), 1.65 (brs, 1H), 0.89 (t, J = 7.8 Hz, 9H), 0.62-0.50 (m, 6H).
Figure imgf000082_0001
To a stirred solution of (3,5-dichlorophenyl)(methyl)sulfane (1.0 g, 5.1 mmol) in THF (15 mL), n-BuLi (1.6 M in THF, 4.8mL, 7.7 mmol) was added dropwise at -78 °C and stirred for 1 h at the same temperature. A solution of DMF (0.6 mL, 7.7 mmol) in THF (3 mL) was added slowly at -78 °C and stirred for 1 h. The reaction mixture was quenched with saturated NH4C1 aq. (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A57-1 (1.4 g, 99%) as colorless oil.
Step 2: l -(2,6-dichloro-4-(methylthio)phenyl)-2-nitroethanol (A57-2)
Compound A57-2 (0.71 g, crude) was obtained as a colorless gum from the reaction of compound A57-1 (0.5 g, 2.44 mmol) and K2C03 (0.13 g, 0.92 mmol) in CH3N02 (5 mL) using a similar procedure to that described in reference example Al, step 1.
Step 3: (l-(2,6-dichloro-4-(methylthio)phenyl)-2-nitroethoxy)triethylsilane (A57-3)
Compound A57-3 (1.0 g, crude) was obtained as colorless gum from the reaction of compound A57-2 (0.71 g, 2.5 mmol), TES-Cl (0.5 mL, 3.02 mmol) and imidazole (0.51 g, 7.55 mmol) in DMF (10 mL) using a similar procedure to that described in reference example A 1, step 2.
Step 4: 2-(2,6-dichloro-4-(methylthio)phenyl)-2-((triethylsilyl)oxy)ethanamine (A57-4)
Compound A57-4 (0.98 g, crude) was obtained as a brown color oil from the reaction of compound A57-3 (1.0 g, 2.53 mmol), Fe (1.42 g, 25.3 mmol) and NH4C1 (1.34 g, 25.3 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A31, step 3.
Step 5:
2-(2,6-dichloro-4-(methylthio)phenyl)-N-(3,5-difluorobenzyl)-2-((triethylsilyl)oxy)ethana mine (A57)
Compound A57 (0.73 g, 55%) was obtained as a colorless gum from the reaction of compound A57-4 (0.98 g, 2.69 mmol), 3,5-difluorobenzaldehyde (0.29 mL, 2.69 mmol) and NaBH4 (0.2 g, 5.36 mmol) in MeOH (10 mL) using a similar procedure to that described in reference example A31 , step 4. 1H NMR (CDC13, 300 MHz): 5 7.10 (s, 2H), 6:87-6.61 (m, 3H), 5.53 (dd, J = 8.6, 4.8 Hz, 1H), 3.82 (s, 2H), 3.23 (dd, J = 12.1, 8.6 Hz, 1H), 2.78 (dd, J = 12.1, 4.8 Hz, 1H), 2.49 (s, 3H), 0.90-0.85 (m, 9H), 0.58-0.50 (m, 6H).
[Reference example A58]
Figure imgf000084_0001
de (A58)
To a stirred solution of compound A35 (0.12 g, 0.29 mmol) in THF/MeOH/water (2:2: 1, 5 mL) was added LiOH (4 M aq. solution, 0.44 mL, 1.76 mmol) dropwise at 0 °C. The mixture was allowed to warm to room temperature while stirring continued for 4 h. The reaction mixture was acidified with HO (1 M, 6 mL) and extracted with EtOAc (3>< 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound A58 (60 mg, 47%) as a yellow solid. LCMS (APCI): 391 (M+H)+.
[Reference example A59]
Figure imgf000084_0002
Ethyl 3 ,5-dichloro-4-(2-((3 ,5-difluorobenzyl)amino)- 1 -hydroxyethyl)benzoate (A59)
To a stirred solution of compound A35-7 (0.2 g, 0.3 mmol) in EtOH (5 mL) was added cone. HC1 (5 mL) and the mixture was stirred at reflux for overnight. The reaction mixture was quenched with water (50 mL) and basified with 10% NaOH solution up to pH 9 and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to afford compound A59 (0.1 g, 92%) as a white solid.
Figure imgf000085_0001
Step 1 : 4,4-dimethylpent-2-ynal (A66-1)
To a stirred solution of 3,3-dimethylbutan-l-yl (2.45 mL, 20 mmol) in THF (20 mL), n-BuLi (2.6 M in hexane, 8.46 mL, 22 mmol) was added at -78 °C dropwise and stirred for 1 h at the same temperature. A solution of DMF (3.85 mL, 50.0 mmol) was added slowly at -78 °C and the reaction mixture was allowed to warm to room temperature for overnight. The reaction mixture was quenched with saturated NH4C1 (100 mL) and extracted with hexane (2 x 100 mL). The collected organic layers were washed with water (3 x 200 mL) and concentrated under reduced pressure to provide compound A66-1. The crude product was used for next step without purification;
Step 2:
N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-4,4-dimethylpent-2-yn-l -amine (A66)
Compound A66 (76.1 mg, 36.6%) was obtained as a pale yellow oil from the reaction of compound Al-3 (160 mg, 0.5 mmol), compound A66-1 (80 mg, 0.726 mmol), NaBH4 (120 mg) and MgS04 (lOOmg) in MeOH (6 mL) and DCM (3mL) using a similar procedure to that described in reference example A31 , step 4. 1H NMR (CDC13, 400 MHz): δ 8.43 (s, 2H), 5.49 (dd, J = 8.5, J = 5.1 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.37 (d, J = 16.4 Hz, 1H), 3.32 (dd, J = 12.0, J = 8.5 Hz, 1H), 2.87 (dd, J = 12.0, J = 5.1. Hz, 1H), 1.21 (s, 9H), 0.89 (t, J = 7.8 Hz, 9H), 0.61-0.50 (m, 6H).
[Reference example A75]
Figure imgf000086_0001
Step 1 : l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3-carbaldehyde (A75-1)
To a stirred suspension of NaH (274 mg, 11.4 mmol) in DMF (20 mL) was added solution of lH-pyrazole-3-carbaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) dropwise at 0 °C and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 °C and SEM-C1 (1.90 g, 11.4 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at the same temperature for 16 h: The reaction mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed water (20 mL), dried over anhydrous Na2S04 and Concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A75-1 (350 mg, 29%) as colorless gum. Step 2: 2-nitro-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)ethanol (A75-2)
Compound A75-2 (428 mg, 64%) was obtained as yellow gum from the reaction of compound A75-1 (350 mg, 1.54 mmol), CH3N02 (1 mL) and K2C03 (85 mg, 0.616 mol) using a similar procedure to that described in reference example Al , step 2.
Step 3:
3 -(2-nitro- 1 -((triethylsilyl)oxy)ethyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazole (A75-3)
Compound A75-3 (604 mg, crude) was obtained as yellow gum from the reaction of compound A75-2 (428 mg, 1.49 mmol), TES-Cl (0.280 mL, 1.78 mmol) and imidazole (303 mg, 4.47 mmol) using a similar procedure to that described in reference example Al, step 3.
Step 4:
2-((triethylsilyl)oxy)-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)ethanamine (A75-4)
Compound A75-4 (600 mg, crude) was obtained as colorless gum from the reaction of compound A75-3 (604 mg, 1.51 mmol), Fe powder (843 mg, 15.1 mmol) and NH4C1 (806 mg, 15.1 mmol) using a similar procedure to that described in reference example A31, step 3.
Step 5:
N-(3,5-difluorobenzyl)-2-((triethylsilyl)oxy)-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-p yrazol-3-yl)ethanamine (A75)
Compound A75 (40 mg, 5%, over 3 steps) was obtained as colorless gum from the reaction of compound A75-4 (600 mg, 1.61 mmol), 3,5-diflurobenzaldehyde (206 mg, 1.45 mmol) and NaBH4 (119 mg, 3.22 mmol) using a similar procedure to that described in reference example A31 , step 4. Ή NMR (CDC13, 300 MHz): δ 7.59 (s, 0.7H), 7.48 (s, 0.3H), 6.39 (s, 1H), 5.38-5.71 (m, 2H), 4.91-5.08 (m, 1H), 3.54-3.61 (m, 2H), 2.95-3.04 (m, 2H), 0.85-0.95 (m, 9H), 0.59-0.62 (m, 6H); LCMS (APCI): 499 (M+H)+.
[Reference example A84]
Figure imgf000088_0001
Step 1 : 2^(2-chloro-6-nitrophenyl)-2-((trimethylsilyl)oxy)acetonitrile (A84-1)
To a stirred solution of 2-chloro-6-nitrobenzaldehyde (1.0 g, 5.4 mmol) in DCM (15 mL) were added TMSCN (1.0 mL, 8.1 mmol) and NMO (0.19 g, 1.6 mmol) at room temperature and stirred for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound A84- 1 (1.0 g, 67%) as a brown color oil.
Step 2: 2-(2-chloro-6-nitrophenyl)-2-((trimethylsilyl)oxy)ethanamine
To a stirred solution of compound A84-1 (0.85 g, 3.0 mmol) in THF (15 mL) was added BHyTHF (1.0 M in THF, 17.9 mL, 17.88 mmol) and stirred at room temperature for 16 h. The reaction mixture was quenched with MeOH and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound A84-2 (0.65 g, 75%) as a brown color gum.
Step 3 : 1 -(2-chloro-6-nitrophenyl)-2-((3,5-difluorobenzyl)amino)ethanol (A84)
Compound A84 (0.57 g, 74%») was obtained as a yellow solid from the reaction of compound A84-2 (0.65 g, 2.24 mmol), 3,5-difluorobenzaldehyde (0.24 mL, 2.24 mmol) and NaBH4 (0.17 g, 4.49 mmol) in MeOH (10 mL) using a similar procedure to that described in reference example A56, step 8. 1H NMR (CDC13, 300 MHz): δ 7.52-7.29 (m, 3H), 6.89-6.66 (m, 3H), 5.22 (dd, J = 10.0, 3.7 Hz, 1H), 3.88 (s, 2H), 3.27-3.19 (m, 1H), 3.07 (dd, J = 12.6, 3.7 Hz, 1H); LCMS (APCI): 343 (M+H)+.
[Reference example A92]
- ste→p 4
Figure imgf000089_0001
Step 1 : (5S)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)dihydrofuran-2(3H)-one (A92-1)
To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (4.0 g, 34.45 mmol) in DCM (20 mL) was added 3,4-dihydro-2H-pyran (3.95 mL, 41.34 mmol) followed by pyridinium p-toluenesulfonate (0.86 g, 3.44 mmol) at room temperature and the mixture was stirred for 16 h. The reaction mixture was diluted with DCM (20 mL), quenched with water (40 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2S04, and - concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound A92-1 (5.85 mg, 85%) as a colorless gum.
Step 2: (2S)-5-methyl-l-((tetrahydro-2H-pyran-2-yl)oxy)hexane-2,5-diol (A92-2)
To a stirred solution of compound A92-1 (5.85 g, 29.1 mmol) in THF (50 mL) was added methyl magnesium bromide (3.0 M in Et20, 22.4 mL, 67.2 mmol) dropwise at 0 °C for 10 min and the mixture was stirred at 0 °C for 4 h. The mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 90% EtOAc/hexane as eluent) to provide compound A92-2 (6.09 g, 90%) as a colorless gum.
Step 3: (S)-(5,5-dimethyltetrahydrofuran-2-yl)methanol (A92-3)
To a stirred solution of compound A92-2 (1.03 g, 4.43 mmol) in MeOH (8 mL) was added p-toluenesulfonic acid monohydrate (421 mg, 2.2 mmol) at room temperature and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature, quenched with water (15 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 35% EtOAc/hexane as eluent) to provide compound A92-3 (330 mg, 57%) as a colorless gum.
Step 4: (S)-(5,5-dimethyltetrahydrofuran-2-yl)methyl methanesulfonate (A92-4)
To a stirred solution of compound A92-3 (300 mg, 2.30 mmol) in DCM (6 mL) was added Et3N (0.64 mL, 4.6 mmol) followed by methanesulfonyl chloride (0.21 mL, 2.76 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was allowed to warm to room temperature over a period of 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 35% EtOAc/hexane as eluent) to provide compound A92 -4 (310 mg, 64%) as a colorless gum. - Step 5:
2-(3,5-dichloropyridin-4-yl)-N-(((S)-5,5-dimethyltetrahydrofuran-2-yl)methyl)-2-((triethyl silyl)oxy)ethanamine (A92)
A mixture of compound A92-4 (140 mg, 0.67 mmol), compound Al-3 (216 mg, 0.67 mmol), Na2C03 (710 mg, 6.7 mmol) and isopropanol (4 mL) was taken in a microwave vial. The vial was capped and the mixture was subjected to microwave irradiation at 120 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water (15 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2%
MeOH/DCM as eluent) to provide compound A92 (40 mg, 14%) as a colorless gum.
Figure imgf000091_0001
Step 1 : l-(2-chloro-6-methoxyphenyl)-2-nitroethanol (A93-1)
Compound A93-1 (1.35 g, crude) was obtained as a colorless oil from the reaction of 2-chloro-6-methoxybenzaldehyde (1.0 g, 5.88 mmol) and K2C03 (0.3 g, 2.2 mmol) in CH3N02 (10 mL) using a similar procedure to that described in reference example Al, step 1.
Step 2: (l-(2-chloro-6-methoxyphenyl)-2-nitroethoxy)triethylsilane (A93-2)
Compound A93-2 (2.14 g, crude) was obtained as a colorless oil from the reaction of compound A93-1 (1.35 g, 5.84 mmol), TES-Cl (1.17 mL, 7.01 mmol) and imidazole (1.19 g, 17.53 mmol) in DMF (10 mL) using a similar procedure to that described in reference example A 1, step 2.
Step 3: 2-(2-chloro-6-methoxyphenyl)-2-((triethylsilyl)oxy)ethanamine (A93-3) Compound A93 -3 (1.6 g, 84%) was obtained as a colorless oil from the reaction of compound A93-2 (2.14 g, 6.2 mmol), Fe (3.48 g, 62.0 mmol) and NH4C1 (3.3 g, 62.0 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A 1, step 3.
Step 4:
2-(2-chloro-6-methoxyphenyl)-N-(3,5-difluorobenzyl)-2-((triethylsilyl)oxy)ethanamine
(A93)
Compound A93 (1.2 g, 54%) was obtained as a colorless gum from the reaction of compound A93-3 (1.6 g, 5.16 mmol), 3,5-difluorobenzaldehyde (0.56 mL, 5.16 mmol) and NaBH4 (0.39 g, 10.2 mmol) in MeOH (10 mL) using a similar procedure to that described in reference example Al, step 4. lR NMR (CDC1 , 300 MHz): δ 7.13 (t, J = 8.1 Hz, 1H), 6.95-6.60 (m, 5H), 5.58 (dd, J = 8.6, 4.7 Hz, 1H), 3.83-3.77 (m, 5H), 3.28 (dd, J = 12.0, 8.7 Hz, 1H), 2.78 (dd, J = 12.0, 4.7 Hz, 1H), 0.87-0.82 (m, 9H), 0.60-0.46 (m, 6H); LCMS (APCI): 442 (M+H)+. Reference example A94]
Figure imgf000092_0001
Step 1 : (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (A94-1)
To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (2.0 g, 17.2 mmol) in DCM (20 mL) was added Et3N (4.8 mL, 34.44 mmol) followed by
p-toluenesulfonyl chloride (3.61 g, 18.94 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound A94-1 (4.06 g, 87%) as a white solid.
Step 2: (R)-(5,5-dimethyltetrahydrofuran-2-yl)methanol (A94-2)
To a stirred solution of compound A94-1 (1.63 g, 6.03 mmol) in THF (20 mL) was added MeLi (3.0 M in diethoxymethane, 4.4 mL, 13.26 mmol) dropwise at -78 °C for 10 min and the mixture was stirred at -78 °C for 1 h. The mixture was allowed to warm to room temperature over a period of 4 h. The reaction mixture was quenched with saturated aqueous NaCl, diluted with water (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 35% EtOAc/hexane as eluent) to provide compound A94-2 (220 mg, 28%) as a colorless gum.
Step 3: (R)-(5,5-dimethyltetrahydrofuran-2-yl)methyl methanesulfonate (A94-3)
Compound A94-3 (351 mg, 61%) was obtained as a colorless gum from the reaction of compound A94-2 (360 mg, 2.76 mmol), Et3N (0.77 mL, 5.52 mmol) and
methanesulfonyl chloride (0.25 mL, 3.31 mmol) in DCM (5.0 mL) using a similar procedure to that described in reference example A92, step 4.
Step 4:
2-(3,5-dichloropyridin-4-yl)-N-(((R)-5,5-dimethyltetrahydrofuran-2-yl)methyl)-2-((tri silyl)oxy)ethanamine (A94)
Compound A94 (32 mg, 8%) was obtained as a colorless gum from the reaction of compound A94-3 (200 mg, 0.96 mmol), compound Al-3 (247 mg, 0.77 mmol) and
Na2C03 (508 mg, 4.8 mmol) in isopropanol (3.0 mL) using a similar procedure to that described in reference example A92, step 5.
[Reference example A103]
Figure imgf000094_0001
Step 1 : N-methoxy-N-methyl-l-(trifluoromethyl)cyclopropanecarboxamide (A103-1) To a mixture of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (150 mg, 0.974 mmol), 1 -hydroxybenzotrizole monohydrate (224 mg, 1.46 mmol),
1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride ( 142 mg, 1.46 mmol) in DMF (5 mL) was added DIPEA (0.50 mL, 2.92 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with water and brine, dried over MgS04 and concentrated under reduced pressure to provide compound A103-1 (164 mg, 85%) as a pale yellow oil.
Step 2: l-(trifluoromethyl)cyclopropanecarbaldehyde (A103-2)
To a stirred solution of compound A 103-1 (164 mg, 0.832 mmol) in DCM (2 mL) was added diisobutylaluminum hydride (1 M in hexane, 1.0 mL, 1.0 mmol) at -78 °C under nitrogen atmosphere. After 0.5 h, the mixture was allowed to warm to 0 °C and stirred for 0.5 h. The reaction mixture was quenched with sat. KHS04 aq. (10 mL) and extracted with DCM (2 x 4 mL). The combined organic layers were directly used in the next step without further purification.
Step 3:
2- (3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)-N-((l-(trifluoromethyl)cyclopropyl)rriet hyl)ethanamine (A103)
Compound Al-3 (0.20 g, 0.622 mmol) was dissolved in DCM solution containing compound A103-2. MgSC (0.2 g) was added to this solution and the mixture was stirred for 2 h. MeOH (10 mL) and NaBH4 (0.2 g) were added to the mixture and the mixture was stirred for 0.5 h. The reaction mixture was quenched with water and extracted with EtOAc. The collected organic layer was washed with brine, dried over MgS04 and concentrated under reduced pressure. The crude material was purified by silicagel column chromatography eluting with 20% EtOAc in heptane to give compound A 103 (87 mg, 32%) as a colorless oil. Ή NMR (CDC13, 400 MHz) δ: 8.43 (2H, s), 5.45 (1H, dd, J = 8.5, 4.6 Hz), 3.24 (1H, dd, J= 12.2, 8.8 Hz), 2.86 (2H, dd, J = 24.4, 13.2 Hz), 2.76 (1H, dd, J= 12.2, 4.4 Hz), 0.97-0.86 (13H, m), 0.56-0.52 (6H, m).
[Reference example AIT 1 ]
Figure imgf000095_0001
Step 1 : 2,6-dichloro-4-methylbenzoic acid (Al l 1-1)
To a stirred solution of l ,3-dichloro-5-methylbenzene (2.0 g, 12.4 mmol) in THF (20 mL) was added n-BuLi (2.0 M in hexane, 9.3 mL, 18.6 mmol) at -78 °C dropwise over a period of 10 miri and mixture was stirred at -78 °C for 30 min. A dry-ice was added to the reaction mixture slowly and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was slowly warmed to room temperature, quenched with 6 M HC1 (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al 11 -1 (1.1 g, 44%) as a white solid.
Step 2: 2,6-dichloro-4-formylbenzoic acid (Al 11-2)
To a stirred solution of compound Al l 1-1 (1.1 g, 5.3 mmol) in DCM (20 mL) was added NBS (2.3 g, 13.4 mmol) and diphenyl oxalate(65 mg, 0.27 mmol) and placed at reflux for 40 h. The reaction mixture was brought to room temperature and evaporated the solvent. To the residue, EtOAc (10 mL) was added and the obtained solids were filtered through Buckner funnel. The filtrate was evaporated and the crude product was dissolved in EtOH (20 mL) and heated to 50 °C. A solution of silver(I) nitrate (1.37 g, 8.0 mmol) in hot water (3 mL), was added to the reaction mixture dropwise and continued at the same temperature for 45 min. The reaction mixture was quenched with 1 M HC1 (10 mL) and the obtained solids were filtered and washed with EtOH (30 mL). Filtrate was evaporated and remaining aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al 11 -2 (1.6 g, crude) as a brown oil.
Step 3: methyl 2,6-dichloro-4-formylbenzoate (Al l 1-3)
To a stirred solution of compound Al l 1-2 (1.1 g, 5.0 mmol) in DMF (10 mL) was added K2C03 (1.0 g, 7.5 mmol) at 0 °C followed by slow addition of Mel (0.94 mL, 15.0 mmol) and the reaction mixture was stirred at the same temperature for 30 min. Then reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound Al l l-3 (0.59 g, 50%) as a white solid.
Step 4: methyl 2,6-dichloro-4-(difluoromethyl)benzoate (Al 11 -4)
To a stirred solution of compound Al l l-3 (0.36 g, 1.5 mmol) in DCM (10 mL) was added DAST (0.37 mL, 2.8 mmol) at -78 °C dropwise followed by a drop addition of MeOH and the reaction was stirred at the same temperature for 15 min and brought to 0 °C. The reaction mixture was stirred for 30 min at the same temperature and 16 h at room temperature. The reaction mixture was quenched with saturated NaHC03 (20 mL) at 0 °C and stirred for 20 min and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al l 1-4 (0.37g, 94%) as a colorless oil.
Step 5: (2,6-dichloro-4-(difluoromethyl)phenyl)methanol (Al l 1 -5)
To a stirred solution of compound Al l 1-4 (1.44 g, 5.64 mmol) in THF (10 mL) was added LiAlH4 (2.0 M in THF, 4.23 mL, 8.46 mmol) in THF (10 mL) at -78 °C dropwise for 15 min and brought to 0 °C. The reaction mixture was stirred for 30 min at the same temperature and 16 h at room temperature. The reaction mixture was quenched with 1 M HC1 (20 mL) at 0 °C and stirred for 20 min and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al 11 -5 (0.59 g, 45%) as a colorless oil.
Step 6: 2,6-dichloro-4-(difluoromethyl)benzaldehyde (Al l 1-6)
Compound Al 11 -6 (0.38 g, 65%) was obtained as a colorless oil from the reaction of compound Al l 1-5 (0.59 g, 2.46 mmol) and Dess-Martin periodinane (2.1 g, 4.92 mmol) in DCM (10 mL) using a similar procedure to that described in reference example A56, step 4.
Step 7: 2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((trimethylsilyl)oxy)acetonitrile (Al l 1 -7)
To a stirred solution of compound Al l 1-6 (0.38 g, 1.6 mmol) in DCM (15 mL) were added TMSCN (0.31 mL, 2.5 mmol) and NMO (60 mg, 0.5 mmol) at room temperature and stirred for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al 11-7 (0.53 g, 97%) as a yellow solid.
Step 8 2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((trimethylsilyl)oxy)ethanamine , (Al l 1 -8)
To a stirred solution of compound Al l 1-7 (0.53 g, 1.6 mmol) in THF (10 mL) was added BH3 THF (8.2 mL, 8.1 mmol) and stirred at room temperature for 16 h. The reaction mixture was quenched with MeOH and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get compound Al 11-8 (0.5 g, crude) as a yellow oil.
Step 9: l-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-((3,5-difluorobenzyl)amino)ethanol (Λ1 1 1) .
Compound Al l 1 (0.21 g, 36%) was obtained as a colorless gum from the reaction of compound Al l 1-8 (0.5 g, 1.52 mmol), 3,5-difluorobenzaldehyde (0.16 mL, 1.52 mmol) and NaBH4 (0.11 g, 3.0 mmol) in MeOH (5 mL) using a similar procedure to that described in reference example A56, step 8. Ή NM (CDC13, 400 MHz): δ 7.44 (s, 2H), 6.89-6.42 (m, 4H), 5.56-5.25 (m, 1H), 3.87 (s, 2H), 3.26 (dd, J = 12.8, 9.6 Hz, 1H), 2.91- 2.86 (m, 1H).
[Reference example
Figure imgf000099_0001
To a stirred solution of 4-(hydroxymethyl)cyclohexanone (1.0 g, 7.8 mmol) in THF (20 mL) was added methyl magnesium bromide (3.0 M in Et20, 7.8 mL, 23.4 mmol) dropwise at 0 °C for 5 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtO Ac (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 80% EtOAc/hexane as eluent) to provide compound Al l 2-1 (300 mg, 27%) as a white solid.
Step 2: 4-hydroxy-4-methylcyclohexanecarbaldehyde (A 112-2)
Compound Al 12-2 (49 mg, crude) was obtained as a yellow foam from the reaction of compound Al l 2-1 (50 mg, 0.348 mmol) and Dess-Martin periodinane (206 mg, 0.48 mmol) in DCM (5.0 mL) using a similar procedure to that described in reference example A56, step 4.
Step 3:
4-(((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)amino)methyl)-l-methylcycloh exanol (A 1 12)
To a stirred solution of compound Al l 2-2 (49 mg, 0.34 mmol) in DCM (15 mL) was added compound Al -3 (109 mg, 0.34 mmol) followed by NaBH(OAc)3 (108 mg, 0.51 mmol) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with aqueous saturated NaHC03 (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 5% MeOH/DCM as eluent) to provide compound Al 12 (58 mg, 37% over two steps) as a yellow gum.
[Reference example Al 18]
Figure imgf000100_0001
A1 -3 A118
N-(2-bromobenzyl)-2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (Al 18) Compound Al 18 (1.2 g, 79%) was obtained as a colorless oil from the reaction of compound Al-3 (1.0 g, 3.16 mmol), 2-bromobenzaldehyde (576 mg, 3.11 mmol) and NaBH4 (172 mg, 4.67 mmol) in MeOH (40 mL) using a similar procedure to that described in reference example Al, step 4. 1H NMR (CDC13, 400 MHz): δ 8.41 (s, 2H), 7.53-7.51 (m, 1H), 7.37-7.35 (m, 1H), 7.28-7.25 (m, 1H), 7.13-7.08 (m, 1H), 5.55 (dd, J = 8.2, 5.2 Hz, 1H), 3.94-3.85 (m, 1H), 3.20 (dd, J = 12.1, 8.4 Hz, 1H), 2.88 (d, J = 4.8 Hz, 0.5H), 2.86 (dd, J = 12.1 , 5.1 Hz, 0.5H), 0.89-0.86 (m, 9H), 0.58-0.51 (m, 6H).
[Reference example Al 19] step 4
Figure imgf000101_0001
Step 1 : l,3-dibromo-2,2-dimethylpropane (Al 19-1)
To a stirred solution of triphenylphosphine (26.2 g, 0.1 mol) in CH3CN (50 mL) was added a solution of bromine (5.13 mL, 0.10 mol) in CH3CN (30 mL) dropwise at 0 °C. 2,2-Dimethylpropane-l,3-diol (5.1 g, 0.05 mol) was added in portion to the reaction and the reaction mixture was stirred at 90 °C for 16 h. The solvent was removed under reduced pressure. The residue was suspended in MTBE (150 mL), and resulting solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in CH3CN and extracted with hexane (3 x 100 mL). The combined hexane extracts were concentrated under reduced pressure to provide compound Al l 9-T (6.5 g, 59%) as brown oil.
Step 2: dipentyl 3,3-dimethylcyclobutane-l,l-dicarboxylate (A119-2)
The sodium (0.98 g, 43.0 mmol) was added in portion to pentanol (25 mL) and the mixture was stirred at 50 °C to get a clear solution. The reaction mixture was heated to 70 °C, and then diethyl malonate (3.50 g, 26.0 mmol) was added over a period of 5 min. The reaction mixture was heated to 130 °C and compound Al l 9-1 (5.0 g, 21 mmol) was added dropwise over a period of 10 min. The reaction mixture was heated at 130 °C for 4 h. The solvent was removed under vacuum at 100 °C. The residue was quenched with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were concentrated under reduced pressure to provide compound Al l 9-2 (6 g, crude) as brown oil. The crude product was used for next step without purification. Step 3: 3,3-dimethylcyclobutane-l,l-dicarboxylic acid (A119-3)
To a solution of compound A 119-2 (6 g, crude) in EtOH/water (60 mL, 2: 1) was added KOH solution (40% aqueous solution, 10 mL) and the reaction mixture was stirred at 100 °C for 4 h. After removing the solvent under reduced pressure, the residue was suspended in water (100 mL) and washed with MTBE. The aqueous layer was acidified to pH 1 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound Al l 9-3 (2.5 g, crude) as brown semi-solid gum. The crude product was used for next step without purification.
Step 4: 3,3-dimethylcyclobutanecarboxylic acid (Al 19-4)
Compound Al 19-3 (2.5 g, crude) was heated neat at 200 °C for 2 h to provide compound Al l 9-4 (900 mg, crude) as light brown gum.
Step 5: (3,3-dimethylcyclobutyl)methanol (Al l 9-5)
To a stirred suspension of LiAlH4 (534 mg, 14.0 mmol) in THF (20 mL) was added a solution of compound A 119-4 (900 mg, 7.0 mmol) in THF ( 10 mL) at 0 °C and the mixture was stirred at the same temperature for 3 h. The reaction mixture was quenched with water (3 mL) and 20% aqueous NaOH (3 mL) and stirred at room temperature for 10 min. The solid was filtered over a pad of celite and the organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S0 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20%
EtOAc/hexane as eluent) to provide compound Al l 9-5 (160 mg, 20%) as light yellow oil. Step 6: 3, 3 -dimethyl cyclobutanecarbaldehyde (A119-6)
To a stirred solution of compound Al 19-5 (160 mg, 1.4 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.20 g, 2.8 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (10 mL) and quenched with aqueous Na2S208 (5 mL) and NaHC03 solution (5 miL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound Al 19-6 (150 mg, quant.) as yellow oil. The crude product was used for next step without purification.
Step 7:
2-(3,5-dichloropyridin-4-yl)-N-((3,3-dimethylcyclobutyl)methyl)-2-((triethylsilyl)oxy)etha namine (Al 19)
The mixture of compound Al l 9-6 (150 mg, 1.33 mmol) and compound Al-3 (300 mg, 0.97 mmol) in MeOH (10 mL) was stirred at room temperature for 3 h. NaBH4 (75 mg, 1.99 mmol) was added in portion and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound Al 19 (190 mg, 36%) as yellow gum. 1H NMR (CDC13, 400 MHz): δ 8.42 (s, 2H), 5.46-5.52 (m, 1H), 3.16-3.23 (m, 1H), 2.71-2.79 (m, 1H), 2.53-2.69 (m, 2H), 1.42- 1.62 (m, 5H), 1.23-1.38 (m, 6H), 0.84-0.92 (m, 9H), 0.49-0.58 (m, 6H).
Figure imgf000103_0001
Step 1 : ethyl 4-methylenecyclohexanecarboxylate (A 122-1) Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a stirred solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0 °C and stirred for 40 min at the same temperature. A solution of ethyl 4-oxocyclohexanecarboxylate (2.04 g, 12 mmol) in THF (20 mL) was added slowly at 0 °C and stirred for 2 h from 0 °C to room temperature. The reaction was quenched with saturated NH4C1 aq. and extracted with hexane. The collected organic layer was dried over MgS04 and concentrated under reduced pressure. The solvent ( 100 mL, hexane/Et20 = 5/1) was added to the residue and stirred for 30 min. The suspension was filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silicagel chromatography (5% EtOAc/hexane as eluent) to provide compound A122-1 (1.478 g, 73%) as a colorless oil.
Step 2: ethyl l-(bromomethyl)-4-methylenecyclohexanecarboxylate (A 122-2)
n-BuLi (2.6 M in hexane, 2.5 mL, 6.6 mmoL) was added dropwisely to a solution of diisopropylamine (0.93 mL, 6.6 mmol) in THF (20 mL) at -78 °C and stirred for 30 min at the same temperature. Hexamethylphosphoramide (4 mL) was added to the reaction mixture and stirred for 20 min at the same temperature. A solution of compound A 122-1 (1.01 g, 6 mmol) in THF (5 mL) was added and stirred for 1 h at the same temperature. A solution of dibromomethane (2.1 mL, 30 mmol) was added to the reaction mixture and the mixture was allowed to warm to room temperature for 1.5 h. The reaction mixture was diluted hexane (80 mL) and AcOEt (20 mL). The collected organic layer was washed with water, saturated NH4C1 aq., brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound A122-2 (1.39 g, 89%) as a pale yellow oil.
Step 3: ethyl 4-methylbicyclo[2.2.1]heptane-l-carboxylate (A122-3)
To a stirred solution of compound A 122-2 (783 mg, 3 mmol) in toluene (65 mL) was added tributyltin hydride (0.888 mL, 3.3 mmol) and 2,2'-azobis(isobutyronitrile) (25 mg) in toluene (20 mL) and the mixture was stirred at 110 °C for 1 h. The reaction mixture was cooled down and concentrated under reduced pressure. DCM (20 mL) and a solution of KF (1.0 g) in water (0.31 mL) were added to the residue and the mixture was stirred for 1 h. The reaction mixture was filtrated with anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10%
EtOAc/hexane as eluent) to provide compound A 122-3 (501 mg, 92%) as a colorless oil. Step 4: 4-methylbicyclo[2.2.1]heptane-l-carboxylic acid (A122-4)
To a stirred solution of compound A122-3 (500 mg, 2.74 mmol) in MeOH/water (8 mL, 3:1) was added a solution of LiOH aq. (4 M, 2 mL, 8 mmol). The mixture was stirred at room temperature for 2.5 h and stirred at 50 °C for 1.5 h. The organic solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and hexane (10 mL). The aqueous layer was acidified with 6 M aqueous HC1 to pH 1 and extracted with DCM. The organic layers were dried over MgS04 and concentrated under reduced pressure to provide compound A122-4 (313 mg, 74%) as a pale yellow solid. Step 5: N-methoxy-N,4-dimethylbicyclo[2.2.1]heptane-l-carboxamide (A122-5)
To a mixture of compound Al 22-4 (302 mg, 1.96mmol), 1 -hydroxybenzotrizole monohydrate (460 mg, 3 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (466 mg, 3 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (293 mg, 3 mmol) in DMF (10 mL) was added DIPEA (1.03 mL, 6 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with saturated NH4C1 aq., brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (30% EtOAc/hexane as eluent) to provide compound A122-5 (271.4 mg, 70%) as a colorless oil. Step 6: 4-methylbicyclo[2.2.1]heptane-l-carbaldehyde (A122-6)
To a solution of compound A 122-5 (271 mg, 1.37 mmol) in Et20 (5 mL) was added a suspension of LiAlH4 (52 mg, 1.37 mmol) in Et20 (2 mL) at 0 °C and stirred for 45 min at the same temperature. The reaction mixture was quenched with saturated KHS04 aq. (5 mL) at 0 °C and stirred for 30 min at room temperature and extracted with Et20. The organic layer was dried with MgS04 and concentrated under reduced pressure to provide compound A 122-6 (163 mg, 86%) as a colorless oil. The crude product was used for next step without purification.
Step 7:
2-(3,5-dichloropyridin-4-yl)-N-((4-methylbicyclo[2.2.1]heptan-l-yl)methyl)-2-((triethylsil yl)oxy)ethanamine (A122)
Compound A 122 (177 mg, 80%) was obtained as a pale yellow oil from the reaction of compound Al -3 (160 mg, 0.50 mmol), compound A 122-6 (82 mg, 0.59 mmol), NaBH4
(120 mg) and MgS04 (200mg) in MeOH (4 mL) and DCM (3mL) using a similar procedure to that described in reference example A31 , step 4. 1H NMR (CDC13, 400 MHz): δ 8.42 (s, 2H), 5.50 (dd, J = 8.7, J = 4.6 Hz, 1H), 3.24 (dd, J = 12.6, J = 8.7 Hz, 1H), 2.78 (dd, J = 12.6, J = 4.6 Hz, 1H), 2.75 (d, J = 11.7 Hz, 1H), 2.67 (d, J = 11.7 Hz, 1H), 1.54-1.32 (m, 8H), 1.10-1.08 (m, 5H), 0.89 (t, J = 8.0 Hz, 9H), 0.58-0.49 (m, 6H).
Figure imgf000106_0001
Step 1 ethyl cyclopentanecarboxylate (A124-1) To a solution of cyclopentanecarboxylate (1.14 g, 10 mmol) in EtOH (5mL) was added H2S04 (0.1 mL) at room temperature. The mixture was allowed to warm to 80 °C and stirred at the same temperature for 3.5 h. The reaction mixture was cooled down to room temperature and poured into saturated NaHC03 aq. (40 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A 124-1 (1.01 g, 71 %) as a pale yellow oil. The crude product was used for next step without purification.
Step 2: ethyl 1 -fluorocyclopentanecarboxylate (A 124-2)
n-BuLi (2.6 M in hexane, 4.0 mL, 10.5 mmoL) was added dropwisely to a solution of diisopropylamine (1.55 mL, 11 mmol) in THF (40 mL) at -78 °C and stirred for 30 min at the same temperature. A solution of compound A 124-1 (1.00 g, 7 mmol) in THF (10 mL) was added to the mixture and the mixture was stirred for 50 min at the same temperature. The reaction mixture was allowed to warm to 0 °C for 1 h. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (3.47 g, 10 mmol) in THF (10 mL) was added to the mixture and the mixture was stirred for 1 h at the same temperature. The reaction mixture was allowed to warm to room temperature for overnight. The reaction was quenched with saturated NH4C1 aq. and extracted with EtOAc. The collected organic layer was concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound A 124 -2 (911 m g, 81%) as a yellow oil.
Step 3: 1-fluorocyclopentanecarboxylic acid (A124-3)
To a stirred solution of compound A 124-2 (910 mg, 5.68 mmol) in EtOH/THF/water (7 mL, 4:2: 1) was added a solution of LiOH aq. (4 M, 3 mL, 12 mmol). The mixture was stirred at room temperature for 2.5 h. The organic solvent was removed under reduced pressure. The residue was acidified with 2 M aqueous HC1 to pH 1 and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A124-3 (709 mg, 95%) as a brown oil. The crude product was used for next step without purification.
Step 4: 1-fluoro-N-methoxy-N-methylcyclopentanecarboxamide (A 124-4)
To a mixture of compound A 124-3 (709 mg, 5.37 mmol), 1-hydroxybenzotrizole (986 mg, 6.44 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 6.44 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (628 mg, 6.44 mmol) in DMF (10 mL) was added triethylamine (1.12 mL, 8.05 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with 2 M aqueous HC1 (30 mL) and extracted with EtOAc. The collected organic layer was washed with water, brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% EtOAc/hexane as eluent) to provide compound A 124-4 (543 mg, 58%) as a yellow oil.
Step 5: 1-fluorocyclopentanecarbaldehyde (A124-5)
To a solution of compound A124-4 (140 mg, 0.8 mmol) in Et20 (20 mL) was added LiAlH4 (33 mg, 0.88 mmol) at 0 °C and stirred for 5 h at the same temperature. The reaction mixture was quenched with saturated KHS04 aq. (5 mL) at 0 °C and extracted with Et20. The combined organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A 124-5. The crude product was used for next step without purification.
Step 6:
2-(3,5-dichloropyridin-4-yl)-N-((l-fluorocyclopentyl)methyl)-2-((triethylsilyl)oxy)ethana mine (A 124)
Compound A124 (207 mg, 68%) was obtained from the reaction of compound Al-3 (233 mg, 0.73 mmol), compound A 124-5 (93 mg, 0.8 mmol), NaBH(OAc)3 (231 mg, 1.09 mmol), MgS04 (93 mg) and AcOH (0.042 mL, 0.73 mmol) in DCM (2 mL) using a similar procedure to that described in reference example A31 , step 4. 1H NMR (CDC13, 400 MHz): 6 8.43 (s, 2H), 5.49 (dd, J = 8.5, J = 4.5 Hz, 1H), 3.26 (dd, J = 12.6, J = 8.5 Hz, 1H), 2.87 (d, J = 21.0 Hz, 2H), 2.83 (dd, J = 12.6, J = 4.5 Hz, 1H), 1.93-1.60 (m, 8H), 0.88 (t, J = 7.8 Hz, 9H), 0.60-0.49 (m, 6H).
Figure imgf000109_0001
Step 1 : 3-methylenecyclobutanecarboxylic acid (A141-1)
To a stirred solution of KOH (10 g, 178 mmol) in water (15 mL) and EtOH (15 mL) was added 3 -methyl enecyclobutanecarbonitrile (3.92 g, 42 mmol) at room temperature for 10 min. The mixture was allowed to warm to 90 °C and stirred at the same temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) at 0 °C. The mixture was acidified with 6 M aqueous HCl to pH 1 and extracted with DCM. The organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A141-1 (4.65 g, 98%) as a colorless oil. The product was used for next step without futher purification.
Step 2: methyl 3-methylenecyclobutanecarboxylate (A141-2)
Trimethylsilyldiazomethane (2.0 M in hexane, 25 mL, 50 mmol) was added to a stirred solution of compound A141-1 (4.64 g, 41.4 mmol) in DCM (25 mL) and MeOH (5 mL) dropwise at 0 °C for 5 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 30 min. The reaction mixture was quenched with AcOH (0.45 mL) and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% DCM/hexane as eluent) to provide compound A141 -2 (3.8 g, 73%) as a colorless oil.
Step 3: methyl spiro[2.3]hexane-5-carboxylate (A141-3)
To a solution of diethylzinc (1.0 M in hexane, 46 mL, 46 mmol) in DCM (200 mL) was added a solution of TFA (3.54 mL, 46 mmol) in DCM (50 mL) dropwise at 0 °C for 30 min. A solution of diiodomethane (3.7 mL, 46 mmol) in DCM (50 mL) was added dropwise at 0 °C for 45 min. The mixture was stirred at the same temperature for 1 h. A solution of compound A141-2 (2.52 g, 20 mmol) in DCM (30 mL) was added to the reaction mixture. The mixture was allowed to warm to room temperature for overnight. The reaction mixture was quenched with saturated NH4C1 aq. (200 mL) and extracted with DCM. The collected organic layer was dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% EtOAc/hexane as eluent) to provide compound Al 41-3 (1.77 g, 63%) as a colorless oil.
Step 4: spiro[2.3]hexane-5-carboxylic acid (A141-4)
To a stirred solution of LiOH (4 M in water, 10 mL, 40 mmol) in water (10 mL) and MeOH (20 mL) was added compound A141-3 (1.76 g, 12.6 mmol) at room temperature. The mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure to ca. 20 mL of solution. The solution was acidified with 6 M aqueous HC1 to pH 1 and extracted with DCM. The organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A141-4 (1.51 g, 95%) as a colorless oil. The product was used for next step without futher purification. Step 5: N-methoxy-N-methylspifo[2.3]hexane-5-carboxamide (A141-5) To a mixture of compound A l 41 -4 (1.51 mg, 12.0 mmol), 1 -hydroxybenzotrizole monohydrate (2.30 g, 15 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.33 g, 15 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (1.46 g, 15 mmol) in DMF (20 mL) was added DIPEA (3.43 mL, 20 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water and extracted with hexane and EtOAc. The collected organic layer was washed with 1 M HC1 aq. (100 mL), water, saturated Na2C03 aq. (2 x 100 mL), brine, dried over MgSG4 and concentrated under reduced pressure. The residue was purified by silicagel
chromatography (75% EtOAc/hexane as eluent) to provide compound Al 41 -5 (1.72 g, 84%) as a colorless oil.
Step 6: spiro[2.3]hexane-5-carbaldehyde (A141-6)
To a solution of compound A141-5 (677 mg, 4 mmol) in Et20 (15 mL) was added a suspension of LiAlH4 (152 mg, 4 mmol) in Et20 (5 mL) at 0 °C over 5 min and stirred for 2 h at the same temperature. The reaction mixture was quenched with saturated KHSO4 aq. (10 mL) at 0 °C and extracted with Et20. The combined organic layer was dried with MgS04 and concentrated under reduced pressure to provide compound Al 41-6 (351 mg, 80%) as a colorless oil. The crude product was used for next step without purification. Step 7:
2-(2,4,6-trichlorophenyl)-N-(spiro[2.3]hexan-5-ylmethyl)-2-((triethylsilyl)oxy)ethanamine (A141)
Compound A141 (123 mg, 39%) was obtained as a pale yellow oil from the reaction of 2-(2,4,6-trichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.7 mmol), compound A141-6 (100 mg, 0.91 mmol), NaBH4 (212 mg) and MgS04 (lOOmgj in MeOH (1.4 mL) and THF (3.5 mL) using a similar procedure to that described in reference example A31, step 4. 1H NMR (CDC13, 400 MHz): δ 7.29 (s, 2H), 5.53 (dd, J = 9.0, J = 4.6 Hz, 1H), 3.26 (dd, J = 12.2, J = 8.8 Hz, 1H), 2.85-2.71 (m, 3H), 2.62-2.51 (m, 1H), 2.17-2.10 (m, 2H), 1.86-1.81 (m, 2H), 0.87 (t, J = 7.8 Hz, 9H), 0.57-0.50 (m, 6H), 0.43-0.33 (m, 4H).
[Reference example A 194]
l-(2,6-dichloro-3-fluorophenyl)-2-(((l-(trifluoromethyl)cyclopropyl)methyl)amino)ethanol
Figure imgf000112_0001
Step 1 : 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile
To a 200 riil RBF was charged with solution of 2,6-dichloro-3-fluorobenzaldehyde (2.29 g, 11.87 mmol), DCM (23 ml), TMSCN (1.9 ml, 14.24 mmol), and zinc iodide (0.379 g, 1.187 mmol) was added. The mixture was stirred at room temperature for 4 h. Then the mixture was washed with water (2x20 ml) and brine. Organic layer was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, eluent: 0% to 30% EtO Ac/heptane) to provide
2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (1.435 g, 4.91 mmol,
41.4 % yield) as colorless oil. Ή NMR (400 MHz, CDC13) δ 7.32-7.42 (m, 1 H);
7.12-7.24 (m, 1 H); 6.17-6.30 (m, 1 H); 0.12-0.33 (m, 9 H).
Step 2: 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde
To a 100 mL three-necked RBF were added
2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (0.50 g, 1.711 mmol) and DCM (9 ml). The reaction mixture was purged with nitrogen and cooled to -64 °C. Under a nitrogen atmosphere, diisobutylaluminum hydride, 1.0 M solution in hexane (2.6 ml, 2.6 mmol) was added dropwise. The mixture was stirred at -64 °C. After 2 h, the reaction was quenched. While maintaining temp <-65 °C, MeOH (1.4 ml, 34.2 mmol) was carefully added dropwise to the reaction mixture followed by saturated Rochelle salt solution (5mL). The mixture was allowed to reach room temperature and stirred for 30 min. Water and DCM were added and the aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous MgS04, and concentrated to afford 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde as a colorless oil (0.517 g, crude).
Step 3:
1- (2,6-dichloro-3-fluorophenyl)-2-(((l-(trifluoromethyl)cyclopropyl)methyl)amino)ethanol
To a solution of crude
2- (2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (0.258 g, 0.874 mmol) in MeCN (9 ml) was added (l-(trifluoromethyl)cyclopropyl)methanamine (0.122 g, 0.874 mmol) followed by AcOH (0.050 ml, 0.874 mmol). The reaction mixture was stirred at room temperature for 1 h. Then NaBH(OAc)3 (0.370 g, 1.748 mmol) was added. The reaction mixture was stirred at room temperature for 23 h. Then it was quenched by adding saturated aqueous NaHC03 solution and stirred for 30 min. It was extracted with DCM (2x5 mL). The combined organic layer was washed with brine, dried over anhydrous MgS04, and concentrated under reduced pressure to provide a yellow oil. The yellow oil was dissolved in 2 mL of THF. Then TBAF, 1.0 M solution in THF (0.874 ml, 0.874 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. It was quenched with saturated aqueous NaHC03 and extracted with DCM. The combined organic layer was dried over anhydrous MgS04 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, eluent : 0% to 50% EtO Ac/heptane) to provide 1- (2,6-dichloro-3-fluorophenyl)-2-(((l-(trifluoromethyl)cyclopropyl)niethyl)amino)ethanol (116 mg, 0.335 mmol, 38.3% yield) as a yellow oil. 1H NMR (400 MHz, CDC13) δ
7.25-7.31 (m, 1H), 7.06 (dd, J=8.9, 8.0 Hz, 1H), 5.45 (dd, J=9.7, 4.5 Hz, 1H), 3.45 (br. s., lH), 3.28 (dd, J=12.6, 9.8 Hz, 1H), 2.89-2.92 (m, 3H), 0.99 - 1.04 (m, 2H), 0.69-0.76 (m, 2H); LCMS: 346.0 [M+H]+.
[Reference example A224] ,
2- (2,6-dichlorlo-4-fluorophenyl)-N-((l-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)eth anamine
Figure imgf000114_0001
A mixture of 1 -methylcyclopropanecarbaldehyde (31.6 mg, 0.375 mmol) and 2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (127 mg, 0.375 mmol) in MeOH (1.9 ml) was stirred at room temperature for 3 h. NaBH4 (14.20 mg, 0.375 mmol) was added in portions and the mixture was stirred at room temperature for 40 min. The mixture was was concentrated and purified by prep TLC eluted with 5% MeOH/DCM to provide
2-(2,6-dichlOro-4-fluorophenyl)-N-((l-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)eth anamine (111 mg, 0.273 mmol, 72.8% yield). 1H NMR (500 MHz, CDC13) 5 7.29 (s, 1H), 7.06-7.10 (m, 2H), 5.56 (br. s., 1H), 3.33 (t, J=10.51 Hz, 1H), 2.81 (d, J=9.17 Hz, 1H), 2.60-2.67 (m, 1H), 2.44 (d, J=11.86 Hz, 1H), 1.46-1.59 (m, 1H), 1.13 (s, 3H), 0.85-0.96 (m, 9H), 0.50-0.63 (m, 6H), 0.36 (br. s., 2H), 0.30 (br. s., 2H); LCMS (ESI) m/z 406.0
(M+H)+. [Reference example A258]
2-(2,6-dichlorophenyl)-N-((l-methylcyclopropyl)m
Figure imgf000115_0001
To a mixture of 1-methylcyclopropanecarbaldehyde (32.8 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHC03. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated then purified by prep TLC eluted with 5% MeOH/DCM to provide
2-(2,6-dichlorophenyl)-N-((l-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)ethanamine (95 mg, 0.245 mmol, 62.7 %yield). IH NMR (500 MHz, CDC13) δ 7.28-7.30 (m, 2H), 7.12-7.16 (m, lH), 5.65 (br. s., 1H), 3.37-3.44 (m, 1H), 2.82-2.90 (m, 1H), 2.69 (br. s., lH), 2.48 (d, J=11.86 Hz, 1H), 1.60 (br. s., lH), 1.15 (s, 3H), 0.87-0.92 (m, 9H), 0.51-0.63 (m, 6H), 0.28-0.44 (m, 4H); LCMS (ESI) m/z 388.3 (M+H)+.
[Reference example A2
Figure imgf000115_0002
Step 1 : 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)0xy)acetonitrile A 100 ml RBF was charged with solution of 2,6-dichlorobenzaldehyde (5.08 g, 29.0 mmol) and TMSCN (4.64 ml, 34.8 mmol) in DCM (60 ml). Zinc iodide (0.926 g, 2.90 mmol) was added and the mixture was stirred at ambient temperature for 3 h. Reaction mixture was diluted with DCM (200 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), organic layer was filtered through celite and concentrated. The residue was purified by flash chromatography on 100 g Biotage SNAP cartridge using 0-40% EtO Ac in heptane to afford
2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (3.01 g, 38%)
Step 2: 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde.
To a solution of 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (1.372 g, 5.00 mmol) in DCM (23.16 ml), diisobutylaluminum hydride 1.0 M solution in hexane (7.50 ml, 7.50 mmol) was added at -78 °C dropwise over 20 min. Reaction was carefully quenched first with MeOH (1 ml, 24.97 mmol) and then with Rochelle salt 1.5 M (5.00 ml. 7.50 mmol). The flask was removed from the bath and allowed to reach ambient temperature and extracted with EtO Ac (20 ml). The organic layer was separated and washed with brine, filtered through celite pad and concentrated to obtain
2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (1.34 g, 97%) as a white solid. Step 3:
2-(2,6-dichlorophenyl)-N-((l-(trifluoromethyl)cyclopropyl)methyl)-2-((trimethylsilyl)oxy) ethanamine.
To a solution of crude 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (0.35 g, 1.263 mmol) in DCM (6.31 ml) was added
(l-(trifluoromethyl)cyclopropyl)methanamine (0.176 g, 1.263 mmol) and NaBH(OAc)3 (0.374 ml, 2.53 mmol) and stirred for 2 h at ambient temperature. The reaction was quenched with aqueous sat NH4C1 solution and diluted with DCM (50 mL). Organic layer was passed through phase seperator and concentrated to obtain
2-(2,6-dichlorophenyl)-N-((l-(trifluoromethyl)cyclopropyl)methyl)-2-((trimethylsilyl)oxy) ethanamine (0.378 g, 70%) as light yellow oil. This was used in next step without further purification.
[Reference example A260]
2- 2,6-dichlorophenyl)-N-((l-methylcyclobutyl)methyl)-2-((triethylsilyl)oxy)ethanamine
Figure imgf000117_0001
To a mixture of 1 -methylcyclobutanecarbaldehyde (38.3 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHC03. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated and then purified by prep TLC eluted with 5% MeOH/DCM to provide
2-(2,6-dichlorophenyl)-N-((l-methylcyclobutyl)methyl)-2-((triethylsilyl)oxy)ethanamine (89 mg, 0.221 mmol, 56.7% yield). 1H NMR (500 MHz, CDC13) δ 7.18-7.22 (m, 2H), 6.98-7.10 (m, 1H), 5.57 (br. s., 1H), 3.30 (t, J=10.70 Hz, 1H), 2.74 (br. s., 1H), 2.60 (br. s., 1H), 2.51 (d, J=10.03 Hz, 1H), 1.68-1.89 (m, 4H), 1.60 (br. s., 2H), 1.47 (br. s., 1H), 1.03-1.14 (m, 3H), 0.76-0.84 (m, 9H), 0.41-0.54 (m, 6H); LCMS (ESI) m/z 402.4 (M+H)+.
[Reference example A262]
2-(2,6-dichlorophenyl)-N-((5-fluorospiro[2.3]hexan-5-yl)methyl)-2-((triethylsilyl)oxy)etha namine F
Figure imgf000118_0001
Spiro[2.3]hexane-5-carbaldehyde (300 mg, 2.72 mmol) and
N-ethyl-N-isopropylpropan-2-amine (546 μΐ, 3.13 mmol) were combined in MeCN (5 mL) and trimethylsilyl trifluoromethanesulfonate (517 μΐ, 2.86 mmol) was added dropwise. The solution was stirred for 30 min and selectfluor (1061 mg, 3.00 mmol) in MeCN (5 mL) was added. The solution was stirred and sonicated for an additional 30 min.
2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (785 mg, 2.451 mmol) and AcOH (187 μΐ, 3.27 mmol) were added. The solution was stirred for 30 min and NaBH(OAc)3 (1154 mg, 5.45 mmol) was added and the solution was stirred for an additional 2 h. The solution was quenched with saturated NaHC03, the aqueous layer was extracted with ethyl aceate and the combined organic layers were washed with brine and dried over anhydrous Na2S04, filtered and concentrated. The product was purified via silica gel column chromatography (40 g column) using 0-100% EtOAc in heptane to afford
2-(2,6-dichlorophenyl)-N-((5-fluorospiro[2.3]hexan-5-yl)methyl)-2-((triethylsilyl)oxy)etha namine (300 mg, 0.694 mmol, 25.5%yield). MS m/z = 432 [M+H]+.
[Reference example A267]
2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine
Figure imgf000119_0001
To a solution of 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 μΐ) was added spiro[2.5]octane-6-carbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 μΐ, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for overnight. The mixture was quenched with 0.5 M NaOH and mixture was stirred at rt for 30 min. Evolution of gas was observed. The layers were separated. The organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtO Ac in hexane to give
2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine. [Reference example A275] ;
N-(2-(3 -chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan- 1 -amine
Figure imgf000119_0002
Step 1 : 3-chloroquinolin-4(lH)-one (A275-1)
A mixture of 4-hydroxyquinoline (5.33 g, 36.7 mmol) in AcOH (184 mL) was treated with N-chlorosuccinimide (6.37 g, 47.7 mmol) and the yellow homogeneous mixture was stirred and heated at 60 °C. After 3 h, the mixture was cooled to room temperature and concentrated in vacuo. Saturated aqueous NaHC03 solution (300 mL) was added until pH became -8:5. The resulting solid was collected by filtration, washed with water (300 mL), and dried under high vacuum to give 3-chloroquinolin-4(lH)-one
(A275-1) as a yellow solid. 1H NM'R (400 MHz, DMSO-d6) δ 12.28 (IH, br. s.), 8.40 (IH, d, J=6.5 Hz), 8.15 (IH, dd, J=8.2, 1.4 Hz), 7.65-7.73 (IH, m), 7.58-7.63 (IH, m), 7.39 (IH, ddd, J=8.1, 6.9, 1.2 Hz); LCMS (ESI) m/z 180.1 (M+H)+.
Step 2: 4-bromo-3-chloroquinoline (A275-2)
To a cooled suspension of 3-chloroquinolin-4(lH)-one (A275-1) (5.15 g, 28.7 mmol) in DMF (43.4 mL) at 0 °C was added phosphorous tribromide (2.77 mL, 29.5 mmol) dropwise over 3 min and then the mixture became orange homogenous mixture. After 4 min, yellow precipitates were formed and the yellow heterogeneous mixture was further stirred at 0 °C for 15 min. After 15 min, the cooling bath was removed and the yellow heterogeneous mixture was stirred at room temperature. After 15 h, the mixture was poured into ice water (300 mL) and stirred at 0 °C for 20 min. The mixture was then neutralized by the addition of 2 M NaOH solution (50 mL) until pH was >9 (pH paper). The resulting precipitate was collected by filtration, washed the solid with water (400 mL), and dried under high vacuum to give 4-bromo-3-chloroquinoline (A275-2) as off-white solid. Ή NMR (400 MHz, DMSO-d6) δ 8.96 (IH, s), 8.20 (IH, dd, J=8.2, 1.6 Hz), 8.12 (IH, dd, J=8.3, 0.9 Hz), 7.81-7.93 (2H, m); LCMS (ESI) m/z 242.0 [M+H (79Br)]+ and 243.9
[M+H (81Br)]+.
Step 3: 3-chloroquinoline-4-carbaldehyde (A275-3)
A flask was charged with 4-bromo-3-chloroquinoline (A275-2) (1.00 g, 4.12 mmol) and THF (16.5 mL) under nitrogen, and the solution was cooled to -78 °C. To the cooled mixture was added n-butyllithium (2.5 M solution in hexane, 1.65 mL, 4.12 mmol) and the mixture was stirred at -78 °C for 1 hour. To the mixture was added DMF (1.60 mL, 20.6 mmol) dropwise, and the mixture was allowed to warm to room temperature. After 4 h, the mixture was quenched with saturated aqueous NH4C1 (20 mL). The mixture was was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (1 x 50 mL). The organic extract was dried over MgS04. The solution was filtered and concentrated in vacuo to give the crude material as a brown syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give 3-chloroquinoline-4-carbaldehyde (A275-3) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (IH, s), 9.10 (IH, s), 8.68-8.73 (IH, m), 8.15 (IH, dd, J=8.5, 0.9 Hz), 7.79-7.92 (2H, m); LCMS (ESI) m/z 192.1 (M H I)' .
Steps 4 : 1 -(3 -chloroquinolin-4-yl)-2-nitroethanol (A275 -4)
To a brown clear solution of 3-chloroquinoline-4-carbaldehyde (A275-3) (0.362 g, 1.89 mmol) in THF (1.9 mL) at room temperature was added potassium carbonate (0.078 g, 0.566 mmol) and nitromethane (1.420 mL, 26.4 mmol). The brown homogeneous mixture was stirred at room temperature. After 4 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extract was washed with saturated NaCl (1 x 50 mL), and dried over Na2S04. The solution was filtered, concentrated in vacuo, and dried under high vacuum to give
l-(3-chloroquinolin-4-yl)-2-nitroethanol (A275-4) as a brown solid. Ή NMR (400 MHz, DMSO-d6) δ 8.88-8.93 (IH, m), 8.73 (IH, dd, J=8.6, 0.8 Hz), 8.08 (IH, dd, J=8.4, 1.0 Hz), 7.82 (IH, ddd, J=8.4, 6.9, 1.5 Hz), 7.72 (IH, ddd, J=8.5, 6.9, 1.4 Hz), 6.91 (IH, dd, J=4.5, 1.0 Hz), 6.26 (IH, ddd, J=10.0, 4.6, 3.6 Hz), 5.03-5.12 (IH, m), 4.94-5.01 (IH, m);
LC-MS (ESI) m/z 253.1 (M+H)+.
Step 5: 3-chloro-4-(2-nitro-l-((triethylsilyl)Oxy)ethyl)quinoline (A275-5) To a brown clear solution of l-(3-chloroquinolin-4-yl)-2-nitroethanol (A275-4) (0.423 g, 1.68 mmol) in DMF (4.19 mL) at room temperature was added imidazole (0.342 g, 5.03 mmol) and triethylsilyl chloride (0.341 mL, 2.01 mmol). The mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extract was washed with 1 M LiCl (1 x 50 mL) and brine (1 x 50 mL), and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, and dried under high vacuum to give 3-chloro-4-(2-nitro-l-((triethylsilyl)oxy)ethyl)quinoline (A275-5). Ή NMR (400 MHz, DMSO-d6) δ 8.95 (1H, s), 8.67 (1H, d, J=7.4 Hz), 8.10 (1H, dd, J=8.4, 0.8 Hz), 7.84 (1H, td> J=7.6, 1.4 Hz), 7.71-7.79 (1H, m), 6.38 (1H, dd, J=9.8, 2.5 Hz), 5.14-5.23 (1H, m), 5.03-5.11 (1H, m), 0.65-0.74 (9H, m), 0.32-0.51 (6H, m); LCMS (ESI) m/z 367.1 (M+H)+.
Step 6: 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6)
To a clear yellow solution of 3-chloro-4-(2-nitro- 1 -((triethylsilyl)oxy)ethyl)quinoline (0.511 g, 1.39 mmol) in EtOH (7.96 mL) and water (1.99 mL) at room temperature was added iron powder (0.778 g, 13.9 mmol) and ammonium chloride (0.745 g, 13.9 mmol). The dark brown mixture was stirred and heated at 60 °C. After 4 h, the mixture was cooled to room temperature and filtered through a celite pad and washed the pad with MeOH (3 χ 30 mL). The combined filtrates were concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The mixture (pH -4.0) was washed with saturated aqueous NaHC03 (1 x 50 mL), water (1 x 50 mL), and brine (1 x 50 mL), dried over anhydrous Na2S04, concentrated in vacuo, and dried under high vacuum to give 2-(3-chloroquiriolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) as a yellow syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (IH, s), 8.72 (IH, d, J=8.2 Hz), 8.04 (IH, dd, J=8.4, 1.0 Hz), 7.76 (IH, ddd, J=8.4, 6.9, 1.4 Hz), 7.64 (IH, ddd, J=8.5, 7.0, 1.3 Hz), 5.52 (IH, dd, J=7.6, 5.5 Hz), 3.16 (IH, dd, J=13.0, 7.9 Hz), 2.88 (IH, dd, J=13.0, 5.4 Hz), 1.74 (IH, br. s.), 0.71-0.80 (1 H, m), 0.71-0.80 (9H, m), 0.37-0.57 (6H, m); LCMS (ESI) m/z 337.1 (M+H)+.
Step 7:
N-(2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-l -amine (A275)
To a yellow clear solution of
2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) (0.217 g, 0.644 mmol) in DCM (2.15 mL) was added trimethylacetaldehyde (0.077 mL, 0.71 mmol), AcOH (0.045 mL, 0.77 mmol), and NaBH(OAc)3 (0.205 g, 0.966 mmol). The yellow
homogeneous mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (20 mL) and neutralized with 0.5 M NaOH (10 mL) to pH -9.0. The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was washed with saturated NaCl (1 x 50 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give
N-(2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-l -amine (A275) as colorless syrup. Ή NMR (400 MHz, DMSO-d6) δ 8.84 (IH, s), 8.75 (IH, d, J=7.2 Hz), 8.04 (IH, dd, J=8.4, 1.0 Hz), 7.77 (IH, ddd, J=8.4, 6.9, 1.4 Hz), 7.61-7.68 (IH, m), 5.70 (IH, dd, J=7.7, 5.0 Hz), 3.26 (IH, dd, J=12.6, 8.1 Hz), 2.85 (IH, dd, J=12.6, 5.0 Hz), 2.23-2.39 (2H, m), 1.72 (IH, br. s.), 0.81 (9H, s), 0.72-0.79 (9H, m), 0.36-0.56 (6H, m); LCMS (ESI) m/z 407.1 (M+H)
[Reference example A281]
2-(3,5-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2-yl)methyl)-2-((triethylsilyl)ox
Figure imgf000124_0001
To a clear solution of 5-methyltetrahydrofuran-2-methanol in DCM was added
Dess-Martin periodinane (1.2 eq.). The mixture was stirred at room temperature overnight. The crude mixture was directly added to a solution of
2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (1 eq.) in DCM followed by AcOH (1.2 eq.) and NaBH(OAc)3 (1.5 eq.). The reaction mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous Na2S203 and saturated NaHC03. The reaction mixture was extracted with DCM. The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide
2-(3,5-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2-yl)methyl)-2-((triethylsilyl)ox y)ethanamine (A281) as a light-yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (2H, s), 5.34-5.46 (1H, m), 3.71-3.90 (2H, m), 3.10 (1H, dt, J=12.5, 8.1 Hz), 2.90 (1H, td, J=12.1 , 6.0 Hz), 2.52-2.67 (2H, m), 1.71-2.07 (3H, m), 1.47-1.64 (1H, m), 1.19-1.38 (1H, m), 1.1 1 (3H, t, J=6.3 Hz), 0.77-0.89 (9H, m), 0.40-0.62 (6H, m); LCMS (ESI) m/z 419.1 (M+H)+. [Reference example A294]
N-(2-(3,5-dichloropyridin-4-yl)-2-((trie^
Figure imgf000125_0001
Step 1 : 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (A294-1)
To a clear solution of 3,3,3 -trifluoro-2,2-dimethylpropionic acid (5.000 g, 32.0 mmol) in MeCN (22.88 ml) was added triethylamine (9.82 ml, 70.5 mmol) followed by HATU (12.79 g, 33.6 mmol) and the mixture was stirred at room temperature. After 15 min, to the dark clear mixture was added Ν,Ο-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) and the mixture was stirred at room temperature. After 18 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N HC1 (2 x 100 mL), and sat. NaCl - (5 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a orange solid. The orange solid was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (5.0503 g, 25.4 mmol, 79% yield) as yellow liquid. Ή NMR (300 MHz, CDC13) δ 3.71 (3H, s), 3.22 (3H, s), 1.51 (6H, d, J=0.7 Hz); LCMS (ESI) m/z 200.1 (M+H)+.
Step 2: 3,3,3-trifluoro-2,2-dimethylpropanal
To a 250-mL of three neck round-bottomed flask equipped with goose neck for nitrogen and for thermocouple was added lithium aluminium hydride, 1 M solution in Et20 (25.3 ml, 25.3 mmol) at 0 °C. To the cooled mixture was added a solution of
3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (A294-1) (5.0325 g, 25.3 mmol) in Et20 (47.7 ml) dropwise over 35 min at 0 °C. After the completion of the addition, the reaction mixture was further stirred at 0 °C. After 2 h, the mixture was carefully quenched at 0 °C with water (0.96 mL), NaOH (15%, 0.96 mL) and water (2.88 mL) and the mixture was vigourouly stirred for 40 min. The reaction mixture was diluted with Et20 (50 mL), treated with Na2S04 and then filtered through a Celite pad, washed with Et20 (100 mL). The filtrate was concentrated in vacuo to provide 3,3,3-trifluoro-2,2-dimethylpropanal (A294-2) (3.2304 g, 23.06 mmol, 91 % yield) as yellow liquid. 1H NMR (400 MHz, CDC13) 6 9.69 (1H, d, J=l .4 Hz), 1.31 (6H, s).
Step 3:
N-(2-(3,5-dichIoropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dimethylpro pan- 1 -amine (A294)
To a yellow clear mixture of
2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (3.57 g, 11.11 mmol) in DCM (37.0 mL) was added 3,3,3-trifluoro-2,2-dimethylpropanal (11.11 mmol) in DCM followed by AcOH (0.770 ml, 13.33 mmol) and NaBH(OAc)3 (3.53 g, 16.67 mmol). The yellow heterogeneous mixture was stirred at room temperature. After 8 h, the mixture was quenched with saturated NaHC03 (100 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as orange syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to provide
N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dimethylpro pan-l-amine (A294) (3.4393 g, 7.72 mmol, 69.5% yield) as colorless oil. 1H NMR (400 MHz, CDC13) δ 8.44 (2H, s), 5.48 (1H, dd, J=7.7, 4.4 Hz), 3.27 (lH, dd, J=12.3, 8.4 Hz), 2.58-2.83 (3H, m), 1.25-1.44 (1H, m), 1.10 (6H, s), 0.85-0.94 (9H, m), 0.47-0.64 (6H, m) ; LCMS (ESI) m/z 445.1 (M+H)+.
The following secondary amines were prepared using similar procedure in reference examples described above:
Figure imgf000128_0001

Figure imgf000129_0001
Figure imgf000130_0001
A62 A63 A64
Figure imgf000131_0001
130
Figure imgf000132_0001
Figure imgf000133_0001
A133 A134 A135
Figure imgf000134_0001
A152 A153 A154
Figure imgf000135_0001
A170 A171 A172
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001

Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Step 1 : 2-(3,5-dichloropyridin-4-yl)ethanol (B 1 - 1 )
To a solution of 3,5-dichloropyridine (4.0 g, 27.0 mmol) in THF (70 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene, 22.0 mL, 39.6 mmol) at -78 °C and the mixture was stirred at the same temperature for 2 h, and then ethylene oxide (1.2 M in THF, 25 ml, 30.0 mmol) was added. The reaction mixture was allowed to warm to room temperature gradually and stirred for 1 h at room temperature. The reaction mixture was quenched by adding saturated aqueous NH4C1 solution and extracted with EtOAc. The organic layer was washed with brine (2 times) and dried over MgS04. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound B 1-1 (3.1 g, 60%) as a yellow solid.
Step 2: 4-(2-azidoethyl)-3,5-dichloropyridine (Bl-2)
To a solution of compound Bl-1 (3.1 g, 16.2 mmol) in THF (60 mL) were added DIAD (6.3 mL, 32.0 mmol), triphenylphosphine (8.52 g, 32.5 mmol) and DPPA (6.98 mL, 32.5 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature gradually and stirred at room temperature for 4.5 h. The reaction mixture was quenched by adding water and extracted with EtOAc. The organic layer was washed with brine (x 2) and dried over MgS04. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound Bl-2 (2.4 g, 68%) as a yellow oil. Step 3: 2-(3,5-dichloropyridin-4-yl)ethanamine (Bl-3)
To a solution of compound Bl-2 (2.4 g, 11.1 mmol) in THF (25 mL) was added triphenylphosphine (2.9 g, 22.1 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, and then water (2.5 mL) was added. The reaction mixture was allowed to warm to room temperature gradually and stirred at room temperature for 22 h. The reaction mixture was quenched by adding 2.M aqueous HC1 (10 mL) and diluted with EtOAc. The aqueous layer was washed with EtOAc x 3, and then basified with 2 M aqueous NaOH to pH 12. The aqueous layer was extracted with EtOAc, washed with brine (x 2) and dried over MgS04. Drying the solution under high vacuum yielded compound Bl-3 (1.9 g, 90%) as a white solid.
Step 4: 2-(3,5-dichloropyridin-4-yl)-N-(4-fluorobenzyl)ethanamine (Bl)
To a solution of compound Bl-3 (2.9 g, 15.2 mmol) in MeOH (30 mL) was added 4-fluorobenzaldehyde (1.89 g, 15.2 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and NaBH4 (1.16 g, 30.4 mmol) was added gradually. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgS04. After the solvent was removed, the residue was purified by column
chromatography on silica gel to give compound Bl (3.4 g, 75%) as a pale yellow solid.
[Reference example B2]
Figure imgf000148_0001
Step l : l,3-dichloro-5-fluoro-2-(2-nitrovinyl)benzene (B2-1)
To a stirred solution of compound A31-1 (1.3 g, 5.1 mmol) in dioxane (10 mL) was added 6 M HC1 (20 mL) at room temperature and the mixture was stirred at reflux for overnight. The reaction mixture was neutralized with 10% NaOH solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound B2-1 (0.22 g, 18%) as a colorless oil.
Step 2: 2-(2,6-dichloro-4-fluorophenyl)ethanamine (B2-2)
To a stirred solution of LiBH4 (3.0 M, 4.2 mL, 12.5 mmol) in THF (5 mL) was added TMS-Cl (3.2 mL, 25.2 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 30 min. N2 gas was bubbled through the reaction mixture for 5 min to remove remaining trimethylsilane that had formed. A solution of compound B2-1 (0.22 g, 3.1 mmol) in THF (2 mL) was added dropwise to the mixture at room temperature and later refluxed for 1 h. The reaction mixture was cooled to 0 °C and quenched with MeOH (10 mL) carefully. Solvent was evaporated under reduced pressure and the residue was partitioned between 20% KOH (10 mL) and DCM (20 mL). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to give compound B2-2 (0.21 g, 99%) as a colorless oil.
Step 3: 2-(2,6-dichloro-4-fluorophenyl)-N-(3,5-difluorobenzyl)ethanamine (B2)
Compound B2 (0.21 g, 69%) was obtained as a colorless gum from the reaction of compound B2-2 (0.19 g, 0.91 mmol), 3,5-difluorobenzaldehyde (0.1 mL, 0.91 mmol) and NaBH4 (70 mg, 1.8 mmol) in MeOH (5 mL) using a similar procedure to that described in reference example Bl, step 4. Ή NMR (CDC13, 300 MHz): δ 7.13-7.05 (m, 2H), 6.87- 6.59 (m, 3H), 3.83 (s, 2H), 3.12-2.80 (m, 4H).
[Reference example B3]
Figure imgf000150_0001
B1-1 B3-1 B3
Step 1 : 2-(3,5-dichloropyridin-4-yl)acetaldehyde (B3-1)
Compound Bl-1 (1.0 g, 5.21 mmol) was dissolved in DCM (26.0 ml) and
Dess-Martin periodinane (2.43 g, 5.73 mmol) was added. The solution was stirred for 1 h. The reaction mixture was quenched with 50 ml of 5% Na2S203, the organic layer was washed with saturated NaHC03 dried with anhydrous Na2S04 and concentrated. The product was purified by silica gel column chromatography (40 g column) using 0-100 % EtOAc in heptane to afford compound B3-1 (750 mg, 3.95 mmol, 76 % yield). LC/MS (ESI+) m/z = 189.9 (M+H)+.
Step 2: N-(2-(3,5-dichloropyridin-4-yl)ethyl)-2,2-dimethylpropan-l -amine (B3)
Compound B3-1 (0.65 g, 3.42 mmol) was dissolved in DCM (17 ml) under inert atmosphere, then 2,2-dimethylpropan-l -amine (0.605 ml, 5.13 mmol) was added followed by glacial AcOH (0.198 ml, 3.42 mmol). The solution was stirred for 15 min and then NaBH(OAc)3 (1.450 g, 6.84 mmol) was added. The solution was quenched with 15 ml of saturated NaHC03 and stirred for 45 min. The organic layer was separated and concentrated. The product was purified via silica gel column chromatography (40 g column) using 0-100 % EtOAc in heptane to afford compound B3 (775 mg, 2.97 mmol, 87% yield). LC/MS (ESI+) m/z = 261.0 (M+H)+.
[Reference example B13]
Figure imgf000151_0001
Step 1 : l-(3,5-dichloropyridin-4-yl)-2-((3,5-difluorobenzyl)amino)ethanol (B13-1)
To a stirred solution of
2-(3,5-dichloropyridin-4-yl)-N-(3,5-difluorobenzyl)-2-((triethylsilyl)oxy)ethanamine (0.2 g, 0.44 mmol) in THF (5 mL) was added TBAF (1.0 M in THF, 0.9 mL, 0.88 mmol) dropwise at 0 °C, and the mixture was allowed to warm up from 0 °C to room temperature while stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc (2x20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2S04. Solvent was evaporated under reduced pressure to provide compound B13-1 (0.2 g, crude) as brown color gum. Step 2: tert-butyl
(2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamate (B13-2)
To a stirred solution of compound B13-1 (0.2 g, 0.6 mmol) in DCM/water (4:1, 5 mL) were added NaHC03 (0.1 g, 1.2 mmol) and (Boc) 20 (0.19 g, 0.9 mmol) in DCM (2 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound B13-2 (0.17 g, 65%) as a colorless oil. Step 3 : tert-butyl
(2-(3,5-dichloropyridin-4-yl)-2-methoxyethyl)(3,5-difluorobenzyl)carbamate (B 13-3) To a stirred solution of compound B13-2 (0.1 g, 0.2 mmol) in THF (5 mL) was added NaH (14 mg, 0.5 mmol) followed by dropwise addition of Mel (44 xL, 0.7 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound B13-3 (0.11 g, 99%) as a colorless oil.
Step 4: tert-butyl
2-(3,5-dichloropyridin-4-yl)-N-(3,5-difluorobenzyl)-2-methoxyethanamine (B 13)
To a stirred solution of compound B13-3 (0.28 g, 0.6 mmol) in dioxane (5 mL) was added 4 M HCl (in dioxane, 1.9 mL, 7.4 mmol) at room temperature and the mixture was stirred for overnight. Solvent was evaporated under reduced pressure to provide compound B13-3 (0.1 g, 48%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 8.45 (s, 2H), 6.90-6.63 (m, 3H), 5.14 (dd, J = 8.9, 4.1 Hz, 1H), 3.89-3.77 (m, 2H), 3.30-3.23 (m, 4H), 2.78 (dd, J = 12.6, 4.1 Hz, 1H).
[Reference example B 15]
Figure imgf000152_0001
Step 1 : 3,5-dichloro-4-iodopyridine (B15-1)
To a stirred solution of 3,5-dichloropyridine (3.0 g, 20.4 mmol) in THF (15 mL) was added LD A (2.0 M solution in THF/heptane/ethylbenzene, 12.14 mL, 24.4 mmol) dropwise at 0 °C and the mixture was stirred at the same temperature for 1 h. A solution of iodine (2.7 g, 21.4 mmol) in THF (10 mL) added dropwise to above mixture. Upon completion of addition, the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound B15-1 (3.2 g, 57%) as a yellow gum.
Step 2: ethyl-2-(3,5-dichloropyridin-4-yl)-2,2-difluoroacetate (B15-2)
The mixture of compound B15-1 (530 mg, 0.83 mmol), ethyl
2-bromo-2,2-difluoroacetate (0.12 ml, 1.38 mmol) and Cu (800 mg, 12.5 mmol) in DMSO (10 mL) was heated to 55 °C for 16 h. The reaction mixture was cooled to room temperature and quenched with saturated NH4C1 solution (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound B 15-2 (315 mg, 60%) as yellowish brown gum.
Step 3: 2-(3,5-dichloropyridin-4-yl)-2,2-difluoroethanol (B15-3)
To a stirred solution of compound B 15-2 (315 mg, 1.16 mmol) in EtOH (10 mL) was added solid NaBH4 (16.2 mg, 1.74 mmol) in portions at 0 °C. The mixture was warmed to room temperature and stirred at the same temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 55% EtOAc/hexane as eluent) to provide compound B 15-3 (180 mg, 44%) as a colorless gum.
Step 4: 4-(2-azido-l,l-difluoroethyl)-3,5-dichloropyridine (B15-4)
To a stirred solution of compound B15-3 (140 mg, 0.72 mmol) in THF (5 mL) were added DIAD (0.31 mL, 1.60 mmol), DPPA (0.34 mL, 1.60 mmol) and PPh3 (420 mg, 1.60 mmol) at 0 °C. The mixture was warmed to room temperature and stirred at the same temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc hexane as eluent) to provide compound B15-4 (80 mg, 55%) as a yellow gum.
Step 5: 2-(3,5-dichloropyridin-4-yl)-2,2-difluoroethanamine (B15-5)
To a stirred solution of compound B 15-4 (80 mg, 0.31 mmol) in EtOAc (2 mL) were added (CH3)3P (0.47 mL, 0.47 mmol) and H20 (0.5 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure to provide compound B15-5 (60 mg) as a yellow gum. The crude residue was used for next step without purification.
Step 6: 2-(3,5-dichloropyridin-4-yl)-N-(3,5-difluorobenzyl)-2,2-difluoroethanamine (B15) A mixture of compound B15-5 (113 mg, 0.49 mmol), 3,5-difluorobenzaldehyde (70 mg, 0.49 mmol) and NaBH(OAc)3 (316 mg, 1.49 mmol) in DCM was stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20%
EtOAc/hexane as eluent) to provide compound B15 (66 mg, 38%) as a white solid. Ή NMR (CDC13, 300 MHz): δ 8.54-8.53 (m, 2H), 6.73-6.66 (m, 3H), 3.86 (s, 2H), 3.36-3.45 (t, J = 28.7 Hz, 2H); LCMS (APCI): 353 (M+H)+.
Figure imgf000155_0001
acetate (404 mg, 5.25 mmol) in nitromethane (6 mL) was stirred at 100 °C for 20 min. The reaction mixture was cooled, diluted with water and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over MgS04 and concentrated under reduced pressure. The crude material was purified by silicagel column
chromatography (50-100% EtO Ac/heptane) to give compound B19-1 (224 mg, 58%) as an orange solid.
Step 2: 2-(4-chloro-lH-indol-3-yl)ethanamine (B19-2)
A solution of compound B19-1 (1.46 g, 6.56 mmol) in THF (25 mL) was added to a stirred slurry of lithium aluminum hydride (995 mg, 26.2 mmol) in THF (50 mL) at room temperature. The mixture was refluxed for 2 h and allowed to cool to room temperature. The reaction was quenched by dropwise addition of water (1.3 mL), followed by 15% NaOH aq. (1.3 mL), followed again by water (3.25 mL). After stirring vigorously for 14 h the mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved with EtOAc and then extracted with 2 N HCl aq. (2 x 20 mL). The combined aqueous layers were basified by adding 5 N NaOH aq. and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give compound B19-2 (1.02 g, 80%) as a dark red syrup.
Step 3:
(lR,3r,5S)-N-(2-(4-chloro-lH-indoW
(B19)
Compound B19 (22 mg^ 14%) was obtained from the reaction of compound B19-2 (100 mg, 0.514 mmol), compound C22-5 (128 mg, 1.03 mmol), NaBH(OAc) (326 mg, 1.54 mmol) and AcOH (0.108 mL, 2.05 mmol) in DCM (2 mL) using a similar procedure to that described in reference example A31, step4. 1H NMR (CDC13, 400 MHz) δ: 8.09 (l l l. br s). 7.26-7.22 (lH, m), 7.07-7.05 (3H, m), 3.57-3.47 (lH, m), 3.13 (2H, t, J = 7.3 Hz), 2.89 (2H, t, J= 7.3 Hz), 2.17-2.10 (2H, m), 1.03-0.93 (10H, m).
mL,
Figure imgf000156_0001
139 mmo ) was a e to a stirre m xture o R)-(- -5-( ydroxymet yl)-2-pyrro none (5.353 g, 46.5 mmol) and p-toluenesulfonic acid monohydrate (0.126 g, 0.662 mmol) in toluene (100 mL). The reaction mixture was refluxed for 1.5 h and allowed to stir at room temperature overnight. Solvent was evaporated to afford
(i?)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (7.22 g, 100% yield) as a light yellow solid. Ή NMR (400 MHz, DMSO-d6) δ 4.18 (tt, J=8.8, 6.2 Hz, IH), 4.00 (dd, J=8,l, 5.8 Hz, IH), 3.40 (t, J=8.6 Hz, IH), 2.69 (ddd, J=16.4, 12.1, 8.6 Hz, IH), 2.33 (dd, J=16.3, 9.1 Hz, IH), 2.02-2.11 (m, IH), 1.73 (tt, J=12.1, 8.9 Hz, IH), 1.53 (s, 3H), 1.33 (s, 3H). m/z (ESL +ve) 156 (M+H).
Step 2:
(7ai?)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3/ )-one
To a solution of (7?)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (6.68 g, 43.0 mmol) in THF (100 mL) cooled to -78 °C, was added lithium diisopropylamide, 2.0 M solution in THF/heptane/ethylbenzene (43.0 mL, 86 mmol) and stirred at -78 °C for 1 h. The resulting mixture was treated with acetone,99.8%, extra dry, acroseal (6.32 mL, 86 mmol) at -78 °C and then allowed to warm up to room temperature for 16 h. The reaction was quenched with sat. NH4CI and extracted with EtOAc (2 x 200 mL). The combined extracts were washed with brine, dried over Na2S04, filtered and concentrated to provide
(7ai?)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one
(6.088 g, 28.5 mmol, 66.3% yield) as a yellow oil. Ή NMR (400 MHz, DMSO-d6) δ 4.50
(s, IH), 4.07 - 4.18 (m, IH), 3.98 (dd, J=8.0, 5.7 Hz, IH), 3.32 - 3.35 (m, IH), 2.50 - 2.56
(m, IH), 2.22 (ddd, J=13.4, 7.2, 2.0 Hz, IH), 1.83 (ddd, J=13.3, 10.4, 7.6 Hz, IH), 1.54 (s,
3H), 1.32 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H). m/z (ESI, +ve) 214 (M+H).
Step 3 : (i?)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[l ,2-c]oxazol-5(3H)-one
To a solution of (7ai?)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo -[l,2-c]oxazol-5(3H)-one (5.06 g, 23.73 mmol) in DCM (50 mL) at room temperature was added methanesulfonyl chloride (2.75 mL, 35.6 mmol) followed by triethylamine (16.50 mL, 119 mmol) and then heated at 55 °C for 1 h. The resulting mixture was treated with additional methanesulfonyl chloride (2.75 mL, 35.6 mmol) and heated for another 1 h. The reaction mixture was allowed to cool to room temperature, quenched with water (50 mL) and extracted with DCM (2 x 100 mL). The combined extracts were washed with brine, dried over MgS04, filtered and concentrated to provide crude
(i?)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[l,2-c]oxazol-5(3H)-one as a brown oil, which was used in the next step without purification, m/z (ESI, +ve) 196 (M+H).
Step 4: (/?)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one
To a solution of
(i?)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[l ,2-c]oxazol-5(3H)-one (4.63 g, 23.73 mmol) in MeOH (50 mL) at room temperature was added /7-toluenesulfonic acid monohydrate (0.451 g, 2.373 mmol) and then heated at 60 °C for 45 min. The solvent was evaporated and the crude material was absorbed onto a plug of silica gel and was purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 10% MeOH in DCM to give
(i?)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol, 60.4% yield) as an yellow solid. Ή NMR (400 MHz, CDC13) δ 6.60 (br. s., IH), 3.74 (td, J=8.0, 3.9 Hz, 1H), 3.67 (dd, J=l l .l, 3.6 Hz, IH), 3.44 (dd, J= 11.1, 7.3 Hz, IH), 2.75-2.86 (m, IH), 2.81 (dd, J=16.5, 8.7 Hz, IH), 2.33-2.43 (m, IH), 2.23 (s, 3H), 1.77 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Step 5: (5i?)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one
A mixture of (i?)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol) and platinum (iv) oxide (0.325 g, 1.432 mmol) in EtOAc (40 mL)/MeOH (4 mL) at room temperature was stirred in the pressure bottle reactor under H2 (28 psi to 2 psi) overnight. The resulting mixture was filtered through a pad of Celite, washed with EtOAc, and concentrated to give (5/?)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one (2.251 g, 14.32 mmol, 90% yield) as a light yellow solid. Ή NMR (400 MHz, CDC13) δ 6.56-6.71 (m, 1H), 3.64-3.80 (m, 2H), 3.37-3.53 (m, lH), 2.48 (td, J=9.9, 4.5 Hz, 2H), 2.14-2.27 (m, 1H), 1.97-2.13 (m, 1H), 1.50 (ddd, J=l 2.7, 10.7, 8.3 Hz, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H). m/z (ESI, +ve) 158 (M+H).
Step 6: ((2i?)-4-isopropylpyrrolidin-2-yl)methanol
To a solution of (5i?)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one (2.251 g, 14.32 mmol) in THF (25 mL) was added lithium aluminium hydride, 1.0 M solution in THF (20.05 mL, 20.05 mmol) at room temperature dropwise slowly. The resulting mixture was then refluxed at 75 °C for 2 h. Additional lithium aluminium hydride, 1.0 M solution in THF (20.05 mL, 20.05 mmol) was added and the mixture was refluxed overnight. After 18 h, the reactiom mixture was allowed to cool to 0 °C. The reaction was quenched by adding saturated aqueous solution of Rochelle's salt. The reaction mixture was stirred vigorously for 1 h and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were combined, washed with brine, dried over MgS04, filtered and concentrated in vacuo to provide ((2i?)-4-isopropylpyrrolidin-2-yl)methanol (1.645 g, 11.49 mmol, 80%> yield) as a ligh yellow oil. The crude material was used in the next step without further purification, m/z (ESI, +ve) 144 (M+H).
Step 7:(3aif)-5-isopropyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide
A solution of ((2i?)-4-isopropylpyrrolidin-2-yl)methanol (1.639 g, 11.44 mmol) and triethylamine (3.18 mL, 22.89 mmol) in DCM (100 mL) was cooled to -78 °C. To this mixture was added sulfuryl chloride, 1.0 M solution in DCM (13.73 mL, 13.73 mmol) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated onto a plug of silica gel and purified by ISCO, chromatograph through a REDISEP™ pre-packed scilica gel column (40 g), eluting with a gradient of 0% to 10% MeOH (with 2 M NH3) in DCM to give
(3ai?)-5-isopropyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide (211.9 mg, 1.032 mmol, 9 %yield) as light yellow oil. m/z (ESI, +ve) 206 (M+H).
Step 8: 3,5-dichloro-4-(((2i?)-4-isopropylpyrrolidin-2-yl)methyl)pyridine
To a solution of 3,5-dichloropyridine (228 mg, 1.542 mmol) in THF (2.6 mL) at -78 °C was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (0.976 mL, 1.953 mmol) dropwise. After stirring for 45 min, a solution of
(3ai?)-5-isopropyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide (211 mg, 1.028 mmol) in THF (3.0 mL) was added dropwise at -78 °C. The resulting mixture was allowed to warm to room temperature and then stirred for 3 h. After evaporation of the solvent, the resulting brown solid was treated with 2 N HC1 (3 mL) and EtOH (3 mL) and heated at 80 °C for 2 h. The reaction mixture was concentrated to remove the EtOH. The resulting mixture was treated with ice and basified with 2 N NaOH to pH~10 and extracted with EtOAc (2 x 10 mL). The extracts were dried, evaporated and purified by ISCO, chromatograph through a REDISEP™ pre-packed scilica gel column (12 g), eluting with a gradient of 0% to 5% MeOH (with 2 M NH3) in DCM to give
3,5-dichloro-4-(((2i?)-4-isopropylpyrrolidin-2-yl)methyl)pyridine (102 mg, 0.373 mmol, 36.3% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 3.35-3.51 (m, 1H), 2.84-3.08 (m, 3H), 2.35-2.44 (m, 1H), 1.80-1.93 (m, 1H), 1.55-1.69 (m, 1H), 1.31-1.49 (m, 2H), 1.02-1.17 (m, 1H), 0.85 (t, J=6.7 Hz, 6H). m/z (ESI, +ve) 273 (M+H).
[Reference example B52]
(R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine
Figure imgf000161_0001
Step 1 : (R)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one .,
To a stirred suspension of (R)-(-)-5-(hydroxymethyl)-2-pyrrolidinone (2.20 g, 19.1 1 mmol) and p-toluenesulfonic acid (0.018 g, 0.096 mmol) in toluene (54.6 ml),
2,2-dimethoxypropane (7.02 ml, 57.3 mmol) was added and the reaction was refluxed for 2 h. The reaction was equipped with a Dean-Stark then 2,2-dimethoxypropane (7.02 ml, 57.3 mmol) was added and the reaction was refluxed overnight. Solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (3.04 g, 19.59 mmol, 103% yield) as yellow oil. Ή NMR (400 MHz, CDC13) δ 4.27 (tt, J=6.01, 9.00 Hz, 1H), 4.09 (dd, J=5.65, 8.24 Hz, 1H), 3.43-3.50 (m, 1H), 2.81 (ddd, J=8.53, 12.19, 16.65 Hz, 1H), 2.55 (ddd, J=1.01, 9.15, 16.64 Hz, 1H), 2.13-2.23 (m, 1H), 1.72-1.80 (m, 1H), 1.66-1.72 (m, 3H), 1.48 (s, 3H).
Step 2: (R)-6,6-diallyl-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one
To a solution of (R)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (2.55 g, 16.43 mmol) in THF (54.8 ml) cooled to -78 °C, was added lithium diisopropylamide (14.79 ml, 29.6 mmol) solution. The solution was stirred at this temperature for 1 h before adding allyl bromide (2.133 ml, 24.65 mmol). The reaction mixture was warmed to rt (1 h) then cooled to -78 °C prior addition of lithium diisopropylamide (14.79 ml, 29.6 mmol). The mixture was stirred at -78 °C for 1 h before adding allyl bromide (2.133 ml, 24.65 mmol). The mixture was slowly warm to rt and stirred overnight.The reaction was quenched with sat. NH4C1 and extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide
(R)-6,6-diallyl-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (3.31 g, 14.07 mmol, 86% yield) as light-yellow, oil. IH NMR (400 MHz, CDC13) δ 5.66-5.90 (m, 2H), 5.06-5.19 (m, 4H), 4.01-4.11 (m, 2H), 3.29-3.38 (m, IH), 2.32-2.48 (m, 2H), 2.20-2.29 (m, IH), 2.12 (dd, J=8.97, 13.79 Hz, IH), 1.86-1.98 (m, IH), 1.73-1.84 (m, IH), 1.65 (s, 3H), 1.46 (s, 3H). Step 3: (R)-3,3-diallyl-5-(hydroxymethyl)pyrrolidin-2-one
To a solution of
(R)-6,6-diallyl-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (0.75 g, 3.19 mmol) in MeOH (12 ml) was added p-toluenesulfonic acid monohydrate (0.061 g, 0.319 mmol). The resulting mixture was heated at reflux for 2 h. TLC showed complete conversion.
Solvent was evaporated and the crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 0% to 6% MeOH in DCM, to provide
(R)-3,3-diallyl-5-(hydroxymethyl)pyrrolidin-2-one (0.62 g, 3.18 mmol, 100% yield) as white oil. 1H NMR (400 MHz, CDC13) δ 6.68 (br. s., IH), 5.67-5.86 (m, 2H), 5.06-5.20 (m, 4H), 3.62-3.74 (m, 2H), 3.36-3.45 (m, IH), 2.37 (ddd, J=6.45, 1 1.86, 13.15 Hz, 2H), 2.19 (ddd, J=4.79, 8.40, 13.45 Hz, 2H), 1.99 (dd, J=7.72, 13.37 Hz, IH), 1.69 (dd, J=7.44, 13.40 Hz, IH).
Step 4: (R)-(4,4-diallylpyrrolidin-2-yl)methanol
To a solution of (R)-3,3-diallyl-5-(hydroxymethyl)pyrrolidin-2-one (0.43 g, 2.202 mmol) in THF (5.51 ml) cooled to 0 °C, lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added. The mixture was stirred at room temperature overnight. Extra lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added and it was refluxed for 6 h. More lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0 °C prior to addition of aq. Rochelle's salt into the mixture slowly. The resulting slurry solution was extracted with EtOAc (10 mL). The combined extracts were washed with brine, dried and concentrated to afford
(R)-(4,4-diallylpyrrolidin-2-yl)methanol (0.34 g, 1.876 mmol, 85% yield) as colorless oil. Ή NMR (400 MHz, CDC13) δ 5.72-5.88 (m, 2H), 5.00-5.17 (m, 4H), 3.49-3.59 (m, IH), 3.30-3.46 (m, 2H), 2.79 (d, J=11.30 Hz, IH), 2.67 (d, J=11.35 Hz, IH), 2.08-2.19 (m, 4H), 1.72 (dd, J=6.97, 13.04 Hz, IH), 1.22-1.39 (m, IH).
Step 5: (R)-5,5-diallyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide
A solution of triethylamine (2.460 ml, 17.65 mmol) and
(R)-(4,4-diallylpyrrolidin-2-yl)methanol (1.60 g, 8.83 mmol) in DCM (44.1 ml) was cooled to -78 °C. To this mixture was added sulfuryl chloride (0.859 ml, 10.59 mmol) in DCM (44 mL) dropwise in 1 h. The reaction was maintained at this temperature for 3 h, then allowed to warm to room temperature and stirred overnight. The mixture was washed with aq. 1 N HC1 (30 ml x 2), brine (30 ml), dried, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R)-5,5-diallyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide (0.66 g, 2.71 mmol, 30.7% yield) as light-yellow oil. IH NMR (400 MHz, CDC13) δ 5.71-5.86 (m, 2H), 5.10-5.20 (m, 4H), 4.57 (dd, J=6.63, 8.76 Hz, IH), 4.24-4.36 (m, IH), 4.19 (dd, J=4.66, 8.76 Hz, IH), 3.21-3.32 (m, 2H), 2.19-2.29 (m, 4H), 2.03-2.18 (m, IH), 1.57-L63 (m, IH).
Step 6: (R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine To a solution of 3,5-dichloropyridine (1.069 g, 7.22 mmol) in THF (12.04 ml) at -78 °C was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (4.57 ml, 9.15 mmol) dropwise. After stirring for 1 h, a solution of
(R)-5,5-diallyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1 ,1 -dioxide (1.172 g, 4.82 mmol) in THF (10 mL) was aded dropwise at -78 °C and the mixture was allowed to warm to room temperature with stirring for 6 h. After evaporatin of the solvent, the resulting beige foam was treated with hot 2 N HC1 (12 ml) and EtOH (12 ml) overnight. The mixture was cooled to room temperature and basified with 1 N NaOH and extracted with EtOAc. The extracts were dried, evaporated and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 1% to 6% MeOH in DCM, to provide (R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine (0.70 g, 2.249 mmol, 46.7% yield) as yellow oil. 1H NMR (400 MHz, CDC13) δ 8.46 (s, 2H), 5.66-5.86 (m, 2H), 5.03-5.18 (m, 4H), 3.59-3J2 (m, 1H), 3.25 (d, J=7.15 Hz, 1H), 2.97 (d, J=11.51 Hz, 1H), 2.82 (d, J=1 1.51 Hz, 1H), 2.10-2.28 (m, 4H), 1.78 (dd, J=13.06, 6.95 Hz, 1H), 1.51-1.61 (m, 1H); LCMS (ESI) m/z 311.0 (M+H)+.
[Reference example B53]
(R)-3-((3,5-dichloro yridin-4-yl)methyl)-2-azaspiro[4.4]non-7-ene
Figure imgf000164_0001
A mixture (R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine (3.1 g, 9.96 mmol) and grubbs catalyst 2nd generation (1.691 g, 1.992 mmol) in DCM (996 ml). The mixture was stirreded at 40 °C for 20 h. The mixture was concentrated and absorbed onto a plug of silica gel and purified by chromatography through a Biotage column (100 g), eluting with a gradient of 1% to 50% 1 M NH3 MeOH in DCM, to provide (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]non-7-ene (1.0 g, 3.53 mmol, 35.5% yield) as dark-brown oil. 1H NMR (400 MHz, CDC13) δ 8.45 (s, 2H), 5.61-5.72 (m, 2H), 3.69-3.82 (m, 1H), 3.25 (br. s., 2H), 3.05 (d, J=10.47 Hz, 1H), 2.89-2.97 (r , 1H), 2.47 (br. s., 2H), 2.23-2.37 (m, 2H), 1.93 (dd, J=6.84, 12.59 Hz, 1H), 1.69-1.82 (m, 1H); LCMS (ESI) m/z 283.0 (M+H)+.
[Reference example B54]
(R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]
Figure imgf000165_0001
A, mixture of (R)-3 -((3 ,5 -dichloropyridin-4-yl)methyl)-2-azaspiro [4.4]non-7-ene (0.090 g, 0.318 mmol) and palladium 10 wt. % on activated carbon (0.034 g, 0.032 mmol) in EtOAc (4 ml) was stirred under hydrogen balloon at room temperature for 3 h. Starting material was converted to the desired project with mono-chloro product (~ 4:1). The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 5% to 50% 1 M NH3 MeOH in DCM, to provide
(R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]nonane (0.053 g, 0.186 mmol, 58.5% yield) as a brown oil. 1H NMR (400 MHz, CDC13) δ 8.42-8.50 (m, 2H), 3.63-3.83 (m, 1H), 3.28 (br. s., 2H), 3.02 (d, J=10.37 Hz, 1H), 2.87 (br. s., 1H), 1.73-1.83 (m, 1H), 1.54-1.72 (m, 9H), 1.42-1.53 (m, lH); LCMS (ESI) m/z 285.0 (M+H)+.
The following secondary amines were prepared using similar procedure in reference
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001

Figure imgf000169_0001
Figure imgf000170_0001
[Reference example C 1 ]
Figure imgf000170_0002
A31-3 C1
N-(2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)-4,4-dimethylcyclo ne (CI)
To a stirred solution of compound A31-3 (107 mg, 0.32 mmol) in DCM (2 mL) were added 4,4-dimethylcyclohexanone (40 mg, 0.32 mmol), NaBH(OAc)3 (83 mg, 0.38 mmol) and AcOH (101 mg, 0.47 mmol). The resulting mixture was stirred at room temperature for 17 h, then quenched with 0.5 M NaOH aq. (10 mL) and extracted with EtOAc (2 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent : 5% to 30% EtOAc/hexane) to yield compound CI (122 mg, 86%) as colorless syrup. Reference example C22]
Figure imgf000171_0001
Step 1 : (lS,3R,4R,6R)-4-bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (C22-1)
A suspension of (+)-3-carene (4.09 g, 30 mmol), CaC03 (3.90 g, 39 mmol) and NBS (6.94 g, 39 mmol) in water (15 mL) and 1,4-dioxane (30 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (75 mL) and extracted with Et20 (100 mL). The organic layer was washed with water (3 x 50 mL), saturated Na2S203 aq. (50 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound C22-1 (4.53 g, 65%) as a white solid.
Step 2: l-((lR,3r,5S)-6,6-dimethylbicyclo[3.L0]hexan-3-yl)ethanone (C22-2)
To a solution of compound C22-1 (4.53 g, 19.4 mmol) in water (9 mL) and
1,4-dioxane (127 mL) was added silver(I) oxide (12.16g, 52.5 mmol) and stirred at room temperature for 22 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with Et20. The organic layer was washed with water, dried over MgS04 and
concentrated under reduced pressure to provide compound C22-2 (2.86 g, 99%) as a pale yellow oil. The crude product was used for next step without purification.
Step 3: (lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-yl acetate (C22-3)
To a solution of compound C22-2 (2.86 g, 18.8 mmol) in DCM (57 mL) was added m-chloroperoxybenzoic acid (6.02 g, 24.4 mmol) at 0 °C and stirred at room temperature for 15 h. The reaction mixture was quenched with 0.2 M aqueous NaOH and extracted with DCM (80 mL and 2 x 50 mL). The collected organic layers were washed with saturated NaHC03 aq., water and brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound C22-3 (2.35 g, 74%) as a colorless gum.
Step 4: (lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-ol (C22-4)
To a solution of compound C22-3 (2.35 g, 14.0 mmol) in EtOH/water (63 mL, 2: 1) was added a solution of LiOH aq. (4 M, 21 mL, 84 mmol). The mixture was stirred at room temperature for 2.5 h. The mixture was diluted with water and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (35% EtOAc/hexane as eluent) to provide compound C22-4 (1.54 g, 88%) as a colorless oil.
Step 5: (1R,5S)- 6,6-dimethylbicyclo[3.1.0]hexan-3-one (C22-5)
Compound C22-4 (240 mg, 1.9 mmol) was dissolved in DCM (5 mL) and
Dess-Martin periodinane (968 mg, 2.28 mmol) was added. The reaction mixture was stirred for 3 h. The reaction mixture was quenched with 5% Na2S203 and extracted with Et20 (30 mL). The organic layer was washed with saturated NaHC03 aq. twice, dried over MgS04 and concentrated under reduced pressure to provide compound C22-5 (261 mg, quant.) as a colorless gum. The crude product was used for next step without purification.
Step 6:
(lR,3r,5S)-N-(2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)-6,6-dimethylbic yclo[3.1.0]hexan-3-amine (C22) Compound C22 (75 mg, 74%) was obtained from the reaction of compound A31-3 (77 mg, 0.228 mmol), compound C22-5 (31 mg, 0.250 mmol), NaBH(OAc)3 (72 mg, 0.341 mmol) and AcOH (0.013 mL, 0.228 mmol) in DCM (2 mL) using a similar procedure to that described in reference example A31 , step 4. 1H NMR (CDC13, 400 MHz): δ 7.04 (d, J = 8.3 Hz, 2H), 5.48 (dd, J = 9.2, J = 4.5 Hz, 1H), 3.60-3.51 (m, 1H), 3.19 (dd, J = 12.2, J = 9.2 Hz, 1H), 2.65 (dd, J = 12.2, J = 4.5 Hz, lH), 2.17-2.07 (m, 2H), 1.06-0.97 (m, 10H), 0.87 (t, J = 8.0 Hz, 9H), 0.58-0.47 (m, 6H).
[Reference example C45]
Figure imgf000173_0001
Step 1 : l-(2,6-dichloro-4-methylphenyl)-2-nitroethanol (C45-1)
Compound C45-1 (1.25 g, 96%) was obtained as a colorless gum from the reaction of 2,6-dichloro-4-methylbenzaldehyde (1.0 g, 5.3 mmol) and K2C03 (0.28 g, 2.0 mmol) in CH3N02 (10 mL) using a similar procedure to that described in example Al , step 2.
Step 2: (l-(2,6-dichloro-4-methylphenyl)-2-nitroethoxy)triethylsilane (C45-2)
Compound C45-2 (1.8 g, crude) was obtained as colorless gum from the reaction of compound C45-1 (1.25 g, 1.0 mmol), TES-Cl (1.0 mL, 1.2 mmol) and imidazole (1.2 g, 3.0 mmol) in DMF (10 mL) using a similar procedure to that described in reference example Al, step 3.
Step 3: 2-(2,6-dichloro-4-methylphenyl)-2-((triethylsilyl)oxy)ethanamine (C45-3)
Compound C45-3 (1.56 g, 94%) was obtained as a brown color oil from the reaction of compound C45-2 (1.8 g, 4.9 mmol), Fe (2.76 g, 49.3 mmol) and NH4C1 (2.62 g, 49.3 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A31 , step 3.
Step 4:
(lR,3r,5S)-N-(2-(2,6-dichloro-4-methylpheny
cyclo[3.1.0]hexan-3-amine (C45)
Compound C45 (75 mg, 44%) was obtained from the reaction of C45-3 (130 mg, 0.389 mmol), ketone C22-5 (49 mg, 0.394 mmol), NaBH(OAc)3 (125 mg, 0.590 mmol) and AcOH (0.023 mL, 0.402 mmol) in DCM (3 mL) using a similar procedure to that described in reference example A31, step 4. 1H NMR (CDC13, 400 MHz) δ: 7.07 (2H, s), 5.49 (1H, dd, J= 9.3, 4.4 Hz), 3.61-3.52 (1H, m), 3.20 (1H, dd, J= 12.2, 9.3 Hz), 2.64 (1H, dd, J= 12.2, 4.4 Hz), 2.27 (3H, s), 2.17-2.08 (2H, m), 1.08-0.97 (10H, m), 0.86 (9H, t, J= 7.8 Hz), 0.56-0.49 (6H, m).
Figure imgf000174_0001
Step 1 : l-(2,6-dichlorophenyl)-2-nitroethanol (C46-1)
Compound C46-1 (0.67 g, crude) was obtained as a yellow gum from the reaction of 2,6-dichlorobenzaldehyde (0.5 g, 2.85 mmol) and K2C03 (0.15 g, 1.08 mmol) in CH3N02 (10 mL) using a similar procedure to that described in reference example Al, step 2.
Step 2: (l-(2,6-dichlorophenyl)-2-nitroethoxy)triethylsilane (C46-2)
Compound C46-2 (0.95 g, 52%) was obtained as a colorless oil from the reaction of compound C46-1 (0.67 g, 2.83 mmol), TES-Cl (0.57 mL, 3.4 mmol) and imidazole (0.58 g, 8.5 mmol) in DMF (10 mL) using a similar procedure to that described in reference example A 1, step 3. Step 3 : 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (C46-3)
Compound C46-3 (0.86 g, crude) was obtained as a colorless oil from the reaction of compound C46-2 (0.95 g, 2.84 mmol), Fe (1.59 g, 28.4 mmol) and NH4C1 (1.51 g, 28.4 mmol) in EtOH/water (4: 1, 20 mL) using a similar procedure to that described in reference example A31, step 3. ,
Stepp 4:
(lR,3r,5S)-N-(2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethyl)-6,6-dimethylbicyclo[3.1. 0]hexan-3 -amine (C46) t
Compound C46 (94 mg, 78%) was obtained from the reaction of compound C46-3 (90 mg, 0.281 mmol), ketone C22-5 (42 mg, 0.337 mmol), NaBH(OAc)3 (89 mg, 0.421 mmol) and AcOH (0.016 mL, 0.281 mmol) in DCM (2 mL) using a similar procedure to that described in reference example A31 , step 4. Ή NMR (CDC13, 400 MHz) δ:
7.30-7.26 (2H, m), 7.09 (1H, t, J= 7.8 Hz), 5.53 (1H, dd, J= 9.3, 4.4 Hz), 3.62-3.53 (1H, m), 3.23 (1H, dd, J= 12.2, 9.3 Hz), 2.66 (1H, dd, J= 12.2, 4.4 Hz), 2.17-2.10 (2H, m), 1.04-0.99 (8H, m), 0.90-0.84 (l lH, m), 0.60-0.45 (6H, m).
[Reference Example C80]
(lR,3r,5S)-N-(2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)-6,6-dimethylbic yclo[3.1.0]hexan-3 -amine
Figure imgf000175_0001
Step 1 : l-(2,6-dichloro-3-fluorophenyl)-2-nitroethanol
In a 3-necked 100 mL RBF, freshly ground potassium carbonate (0.486 mmol) was added to a solution of 2,6^dichloro-3-fluorobenzaldehyde (2.26 g, 11.71 mmol) in THF (12 ml) at room temperature. Then nitromethane (8.88 ml, 164 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give
1- (2,6-dichloro-3-fluorophenyl)-2-nitroethanol (2.97 g, 11.69 mmol, 100% yield) as a yellow oil. Ή NMR (400 MHz, CDC13) δ 7.36 (dd, J=8.9, 4.8 Hz, 1 H), 7.17 (dd, J=8.9, 7.8 Hz, 1 H), 6.27 (m, 1 H), 5.19 (dd, J=13.3, 10.1 Hz, 1 H), 4.57 (dd, J=13.3, 3.4 Hz, 1 H), 3.20 (br. s., 1 11). '
Step 2 : 2-(2,6-dichloro-3 -fluorophenyl)-2-((triethylsilyl)oxy)ethanamine
To a 100 mL three-necked RBF were added
(l-(2,6-dichloro-3-fluorophenyl)-2-nitroethoxy)triethylsilane (3.64 g, 9.88 mmol) in EtOH (16 ml) and water (4 ml) at room temperature followed by addition of iron (5.52 g, 99 mmol) and ammonium chloride (5.29 g, 99 mmol). The flask was purged with nitrogen and was heated to 60 °C under nitrogen for 3 h. The mixture was cooled to room
temperature, diluted with 40 mL of MeOH, sonicated for 10 min. Then the solution was decanted through a pad of celite. This process was repeated for three times. The filtrate was concentrated to -30 mL and diluted with EtOAc (120 mL). The solid was filtered off and discarded. The filtrate was concentrated under reduced pressure. It was diluted with 50 mL of EtOAc, washed with water, brine, dried over anhydrous MgS04, and concentrated to give 2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine hydrochloride as an off-white solid. The HC1 salt was dissolved with 50 mL of DCM. The suspension was basicified w/ satd' aq NaHC03 (pH=9). The organic layer was separated, washed with brine, dried over anhydrous MgS04, and concentrated to give
2- (2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (2.73 g, 8.07 mmol, 82% yield) as a brown oil. 1H NMR (400 MHz, CDC13) δ Ί 23-1.29 (m, 1H), 6.99-7.06 (m, 1H), 5.35 (dd, J=8.6, 4.9 Hz, 1H), 3.29 (dd, J=13.1, 8.7 Hz, 1H), 2.92 (dd, J=13.2, 4.9 Hz, lH), 0.83-0.93 (m, 9H), 0.46-0.61 (m, 6H); LCMS: 338.2 [M+H]+.
Step 3:
(lR,3r,5S)-N-(2-(2,6-dichloro-3-fluoro^^
yclo[3.1.0]hexan-3-amine
(lR,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-one (0.181 g, 1.457 mmol) and
2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (0.493 g, 1.457 mmol) were combined in dry EtOH (7 ml) under nitrogen at room temperature and
tetraisopropoxytitanium (0.86 ml, 2.91 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then, NaBH4 (0.083 g, 2.186 mmol) was added. After 2 h, the reaction solution was quenched with saturated aqueous ammonium chloride (3 mL) and then basified with saturated NaHC03. The EtOH was then removed under reduced pressure, and the solution was diluted with water EtOAc. Celite was added and the solution was vigorously mixed for 15 min. The solution was then filtered through a pad of celite. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried over anhydrous Na2S04, filtered and concentrated to afford a yellow oil. The crude material was purified by column chromatography ( silica gel, eluent : 0% to 10% EtO Ac / heptane) to provide
(lR,3r,5S)-N-(2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)-6,6-dimethylbic yclo[3.1.0]hexan-3-amine (414 mg, 0.927 mmol, 63.6% yield) as colorless oil.
1H NMR (400 MHz, CDC13) δ 7.24 (dd, J=8.9, 4.9 Hz, 1H), 6.98-7.04 (m, 1H), 5.54 (br. s., 1H), 3.59 (t, J=8.8 Hz, 1H), 3.18-3.31 (m, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.15 (d, J=8.1 Hz, 1H), 1.22-1.34 (m, 4H), 1.06 (d, J=5.8 Hz, 2H), 0.99 (d, J=5.0 Hz, 6H), 0.84-0.93 (m, 9H), 0.47-0.59 (m, 6 H); LCMS: 446.2 [M+H]+. The following secondary amines were prepared using similar procedure in reference examples disclibed above.
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
C64 C65 C66
Figure imgf000182_0001
Figure imgf000183_0001
[Reference example Dl]
Figure imgf000184_0001
D1-5 D1
Step 1 : tert-butyl 2-(trans4-(ethoxycarbonyl)cyclohexyl)hydrazinecarboxylate (Dl-1)
To a solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.0 g, 29.0 mmol) and tert-butyl carbazate (3.9 g, 29.4 mmol) in dichlorometane (250 mL) and AcOH (4 mL) was added NaBH(OAc)3 (18.7 g, 88.0 mmol) gradually at 0 °C. After addition, the mixture was stirred at the same temperature for 3 h, then allowed to warm to room temperature and stirred for 20 h. The reaction mixture was poured into saturated aqueous Na2C03 solution and extracted with DCM. The DCM extracts were washed with brine x 2 and dried over MgS04. After the solvent was removed, the residue was purified by column
chromatography on silica gel to give compound Dl-1 (3.0 g, 36%) as a white solid.
Step 2: ethyl trans-4-hydrazinylcyclohexanecarboxylate hydrochloride (Dl-2)
To a solution of compound Dl -1 in EtOH (25 mL) was added 4 M HCI (in THF, 25 mL, 100 mmol) and the mixture was stirred at room temperature for 16 h. Drying the solution under high vacuum yielded compound Dl-2 (2.8 g, quant.) as a white solid.
Step 3: benzyl 4,4,4-trifluoro-3-oxobutanoate (Dl-3)
To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (17.0 g, 92.3 mmol) in toluene (80 mL) was added benzylalcohol (11.4 mL, 109.6 mmol). The mixture was stirred at 120 °C by using Dean-Stark for 5 h, and then the reaction mixture was cooled to 0 °C. Drying the solution under high vacuum yielded compound Dl-3 (21.2 g, quant.) as a colorless oil, which was used to the next step without further purification.
Step 4: benzyl 2-((dimethylamino)methylene)-4,4i4-trifluoro-3-oxobutanoate (Dl-4)
To a solution of compound Dl-3 (21.2 g, 92.3 mmol) and AcOH (10.6 mL, 184.7 mmol) in THF (100 mL) was added Ν,Ν-dimethylformamide diisopropyl acetal (38.6 mL, 184.7 mmol) dropwise over 25 min, and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into saturated aqueous NaHC03 solution and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgS04. After the solvent was removed, the residue was purified by column
chromatography on silica gel to give compound Dl-4 (17.1 g, 91%) as a yellow oil.
Step 5 : benzyl
1 -(trans-4-(ethoxycarbonyl)cyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylate (Dl-5)
To a solution of compound Dl-2 (2.8 g, 10.5 mmol) in EtOH (50 mL) were added DIPEA (3.2mL, 12.6 mmol) and compound Dl-4 (3.3 g, 11.0 mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched by adding brine and extracted with EtOAc. The organic layer was washed with brine (x 2) and dried over MgS04. After the solvent was removed, the residue was purified by column
chromatography on silica gel to give compound Dl-5 (3.5 g, 78%) as a colorless oil.
Step 6:
1 -(trans-4-(ethoxycarbonyl)cyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid (Dl)
Compound Dl-5 (3.5 g, 8.2 mmol) and 10% Pd on carbon (300 mg) in EtOAc (40 mL) was hydrogenated in H2 atmosphere (1 atm) at room temperature for 25 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. Drying the solution under high vacuum yielded compound Dl (2.6 g, 95%) as a white solid. [Reference example D2]
Etc> \— ' step ! EKJ ^ O-1 step 2 EtCi -A>J step 3 EtO ^-/~ step 4
D2-1 D2-2 D2-3
Figure imgf000186_0001
D2-4 D2-5
Step 1 : ethyl- l,4-dioxaspiro[4.5]decane-8-carboxylate (D2-1)
The mixture of ethyl-4-oxocyclohexanecarboxylate (10 g, 58.75 mmol), ethylene glycol (4.97 ml, 88.13 mmol) and p-TsOH (cat.) in toluene (80 mL) was refluxed for 16 h in a flask equipped with Dean-Stark adapter. Upon reaction completion, the mixture Was cooled to room temperature and solvent was removed under reduced pressure to provide compound D2-1 (9.6 g, crude) as brown oil. The crude product was used in the next step without purification. 1H NMR (CDC13, 400 MHz): δ 4.15-4.09 (m, 2H), 3.95 (s, 4H), 2.36-2.03 (m, 1H), 1.97-1.91 (m, 2H), 1.85-1.75 (m, 4H), 1.66-1.52 (m, 2H), 1.26-1.27 (m, 3H).
Step 2: ethyl-8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (D2-2)
To a stirred solution of compound D2-1 (5.1 g, 23.83 mmol) in THF (15 mL) was added LDA (2.0 M in THF/heptane/ethylbenzene, 17.8 mL, 35.74 mmol) dropwise at - 78 °C over a period of 15 min. The mixture was stirred at -78 °C for 30 min. A solution of iodomethane (2.23 mL, 35.74 mmol) in THF (1 mL) was added to the mixture dropwise, and the whole was stirred at -78 °C for 30 min. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% EtOAc/hexane as eluent) to provide compound D2-2 (2.7 g, 50%) as colorless oil. Ή NMR (CDC13, 400 MHz): δ 4.14 (q, J = 7.2 Hz, 2H), 3.93 (s, 4H), 2.15-2.10 (m, 2H), 1.65-1.60 (m, 4H), 1.54-1.49 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1 .18 (s. 311).
Step 3 : ethyl- 1 -methyl-4-oxocyclohexanecarboxylate (D2-3)
To a solution of compound D2-2 (8.4 g, 36.84 mmol) in acetone (100 mL) was added HCl (3 M in water* 50 mL) dropwise at room temperature, and the whole was stirred at room temperature for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound D2-3 (6.3 g) as a light yellow oil. The crude product was used in the next step without purification. 1H NMR (CDC13, 400 MHz): δ 4.22 (q, J = 7.0 Hz, 2H), 2.47-2.38 (m, 4H), 2.34-2.30 (m, 2H), 1.72-1.64 (m, 2H), 1.31- 1.29 (m. 611).
Step 4: tert-butyl-2-(trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)hydrazinecarboxylate (D2-4)
To a mixture of compound D2-3 (30 g, 163.0 mmol) and tert-butylhydrazine carboxylate (21.5 g, 163.0 mmol) in isopropanol (200 mL) was added and AcOH (catalytic amount) and the mixture was stirred at room temperature for 2 h. Upon completion of imine formation (monitored by TLC), the mixture was cooled to 0 °C, and solid NaBH3CN (30.7 g, 489.1 mmol) was added in portions. The pH of reaction mixture was adjusted to 5-6 using AcOH, and stirring continued for 3 h at room temperature. The mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S0 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) (Note: Polar spot was the trans-isomer) to provide compound D2-4 (12.0 g, 34%) as a white solid.
Step 5: ethyl trans-4-hydrazinyl-l-methylcyclohexanecarboxylate hydrochloride (D2-5)
To a solution of compound D2-4 (36.0 g, 120.0 mmol) in EtOH (100 mL) was added HC1 (4 M in 1,4-dioxane, 350 mL) dropwise at 0 °C, and the whole was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and residue was triturated with Et20 to get compound D2-5 (31.0 g, 95%) as white solid. The crude product was used in the next step without purification. LH NMR (CDC13, 400 MHz): δ 7.24-7.00 (brs, 4H), 4.13 (q, J = 7.2 Hz, 2H), 3.44 (brs, 1H), 2.08-2.05 (m, 2H), 1.97-1.90 (m, 2H), 1.81-1.80 (m, 4H), 1.30-1.26 (m, 6H).
Step 6:
benzyl- l-(trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylate (D2-6)
To a solution of compound D2-5 (31.0 g, 113.9 mmol) in EtOH (150 mL) was added DIPEA (39.4 mL, 227.9 mmol) dropwise and the mixture was stirred at room temperature for 5 min. A solution of compound Dl-4 (37.7 g, 125.3 mmol) in EtOH (10 mL) was added dropwise, and the whole was stirred at room temperature for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15% EtOAc/hexane as eluent) to provide compound D2-6 (20.0 g, 40%) as brown gum. 1H NMR (CDC13, 400 MHz): δ 7.94 (s, 1H), 7.40- 7.35 (m, 5H), 5.30 (s, 2H), 4.36 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.24-2.19 (m, 2H), 1.88-1.87 (m, 6H), 1.3 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).
Step 7: trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxyl ic acid (D2)
A fnixture of compound D2-6 (20.0 g, 45.6 mmol) and 5% Pd on carbon (10.0 g, 50% by weight) in MeOH (200 mL) was stirred under ¾ atmosphere (1 atm) for 4 h.
The mixture was filtered through a pad of celite, washed with EtOAc (3 x 100 mL) and concentrated under reduced pressure. The residue was triturated with 10% EtOAc/hexane (2 x 25 mL) to provide compound D2 (13.0 g, 82%) as white solid. Ή NMR (CDC13, 300 MHz): δ 8.03 (s, lH), 4.42- 4.41 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.25-2.21 (m, 2H), 1.92-1.88 (m, 6H), 1.35 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). HBoc
Figure imgf000189_0001
D2-1 D19-2 D19-3
HO rr . Hjcpi — step > 5 →
Figure imgf000189_0002
step 6 Η0Κ C Ν |' I0Ε, step 7
D19-4 D19-5 D19-6
Figure imgf000189_0003
Step 1 : l ,4-dioxaspiro[4.5]decan-8-ylmethanol (D19-1)
To a suspension of LiAlH4 (5.69 g, 150 mmol) in THF (100 mL) was added a solution of compound D2-1 (21.4 g, 100 mmol) in THF (100 mL) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, quenched with water (7 mL) and 6 M NaOH (7 mL) and stirred at room temperature for 20 min. Na2S04 (10 g) was added to the mixture, filtered over a pad of celite and washed with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), water (100 mL) and concentrated under reduced pressure to provide compound D19-1 (17.0 g, quant) as colorless oil. The crude product was used for next step without purification.
Step 2: 4-(hydroxymethyl)cyclohexanone (D19-2)
To a stirred solution of compound D19-1 (17.0 g, 9.88 mmol) in acetone (100 mL) was added aqueous HCl (2 M, 38 mL) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure to obtain compound D19-2 (7.5 g, 51%) as colorless gum.
Step 3: tert-butyl 2-(trans-4-(hydroxymethyl)cyclohexyl)hydrazinecarboxylate (D19-3) A mixture of compound D19-2 (2.0 g, 15.5 mmol) and Boc-hydrzine (2.26 g, 17 mmol) in isopropanol (20 mL) was stirred at room temperature for 16 h. Na(CN)BH3 (2.92 g, 45.6 mmol) and AcOH (1 mL, cat.) were added and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane as eluent) to obtain compound D19-3 (820 mg, 22%) as a white semi solid.
Step 4: (trans-4-hydrazinylcyclohexyl)methanol hydrochloride (D19-4)
To a stirred mixture of compound D19-3 (1.8 g, 7.3 mmol) in dioxane (40 mL) was added HCl (20 mL, 73 mmol, 4 M in dioxane) and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, dried on high vacuum pump to provide compound D19-4 (1.7 g, crude) as an off white solid.
Step 5 : ethyl-5-amino- 1 -(trans-4-(hydroxymethyl)cyclohexyl)- 1 H-pyrazole-4-carboxylate (D19-5) To a solution of compound D19-4 (720 mg, 3.31 mmol) in EtOH (20 mL) were added ethyl-2-cyano-3-ethoxyacrylate (448 mg, 2.65 mmol) and NaOAc (571 mg, 6.96 mmol) and the mixture was stirred at 70 °C for 18 h. The solvent was removed under reduced pressure, the residue was suspended in water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 30% CH3CN/water as eluent) to provide compound D19-5 (320 mg, 37%) as reddish brown solid.
Step 6 : ethyl-5-chloro- 1 -(trans-4-(hydroxymethyl)cyclohexyl)- 1 H-pyrazole-4-carboxylate (D19-6)
To a suspension of CuCl (103 mg, 1.04 mmol) in CH3CN (5 mL) was added tert-butyl nitrite (0.134 mL, 1.125 mmol) dropwise at 0 °C. A solution of compound D19-5 (200 mg, 0.749 mmol) in CH3CN (4 mL) was added dropwise to above mixture at 0 °C and stirred at the same temperature for 5 min. The mixture was stirred at room temperature for 30 min and at 70 °C for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 40%) EtOAc/hexane as eluent) to provide compound D19-6 (68 mg, 31%) as a brown semi solid.
Step 7: trans-4-(5-chloro-4-(ethoxycarbonyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (D19-7)
To a suspension of H5I06 (159 mg, 0.698 mmol) in CH3CN was added Cr03 (0.6 mg, 0.0061 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0 °C and a solution of compound D19-6 (100 mg, 0.349 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30 min. The organic solvent was removed under reduced pressure, residue was suspended in water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure to provide compound D19-7 (105 mg, quant) as an off-white solid.
Step 8:
ethyl- 1 -(trans-4-(tert-butoxycarbonyl)cyclohexyl)-5-chloro- 1 H-pyrazole-4-carboxylate (D19-8)
To a mixture of compound D19-7 (105 mg, 0.35 mmol) and Boc anhydride (152 mg, 0.70 mmol) in t-BuOH (5 mL) was added DMAP (13 mg, 0.105 mmol) and the mixture was stirred at 35 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 90% CH3CN/water as eluent) to provide compound D 19-8 (70 mg, 56%) as colorless gum.
Step 9: l-(trans-4-(tert-butoxycarbonyl)cyclohexyl)-5-chloro-lH-pyrazole-4-carboxylic acid (D1 )
To a stirred solution of compound D19-8 (70 mg, 0.233 mmol) in THF/MeOH (4 mL, 1 : 1) was added a solution of LiOH (44 mg, 1.86 mmol) in water (1 mL). The mixture was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure. The residue was diluted with water (5 mL), acidified with 20% aqueous KHS04 to pH 4 and extracted with EtOAc (3 x 10 mL) to provide compound D19 (62 mg, 90%) as white solid. Ή NMR (CDC13, 300 MHz): δ 8.01 (s, 1H), 4.29-4.37 (m, 1H), 2.25-2.43 (m, 1H), 2.10-2.19 (m, 2H), 1.99-2.09 (m, 4H), 1.52-1.65 (m, 2H), 1.45 (s, 9H).
[Reference example D20]
Figure imgf000193_0001
Step 1 : benzyl 3-cyclopropyl-3-oxopropanoate (D20-1)
A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 32.0 mmol), benzyl alcohol (8.2 mL, 80.0 mmol) and LiOCl (680 mg, 6.4 mmol) in toluene (50 mL) was refluxed for 48 h in flask equipped with a Dean-stark apparatus. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure to provide compound D20-1 (5.2 g, crude) as a brown oil.
Step 2: benzyl 2-(cyclopropanecarbonyl)-3-(dimethylamino)acrylate (D20-2)
A mixture of compound D20-1 (1.0 g, 4.58 mmol) and dimethylformamide dimethylacetal (0.61 mL, 4.58 mmol) in 1,4-dioxane (25 mL) was stirred at 100 °C for 13 h. The reaction mixture was quenched with water (20 mL) and extracted with EtO Ac (2 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over Na2S04 and concentrated under reduced pressure to provide compound D20-2 (1.2 g, crude) as a yellowish brown gum.
Step 3 : benzyl
5-cyclopropyl- 1 -(trans-4-.(ethoxycarbonyl)cyclohexyl)- 1 H-pyrazole-4-carboxylate (D20-3 )
To a solution of compound D 1-2 (809 mg, 2.67 mmol) in EtOH (20 mL) was added DIPEA (0.45 mL, 2.61 mmol) dropwise. The mixture was stirred at room temperature for 5 min, thereafter, a solution of compound D20-2 (600 mg, 2.18 mmol) in EtOH (5 mL) was added dropwise and reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25. mL), dried over anhydrous Na2S04 and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound D20-3 (425 mg, impure) as yellow gum.
Step 4 : 5 -cyclopropyl- 1 -(trans-4-(ethoxycarbonyl)cyclohexyl)- 1 H-pyrazole-4-carboxylic acid (D20)
To a stirred solution of compound D20-3 (425 mg, 1.07 mmol) in THF/MeOH (20 mL, 1 : 1) was added 10% Pd on carbon (80 mg, 20% by weight) and the mixture was stirred under H2 atmosphere (1 atm) for 2 h. The mixture was filtered through pad of celite and washed with EtO Ac (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with 10% EtOAc/hexane (2 x 20 mL) to provide compound D20 (200 mg, crude) as white solid.
[Reference example D22]
Etcf V step 1 Etc 1 step 2 EtO^ step s Et0 BOC-NH step 4 D2-1 D22-1 D22-2 D22-3
Figure imgf000194_0001
NH2 step s Eto FjC o step 6 Eto F ¾
D22-4 D22-5 D22
Step 1 : ethyl 8-ethyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (D22-1)
To a stirred solution of compound D2-1 (2.1 g, 9.80 mmol) in THF (24 mL) was added LDA (2.0 M in THF/heptane/ethylbenzene, 7.3 mL, 14.7 mmol) dropwise at -78 °C for 5 min. The mixture was stirred at -78 °C for' 15 min before the addition of EtBr (1.09 mL, 14.7 mmol). The reaction mixture was stirred at -78 °C for 1 h. The mixture was allowed to warm to room temperature and stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtO Ac (2 x 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound D22-1 (2.07 g, 87%) as a colorless gum.
Step 2: ethyl l-ethyl-4-oxocyclohexanecarboxylate (D22-2)
To a stirred solution of compound D22-1 (2.07 g, 8.54 mmol) in acetone (60 mL) was added aqueous HC1 (2 M solution, 40 mL) at room temperature. The mixture was stirred at the same temperature for 16 h. Acetone was removed under reduced pressure. The residue was basified with aqueous NaHC03 solution and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to give compound D22-2 (1.85 g, 99%) as a colorless gum.
Step 3: tert-butyl 2-(trans-4-(ethoxycarbonyl)-4-ethylcyclohexyl)hydrazinecarboxylate (D22-3)
Compound D22-3 (1.57 g, 53%) was obtained as a white solid from the reaction of compound D22-2 (1.87 g, 9.43 mmol), tert-butyl hydrazinecarboxylate (1.24 g, 9.4 mmol), AcOH (cat) and NaBH3CN (1.78 g, 28.29 mmol) in isopropanol (20 mL) using a similar procedure to that described in reference example D2, step 4.
Step 4: ethyl trans- l-ethyl-4-hydrazinylcyclohexanecarboxylate hydrochloride (D22-4)
Compound D22-4 (1.36 g, 100%) was obtained as a white solid from the reaction of compound D22-3 (1.50 g, 4.78 mmol) and HC1 (4 M in 1,4-dioxane, 8.3 mL, 33.4 mmol) using a similar procedure to that described in reference example D2, step 5,
Step 5: benzyl
l-(trans-4-(ethoxycarbonyl)-4-ethylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carbox ylate (D22-5)
Compound D22-5 (820 mg, 86%) was obtained as a colorless gum from the reaction of compound D22-4 (600 mg, 2.1 mmol), compound Dl-4 (669 mg, 2.2 mmol) and DIPEA (0.43 mL, 2.52 mmol) in EtOH (12 mL) using a similar procedure to that described in reference example D2, step 6.
Step 6:
1 -(trans-4-(ethoxycarbonyl)-4-ethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carbox ylic acid (D22)
Compound D22 (285 mg, 98%) was obtained as a white solid from the reaction of compound D22-5 (363 mg, 0.80 mmol), 5% Pd on carbon (85 mg, 30% by weight) and H2 (1 atm) in MeOH (6 mL) using a similar procedure to that described in reference example D2, step 7.
[Reference example D26]
Figure imgf000196_0001
Step 1 : benzyl-4,4-difluoro-3-oxobutanoate (D26-1)
Compound D26-1 (7.5 mg, crude) was obtained as a yellow oil from the reaction of ethyl-4,4-difluoro-3-oxobutanoate (5 g, 0.12 mmol) and BnOH (3.25 g, 30.0 mmol) in toluene (50 mL) using a similar procedure to that described in reference example Dl, step 3.
Step 2: benzyl-2-((dimethylamino)methylene)-4,4-difluoro-3-oxobutanoate (D26-2) Compound D26-2 (5.8 g, crude) was obtained as a yellow oil from the reaction of compound D26-1 (5.3 g, 23.2 mmol), dimethyl formamide dimethylacetal (6.2 mL, 46.4 mmol) and AcOH (2.05 mL, 46.4 mmol) in THF (50 mL) using a similar procedure to that described in reference example Dl, step 4.
Step 3: - benzyl-5-(difluoromethyl)-trans-4-(ethoxycarbonyl)cyclohexyl)-lH-pyrazole-4-carboxylat e (D26-3)
Compound D26-3 (520 mg, 16%) was obtained as a pale yellow solid from the reaction of compound D26-2 (1.50 g, 5.28 mmol), compound Dl-2 (1.6 g, 5.28 mmol) and DIPEA (1.8 mL, 10.5 mmol) in EtOH (30 mL) using a similar procedure to that described in reference example Dl, step 5.
Step 4: 5-(difluoromethyl)-trans-4-(ethoxycarbonyl)cyclohexyl)- 1 H-pyrazole-4-carboxylic acid (D26)
Compound D26 (255 mg, 63%) was obtained as a white solid from the reaction of compound D26-3 (520 mg, 1.28 mmol) and 5% Pd on carbon (70 mg, 30% by weight) in EtOH (30 mL) using a similar procedure to that described in reference example Dl, step 6. LCMS (APCI): 317 (M+H)+.
[Reference example D27] oH
Figure imgf000197_0001
Step 1 : benzyl 2-((dimethylamino)methylene)-3-oxobutanoate (D27-1)
To a stirred benzyl 3-oxobutanoate (1.1 g, 5.7 mmol), dimethylformamide dimethylacetal (1 mL, 7.4 mmol) was added dropwise at room temperature. The mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3 x 10 mL) to provide compound D27-1 as a brown oil (1.4 g, quant.).
Step 2: benzyl
1 -((trans-4-(ethoxycarbonyl)cyclohexyl)-5 -methyl- 1 H-pyrazole-4-carboxylate (D27,-2) To a solution of compound Dl-2 (1.12 g, 4.3 mmol) in EtOH (10 mL) was added DIPEA (1.2 mL, 6.7 mmol) dropwise. The mixture was stirred at room temperature for 5 min. A solution of compound D27-1 (0.97 g, 3.94 mmol) in EtOH (5 mL) was added dropwise and.the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound D27-2 (0.78 g, 54%) as a white solid.
Step 3: l-((trans-4-(ethoxycarbonyl)cyclohexyl)-5-methyl-lH-pyrazole-4-carboxylic acid (D27)
To a stirred solution of compound D27-2 (0.78 g, 2.1 mmol) in MeOH (10 mL) was added 5% Pd on carbon (0.19 g, 25% by weight) and the mixture was stirred under H2 atmosphere (1 atm) for 2 h. The mixture was filtered through a pad of celite and washed with MeOH (3 x 20 mL). The filtrate was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was triturated with 5% EtOAc/hexane (20 mL) to provide compound D27 (0.5 g, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6): 5 1.19 (t, J= 7.2 Hz), 1.56 (m, 2H), 1.88 (m, 4H), 2.00 (m, 2H), 2.35 (m, 1H), 2.50 (s, 3H), 4.07 (q, J=7.2 Hz, 2H), 4.20 (m, 1H), 7.72 (s, 1H), 12.10 (s, 1H). [Reference example D28]
Figure imgf000199_0001
D28-1 D28-2 D28-3 D28-4
HO MsO 0 — O £¾- HBn f¾-NHBn
Eto — step* 6· ° _c
Et0 step T 7 EtO "© ^-NHBn ~ step 8 Ε EΚtOΗ } ' "ΝΗ2
Figure imgf000199_0002
step 12 E
D28-i2 D28-13 D28
Step 1 : 1,5-di-tert-butyl 3-ethyl 3-acetylpentane-l,3,5-tricarboxylate (D28-1)
To a stirred solution of ethyl 37oxobutanoate (45 g, 345 mmol) and Triton-B (40%, weight% solution in water, 1.08 mg, 6.90 mmol) in tert-BuOH (54 mL) was added tert-butyl acrylate (100.72 g, 691 mmol) dropwise over a period of 30 min under N2 atmosphere. The solution was stirred at room temperature for 24 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer was washed with EtO Ac (2 x 50 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2S04 and concentrated under reduced pressure to provide compound D28-1 (140 g, quant) as a pale yellow oil. 1H NMR (CDC13, 400 MHz): δ 4.20 (q, J = 7.2 Hz 2H), 2.24-2.09 (m, 8H), 1.58 (s, 3H), 1.43 (s, 18H), 1.31 (t, J = 7.2 Hz, 3H).
Step 2: 4-acetyl-4-(ethoxycarbonyl)heptanedioic acid (D28-2)
To a stirred solution of compound D28-1 (140 g, 326 mmol) in DCM (350 mL) was added TFA (350 mL) in DCM (350 mL) at 0 °C and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was co-evaporated with toluene (3 x 200 mL) to provide compound D28-2 (85 g, quant.) as an off-white solid.
Step 3: ethyl- l-acetyl-4-oxocyclohexanecarboxylate (D28-3)
To a stirred suspension of compound D28-2 (85 g, 310 mmol) in acetic anhydride (255 mL) was added pyridine (27 mL) and the mixture was stirred at 145 °C for 2 h. The solvent was removed under reduced pressure, the residue was suspended in water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14%
EtOAc/hexane as eluent) to provide compound D28-3 (11 g, 17%) as brown gum. !H NMR (CDCI3, 400 MHz): δ 4.28 (q, J = 7.2 Hz, 2H), 2.44-2.42 (m, 6H), 2.23-2.20 (m, 5H), 1.31 (t, J = 7.2 Hz, 3H).
Step 4: ethyl 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-l-carboxylate (D28-4)
To a stirred mixture of compound D28-3 (25.0 g, 117 mol) and benzyl amine (38.6 mL, 353 mol) in toluene (250 mL) was added p-TsOH (0.22 g, 1.17 mmol), and the mixture was refluxed for 8 h in a flask equipped with a Dean-Stark adapter. The reaction mixture was cooled to room temperature. HC1 (3 M, 250 mL) was added to the reaction mixture, and the whole was stirred for 30 min. The mixture was neutralized with aqueous solution of 6 M NaOH to pH 7. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc/hexane as eluent) to provide compound D28-4 (30 g, 85%) as an off-white solid. Ή NMR (CDC13, 400 MHz): δ 7.40-7.21 (m, 5H), 6.44-6.32 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.74 (s, 1H), 2.45 (s, 2H), 2.30-2.20 (m, 2H), 2.10-1.95 (m, 2H), 1.89-1.75 (m, 4H), 1.27 (t, J = 6.8 Hz, 3H). Step 5: ethyl-4-(benzylamino)-2-hydroxybicyclo[2.2.2]octane-l-carboxylate (D28-5)
To a stirred solution of compound D28-4 (30.0 g, 99.0 mmol) in EtOH (300 mL) was added solid NaBH4 (5.64 g, 148 mmol) in portions at 0 °C. The whole was stirred at room temperature for 30 min. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (80%
EtOAc/hexane as eluent) to provide compound D28-5 (14 g, 46%) as a white solid.
Step 6: ethyl-4-(benzylamino)-2-((methylsulfonyl)oxy)bicyclo[2.2.2]octane- 1 -carboxylate (D28-6)
To a stirred solution of compound D28-5 (14.0 g, 46.0 mmol) and Et3N (12.8 mL,57.5 mmol) in THF/toluene (125 mL, 1 :4) was added MsCl (4.47 mL, 57.5 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (100 mL) and extracted with toluene (50 mL). The organic layer was separated, dried over Na2S04 and concentrated under reduced pressure to provide compound D28-6 (14 g, crude). The crude product was used in the next step without purification.
Step 7: ethyl-4-(benzylamino)bicyclo[2.2.2]oct-2-ene-l -carboxylate (D28-7)
To a stirred solution of compound D28-6 (17.6 g, 46.3 mol) and Nal (1.38 g, 9.25 mmol) in toluene (170 mL) were added DBU (34.65 mL, 231 mmol) and DMA (50 mL), and the whole was stirred at 120 °C for 43 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound D28-7 (8 g, 61 %, over two steps) as an off-white solid. Ή NMR (CDC13, 400 MHz): δ 7.36-7.32 (m, 5H), 6.44 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 8.8 Hz, lH), 4.19 (q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 2.04-1.97 (m, 2H), 1.65-1.50 (m, 6H), 1.28 (t, J = 7.2 Hz, 3H).
Step 8: ethyl-4-aminobicyclo[2.2.2]octane-l-carboxylate (D28-8)
To a stirred solution of compound D28-7 (8.0 g, 28.0 mmol) in MeOH (80 mL) was added 10% Pd on carbon (1.6 g, 20% by weight) and the whole was stirred for 5 h under H2 atmosphere (1 atm). The reaction mixture was filtered through a pad of celite and washed with MeOH (2 x 30 mL). The filtrate was concentrated under reduced pressure to provide compound D28-8 (5.2 g, 94%) as a colorless gum. 1H NMR (CDC13, 400 MHz): δ 4.00 (q, J = 7.2 Hz, 2H), 1.88-1.84 (m, 4H), 1.56-1.55 (m, 8H), 1.15 (t, J = 7.2 Hz, 3H). Step 9: tert-butyl 4-cyanobenzylidenecarbamate (D28-9)
A mixture of 4-formylbenzonitrile (12.0 g, 9.16 mol) and tert-butyl
(triphenylphosphoranylidene)carbamate (36.3 g, 9.61 mol) in toluene (60 mL) was refluxed for 18 h. The precipitated solid was filtered off. The filtrate was concentrated under reduced pressure to provide compound D28-9 (13 g, crude) as a colorless gum.
Step 10: tert-butyl 3-(4-cyanophenyl)-l ,2-oxaziridine-2-carboxylate (D28-10, mixture of cis- and trans- isomer)
To a stirred solution of compound D28-9 (13 g, 1.67 mmol) in CHC13 (220 mL) was added a pre-cooled solution of K2C03 (50 g) in water (400 mL) at 0 °C, and the mixture was stirred vigorously. A pre-cooled solution of Oxone (80 g) in water (800 mL) was added, and the whole was stirred at 0 °C for 50 min. The reaction mixture was subjected to ten such cycles. The combined organic layer was separated, washed with water (200 mL), brine (200 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 45-50% CH3CN/water as eluent) to provide compound D28-10 (1.3 g, 14% over two steps) as a white solid. Ή NMR (CDC13, 400 MHz, mixture of cis- and trans-): δ 7.73- '
7.58 (m, 6.5H), 5.29 (s, 0.3H), 5.06 (s, 1H), 1.57 (s, 3H), 1.55 (s, 9H).
Step 11 : tert-butyl 2-(4-(ethoxycarbonyl)bicyclo[2.2.2]octan-l-yl)hydrazinecarboxylate
(D28-11)
A mixture of compound D28-8 (0.8 g, 4.04 mmol) and compound D28-10 (1.03 g, 4.24 mmol) in DCM (20 mL) was stirred for 3 h at 0 °C. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound D28-11 (0.6 g, 50%) as a white solid.
Step 12: ethyl-4-hydrazinylbicyclo [2.2.2] octane- 1-carboxylate hydrochloride (D28-12) A mixture of compound D28-11 (0.6 g, 1.92 mmol) and 4 M HC1 in dioxane (4.80 mL, 19.2 mmol) was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was co-evaporated with hexane twice to provide compound D28-12 (0.58 g, crude) as a white solid.
Step 13: benzyl
1 -(4-(ethoxycarbonyl)bicyclo[2.2.2]octan- 1 -yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxy late (D28-13)
To a stirred mixture of compound D28-12 (0.58 g, 2.04 mmol) and DIPEA (0.69 mL, 4.08 mmol) in EtOH (10 mL) was added a solution of compound Dl-4 (0.64 g, 2.15 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc hexane as eluent) to provide compound D28-13 (0.2 g, 21%) as a light yellow gum. 1H NMR (CDCI3, 400 MHz): δ 7.81-7.80 (s, 1H), 7.39-7.25 (m, 5H), 5.29 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 2.27-2.23 (m, 6H), 2.02-1.99 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H).
Step 14:
1 -(4-(ethoxycarbonyl)bicyclo[2.2.2]octan- 1 -yl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxy lie acid (D28)
To a stirred solution of compound D28-13 (0.2 g, 0.44 mmol) in MeOH was added 10% Pd on carbon (40 mg, 30% by weight), and the whole was stirred under H2
atmosphere (1 atm) for 5 h. The reaction mixture was filtered through a pad of celite, washed with MeOH (3 x 30 mL). The fitrate was concentrated under reduced pressure. The residue was triturated with hexane (2 x 10 mL) and the resulting solid was filtered to provide compound D28 (0.15 g, 93%) as a white solid. Ή NMR (CDC13, 400 MHz): δ 7.90 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.30-2.26 (m, 6H), 2.04-2.00 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H).
Figure imgf000204_0001
Step 1 :
benzyl-5-(difluoromethyl)-trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)-lH-pyrazole-4-c arboxylate (D30-1)
Compound D30-1 (1.91 g, 50%) was obtained as a pale yellow solid from the reaction of compound D26-2 (2.7 g, 9.55 mmol), compound D2-5 (2.6 g, 9.55 mmol) and DIPEA (3.3 mL, 19.1 mmol) in EtOH (50 mL) using a similar procedure to that described
Figure imgf000205_0001
5-amino- 1 -(trans-4-(cthoxycarbonyl)-4-methylcyclohexyI)- 1 H-pyrazole-4-carbpxylate (D33-1)
To " a solution of ethyl 2-cyano-3-ethoxyacrylate (19 g, 70 mmol) and compound D2-5 (11.96 g, 70 mmol) in EtOH (100 mL) was added sodium acetate (11.54 g, 140 mmol) and the mixture was refluxed for 6 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound D33-1 (16 g, 45%) as a yellow solid.
Step 2: ethyl
5-chloro- 1 -(trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)- 1 H-pyrazole-4-carboxylate (D33-2)
To a stirred mixture of copper (I) chloride (0.77 g, 7.8 mmol) in CH3CN (10 mL) at 0 °C was added tert-butyl nitrite (0.92 mL, 7.8 mmol). A solution of compound D33-1 (1.26 g, 3.9 mmol) in CH3CN (10 mL) was added dropwise to the mixture at the same temperature. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1 h and at 60 °C for another 1 h. The reaction mixture was quenched with 6 M HC1 (10 mL) at 0 °C and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound D33-2 (0.3 g, 37%) as a colourless gum.
Step 3:
5-chloro-l-(trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)-lH-pyrazole-4-carboxylic acid (D33)
To a solution of compound D33-2 (0.6 g, 1.75 mmol) in EtOH (10 mL) was added 1 N NaOH solution dropwise at room temperature. The mixture was stirred for 45 min. The reaction mixture pH was adjusted to 3 and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 80% CH3CN/water as eluent) to provide compound D33 (0.4 g, 55%) as an off-white solid. e-4
Figure imgf000207_0001
Step 1 : (l S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (Racemic)
To a Parr flask was added 10% palladium on carbon (wet degussa type) (4.47 g, 4.20 mmol) in EtOH (378 ml). Then ethyl 2-methyl-4-oxo-2-cyclohexene- 1 -carboxylate (23.65 ml, 140 mmol) and 5 N hydrochloric acid (1.679 ml, 8.40 mmol) were added into the reaction mixture. The atmosphere of the flask was degassed, and then filled with hydrogen (50 psi). The mixture was allowed to stir under hydrogenation conditions 30 min. The progress of the reaction was monitored by LC/MS and TLC (50% EtOAc/hexane; potassium permanganate stain), which suggested reaction completion. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOH. The mixture was concentrated in- vacuo. The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g), eluting with a gradient of 0-50% EtOAc in hexane, to provide (l S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (18.277 g, 99 mmol, 70.9% yield) (Racemic) as light-yellow oil. Ή NMR (400 MHz, CDC13) 5 4.19 (dtt, 2H), 2.85 (td, J=4.25, 8.31 Hz, IH), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.06, 8.75, 14.72 Hz, IH), 2.01-2.21 (m, 2H), 1.29 (t, J=7.14 Hz, 3H), 0.98 (d, J=6.85 Hz, 3H); LCMS (ESI) m/z 185.0 (M+H)+.
Step 2: (lS,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (Chiral)
(lS,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (Racemic) was separated into chiral peak 1 and chiral peak 2 by normal phase HPLC ; Varian Cardinals SD1 normal phase system (10 x 50 cm ; 20 micron AS column). Method : 10% EtOH in Heptane Flow Rate : 400 ml/min. Detection : 220 nm, 300 nm. This purification method provided peak 1 (lS,2R)-ethyl 2-methyl-4-oxocyclohexane.carboxylate (>98% ee) as colorless oil. 'H NMR (400 MHz, CDC13) δ 4.19 (ddquin, 2H), 2.85 (td, J=4.25, 8.31 Hz, IH), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.16, 8.66, 14.72 Hz, IH), 2.01-2.21 (m, 2H), 1.24-1.32 (m, 3H), 0.98 (d, J=6.85 Hz, 3H) ; LCMS (ESI) m/z 185.0 (M+H)+. Peak 2 (lR,2S)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (>95% ee) as colorless oil. Ή NMR (400 MHz, CDC13) δ 4.19 (ddquin, 2H), 2.85 (td, J=4.13, 8.36 Hz, IH), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.16, 8.66, 14.72 Hz, IH), 2.01-2.21 (m, 2H), 1.29 (t, J=7.14 Hz, 3H), 0.98 (d, J=6.85 Hz, 3H) ; LCMS (ESI) m/z 185.0 (M+H)+.
Step 3: tert-butyl 2-((lS,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)
hydrazinecarboxylate
To a 500-mL 3-neck round-bottomed flask was added (1 S,2R)-ethyl ,
2-methyl-4-oxocyclohexanecarboxylate (10.00 g, 54.3 mmol) in chloroform (201 ml).
Then AcOH, glacial (3.13 ml, 54.3 mmol), and tert-butyl carbazate (7.89 g, 59.7 mmol) was added into the reaction mixture. The flask was placed into a pre-heated bath (30 °C) and allowed to stir 10 min. Then NaBH(OAc)3 (34.5 g, 163 mmol) was slowly added into the reaction mixture in small portions. The bath was removed after the addition and the overall mixture was allowed to stir under inert atmosphere 16 h. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/DCM; Ninhydrin stain) which suggested reaction completion . The mixture was neutralized with the slow addition of sat. aq. NaHC03 to the reaction mixture. After the material was neutralized, the layers were separated and the aqueous layer was extracted with DCM (3x). The combined organic extracts were dried over Na2S04, filtered and concentrated in-vacuo. The crude sample was analyzed by TLC (30% EtOAc/hexane; ninhydrin stain; Peak 1 : Rf= 0.46 & Peak 2: Rf= 0.38) The crude material was divided into two portions and purified by chromatography through an Interchim (25 micron) silica-gel column (300 g) *(Two 300 Gram Columns were used), eluting with a gradient of 0-30% EtOAc in hexane, to provide tert-butyl 2-((l R,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl) hydrazinecarboxylate (8.512 g, 28.3 mmol, 52,2% yield) (Peak 1 ; Cis) 1H NMR (400 MHz, CDC13) δ 6.03-6.28 (m, 1H), 4.07-4.16 (m, 2H), 3.59-3.90 (m, 1H), 2.76-2.97 (m, 1H), 2.55 (d, J=2.74 Hz, 1H), 2.01 (dd, J=3.03, 13.40 Hz, 1H), 1.59-1.77 (m, 3H), 1.49-1.56 (m, 2H), 1.46 (s, 10H), 1.19-1.31 (m, 3H), 1.02 (d, J=7.04 Hz, 3H) ; LCMS (ESI) m/z 301.1 (M+H)+ and tert-butyl 2-((l S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl) hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans) 1H NMR (400 MHz, DMSO-d6) δ 7.89-8.27 (m, 1H), 5.75 (s, 1H), 4.08-4.19 (m, 1H), 2.74-2.93 (m, 1H), 2.21-2.46 (m, 2H), 1.99 (s, 1H), 1.66 (d, J=3.91 Hz, 3H), 1.38 (s, 9H), 1.14-1.26 (m, 5H), 0.79 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+.
Step 4: (lS,2R,4S)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate hydrochloride
To a 250-mL round-bottomed flask was added tert-butyl
2-((l S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol) in EtOH (56.5 ml). Then hydrogen chloride, 4.0 M solution in 1,4-dioxane (72.0 ml, 288 mmol) was added into the reaction mixture. The overall mixture was allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by TLC (30% EtOAc in hexane; ninhydrin stain), which suggested reaction completion. The mixture was concentrated in-vacuo. The residue was diluted with hexane and concentrated in-vacuo. This gave (1 S,2R,4S)-ethyl
4-hydrazinyl-2-methylcyclohexanecarboxylate hydrochloride (4.60 g) as white solid.
This material was carried into the next step of the synthesis, without further purification. LCMS (ESI) m/z 201.2 (M+H)+.
Step 5: benzyl
1- ((l S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylate
To a 250-mL round-bottomed flask was added (lS,2R,4S)-ethyl
4-hydrazinyl-2-methylcyclohexanecarboxylate hydrochloride (4.00 g, 16.90 mmol) and DIPEA (4.43 ml, 25.3 mmol) in EtOH (84 ml). Then a solution of (Z)-benzyl
2- ((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (5.09 g, 16.90 mmol) in EtOH (84 ml) was added dropwise into the reaction mixture. The overall reaction mixture was allowed to stir under inert atmosphere, while at ambient temperature overnight. The progress of the reaction was monitored by LC/MS and TLC (30%
EtOAc/hexane) which showed mostly desired material LCMS (ESI) m/z 461.2 (M+Na)+, without any starting material remaining. The reaction mixture was concentrated in-vacuo. The crude material was purified by chromatography through an Interchim (25 micron) silica-gel column (200 g), eluting with a gradient of 0-30% EtOAc in hexane, to provide benzyl
1 -((1 S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-l H-pyrazole-4 -carboxylate (5.631 g, 12.84 mmol, 76% yield) as light-yellow oil. Ή NMR (400 MHz, DMSO-d6) δ 8.14 (s, IH), 7.32-7.45 (m, 5H), 5.30 (s, 2H), 4.55-4.65 (m, IH), 4.02-4.15 (m, 2H), 2.65 (td, J=4.50, 1 1.54 Hz, IH), 2.13 (dt, J=4.50, 12.42 Hz, IH), 1.95-2.04 (m, 2H), 1.73 (d, J=4.89 Hz, 3H), 1.16-1.23 (m, 3H), 0.92 (d, J=7.04 Hz, 3H) ; LCMS (ESI) m/z 461.2 (M+Na)+.
Step 6:
l-((lS,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluor0methyl)-lH-pyrazole-4 -carboxylic acid
*(Hydrogenation was performed with suitcase apparatus)
A pressurized vial was charged with palladium 10 wt. % (dry basis) on activated carbon, wet (1.367 g, 1.284 mmol) while under a stream of N2 (gas). Then a solution of benzyl
l-((l S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylate (5.631 g, 12.84 mmol) in a 1 : 1 mixture of EtOH (32.1 ml)/EtOAc (32.1 ml) was added into the vial. The reaction mixture atmosphere was purged with hydrogen gas (3x). The reaction was stirred vigourously under hydrogenation (35 psi) conditions for 2.5 h. The progress of the reaction was monitored by LC/MS, which suggested reaction completion LCMS (ESI) m/z 371.2 (M+Na) . The mixture was filtered through a plug of celite and the filtrate was concentrated in- vacuo. The residue was diluted with hexane and agitated. The precipitate was collected by filtration and the solids were rinsed with hexane. This gave
l-((l S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid (3.810 g, 10.94 mmol, 85% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-8.21 (m, IH), 4.47-4.69 (m, IH), 4.01-4.16 (m, 2H), 2.56-2.70 (m, IH), 2.12 (dt, J=4.21, 12.37 Hz, IH), 1.93-2.06 (m, 2H), 1.71-1.90 (m, 3H), 1.19 (t, J=7.04 Hz, 3H), 0.92 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 371,2 (M+Na)+
[Reference example D43]
l-((lR,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylic acid compound with
l-((l S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid (1 : 1) (D43)
Figure imgf000212_0001
racemic mixture of D43-1
(1 R,3S,4S) and (1S,3R,4R) racemic mixture of first fraction (1 ,4-cis) (1S,3S,4S) and (1 R,3R,4R) sedond fraction (1 ,4-trans)-
Step 2
NH2 HCI
"NH r * F3d I r * F3d J step 4 F,d 5 Step 3 Γ
D43 D43-3 D43-2 racemic mixture racemic mixture racemic mixture
including (1 R,3R,4R)-isomer including (1 R,2R,4R)-isomer
Step 1 : tert-butyl
2-((lR,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate compound with tert-butyl
2-((l S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (1 :1) (D43-1)
To a homogeneous racemic mixture of (lR,2R)-ethyl
2-methyl-4-oxocyclohexanecarboxylate compound with (lS,2S)-ethyl
2-methyl-4-oxocyclohexanecarboxylate (1 :1) (1.600 g, 8.68 mmol) was added tert-butyl carbazate (1.263 g, 9.55 mmol), AcOH (1.038 ml, 17.98 mmol), and NaBH(OAc)3 (6.00 g, 28.3 mmol). The light-yellow heterogeneous mixture was stirred at room temperature. After 24 h, LCMS (ESI) and TLC indicated that the reaction was complete, two peaks with 323.1 (M+Na).
[TLC]: (30% of EtOAc in Hexane, stained with phosphomolybdic acid in EtOH)
Rf of reactant=0.47, Rf of 1 ,4-cis-desired product=0.42, Rfof 1 ,4-trans-desired
product=0.25. The reaction mixture was poured into saturated aqueous NaHC03 solution (150 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a colorless oil. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a' gradient of 0% to 25% EtOAc in hexane to provide two fractions: ,
First fraction for higher spot (1,4-cis): (Rf=0.42 at 30% of EtOAc in Hexane) tert-butyl 2-((lR,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate compound with tert-butyl
2-((l S,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (1 : 1)
(1.4418 g, 4.80 mmol, 55.3% yield) as light-yellow syrup : 1H NMR (300 MHz, CDC13) δ 6.05 (1 H, br. s.), 4.14 (2 H, q, J=7.1 Hz), 3.25 (1 H, br. s.), 1.12 - 2.22 (21 H, m), 0.88 (3
H, d, J=6.6 Hz); LCMS (ESI) m/z 301.1 (M+H)+ and m/z 323.1 (M+Na)+.
Second fraction for lower spot (1,4-trans): Desired product (Rf=0.25 at 30% of EtOAc in Hexane) tert-butyl
2-((lR,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate compound with tert-butyl
2-((l S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (1 : 1) (D43-1) (0.5467 g, 1.820 mmol, 20.96% yield) as off-white syrupy solid. 1H NMR (300 MHz, CDC13) δ 6.05 (1H, br. s.), 4.06-4.23 (2H, m), 2.81-2.99 (1H, m), 1.65-2.07 (5H, m),
I .39-1.56 (10H, m), 1.20-1.31 (4H, m), 0.99-1.16 (1H, m), 0.79-0.96 (4H, m); LCMS (ESI) m/z 323.1 (M+Na)+. [NOTE]: The second fraction was used in Step 2.
Step 2: (lR,2R,4R)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate compound with (lS,2S,4S)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate (1 : 1) dihydrochloride (D43-2)
To a mixture of tert-butyl
2-(( 1 R,3R,4R)-4-(ethoxycarbonyl)-3 -methylcyclohexyl)hydrazinecarboxylate compound with tert-butyl
2-((l S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (1 :1) (D42-1) (0.5245 g, 1.746 mmol) in EtOH (4.37 ml) was added hydrogen chloride, 4 M in
1,4-dioxane (4.37 ml, 17.46 mmol). The clear light-yellow mixture was stirred at room temperature. After 42 h (white heterogeneous mixture), LC-MS (ESI) showed that the reaction was complete, the desired product (m/z 201.2 (M+1)) was formed.. The mixture was concentrated in vacuo to provide (lR,2R,4R)-ethyl
4-hydrazinyl-2-methylcyclohexanecarboxylate compound with (lS,2S,4S)-ethyl
4-hydrazinyl-2-methylcyclohexanecarboxylate (1 : 1) dihydrochloride (D43-2) as light-yellow solid. Ή NMR (300 MHz, DMSO-d6) δ 4.07 (2H, q, J=7.0 Hz), 2.88-3.05 (1H, m), 2.04 (2H, t, J=11.6 Hz), 1.80-1.96 (2H, m), 1.52-1.73 (1H, m), 1.12-1.46 (5H, m), 0.78-1.08 (4H, m); LCMS (ESI) m/z 201.2 (M+H)+.
Step 3 : benzyl
1 -(( 1 R,3R,4R)-4-(ethoxycarbonyl)-3 -methylcyclohexyl)-5 -(trifluoromethyl)- 1 H-pyrazole- 4-carboxylate compound with benzyl
l-((l S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylate (l :l) (D43-3)
To a mixture of (lR,2R,4R)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate compound with (1 S,2S,4S)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate (1 : 1) dihydrochloride (D42-2) (0.413 g, 1.745 mmol) in EtOH (13.42 ml) was added DIPEA (0.669 ml, 3.84 mmol) followed by a solution of (Z)-benzyl
2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (0.526 g, 1.745 mmol) in EtOH (5 mL). The clear brown mixture was stirred at room temperature. After 15 h, LC-MS (ESI) showed that the reaction wasa complete, the desired product (m/z 439.1 (M+l)) was formed. The reaction mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a brown syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 10% EtOAc in hexane to give benzyl
l-((lR,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylate compound with benzyl
1 -((1 S,3 S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4 -carboxylate (1 : 1) (D43-3) (0.4258 g, 0.971 mmol, 55.7% yield) as yellow syrup: lH NMR (300 MHz, DMSO-d6) δ 8.06-8.17 (1H, m), 7.29-7.50 (5H, m), 5.29 (2H, s), 4.42-4.60 (1H, m), 4.10 (2H, q, J=7.1 Hz), 1.48-2.13 (8H, m), 1.19 (3H, t, J=7.1 Hz), 0.89 (3H, d, J=6.0 Hz); LCMS (ESI) m/z 439.1 (M+H)+.
Step 4:
l-((lR,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylic acid compound with
l-((lS,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxy lie acid (l : l) (D43)
A pressurized vial was charged with palladium 10 wt. % on activated carbon (0.103 g, 0.097 mmol) while under a stream of nitrogen gas. Then a solution of benzyl l-((l R,3R,4R)-4-(ethoxycarbonyl)-3-mcthylcyclohexyl)-5-(trilluoromcthyl)-l H-pyrazole- 4-carboxylatc compound with benzyl
1 -((1 S S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoi mcthyl)-l I I-pyrazole-4 -carboxylate (1 : 1) (D43-3) (0.4258 g. 0.971 nimol) in a 1 :1 mixture of EtOH (2.428 ml)/EtOAc (2.428 ml) was added into the vial. The reaction atmosphere was purged with hydrogen gas (3 times). The reaction was stirred vigourously under hydrogenation (33 psi) at 21 °C. After 3 h. LC.VIS (ESI) showed that the reaction was complete . The reaction mixture was purged with nitrgen gas for 30 min. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOAc. The filtrate was concentrated in vacuo to give
1 -(( 1 R,3R,4R)-4-(ethoxycarbonyl)-3 -methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole- 4-carboxylic acid compound with
1 -((1 S,3S.4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluorometh l)-l 11-pyrazole-4 -carboxylic acid (1 : 1 ) (D43) (0.3224 g, 0.926 mmol, 95% yield) as light-yellow solid: 'H NMR (300 MHz, DMSO-d6) 5 13.14 (lH, br: s.), 8.01 (lH, s), 4:40-4.59 (1H, m), 4.10 (21 L q, .7=7.0 Hz), 1.48-2.16 (8H. m), 1.20 (311. t. J 7.1 Hz), 0.89 (311, d, J 6.0 Hz): LCMS (ESI) m/z 349.1 (M+H)+,
[Reference example D48]
1 -((3aS,5R,7aS)-3a-(methoxycarbonyl)octahydro- 1 H-inden-5÷yl)-5-(trifluoromethyl)- lH-p razole-4-carbox lic acid
Figure imgf000216_0001
Step 1 : methyl 2-oxo-l-(3-oxobutyl)cyclopentanecarboxylate
A solution of methyl 2-oxocyclopentanecarboxylate (2.000 ml, 14.07 mmol), methyl vinyl ketone (1.381 ml, 16.88 mmol) and triethylamine (2.94 ml, 21.10 mmol) in toluene (20 mL) was heated at 40 PC for 24 h. The reaction was brought to room temperature, diluted with EtOAc, washed with sat. NH4CI, dried over Na2SO_i, filtered, concentrated and chromatographed on silica gel using 0-50% heptane/EtOAc to afford a colorless oil as methyl 2-oxo-l-(3-oxobutyl)cyclopentanecarboxylate (2.0 g, 9.42 mmol, 67.0% yield). Step 2: methyl 5-(pyrrolidin-l-yl)-2,6,7,7a-tetrahydro-lH-indene-7a-carboxylate
A solution of methyl 2-oxo-l-(3-oxobutyl)cyclopentanecarboxylate (2.0 g, 9.42 mmol, 67.0 % yield) and pyrrolidine (2.354 ml, 28.1 mmol) in dry toluene (25 mL) was heated to reflux under N2 atmosphere in a Dean-Stark trap for 16 h. The reaction went to completion and concentrated. The residue was dissolved in EtOAc, washed with water, brine, dried over Na2SOz|., filtered and concentrated to afford a greenish oil as methyl
5-(pyrrolidin-l-yl)-2,6,7,7a-tetrahydro-lH-indene-7a-carboxylate (3.3 g, 13.34 mmol, 95% yield) to be used as is.
Step 3: methyl 6-oxo-2,3,3a,4,5,6-hexahydro-lH-indene-3a-carboxylate
The crude enamine from Step 2 was dissolved in toluene (20 mL) and a solution of sodium acetate (1.360 ml, 25.3 mmol) in AcOH/water (4/4 mL) was added and the resulting mixture was heated to reflux under N2 atmosphere for 2 h. The reaction went to completion, diluted with EtOAc, washed with water, sat. NH4CI, sat. NaHCC^, brine, dried over Na2SO_i, filtered, concentrated and chromatographed on silica gel using 0-30% heptane/EtOAc to afford methyl 6-oxo-2,3,3a,4,5,6-hexahydro-lH-indene-3a-carboxylate (1.32 g, 6.80 mmol, 48.3% yield) as a bright yellow oil. MS m/z=\952 [M+H]+.
Step 4: (3aS,7aR)-methyl 6-oxooctahydro-lH-indene-3a-carboxylate
To a stirred solution of methyl ό-οχο-2,3, 3a,4,5,6-hexa ydro-lH-indene-3a-carboxylate (1.32 g, 6.80 mmol) in EtOH (30 mL) was added palladium, 10 wt.%(dry basis) on activated carbon, wet, degussa type el 01 ne/w (0.120 ml, 6.80 mmol) and the resulting mixture underwent hydrogenation using the hydrogenation kit for 3 h. The mixture was filtered through celite, concentrated and chromatographed on silica gel using 0-25% heptane/hexane to afford (3aS,7aR)-methyl 6-oxooctahydro-lH-indene-3a-carboxylate (0.278 g, 1.417 mmol, 20.84% yield) and (3aS,7aS)-methyl 6-oxooctahydro-lH-indene-3a-carboxylate (0.394 g, 2.008 mmol, 29.5% yield) as colorless oil. MS m/z=\ 81.2 [M+H]+.
Steps 5 through 8. ' -
1 -((3aS,5R,7aS)-3a-(methoxycarbonyl)octahydro- 1 H-inden-5-yl)-5-(trifluoromethyl)- 1 H-p yrazole-4-carboxylic acid was prepared from (3aS,7aR)-methyl
6-oxooctahydro-lH-indene-3a-carboxylate using similar procedures as in example D22. MS m/z=361.2 [M+H]+.
[Example D55]
tra/7i-l-(4-(Ethoxycarbonyl)-3,3-dimethylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4- carboxylic acid (racemic mixture)
Figure imgf000218_0001
Step l :
Ethyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (racemic mixture)
Methyllithium (170 mL of a 1.6 M solution with Et20, 260 mmol) was added to a stirring mixture of copper (I) iodide (25 g, 130 mmol) and Et20 (130 mL), at—40 °C under a nitrogen atmosphere. After stirring for 10 min at—40 °C, ethyl
2-methyl-4-oxo-2-cyclohexene-l-carboxylate (12 g, 66 mmol) was added. After stirring for 30 min at -40 °C, the reaction mixture was allowed to warm to -20 °C. After stirring for 90 min at -20 °C, saturated aqueous ammonium chloride and EtOAc were added sequentially, the mixture was partitioned between more saturated aqueous ammonium chloride and EtOAc, the layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (2x) and brine, dried (Na2S04), filtered, and the filtrate was concentrated. The residue was dissolved with DCM, silica gel (39 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 19: 1 to 9:1 hexane— EtOAc) to give ethyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (8.9 g, 68% yield; racemic mixture) as a clear yellow oil.
Step 2:
tert-Butyl tr w-2-4-(ethoxycarbonyl)-3 ,3 -dimethylcyclohexyl)hydrazinecarboxylate (racemic mixture)
NaBH(OAc)3 (29 g, 140 mmol) was added to a stirring solution of ethyl
2,2-dimethyl-4-oxocyclohexanecarboxylate (8.9 g, 45 mmol, from Step 1 ; racemic material), tert-butyl carbazate (6.5 g, 49 mmol), glacial AcOH (7.8 mL, 140 mmol), and THF (90 mL). After stirring for 26 h, the reaction mixture was added to saturated aqueous NaHC03, the mixture was stirred for 60 min, partitioned between EtOAc and more saturated aqueous NaHC03, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHC03 and brine, dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, silica gel (42 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 9: 1 to 4: 1 hexane— EtOAc) and the isolated material containing the desired product was re-subjected to flash chromatography on silica gel (5:1 hexane— EtO Ac) to give tert-butyl tra«5-2-4-(ethoxycarbonyl)-3,3-dimethylcyclohexyl)hydrazinecarboxylate (0.79 g, 5.6% yield; racemic mixture) as a clear colorless oil.
Step 3:
Ethyl tra«5-4-hydrazinyl-2,2-dimethylcyclohexanecarboxylate hydrochloride (racemic mixture) ■ «'
Hydrogen chloride (3.1 mL of a 4.0 M solution with 1,4-dioxane, 13 mmol) was added to a stirring solution of tert-butyl
tra«5-2-4-(ethoxycarbonyl)-3,3-dimethylcyclohexyl)hydrazinecarboxylate (0.79 g, 2.5 mmol, from Step 2; racemic material) and EtOH (5.0 mL), and then the reaction mixture was heated at 60 °C. After stirring for 3 h at 60 °C, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give ethyl trara-4-hydrazinyl-2,2-dimethylcyclohexanecarboxylate hydrochloride (0.63 g, 100% yield; racemic mixture) as an off-white solid.
Step 4:
Benzyl
trans- 1 -4-(ethoxycarbonyl)-3 ,3-dimethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-ca rboxylate (racemic mixture)
A solution of (Z)-benzyl
2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (0.76 g, 2.5 mmol) and EtOH (2.4 mL) was added to a stirring solution of ethyl
tra«5-4-hydrazinyl-2,2-dimethylcyclohexanecarboxylate hydrochloride (0.63 g, 2.5 mmol, from Step 3; racemic mixture), DIPEA (0.96 mL, 5.5 mmol), and EtOH (6.0 mL). After stirring for 20 h, the reaction mixture was concentrated under reduced pressure, the residue was partitioned between EtOAc and saturated aqueous NaHC03, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHC03 and brine, dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, silica gel (5.0 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (19: 1 hexane— EtOAc) to give benzyl
trans- 1 -4-(ethoxycarbonyl)-3 ,3 -dimethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-ca rboxylate (0.76 g, 67% yield; racemic mixture) as a clear colorless oil. 1H NMR (400 MHz, CDC13) δ 7.94 (s, 1H), 7.46-7.29 (m, 5H), 5.30 (s, 2H), 4.67-4.52 (m, 1H), 4.25-4.05 (m, 2H), 2.35-2.23 (m, 1H), 2.12-1.84 (m, 5H), 1.69 (dd, J= 3.2, 12.8 Hz, 1H), 1.27 (t, J= 7.1 Hz, 3H), 1.09 (s, 3H), 1.07 (s, 3H) . LCMS (ESI): 453.0 (M+H)+.
Step 5:
trans- 1 -(4-(Ethoxycarbonyl)-3 ,3 -dimethyl cyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4- carboxylic acid (racemic mixture)
A stirring mixture of benzyl
trans- 1 -4-(ethoxycarbonyl)-3 ,3 -dimethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-ca rboxylate (0.76 g, 1.7 mmol, from Step 4; racemic mixture), palladium (0) (10 wt. % dry basis, wet) on activated carbon (0.18 g, 0.17 mmol), EtOAc (4.2 mL), and EtOH (4.2 mL) was exposed to gaseous hydrogen (33 psi). After stirring for 2 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give
trans- 1 -(4-(ethoxycarbonyl)-3 ,3 -dimethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4- carboxylic acid (0.59 g, 97% yield; racemic mixture) as a colorless solid. LCMS (ESI): 363.0 (M+H)+.
[Reference example D60] l-(((+/-)-cis)-2-allylcyclohexyl)-5-(trifluoroniethyl)-lH-pyrazole-4-carboxylic acid as a racemate (D60)
Figure imgf000222_0001
Step 1 : tert-butyl 2-(((+/-)cis)-2-allylcyclohexyl)hydrazinecarboxylate as a racemate
To a solution of tert-butyl carbazate (0.966 g, 7.31 mmol), 2-allyIcyclohexanone (1.00 g, 7.24 mmol), and AcOH (1.00 ml, 17.47 mmol) at 0 °C was added NaBH(OAc)3 (4.60 g, 21.71 mmol) and the mixturew was stirred at room temperature overnight. The reaction mixture was added slowly to a saturated aqueous solution of Na2C03. The layers were separated and the aqueous layer was extracted with DCM twice. The organics were pooled, washed with brine, dried over Na2S04, decanted and concentrated in vacuo to provide a colorless syrup. NMR indicated—0.16: 1 mixture of isomers. The syrup was purified by silical gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane. The first eluting peak was collected and concentrated in vacuo to provide tert-butyl 2-(((+/-)cis)-2-allylcyclohexyl)hydrazinecarboxylate as a racemate. Step 2: (((+/-)cis)-2-allylcyclohexyl)hydrazine dihydrochloride as a racemate
4 M HC1 in dioxane (1 1.79 ml, 47.2 mmol) was added to a solution of tert-butyl 2-(((+/-)cis)-2-allylcyclohexyl)hydrazinecarboxylate as a racemate (1.20 g, 4.72 mmol) in EtOH (11.79 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to provide (((+/-)cis)-2-allylcyclohexyl)hydrazine dihydrochloride as a racemic, white solid.
Step 3: ethyl
1 -(((+/-)cis)-2-allylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylate as a racemate
A solution of (Z)-ethyl
2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (1.073 g, 4.49 mmol) in EtOH (1 1 raL) was added slowly to a solution of (((+/-)cis)-2-allylcyclohexyl)hydrazine dihydrochloride as a racemate (1.07 g, 4.71 mmol) and DIPEA (1.724 ml, 9.87 mmol) in EtOH (22.43 ml) at room temperature. After 6 h, the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2S04, decanted and concentrated in vacuo to provide an orange oil. The mixture was purified by silica gel column chromatography eluting with a gradient of 0% to 35% EtOAc in hexane to provide ethyl
1 -(((+/-)cis)-2-allylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylate as a racemate as a pale yellow oil.
Step 4: l-(((+/-)-cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid as a racemate
A solution of lithium hydroxide hydrate (1.265 g, 30.2 mmol) in water was added to a solution of ethyl
l-(((+/-)cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate as a racemate (0.996 g, 3.02 mmol) in THF and MeOH and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting turbid solution was diluted with water to provide a clear solution. The pH was adjusted to 1 by adding 1 M HC1 and the mixture was stirred vigorously for 30 min. The resulting precipitate was collected by vacuum filtration to provide l-(((+/-)-cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid as a racemate (D60) as a white solid.
[Reference example D68 (cis and trans)]
l-((lr,4r)-4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid and
1 -((1 s,4s)-4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole- -carboxylic acid
Figure imgf000224_0001
To a solution of Cul (5.8 g, 30 mmol, 3.24 eq) in Et20 (100 mL) maintained under N2 at 0 °C was added a solution of 3.0 M MeLi (21.3 mL, 64 mmol, 6.8 eq) in
dimethoxyethane dropwise. The resulting solution was stirred at 0 °C for 10 min and the ether solvent was removed from the reaction under vacuum (120 torr) at 0 °C. DCM (100 mL) was then added to, the residue and the reaction was cooled to -78 °C. TMSC1 (4.4 mL, 35 mmol, 3.7 eq) was added followed by ethyl
2-(l,4-dioxaspiro[4.5]decan-8-ylidene)acetate (JW Pharmlab, Levittown, PA; 2.127 g, 9.4 mmol) in DCM (10 mL). The reaction mixture was stirred overnight and quenched with aqueous NH4C1 solution. The black suspension was filtered through celite and the organic layer was separated, washed, dried and purified by silica gel chromatography (EtOAc/hexane, up to 15%) on 80 g gold column to give ethyl
2-(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)acetate (1.6 g, 6.60 mmol, 70.2% yield) as a colorless liquid: Ή NMR (500 MHz, CDC13) δ 1.07 (s, 3H), 1.19-1.33 (m, 3H), 1.49-1.67 (m, 8H), 2.27 (s, 2H), 3.94 (s, 4H), 4.09-4.16 (m, 2H).
Step 2: ethyl 2-(l-methyl-4-oxocyclohexyl)acetate
Water (0.5 mL) was added to a stirring solution of ethyl
2-(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)acetate (1.6 g, 6.60 mmol) and formic acid (10 mL) at room temperature. Analysis of the reaction mixture by LCMS indicated that the starting material was consumed and the desired product had formed. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and brine, the layers were separated, the organic material was washed with brine (2x), dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid ethyl 2-(l-methyl-4-oxocyclohexyl)acetate (1.6 g, 8.07 mmol, 86% yield): 1H NMR (500 MHz, CDC13) δ 1.22-1.31 (m, 6H), 1.77-1.91 (m, 4H), 2.39-2.43 (m, 6H), 4.12-4.23 (m, 2H).
Step 3 : tert-butyl 2-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)hydrazinecarboxylate
Ethyl 2-(l-methyl-4-oxocyclohexyl)acetate (1.5 g, 7.57 mmol) and tert-butyl carbazate (1.100 g, 8.32 mmol) were dissolved in chloroform (30 mL), and AcOH (1.0 mL) and NaBH(OAc)3 (5.65 g) were added under ice-cooling. The mixture was allowed to gradually return to room temperature, and the mixture was stirred for 4 h. The reaction mixture was poured into saturated aqueous NaHC03 solution, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:EtOAc, 100%-35%) to give tert-butyl 2-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)hydrazinecarboxylate (1.72 g, 5.47 mmol, 72.3% yield) as a mixture of isomers (colorless oil). LCMS = 315.4 (M+H)+. Step 4: ethyl 2-(4-hydrazinyl-l-methylcyclohexyl)acetate hydrochloride
tert-Butyl 2-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)hydrazinecarboxylate (1.7 g, 5.41 mmol) in EtOH (5 mL) was added HC1 (4 M in 1,4-dioxane, 10 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 4 h and concentrated to give a white solid, used without further purification in the next step.
Step 5: benzyl : ,·
1 -(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carbo xylate
A solution of (Z)-benzyl
2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl
2-(4-hydrazinyl-l-methylcyclohexyl)acetate hydrochloride (1.6 g, 6.38 mmol) and DIPEA (2.452 ml, 14.04 mmol) in EtOH (31.9 ml) at ambient temperature. The reaction was allowed to stir overnight. The solvent was removed and the residual oil was purified using a 40 g REDISEP™ Gold Si02 column eluting with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and
concentrated in vacuo to provide benzyl
l-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carbo xylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS = 453.4 (M+H)+.
Step 6:
l-((lr,4r)-4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid and 1 -((1 s,4s)-4-(2-ethoxy-2-oxoethyl)-4-methyIcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole- 4-carboxylic acid
Benzyl
1 -(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoroniethyl)- 1 H-pyrazole-4-carbo xylate (2.1 g, 4.64 mmol) was dissolved in EtOH (10 mL) and EtOAc (10 mL) and added to wet Pd/C (10%, 210 mg) in a pressure flask under N2 . The reaction mixture was equipped with a pressure gauge and one arm was connected vacuum and the other to hydrogen cylinder. The pressure was set to 20 psi and the reaction system was connected to hydrogen and open to vacuum twice. Then the valves were closed and the reaction mixture was stirred for 2 h. The pressure of the gauge was 5 psi and LCMS showed completion. Filtration, through celite and removal of solvents gave an oil (1.5 g). The material was separated by prep SFC: 150x50 mm AD-H column with 18 mL/min MeOH (20 mM NH3) + 162 g/min C02, 10% co-solvent at 180 g/min. Temp. = 29°C, Outlet pressure = 100 bar, Wavelength = 230 nm. Injected 0.5 mL of 1 ,500 mg sample dissolved in 20 mL 1 : 1
MeOF DCM; c= 75 mg/mL and 37.5 mg per injection. Cycle time 11 min, run time 15 min, to give Peak 1 : white solid
l -((lr,4r)-4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid (600 mg, 1.656 mmol, 35.7% yield): 1H NMR (500 MHz, CD2C12) δ 1.14 (s, 3H), 1.23-1.28 (m, 3H), 1.46-1.58 (m, 2H), 1.67-1.77 (m, 2H), 1.79-1.87 (m,. 2H), 2.16-2.28 (m, 4H), 4.08-4.14 (m, 2H), 4.32 (tt, J=11.7, 4.1 Hz, 1H), 6.76 (br. s, 1H), 7.94 (s, 1H). LCMS = 363.3 (M+H)+; Peak 2:
l-((ls,4s)-4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylic acid (700 mg, 1.932 mmol, 41.6% yield): 1H NMR (500 MHz, CDC13) δ 1.09 (s, 3H), 1.25-1.28 (m, 3H), 1.33-1.43 (m, 2H), 1.82-L88 (m, 4H), 2.17-2.32 (m, 2H), 2.47 (s, 2H), 4.12-4.17 (m, 2H), 4.35 (tt, J=l 1.7, 3.9 Hz, 1H), 6.72 (br. s, 1H), 7.98 (s, lH). LCMS = 363.4 (M+H)+.
The following pyrazole carboxylic acids were prepared using similar procedure in reference examples described above.
Figure imgf000229_0001
D3 D4 D5
Figure imgf000229_0002
D9 D10 D11
D15 D16 D17
Figure imgf000229_0004
D18 D21 D23
Figure imgf000229_0005
Figure imgf000230_0001
D38 D39 D80
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
[Example 1]
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(4-fluorobenzyl)carbamoyl)-5-(trifluo romethyl)- 1 H-pyrazol- l-yl)cyclohexanecarboxylic acid
Figure imgf000234_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-(triethylsilyloxy)ethyl)(4-fluorobenzyl)carbamo yl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (1-1)
To a mixture of acid Dl (6.22 g, 18.6 mmol) and amine Al (8.67 g, 20.4 mmol) in DMF (100 mL) were added HATU (8.48 g, 22.3 mmol) and DIPEA (4.74 mL, 27.9 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure to afford compound 1-1 (15 g, crude) as a brown gum.
Step 2: ethyl *
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(4-fluorobenzyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate ( 1 -2)
To a stirred solution of compound 1-1 (15 g, 20.2 mmol) in THF (20 mL) was added TBAF (1.0 M in THF, 40.4 mL, 40.4 mmol) dropwise at 0 °C, and the mixture was allowed to warm up from 0 °C to room temperature while stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4CI (Ϊ00 mL) and extracted with EtOAc (2*150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 70% EtOAc/hexane) to provide compound 1-2 (9.9 g, 84% over two steps) as a yellow-brown gum. Ή NMR (CDCI3) rotomers present δ 8.42 and 8.38 (2H, 2xs) ; 7.57 and 7.53 (IH, 2xs) ; 7.41-7.35 and 7.14-7.09 (4H, 2xm) ; 5.61-5.45 (IH, m) ; 5.10-4.50 (3H, m) ; 4.25-3.90 (4H, m) ; 3.31-3.15 (IH, m) ; 2.23-2.16 (6H, m) ; 1.65-1.51 (2H, m) ; 1.28-1.23 (3H, m); LCMS: 631 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(4-fluorobenzyl)carbamoyl)-5-(trifluo romethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate (1-3)
To a stirred solution of compound 1-2 (9.9 g, 15.6 mmol) in DCM (120 mL) was added Dess-Martin periodinane (21.9 g, 21.9 mmol) in portions, and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with NaHC03 (50 mL, sat. aq.) and Na2S203 (50 mL, sat. aq.), then extracted with DCM (2 150 mL). The combined organic layers were washed with water (100 mL), brine (lOO rnL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 10% EtOAc/hexane) to yield compound 1-3 (9.12 g, 92%) as a white solid.. 1H NMR (CDC13) rotomers present δ 8.74 and 8.67 (2H, 2xs) ; 7.85 and 7.79 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7.41-7.37 and 7.22-7.15 (3H, 2xm); 4.73-151 (4H, m) ; 4.27-4.21 (IH, m) ; 4.07 (2H, q, J = 7.2 Hz) ; 2.50-2.48 (IH, m) ; 2.06-1.93 (6H, m) ; 1.59-1.54 (2H, m) ; 1.18 (3H, t, J = 6.9 Hz); LCMS: 629 (M+H)+. Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(4-fluorobenzyl)carbamoyl)-5-(trifluo romethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (1) To a stirred solution of compound 1-3 (9.12 g, 14.5 mmol) in a mixture of
THF/water/EtOH (77 mL, 7:1 :7) was added LiOH (4.0 M aq. solution, 4.45 mL, 57.9 mmol) dropwise at 0 °C. The mixture was allowed to warm to room temperature while stirring continued for 4 h. The reaction mixture was acidified with HC1 (1 M, 60 mL) and extracted with EtOAc (3 χ 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04 and concentrated under reduced pressure to provide the compound of example 1 (8.0 g, 94%) as a white solid. 1H NMR (CDC13) rotomers present δ 8.53 and 8.47 (2H, 2xs) ; 7.69 and 7.60 (IH, 2xs) ; 7.31-7.28 (IH, m) ; 7.16-7.12 (IH, m) ; 7.06-7.02 (2H, m) ; 4.83 and 4.65 (2H, 2xs) ; 4.61 and 4.30 (2H, 2xs), 4.27-4.21 (IH, m) ; 2.78 (IH, m) ; 2.44-2.40 (2H, m) ; 2.26-2.15 (2H, m) ; 1.96-1.86. (2H, m) ; 1.74-1.67 (2H, m); LCMS (ESI): 601.2 (M+H)+.
[Example 2]
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-
Figure imgf000236_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl )carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (2- 1 ) To a solution of acid D2 (12.5 g, 35.9 mmol) and (COCl)2 (4.62 mL, 39.51 mmol) in DCM (150 mL) was added DMF (catalytic amount), and the whole was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in DCM (10 mL) and added dropwise to a mixture of amine A31 (18.3 g, 39.5 mmol) and Et3N (10.0 mL, 71.8 mmol) in DCM (150 mL) at 0 °C. Upon completion of reaction (monitored by TLC), the mixture was quenched with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 0-10% EtOAc/hexane as eluent) to provide compound 2-1 (27.0 g, 91%) as a colorless gum, 1H NMR (CDC13) rotomers present δ 7.54 and 7.47 (1H, 2xs) ; 7.02-6.98 (2H, m) ; 6.87-6.86 and 6.56-6.54 (2H, 2xm) ; 6.73-6.71 (1H, m) ;
5.90-5.88 and 5.50-5.47 (1H, 2xm) ; 4.99-4.29 (2H, m) ; 4.18-4.12 and 3.30-3.26 (4H, 2xm) ; 3.87-3.81 (1H, m) ; 2.21-2.16 (2H, m) ; 1.89-1.88 (6H, m) ; 1.35-1.24 (6H, m) ;
0.91-0.84 (9H, m) ; 0.58-0.48 (6H, m).
Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoy l)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methyl cyclohexanecarboxylate (2-2)
Compound 2-2 was prepared using a similar procedure to that described in example
1, step 2.
Step 3: ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5- (trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (2-3)
Compound 2-3 was prepared using a similar procedure to that described in example 1, step 3.
Step 4: trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5- (trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid (2)
The compound of example 2 was prepared using a similar procedure to that described in example 1, step 4. 1H, NMR (CDC13) rotomers present δ 8.55 and 8.49 (2H, 2xs) ; 7.66 and 7.62 (1H, 2xs) ; 6.85-6.69 (3H, m) ; 4.83 and 4.70 (2H, 2xs) ;4.62 and 4.34 (2H, 2xs) ; 4.29-4.21 (1H, m) ; 2.25-2.17 (2H, m) ; 1.94-1.88 (6H, m) ; 1.41 and 1.40 (3H, 2xs) LCMS (ESI): 650.2 (M+H)+.
[Example 3]
trans-4-(4-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen-3-yl)-2-oxoethyl)carbamoyl)-5-(t rifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000238_0001
Step 1 and 2: ethyl
trans-4-(4-((3,5-difluorobenzyl)(-2-(2,4-dimethylthiophen-3-yl)-2-hydroxyethyl)carbamoyl) -5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (3-2)
To a mixture of acid Dl (162 mg, 0.48 mmol) and amine A56 (200 mg, 0.48 mmol) in DMF (4 mL) were added DIPEA (0.12 mL, 0.72 mmol) and HATU (221 mg, 0.58 mmol) at room temperature and stirred at the same temperature for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure to provide a yellow residue.
To a stirred solution of the yellow residue was added TBAF (1 M in THF, 0.96 mL, 0.96 mmol) dropwise at room temperature. The mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHC03 solution and extracted with EtO Ac (2x20 mL). The organic layers were washed with brine (2 x 10 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtO Ac/hexane as eluent) to provide compound 3-2 (290 mg, 97%) as a colorless gum.
Step 3: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen-3-yl)-2-oxoethyl)carbamoyl)-5-(t rifluoromethyl)-lH-pyrazol-l-yl)cyelohexanecarboxylate (3-3)
To a stirred solution of compound 3-2 (290 mg, 0.47 mmol) in DCM (8 mL) was added Dess-Martin periodinane (401 mg, 0.94 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous Na2S203 and NaHC03, and extracted with EtO Ac (2x20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 3-3 (220 mg, 78%) as a colorless gum. Step 4:
trans-4-(4-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen-3-yl)-2-oxoethyl)carbamoyl)-5-(t rifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (3)
To a solution of compound 3-3 (220 mg, 0.37 mmol) in EtOH (1 mL), THF (1 mL) and H20 (0.2 mL) was added LiOH (4 M aqueous solution, 0.55 mL, 2.2 mmol) dropwise, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by dropwise addition of 1 M aqueous HC1 (pH was adjusted to 4.0) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 56% water/CH3CN as eluent) to provide the compound of example 3 (56 mg, 26%) as a white solid. Ή NMR (DMSO-d6) rotamers present δ 7.63 and 7.50 (1H, 2xs) ; 7.14 and 7.09 (1H, 2xs) ;
6.83-6.81 (1H, m) ; 6.77-6.68 (2H, m) ; 4.78 and 4.69 (2H, 2xs) ; 4.59 and 4.28 (2H, 2xs) ; 4.27-4.18 (1H, m) ; 2.49-2.38 (4H, m) ; 2.25-2.18 (5H, m) ; 2.10-1.97 (4H, m) ; 1.70-1.57 (2H, m); LCMS (APCI): 584 (M+H)+.
[Example 4]
trans-4-(4-((2-(2,6-dichloro-4-(methylsulfonyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000240_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-(methylthio)phenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluoro benzyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (4-1)
Compound 4-1 (0.44 g, crude) was obtained as a brown color gum from the reaction of amine A57 (0.26 g, 0.52 mmol), acid Dl (0.17 g, 0.52 mmol), HATU (0.24 g, 0.63 mmol) and DIPEA (0.13 mL, 0.79 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-(methylthio)phenyl)-2-hydroxyethyl)(3,5-difluorobenzyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate ,(4-2)
Compound 4-2 (0.38 g, 91%) was obtained as brown color gum from the reaction of compound 4-1 (0.44 g, 0.59 mmol) and TBAF (1.0 M in THF, 0.31 mL, 1.19 mmol) in THF (10 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-(2,6-dichloro-4-(methylthio)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbam oyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (4-3)
Compound 4-3 (0.1 g, 26%) was obtained as a colorless gum from the reaction of compound 4-2 (0.38 g, 0.61 mmol) and Dess-Martin periodinane (0.52 g, 1.22 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4: ethyl
trans-4-(4-((2-(2,6-dichloro-4-(methylsulfonyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyI)-5 -(trifluoromethyl)- 1 H-pyrazol- l-yl)cyclohexanecarboxylate (4-4)
To a stirred solution of compound 4-3 (0.1 g, 0.1 mmol) in DCM (5 mL) was added m-CPBA (84 mg, 0.48 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with 10% NaOH solution (20 mL), water (30 mL), brine (30 mL), dried over Na2S04 and
concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound 4-4 (0.17 g, 65%) as a colorless oil.
Step 5:
trans-4-(4-((2-(2,6-dichloro-4-(methylsulfonyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (4)
The compound of example 4 (50 mg, 52%) was obtained as a white solid from the reaction of compound 4-4 (0.1 g, 0.13 mmol) and LiOH (20 mg, 0.82 mmol) in
THF/MeOH/water (2:2:1, 5 mL) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 12.21 (IH, brs) ; 8.10 and 8.03 (2H, 2xs) ; 7.88 and 7.86 (IH, 2xs) ; 7.20-7.14 (IH, m) ; 7.11-7.08 and 6.95-6.92 (2H, 2xm) ; 4.85 and 4.73 (2H, 2xs) ; 4.69 and 4.57 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 3.37 and 3.32 (3H, 2xs) ;
2.35-2.29 (IH, m) ; 2.07-2.02 (2H, m) ; 1.98-1.90 (4H, m) ; 1.60-1.49 (2H, m); LCMS (APCI): 696 (M+H)+.
[Example 5]
N-(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-N-(3,5-difluorobenzyl)-l-(trans-4-(hydroxyca rbamoyl)cyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide
Figure imgf000242_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl)car bamoyl)-5 -(trifluoron ethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (5- 1 )
Compound 5-1 (633 mg, crude) was obtained as a brown gum from the reaction of acid Dl, amine Al 8 (400 mg, 0.89 mmol), HATU (408 mg, 1.07 mmol) and DIPEA (0.23 mL, 1.34 mmol) in DMF (6.0 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (5-2)
Compound 5-2 (410 mg, 71%) was obtained as a yellow solid from the reaction of compound 5-1 (633 mg, 0.83 mmol) and TBAF (1 M in THF, 1.65 mL, 1.65 mmol) in THF (3.0 mL) using a similar procedure to that described in example 1. LCMS: 649 (M+H)+. Step 3:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (5-3)
Compound 5-3 (185 mg, 86%) was obtained as a white solid from the reaction of compound 5-2 (224 mg, 0.34 mmol) and LiOH H20 (87 mg, 2.06 mmol) in THF (3.0 mL), EtOH (2.0 mL) and water (2.0 mL) using a similar procedure to that described in example 1.
Step 4:
l-(trans-4-(((tert-butyldimethylsilyl)oxy)carbamoyl)cyclohexyl)-N-(2-(3,5-dichloropyridin -4-yl)-2-hydroxyethyl)-N-(3,5-difluorobenzyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxa mide (5-4)
Compound 5-4 (173 mg, 84%) was obtained as a white solid from the reaction of compound 5-3 (170 mg, 0.27 mmol), 0-(tert-butyldimethylsilyl)hydroxylamine (41 mg, 0.27 mmol), HATU (124 mg, 0.32 mmol) and DIPEA (0.07 mL, 0.41 mmol) in DMF (3.0 mL) using a similar procedure to that described in example 1. LCMS: 750 (M+H)+. Step 5:
l-(trans-4-(((tert-butyldimethylsilyl)oxy)carbamoyl)cyclohexyl)-N-(2-(3,5-dichloropyridin -4-yl)-2-oxoethyl)-N-(3,5-difluorobenzyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (5-5)
Compound 5-5 (100 mg, 58%) was obtained as a colorless gum from the reaction of compound 5-4 (173 mg, 0.23 mmol) and Dess-Martin periodinane (117 mg, 0.27 mmol) in DCM (20.0 mL) using a similar procedure to that described in example 1. LCMS: 748 (M i l) .
Step 6:
N-(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-N-(3,5-difluorobenzyl)-l-(trans-4-(hydroxyca rbamoyl)cyclohexyl)-5-(trifluorome,thyl)-lH-pyrazole-4-carboxamide (5)
To a stirred solution of compound 5-5 (100 mg, 0.13 mmol) in THF (8 mL) was added TBAF (1 M in THF, 0.20 mL^ 0.20 mmol) dropwise and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (2 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 7% MeOH/DCM as eluent) to provide the compound of example 5 (19 mg, 22%) as a white solid. 1H NMR (CDC13) rotamers present δ 8.54 and 8.48 (2H, 2xs) ; 7:64 and 7.60 (1H, 2xs) ; 6.84-6.68 (3H, m) ; 4.82-4.25 (5H, m) ; 2.23-2.04 (7H, m) ; 1.83-1.73 (2H, m); LCMS (APCI): 634 (M+H)+.
[Example 6| N-(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-N-(3,5-difluorobenzyl)-l-(trans-4-(methoxyca rbamoyl)cyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxamide
Figure imgf000245_0001
Step 1 :
N-(2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)-N-(3,5-difluorobenzyl)-l-(trans-4-(metho xycarbamoyl)cyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (6-1)
To a mixture of compound 5-3 (75 mg, 0.12 mmol) and O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) in DMF (3 mL) were added HATU (55 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.30 mmol) and mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2S04 and concentrated under reduced pressure to afford crude compound 6-1 (65 mg, 82%) as a white foam. LCMS: 650 (M+H)+.
Step 2:
N-(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-N-(3,5-difluorobenzyl)-l-(trans-4-(methoxyca rbamoyl)cyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (6)
The compound of example 6 (15 mg, 23%) was obtained as a white solid from the reaction of compound 6-1 (65 mg, 0.099 mmol) and Dess-Martin periodinane (85 mg, 0.19 mmol) in DCM (5.0 mL) using a similar procedure to that described in example 1. Ή NMR (CDC13) rotamers present δ 8.54 and 8.48 (2H, 2xs) ; 8.07 (IH, brs) ; 7.64 and 7.60 (IH, 2xs) ; 6.84-6.68 (3H, m) ; 4.82-4.25 (5H, m) ; 3.81 and 3.78 (3H, 2xs) ; 2.10-2.01 (7H, m) ; 1.84-1.75 (2H, m); LCMS (APCI): 648 (M+H)+. [Example 7]
trans-4-(4-((3,5-difluorobenzyl)(2-(2-hydroxy-6-methoxyphenyl)-2-oxoethyl)carbamoyl)-5 -(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid
Figure imgf000246_0001
Step 1 : ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2,6-dimethoxyphenyl)-2-((triethylsilyl)oxy)ethyl)carba moyl)-5-(trifluoromethyl)- lH-pyrazol- 1 -yl)cyclohexanecarboxylate (7-1 )
Compound 7-1 (0.23 g, crude) was obtained as a brown color gum from the reaction of amine A67 (0.13 g, 0.3 mmol), acid Dl (0.1 g, 0.3 mmol), HATU (0.13 g, 0.35 mmol) and DIPEA (76 μΕ, 0.44 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2,6-dimethoxyphenyl)-2-hydroxyethyl)carbamoyl)-5-(t rifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate (7-2)
Compound 7-2 (0.22 g, crude) was obtained as brown color gum from the reaction of compound 7-1 (0.23 g, 0.3 mmol) and TBAF (1.0 M in THF, 0.61 mL, 0.6 mmol) in THF (5 mL) using a similar procedure to that described in example 1. Step 3: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2,6-dimethoxyphenyl)-2-oxoethyl)carbamoyl)-5-(triflu oromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (7-3)
Compound 7-3 (0.16 g, 73%) was obtained as a colorless gum from the reaction of compound 7-2 (0.22 g, 0.34 mmol) and Dess-Martin periodinane (0.29 g, 0.69 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2-hydroxy-6-methoxyphenyl)-2-oxoethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (7-4)
To a stirred solution of compound 7-3 (50 mg, 0.07 mmol) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 1.5 mL, 1.4 mmol) at room temperature and the mixture was stirred for 16 h. Solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 7-4 (32 mg, 65%) as a brown color gum.
Step 5:
trans-4-(4-((3,5-difluorobenzyl)(2-(2-hydroxy-6-methpxyphenyl)-2-oxoethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (7)
The compound of example 7 (15 mg, 50%) was obtained as a white solid from the reaction of compound 7-4 (32 mg, 0.05 mmol) and LiOH (6.2 mg, 0.25 mmol) in
THF/MeOH/water (2:2: 1, 5 mL) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 11.81 (1H, brs) ; 10.89 (1H, brs) ; 7.76 and 7.64 (1H, 2xs) ; 7.42-7.23 (lH, m) ; 7.18-6.86 (3H, m) ; 6.61-6.46 (2H, m) ; 4.82-4.51 (4H, m) ; 4.25-4.13 (1H, m) ; 3.84 and 3.65 (3H, 2xs) ; 2.28-2.21 (1H, m) ; 2.03-1.89 (6H, m) ; 1.55-1.44 (2H, m); LCMS (APCI): 596 (M+H)+. [Example 8]
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(lH-pyrazol-3-yl)ethyl)carbamoyl)-5-(trifluorom ethyl)- lH-pyrazol-l-yl)cyclohexanecarboxylic acid
Figure imgf000248_0001
Step 1 : ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-((triethylsilyl)oxy)-2-(l-((2-(trimethylsilyl)ethoxy)meth yl)- 1 H-pyrazol-3 -yl)ethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecar boxylate (8-1)
Compound 8-1 (34 mg, impure) was obtained as a colorless gum from the reaction of amine A75 (40 mg, 0.080 mmol), acid Dl (26 mg, 0.080 mmol), HATU (36.4 mg, 0.096 mmol) and DIPEA (0.020 mL, 0.120 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-hydroxy-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyr azol-3-yl)ethyl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate
(8-2)
Compound 8-2 (25 mg, crude) was obtained as a colorless gum from the reaction of compound 8-1 (34 mg, 0.048 mmol) and TBAF (1 M in THF, 0.10 mL, 0.10 mmol) in THF (3 mL) using a similar procedure to that described in example 1. Step 3: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol -3-yl)ethyl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate (8-3) Compound 8-3 (40 mg, 50%) was obtained as an off-white solid from the reaction of compound 8-2 (80 mg, 0.114 mmol) and Dess-Martin periodinane (97 mg, 0.228 mmol) in DCM (5 mL) using a similar procedure to that described in example 1.
Step 4:
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(lH-pyrazol-3-yl)ethyl)carbamoyl)-5-(trifluorom ethyl)- lH-pyrazol-l-yl)cyclohexanecarboxylic acid (8)
To a stirred solution of compound 8-3 (75 mg, 0.107 mmol) in 1 ,4-dioxane (2 mL) was added HC1 (12 M, 0.5 mL). The mixture was stirred at 80 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 1 ,4-dioxane (2 mL) and NH4OH (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography (CI 8 silica gel, 70% CH3CN/water as eluent) to provide the compound of example 8 (10 mg, 16%) as a white solid. 1H NMR (CD3OD) rotamers present δ 7.74-7.50 (2H, m) ; 6.98-6.95 (1H, m) ; 6.87-6.78 (3H, m) ; 5.00 and 4.78 (2H, 2xs) ; 4.74 and 4.64 (2H, 2xs) ; 4.28-4.21 (1H, m) ; 2.36-2.28 (1H, m) ;
2.17-2.09 (2H, m) ; 2.02-1.93 (4H, m) ; 1.62-1.55 (2H, m); LCMS (APCI): 540 (M+H)+.
[Example 9]
4-(4-((3,5-difluorobenzyl)(2-(2,6-dihydroxyphenyl)-2-oxoethyl)carbamoyl)-5-(trifluoromet hyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000250_0001
Step 1 : ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-(2-hydroxy-6-methoxyphenyl)-2-oxoethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (9- 1 )
To a solution of compound 7-4 (50 mg, 0.082 mmol) in dichloroethane (3 mL) was added BBr3 (0.822 mL, 0.822 mmol, 1 M in DCM) dropwise, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to yield compound 9-1 as a brown oil (50 mg, quant.).
Step 2:
4-(4-((3,5-difluorobenzyl)(2-(2,6-dihydroxyphenyl)-2-oxoethyl)carbamoyl)-5-(trifluoromet hyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (9)
To compound 9-1 (50 mg, 0.082 mmol) was added excess BBr3 (1 M in DCM) dropwise, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 55% water/CH3CN as eluent) to provide the compound of example 9 (3 mg, 6%) as a white solid. Ή NMR (DMSO-d6) rotamers present δ 11.91 (IH, brs) ; 7.79 and 7.61 (IH, 2xs) ; 7.28-6.88 (4H, m) ; 6.36-6.02 (2H, m) ; 4.89-4.13 (5H, m) ; 2.29-2.22 (IH, m) ; 2.05-1.83 (6H, m) ; 1.55-1.46 (2H, m) ;
LCMS (ESI): 582 (M+H)+.
[Example 10] trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2,2-difluoroethyl)(3,5-difluorobenzyl)carbam -5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000251_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2,2-difluoroethyl)(3,5-difluorobenzyl)carbamoyl) -5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (10-1)
To a mixture of acid Dl (56.7 mg, 0.16 mmol) and amine B15 (60 mg, 0.016 mmol) in pyridine (4 mL) was added POCl3 (0.02 mL, 0.25 mmol) dropwise at 0 °C and stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated KHP04 solution (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15%
EtOAc/hexane as eluent) to provide compound 10-1 (25 mg, 22%) as a pale yellow solid. Step 2:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2,2-difluoroethyl)(3,5-difluoroberizyl)carbamoyl) -5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yi)cyclohexanecarboxylic acid (10)
The compound of example 10 (11 mg, 46%) was obtained as a white solid from the reaction of compound 10-1 (25 mg, 0.37 mmol) and LiOH (27 mg, 0.11 mmol) in EtOH (0.5 mL), THF (0.5 mL) and ¾0 (0.2 mL) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 8.75 and 8.69 (2H, 2xs) ; 7.91 and 7.74 (1H, 2xs) ; 7.21-6.75 (3H, m) ; 4.86 and 4.76 (2H, 2xs) ; 4.63-4.00 (3H, m) ;
2.34-2.23 (1H, m) ; 2.09-1.77 (6H, m) ; L61-1.44 (2H, m) ; LCMS (APCI): 641 (M+H)+. [Example 11]
trans-4-(4-((2-(2-amino-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000252_0001
Step 1 : ethyl
trans-4-(4-((2-(2-chloro-6-nitrophenyl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol- 1 -yl)cyclohexanecarboxylate ( 11 - 1 )
Compound 11-1 (0.40 g, crude) was obtained as a pale yellow color gum from the reaction of amine A84 (0.2 g, 0.58 mmol), acid Dl (0.19 g, 0.58 mmol), HATU (0.26 g, 0.7 mmol) and DIPEA (0.14 mL, 0.87 mmol) in DMF (10 mL) using a similar procedure to that described in example 1.
Step 2: ethyl ( '
trans-4-(4-((2-(2-chloro-6-nitrophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(trifl uoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxy late ( 11 -2)
Compound 11-2 (0.28 g, 70%) was obtained as a colorless gum from the reaction of compound 11-1 (0.40 g, 0.6 mmol) and Dess-Martin periodinane (0.51 g, 1.2 mmol) in DCM (10 mL) using a similar procedure to that described in example 1. Step 3: ethyl
trans-4-(4-((2-(2-amino-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate ( 11 -3)
Compound 11-3 (70 mg, 74%) was obtained as a yellow color gum from the reaction of compound 11-2 (0.1 g, 0.15 mmol), Fe (85 mg, 1.52 mmol) and NH4Cl (81 mg, 1.52 mmol) in EtOH/water (4: 1, 5 mL) using a similar procedure to that described in reference example A56, step 7.
Step 4:
trans-4-(4-((2-(2-amino-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (11)
The compound of example 11 (8 mg, 33%) was obtained as a yellow solid from the reaction of compound 11-3 (20 mg, 0.03 mmol) and LiOH (3.8 mg, 0.16 mmol) in
THF/MeOH/water (2:2:1, 5 mL) using a similar procedure to that described in example 1. 'H NMR (DMSO-d6) rotamers present δ 12.17 (1H, brs) ; 7.79 and 7.79 (1H, 2xs) ;
7.17-6.93 (4H, m) ; 6.70-6.54 (2H, m) ; 5.80 (1H, brs) ; 5.53 (1H, brs) ; 4.77-4.59 (4H, m) ; 4.23-4.16 (1H, m) ; 2.29-2.22 (1H, m) ; 2.06-1.88 (6H, m) ; 1.57-1.46 (2H, m) ; LCMS (APCI): 599 (M+H)+.
[Example 12]
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(2,4,6-trihydroxypyrimidin-5-yl)ethyl)carbamoyl) -5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylic acid
Figure imgf000254_0001
Step 1 : ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-((triethylsilyl)oxy)-2-(2,4,6-tris(benzyloxy)pyrimidin-5- yl)ethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (12-1)
Compound 12-1 was obtained (0.45 g, crude) as a brown color gum from the reaction of amine A85 (0.3 g, 0.4 mmol), acid Dl (0.14 g, 0.4 mmol), HATU (0.19 g, 0.5 mmol) and DIPEA (0.11 mL, 0.6 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-hydroxy-2-(2,4,6-tris(benzyloxy)pyrimidin-5-yl)ethyl)c arbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (12-2)
Compound 12-2 was obtained (0.31 g, 79%) as a brown color gum from the reaction of compound 12-1 (0.45 g, 0.4 mmol) and TBAF (1 M in THF, 0.9 mL, 0.8 mmol) in THF (10 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(2,4,6-tris(benzyloxy)pyrimidin-5-yl)ethyl)carba moyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (12-3)
Compound 12-3 was obtained (0.31 g, quant.) as a colorless gum from the reaction of compound 12-2 (0.31 g, 0.3 mmol) and Dess-Martin periodinane (0.29 g, 0.7 mmol) in DCM (10 mL) using a similar procedure to that described in example 1. Step 4:
trans-4-(4-((3,5-difluorobenzyl)(2-oxo-2-(2,4,6-trihydroxypyrimidin-5-yl)ethyl)carbamoyl) 15-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (example 12)
To a stirred solution of compound 12-3 (0.1 g, 0.1 mmol) in dioxane (5 mL) was added 6 M HC1 (5 mL) at room temperature and the mixture was stirred at 80 °C for 2 h. 10% NaOH solution was added to the reaction mixture up to pH 5 and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 75% water/CH3CN as eluent) to provide the compound of example 12 (8 mg, 12%) as a white solid. Ή NMR (DMSO-d6) rotamers present δ 7.78 and 7.72 (1H, 2xs) ; 7.18-6.89 (3H, m) ;
4.92-4.56 (4H, m) ; 4.22-4.15 (1H, m) ; 2.33-2.25 (1H, m) ; 2.05-1.87 (6H, m) ; 1.57-1.46 (2H, m) ; LCMS (APCI): 600 (M+H)+.
[Example 13]
trans-4-(4-((2-(2-acetamido-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid
Figure imgf000255_0001
Step 1 : ethyl
trans-4-(4-((2-(2-acetamido-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (13-1)
To a stirred solution of compound 11-3 (45 mg, 0.07 mmol) in 1 : 1 mixture of pyridine and DCM (5 mL) was added CH3COCl (6 μί, 0.08 mmol) at 0 °C and stirred for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound 13-1 (50 mg, quant.) as a yellow solid.
Step 2:
trans-4-(4-((2-(2-acetamido-6-chlorophenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (13)
The compound of example 13 (25 mg, 52%) was obtained as a white solid from the reaction of compound 13-1 (50 mg, 0.07 mmol) and LiOH (9 mg, 0.37 mmol) in
THF/MeOH/water (2:2: 1 , 5 mL) using a similar procedure to that described in example 1. 'H NMR (DMSO-d6) rotamers present δ 10.10 and 9.74 (1H, 2xs), 7.80 and 7.78 (1H, 2xs) ; 7.59-6.91 (6H, m) ; 4.82-4.61 (4H, m) ; 4.26-4.15 (1H, m) ; 2.34-2.24 (1H, m) ; 2.07-1.89 (9H, m) ; 1.58-1.47 (2H, m); LCMS (APCI): 641 (M+H)+.
[Example 14]
trans-4-(4-((2.(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((S)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000256_0001
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(((S)-5,5-dimethyr -2-yl)methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (14-1)
Compound 14-1 (42 mg, 61%) was obtained as a yellow foam from the reaction of acid Dl (31 mg, 0.09 mmol), amine A92 (40 mg, 0.09 mmol), HATU (42 mg, 0.11 mmol) and DIPEA (0.024 mL, 0.138 mmol) in DMF (3.0 mL) using a similar procedure to that described in example 1. LCMS (APCI): 749 (M+H)+.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(((S)-5,5-dimethylTHF-2-yl)meth yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (14-2)
, Compound 14-2 (22 mg, 62%) was obtained as a colorless gum from the reaction of compound 14-1 (42 mg, 0.056 mmol) and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) in THF (3.0 mL) using a similar procedure to that described in example 1.
LCMS (APCI): 635 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((S)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (14-3)
Compound 14-3 (15 mg, 70%) was obtained as a colorless gum from the reaction of compound 14-2 (22 mg, 0.034 mmol) and Dess-Martin periodinane (29 mg, 0.069 mmol) in DCM (4.0 mL) using a similar procedure to that described in example 1.
LCMS (APCI): 633 (M+H)+.
Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((S)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (14)
The compound of example 14 (7.5 mg, 54%) was obtained as a white solid from the reaction of compound 14-3 (15 mg, crude) and LiOH H20 (8 mg, 0.19 mmol) in
MeOH/THF/FLO (4 mL, 1 : 1 :0.5) using a similar procedure to that described in example 1 : 1H NMR (DMSO-d6) rotamers present δ 12.16 (lH, brs), 8.79 and 8.72 (2H, 2xs) ; 7.84 and 7.69 (1H, 2xs) ; 5.01-4.76 (2H, m) ; 4.30-3.81 (3H, m) ; 2.33-2.26 (1H, m) ; 2.06-1.45 (13H, m) ; 1.19-1.04 (6H, m) ; LCMS (APCI): 605 (M+H)+.
[Example 15]
trans-4-(4-((2-(2-chloro-6-hydroxyphenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(t
Figure imgf000258_0001
Step 1 : ethyl
trans-4-(4-((2-(2-chloro-6-methoxyphenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl) carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (15-1)
Compound 15-1 (0.41 g, crude) was obtained as a brown color gum from the reaction of amine A93 (0.23 g, 0.52 mmol), acid Dl (0.17 g, 0.52 mmol), HATU (0.23 g, 0.62 mmol) and DlPEA (0.133 mL, 0.78 mmol) in DMF (10 mL) using a similar procedure to that described in example 1. Step 2: ethyl ^
trans-4-(4-((2-(2-chloro-6-methoxyphenyl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl )-5-(trifiuoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (15 -2)
Compound 15-2 (0.36 g, crude) was obtained as a yellow color gum from the reaction of compound 15-1 (0.41 g, 0.54 mmol) and TBAF (1.0 M in THF, 1.1 mL, 1.08 mmol) in THF (10 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-(2-chloro-6-methoxyphenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-( trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (15-3)
Compound 15-3 (0.25 g, 70%) was obtained as a white solid from the reaction of compound 15-2 (0.36 g, 0.56 mmol) and Dess-Martin periodinane (0.47 g, 1.12 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4: ethyl .
trans-4-(4-((2-(2-chloro-6-hydroxyphenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(t rifluoromethyl)- 1 H-pyrazol- l-yl)cyclohexanecarboxylate (15-4)
To a stirred solution of compound 15-3 (0.25 g, 0.39 mmol) in DCM (10 mL) was added BBr3 (1.0 M in DCM, 3.9 mL, 3.9 mmol) at room temperature and the mixture was stirred for 16 h. Solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 15-4 (85 mg, 35%) as a yellow oil.
Step 5:
trans-4-(4-((2-(2-chloro-6-hydroxyphenyl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(t rifluoromethyl)-! H-pyrazol- l-yl)cyclohexanecarboxylic acid (15) The compound of example 15 (55 mg, 68%) was obtained as a white solid from the reaction of compound 15-4 (85 mg, 0.13 mmol) and LiOH (16.3 mg, 0.67 mmol) in THF/MeOH/water (2:2:1, 5 mL) using a similar procedure to that described in example 1. Ή NMR (DMSO-d6) rotamers present 5 7.76 and 7.74 (1H, 2xs) ; 7.28-6.78 (6H, m) ; 4.75-4.52 (4H, m) ; 4.26-4.15 (1H, m) ; 2.33-2.26 (1H, m) ; 2.07-1.90 (6H, m) ; 1.58-1.47 (2H, m) ; LCMS (APCI): 600 (M+H)+.
[Example 16]
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((R)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000260_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(((R)-5,5-dimethylTH^ -2-yl)methyl)carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- 1 -yl)cyclohexanecarboxylate (16-1)
Compound 16-1 (29 mg, 52%) was obtained as a colorless gum from the reaction of acid Dl (25 mg, 0.074 mmol), amine A94 (32 mg, 0.074 mmol), HATU (34 mg, 0.088 mmol) and DIPEA (0.019 mL, 0.11 mmol) in DMF (3.0 mL) using a similar procedure to that described in example 1. LCMS (APCI): 749 (M+H)+. Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(((R)-5,5-dimethylTHF-2-yl)met hyl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate (16-2)
Compound 16-2 (25 mg, crude) was obtained as a colorless gum from the reaction of compound 16-1 (29 mg, 0.038 mmol) and TBAF (1 M in THF, 0.076 mL, 0.076 mmol) in THF (3.0 mL) using a similar procedure to that described in example 1. LCMS (APCI): 635 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((R)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylate (16-3)
Compound 16-3 (23 mg, crude) was obtained as a colorless gum from the reaction of compound 16-2 (25 mg, crude) and Dess-Martin periodinane (33 mg, 0.078 mmol) in DCM (4.0 mL) using a similar procedure to that described in example 1. LCMS (APCI): 633 (M+H)+.
Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(((R)-5,5-dimethylTHF-2-yl)methyl)c arbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (16)
The compound of example 16 (8.5 mg, 39%) was obtained as a white solid from the reaction of compound 16-3 (23 mg, crude) and LiOH H20 (12 mg, 0.29 mmol) in
MeOH/THF/H20 (4 mL, 1 : 1 :0.5) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 12.19 (IH, brs), 8.79 and 8.72 (2H, 2xs) ; 7.84 and 7.69 (IH, 2xs) ; 5.01-4.76 (2H, m) ; 4.27-3.80 (3H, m) ; 2.33-2.26 (IH, m) ; 2.06-1.45 (13H, m) ; 1.19-1.04 (6H, m) ; LCMS (APCI): 605 (M+H)+.
[Example 17] trans-4-(5-cyclopropyl-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-! H-pyrazol- l-yl)cyclohexanecarboxylic acid
Figure imgf000262_0001
Step J : ethyl
trans-4-(5-cyclopropyl-4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(3,5-difl uorobenzyl)carbamoyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (17-1)
Compound 17-1 (130 mg, crude) was obtained as a colorless gum from the reaction of acid D20 (200 mg, 0.56 mmol), amine A18 (233 mg, 0.52 mmol), HATU (296 mg, 0.78 mmol) and DIPEA (0.165 mL, 0.97 mmol) in DMF (10 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(5-cyclopropyl-4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,5-difluorobenzy l)carbamoyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (17-2)
Compound 17-2 (80 mg, impure) was obtained as a colorless gum from the reaction of compound 17-1 (80 mg, 0.128 mmol) and TBAF (1 M in THF, 0.190 mL, 0.190 mmol) in THF (4 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(5-cyclopropyl-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-! H-pyrazol- 1 -yl)cyclohexanecarboxylate (17-3) Compound 17-3 (60 mg, 75%) was obtained as an off-white solid from the reaction of compound 17-2 (80 mg, 0.128 mmol) and Dess-Martin periodinane (110 mg, 0.250 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4:
trans-4-(5-cyclopropyl-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (17)
The compound of example 17 (8 mg, 12%) was obtained as a white solid from the reaction of compound 17-3 (70 mg, 0.113 mmol) and LiOH (8.4 mg, 0.330 mmol) in EtOH/THF/water (5mL, 2:2:1) using a similar procedure to that described in example 1. 1H NMR (DMSO-dg) rotamers present δ 8.76 and 8.69 (2H, 2xs) ; 7.46 and 7.35 (1H, 2xs) ; 7.18-7.12 and 6.95-6.91 (3H, m) ; 4.76-4.62 (4H, m) ; 4.44-4.36 (1H, m) ; 2.26-2.17 (1H, m) ; 2.03-2.00 (2H, m) ; 1.87-1.83 (5H, m) ; 1.57-1.47 (2H, m) ; 0.95-0.90 (2H, m) ; 0.68-0.64 (2H, m) ; LCMS (APCI): 591 (M+H)+.
[Example 18]
trans-4-(4-((2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid
Figure imgf000263_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-hydroxyethyl)(3,5-difluorobenzyl )carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (18-1)-
Compound 18-1 (0.18 g, crude) was obtained as a brown color gum from the reaction of amine Al l l (0.10 g, 0.26 mmol), acid Dl (87 mg, 0.26 mmol), HATU (0.12 g, 0.31 mmol) and DIPEA (67 μΐ., 0.39 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (18-2)
Compound 18-2 (0.12 g, 67%) was obtained as a colorless gum from the reaction of compound 18-1 (0.18 g, 0.26 mmol) and Dess-Martin periodinane (0.22 g, 0.52 mmol) in DCM (5 mL) using a similar procedure to that described in example 1.
Step 3:
trans-4-(4-((2-(2,6-dichloro-4-(difluoromethyl)phenyl)-2-oxoethyl)(3,5-difluorobenzyl)car bamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- l-yl)cyclohexanecarboxylic acid (18)
The compound of example 18 (15 mg, 26%) was obtained as a white solid from the reaction of compound 18-2 (60 mg, 0.08 mmol) and LiOH (11 mg, 0.43 mmol) in
THF/MeOH/water (2:2: 1, 5 mL) using a similar procedure tb that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 12.20 (1H, brs) ; 7.87-7.75 (3H, m) ; 7.21-6.88 (4H, m) ; 4.84 and 4.72 (2H, 2xs) ; 4.68 and 4.57 (2H, 2xs) ; 4.28-4.17 (1H, m) ; 2.34-2.27 (1H, m) ; 2.07-1.90 (6H, m) ; 1.59-1.49 (2H, m) ; LCMS (APCI): 668 (M+H)+.
[Example 19] trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((4-hydroxy-4-methylcyclohexyl)met hyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000265_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)((4-hydroxy-4-methylc yclohexyl)methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylat e (19-1)
Compound 19-1 (72 mg, crude) was obtained as a colorless gum from the reaction of acid Dl (44 mg, 0.129 mmol), amine Al l 2 (58 mg, 0.129 mmol), HATU (59 mg, 0.155 mmol) and DIPEA (0.034 mL, 0.194 mmol) in DMF (4.0 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)((4-hydroxy-4-methylcyclohexyl) methyl)carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (19-2)
Compound 19-2 (46 mg, 55% over two steps) was obtained as a colorless gum from the reaction of compound 19- 1 (72 mg, crude) and TBAF ( 1 M in THF, 0.18 mL, 0.18 mmol) in THF (4.0 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((4-hydroxy-4-methylcyclohexyl)met hyl)carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- 1 -yl)cyclohexanecarboxylate (19-3) Compound 19-3 (45 mg, crude) was obtained as a colorless gum from the reaction of compound 19-2 (46 mg, 0.071 mmol) and Dess-Martin periodinane (60 mg, 0.14 mmol) in DCM (5.0 mL) using a similar procedure to that described in example 1.
Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((4-hydroxy-4-methylcyclohexyl)met hyl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid (19)
The compound of example 19 (16 mg, 38%) was obtained as a white solid from the reaction of compound 19-3 (45 mg, 0.069 mmol) and LiOH H20 (18 mg, 0.41 mmol) in EtOH/THF/H20 (4 mL, 1 : 1 :0.5) using a similar procedure to that described in example 1. Ή NMR "(DMSO-d6) rotamers present δ 12.24 (1H, brs) ; 8.80 and 8.73 (2H, 2xs) ; 7.80 and 7.70 (1H, 2xs) ; 4.83 and 4.67 (2H, 2xs) ; 4.28-4.18 (1H, m) ; 3.93 and 3.87 (1H, 2xs) ; 3.49-3.47 and 3.18-3.11 (1H, 2xm) ; 2.33-2.25 (1H, m) ; 2.06-1.90 (6H, m) ; 1.58-1.01 (14H, m) ; LCMS (APCI): 617 (M-H)".
[Example 20]
trans-4-(4-((2-(3,5-Dichloropyridin-4-yl)-2-oxoethyl)(3,5'difluorobenzyl)carbamoyl)-5-(di fluoromethyl)-lH-pyrazol-l-yl)cyclohexanecarboxylic acid
Figure imgf000266_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)^
bamoyl)-5-(difluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (20- 1 )
Compound 20-1 (130 mg, 55%) was obtained as a white solid from the reaction of acid D26 (100 mg, 0.31 mmol), amine Al 8 (105 mg, 0.31 mmol), (COCl)2 (0.03 mL, 0.37 mmol), Et3N (0.08 mL, 0.63 mmol) and DMF (cat) in DCM using a similar procedure to that described in example 2. · Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(difluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (20-2)
Compound 20-2 (101 mg, 91%) was obtained as an off-white solid from the reaction of compound 20-1 (130 mg, 0.54 mmol) and TBAF (1.0 M solution in THF, 0.24 mL, 0.24 mmol) in THF (4 mL) using a similar procedure to that described in example 2.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(dif luoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (20-3)
Compound 20-3 (30 mg, 33%) was obtained as an off-white solid from the reaction of Compound 20-2 (101 mg, 0.15 mmol) and Dess-Martin periodinane (101 mg, 0.23 mmol) in DCM (8 mL) using a similar procedure to that described in example 2.
Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(dif luoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylic acid (20)
To a solution of compound 20-3 (106 mg, 0.17 mmol) in dioxane (6 mL) was added 6 M HC1 (6 mL) and heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, added H20 and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 75% C¾CN /water as eluent) to provide the compound of example 20 (36 mg, 62%) as a white solid.. 1H NMR (DMSO-d6) rotamers present δ 8.76 and 8.69 (2H, 2xs) ; 7.77 and 7.67 (IH, 2xs) ; 7.45-7.00 (4H, m) ; 4.91-4.70 (4H, m) ; 4.36-4.29 (IH, m) ; 2.31-2.24 (IH, m) ; 2.06-2.02 (2H, m) ; 1.94-1.89 (4H, m) ; 1.56-1.45 (2H, m) ; LCMS (ESI): 599 (M+H)+.
[Example 21]
trans-4-(4-((2-(2-amino-4-chloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)- 5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000268_0001
Step 1 : ethyl
trans-4-(4-((2-(2-azido-4-chloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5 -(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (21-1)
To a stirred solution of ethyl
trans-4-(4-((2-(2,4-dichloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(trif luoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylate (100 mg, 0.15 mmol) in DMF (5 mL) was added NaN3 (50 mg, 0.7 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 21-1 (60 mg, 59%) as a brown oil.
Step 2: ethyl
trans-4-(4-((2-(2-amino-4-chloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)- 5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (21 -2)
To a stirred solution of compound 21-1 (60 mg, 0.09 mmol) in THF (5 mL) was added Me3P (1.0 M in THF, 0.18 mL, 0.18 mmol) at 0 °C and mixture was stirred at room temperature for 2 h. H20 (0.06 mL) was added to the reaction mixture at 0 °C and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 21-2 (40 mg, 69%) as a yellow oil.
Step 3:
trans-4-(4-((2-(2-arnino-4-chloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)- 5-(trifluoromethyl)-l H-pyrazol- l-yl)cyclohexanecarboxylic acid (21)
To a stirred solution of compound 21-2 (40 mg, 0.06 mmol) in THF/MeOH (4 mL, 1 :1) was added a solution of LiOH (7.7 mg, 0.3 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL), acidified with 0.5 M HC1 (to pH 5) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CI 8 silica gel, 70% CH3CN/water as eluent) to provide the compound of example 21 (25 mg, 66%) as a white solid. Ή NMR (DMSO-d6) rotamers present δ 12.14 (1H, brs) ; 8.75 and 8.46 (1H, 2xs) ; 7.91 (2H, brs) ; 7.73 and 7.49 (1H, 2xs) ; 7.16-7.01 (2H, m) ; 6.89-6.85 (1H, m) ; 6.78 and 6.73 (1H, 2xs) ; 5.02 and 4.83 (2H, 2xs) ; 4.65 and 4.55 (2H, 2xs) ; 4.20-4.12 (1H, m) ; 2.33-2.21 (1H, m) ; 2.04-1.79 (6H, m) ; 1.56-1.43 (2H, m) ; LCMS (APCI): 600 (M+H)+,
[Example 22]
trans-4-(4-((2-cyanobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)carbamoyl)-5-(trifluo
Figure imgf000270_0001
Step 1 : ethyl
trans-4-(4-((2-bromobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)carba moyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyelohexanecarboxylate (22- 1 )
Compound 22-1 (310 mg, crude) was obtained as a yellow oil from the reaction of amine A118 (200 mg, 0.40 mmol), acid Dl (136 mg, 0.40 mmol), HATU (232 mg, 0.61 mmol) and DIPEA (0.14 mL, 0.81 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl
trans-4-(4-((2-bromobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)carbamoyl)-5-(tr ifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (22-2) Compound 22-2 (175 mg, 73%) was obtained as an off-white solid from the reaction of compound 22-1 (310 mg, 0.38 mmol) and TBAF (1.0 M solution in THF, 0.57 mL, 0.57 mmol) in THF (4 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-bromobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)carbamoyl)-5-(trifluo romethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (22-3)
Compound 22-3 (150 mg, 86%) was obtained as an off-white solid from the reaction of compound 22-2 (175 mg, 0.25 mmol) and Dess-Martin periodinane (161 mg, 0.37 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4: ethyl
trans-4-(4-((2-cyanobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)carbamoyl)-5-(trifluo romethyl)- 1 H-pyrazol- l-yl)cyclohexanecarboxylate (22-4)
A mixture of compound 22-3 (100 mg, 0.14 mmol) and Zn(CN)2 (34 mg, 0.28 mmol) in DMA (8 mL) was purged with argon for 10 min. Pd(PPh3)4 (33.4 mg, 0.02 mmol) was added and the mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) to provide compound 22-4 (27 mg, 29%) as an off-white solid.
Step 5:
trans-4-(4-((2-cyanobenzyl)(2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)carbamoyl)-5-(trifluo romethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (22)
The compound of example 22 (15 mg, 39%) was obtained as a white solid from the reaction of compound 22-4 (40 mg, 0.06 mmol) and LiOH (4.3 mg, 0.03 mmol) in EtOH (2 mL), THF (2 mL) and H20 (1 mL) using a similar procedure to that described in example 1. Ή NMR (DMSO-d6) rotamers present δ 8.56-8.50 (2H, m) ; 7.91 (2H, brs) ; 7.94 (IH, s) ; 7.54-7.42 and 7.17 (3H, m and s) ; 7.08 (IH, s) ; 5.62-5.58 and 4.64-4.59 (IH, 2xm) ; 4.33-4.17 (IH, m) ; 2.39-2.33 (IH, m) ; 2.10-1.93 (7H, m) ; LCMS (APCI): 608 (M+I I) .
[Example 23]
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((3,3-dimethylcyciobutyl)methyl)carb amoyl)-5-(trifluoromethyl)-l H-pyrazol- 1 -yl)cyclohexanecarboxylic acid
Figure imgf000272_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)((3,3-dimethylcyclobut yl)methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (23- 1 ) Compound 23-1 (180 mg, crude) was obtained as a yellow gum from the reaction of amine Al 19 (190 mg, 0.455 mmol), acid Dl (167 mg, 0.50 mmol), oxaly chloride (0.086 mL, 1.0 mmol), Et3N (0.10 ml, 0.68 mmol) and DMF (cat) in DCM (10 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)((3,3-dimethylcyclobutyl)methyl) carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (23-2) Compound 23-2 (60 mg, 20%, over 2 steps) was obtained as a colorless gum from the reaction of compound 23-1 (180 mg, 0.245 mmol) and TBAF (0.5 mL, 0.5 mmol, 1 M in THF) in THF (3 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((3,3-dimethylcyclobutyl)methyl)carb amoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylate (23 -3 )
Compound 23-3 (60 mg, quant) was obtained as a white solid from the reaction of compound 23-2 (60 mg, 0.096mmol) and Dess-Martin periodinane (83 mg, 0.193 mmol) in DCM (10 mL) using a similar procedure to that described in example 1.
Step 4: „
tans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)((3,3-dimethylcyclobutyl)methyl)carba moyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)cyclohexanecarboxylic acid (23 )
The compound of example 23 (30 mg, 52%) was obtained as an off-white solid from the reaction of compound 23-3 (60 mg, 0.097 mmol) and LiOH (19 mg, 0.048 mmol) in THF/water/MeOH (5 mL, 2:2: 1) using a similar procedure to that described in example 1. lH NMR (CD3OD) rotamers present δ 8.65 and 8.58 (2H, 2xs) ; 7.74 and 7.57 (IH, 2xs) ; 4.81 and 4.63 (2H, 2xs) ; 4.36-4.24 (IH, m) ; 3.62 and 3.42 (2H, 2xd, J=7.5 Hz) ; 2.67-2.34 (2H, m) ; 2.21-2.02 (6H, m) ; 1.92-1.81 (2H, m) ; 1.70-1.56 (3H, m) ; 1.37-1.29 (IH, m) ; 1.15-0.93 (6H, m); LCMS (APCI): 591 (M+H)+.
[Example 186]
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid
Figure imgf000274_0001
Step 1 : ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl) -5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (186-1)
Compound 186-1 was obtained from the reaction of amine A3 (60 mg, 0.153 mmol), acid D2 (56 mg, 0.161 mmol), oxaly chloride (0.028 mL, 0.322 mmol), 1 N NaOH (0.92 mL, 0.920 mmol) and DMF (cat) in DCM (1 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(trifluor omethyl)- 1 H-pyrazol- 1 -yl)— 1 -methylcyclohexanecarboxylate ( 186-2)
Compound 186-2 (89 mg, 96% over 2 steps) was obtained as a colorless syrup from the reaction of compound 186-1 (crude) and TBAF (0.169 mL, 0.169 mmol, 1 M in THF) in THF (1 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluorome thyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (186-3)
Compound 186-3 (69 mg, 78%) was obtained as a white solid from the reaction of compound 186-2 (89 mg, 0.147 mmol) and Dess-Martin periodinane (87 mg, 0.205 mmol) in DCM (2 mL) using a similar procedure to that described in example 1. Step 4:
trans-4-(4-((2-(3,5-Dichloropyridin-4-yl)-2-oxoethyl)-(2,2-dimethylpropyl)carbamoyl)-5-(t rifluoromethyl)pyrazol-l -yl)-l-methylcyclohexane-l-carboxylic acid (186)
The compound of example 186 (51 mg, 77%) was obtained as a white solid from the reaction of compound 186-3 (69 mg, 0.114 mmol) and 4 N LiOH (0.228 mL, 0.912 mmol) in THF/water/MeOH ( 1 mL, 2:1 :2) using a similar procedure to that described -in example 1. 1H NM (CDCI3) rotamers present δ 8.57 and 8.50 (2H, 2xs) ; 7.71 and 7.57 (1H, 2xs) ; 4.87 and 4.53 (2H, 2xs) ; 4.25-4.18 (IH, m) ; 3.43-3.35 (2H, m) ; 2.25-2.15 (2H, m) ; 1.95-1.85 (6H, m) ; 1.42 and 1.40 (3H, 2xs) ; 1.01 and 0.85 (9H, 2xs) ; LCMS (ESI) :
577.2 (M+H)+.
[Example 233]
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-(2,2-dimethylpropyl)carbamoyl)-5-(trifluor ometh l)pyrazol-l-yl)bicyclo[2.2.2]octane-l-carboxylic acid
Figure imgf000275_0001
Step 1 : ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl)-5-(tri fluoromethyl)-lH-pyrazol-l-yl)bicyclo[2.2.2]octane-l-carboxylate (233-1)
Compound 233-1 was obtained from the reaction of amine A3 (58 mg, 0.148 mmol), acid D28 (50 mg, 0.139 mmol), oxaly chloride (0.024 mL, 0.278 mmol), 1 N NaOH (0.833 mL, 0.833 mmol) and DMF (cat) in DCM (1 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2 -hydro
hyl)- 1 H-pyrazol- 1 -yl)bicyclo[2.2.2]octane^ 1 -carboxylate (233 -2)
Compound 233-2 (67 mg, 78% over 2 steps) was obtained as a colorless syrup from the reaction of compound 233-1 (crude) and TBAF (0.148 mL, 0.148 mmol, 1 M in THF) in THF (1 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)bicyclo [2.2.2] octane- 1 -carboxylate (233-3)
Compound 233-3 (56 mg, 84%) was obtained as a white solid from the reaction of compound 233-2 (67 mg, 0.108 mmol) and Dess-Martin periodinane (64 mg, 0.151 mmol) in DCM (2 mL) using a similar procedure to that described in example 1.
Step 4: . :
4-(4T((2-(3,5-dichloropyridin-4-yl)-2-oxoet
omethyl)p\ razol-1 ->i)bicyclo|2.2.2]octane- 1 -carboxylic acid (233) : ;
: : The compound of example 233 (2 mg, 51 %) was obtained as a white solid from the reaction of compound 233-3 (56 mg, 0.091 mmol) and 4 N LiOH (0.091 mL, 0.363 mmol) in THF/water/MeOH (0.7 mL, 3: 1 :3) using a similar procedure to that described in example 1. 1H NMR (CDCI3) rotamers present 6 8.57 and 8.50 (211, 2xs) ; 7.64 and 7.49 (1H, 2xs) : 4.84 and 4.50 (2H, 2xs) ; 3.61 -3.26 (211, m) ; 2.32-2.22 (611. m) ; 2.08-2.04 (611, m) ; 1.01 and 0.85 (9H; 2xs) ; LCMS (ESI) : 589.2 (M-H)' .
[Example 276] trans-4-(5-chloro-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-(2,2-dimethylpropyl)carbam oyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid
Figure imgf000277_0001
Step 1 : ethyl
trans-4-(5-chloro-4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)ca rbamoyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (276- 1 )
Compound 276-1 was obtained from the reaction of amine A3 (124 mg, 0.31 mmol), acid D33 (100 mg, 0.31 mmol), oxaly chloride (0.082 mL, 0.95 mmol), Et3N (0.088 ml, 0.66~mmol) and DMF (cat) in DCM (5 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
trans-4-(5-chloro-4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)- 1 H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (276-2)
Compound 276-2 (160 mg, 88%, over 2 steps) was obtained as white solid from the reaction of compound 276-1 (crude) and TBAF (0.5 mL, 0.5 mmol, 1 M in THF) in THF (2 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(5-chloro-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-lH-p yrazol-l-yl)-l -methylcyclohexanecarboxylate (276-3) Compound 276-3 (130 mg, 81%) was obtained. as an off-white solid from the reaction of compound 276-2 (160 mg, 0.279 mmol) and Dess-Martin periodinane (233 mg, 0.56 mmol) in DCM (10 mL) using a similar procedure to that described in example 1. Step 4:
trans:4-(5-chloro-4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-(2,2-dimethylpropyl)carbam oyl)pyrazol- l-yl)-l -methyl cyclohexane-l-carboxylic acid (276)
The compound of example 276 (60 mg, 47%) was obtained as a white solid from the reaction of compound 276-3 (130 mg, 0.224 mmol) and LiOH (26.9 mg, 1.123 mmol) in THF/EtOH/water (11 mL, 5:5:1) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present δ 12.25 (1H, brs) ; 8.77 and 8.72 (2H, 2xs) ; 7.79 and 7.73 (1H, 2xs) ; 4.84 and 4.77 (2H, 2xs) ; 4.36-4.28 (1H, m) ; 2.02-1.72 (8H, m) ; 1.21 (3H, s) ; 0.95 and 0.74 (9H, 2xs) ; LCMS (APCI): 545 (M+H)+.
[Example 277]
trans-4-(4-((2-(2,6-dichloro-4-methylphenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbicyclo[ 3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexaneca
Figure imgf000278_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-methylphenyl)-2-((triethylsilyl)oxy)ethyl)((lR,3r,5S)-6,6-di methylbicyclo[3.1.0]hexan-3-yl^
lcyclohexanecarboxylate (277-1)
Compound 277- 1 was obtained from the reaction of amine C45 (74 mg, 0.167 mmol), acid D2 (55 mg, 0.158 mmol), HATU (72 mg. 0.190 mmol) and DIPEA (0.055 ml. 0.320 mmol) in DMF (2 mL) using a similar procedure to that described in example 1 Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-methylphenyl)-2-hydroxyethyl)((lR,3r,5S)-6,6-dimethylbicy clo[3.1 :.0]hexan-3-yl)carbamoyl)-5-(trifiuOfOmethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexa necarboxylate (277-2)
Compound 277-2 (85 mg, 82% over 2 steps) was obtained as a yellow semi-solid from the reaction of compound 277-1 (crude) and TBAF (0.3 mL, 0.3 mmol, 1 M in THF) in THF (2 mL) using a similar procedure to that described in example 1
Step 3: ethyl
trans-4-(4-((2-(2,6-dicW
3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- -yl)- 1 -methylcyclohexaneca rboxylate (277-3)
Compound 277-3 (80 mg, 95%) was obtained as a pale yellow semi- solid from the reaction of compound 277-2 (85 mg, 0.129mmol) and Dess-Martin periodinane (66 mg, 0.155 mmol) in DCM (2 mL) using a similar procedure to that described in example 1. !
Step 4:
trans-4-(4-((2-(2,6-dichloro-4-methylphenyl)-2-((triethylsilyl)oxy)ethyl)((m^
methylbicyclo[3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol-1 -yl j-1 -methy lcyclohexanecarboxylate: (277) ; :
The compound of example; 277 (58 mg, 75%) was obtained as a white solid from the reaction of compound 277-3 (80 mg, 0.122 mmol) and 4 N LiOH (0.31 mL, 1.22 mmol) in THF/water/MeOH (1.5 mL, 2:1 :2) using a similar procedure to that described in example 1. Ή NMR (C CI3) rotamers present δ 7.69 and 7.54 (I I I, 2xs) ; 7.16 and 7.08 (2H, 2xs) ; . 5.10-5.00 and 4.36-4.14 (211, 2xm) ; 4.59 and 4.39 (2H, 2xs) ; 2.35 and 2.31 (311, 2xs) ; 2.31-1.85 (lOH, m) ; 1.42 and 1.39 (3H, 2xs) ; 1.39-1.23 (2H, m) ; 1.09-0.95 (8H, m) ; LCMS (ESI) : 628.3 (M+H)+.
[Example 278 ]
trans-4-(4-((2-(2,6-dichl0rophenyl)-2-oxoethyl)((lR,3r,5S)-6
n-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic
Figure imgf000280_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethyl)((lR,3r,5S)-6,6-dimethylbi yclo[3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoro methyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohex anecarbox ate (278-1 )
Compound 278-1 was obtained from the reaction of amine C46 (94 mg, 0.219 mmol), acid D2 (76 mg, 0.219 mmol), oxaly chloride (0.038 mL, 0.438 mmol), DIPEA (0.114 mL, 0.657 mmol) and DMF (cat) in DCM (1 mL) using a similar procedure to that described in example 2. Step 2: ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((lR,3r,5S)-6,6-dimethylbi hexan-3 -yl)carbamoyl)^5 (trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxy late (278-2)
Compound 278-2 (102 mg, 72% over 2 steps) was obtained as a colorless oil from the reaction of compound 278-1 (crude) and TBAF (0.22 mL, 0.22 mmol, 1 M in THF) in THF ( 1 mL) using a similar procedure to that described in example 1 ; : M
Step 3: ethyl
trans-4-(4-((2^(2,6-dichlorophenyl)-2-oxoethyl)((l R,3r,5S)-6,6-dimethylbicyclo[3.1.OJhexa n-3-yl)carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-l-methylcyclohexanecarboxylate (278-3)
Compound 278-3 (84 mg, 83%) was obtained as a white solid from the reaction of compound 278-2 (102 mg, 0.158mmol) and Dess-Martin periodinane (100 mg, 0.237 mmol) in DCM (1 mL) using a similar procedure to that described in example 1.
Step 4:
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((lRi3r,5S)-6,6-dimethylbicyclo[3.1.0]hexa n-3 -yl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylie acid (278)
The compound of example 278 (35 mg, 44%) was obtained as a white solid from the reaction of compound 278-3 (84 mg, 0.131 mmol) and 4 N LiOH (0.33 mL, 1.31 mmol) in THF/water/MeOH (1.5 mL, 2:1 :2) using a similar procedure to that deseribed in example ! "i I NMR (CDC13) rotamers present δ 7.70 and 7.55 (1H, 2xs) ; 7.36-7.26 (311, m) ;
5.10-5.00 and 4.37-4.15 (21 L 2xm) ; 4.61 and 4.42 (211. 2xs) ; 2.31-1.87 (1 OH, m) ; 1.42 and 1.39 (3H, 2xs) ; 1.39-1.23 (2H, m) ; 1.09-0.95 (8H, m) ; LCMS (ESI) : 614.2 (M+H)+ [Example 330]
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-((l-(trifluoromethyl)cyclopropyl)m hyl)carbamoyl)-5-(trifluoromethyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid
Figure imgf000282_0001
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)((l-(trifluoromethyl)cy clopropyl)methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanec arboxylate (330-1)
Compound 330-1 was obtained from the reaction of amine A103 (44 mg, 0.098 mmol), acid D2 (34 mg, 0.098 mmol), oxaly chloride (0.017 mL, 0.196 mmol), 1 N NaOH (0.49 mL, 0.491 mmol) and DMF (cat) in DCM (1 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl) methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (330-2)
Compound 330-2 (37 mg, 58% over 2 steps) was obtained as a colorless oil from the reaction of compound 330-1 (crude) and TBAF (0.098 mL, 0.098 mmol, 1 M in THF) in THF (1 mL) using a similar procedure to that described in example 1. Step 3 : ethyl
trans-4-(4-((2-(3 ,5-dichloropyridin-4-yl)-2-oxoethyl)(( 1 -(trifluoromethyl)cyclopropyl)meth yl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (330-3)
Compound 330-3 (31 mg, 83%) was 3 < obtained as a colorless oil from the reaction of
330-2 (37 mg, 0.056 mmol) and Dess-Martin periodinane (36 mg, 0.085 mmol) in DCM (1 mL) using a similar procedure to that described in example 1
Step 4:
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)-((l-(trifluoromethyl)cyclopropyl)met hyl)carbamoyl)-5-(trifluoromethyl)pyrazol-l -yl)- 1 -methylcyclohexane- 1 -carboxylic acid
(330);
The compound of example 330 (17 mg, 58%) was obtained as a white solid from the reaction of compound 330-3 (31 mg, 0.047 mmol) and 4 N LiOH (0.12 mL, 0.467 mmol) in THF/water/MeOH (0.75 mL, 2: 1 :2) using a similar procedure to that described in example 1. H NMR (CDC13) rotamers present δ 8.59 and 8.52 (2H, 2xs) ; 7.65 and 7.54 (1H, 2xs) ; 4.95 and 4.58 (2H, 2xs) ; 4.28-4.20 (1H, m) ; 3.84 and 3.74 (2H, 2xs) :
2.26-2.16 (2H, m) ; 1.95-1.85 (6H, m) ; 1.42 and 1.41 (3H, 2xs) ; 1.12-1.06 (4H, m) ; LCMS (ESI) : 629.2 (M+H)+. . ,
[Example 343]
trans-4-(4-((2-(4-chloro-lH-indol-3-yl)ethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3 -yl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000284_0001
trans-4-(4-((2-(4-chloro- 1 H-indol-3-yl)ethyl)((l R,3r,5S)-6,6-dimethylbicyclo[3.1.OJhexan- 3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (343-1)
Compound 343-1 (42 mg, 91%) was obtained as a yellow gum from the reaction of amine.. B 19- (22 mg, 0.073 mmol), acid D2 (25 mg, 0.073 mmol), HATU (33 mg, 0.087 mmol) and DIPEA (0.037 mL, 0.218 mmol) in DME (1 mL) using a similar procedure to that described in example 1.
Step 2:
trans-4-(4-((2-(4-chloro-lH-indol-3-yl)ethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3 -yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid (343)
The compound of example 343 ( 31 mg, 78%) was obtained as a white solid from the reaction of compound 343-1 (42 mg, 0.066 mmol) and 4 N LiOH (0.066 mL, 0.265 mmol) in THF/water/MeOH (0.5 mL, 2: 1 :2) using a similar procedure to that described in example 1. 'i l N.MR (CDC13) rotamers present δ 8:20 (1H, brs) ; 7.53-6.90 (5H, m) ; 4.68-4.61 and 4.29-4.02 (2H, 2xm) ; 3.64-3.61 and 3.53-3.49 (2H, 2xm) ; 3.35-3.32 and 3.04-3.00 (2H, 2xm) ; 2.28-1.86 (811. m) ; 1.70-1.60 (2H, m) ; 1.41 and 1.39 (311. 2xs) ; 1.28-0.85 (lOH, m) ; LCMS (ESI) : 606.0 (M+H)+i
Figure imgf000285_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)(4,4-dimethylcyclo hexyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (361 -1 )
Compound 361-1 was obtained from the reaction of amine C I (89 mg, 0.199 mmol), acid D2 (60 mg, ().172mmol). oxaly chloride (0.044 mL, 0.517 mmol). DIPEA (0,090 mL, 0.517 mmol) and DMF (cat) in DCM (2 mL) using a similar procedure to that described in example 2.
Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-methylphenyl)-2-hydroxyethyl)(4,4-dimethylcyc
bamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (377-2) Compound 361-2 (100 mg, 88% over 2 steps) was obtained from the reaction of 361-1 (crude) and TBAF (0.26 mL, 0.258 mmol, 1 M in THF) in THF (2 mL) using a similar procedure to that described in example 1.
Step 3: ethyl
trans-4-(4-(((S)-2-(2,6-dichloro-4-methylphenyl)-2-hydroxyethyl)(4,4-dimethylcyclohexyl) carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexariecarboxylate and ethyl
trans-4-(4-(((R)-2-(2,6-dichloro-4-methylphenyl)-2-hydroxyethyl)(4,4-dimethylcyclohexyl )carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methyl cyclohexanecarboxylate (361-3 and 362-1)
Compound 361-2 (100 mg, 0.151 mmol) was purified by chiral HPLC (250 x 20 mm DAICEL CHIRALPAK™ IA 5 μηι column with 16 mL/min n-hexane/IPA (96/4)) to give 361-3 (49 mg, 49%) as the first eluting isomer and compound 362-1 (48 mg, 48%) as the second eluting isomer.
Step 4:
trans-4-(4-(((2R)-2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)-(4,4-dimethylcyclohexy l)carbamoyl)-5-(trifluoromethyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid or trans-4-(4-(((2S)-2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)-(4,4-dimethylcyclohexy l)carbamoyl)-5-(trifluoromethyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid (361)
The compound of example 361 (37 mg, 79%) was obtained as a white solid from the reaction of compound 361-3 (49 mg, 0.074 mmol) and 4 N LiOH (0.25 mL, 1.00 mmol) in EtOH/water (1.5 mL, 2: 1) using a similar procedure to that described in example 1.
LCMS (ESI) : 636.3 (M+H)+.
Step 5: trans-4-(4-(((2R)-2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)-(4j>4-dimethylcyclohexy l)carbamoyl)-5-(trifluoromethyl)pyrazol- 1 -yl)- 1 -methylcyclohexane- 1 -carboxylic acid or trans-4-(4-(((2S)-2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)-(4,4-dimethylcyclohexy l)carbamoyl)-5-(trifluoromethyl)pyrazol-l -yl)-l -methylcyclohexane- 1 -carboxylic acid (362)
The compound of example 362 (39 mg, 85%) was obtained as a white solid from the reaction of compound 362-1 (48 mg, 0.073 mmol) and 4 N LiOH (0.25 mL, 1.00 mmol) in EtOH/water (1.5 mL, 2: 1) using a similar procedure to that described in example 1. Ή NMR (CDC13) rotamers present δ 7.57 and 7.56 (1H, 2xs) ; 7.11 and 7.05 (2H, 2xd, J=7.8 Hz) ; 5.62-5.47 (1H, m) ; 4.86 (1H, brs) ; 4.70-4.64 and 4.09-4.02 (1H, 2xm) ; 4.30-4.20 (lH, m) ; 3.46-3.26 (2H, m) ; 2.31-2.18 (2H, m> ; 1.99-1.66 (8H, m) ; 1.47-1.26 (7H, m) ; 1.12-0.86 (8H, m) ; LCMS (ESI) : 636.0 (M+H)+.
[Example 569] .
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)(spiro[25]oct-6-ylmethyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000287_0001
Step 1 and Step 2: ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl )-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate To a solution of
1- ((trans)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-car boxylic acid (0.157 g, 0.452 mmol) and oxalyl chloride (0.049 ml, 0.565 mmol) in DCM (4.52 ml) was added DMF (1 drop) and the mixture was stirred at room temperature. After
1 h, the reaction mixture was concentrated in vacuo. To the residue was added a solution of
2- (2,6-dichlorophenyl)-N-(spiro [2.5] octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine (0.200 g, 0.452 mmol) in THF (4.5 mL) followed by DIPEA (0.158 ml, 0.904 mmol) and the mixture was stirred at room temperature. After 17 h, to the reaction mixture was added TBAF solution, 1.0 M in THF (0.904 ml, 0.904 mmol) and the mixture was stirred at room temperature. After 7 h, the reaction mixture was diluted with water (50 mL) and brine (50 mL). The reaction mixture was extracted with EtOAc (2 x 50 mL). The organic extract was washed with satd NaCl (1 x 50 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column
chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to provide ethyl trans-4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl )-5-(trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (0.0815 g, 0.124 mmol, 27.4% yield) a colorless gum.
Step 3: ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl)-5-( trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a solution of ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl )-5-(trifluoromethyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (0.0815 g, 0.124 mmol) in DCM (1.238 ml) was added Dess-Martin periodinane (0.079 g, 0.186 mmol) and the mixture was stirred at room temperature. After 6 h, the mixture was quenched with saturated aqueous Na2S203 (50 mL) and saturated aqueous NaHC03 (50 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The organic extract was dried over
Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 35% EtOAc in heptane to provide ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl)-5-( trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (0.0685 g, 0.104 mmol, 84% yield) as a colorless syrup.
Step 4:
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)(spiro[25]oct-6-ylmethyl)carbamoyl)-5-(tri fiuoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
To a solution of ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)(spiro[2.5]octan-6-ylmethyl)carbamoyl)-5-( trifluoromethyl)-l H-pyrazol- l-yl)-l-methylcyclohexanecarboxylate (0.0685 g, 0.104 mmol) in THF (0.750 mL) was added a solution of lithium hydroxide hydrate (0.044 g, 1.043 mmol) in water (0.500 mL) and the mixture was stirred and heated at 50 °C overnight. The THF and MeOH were removed in vacuo and the turbid solution was diluted with water (3 mL) to provide a clear solution. 1 M HC1 was added to adjust the pH to 1. The mixture was stirred for 30 min before collecting the precipitate by vacuum filtration to provide a white solid. The solid was purified by silica gel column chromatography eluting with a gradient of 0% to 5% MeOH in DCM to provide Example 569 (0.0457 g, 0.073 mmol, 69.7% yield) as white solid. Ή NMR (400 MHz, CD3OD) δ 7.40-7.79 (4H, m), 5.30-5.54 (1H, m), 4.87 (lH, s), 4.64 (1H, s), 4.22-4.36 (1H, m), 3.50 (2H, d, J=7.2 Hz), 2.12-2.30 (2H, m), L54-1.98 (ΙΟΗ, η ), 1.27-1.41 (5H, m), 0.78-1.05 (3H, m), 0.07-0.37 (4H, m), (rotamers present); LCMS (ESI) m/z 628.2 (M+H)+.
[Example 688]
tram-4-(4-(((2i?)-2-((3,5-dichloro-4-pyridinyl)methyl)-4,4-dimethyl-i-pyrrolidi carbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000290_0001
Step 1 : Prepared according to WO patent: 2013004290A1. To a stirred suspension of (i?)-(-)-5-(hydroxymethyl)-2-pyrrolidinone (Sigma Aldrich Chemical Company, St. Louis, MO, 5.36 g, 46.5 mmol) and -toluenesulfonic acid (44 mg, 0.233 mmol) in toluene (100 mL), 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 1.5 h. The reaction was equipped with a Dean-Stark apparatus then additional 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 36 h. The solvent was evaporated to afford
(i?)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one as an orange waxy solid. MS (ESI) 156.1 [M + Hf. The crude material was taken to the next step without further purification. Step 2: Prepared according to WO patent: WO2013004290A1. To a solution of
(i?)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (3.50 g, 22.55 mmol) in THF (75 mL) cooled to -78 °C, was added lithium diisopropylamide (2.0M
heptane/THF/ethylbenzene, 20.30 mL, 40.6 mmol) solution. The solution was stirred at this temperature for 1 h before adding iodomethane (2.12 mL, 33.8 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, then cooled to -78 °C prior addition of lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, 20.30 mL, 40.6 mmol). The mixture was stirred at -78 °C for 1 h before adding additional iodomethane (2.12 mL, 33.8 mmol). The mixture was slowly warmed to room temperature and stirred overnight (16 h). The reaction was quenched with a saturated solution of ammonium chloride and extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated to provide crude (i?)-3, 3,6,6
tetramethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one as an orange tar. MS (ESI) 184.1 [M + H]+.
Step 3: Prepared according to WO patent: 2013004290. To a solution of
(i?)-3,3,6,6-tetramethyltetrahydropyrrolo[l,2-c]oxazol-5(3H)-one (4.13 g, 22.54 mmol) in MeOH (90 mL) was added p-toluenesulfonic acid monohydrate (0.429 g, 2.254 mmol). The resulting mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure (rotary evaporator) and the crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-20% MeOH in DCM) affording
(i?)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.31 mmol, 90% yield) as a white semi-solid. MS (ESI) 144.1 [M + H]+.
Step 4: Prepared according to US patent: 20070032433 Al . To a solution of
(i?)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.30 mmol) in THF (50.8 mL) cooled to 0 °C, lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added. The mixture was stirred at room temperature overnight (16 h).
Additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the solution was refluxed for 6 h. The reaction mixture was cooled and additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0 °C in an ice bath prior to addition of water (3.67 mL) followed by 15% aqueous NaOH (3.67 mL) and water (10.9 mL). It was then stir vigorously at room temperature for 1 h and filtered on a medium porosity sintered glass frit with cotton and celite washing with EtOAc. The solution was then concentrated affording crude (i?)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.73 mmol, 87% yield) as yellow viscous oil. MS (ESI) 130.1 [M + H]+.
Step 5: A solution of triethylamine (4.94 mL, 35.4 mmol) and
(i?)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to -78 °C. To this mixture was added sulfuryl chloride (1.0 M in DCM, 21.27 mL, 21.27 mmol) over 15 seconds. The reaction was maintained at this temperature for ~ 3 h, allowed to warm to room temperature and stirred overnight (16 h). The mixture was washed with aqueous 1 N HC1 (30 mL x 2), brine (40 mL), dried over MgS04, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (i?)-5,5-dimethyltetfahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1 , 1 -dioxide (708 mg, 3.70 mmol, 21 % yield) as a white crystalline solid. MS (ESI) 192.1 [M + H]+.
Step 6: To a solution of 3,5-dichloropyridine (796 mg, 5.38 mmol) in THF (9.0 mL) at -78 °C was added lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, 3.41 mL, 6.82 mmol) dropwise. After stirring for 1 h at this temperature, a solution of (i?)-5,5-dimethyltetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1 ,1-dioxide (686 mg, 3.59 mmol) in THF (9.0 mL) was added dropwise at -78 °C and the mixture was allowed to warm to room temperature over 3 h and then stirred at room temperature for 4 h. After evaporation of the solvent, the resulting beige foam was treated with hot (80 °C) 2 N HC1 (8 mL) and EtOH (8 mL) overnight. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and the mixture was treated with ice and basified with 5 N NaOH (8 mL) and extracted with EtOAc (2 x 75 mL). The organic extracts were dried, evaporated and purified by chromatography on an ISCO Combiflash™ RF (25 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording
(i?)-3,5-dichloro-4-((4,4-dimethylpyrrolidin-2-yl)methyl)pyridine (748 mg, 2.89 rnrnoLj 80% yield) as an orange oil. MS (ESI) 259.1, 261.0. [M + H]+.
Step 7:
1 -(( 1 r,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-car boxylic acid (445 mg, 1.28 mmol) was treated with DCM (8 mL) and three drops of DMF, cooled to 0 °C in an ice bath and treated with oxalyl chloride (0.16 mL, 1.82 mmol) slowly dropwise. The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 1.5 h. The volatiles were removed under reduced pressure (rotary evaporator) and the crude acid chloride was treated with DCM (10 mL), cooled in an ice bath and treated with (i?)-3,5-dichloro-4-((4,4-dimethylpyrrolidin-2-yl)methyl)pyridine (315 mg, 1.22 mmol) (in DCM 5 mL) slowly dropwise followed by DIPEA (0.64 mL, 3.65 mmol). The solution was removed from the ice bath and allowed to warm to rt and stirred for 1 h. The solvent was evaporated and the crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Thomson SingleStep column, using a gradient of 0-40% EtOAc in heptane) to provide (li?,4r)-ethyl 4-(4-((^)-2-((3,5-dichloropyridin-4-yl)m
uoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (489 mg, 0.83 mmol, 68% yield) as a light yellow amorphous solid after drying in a vacuum oven over 48hrs at 40 °C. MS (ESI) 589.3/591.2 [M + H]+.
Step 8: To a mixture of (li?,4r)-ethyl
4-(4-((i?)-2-((3,5-dichloropyridin-4-yl)methyl)-4,4-dimethylpyrrolidine-l-carbonyl)-5-(trifl uoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (464 mg, 0.787 mmol) in THF (3.9 mL) and MeOH (3.9 mL) was added lithium hydroxide monohydrate (1.0 M aqueous solution, 3.9 mL, 3.94 mmol). The mixture was stirred at room temperature overnight (16 h). The organics were removed under reduced pressure (rotary evaporator) and the aqueous solution was acidified with 1 N HC1 leading to the formation of a precipitate. The mixture was extracted with EtOAc (2 x 40 mL). The combined extracts were washed with brine, dried over anhydrous MgS04, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO
Combiflash™ RF (40 g Thomson SingleStep column, using a gradient of 0-8% MeOH in DCM) affording
(li?,4r)-4-(4-((i?)-2-((3,5-dichloropyridin-4-yl)methyl)-4,4-dimethylpyrrolidine-l-carbonyl )-5-(trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylic acid (258 mg, 0.46 mmol, 59% yield) as white amorphous foam. MS (ESI) 561.0, 563.1 [M + H]+.
[Example 692]
trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)ca rbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000295_0001
Step 1 and Step 2: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylprop yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a slightly cloudy solution of _
l-((lr,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4-car boxylic acid (1.0102 g, 2.90 mmol) in DCM (29.0 ml) was added oxalyl chloride (0.307 ml, 3.63 mmol) followed by DMF (1 drop) and the light-yellow slightly cloudy reaction mixture was stirred at room temperature. After 3 h, the mixture was concentrated in vacuo to give ethyl
trans-4-(4-(chlorocarbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecar boxylate as light-yellow syrup. To the residue was added a solution of
N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dimethylpro pan-1 -amine (1.292 g, 2.90 mmol) in THF (29.0 ml) followed by DIPEA (2.021 ml, 1 1.60 mmol) and the mixture was stirred at room temperature. After 19 h, LCMS (ESI) showed that ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(3,3,3-trifluoro-2,2-dim ethylpropyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarbbx ylate was formed: LCMS (ESI) m/z 775.1 (M+H)+.
To the reaction mixture was added TBAF solution, 1.0 M in THF (11.60 ml, 11.60 mmol) and the mixture was stirred at room temperature. After 30 min, LC-MS (ESI) showed that the reaction was complete. The reaction mixture was diluted with water (100 mL) and brine (100 mL). The reaction mixture was extracted with EtOAc (2 x 100 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to provide ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylprop yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (1.6938 g, 2.56 mmol, 88% yield) as a white gummy solid. Ή NMR (400 MHz,
DMSO-de) δ 8.46-8.63 (2H, m), 7.71 -7.83 (1H, m), 6.1 1 (1H, d, J=4.1 Hz), 5.19-5.33 (1H, m), 4.27 (1H, t, J=11.0 Hz), 4.09 (2H, q, J=7.2 Hz), 3.39-3.97 (4H, m), 2.02-2.19 (2H, m), 1.66-1.97 (6H, m), 1.14-1.30 (12H, m), NMR showed several peak sets due to
diastereomers and rotamers; LCMS (ESI) m/z 661.1 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)ca rbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a clear solution of ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylprop yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (1.6826 g, 2.54 mmol) in DCM (25.4 ml) was added Dess-Martin periodinane (1.618 g, 3.82 mmol). The white cloudy mixture was stirred at room temperature. After 1 h, the mixture was quenched with saturated aqueous Na2S203 (50 mL) and saturated aqueous NaHC03 (50 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 30% EtOAc in heptane to provide ethyl
trans-4-(4-((2-(3 ,5-dichloropyridin-4-yl)-2-oxoethyl)(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)ca rbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (1.5825 g, 2.400 mmol, 94% yield) as a white gummy solid. Ή NMR (400 MHz, CDC13) δ 8.45-8.64 (2H, m), 7.51-7.78 (1H, m), 4.52 (2H, s), 4.09-4.30 (3H, m), 3.70 (2H, br. s.), 2.12-2.32 (2H, m), 1.79-2.00 (6H, m), 1.02-1.46 (12H, m), rotamers present; LCMS (ESI) m/z 659.0 (M+H)+.
Step 4:
trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)ca rbamoyl)-5 -(trifiuoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
To a clear mixture of ethyl
trans-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpfopyl)ca rbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (1.5739 g, 2.387 mmol) in THF (9.55 ml), EtOH (9.55 ml), and water (4.77 ml) was added 2 M LiOH in water (11.93 ml, 23.87 mmol). After adding 2 M LiOH solution, the white
heterogeneous mixture became yellow cloudy mixture. The yellow cloudy mixture was stirred and heated at 60 °C. After 15 h, the reaction mixture was concentrated in vacuo to remove THF and EtOH. The resulting aqueous solution was diluted with water (30 mL). The pH of the solution was adjusted to -3.0 with 1 N HCl and the resulting precipitate was collected by vacuum filtration, wash with water, and freeze-dried on lyophilizer overnight to provide example 692 (1.3955 g, 2.210 mmol, 93% yield) as white solid. Ή NMR (400 MHz, DMSO-d6) δ 12.27 (1H, br. s.), 8.58-8.83 (2H, m), 7.75-8.02 (1H, m), 4.68^5.43 (2H, m), 4.26 (1H, t, J=11.0 Hz), 3.46-3.90 (2H, m), 1.97-2.17 (2H, m), 1.69-1.92 (6H, m), 1.00- 1.39 (9H, m), rotamers present; LCMS (ESI) m/z 631.0 (M+H)+.
[Example 713]
(lr,4r)-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluorospiro[2.3]hexan-5-yl)rnethyl)car
Figure imgf000298_0001
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)(3,5-difluoroben^ )carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
l-((lr,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluororriethyl)-lH-pyrazole- 4-carboxylic acid (3.48g, 9.99 mmol) was dissolved in DCM (30 ml) and thionyl chloride (0.875 ml, 11.99 mmol) was added followed by 1 drop of DMF. The reaction was rrefluxed for 2.5 h. The solvents were removed in vacuo and the residue was placed in the freezer overnight. The solidified material was then dried under vacuo for 1 h to afford (ls,4s)-ethyl
4-(4-(chlorocarbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate.
2-(2,6-dichlorophenyl)-N-((5-fluorospiro[2.3]hexan-5-yl)methyl)-2-((triethylsilyl)oxy)etha namine (150 mg, 0.347 mmol) was dissolved in 2 ml of DCM and (ls,4s)-ethyl 4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate (127 mg, 0.347 mmol) dissolved in 2 ml of DCM was added, followed by triethylamine (242 μΐ, 1.734 mmol). The solution was stirred for 1 h and was concentrated to afford crude (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethyl)((5-fluorospiro[2.3]hexan-5-yl)me thyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyiate (265 mg, 0.3.47 mmol, 100% yield).
Step 2: (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)carba moyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyiate
To a stirred solution of (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethyl)((5-fluorospiro[2.3]hexan-5-yl)me thyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyiate (265 mg, 0.347 mmol) in 2 ml of THF was added TBAF (695 μΐ, 0.695 mmol), and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)carba moyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyiate (225 mg, 0.347 mmol, 100% yield). MS m/z =648 [M+H]+.
Step 3: (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)carbamoy l)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyiate
(lr,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)carba moyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (225 mg, 0.347 mmol) was dissolved in 10 ml of DCM and Dess-Martin periodane (184 mg, 0.434 mmol) was added. The solution was stirred for 1 h. The solution was quenched with 5% Na2S203, washed with saturated NaHC03, dried with Na2S04 and concentrated. The product was purified via silica gel column chromatography (40 g column) using 0-100 % EtO Ac in heptane to afford (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluqrospiro[2.3]hexan-5-yl)methyl)carbamoy l)-5-(trifluoromethyl)- 1 H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (140 mg, 0.217 mmol, 62.4% yield). MS m/z =646 [M+H]+.
Step 4:
(lr,4r)-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
(lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)carbamoy l)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (140 mg, 0.217 mmol) and lithium hydroxide (100 mg, 4.18 mmol) were combined in 5 ml of MeOH, 5 ml of THF, and 2 ml of water. The solution was heated at 50 °C for 3 h. The solution was made acidic with 6 N HC1 and diluted with water. The product was extracted with EtO Ac, dried with Na2S04, filtered and concentrated to afford
(lr,4r)-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((5-fluorospiro[2.3]hexan-5-yl)methyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
(115mg, 0.186 mmol, 86% yield). 1H NMR (400 MHz, CD3OD mixture of rotamers) δ 7.88 (s, 0.2H) 7.66 (s, 0.8H) 7.40-7.50 (m, 3H) 4.11 (m, 3H) 2.43-2.61 (m, 2H) 2.15-2.32 (m, 3H) 1.81-2.05 (m, 7H) 1.17-1.43 (m, 5H) 0.42 - 0.70 (m, 4H) LC/MS (ESI+) m/z = 618 (M+H)+.
[Example 716]
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)((l-methylcyclopropyl)methyl) carbanioyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000301_0001
Ste 1 : ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-((trietliylsilyl)oxy)ethyl)((l-methylcyclopro pyl)methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxy late
This compound was prepared using similar procedure described for examples 1, step 1 without chromatography purification. LCMS (ESI) m/z 735.8 (M+H)+.
Step 2: ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-hydroxyethyl)((l-methylcyclopropyl)methy l)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
This compound was prepared using similar procedure described for examples 1, step
2 without chromatography purification. LCMS (ESI) m/z 623.9 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)((l-methylcyclopropyl)me bamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate This compound was prepared using similar procedure described for examples 1 , step
3. 1H NMR (500 MHz, CDC13) rotamers present δ 7.65 and 7.58 (2xs, 1H), 7.16 and 7.15
(2xs, 1H), 7.09 and 7.08 (2xs, 1H), 4.98 (s, 1H), 4.60 (s, 1H), 4.22-4.33 (m, 1H), 4.15-4.22
(m, 2H), 3.36 (s, 1H), 2.15-2.31 (m, 2H), 1.84-1.99 (m, 6H), 1.39 and 1.37 (2xs, 3H), 1.30 (td, J=7.09, 2.32 Hz, 3H), 1.12 and 0.98 (2xs, 3H), 0.48-0.56 (m, 1H), 0.34-0.43 (m, 3H); LCMS (ESI) m/z 619.8 (M+H)+.
Step 4:
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)-2-oxoethyl)((l -methylcyclopropyl)methyl) carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
This compound was obtained as a white solid using similar procedures described for example 1, step 4. 1H NMR (500 MHz, DMSO-d6) rotamers present δ 12.29 (s, lH), 7.52-7.82 (m, 3H), 5.17 and 4.87 (2xs, 1H), 4.69 (s, 1H), 4.18-4.32 (m, 1H), 3.52 and 3.38 (2xs, 1H), 3.32 and 3.22 (2xs, 1H), 2.00-2.16 (m, 2H), 1.73-1.91 (m, 6H), 1.24 and 1.08 (2xs, 3H), 1.05 and 0.91 (2xs, 3H), 0.44-0.57 (m, 1H), 0.23-0.38 (m, 3H); LCMS (ESI) m/z 592.1 (M t H) .
[Example 729]
Figure imgf000302_0001
Step 1 : (lr,4r)-ethyl ' .
4-(4-((2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)ethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylat e.
To a solution of
2-(2,6-dichlorophenyl)-N-((l-(trifluoromethyl)cyclopropyl)methyl)-2-((trimethylsilyl)oxy) ethanamine (0.15 g, 0.375 mmol) in DCM (3 mL) was added ethyl
4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate (0.137 g, 0.375 mmol) followed by triethylamine (0.104 mL, 0.749 mmol) and stirred at ambient temperature for 15 min. Reaction mixture was loaded on a 25 g column
(MPLC) and eluted with Hex :EtO Ac (0-50%) to obtain ( 1 r,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)ethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylat e (0.177 g, 0.242 mmol, 65%) as clear oil.
Step 2 : (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl)methyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a solution of (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)ethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylat e (0.177 g, 0.242 mmol) in 2-Me-THF (0.808 ml) was added tetra-nrbutylammonium fluoride (0.291 ml, 0.291 mmol) The mixture was stirred at ambient temperature for lh. The reaction mixture was quenched with saturated aqueous NH4C1 (1 mL) and diluted with EtOAc (50 mL) and water (20 mL). The organic layer was concentrated under reduced pressure to afford (lr,4r)-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl)methyl)car bamoyl)-5-(trifluorornethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate as an off-white solid. This was dissolved in DCM (3 mL) and dess-martin periodinane (0.134 g 0.315 mmol) was added and the reaction mixture was stirred at ambient temperature for 16h. To this was then added Na2S203 (5 mL) followed by saturated NaHC03 (2 mL) and DCM (20 mL) and stirred for 15 min. Organic layer was passed through phase seperator and concentrated. The crude mixture was purified by MPLC (25 g column) and eluting with Hex.EtOAc (10-40%) to obtain (lr,4r)-ethyl
4-(4-((2-(2j6-dichlQrophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl)methyl)carbam oyl)-5-(trifluoro methyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (0.13 g, 82%) as amorphous white solid.
Step 3:
(lr,4r)-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl)methyl) carbamoyl)-5-(triflUoromethyl)-l H-pyrazol- l-yl)-l -methylcyclohexahecarboxylic acid.
To a solution of ( lr,4r)-cthyl
4-(4-((2-(2,6-dichl0rophenyl)-2-ox0ethyl)((l-(trifluoromethyl)cyclopropyl)methyl)carbarn oyl)-5-(trifluoromethyl)-l H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (0.13 g, 0.198 mmol) in 2Me-THF (0.660 ml). MeOH (0.660 ml) and water (0.660 ml) was added lithium hydroxide (0.047 g. 1.980 mmol) : and stirred at 40 °C for 1 h. Reaction mixture was acidified with 2 N HC1 to pH 2 and extracted with EtOAc (2 x 30 mL). Organic layer was dried on anhydrous Na2S04 filtered and concentrated to obtain
( 1 r.4r)-4-(4-((2-(2.6-dichlorophen\ l)-2-oxocthyI)(( 1 -(trinuoromethyl)e> clopropyl)methyl) carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-l-methylcyclohexanecarboxylic acid (O.lg, 75%) as amorphous white solid. IH NMR δ (DMSO-d6) rotamers present 12.22 (IH, brs) : 9.79 (I I I. 2xs) ; 7.69 and 7.67 (I H. 2xs) : 7.55 and 7.54 (1 H, 2xs) : 7.46 and 7.44 (IH, 2xs) ; 5.19 (I H. m) ; 4.30-4.20 (2H, m) ; 3.78 (2H, rh) ; 2.28-2.20 (211, m) ; 2.18-1.98 (311. m) ; 1.88-1.47 (8H, m) ; 1.24 and 1 .23 (3H, 2xs) LCMS (ESI): 628.0 (M l I I)". [Example 759]
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l -methylcyclopropyl)methyl)carbamoyl)-
Figure imgf000305_0001
Step 1 : trans-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a solution of
1- (trans-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5 -(trifluoromethyl)- lH-pyrazole-4-carbo xylic acid (2.88 g, 8.27 mmol) in DCM thionyl chloride (0.663 ml, 9.10 mmol) was added followed by 1 drop of DMF. The flask was then equipped with reflux condenser and the mixture was then stirred for 4 h at 40 °C and then stirred overnight at rt. The solvents were removed in vacuo and the residue was dried in vacuo to afford trans-ethyl
4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate (2.87 g, 95% yield) which was used without further purification. To a solution of
2- (2,6-dichlorophenyl)-N-((l-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)ethanamine (95 mg, 0.245 mmol) in DCM (1.2 ml) was added DIPEA (85 μΐ, 0.489 mmol) and trans-ethyl
4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate (90 mg, 0.245 mmol). After 45 min, TBAF (1 M solution in THF) (905 μΐ, 0.905 mmol) was added. After 2 h, 1 M aq. HC1 was added to the reaction mixture. Organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with sat. aq. NaHC03, dried with Na2S04 and concentrated to provide crude trans-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5 -(trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (206 mg) which was used without purification in the next step.
Step 2: trans-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5-(trif luoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
To a solution of trans-ethyl
4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5 -(trifluoromethyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (206 mg, 0.341 mmol) in DCM (3.5 ml) was added Dess-Martin periodinane (217 mg, 0,51 1 mmol).
After 40 min 1 M aq. Na2S203 and sat. aq. NaHC03 were added. The mixture was stirred for 1 h, organic layer was separated, the aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative TLC eluted with 30% EtOAc/heXane to provide trans-ethyl
4- (4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5-(trif luoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate ( 100 mg, 0.166 mmol, 48.7% yield).
Step 3:
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclopropyl)methyl)carbamoyl)-
5- (trifluoromethyl)-l H-pyrazol- l-yl)-l-methylcyclohexanecarboxylic acid To a mixture of trans-ethyl
4- (4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclopropyl)methyl)carbamoyl)-5-(trif luoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (100 mg, 0.166 mmol) in MeOH (1.5 mL), THF (1.5 mL), and water (1 mL) was added lithium hydroxide monohydrate (69 mg, 1.66 mmol). The mixture was heated at 50 °C for 90 min. Most of the MeOH and THF were removed in vacuo. The mixture was brought to pH 1 with 1 M aq. HC1. The mixture was stirred for 15 min, precipitated solid was filtered, washed with waterand dried in vacuo to afford
trans-4-(4-((2-(2,6-dichlorophe yl)-2-oxoethyl)((l-methylcyclopropyl)methyl)carbamoyl)-
5- (trifluoromethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylic acid (82 mg, 0.143 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) mixture of rotamers and keto-eiiol tautomers δ 12.24 (br. s, 1H), 9.59 (s, 0.2H), 7.80 (s, 0.2H), 7.73 (s, 0.55H), 7.72 (s, 0.25H), 7.32-7.63 (m, 3H), 5.15 (s, 0.2H), 4.88 (br. s, 0.5H), 4.70 (br. s, 1.1H), 4.15-4.35 (m,. lH), 3.52 (s, 0.4H), 3.32 (s, 1.1H), 3.22 (s, 0.5H), 1.99-2.16 (m, 2H), 1.70-1.93 (m, 6H), 1.21-1.28 (m, 3H), 0.88-1.11 (m, 3H), 0.45-0.58 (m, 2H), 0.23-0.35 (m, 2H). LCMS (APCI): 574.3 (M+H)+.
[Example 760]
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclobutyl)methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000308_0001
Step 1 : ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethyl)((l-methylcyclobutyl)meth^ l)carbamoyl)-5-(trifluoroniethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
This compound was prepared using similar procedure described for example 1 , step
1 without chromatography purification.
Step 2: ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-hydroxyethyl)((l-methylcyclobutyl)methyl)carbamo yl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
This compound was prepared using similar procedure described for example 1 , step
2 without chromatography purification. LCMS (ESI) m/z 618.3 (M+H)+.
Step 3: ethyl
trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclobutyl)methyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
This compound was prepared using similar procedure described for example 1 , step 3. 1H NMR (500 MHz, DMSO-d6) rotamers present δ 7.44-7.77 (m, 4H), 4.63 (2xs, 2H), 4.26 (m, 1H), 4.09 (q, J=7.13 Hz, 2H), 3.48 (br. s., 2H), 1.98-2.13 (m, 4H), 1.82-1.96 (m, 3H), 1.74-1.82 (m, 5H), 1.58-1.67 (m, 2H), 1.14-1.28 (m, 9H); LCMS (ESI) m/z 616.3 (M+H)+.
Step 4: trans-4-(4-((2-(2,6-dichlorophenyl)-2-oxoethyl)((l-methylcyclobutyl)methyl)carbarhoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
This compound was obtained as a white solid using similar procedure described for example 1, step 4. 1H NMR (500 MHz, DMSO-d6) rotamers present δ 12.18 (br. s., 1H), 9.58 (d, J=1.10 Hz, 1H), 7.66 (s, 1 H), 7.27-7.48 (m, 3H), 5.05 (d, J=1.22 Hz, 1H), 4.09-4.22 (m, 1H), 3.55-3.61 (m, 1H), 1.91-2.05 (m, 4H), 1.67-1.85 (m, 8H), 1.44-1.61 (m, 2H), 1.16 (s, 3H), 1.10 (s, 3H); LCMS (ESI) m/z 588.3 (M+H)+.
[Example 785]
(15,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2,2-dimethylcyclohexanecarboxylic acid
Figure imgf000309_0001
Step 1 : Ethyl
traw-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)- 1 H-pyrazol- l-yl)-2,2-dimethylcyclohexanecarboxylate (racemic mixture).
Oxalyl chloride (64 μί, 0.72 mmol) and DMF (1 drop) were added sequentially to a stirring solution of
trans- 1 -(4-(ethoxycarbonyl)-3 ,3-dimethylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4- carboxylic acid (0.20 g, 0.55 mmol; racemic mixture) and DCM (5.5 mL). After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved with THF (4.5 mL), and then a solution of
N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-l -amine (0.22 g, 0.55 mmol) and THF (1.0 mL) was added followed by DIPEA (0.29 mL, 1.7 mmol). After stirring for 30 min, TBAF (1.7 mL of a 1.0 M solution with THF, 1.7 mmol) was added. After stirring for 1 h, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHC03, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHC03 (2x) and brine, dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM (5.5 mL) and the resulting solution was treated with Dess-Martin periodinane (0.26 g, 0.60 mmol). After stirring for 10 min, the reaction mixture was concentrated under reduced pressure, the residue was partitioned between THF— EtOAc (1 : 1 vol/vol) and saturated aqueous NaHC03, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHC03 and brine, dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, silica gel (1.0 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 9: 1 to 4:1 hexane-EtOAc) to give ethyl
tra« -4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylate (0.27 g, 80% overall yield; racemic mixture) as a colorless solid.
Step 2: Ethyl
(15,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2,2-dimethylcyclohexanecarboxylate.
Ethyl trara-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylate (0.22 g, from Step 1 ; racemic mixture) was resolved using preparative high-performance liquid
chromatography (CHIRALPAK™ AD-H column from Chiral Technologies, Inc., West Chester, PA (250 mm x 30 mm, 5 μη column) eluting with a mixture of heptane/EtOH (90: 10 v/v) at a flow rate of 50 mL/min) to give two products in greater than 97% enantiomeric excess.
Peak 1 : Ethyl
(li?,4i?)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylate (0.10 g) as a colorless solid. Peak 2: Ethyl
(lS,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylate (0.098 g) as a colorless solid.
Step 3:
(15',45)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylic acid .
NaOH (1.6 mL of a 1.0 M aqueous solution, 1.6 mmol) was added to a stirring solution of ethyl
(15',4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylate (0.098 g, 0.16 mmol, from Step 2), THF (1.6 mL), and EtOH (1.6 mL), and then the reaction mixture was heated at 60 °C. After stirring for 40 h, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved with water (10 mL), concentrated hydrochloric acid (10 drops) was added to the solution, the resulting heterogeneous mixture was filtered, the filter cake was washed with water, dissolved with Et20, the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, the solution was filtered, and the filtrate was concentrated under reduced pressure to give
(15',45)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)-2,2-dimethylcyclohexanecarboxylic acid (0.082 g, 88% yield) as a colorless solid.
Ή NMR (400 MHz, CDC13) major rotamer/tautomer (carboxylic acid proton not observed) δ 8.50 (s, 2H), 7.55 (s, 1H), 4.61-4.35 (m, 3H), 3.70-3.16 (m, 2H), 2.47-2.31 (m, 1H), 2.16-1.86 (m, 5H), 1.81-1.57 (m, 1H), 1.17 (br. s., 3H), 1.10 (br. s., 3H), 1.01 (br. s., 9H); LCMS (ESI): 591.0 (M+H)+.
[Example 754]: made from the racemic ethyl ester from Step 1 of example 785.
[Example 784]: made from the (li?,4/?)-ethyl ester from Step 2 example 785.
[Example 807]: made in the same manner as example 754.
[Example 791]
(trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)-lH-pyrazol-lTyl)-l-methylcyclohexyl)acetic acid
Figure imgf000312_0001
2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexyl)acetate
Steps 1 and 2 were conducted in a similar manner to Example 1 to give ethyl 2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexyl)acetate.
Step 3: ethyl ^
2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluor omethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexyl)acetate
To a solution of ethyl
2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- l-yl)-l-methylcyclohexyl)acetate (134.7 mg, 0.217 mmol) in DCM (2 mL) was added Dess-Martin periodinane (129 mg, 0.303 mmol). The resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched with NaHC03 (5 mL, sat. aq.) and Na2S203 (5 mL, sat. aq.), then extracted with CH2C12 (2x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (24 g Gold, 0% -50% EtOAc/Hexane) to yield pure white solid as ethyl
2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluor omethyl)- 1 H-pyrazol- l-yl)-l-methylcyclohexyl)acetate (85.5 mg, 0.138 mmol, 63.7% yield). LCMS = 618 (M+H)+.
Step 4:
(trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(tr ifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexyl)acetic acid.
To solution of ethyl 2-((lr,4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifIuor omethyl)-lH-pyrazol-l-yl)-l-methylcyclohexyl)acetate (85.5 mg, 0.138 mmol) in THF (2 mL)/EtOH (0.500 mL) was added LiOH, 1 M aqueous (0.552 mL, 0.552 mmol). The reaction mixture was stirred at ambient temperature overnight. Solvent was partially removed. The aqueous solution was acidified to pH 2. The resulting precipitate was filtered, washed with water and allowed to dry in the open air to afford pure white solid as 2-((lri4r)-4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluor omethyl)-lH-pyrazol-l-yl)-l-methylcyclohexyl)acetic acid (82 mg, 0.139 mmol, 100% yield) as mixture of tautomers. 1H NMR (500 MHz, DMSO-d6) δ 0.90-1.01 (m, 9H) 1.05-1.14 (m, 3H) 1.46-1.59 (m, 2H) 1.61-1.83 (m, 4H) 2.00-2.21 (m, 2H) 3.49 (s, 2H) 4.05-4.23 (m, 1H) 5.34 (s, 1H) 7.75 (s, 1H) 8,62 (s, 2H) 9.88 (s, 1H). LCMS = 590.0
Figure imgf000314_0001
Figure imgf000314_0002
trara-4-(4-(((2S,4iS)-2-((3,5-dichloro-4-pyridinyl)carbonyl)-4-phenoxy-l-pyrrolidinyl) carbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was prepared according to example 822 using (2S',45)-Boc-4-phenoxy-pyrrolidine-2-carboxylic acid (Chem Impex Int'l, Wood Dale, IL, 2.07 g, 6.74 mmol). The mixture of epimers was separated using prepartory SFC under the following conditions. Step 1 : Preparative SFC: OX-H (5 um, 21 mm x 25 cm), Organic modifier: 15% MeOH. F=70 ml/min, T=40 °C, BPR=100 bar, 220 nm. P=15 bar. All sample (605 mg) dissolved in MeOH (10 mL) -60 mg/ml, 0.5 ml inj.
Step 2: Preparative SFC: Reprocessing Peak 2. OX-H (5 urn, 21 mm x 25 cm), Organic modifier: 25% MeOH. F=70 ml/min, T=40 °C, BPR=100 bar, 220 nm. P=165 bar. All sample dissolved in MeOH (10 mL), -60 mg/ml), 1.0 mL inj.
Step 3: Preparative SFC: Recycling Peak 1 collection. OX-H (5 um, 21 mm x 25 cm) Organic modifier: 25% MeOH. F=70 ml/min, T=40 °C, BPR=100 bar, 220 nm. P=165 bar. All sample dissolved in MeOH (10 mL), 1.0 ml inj. MS (ESI) 639.0, 641.0 [M + H]+. Note: this epimer was the second eluting peak under the separation conditions described above.
[Example 796]
Figure imgf000315_0001
trara-4-(4-(((2i?,45)-2-((3,5-dichloro-4-pyridinyl)carbohyl)-4-phenoxy-l-pyrrolidinyl) carbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was isolated (107 mg, 0.17 mmol, 11 % yield) as a light yellow amorphous solid following preparatory SFC separation of the mixture of epimers (at the C2 position of the pyrrolidine) from Example 712. MS (ESI) 639.0, 641.0 [M + H]+. Note: this epimer was the third eluting peak under the separation conditions described above for example 795. [Example 797]
Figure imgf000316_0001
tra«^-4-(4-(((25,4 ?)-2-((3,5-dichloro-4-pyridinyl)carbonyl)-4-phenoxy-l-pyrrolidinyl) carbonyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylic acid.
The title compound was isolated (6.7 mg, 10.48 μιηοΐ, 0.7% yield) as a light yellow amorphous solid following preparatory SFC separation of the mixture of epimers (at the C2 position of the pyrrolidine) from example 795. MS (ESI) 639.0, 641.0 [M + H]+. Note: this epimer was the first eluting peak under the separation conditions described above for example 795.
[Example 798]
(lr,4r)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000316_0002
Step 1 : (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluofophenyl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl)m ethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate To a solution of
r-(2,6-dichloro-3-fluorophenyl)-2-(((l-(trifluoromethyl)cyclopropyl)methyl)arnino)ethanol (116 mg, 0.335 mmol) and (lr,4r)-ethyl
4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate (147 mg, 0.402 mmol) in DCM (2.3 mL) was added DIPEA (117 μΐ, 0.670 mmol). The reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was quenched with saturated aqueous NaHC03 and extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford a light-yellow oil. The crude material was purified by column chromatography (silica gel, eluent: 10% to 70% EtO Ac/heptane), to provide (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl)m ethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (150 mg, 0.222 mmol, 66.2% yield) as a white solid. LCMS: 675.9 (M+H)+.
Step 2: (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl)methyl )carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate
A mixture of (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-hydroxyethyl)((l-(trifluoromethyl)cyclopropyl)m ethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (150 mg, 0.222 mmol), TEMPO (3.46 mg, 0.022 mmol), DCM (2.2 mL) and 1 M aq NaHC03 (554 μΐ, 0.554 mmol) was stirred at 0 °C. Then sodium hypochlorite, 5.65-6% (1.5 ml, 1.1 mmol) was added slowly. After 1 h, the reaction was quenched with saturated aqueous Na2S203 at 0 °C and extracted with DCM (10 mL). The organic layer was dried over anhydrous MgS04, and concentrated under reduced pressure to afford colorless residue. The crude material was purified by column chromatography (silica gel, eluent : 0% to 40% EtO Ac/heptane) to provide (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l -(trifluoromethyl)cyclopropyl)methyl )carbamoyl)-5-(trifiuoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (113 mg, 0.168 mmol, 76% yield) as a white solid. Ή NMR (400 MHz, CDC13) δ 7.54 (s, 1H), 7.25-7.30 (m, 1H), 7.15-7.21 (m, 1H), 4.57 (s, 2H), 4.12-4.20 (m, 3H), 3.86 and 3.75 (2H, 2xs,), 2.12-2.29 (m, 2H), 1.81-1.97 (m, 6H), 1.34-1.39 (m, 3H), 1.25-1.31 (m, 3H), 1.07 (d, J=6.4 Hz, 4H); LCMS: 674.1 [M+H]+.
Step 3:
(lr,4r)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
To a mixture of (lr,4r)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl)methyl )carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (113 mg, 0.168 mmol) in MeOH (0.4 mL) and THF (0.4 mL) (1 : 1 ratio) was added 2 N aqueous NaOH (0.42 μΐ, 0.838 mmol). The reaction mixture was heated to 50 °C for 2 h. It was concentrated, cooled to 0 °C and acidified with 1 N aqueous HC1 solution. The white solid was collected, washed with water and dried under reduced pressure to provide
(lr,4r)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((l-(trifluoromethyl)cyclopropyl )methyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid (86 mg, 0.133 mmol, 79% yield). Ή NMR (400 MHz, DMSO-d6) δ 12.26 (br. s., 1H), 7.68 (s, 1H), 7.62 (d, J=6.5 Hz, 2H), 4.88 and 4.71 (2H, 2xs), 4.27 (m, 1H), 3.77 and 3.67 (2H, 2xm), 1.98-2.16 (m, 2H), 1.69-1.90 (m, 6H), 1.20-1.27 (m, 3H), 1.01 (br. s., 4H); LCMS: 645.9[M+H]+.
[Example 813]
(l S,2S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl) -5- trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylic acid
Figure imgf000319_0001
Step 1 and Step 2: (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(trifluoromet hyl)-l H-pyrazol- l-yl)-2-methylcyclohexanecarboxylate with its (lR,2R,4R)-isomer
To a light-yellow clear solution of
l-((lS,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid with its (lR,3R,4R)-isomer (0.3128 g, 0.898 mmol) in DCM (8.98 ml) was added oxalyl chloride (0.095 ml, 1.123 mmol) followed by DMF (1 drop) and the light-yellow clear reaction mixture was stirred at room temperature. After 2 h, The mixture was concentrated in vacuo to give (l S,2S,4S)-ethyl
4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-2-methylcyclohexanecarboxyl ate with its (lR,2R,4R)-isomer as brown syrupy solid. To the residue was added a solution of N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-l -amine (0.352 g, 0.898 mmol) in THF (8.98 ml) followed by DIPEA (0.626 ml, 3.59 mmol). The brown heterogeneous mixture was stirred at room temperature. After 3 h, LC-MS (ESI) showed that the intermediate ( 1 S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl)-5-(tri fluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate with its
(lR,2R,4R)-isomer was formed: LCMS (ESI) m/z 721.1 (M+H)+.
To the reaction mixture was added TBAF solution, 1.0 M in THF (3.59 ml, 3.59 mmol). After 1 hour, the reaction mixture was diluted with water (30 mL) and brine (30 mL). The reaction mixture was extracted with EtOAc (2 x 50 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a orange syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane to provide (1 S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(trifluoromet hyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate with its ( 1 R,2R,4R)-isomer (0.4742 g, 0.781 mmol, 87% yield) as off-white syrupy solid: 1H NMR (300 MHz,
DMSC-d6) δ 8.44-8.63 (2H, m), 7.57-7.71 (1H, m), 6.01 (1H, d, J=4.4 Hz), 5.28 (1H, dt, J=9.0, 4.5 Hz), 4.32 (1H, d, J=7.2 Hz), 4.1 1 (2H, q, J=7.1 Hz), 3.85 (1H, dd, J=14.6, 9.2 Hz), 3.53 (2H, d, J=13.0 Hz), 3.32-3.41 (1H, m), 1.49-2.16 (8H, m), 1.21 (3H, t, J=7.1 Hz), 0.63-0.98 (12H, m), (several peak sets due to diastereomers and rotamers); LCMS (ESI) m/z 607.1 (M+H)+.
Step 3: (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate To a light-yellow clear solution of (1 S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(trifluorornet hyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate with its (lR,2R,4R)-isomer (0.4702 g, 0.774 mmol) in DCM (12.90 ml) was added Dess-Martin periodinane (0.492 g, 1.161 mmol). The white cloudy mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous NaHC03 (30 mL) and saturated aqueous Na2S203 (30 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a colorless syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane to give (lS,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate with its (lR,2R,4R)-isomer (0.437 g, 0.722 mmol, 93% yield) : 1H NMR (400 MHz, CDC13) δ 8.46-8.61 (2H, m), 7.51-7.74 (1H, m), 4.49-4.92 (2H, m), 4.25-4.39 (1H, m), 4.18 (2H, q, J-7.1 Hz), 3.29-3.61 (2H, m), 1.63-2.18 (8H, m), 1.29 (3H, t, J=7.1 Hz), 0.81-1.06 (12H, m), rotamers present; LCMS (ESI) m/z, 605.0 (M+H)+.
The racemic mixture was separated by SFC to give two fractions:
The stereochemisty of each fraction was arbitrarily assigned.
First peak on SFC IA column: (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate (0.1588 g, 0.262 mmol, 33.9% yield) as white solid: Ή NMR (300 MHz, DMSO-d6) δ 8.68-8.87 (2H, m), 7.71-7.89 (1H, m), 4.65-4.92 (2H, m), 4.33 (1H, br. s.), 4.10 (2H, q, J=7.0 Hz), 3.24-3.30 (2H, m), 1.49-2.17 (8H, m), 1.20 (3H, t, J=7.1 Hz), 0.73-1.00 (12H, m) ; LCMS (ESI) m/z 605.0 (M+H)+. Second peak on SFC IA column: (lS,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- l-yl)-2-methylcyclohexanecarboxylate (0.1526 g, 0.252 mmol, 32.6% yield) as white solid: Ή NMR (300 MHz, DMSO-d6) δ 8.70-8.87 (2H, m), 7.72-7.89 (1H, m), 4.64-4.93 (2H, m), 4.34 (1H, d, J=5.1 Hz), 4.10 (2H, q, J=7.0 Hz), 3.27 (2H, br. s.), 1.50-2.18 (8H, m), 1.20 (3H, t, J=7.1 Hz), 0.72-1.01 (12H, m) ; LCMS (ESI) m/z 605.0 (M+H)+.
Step 4:
(lS,2S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl) -5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylic acid.
To a mixture of the racemic mixture of (1 S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- l-yl)-2-methylcyclohexanecarboxylate (0.1245 g, 0.206 mmol) in THF (1.645 ml), EtOH (1.645 ml), and water (0.822 ml) was added 2 M LiOH in water (1.028 ml, 2.056 mmol). The yellow homogeneous mixture was stirred and heated at 60 °C. After 17 h, the reaction mixture was concentrated in vacuo to remove THF and EtOH. The resulting aqueous solution was diluted with water (10 mL). The pH of the solution was adjusted to -3.0 with 2 N HC1 and the resulting precipitate was collected by vacuum filtration and freeze-dried on lyophilizer overnight to provide example 813 (0.0939 g, 0.163 mmol, 79% yield) as white solid. 1H NMR (300 MHz, DMSQ-d6) δ 12.19 (1H, br. s.), 8.57-9.91 (2H, m), 7.72-7.88 (1H, m), 4.65-5.39 (2H, m), 4.32 (1 H, d, J=4.5 Hz), 3.22-3.53 (2H, m), 1.46-2.10 (8H, m), 0.72-1.03 (12H, m), rotamers present; LC-MS (ESI) m/z 577.1 (M+H)+. The stereochemisty was arbitrarily assigned as (1 S,2S,4S).
[Example 822]
Figure imgf000323_0001
tra«s-4-(4-(((2^,4S)-4-cyclohexyl-^
carbon l)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000323_0002
Step 1 : (2S,4S)-Boc-4-cyclohexyl-pyrrolidine-2-carboxylic acid (Chem Impex Int'l, Wood Dale, IL, 997 mg, 3.35 mmol) was treated with DCM (25 mL) followed by
Ι,Γ-carbonyldiimidazole (598 mg, 3.69 mmol). The solution was allowed to stir at room temperature for 1.5 h then the reaction mixture was then treated with Ν,Ο-dimethyl hydroxylamine hydrochloride (360 mg, 3.69 mmol) and allowed to stir over the weekend at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with a saturated solution of NaHC03 (30 mL) and brine (30 mL), dried over MgS04, filtered and concentrated affording crude (25',4S)-tert-butyl
4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate (1.1.4 g, 3.35 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 363.2 [M + Na]+. The crude material was used in the next step without further purification.
Step 2: (2SAS)-tert-buty\
4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine- 1 -carboxylate ( 1.14 g, 3.35 mmol) was treated with THF (20 mL), cooled to 0 °C in an ice bath and then treated with lithium aluminum hydride (l .OM solution in THF, 3.35 mL, 3.35 mmol) slowly dropwise over 3 min. The solution was then stirred at 0 °C for 45 min. The reaction mixture was quenched with a solution of sodium potassium tartrate, stirred at room temperature for 20 min, then extracted with EtOAc (3 x 50 mL), washed with brine and dried over MgS04, filtered and
concentrated affording crude (2S,4S)-tert-butyl
4-cyclohexyl-2-formylpyrrolidine-l -carboxylate as a clear, viscous oil. MS (ESI) 304.1 [M + Na]+. The crude material was used in the next step without further purification.
Step 3: (2S,4S)-tert-buty\ 4-cyclohexyl-2-formylpyrrolidine-l -carboxylate (943 mg, 3.35 mmol) was treated with THF (20 mL) and DBU (1.0 mL, 6.70 mmol) and allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness on the rotovap, treated with DCM and a saturated solution of NH4CI and extracted, washed with brine, dried: over MgS04, filtered and concentrated affording a mixture of crude
(2.V.4 )-/t'/7-butyl 4-cyclohexyl-2-formyipyrrolidine-l -carboxylate and (2i?,45 -/ert-butyl 4-cyclohexyl-2-formylpyrrolidine- 1 -carboxylate (470 mg, 1.67 mmol, 99% yield) as a clear, colorless viscous oil: MS (ESI) 304.1 [M + Na]+.
Step 4: Lithium diisopropylamide (2.0 M solution in heptane/THF/ ethylbenzene, 3.51 mL, 7.02 mmol) was added to 3,5-dichloropyridine (820 mg, 5.54 mmol) dissolved in THF (15 mL) cooled at -78 °C and stirred at this temperature for 1 h. (2S,4S)-tert-butyl
4-cyclohexyl-2-formylpyrrolidine-l -carboxylate ( 1.04 g, 3.70 mmol) and its epimer at C2 of the pyrrolidine in THF (11 mL) was added and the solution was removed from the cooling bath and allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2 50 niL) and the organic layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2SAS -/e/7-butyl
4-cyclohexyl-2-((5')-(3 ,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine- 1 -carboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1 ,453.1 [M + Na]+ Step 5 : (2.S\4S)-/er/-butyl
4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-l -carboxylate (1.20 g, 2.79 mmol) and its epimer at C2 of the pyrrolidine was treated with DCM (10 mL) and TFA (7 mL, 91 mmol) and allowed to stir at room temperature for 1.5 h. The reaction mixture was concentrated on the rotovap and the crude residue purified on an ISCO Combiflash™ RF (40 g Grace Reveleris column, using a gradient of 0-20% 2M NF MeOH in DCM) affording
(S)-((2S',4S)-4-cyclohexylpyrrolidin-2-yl)(3,5-dichloropyridinT4-yl)methanol
2,2,2-trifluoroacetate (755 mg, 1.705 mmol, 61% yield) along with its epimer at C2 of the pyrrolidine as a light tan-colored foam. MS (ESI) 329.0, 331.1 [M + I I] .
Step 6: Oxalyl chloride (0.22 mL, 2.55 mmol) was added to a solution of
1 -(( 1 r,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5 -(trifluoromethyl)- 1 H-pyrazole-4-car boxylic acid (593 mg, 1.70 mmol) in DCM ( 10.0 mL), followed by 2 drops of DMF while cooling in an ice bath. The solution was then removed from the ice bath and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness on the rotovap and the crude residue was treated with DCM (10.0 mL) and cooled to 0 °C. The stirring solution was then treated with
(5)-((2iS',45)-4-cyclohexylpyrrolidin-2-yl)(3,5-dichloropyridin-4-yl)methanol
2,2,2-trifluoroacetate (755 mg, 1.70 mmol) and DIPEA (0.89 mL, 5.11 mmol) in DCM (10 mL) and allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on an ISCO Combiflash™ RF (40 g Grace Reveleris column, using a gradient of 0- 100% EtO Ac in heptane) affording ( 1 S,4r)-ethyl
4-(4-((2S,45 -4-cyclohexyl-2-((5)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-l -carbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (640 mg, 0.970 mmol, 57% yield) along with its epimer at C2 of the pyrrolidine as a light tan foam. MS (ESI) 659.2, 661.1 [M + H]+.
Step 7: Dess-Martin Periodinane (823 mg, 1.94 mmol) and (l ?,4r)-ethyl
4-(4-((2i?,45 -4-cyclohexyl-2-((i?)-(3,5-dichl0ropyridin-4-yl)(hydroxy)methyl)pyrrolidine- 1 -carbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylate (640 mg, 0.97 mmol) as a mixture with its epimer at C2 of the pyrrolidine were treated with DCM (10 mL) and allowed to stir at room temperature for 3 h. The reaction was treated with a saturated solution of NaHC03 and solid sodium metabisulfite. The reaction mixture was then extracted with DCM (2 x 75 mL), dried over MgS04, filtered and concentrated affording crude product as a light orange foam. This residue was purified on an ISCO Combiflash™ RF (25 g Grace Reverlis column, using a gradient of 0-70% EtO Ac in heptane) affording (li?,4r)-ethyl
4-(4-((2i?,4S)-4-cyclohexyl-2-(3,5-dichloroisonicotinoyl)pyrrolidine-l-carbonyl)-5-(trifluo romethyl)-l H-pyrazol- l-yl)-l -methylcyclohexanecarboxylate (605 mg, 95%) along with its epimer at C2 of the pyrrolidine as a light yellow foam. MS (ESI) 657.0, 659.0 [M + H]+. Step 8: (15,4r)-ethyl
4-(4-((2S,4S)-4-cyclohexyl-2-(3,5-dichloroisonicotm^
omethyl)-lH-pyrazol-l-yl)-l-methylcyclohexanecarboxylate (454 mg, 0.69 mmol) and its epimer at C2 of the pyrrolidine in THF (3.5 mL) and MeOH (3.5 mL) was treated with lithium hydroxide monohydrate (1.0 M solution, 3.5 mL, 3.45 mmol). The mixture was stirred at room temperature overnight (16 h), the organics were removed under reduced pressure (rotary evaporator) and the resulting aqueous solution was acidified with 1 N HC1 leading to the formation of a precipitate. The mixture was extracted with EtOAc (2 x 40 mL). The combined extracts were washed with brine, dried over anhydrous MgS04, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (25 g Thomson SingleStep column, using a gradient of 0- 100% [ 10% MeOH in DCM] in DCM) affording a mixture of two products epimeric at C2 of the pyrrolidine. This material was subjected to separation on a preparatory SFC using the following conditions: OX column (SN=2121 , 5 um, 21 mm x 25 cm, 50/50/50 p=172), Organic modifier: 25% MeOH with 20 mM NH3. F=70 ml/min, T=40 °C, BPR=100 bar, 220 nm. P=165 bar, all sample (416 mg) dissolved in 8 mL of MeOH, ~'52 mg/ml), 1.0 mL inj. affording
tra«5-4-(4-(((2 ?,4S)-4-cyclohexyl-2-((3,5-dichloro-4-pyridinyl)carbonyl)-l-pyrrolidinyl)ca rbonyl)-5,-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid (55.3 mg, 0.088 mmol, 13% yield) as a light yellow amorphous solid. MS (ESI) 629.1 , 631.1 [M + H]+. Note: this epimer was the first eluting peak under the separation conditions described above.
[Example 823]
Figure imgf000328_0001
tra«5-4-(4-(((2S,4S)-4-cyclohexyl-2-((3,5-dichloro-4-pyridinyl)carbonyl)-l-pyrrolidinyl) carbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was isolated (291 mg, 0.46 mmol, 67% yield) as a light yellow amorphous solid following preparatory SFC separation of the mixture of epimers (at the C2 position of the pyrrolidine) from Example 739. MS (ESI) 629.1, 631.1 [M + H]+. Note: this epimer was the second eluting peak under the separation conditions described above.
Figure imgf000328_0002
tr n5-4-(4-(((25,4i?)-2-((3,5-dichloro-4-pyridinyl)carbonyl)-4-phenyl-l-pyrrolidinyl) carbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
The title compound was prepared according to example 822 using (25',4i?)-l-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (Frontier Scientific, Newark, DE, 1.00 g, 3.43 mmol) and isolated (63.7 mg, 0.10 mmol, 18% yield) as a white amorphous solid. The mixture of epimers was separated using preparative SFC under the following conditions. Column: CHIRALPAK™ AZ-H (Reversed) (250 x 21 mm, 5 μπι), Mobile Phase: 82:18 (A:B), A: Liquid C02, B: EtOH. Flow Rate: 70 mL/min. Column/Oven temp.: 40 °C, 186 - 193 bar inlet pressure. SN: 403121. MS (ESI) 623.0, 625.0 [M + H]+. Note: this epimer was the second eluting peak under the separation conditions described above.
[Example 828]
Figure imgf000329_0001
trara-4-(4-(((2 ?,4i?)-2-((3,5-dichloro-4-pyridinyl)carbonyl)-4-phenyl-l-pyrrolidinyl) carbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was isolated (135 mg, 0.217 mmol, 39% yield) as a white foam following preparatory SFC separation of the mixture of epimers (at the C2 position of the pyrrolidine) from example 827. MS (ESI) 623.0, 625.0 [M + H]+. Note: this epimer was the third eluting peak under the separation conditions described above for example 827.
[Example 845]:
(lS,2R,4S)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbic yclo[3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohex anecarboxylic acid.
Figure imgf000330_0001
Step 1 : (l S,2R,4S)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-hydroxyethyl)(( 1 R,3r,5S)-6,6-dimethylbicyclo[3.
1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarb oxylate.
To a solution of
(lR,3r,5S)-N-(2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethyl)-6,6-dimethylbic yclo[3.1.0]hexan-3-amine (97 mg, 0.217 mmol) and (l S,2R,4S)-ethyl
4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxyl ate (96 mg, 0.261 mmol) in DCM (0.8 mL) was added DIPEA (76 μΐ, 0.434 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NaHC03 solution and extracted with DCM (3x10 mL). The organic layer was combined, dried over anhydrous MgS04, filtered, and concentrated to afford product as yellow residue. The residue was dissolved with THF (0.75 mL), then added TBAF solution, 1.0 M in THF (434 μΐ, 0.434 mmol). The mixture was stirred at room temperature for 0.5 h. It was quenched with saturated aqueous NaHC03 and extracted with DCM. The combined organic layer was washed with water, brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford a light-yellow oil. The crude material was purified by column chromatography (silica gel, elutent: 0% to 40% EtO Ac/heptane) to provide (lS,2R,4S)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-hydroxyethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3. 1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarb oxylate (96 mg, 0.145 mmol, 66.7% yield) as a white solid. LCMS: 662.1 [M+H]+
Step 2: (l S,2R,4S)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]h exan-3-yl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxyl ate
(lS,2R,4S)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-hydroxyethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3. 1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-2-methylcyclohexanecarb oxylate (96 mg, 0.145 mmol) was dissolved in DCM (3 mL) and Dess-Martin periodane (77 mg, 0.181 mmol) was added. It was stirred at room temperature for 3 h. The reaction mixture was quenched with 5% Na2S203, washed with saturated NaHC03, dried with anhydrous Na2S04 and concentrated. The crude product was purified by column chromatography (silica gel, eluent: 0-40% EtO Ac / heptane) to afford (1 S,2R,4S)-ethyl 4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]h exan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxyl ate (90 mg, 0.136 mmol, 94% yield) as a viscous white oil.
LCMS 660.0 [M+H]+.
Step 3:
(lS,2R,4S)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbic yclo[3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohex anecarboxylic acid.
To a mixture of (l S,2R,4S)-ethyl
4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]h exan-3-yl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-rnethylcyclohexanecarboxyl ate (90 mg, 0.136 mmol) in MeOH (0.34 mL) and THF (0.34 niL) (1 : 1 ratio) was added 2 N aq. NaOH (0.34mL, 0.68 mmol). The reaction mixture was heated to 50 °C for 3 h. It was concentrated, cooled to 0 °C and acidified with 1 N aqueous HCl. The white solid was collected, washed with water and dried under reduced pressure to provide
(lS,2R,4S)-4-(4-((2-(2,6-dichloro-3-fluorophenyl)-2-oxoethyl)((lR,3r,5S)-6,6-dimethylbic yclo[3.1.0]hexan-3-yl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol-1 -yl)-2-methylcyclohex anecarboxylic acid (58 mg, 0.092 mmol, 67.3% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.18 (br. s., 1H), 7.87-7.56 (m, 2H), 7.40-7.51 (m, lH), 4.96-5.10 (m, 1H), 4.53-4.77 (m, 1H), 4.11-4.52 (m, 2H), 2.54-2.64 (m, 1H), 1.66-2.24 (m, 10H), 1.35-1.59 (m, 2H), 1.19-1.29 (m, 1H), 0.82-1.14 (m, 15H); LCMS: 632.2 [M+H]+
[Example 853]
trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)((ls,4s)-7-oxabicyclo[221]hept-l-ylm ethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methyl cyclohexanecarboxylic
Figure imgf000332_0001
Step 1 and Step 2: ethyl
trans-4-(4-(((ls,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- hydroxyethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarbo xylate. ·
To a clear solution of
1 -(( 1 r,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5 -(trifluoromethyl)- 1 H-pyrazole-4-car boxylic acid (0.121 g, 0.348 mmol) in DCM (3.48 ml) was added oxalyl chloride (0.037 ml, 0.435 mmol) followed by DMF (1 drop) and the clear reaction mixture was stirred at room temperature. After 5 h, the mixture was concentrated in vacuo to give (lr,4r)-ethyl
4-(4-(chlorocarbonyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyl ate as light-yellow syrup. To the residue was added a solution of
N-((ls,4s)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)-2-(3,5-dichloropyridin-4-yl)-2-((triethyl silyl)oxy)ethanamine (0.150 g, 0.348 mmol) in THF (3.48 ml) followed by DIPEA (0.242 ml, 1.391 mmol). The yellow heterogeneous mixture was stirred at room temperature.
After 13 h, LCMS showed that the intermediate ethyl
trans-4-(4-(((ls,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- ((triethylsilyl)oxy)ethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohe xanecarboxylate was formed: LCMS (ESI) m/z 761.2 (M+H)+. To the reaction mixture was added TBAF solution, 1.0 M in THF (1.391 ml, 1.391 mmol). After 4 h, the reaction mixture was diluted with water (30 mL) and brine (30 mL). The reaction mixture was extracted with EtOAc (2 x 50 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtO Ac in heptane to provide ethyl trans-4-(4-(((ls,4S)-7-oxabicyclo[2 .1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- hydroxyethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarbo xylate (0.1083 g, 0.167 mmol, 48.1% yield) as colorless syrupy solid:
1H NMR (400 MHz, DMSO-d6) δ 8.43-8.59 (2H, m), 7.49-7.84 (1H, m), 5.95-6.04 (1H, m),
5.32-5.63 (1H, m), 3.51-4.54 (8H, m), 1.11-2.22 (22H, m), (diastereomers and rotamers present); LCMS (ESI) m/z 647.2 (M+H)+.
Step 3: ethyl
trans-4-(4-(((ls,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- 0xoethyl)carbamoyl)-5-(trifluororriethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyla te
To a clear solution of ethyl
trans-4-(4-(((ls,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yI)-2- hydroxyethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarbo xylate (0.1015 g, 0.157 mmol) in DCM (2.61 ml) was added Dess-Martin periodinane (0.100 g, 0.235 mmol). The cloudy mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous Na2S203 (30 mL) and saturated aqueous NaHC03 (30 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to provide ethyl
trans-4-(4-(((l s,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- oxoethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyla te (0.0841 g, 0.130 mmol, 83% yield) as colorless syrup. 1H NMR (400 MHz, CDC13) δ 8.43-8.60 (2H, m), 7.51-7.68 (1H, m), 3.71-5.12 (8H, m), 1.21-2.36 (22H, m), rotamers present; LC-MS (ESI) m/z 645.0 (M+H)+.
Step 4:
trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)((ls,4s)-7-oxabicyclo[221]hept-l-ylm ethyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid
To clear solution of ethyl
trans-4-(4-(((ls,4S)-7-oxabicyclo[2.2.1]heptan-l-ylmethyl)(2-(3,5-dichloropyridin-4-yl)-2- oxoethyl)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxyla te (0.0786 g, 0.122 mmol) in THF (0.974 ml), EtOH (0.974 ml), and water (0.487 ml) was added 2 M LiOH in water (0.609 ml, 1.218 mmol). The yellow homogeneous mixture was stirred and heated at 60 °C. After 10 h, the reaction mixture was concentrated in vacuo to remove THF and EtOH. The resulting aqueous solution was diluted with water (10 mL). The pH of the solution was adjusted to -3.0 with 2 N HCl and the resulting precipitate was collected by vacuum filtration, wash with water, and freeze-dried on lyophilizer overnight to provide example 853 as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (1H, br. s.), 8.57-8.84 (2H, m), 7.69-7.86 (1H, m), 4.77-5.00 (2H, m), 4.40-4.53 (1H, m), 4.25 (1H, t, J=11.3 Hz), 3.64-4.06 (2H, m), 1.10-2.20 (19H, m), rotamers present; LCMS (ESI) m/z 617.0 (M+H)+.
[Example 872]
Figure imgf000335_0001
tr «5'-4-(4-((2-(3,5-dichloro-2-n ethoxy-4-pyridinyl)ethyl)(2,2-dimethylpropyl) carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was prepared from
N-(2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-l-amine and 1 -(( 1 r,4r)-4-(ethoxycarbonyl)-4-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4-car boxylic acid by procedures similar to those described in example 545. MS (ESI) 593.2, 595.1 [M + H]+.
[Example 879]
(l S,2S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpro
Figure imgf000336_0001
Step 1 and Step2: (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate compound with (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate (1 :1)
To a slightly cloudy mixture of
1 -(( 1 R,3 R,4R)-4-(ethoxycarbonyl)-3 -methylcyclohexyl)-5 -(trifluoromethyl)- 1 H-pyrazole- 4-carboxylic acid compound with
l-((lS,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-lH-pyrazole-4 -carboxylic acid (1 : 1) (0.300 g, 0.431 mmol) in DCM (17.23 ml) was added oxalyl chloride (0.091 ml, 1.077 mmol) followed by D F (1 drop) and the light-yellow slightly cloudy reaction mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated in vacuo to give (lR,2R,4R)-ethyl
4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxyl ate compound with (lS,2S,4S)-ethyl
4-(4-(chlorocarbonyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxyl ate (1 :1) as light-yellow syrup.
To the yellow syrup was added a solution of
N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dimethylpro pan-l-amine (0,384 g, 0.862 mmol) in THF (17.23 ml) followed by DIPEA (0.600 ml, 3.45 mmol). The yellow homogeneous mixture was stirred at room temperature. After 4 h, LCMS (ESI) showed that the intermediate (l S,2S,4S)-ethyl
4.(4.((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(3,3,3-trifluoro-2,2-di propyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexattecarboxylate including its isomer (1R,2R,4R) was formed: LCMS (ESI) m/z 775.1 (M+H)+.
To the reaction mixture was added TBAF solution, 1.0 M in THF (3.45 ml, 3.45 mmol) and the yellow homogeneous mixture was stirred at room temperature. After 20 min, the reaction mixture was diluted with water (50 mL) and brine (50 mL). The reaction mixture was extracted with EtOAc (2 x 50 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a light- yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to provide (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)car bamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate compound with (lS,2S,4S)-ethyl
4-(4-((2-(3 ,5 -dichloropyridin-4-yl)-2-hydroxyethyl)(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)car bamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate (1 :1) (0.4648 g, 0.351 mmol, 82% yield) as colorless syrup: Ή NMR (400 MHz, DMSO-d6) δ 8.46-8.63 (2H, m), 7.70-7.82 (1H, m), 6.11 (1H, d, J=3.3 Hz), 5.20-5.32 (1H, m), 4.34 (1H, d, J=8.0 Hz), 4.06-4.16 (2H, m), 3.43-3.97 (4H, m), 1.53-2.15 (8H, m), 0.82-1.31 (Ϊ2Η, m), (diastereomers and rotamers); LCMS (ESI) m/z 661.1 (M+H)+.
Step 3: (lS,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbam oyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate
To a clear solution of (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)car bamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate compound with (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)car bamoyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-2-methylcyclohexanecarboxylate (1 : 1) (0.458 g, 0.346 mmol) in DCM (11.54 ml) was added Dess-Martin periodinane (0.441 g, 1.039 mmol). The white cloudy mixture was stirred at room temperature. After 14 h, the mixture was quenched with saturated aqueous Na2S203 (50 mL) and saturated aqueous NaHC03 (50 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2S04. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane to provide (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbam oyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate compound with (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifiuoro-2,2-dimethylpropyl)carbam oyl)r5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate (1 : 1) (0.3795 g, 0.288 mmol, 83% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.85 (2H, m), 7.73-7.99 (1H, m), 4.69-4.93 (2H, m), 4.35 (1H, d, J=3.7 Hz), 4.10 (2H, q, J=7.0 Hz), 3.51-3.87 (2H, m), 1.51-2.15 (8H, m), 0.87-1.23 (12H, m), rotamers present; LCMS (ESI) m/z 659.0 (M+H)+.
The racemic mixture was separated by SFC to give two fractions where the stereochemisty of each fraction was arbitrarily assigned.
First peak on SFC I A column: (lR,2R,4R)-ethyl
4-(4-((2-(3,5-dichloropyndin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbam oyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate (0.1371 g, 0.208 mmol, 43.4% yield) as white solid: lH NMR (400 MHz, CDC13) δ 8.47-8.63 (2H, m), 7.51-7.77 (1H, m), 4.52 (2H, s), 4.26-4.39 (1H, m), 4.18 (2H, q, J=7.1 Hz), 3.70 (2H, br. s.), 1.62-2.17 (8H, m), 1.29 (3H, t, J=7.1 Hz), 1.24 (6H, s), 1.00 (3H, d, J=6.1 Hz), rotamers present; LCMS (ESI) m/z 659.0 (M+H)+.
Second peak on SFC IA column: (lS,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbam oyl)-5-(tf ifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylate (0.1447 g, 0.219 mmol, 45.8% yield) as white powder: 1H NMR (400 MHz, CDC13) δ 8.44-8.64 (2H, m), 7.51-7.77 (1H, m), 4.52 (2H, s), 4.25-4.38 (1H, m), 4.18 (2H, q, J=7.1 Hz), 3.57-3.98 (2H, m), 1.63-2.14 (8H, m), 1.29 (3H, t, J=7.1 Hz), 1.24 (6H, s), 1.00 (3H, d, .7=6.1 Hz), rotamers present; LCMS (ESI) m/z 659.0 (M+H)+.
Step 4:
(lS,2S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2^
pyl)carbamoyl)-5-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylic acid
To a clear solution of (l S,2S,4S)-ethyl
4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbam oyl)-5-(trifluoromethyl)-l H-pyrazol- l-yl)-2-methylcyclohexanecarboxylate (0.1345 g, 0.204 mmol) in THF (1.632 ml), EtOH (1.632 ml), and water (0.816 ml) was added 2 M LiOH in water (1.020 ml, 2.040 mmol). The light-yellow slightly cloudy mixture was stirred and heated at 60 °C. After 4 h, the reaction mixture was concentrated in vacuo to remove THF and EtOH. The resulting aqueous solution was diluted with water (10 mL). The pH of the solution was adjusted to -3.0 with 1 N HCl and the resulting precipitate was collected by vacuum filtration, wash with water, and freeze-dried on lyophilizer overnight to provide example 879 (0.1151 g, 0.182 mmol, 89% yield) as white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.18 (IH, br. s.), 8.59-8.86 (2H, m), 7,73-8.02 (IH, m), 4.65-5.49 (2H, m), 4.33 (IH, d, J=8.4 Hz), 3.44-3.94 (2H, m), 1.48-2.10 (8H, m), 0.85-1.36 (9H, m), rotamers present; LCMS (ESI) m/z 631.1 (M+H)+. The stereochemisty was arbitrarily assigned as (1 S,2S,4S).
[Example 885]
Figure imgf000340_0001
tra«s-4-(4-((2-(3,5-dichloro-2-oxo-l,2-d¾^
carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)- 1 -methylcyclohexanecarboxylic acid.
The title compound was prepared in an analogous manner to example 886 and isolated (36.7 mg, 0.063 mmol, 54% yield) as a white amorphous solid. MS (ESI) 579.0, 581.0 [M + H]+.
Figure imgf000341_0001
(15,2i?,4S)-4-(4-((2-(3,5-dichloro-2-oxo-l,2-dihydro-4-pyridinyl)ethyl)(2,2-dimethylpropy l)carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- l-yl)-2-methylcyclohexanecarboxylic acid
Figure imgf000341_0002
Step 1 : Oxalyl chloride (2.0M in DCM, 0.52 mL, 1.03 mmol) was added to a solution of l-((lS,3 ?,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5r(trifluoromethyl)-lH-pyrazole-4- carboxylic acid (239 mg, 0.687 mmol) in DCM (2.0 mL) followed by 1 drop of DMF while cooling in an ice bath. The solution was removed from the ice bath and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was treated with DCM (2.0 mL) and cooled to 0 °C. The stirring solution was then treated with
N (2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-l -amine (200 mg, 0.687 mmol) in DCM (2 mL) followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and allowed to warm to room temperature and stirred overnight (16 h). The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on an ISCO Combiflash™ RF (25 g Grace Reveleris column, using a gradient of 0-50% EtOAc in heptane) affording (lS,2i?,4S)-ethyl
4T(4-((2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromet hyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate (350 mg, 0.56 mmol, 82% yield) as a white crystalline solid. MS (ESI) 621.2, 623.2 [M + H]+.
Step 2: (lS,2i?,45)-ethyl
4-(4-((2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromet hyl)-lH-pyrazol-l-yl)-2-methylcyclohexanecarboxylate (109 mg, 0.175 mmol) was treated with aqueous hydrochloric acid (5.0 N, 3.00 mL, 15.00 mmol) and hydrochloric acid (4.0 N in 1,4-dioxane, 3.00 mL, 12.00 irimol), fitted with a reflux condenser and heated to 120 °C for 3 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on a Gilson (Gemini™ Phenomenex; 30 x 150 mm, 5 u, using a gradient of 10-95% 0.1%TFA/CH3CN in 0.1 %TF A/water), concentrated in a genevac overnight affording
( 15,,2i?,45)-4-(4-((2-(3 ,5-dichloro-2-oxo- 1 ,2-dihydropyridin-4-yl)ethyl)(neopentyl)carbamo yl)-5-(trifluoromethyl)-lH-pyrazol-l -yl)-2-methylcyclohexanecarboxylic acid (57 mg, 0.098 mmol, 56% yield) as a white amorphous solid. MS (ESI) 579.0, 581.2 [M + H]+.
[Example 887] ethoxy-4-pyridinyl)ethyl)(2,2-dimethy
Figure imgf000343_0001
carbamoyl)-5 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)-2-methylcyclohexanecarboxylic acid
The title compound was prepared from
N-(2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-l -amine and
1 -(( 1 S,3i?,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)- 1 H-pyrazole-4- carboxylic acid by procedures similar to those described in example 872. MS (ESI) 593.2, 595.1 [M + H]+.
The following examples were synthesized similar procedures described above.
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
carboxylic acid
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
cr ethylcyclohexane-l-carboxylicacid
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
yl)bicyclo[2.2.1]heptane-l-carboxylic acid
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
methylcvclohexane-l-carboxylic acid
Figure imgf000376_0001
ylbicyclo2.2.2octane-l-car oxyic acid
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000383_0001
yl)bicycloi2.2.2]octane-l-carboxylic acid
Figure imgf000384_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000385_0001
yl)bicyclo[2.2.2]petane-l-carboxylic acid
Figure imgf000386_0001
Figure imgf000387_0001
met ycyco exane-l-ca r oxy c aci
Figure imgf000388_0001
Figure imgf000389_0001
example structure name
trans-4-(4-((2-(2,6-dichloro-4-fluorophenyl)- n 2-oxoethyl)-(2-(3-fluoropiperidin-l-
353 yl)ethyl)carbamoyl)-5-
HO Ύ "Ϊ CL (trifluoromethyl)pyrazol-l-yl)-l- methylcyclohexane-l-carboxylic acid trans-4-(4-((2-(2-chloro-6-fluorophenyl)-2- hydroxyethyl)((lR,3r,5S)-6,6-
354 - dimethylbicyclo[3.1.0]hexan-3-yl)carbamoyl)- 5-(trifIu0romethyl)-lH-pyrazol-l-yl)-l- methylcyclohexanecarboxylic acid
Figure imgf000390_0001
H., CH trans-4-(4-((2-(2-chloro-6-fluorophenyl)-2- hydroxyethyl)((lR,3r,5S)-6,6-
355 dimethylbicyclo[3.1.0]hexan-3-yl)carbamoyl)- 5-(trifluoromethyi)-lH-pyrazol-l-yl)-l- methylcyclohexanecarboxylic acid trans-4-(4-(((2R)-2-(2-chloro-6- methoxyphenyl)-2-hydroxyethyl)-(2,2-
356 dimethylpropyl)carbamoyl)-5- (trifluoromethyl)pyrazolri-yl)-l- methylcyclohexane-l-carboxylic acid
1
trans-4-(4-(((2S)-2-(2-chloro-6- methoxyphenyl)-2-hydroxyethyl)-(2,2-
357 dimethylpropyl)carbamoyl)-5-
(trifluoromethyl)pyrazol-l-yl)-l- methylcyclohexane-l-carboxylic acid
1 trans-4-(5-chloro-4-((2-(2,6-dichlorophenyl)- 2-oxoethyl)-(2,2-
358
dimethylpropyl)carbamoyl)pyrazol-l-yl)-l- methylcyclohexane-l-carboxylic acid trans-4-(5-chloro-4-((2-(2,6-dichloro-4- methylphenyl)-2-oxoethyl)-(2,2-
359
dimethylpropyl)carbamoyl)pyrazol-l-yl)-l- methylcyclohexane-l-carboxylic acid
Figure imgf000391_0001
Figure imgf000392_0001
methylcyclohexanecarboxylic acid
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
methylcyclohexane-l-carboxylic acid
Figure imgf000397_0001
methylcyclohexanecarboxylic acid
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
yl)cyclohexanecarboxylic acid ο^ο
trans-4-(4-((2-(2,6-dichlorophenyl)-2-
,φ oxoethyl)((3,3-
521 Xj dimethylcyclobutyl)methyl)carbamoyl)
5-(trif luoromethyl)-1 H-pyrazol-1 - ο _ yl)cyclohexanecarboxylic acid
trans-4-(4-((2-(2 ,6-d ichloro-4-
. ,Φ methylphenyl)-2-ox0ethyl)(3,5- difluoro-4-
522
(trifluoromethyl)benzyl)carbamoyl)-5- (trifluoro methyl)- 1 H-pyrazol-1 - yl)cyclohexanecarboxylic acid trans-4-(4-((2-(2,6- dichlorophenyl)ethyl)(2,2-
523 dimethylpropyl)carbamoyl)-5- ,
(trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexanecarboxylic acid trans-4-(4-(((2R)-2-(2,6- dichlorophenyl)-2-hydroxyethyl)(2,2-
524 dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexanecarboxylic acid
Figure imgf000402_0001
trans-4-(4-((2-(2,6-dichlorophenyl)-2-
,Φ oxoethyl)(4,4-
525 dimethylcyclohexyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexanecarboxylic acid trans-4-(4-((2-(2,6- dichlorophenyl)ethyl)(4-
526 (trifluoromethyl)benzyl)carbamoyi)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexanecarboxylic acid trans-4-(4-((2-(2,6-dichlorophenyl)-2- oxoethyl)(4-
527 (trifluoromethyl)benzyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexanecarboxylic acid
Figure imgf000402_0002
Figure imgf000403_0001
yl)cyclohexanecarboxylic acid
Figure imgf000404_0001
yl)cyclohexanecarboxylic acid
Figure imgf000405_0001
F .'::.. :··.· yl)cyco exanecar oxy c acid
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
methylcyclohexanecarboxylic acid
Figure imgf000410_0001
methylcyclohexanecarboxylic acid
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
methylcyclohexanecarboxylic acid
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
methylcyclohexanecarboxylic acid
Figure imgf000418_0001
acid
Figure imgf000419_0001
Figure imgf000420_0001
methylcyclohexanecarboxylic acid
Figure imgf000421_0001
l)-2-
Figure imgf000422_0001
methylcyclohexanecarboxylic acid
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
OH methylcyclohexanecarboxylic acid
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
(1 R,2S,4R)-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)(2,2-
739 dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-2-
Figure imgf000433_0001
methylcyclohexanecarboxylic acid
(trans-4-(4-((2-(2,4-dichloro-6-methyl- 3-pyridinyl)-2-oxoethyl)(2,2-
740 dimethylpropyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)cyclohexyl)acetic acid
trans-4-(4-((2-(2-chloro-6- fluorophenyl)-2-oxoethyl)((1 - (trifluoromethyl)cyclopropyl)methyl)ca
741
rbamoyl)-3-(trifluoromethyl)-1 H- pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid trans-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)((1 -
742 ethylcyclobutyl)methyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid trans-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)(((1 S)-2,2-
743 dimethylcyclopropyl)methyl)carbamo yl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-
Figure imgf000433_0002
1 -methylcyclohexanecarboxylic acid trans-4-(4-((2-(2,6-dichloro-4- methylphenyl)-2-oxoethyl)((1 -
744 o N_ / p ethylcyclobutyl)methyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 -
J? methylcyclohexanecarboxylic acid trans-4-(4-((2-(2 ,6-d ichloro-4- methylphenyl)-2-oxoethyl)(((1 R)-2,2-
745 dimethylcyclopropyl)methyl)carbamo
' ( F F yl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)- 1 -methylcyclohexanecarboxylic acid
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Λ (1 S,2R,4S)-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)(((2S)-5,5-
F \ d imethyltetrahyd ro-2-
774 F furanyl)methyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-2- methylcyclohexanecarboxylic acid
(trans-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2oxoethyl)((1 -
775 methylcyclobutyl)methyl)carbamoyl)- 5-(trif luo ro methyl)- 1 H-py razo I- 1 - yl)cyclohexyl)acetic acid
H
trans-4-(4-((2-cyclopropylethyl)(2-(3,5- dichloro-4-pyridinyl)-2-
776 oxoethyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid
Figure imgf000438_0001
H
,P trans-4-(4-((2-cyclopropylethyl)(2-(2,6 dichloro-4-methylphenyl)-2-
777 oxoethyl)carbamoyl)-5-
0=Y ^
(trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid trans-4-(4-((2-(2-chloro-6-fluoro-4- methylphenyl)-2-oxoethyl)((1 -
778 F methylcyclobutyl)methyl)carbamoyl)- 5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid
CI
trans-4-(4-((2-(2 ,4-d ichloro-6-methyl- 3-pyridinyl)-2-oxoethyl)(2-((2-methyl-
779 2-propanyl)oxy)ethyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid
2-(trans^4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)(3,5-
780 difluorobenzyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -
. yl)cyclohexyl)propanoic acid
Figure imgf000438_0002
Figure imgf000439_0001
methylcyclohexanecarboxylic acid
Figure imgf000440_0001
Figure imgf000441_0001
methylcyclohexanecarboxylic acid
Figure imgf000442_0001
Figure imgf000443_0001
(1 S,2R,4S)-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)((1 S)-
816 spiro[3.3]hept-1 -yl)carbamoyl)-5- (trif luoromethyl)-1 H-pyrazol-1 -yl)-2- methylcyclohexanecarboxylic acid
Figure imgf000444_0001
(1 S,2R,4S)-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)((1 R)-
817 spiro[3.3]hept-1 -yl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-2- methylcyclohexanecarboxylic acid trans-4-(4-((2-(3,5-dichloro-4- pyridinyl)-2-oxoethyl)(((1 S)-2,2-
818 difluorocyclopropyl)methyl)carbamoyl
)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)- 1 -methylcyclohexanecarboxylic acid trans-4-(4-((2-(3,5-dichloro-4- pyrid inyl)-2-oxoethyl)(((1 R)-2 ,2-
819 . difluorocyclopropyl)methyl)carbamoyl
)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-
Figure imgf000444_0002
1 -methylcyclohexanecarboxylic acid
(1 S,2R,4S)-4-(4-((2-(3,5-dichloro-4- pyrid inyl)-2-oxoethyl)((2 R)-tetrahyd ro-
820 2-furanylmethyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-2- methylcyclohexanecarboxylic acid trans-4-(4-((2-(2,6-dichlorophenyl)-2- oxoethyl)(((2R)-5,5- - d imethyltetrahyd ro-2-
821
furanyl)methyl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid trans-4-(4-(((2R,4S)-4-cyclohexyl-2- o-oi ((3,5-dichloro-4-pyridinyl)carbonyl)-1-
822 " pyrrolidinyl)carbonyl)-5- (trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
0 F- F-F 0 dimethylcyclohexanecarboxylic acid
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
F methylcyclohexanecarboxylic acid
Figure imgf000454_0001
methylcyclohexanecarboxylic acid trans-4-(4-((2-(2,6-dichlorophenyl)-2- oxoethyl)(3,3,3-trifluoro-2,2-
893 dimethylpropyl)carbamoyl)-5-
(trifluoromethyl)-l H-pyrazol-1 -yl)-1 - methylcyclohexanecarboxylic acid
Figure imgf000455_0001
The results of high performance liquid chromatography mass spectroscopy (LC/MS) analysis for the above examples were shown in the following tables.
example Exact Mass Obs. Mass example Exact Mass Obs. Mass
24 586.1 587.1 60 585.1 586
25 600.1 601.2 61 601.1 602
26 548.1 549.0 62 550.2 551
27 562.1 563.1 63 567.2 568
28 560.1 561.1 64 568.2 569
29 574.1 575.1 65 555.2 554
30 588.2 569.1 66 657.1 658
31 560.1 561.0 67 647.1 648
32 562.1 563.0 68 607.1 608
33 576.2 579.1 69 565.2 566
34 560.1 561.2 70 633.1 634
35 560.1 561.2 71 590.1 593.0
36 616.2 617.1 72 546.1 547.0
37 614.2 615.1 73 566.1 567.0
38 576.1 577.0 74 578.1 579.1
39 576.1 577.0 75 574.1 575.0
40 582.1 583.0 76 583.1 584.0
41 616.1 617.0 77 614.1 615.0
42 618.1 619.0 78 632.1 633.0
43 618.1 619.0 79 614.1 615.0
44 618.1 619.0 80 618.1 619.0
45 618.1 619.0 81 618.1 619.0
46 572.1 573.0 82 572.1 573.0
47 572.1 573.0 83 572.1 573.0
48 584.1 585.0 84 596.1 597.1
49 598.1 599 85 590.1 591
50 602.1 603 86 634.1 635.0
51 586.1 587 87 634.1 635.0
52 578.2 579 88 599.1 600.0
53 617.1 618 89 643.1 644.1
54 613.1 614 90 602.1 603.0
55 635.1 636 91 603.1 604.0
56 651.1 652 92 586.1 587.0
57 685.1 686 93 586.1 587.0
58 642.1 643 94 593.1 594.2
59 617.1 618 95 592.1 593.1 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
96 621.1 622.0 , 132 602.2 603.1
97 660.1 661 133 579.2 580
98 661.1 662 134 578.2 579
99 583.1 584 135 584.1 587
100 599.1 600.1 136 651.1 652
101 624.1 625.1 137 631.1 632
102 602.2 603.1 138 635.1 636.2
103 583.1 584.0 139 635.1 636.2
104 583.1 584.0 140 630.2 631
105 616.1 617.0 141 598.1 599
106 616.1 617.0 142 564.2 565
107 617.1 618 143 578.2 579
108 617.1 618 144 659.1 660.1
109 634.1 635 145 582.1 583.1
110 586.1 587.1 146 583.1 584
111 609.2 610 147 598.1 599
112 647.1 649 148 606.2 607
113 541.2 542 149 673.2 674.1
114 576.2 577.1 150 614.1 615.0
115 576.2 577.1 151 583.1 585
116 615.1 616.2 152 652.1 653
117 615.1 616.2 153 598.1 599
118 631.1 632 154 603.2 604.3
119 610.2 611 155 618.2 619.1
120 621.1 622 156 646.1 647
121 589.1 , 590.0 157 589.1 590
122 594.2 595 158 589.1 590
123 640.2 641.1 159 580.1 581.0
124 651.1 652 160 616.1 617.1
125 616.2 617.1 161 608.1 609.0
126 616.2 617.1 162 592.1 593
127 701.1 702 163 579.1 580.0
128 625.1 626.2 164 564.1 565
129 625.1 626.0 165 623.0 624
130 618.2 619.1 166 626.1 627.0
131 602.2 603.1 167 623.0 624 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
168 623.0 624 205 602.2 603.3
169 602.2 603.1 206 613.2 614.2
170 607.1 608 207 633.1 634.2
171 607.1 608 208 590.1 591.2
172 589.1 590.0 209 607.1 608.2
173 631.2 632.1 210 599.1 600.2
174 574.1 575.1 211 600.2 601.3
175 610.1 611.0 212 642.1 643.2
176 618.2 619.1 213 642.1 643.2
111 612.1 613.0 214 595.2 596.3
178 614.1 615 215 586.1 587
179 619.1 620 216 624.0 625
180 608.1 609.0 217 633.2 634.3
181 576.1 577.0 , 218 617.1 618.3
182 600.2 601.1 219 647.1 648.2
183 588.2 589 220 647.2 648.3
184 588.2 589.2 221 609.1 610.2
185 560.1 561.2 222 647.2 648.3
187 588.2 589.2 223 588.2 589.3
188 596.1 597.1 224 623.1 624.2
189 635.1 636.0 225 639.1 640.2
190 633.2 634.3 226 643.2 645
191 649.1 650.2 227 629.2 630
192 614.2 615.3 228 614.1 615
193 631.2 632.2 229 616.2 617.3
194 592.1 593.2 230 645.2 646.3
195 582.1 583.2 231 661.1 662.2
196 598.2 597 232 609.2 610.3
197 631.1 632.2 234 633.1 634.2
198 562.1 563.2 235 633.2 634.3
199 631.2 632.3 236 641.2 642
200 j 586.1 587.2 237 627.2 628
201 621.1 622.2 238 615.2 616
202 617.1 618.2 239 663.2 664.3
203 647.2 648.3 240 643.2 644.3
204 600.2 601.3 241 659.1 660.2 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
242 661.2 662.3 281 605.1 606.2
243 623.2 624.3 282 619.2 620.2
244 647.2 648.3 283 615.2 616.3
245 605.1 606.3 284 575.2 576.2
246 621.1 622.2 285 630.2 631.3
247 659.2 660.3 286 590.2 591.3
248 621.2 622.3 287 576.2 579.2
249 619.2 620.3 288 602.2 603.2
250 635.1 636.2 289 663.1 664
251 635.2 636.3 290 591.1 592
252 597.2 598.3 291 591.1 592
253 571.2 572.3 292 623.2 624
254 649.2 650.3 293 639.1 642
255 611.2 612.3 294 560.2 561.2
256 647.1 648.3 295 620.2 621
257 609.2 610.3 296 648.2 649
258 647.2 648.3 297 559.2 560.3
259 625.3 626.4 298 651.1 652.2
260 663.1 664.2 299 618.1 619.2
261 655.2 656 300 631.2 632.2
262 602.1 603 301 633.2 634
263 621.2 622.3 302 607.2 608.3
264 600.2 601.2 303 646.2 647
265 609.2 610.2 304 632.2 633
266 631.2 632.2 305 674.2 675
267 628.2 629.3 306 623.1 626.1
268 611.2 612 307 622.1 623
269 611.2 612 308 635.1 636.1
270 639.2 640.3 309 619.2 620.1
271 635.1 636.2 310 533.2 534.5
272 606.1 607.2 311 659.2 660
273 627.2 628.3 312 590.2 591
274 645.2 646.2 313 578.1 579
275 661.1 662.2 314 574.1 575
279 609.3 610 315 572.2 573.3
280 609.3 610 316 586.1 587.2 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
317 587.2 588.2 355 599.2 600.3
318 606.2 606.6 356 573.2 574.3
319 602.2 603.6 357 573.2 574.3
320 625.2 626.2 358 541.1 544
321 639.2 640.3 359 555.1 558
322 628.2 629.2 360 580.2 581
323 618.2 619.8 363 579.1 580
324 604.1 605.2 364 559.2 560
325 616.2 617.3 365 573.2 574
326 580.1 581.2 366 593.2 594
327 592.1 593.2 367 580.1 581
328 532.3 533.7 368 581.2 583.0
329 640.1 641.2 369 581.2 582.9
331 602.2 603 370 577.3 578.9
332 620.2 619 371 577.3 579\0
333 598.2 599.3 372 615.3 616.9
334 566.2 567.7 373 615.3 617.0
335 610.2 611.3 374 577.2 578.9
336 613.3 614.3 375 577.2 578.9
337 574.2 575.2 376 605.2 607.0
338 551.3 552 377 618.3 620.0
339 605.1 606 378 540.1 541.2
340 588.2 589 379 556.2 557.3
341 611.2 612.3 380 605.2 606.3
342 611.2 612.9 381 568.1 569.2
344 646.2 645 382 548.2 549.3
345 599.2 600 383 600.2 601
346 588.2 589 384 600.2 601
347 607.2 606 385 585.2 586
348 639.1 640 386 596.1 597.8
349 606.3 608 387 594.2 595.9
350 671.1 672 388 594.1 595.1
351 655.1 656 389 581.2 582.3
352 580.2 581.8 390 582.2 583
353 652.2 653 391 582.2 583
354 599.2 600.3 392 618.3 619 example Exact Mass Obs. Mass
393 595.2 596.3
394 608.2 609.3
395 574.1 575.2
396 587.2 588
397 587.2 588
398 580.2 581.3
399 647.2 648
400 645.2 646
401 548.3 549
402 544.2 545
403 544.2 545
404 603.2 604
405 605.2 606
406 607.2 608
407 597.2 598
408 583.2 584
409 598.2 599
410 563.3 564
411 587.2 588
412 654.1 655.2
example Exact Mass Obs. Mass example Exact Mass Obs. Mass
500 567.1 568.1 535 629.2 629.8
501 601.1 602.0, 604.0 536 615:2 616
502 533.2 534.2 536 615.2 615.7
503 572.2 573.2 537 601.2 601.7
504 601.1 602.0, 604.1 537 601.2 602
505 561.2 562.2 538 592.2 593
506 572.2 573.2 539 616.1 617.2
507 572.2 573.1 541 633.1 634.0
508 572.2 573.2 542 576.2 577.1
509 547.2 548 543 630.1 629.0, 631.0
510 587.2 588 544 578.2 579
511 601.2 602.2 545 561.1 562
512 561.2 562.1 546 602.2 603.0
513 586.2 587.2 547 548.2 549.0
514 601.2 602.2 548 572.2 573
515 575.2 576.2 549 588.2 589
516 615.2 616 550 588.2 589.2
517 575.2 575.8 552 576.2 577
518 627.2 628 553 574.2 575.0
519 615.2 615.7 554 560.2 561
520 601.2 601.7 555 600.2 601.0
521 587.2 587.8 556 588.2 589
522 699.1 699.5 557 574.2 575.2
523 547.2 547.7 558 614.2 615.1
524 563.2 564 559 602.2 603.0, 605.0
525 601.2 601.7 560 560.2 561.2
526 635.1 635.6 561 630.2 631.0
527 649.1 649.5 562 574.2 575
528 663.1 664 563 546.1 547
529 591.2 591.7 564 560.2 561.2
530 591.2 592 565 599.2 600
531 591.2 591.7 566 599.2 600.1
532 643.2 644.2 567 585.1 586.0
533 615.2 616.1 568 589.2 590
534 587.2 587.7 569 627.2 628.2
534 587.2 587.7 570 601.2 604.3
535 629.2 629.8 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
571 629.2 630.2 608 585.2 586.1
572 601.2 602.2 609 578.1 579 ,
573 563.2 564.2 610 599.2 600.2
574 563.2 564.0 611 577.1 577.8
575 631.2 632.2 612 627.2 628.2
576 584.2 585 612 627.2 628.2
577 574.1 577 613 585.1 586.1
578 588.2 589.0 614 604.1 604.8
579 645.2 648 615 613.2 614
580 617.2 618 615 613.2 614.1
581 631.2 632.2 616 588.2 589.0
582 586.2 587.0 617 588.2 589.0
583 613.2 614.0 618 612.2 613.1
584 635.2 636.0 619 615.2 588.0
585 597.1 598.2 620 615.2 588.0
586 558.2 559.1 621 572.2 573.2
587 588.2 589 622 600.2 601
588 616.2 617 623 574.1 575.2
589 611.2 612 624 585.1 586.2
590 621.1 622 625 599.2 600.2
591 588.2 589 626 613.2 614
592 588.2 589.0 627 599.2 600
593 578.1 578.9 628 603.2 604.0
594 610.1 611 629 603.2 604
595 585.2 586 630 591.1 592.0
596 571.2 572 631 605.1 606
597 555.2 556 632 599.2 600.2
598 569.2 570 633 600.2 601.1
599 587.2 588.1 634 574.1 575
600 573.1 574 634 574.1 575
601 603.2 604 635 574.1 575.0
602 581.3 582 635 574.1 575.0
603 591.1 592.0 636 573.1 574.0
604 558.2 587.2 636 573.1 574.0
605 605.2027 606.1 637 573.1403 574
606 592.1625 593 637 573.1403 574
607 595.266 596.2 638 618.1617 619 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
639 599.2 600.2 675 590.1 591
640 585.1 586 676 603.2 604
641 599.2 600 677 600.2 601.1
642 585.1 586 678 613.2 614.1
643 589.2 590.2 679 604.2 605.2
644 618.2 619.2 680 604.2 605.2
645 632.2 632.9 681 590.2 591.2
646 604.1 604.8 682 590.2 591.2
647 574.1 575.1 683 601.2 602.2
648 574.1 575 684 601.2 602.2
649 613.2 614.2 685 604.1 605.1
650 613.2 614.2 686 604.1 605.2
651 599.2 600.2 687 590.2 590.9
652 599.2 600.2 688 560.2 561.0,563.1
653 629.2 630.2 689 629.2 630.2
654 629.2 630.2 690 595.1 596.0
655 618.2 619.0 691 605.1 606.1
656 560.1 561.2 692 630.1 631.0
657 573.2 574.2 693 570.2 570.8
658 597.2 598.2 694 591.1 591.8
659 576.2 577.1 694 591.1 591.8
660 604.1 605.2 695 577.1 577.8
661 604.1 605.2 695 577.1 577.8
662 601.2 602.2 696 633.2 633.8
663 601.2 603 696 633.2 633.8
664 619.2 620.2 697 610.1 611.2
665 633.2 634.2 698 605.1 605.8
666 620.2 621.2 698 605.1 605.8
667 592.1 593 699 616.2 617.2
667 592.1 593 700 576.2 577.2
668 573.1 574 701 574.2 574.9
669 573.1 573.9 702 626.2 627.3
670 561.1 562, 562 703 592.1 592.8
671 619.2 620.2 704 589.2 590.2
672 601.2 604 705 604.1 605.0
673 618.2 619.1 706 604.1 605.0
674 618.2 619.1 707 573.1 574.0 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
708 597.1 598.2 737 578.1 580
709 615.2 616.2 738 576.2 578
710 560.1 561.0 739 576.2 578
711 602.2 603.0 740 590.2 591
712 618.1 619 741 611.1 612.2
712 618.1 619 742 602.2 603
713 617.1 618 743 588.2 589.2
713 617.1 618 744 615.2 616.2
714 628.2 629.2 745 601.2 602.1
715 590.2 591 746 574.2 574.9
716 591.1 592.1 747 574.2 574.9
716 591.1 592.1 748 600.2 601.2
717 587.2 588.1 749 600.2 601.2
717 587.2 588.1 750 627.2 628.4
718 601.2 602.2 751 620.2 621.3
718 601.2 602.2 752 575.2 612.2
719 576.2 577.3 753 606.2 607.3
720 576.2 577.3 754 590.2 591
721 613.2 614.2 755 632.1 633.2
722 613.2 614.2 756 602.2 604
723 617.2 618.2 757 608.2 609.3
724 617.2 618.2 758 628.2 629.3
725 617.2 618.2 759 573.1 574.3
726 617.2 618.2 759 573.1 574.3
727 603.2 604.2 760 587.2 588.3
728 603.2 604.2 760 587.2 588.3
729 627.1 628 761 632.1 632.2 (M-H)-
730 588.2 589.1 762 646.1 646.2 (M-H)-
731 601.2 602.1 763 631.2 632.2
732 630.2 631.3 764 593.1 594.2
733 587.2 588.1 765 560.1 561.2
733 587.2 588.1 766 602.1 604
734 574.1 575 767 602.1 604
734 574.1 575 768 646.1 647.3
735 602.2 603 769 589.1 570.2
735 602.2 603 770 560.1 561.2
736 578.1 580 771 574.1 575.2 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
772 599.2 600 809 584.2 585.2
773 618.2 619,1 810 606.1 607
774 618.2 619.1 810 606.1 607
775 588.2 587.9 811 627.1 628
776 574.1 575.2 812 576.2 577.1
111 587.2 588 813 576.2 577.1
118 585.2 586.2 814 621.1 622.2
779 620.2 619.8 815 621.1 622.2
780 646.1 645.7 816 600.2 601.2
781 587.2 589 817 600.2 601.2
782 588.2 590 818 596.1 597
783 631.2 632.0 819 596.1 597
784 590.2 591 820 590.1 591.2
785 590.2 591 821 617.2 618.2
786 646.1 646.3 822 628.2 629.1,631.1
787 613.2 614.2 823 628.2 629.1,631.1
788 574.1 575.2 824 602.2 604
789 646.1 646.3 825 602.2 604
790 646.1 645.5 826 618.2 619.1
791 590.2 590 827 622.1 623.0,625.0
792 590.2 590 828 622.1 623.0,625.0
793 576.2 577.1 829 580.1 581.2
794 575.2 577 830 628.1 629.2, 631.2
795 638.1 639.0,641.0 831 579.1 580.2
796 638.1 639.0,641.0 832 579.1 580.2
797 638.1 639.0,641.0 833 630.2 631.2
798 645.1 645.9 834 602.2 605.2
799 642.1 642.9 835 644.2 647.2
800 606.1 606.9 836 574.1 575.2
801 616.2 619.0 837 574.1 575.2
802 630.1 632 838 617.2 618.2
803 576.2 577.2 839 617.2 618.2
804 575.2 576.2 840 580.1 581.2
805 601.2 602.2 841 610.1 611.0
806 601.2 602.2 842 590.2 591.2
807 602.2 602.9 843 590.2 591.2
808 590.1 591.0 844 590.1 591.0 example Exact Mass Obs. Mass example Exact Mass Obs. Mass
845 631.2 632.2 876 602.2 603
846 585.1 586.2 876 602.2 603
847 578.1 579 877 602.2 603
848 599.2 600 877 602.2 603
849 599.2 600 878 630.1 631.1
850 606.2 607.1 879 630.1 631.1
851 628.2 629.2, 631.2 880 616.1 617.2
852 628.2 629.2, 631.2 881 616.1 617.2
853 616.1 617.0 882 590.2 591.2
854 586.1 587.2 883 590.2 591.2
855 590.2 591.2 884 630.1 631.0
856 590.2 591.2 885 578.2 579.0,581.0
857 590.2 591.2 886 578.2 579.0,581.2
858 585.1 586.2 887 592.2 593.2,595.1
859 585.1 586.2 888 635.2 636
860 588.2 589.2 888 635.2 636
861 590.2 591 889 643.1 644
861 590.2 591 889 643.1 644
862 590.2 591 890 601.2 602
862 590.2 591 890 601.2 602
863 624.1 625 891 671.2 672
863 624.1 625 891 671.2 672
864 630.1 631.1 892 602.2 603.2
865 601.2 603 893 629.1 630.2
866 601.2 603
867 616.1 617.2
868 594.1 595.2
869 594.1 595.2
870 594.1 595.2
871 602.2 603
871 602.2 603
872 592.2 593.2,595.1
873 590.2 591
873 590.2 591
874 590.2 591
874 590.2 591
875 630.1 632 s for the examples, the results of spectrum were shown in the following tables.
Figure imgf000468_0001
δ (400 MHz, CDC13) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.62 and 7.55 (IH, 2xs) ; 4.76 and 4.44 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 3.45 and 3.22 (2H, 2xd, J = 7.8Hz) ; 2.51-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.75-1.64 (9H, m) ; 1.54-1.46 (lH, m) ; 1.16-1.10 (IH, m) ; 1.07-1.01 (IH, m) ; 0.77-0.71 (IH, m) δ (400 MHz, CDCI3) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.62 and 7.55 (IH, 2xs) ; 4.95 and 4.60 (2H, 2xs) ; 4.30-4.22 (IH, m) ; 3.57 and 3.34 (2H, 2xs) ;
2.52-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.15-2.04 (4H, m) ; 1.72-1.62 (2H, m) ; 1.09 and 0.97 (3H, 2xs) ; 0.51-0.32 (4H, m)
δ (400 MHz, CDCI3) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.65 and 7.55 (IH, 2xs) ; 4.74 and 4.42 (2H, 2xs) ; 4.30-4.17 (IH, m) ; 3.61 and 3.34 (2H, 2xt, J = 7.7Hz) ; 2.50-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.12-2.03 (4H, m) ; 1.72-1.38 (5H, m) ; 0.96 (3H, d, J = 6.6Hz) ; 0.77 (3H, d, J = 6.3Hz)
δ (400 MHz, CDCI3) rotomers present 8.58 and 8.52 (2H, 2xs) ; 7.65 and 7.54 (IH, 2xs) ; 4.74 and 4.41 (2H, 2xs) ; 4.30-4.20 (IH, m) ; 3.62-3.58 and 3.33-3.29 (2H, 2xm) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.04 (4H, m) ; 1.72-1.62 (2H, m) ; 1.56-1.51 and 1.42-1.38 (2H, 2xm) ; 0.97 and 0.76 (9H, 2xs)
δ (400 MHz, CDCI3) rotomers present 8.56 and 8.49 (2H, 2xs) ; 7.63 and 7.55 (IH, 2xs) ; 5.19-5.16 and 5.10-5.06 (IH, lxm) ; 4.29-4.27 and 3.99-3.97 (2H, 2xm) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.13-2.03 (4H, m) ; 1.72 and 1.52 (3H, 2xs) ; 1.70-1.63 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.63 and 7.55 (IH, 2xs) ; 4.76 and 4.44 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 3.49 and 3.26 (2H, 2xd, J = 6.8Hz) ; 2.51-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.71-0.97 (1 1H, m) ; 0.90-0.78 (6H, m) δ (400 MHz, CDC13) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.64 and 7.55 (IH, 2xs) ; 4.77 and 4.45 (2H, 2xs) ; 4.29-4.19 (IH, m) ; 3.51 and 3.28 (2H, 2xd, J = 6.8Hz) ; 2.51-2.43 (IH, m) ; 2.27-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.73-1.54 (7H, m) ; 1.27-1.18 (lH, m) ; 0.98-0.84 (3H, m), 0.30-0.10 (4H, m)
δ (400 MHz, CDCI3) rotomers present 8.52 and 8.45 (2H, 2xs) ; 7.69 and 7.60 (IH, 2xs) ; 7.37-7.29 (4H, m) ; 7.17-7.15 (IH, m) ; 4.87 and 4.66 (2H, 2xs) ; 4.64 and 4.30 (2H, 2xs) ; 4.30-4.21 (IH, m) ; 2.49-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.09-2.04 (4H, m) ; 1.71-1.64 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.68 and 7.60 (IH, 2xs) ; 7.33 (2H, d, J = 8.3Hz) ; 7.25 and 7.10 (2H, d, J = 8.3Hz) ; 4.82 and 4.65 (2H, 2xs) ; 4.61 and 4.29 (2H, 2xs) ; 4.29-4.20 (IH, m) ; 2.50-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.1 1-2.03 (4H, m) ; 1.70-1.59 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.55 and 8.49 (2H, 2xs) ; 7.66 and 7.61 (IH, 2xs) ; 6.85-6.69 (3H, m) ; 4.83 and 4.70 (2H, 2xs) ; 4.62 and 4.34 (2H, 2xs) ;
4.28-4.21 (IH, m) ; 2.49-2.43 (IH, m) ; 2.27-2.23 (2H, m) ; 2.10-2.04 (4H, m) ;
1.71-1.60 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.54 and 8.48 (2H, 2xs) ; 7.67 and 7.59 (IH, 2xs) ; 7.26-7.21, 7.15-7.70 and 6.93-6.89 (3H, 3xm) ; 4.92 and 4.71 (2H, 2xs) ; 4.71 and 4:42 (2H, 2xs) ; 4.28-4.18 (IH, m) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.03 (4H, m) ; 1.71-1.59 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.54 and 8.48 (2H, 2xs) ; 7.67 and 7.60 (IH, 2xs) ; 7.19-7.12 and 7.05-6.89 (3H, 2xm) ; 4.80 and 4.67 (2H, 2xs) ; 4.60 and 4.32 (2H, 2xs) ; 4.27-4.19 (I H, m) ; 2.49-2.42 (IH, m) ; 2.26-2.23 (2H, m) ; 2.1 1-2.04 (4H, m) ; 1,70-1.63 (2H, m) δ (400 MHz, CDC13) rotomers present 8.55 and 8.48 (2H, 2xs) ; 7.68 and 7.60 (IH, 2xs) ; 7.19-7.14, 7.06-6.95 and 6.82-6.78 (3H, 3xm) ; 4.87 and 4.73 (2H, 2xs) ; 4.66 and 4.42 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.13-2.03 (4H, m) ; 1.70-1.60 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.56 and 8.49 (2H, 2xs) ; 7.78 and 7.75 (IH, 2xs) ; 7.39 (IH, m) ; 6.35 (IH, m) ; 6.33-6.32 and 6.22-6.21 (IH, 2xm) ; 4.84 and 4.73 (2H, 2xs) ; 4.56 and 4.44 (2H, 2xs) ; 4.33-4.19 (IH, m) ; 2.50-2.42 (IH, m) ;
2.27-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.73-1.62 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.55 and 8.49 (2H, 2xs) ; 7.70 and 7.58 (IH, 2xs) ; 7.41-7.33 (2H, m) ; 6.40 and 6.26 (IH, 2xs) ; 4.70 (2H, s) ; 4.46 and 4.35 (2H, 2xs) ; 4.32-4.18 (IH, m) ; 2.50-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.72-1.59 (2H, m)
δ (400 MHz, CDCI3) rotomers present 8.76-8.36 (5H, m) ; 7.71 and 7.60 (IH, 2xs) ; 4.94 and 4.85 (2H, 2xs) ; 4.74 and 4.66 (2H, 2xs) ; 4.26-4.18 (IH, m) ; 2.49-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.1 1-2.03 (4H, m) ; 1.70-1.59 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 8.56-8.51 and 8.49-8.43 (2H, 2xm) ; 7.88 and 7.82 (IH, 2xs) ; 7.16-6.92 (3H, m) ; 4.78 and 4.77 (2H, 2xs) ; 4.72 and 4.60 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 2.33-2.29 (IH, m) ; 2.28 and 1.83 (3H, 2xs) - 2.07-2.03 (2H, m) ; 1.94-1.91 (4H, m) ; 1.60-1.49 (2H, m)
δ (400 MHz, DMSO-ds) rotamers present 8.78 and 8.71 (IH, 2xs) ; 8.69 and 8.62 (IH, 2xs) ; 7.81 and 7.78 (IH, 2xs) ; 7.18-6.90 (3H, m) ; 4.84 and 4.81 (2H, 2xs) ; 4.70 and 4.59 (2H, 2xs) ; 4.23-4.14 (IH, m) ; 2.33-2.26 (IH, m) ; 2.09-2.02 (2H, m) ; 1.99-1.90 (4H, m) ; 1.58-1.46 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 8.72 and 8.66 (2H, 2xs) ; 7.74 and 7.72 (IH, 2xs) ; 7.18-7.10 (IH, m) ; 7.07 and 6.90 (2H, 2xd, J=6.4 Hz) ; 4.84 and 4.82 (2H, 2xs) ; 4.71 and 4.60 (2H, 2xs) ; 4.22-4.17 (IH, m) ; 2.33-2.27 (IH, m) ; 2.09-L92 (6H, m) ; 1.55-1.49 (2H, m)
δ (400 MHz, CDC13) rotamers present 8.31 and 8.24 (2H, 2xs) ; 7.67 and 7.63 (IH, 2xs) ; 6.83-6.72 (3H, m) ; 4.84 and 4.63 (2H, 2xs) ; 4.47 and 4.20 (2H, 2xs) ;
4.27-4.25 (IH, m) ; 2.49-2.43 (IH, m) ; 2.27-2.23 (2H, m) ; 2.23 and 1.86 (6H, 2xs) ; 2.1 1-2.06 (4H, m) ; 1.68-1.64 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.86 and 7.84 (IH, 2xs) ; 7.57-7.49 (3H, m) ; 7.19-7.13 (IH, m) ; 7.1 1-7.08 and 6.93-6.91 (2H, 2xm) ; 4.81 and 4.72 (2H, 2xs) ; 4.67 and 4.56 (2H, 2xs) ; 4.27-4.19 (IH, m) ; 2.34-2.27 (IH, m) ; 2.06-2.03 (2H, m) ; 1.98-1.92 (4H, m) ; 1.58-1.50 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.75 (IH, s) ; 7.47-7.38 (IH, m) ; 7.18-6.88 (5H, m) ; 4.71 and 4.67 (2H, 2xs) ; 4.53 and 4.52 (2H, 2xs) ; 4.25-4.23 (IH, m) ; 3.77 and 3.67 (3H, 2xs) ; 2.34-2.28 (IH, m) ; 2.06-1.90 (6H, m) ; 1 .59-1.49 (211. m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.86 and 7.84 (IH, 2xs) ; 7.68 and 7.62 (2H, 2xd, J=8.4 Hz) ; 7.19-6.91 (3H, m) ; 4.80 and 4.71 (2H, 2xs) ; 4.65 and 4.55 (2H, 2xs) ; 4.26-4.21 (IH, m) ; 2.35-2.28 (I H, m) ; 2.07-2.06 (2H, m) ; 1.97-1.92 (4H, m) ; 1.60-1.49 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 7.86 and 7.84 (IH, 2xs) ; 7.84 and 7.76 (2H, 2xs) ; 7.19-6.91 (3H, m) ; 4.80 and 4.71 (2H, 2xs) ; 4.65 and 4.56 (2H, 2xs) ;
4.27-4.17 (IH, m) ; 2.34-2.27 (IH, m) ; 2.06-2.02 (2H, m) ; 1.97-1.91 (4H, m) ;
1.59-1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.18 (IH, brs) ; 8.08 and 8.02 (2H, 2xs) ; 7.88 and 7.85 (IH, 2xs) ; 7.19-6.92 (3H, m) ; 4.84 and 4.72 (2H, 2xs) ; 4.68 and 4.57 (2H, 2xs) ; 4.27-4.18 (IH, m) ; 2.35-2.27 (IH, rii) ; 2.07-2.03 (2H, m) ; 1.98-1.93 (4H, m) ; 1.60-1.51 (2H, m)
δ (400 MHz, CD3CN) rotamers present 7.88-7.68 (3H, m) ; 7.02-6.86 (3H, m) ; 4.79 and 4.76 (2H, 2xs) ; 4.62 and 4.56 (2H, 2xs) ; 4.35-4.29 (IH, m) ; 2.47-2.40 (IH, m) ; 2.17-2.12 (2H, m) ; 2.08-2.02 (4H, m) ; 1.67-1.62 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 8.04-7.87 (3H, m) ; 7.75 and 7.52 (IH, 2xs) ; 7.17-7.10 (IH, m) ; 7.06-7.05 and 6.89-6.88 (2H, 2xm) ; 5.08 and 4.96 (2H, 2xs) ; 4.67 and 4.57 (2H, 2xs) ; 4.18-4.17 (IH, m) ; 2.32-2.25 (IH, m) ; 2.04-1.98 (2H, m) ; 1.95-1.81 (4H, m) ; 1.55-1.47 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.77-7.51 (4H, m) ;
7.17-7.07 (IH, m) ; 7.05 and 6.89 (2H, 2xd, J=1.6 Hz) ; 5.07 and 4.93 (2H, 2xs) ; 4.68 and 4.57 (2H, 2xs) ; 4.18-4.17 (IH, m) ; 2.29-2.25 (lH, m) ; 2.05-1.98 (2H, m) ; 1.95-1.81 (4H, m) ; 1.53-1.47 (2H, m)
δ (400 MHz, CDC13) rotamers present 7.76-7.72 and 7.38-7.34 (IH, 2xm) ; 7.58 and 7.50 (IH, 2xs) ; 7.18-7.02 (2H, m) ; 6.83-6.71 (3H, m) ; 4.78 and 4.71 (2H, 2xs) ; 4.62 and 4.51 (2H, 2xs) ; 4.25-4.22 (IH, m) ; 2.45-2.41 (IH, m) ; 2.24-2.21 (2H, m) ; 2.10-2.02 (4H, m) ; 1.66-1.62 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 8.84 and 8.77 (2H, 2xdd, J=4.8, 1.6 Hz) ; 7.89 and 7.71 (2H, 2xdd, J=4.8, 1.6 Hz) ; 7.76 and 7.55 (IH, 2xs) ; 7.15-7.10 (IH, m) ; 7.08-7.06 and 6.91-6.89 (2H, 2xm) ; 5.08 and 4.95 (2H, 2xs) ; 4.70 and 4.59 (2H, 2xs) ; 4.18-4.15 (IH, m) ; 2.33-2.21 (IH, m) ; 2.04-1.79 (6H, m) ; 1.53-1.45 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.10 (IH, brs) ; 7.74 and 7.61 (IH, 2xs) ; 7.40 and 7.34 (IH, 2xs) ; 7.16-6.88 (3H, m) ; 4.74 and 4.68 (2H, 2xs) ; 4.55 and 4.53 (2H, 2xs) ; 4.21-4.12 (IH, m) ; 2.56 and 2.39 (3H, 2xs) ; 2.33-2.21 (IH, m) ; 2.14 and 1,97 (3H, 2xs) ; 2.01-1.99 (2H, m) ; 1.93-1.85 (4H, m) ; 1.55-1.47 (2H, m) δ (400 MHz, DMSO-de) rotamers present 12.20 (IH, brs) ; 7.73 and 7.62 (IH, 2xs) ; 7.16-6.89 (3H, m) ; 4.81 and 4.67 (2H, 2xs) ; 4.61 and 4.55 (2H, 2xs) ; 4.20-4.11 (IH, m) ; 2.73 and 2.49 (3H, 2xs) ; 2,39 and 2.28 (3H, 2xs) ; 2.26-2.17 (IH, m) ; 2.02-1.99 (2H, m) ; 1.96-1.85 (4H, m) ; 1.53-1.43 (2H, m)
δ (400 MHz, CDC13) rotamers present 7.57 and 7.40 (IH, 2xs) ; 6.78-6.65 (3H, m) ; 4.69 and 4.49, (2H, 2xs) ; 4.27 and 3.95 (2H, 2xs) ; 4.25-4.21 (IH, m) ; 2.47-2.37 (2H, m) ; 2.24-2.21 (2H, m) ; 2.09-2.03 (4H, m) ; 1.86-1.77 (2H, m) ; 1.68-1.60 (4H, m) ; 1.51-1.26 (6H, m)
δ (400 MHz, DMSO-de) rotamers present 7.83 and 7.82 (IH, 2xs) ; 7.28 and 7.21 (2H, 2xs) ; 7.18-7.12 (IH, m) ; 7.07 and 6.90 (2H, 2xd, J=1.6 Hz) ; 4.78 and 4.70 (2H, 2xs) ; 4.61 and 4.54 (2H, 2xs) ; 4.26-4.20 (IH, m) ; 2.28-2.21 (IH, m) ; 2.04-2.01 (2H, m) ; 1.99-1.89 (5H, rii) ; 1.54-1.50 (2H, m) ; 1.04-0.96 (2H, m) ; 0.82-0.74 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.84 and 7.82 (IH, 2xs) ; 7.18-7.09 (3H, m) ; 7.08 and 6.91 (2H, 2xd, J=1.6 Hz) ; 4.78 and 4.70 (2H, 2xs) ; 4.61 and 4.54 (2H, 2xs) ; 4.26-4.20 (IH, m) ; 3.83 and 3.78 (3H, 2xs) ; 2.33-2.27 (IH, m) ; 2.05-2.02 (2H, m) ; 1.97-1.91 (4H, m) ; 1.58-1.50 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 7.98 (IH, s) ; 7.76-7.74 (IH, m) ; 7.52-7.50 (IH, m) ; 7.45-7.4ί(1Η, m) ; 7.12-7.05 (3H, m) ; 6.70 (IH, s) ; 5.10-4.76 (4H, m) ; 4.23-4.19 (IH, m) ; 2.27-2.21 (IH, m) ; 2.01-1.98 (2H, m) ; 1.91-1.85 (4H, m) ;
1.55-1.44 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 7.92-7.90 and 7.75-7.73 (2H, 2xm) ; 7.75 and 7.49 (IH, 2xs) ; 7.15-7.08 (IH, m) ; 7.06 and 6.89 (2H, 2xd, J=1.6 Hz) ; 6.88-6.86 and 6.81-6.78 (2H, 2xm) ; 4.96 and 4.76 (2H, 2xs) ; 4.66, and 4.55 (2H, 2xs) ;
4.17-4.14 (IH, m) ; 2.29-2.23 (IH, m) ; 2.04-1.96 (2H, m) ; 1.91-1.83 (4H, m) ;
1.53-1.45 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 7.82 (IH, s) ; 7.18-7.12 (IH, m) ; 7.07 and 6.90 (2H, 2xd, J=1.6 Hz) ; 6.85 and 6.75 (2H, 2xs) ; 4.75 and 4.68 (2H, 2xs) ; 4.58 and 4.53 (2H, 2xs) ; 4.25-4.19 (IH, m) ; 2.30-2.26 (IH, m) ; 2.07-2.02 (2H, m) ; 1.96-1.90 (4H, m) ; 1.58-1.48 (2H, m)
δ (400 MHz, CDC13) rotomers present 8.59 and 8.52 (2H, 2xs) ; 7.64 and 7.55 (IH, 2xs) ; 4.76 and 4.45 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 4.02-3.93 (2H, m) ; 3.50-3.28 (4H, m) ; 2.26-2.23 (2H, m) ; 2.13-2.03 (5H, m) ; 1.76-1.59 (5H, m) ; 1.46-1.36 (IH, m) ; 1.16-1.06 (IH, m)
δ (400 MHz, CDCI3) rotomers present 8.58 and 8.51 (2H, 2xs) ; 7.64 and 7.56 (IH, 2xs) ; 4.91 and 4.57 (2H, 2xs) ; 4.31-4.18 (IH, m) ; 3.54 and 3.26 (2H, d, J = 6.9 Hz) ; 2.50-2.43 (IH, m) ; 2.27-2.23 (2H, m) ; 2.14-2.04 (4H, m) ; 1.72-1.60 (2H, m) ;
1.09-1.01 and 0.91-0.85 (IH, 2xm) ; 0.61-0.56 (2H, m) ; 0.36-0.32 (IH, m) ;
0.15-0.10 (IH, m)
δ (400 MHz, CDCI3) rotomers present 8.57 and 8.50 (2H, 2xs) ; 7.66 and 7.56 (IH, 2xs) ; 5.00 and 4.68 (2H, 2xs) ; 4.27-4.19 (IH, m) ; 3.83-3.57 (2H, m) ; 2.50-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.13-2.04 (4H, m) ; 1.71-1.60 (2H, m) ; 1.43 and 1.28 (6H, d, J = 21.6Hz) δ (400 MHz, CDC13) rotomers present 8.56 and 8.48 (2H, 2xs) ; 7.66 and 7.54 (IH, 2xs) ; 5.12 and 4.82 (2H, 2xs) ; 4.27-4.18 (IH, m) ; 3.46 and 3.13 (2H, 2xs) ; 3.17(3H,
74
s) ; 2.49-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.03 (4H, m) ; 1.70-1.59 (2H, m) ; 1.22 and 1.04 (6H, 2xs) δ (400 MHz, CDC13) rotomers present 8.60 and 8.53 (2H, 2xs) ; 7.66 and 7.57 (IH,
75 2xs) ; 4.94 and 4,62 (2H, 2xs) ; 4.30-4.22 (2H, m) ; 4.04-3.98 (IH, m) ; 2:51-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.14-2.05 (4H, m) ; 1.71-1.62 (2H, m) δ (400 MHz, CDCI3) rotomers present 8.62 (2J, d, J = 5.2 Hz) ; 8.54 and 8.48 (2H, 2xs) ; 7.65 and 7.62 (IH, 2xs) ; 7.25 and 7.13 (2H, 2xd, J = 5.2 Hz) ; 4.86 and 4.70
76
(2H, 2xs) ; 4.66 and 4.34 (2H, 2xs) ; 4.27-4.22 (IH, m) ; 2.49-2.42 ( IH, m) ; 2.27-2.24 (2H, m) ; 2.10-2.05 (4H, m) ; 1.71-1.61 (2H, m) δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.70 and 7.61 (IH, 2xs) ; 7.31-7.25 (IH, m) ; 7.16-7.13 (IH, m) ;7.07-7.03 (2H, m) ; 4.83 and 4.65 (2H,
77
2xs) ;4.62 and 4.30 (2H, 2xs) ; 4.30-4.19 (IH, m) ; 2.26-2.16 (2H, m) ; 1.94-1.86 (6H, m) ; 1.40 (3H, s) δ (400 MHz, CDCI3) rotomers present 8.55 and 8.49 (2H, 2xs) ; 7.66 and 7.62 (IH,
78 2xs) ; 6.85-6.69 (3H, m) ; 4.83 and 4.70 (2H, 2xs) ;4.62 and 4,34 (2H, 2xs) ; 4.29-4.21 (IH, m) ; 2.25-2.17 (2H, m) ; 1.94-1.88 (6H, m) ; 1.41 and 1.40 (3H, 2xs) δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.68 and 7.59 (IH, 2xs) ; 7.31-7.26 (IH, m) ; 7.15-7.12 (IH, m) ; 7.06-7.02 (2H, m) ; 4.83 and 4.65 (2H,
79
2xs) ; 4.61 and 4.30 (2H, 2xs) ; 4.25-4.17 (IH, m) ; 2.43-2.40 (2H, m) ; 2.19-2.1 1 (2H, m) ; 1.97-1.88 (2H, m) ; 1.41-1.34 (2H, m) ; 1.31 (3H, s) δ (400 MHz, CDC13) rotomers present 8.53 and 8.48 (2H, 2xs) ; 7.73 and 7.64 (IH, 2xs) ; 7.31-7.27 (IH, m) ; 7.17-7.13 (IH, m) ; 7.07-7.03 (2H, m) ; 4.83 and 4.65 (2H,
80
2xs) ; 4.62 and 4.30 (2H, 2xs) ; 4.58-4.51 (IH, m) ; 2.67-2.56 (2H, m) ; 2.25-2.14 (4H, m) ; 2.02-1.93 (2H, m)
5.(400 MHz, CDCI3) rotomers present 8.54 and 8.48 (2H, 2xs) ; 7.72 and 7.63 (IH, 2xs) ; 7.31-7.27 (IH, m) ; 7.17-7.13 (IH, m) ; 7.07-7.03 (2H, m) ; 4.83 and 4.65 (2H,
81
2xs) ; 4.62 and 4.30 (2H, 2xs) ; 4.41-4.34 (IH, m) ; 2.46-2.38 (2H, m) ; 2.33-2.27 (2H, m) ; 2.18-1.94 (4H, m) δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.74 and 7.66 (IH, 2xs) ; 7.30-7.27 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07-7.02 (2H, m) ; 5.26-5.14 (IH, m) ;
82
4.83 and 4.64 (2H, 2xs) ; 4.61 and 4.29 (2H, 2xs) ; 3.34-3.27 (IH, m) ; 3.10-2.98 (2H, m) ; 2.86-2.77 (2H, m) δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.74 and 7.65 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7.16-7.12 (IH, m) ; 7.07-7.02 (2H, m) ; 4.90-4.82 (IH, m) ;
83
4.82 and 4.64 (2H, 2xs) ; 4.61 and 4.30 (2H, 2xs) ; 3.12-3.04 (3H, m) ; 2.82-2.76 (2H, m) δ (400 MHz, CDCI3) rotomers present 8.53 and 8.47 (2H, 2xs) ; 7.58 and 7.48 (IH, 2xs) ; 7.31-7.28 (IH, m) ; 7.19-7.15 (IH, m) ; 7.07-7.02 (2H, m) ; 4.82 and 4.66 (2H,
84
2xs) ; 4.64 and 4.40 (2H, 2xs) ; 4.36-4.30 (IH, m) ; 2.50-2.42 (IH, m) ; 2.24-2.03 (9H, m), 1.71-1.59 (2H, m) δ (400 MHz, DMSO-df rotamers present 8.77 and 8.70 (2H, 2xs) ; 7.87 and 7.83 (IH, 2xs) ; 7.20-7.14 (IH, m) ; 7.10 and 6.92 (2H, 2xd, J=1.6 Hz) ; 4.86 and 4.72 (2H,
85
2xs) ; 4.72 and 4.57 (2H, 2xs) ; 4.51-4.49 (IH, m) ; 4.26-4.21 (I H, m) ; 3.87 (IH, brs) ; 2.32-2.29 (2H, m) ; 1.81-1.78 (2H, m) ; 1.60-1.58 (4H, m) δ (400 MHz, CDC13) rotamers present 8.53 and 8.48 (2H, 2xs) ; 7.69 and 7.60 (IH, 2xs) ; 7.31-7.26 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07-7.02 (2H, m) ; 4.83 and 4.65 (2H, 2xs) ; 4.61 and 4.29 (2H, 2xs) ; 4.60-4.52 (IH, m) ; 3.04-2.97 (IH, m) ; 2.91 and 2.90 (3H, 2xs) ; 2.54-2.34 (4H, m) ; 2.13-2.06 (2H, m) ; 2.01-1.91 (2H, m)
8 (400 MHz, CDCI3) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7:70 and 7.61 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7.16-7.12 (IH, m) ; 7.07-7.03 (2H, m) ; 4.82 and 4.65 (2H, 2xs) ; 4.60 and 4.29 (2H, 2xs) ; 4.33-4.23 (IH, m) ; 3.01-2.93 (IH, m) ; 2.90 (3H, s) ; 2.44-2.41 (2H, m) ; 2.26-2.09 (4H, m) ; 1.87-1.76 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7.69 and 7.60 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7, 16-7.12 (IH, m) ; 7.07-7.02 (2H, m) ; 5.45 and 5.29 (2H, 2xs) ; 4.83 and 4.64 (2H, 2xs) ; 4.61 and 4.29 (2H, 2xs) ; 4.29-4.21 (IH, m) ;
2.30-2.24 (IH, m) ; 2.14 -2.03 (6H, m) ; 1.77-1.67 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.52 and 8.47 (2H, 2xs) ; 7.68 and 7.59 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7.16-7.12 (IH, m) ; 7.06-7.02 (2H, m) ; 5.93 (IH, t, J = 5.9Hz) ; 4.82 and 4.64 (2H, 2xs) ; 4.60 and 4.29 (2H, 2xs) ; 4.29-4.23 (IH, m) ; 3.77-3.73 (2H, m) ; 2.30-2.17 (2H, m) ; 2.10 -2.03 (6H, m) ; 1.78-1.71 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.43 and 8.39 (2H, 2xs) ; 7.59 and 7.55 (IH, 2xs) ; 7.38-7.35 and 7.16-7.12 (2H, 2xm) ; 7.07-7.02 (2H, m) ; 5.60-5.45 (IH, m) ; 5.08-5.04, 4.75-4.71 and 3.98-3.88 (IH, 3xm) ; 4.60-4.54 (2H, m) ; 4.29-4.21 (IH, m) ; 3.32-3.20 (IH, m) ; 2.48-2.42 (IH, m) ; 2.25 -2.22 (2H, m) ; 2.10-2.04 (4H, m) ; 1.70-1.60 (2H, m)
δ,(400 MHz, CDCI3) rotamers present 7.58 and 7.52 (IH, 2xs) ; 7.38-7.31 (2H, m) ; 7.26-7.17 (2H, m) ; 7.12-7.00 (3H, m) ; 6.53 and 6.13 (IH, 2xddd, J = 47.5, 9.8, 3.2Hz) ; 5.40, 4.80, 4.63 and 4.58 (2H, 4xd J = 15.1 Hz) ; 4.25-3.92 and 3.34-3.22 (3H, 2xm> ; 2.49-2.43 (IH, m) ; 2.26 -2.22 (2H, m) ; 1.70-1.59 (2H, m) δ (400 MHz, CDC ) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7.67 and 7.59 (IH, 2xs) ; 7.30-7.26 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07-7.02 (2H, m) ; 5;05-4.93 (IH, m) ;
92
4.83 and 4.64 (2Ή, 2xs) ; 4.61 and 4.29 (2H, 2xs), 3.35-3.27 (IH, m) ; 2.50-2.25 (4H, m) ; 2.23-2.09 ( IH, m) ; 2.04-1.95 (IH, m) δ (400 MHz, CDC13) rotamers present 8.53 and 8.48 (2H, 2xs) ; 7.71 and 7.62 (I H, 2xs) ; 7.31-7.26 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07-7.02 (2H, m) ; 4.94-4.78 (2H, m) ;
93
4.65 (IH, s) ; 4.61 and 4.30 (2H, 2xs) ; 3.08-3.00 (IH, m) ; 2.58-2.50 (2H, m) ; 2.26-2.12 (4H, m) δ (400 MHz, CDCI3) rotamers present 7.73 and 7.57 (IH, 2xs) ; 7.13 and 7.06 (2H, 2xd, J=7.8 Hz) ; 4.88 and 4.51 (2H, 2xs) ; 4.24-4.16 (IH, m) ; 3.52-3.32 (2H, m) ;
94
2.25-2.15 (2H, m) ; 1.94-1.84 (6H, m) ; 1.42 and 1 .40 (3H, 2xs) ; 1.01 and 0.83 (9H, 2xs) δ (400 MHz, CDCb) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.68 and 7.54 (IH, 2xs) ; 4.94 and 4.74 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 3.77-3.74 (IH, m) ; 3.63 (IH, t,
95
J=4.9 Hz) ; 3.53 (IH, t, J=5.4 Hz) ; 3.41 (IH, t, J=5.4 Hz) ; 2.50-2.42 ( IH, m) ; 2.26-2.23 (2H, m) ; 2.13-2.03 (4H, m) ; 1.72-1.60 (2H, m) ; 1.16 and 1.15 (9H, 2xs) δ (400 MHz, CDCb) rotamers present 7.39-7.22 (5H, m) ; 7.10-7.01 (3H, m) ; 5.03
96 and 4.74 (2H, 2xs) ; 4.32 and 3,85 (2H, 2xt, J=13.6 Hz) ; 4.20-4.16 (IH, m) ; 2.49-2.42 (IH, m) ; 2.25-2.23 (2H, m) ; 2.09-2.04 (4H, m) ; 1.69-1.59 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 8.23-8.17 (IH, m) ; 7.98 and 7.91 (2H, 2xs) ; 7.87 and 7.84 (IH, 2xs) ; 7.77-7.75 (IH, m) ; 7.19-7.13 (IH, m) ; 7.12-7.08 and
97
6.93-6.91 (2H, m) ; 4.84 and 4.72 (2H, 2xs) ; 4.68 and 4.57 (2H, 2xs) ; 4.26-4.17 (I H, m) ; 2.34-2.25 (IH, m) ; 2.07-2.01 (2H, m) ; 1.99-1.90 (4H, m) ; 1.59-1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.16 ( IH, brs) ; 7.95-7.85 (3H, m) ; 7.19-7.13 (IH, m) ; 7.12-7.08 and 6.94-6.91 (2H, m) ; 4.84 and 4.72 (2H, 2xs) ; 4.69 -
98
and 4.57 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 2.37-2.28 (IH, m) ; 2.07-2.02 (2H, m) ; 1.98-1.90 (4H, m) ; 1.60- 1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.17 (IH, brs) ; 7.81-7.41 (5H, m) ;
99 7.17-6.88 (3H, m) ; 4.88 and 4,83 (2H, 2xs) ; 4.72 and 4.60 (2H, 2xs) ; 4.25-4.12 (IH, m) ; 2.30-2.23 (IH, m) ; 2.05-2.00 (2H, m) ; 1.97-1.88 (4H, m) ; 1.56-1.46 (2H, m) δ (400 MHz, CDC13) rotamers present 7.39-7.30 (3H, m) ; 7.14-6.97 (5H, m) ;
100 4.89-3.46 (6H, m) ; 2.49-2.40 (IH, m) ; 2.26-2.20 (2H, m) ; 2.12-2.03 (4H, m) ; 1.70-1.60 (2H, m) ; 1.46 and 1.28 (3H, 2xd, J=7.3 Hz) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.52 (2H, 2xs) ; 7.63 and 7.55 ( IH,
101 2xs) ; 4.74 and 4.44 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 3:49 and 3.30 (2H, 2xd, J=6.7 Hz) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.13-1.35 (15H, m) δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.72 and 7.56 (IH, 2xs) ; 4.86 and 4.54 (2H, 2xs) ; 4.27-4.17 (IH, m) ; 3.45-3.35 (2H, m) ; 2.50-2.42
102
(IH, m) ; 2.26-2.23 (2H, m) ; 2.11-2.02 (4H, m) ; 1.70-1.12 (12H, m) ; 0.99 and 0.83 (3H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58-8.47 (3H, m) ; 7.76-7.47 (2H, m) ;
103 7.26-7.11 (2H, m) ; 4.94 and 4.82 (2H, 2xs) ; 4.71 and 4.65 (2H, 2xs) ; 4.27-4.18 (IH, m) ; 2.48-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.09-2.05 (4H, m) ; 1.71-1.57 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.63-8.44 (2H, m) ; 8.54 and 8.49 (2H, 2xs) ; 7.97-7.93 (IH, m) ; 7.71 and 7.61 (IH, 2xs) ; 7.52-7.34 (IH, m) ; 4.89 and 4.68 (2H,
104
Γ 2xs) ; 4.68 and 4.39 (2H, 2xs) ; 4.28-4.18 (IH, m) ; 2.49-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.03 (4H, m) ; 1.71-1.60 (2H, m) δ (400 MHz, CDClj) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7.71 and 7.62 (IH, 2xs) ; 7.31-7.26 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07-7.02 (2H, m) ; 4.83 and 4.65 (2H,
105
2xs) ; 4.62 and 4.30 (2H, 2xs) ; 4.36-4.28 (IH, m) ; 2.50-2.46 (2H, m) ; 2.10-1.88 (6H, m) δ (400 MHz, CDC ) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7.92 and 7.80 (IH, 2xs) ; 7.31-7.26 (IH, m) ; 7.17-7.14 (IH, m) ; 7.07-7.03 (2H, m) ; 4.84 and 4.65 (2H,
106
2xs) ; 4.62 and 4.31 (2H, 2xs) ; 4.49-4.39 (IH, m) ; 2.43-2.31 (4H, m) ; 2.11-2.03 (2H, m) ; 1.84-1.75 (2H, m) δ (400 MHz, DMSO-dfi) rotamers present 12.14 (IH, brs) ; 7.90-7.53 (4H, m) ;
107 7.17-6.86 (3H, m) ; 4.90 and 4.86 (2H, 2xs) ; 4.72 and 4.60 (2H, 2xs) ; 4.26-4.12 (IH, m) ; 2.34-2.26 (IH, m) ; 2.05-2.01 (2H, m) ; 1.98-1.89 (4H, m) ; 1.58-1.46 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.15 (IH, brs) ; 7.58-6.70 (7H, m) ;
108 4.88-3.62 (6H, m) ; 2.35-2.29 (IH, m) ; 2.09-1.86 (6H, m) ; 1.59-1.45 (2H, m) ; 1.40 and 1.22 (3H, 2xd, J=7.0 Hz) δ (400 MHz, DMSO-d6) rotamers present 8.62 and 8.53 (2H, 2xs) ; 7.81 and 7.68 (IH,
109 2xs) ; 7.21-6.81 (3H, m) ; 5.32-3.40 (6H, m) ; 3.18 and 2.93 (3H, 2xs) ; 2.34-2.26 ( 1 H, m) ; 2.08- 1.90 (6H, m) ; 1.60- 1.47 (2H, m) δ (400 MHz, CDC13) rotamers present 8.58 and 8.52 (2H, 2xs) ; 7.73 and 7.56 (IH, 2xs) ; 4.89 and 4.63 (2H, 2xs) ; 4.49 and 4.14 (2H, 2xs) ; 4.32-4.20 (IH, m) ;
1 10
2.50-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.14-2.04 (4H, m) ; 1.72-1.62 (2H, m) ; 1.20 (9H, s) δ (400 MHz, DMSO-d6) rotamers present 7.73 and 7.63 (IH, 2xs) ; 7.39-7.30 (IH, m) ; 7.19-6.85 (3H, m) ; 6.71 and 6.64 (2H, 2xd, J=8.4 Hz) ; 4.64-4.38 (4H, m) ;
I'l l
4.27-4.15 (IH, m) ; 3.70 and 3.62 (6H, 2xs) ; 2.35-2.23 (IH, m) ; 2.09-1.90 (6H, m) ; 1 .58- 1.47 (211, m)
Figure imgf000482_0001
δ (400 MHz, CD3OD) rotamers present 7.59 (IH, s) ; 7.38 and 7.33 (2H, 2xd, J=8.0 Hz) ; 7.17 (IH, t, J =8.0 Hz) ; 6.83-6.78 (IH, m) ; 6.49 and 6.35 (2H, 2xd, J=6.0 Hz) ; 4.57 and 4.34 (2H, 2xs) ; 4.25 and 4.10 (2H, 2xs) ; 4.25-4.17 (IH, m) ; 2.17-1.84 (9H, m) ; 1.65-1.54 (4H, m) ; 1.30-1.28 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.07 and 8.02 (2H, 2xs) ; 7.63 and 7.53 (IH, 2xs) ; 6,85-6.67 (3H, m) ; 4.81-4.21 (5H, m) ; 3.89 and 3.83 (6H, 2xs) ; 2.48-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.1 1-2.06 (4H, m) ; 1.71-1.60 (2H, m)
δ (400 MHz, DMSO-de) rotamers present 7.81 and 7.79 (IH, 2xs) ; 7.50 and 7.44 (2H, 2xd, J=8.6 Hz) ; 7.21-6.83 (3H, m) ; 4.80 and 4.52 (2H, 2xs) ; 4.27-4.15 (IH, m) ; 3.62-2.89 (4H, m) ; 2.34-2.24 (IH, m) ; 2.07-1.88 (6H, m) ; 1.60-1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 9.33-8.95 (2H, m) ; 8.81-8.64 (2H, m) ; 8.1 1 and 7.91 (IH, 2xs) ; 5.32-4.59 (4H, m) ; 4.26-4.18 (IH, m) ; 3.67-3.25 (3H, m) ; 2.87-2.79 (lH, m) ; 2.34-2.28 (IH, m) ; 2.05-1.43 (13H, m)
δ (400 MHz, DMSO-d6) rotamers present 11.61 (IH, brs) ; 7.79 and 7.75 (IH, 2xs) ; 7.16-7.07 (2H, m) ; 6.89 (IH, d, J=6.4 Hz) ; 6.04 and 5.97 (IH, 2xs) ; 4.67 and 4.62 (2H, 2xs) ; 4.59 and 4.58 (2H, 2xs) ; 4.24-4.13 (IH, m) ; 2.26-2.18 (IH, m) ; 2.20 and 2.03 (3H, 2xs) ; 2.03-2.00 (2H, m) ; 1.90-1.88 (4H, m) ; 1.71 and 1.61 (3H, 2xs) ; 1.56-1.47 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.70 and 7.56 (IH, 2xs) ; 4.84 and 4.50 (2H, 2xs) ; 4.29-4.19 (IH, m) ; 3.40-3.12 (2H, m) ; 2.49-2.42 (IH, m) ; 2:26-2.23 (2H, m) ; 2.13-1.94 (6H, m) ; 1.74-1.36 (15H, m) δ (400 MHz, DMSO-d6) rotamers present 7.93-7.68 (4H, m) ; 7.18-6.90 (3H, m) ; 4.88-4.14 (5H, m) ; 2.34-2.26 (IH, m) ; 2.09-1.88 (6H, m) ; 1.59-1.49 (2H, m) δ (400 MHz, CDC 13) rotamers present 8.57-8.50 (2H, m) ; 7.65-7.53 (IH, m) ;
125 4.72-4.42 (2H, m) ; 4.30-4.18 (IH, m) ; 3.78-3.32 (2H, m) ; 2.51-1.19 (15H, m) ;
0.82-0.69 (9H, m)
δ (400 MHz, CDC13) rotamers present 8.57-8.50 (2H, m) ; 7.66-7.53 (IH, m) ;
126 4.73-4.42 (2H, m) ; 4.30-4.19 (IH, m) ; 3.78-3.32 (2H, m) ; 2.48-1.19 (15H, m) ;
0.82-0.69 (9H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 7.86-7.74 (3H, m) ;
127 7.19-6.91 (3H, m) ; 4.82-4.56 (4H, m) ; 4.28-4.17 (IH, m) ; 2.35-2.27 (IH, m) ;
2.07-1.92 (6H, m) ; 1.60-1.49 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.54 and 8.48 (2H, 2xs) ; 7.73 and 7.63 (IH,
129 2xs) ; 7.31-7.26 (IH, m) ; 7.14-7.03 (3H, m) ; 4.83 and 4.65 (2H, 2xs) ; 4.62 and 4.31
(2H, 2xs) ; 4.31-4.23 (IH, m) ; 2.60-2.41 (4H, m) ; 2.17-2.01 (4H, m)
δ (400 MHz, CDCI3) rotamers present 8.58 and 8.51 (2H, 2xs) ; 7.66 and 7.54 (IH,
130 2xs) ; 4.83-4.45 (2H, m) ; 4.29-4.17 (IH, m) ; 3.73-3.21 (4H, m) ; 2.50-2.41 (IH, m) ;
2.26-2.22 (2H, m) ; 2.13-1.94 (4H, m) ; 1.74-1.34 (7H, m) ; 1.23-1.06 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.60-8.50 (2H, m) ; 7.65-7.54 (IH, m) ;
131 4.80- 4.46 (2H, m) ; 4.31-3.99 (2H, m) ; 2.51-2.43 (IH, m) ; 2.27-1.93 (9H, m) ;
1.81- 1.56 (4H, m) ; 0.89-0.76 (9H, m)
δ (400 MHz, CDCI3) rotamers present 8.60-8.50 (2H, m) ; 7.65-7.54 (IH, m) ;
132 4.86-4.46 (2H, m) ; 4.31-3.98 (2H, m) ; 2.50-2.44 (IH, m) ; 2.27-1.99 (9H, m) ;
1.82- 1.62 (4H, m) ; 0.89-0.76 (9H, m)
δ (400 MHz, CDCI3) rotamers present 8.98 and 8.93 (IH, 2xs) ; 7.66 and 7.63 (IH,
133 2xs) ; 6.84-6,74 (3H, m) ; 4.84-4.23 (5H, m) ; 2.45 and 2.04 (6H, 2xs) ; 2.28-2.02
(7H, m) ; 1.71-1.60 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 8.37 and 8.31 (IH, 2xd, J=5.1 Hz) ; 7.89 and 7.81 (IH, 2xs) ; 7.18-6.92 (4H, m) ; 4.75-4.61 (4H, m) ; 4.27-4.14 (IH, m) ; 2.37
134
and 2.22 (3H, 2xs) ; 2.33-2.25 (IH, m) ; 2.06-1.87 (6H, m) ; 1.89 and 1.73 (3H, 2xs) ; 1.58-1.46 (2H, m) δ (400 MHz, CDC13) rotamers present 8.52 (2H, s) ; 7.62 (IH, s) ; 6.86-6.74 (3H, m) ;
135 4.79 (2H, s) ; 4.67 and 4.49 (2H, 2xs) ; 4.35-4.30 (IH, m) ; 2.47-2.41 (IH, m) ; 2.26-2.23 (2H, m) ; 2.07-1.93 (4H, m) ; 1.72-1.62 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 8.02-7.72 (4H, m) ; 7.17-6.87 (3H, m) ;
136 4.88-4.62 (4H, m) ; 4.26-4.12 (IH, m) ; 2.33-2.24 (IH, m) ; 2.05-1.89 (6H, m) ; 1.57-1,47 (2H, m) δ (400 MHz, DMSO-dfi) rotamers present 7.85 and 7.83 (IH, 2xs) ; 7.42 and 7.25 (2H,
137 2xd, J=0.7 Hz) ; 7.18-6.90 (3H, m) ; 4.79-4.55 (4H, m) ; 4.27-4.16 (IH, m) ; 2.34-2.28 (4H, m) ; 2.07-1.90 (6H, m) ; 1.59-1.48 (2H, m) δ (400 MHz, CDCI3) rotamers present 7.57 and 7.55 (IH, 2xs) ; 7.35-7.18 (3H, m) ; 6.92 and 6.65 (2H, 2xd, J=5.7 Hz) ; 6.78-6.72 (IH, m) ; 6.61-6.46 and 6.19-6.04 (IH,
138
2xm) ; 5.01-4.62 (2H, m) ; 4.27-4.15 (2H, m) ; 4.02-3.93 and 3.39-3.26 (IH, 2xm) ; 2.28-2.18 (2H, m) ; 1.96- 1.90 (6H, m) ; 1.42 and 1.39 (3 H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.57 and 7.55 (IH, 2xs) ; 7.35-7.18 (3H, m) ; 6.92 and 6.65 (2H, 2xd, J=6.1 Hz) ; 6.78-6.72 (IH, m) ; 6.61-6.46 and 6.19-6.04 (I H,
139
2xm) ; 5.01-4.62 (2H, m) ; 4.27-4.15 (2H, m) ; 4.02-3.93 and 3.39-3.26 (IH, 2xm) ; 2.26-2.19 (2H, m) ; 1.96-1.90 (6H, m) ; 1.42 and 1.39 (3H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 9.45 (IH, brs) ; 8.74 and 8.68 (2H, 2xs) ; 7.86 and 7.74 (IH, 2xs) ; 7.13 and 6.98 (2H, 2xd, J=8.5 Hz) ; 6.75-6.69 (2H, m) ; 4.66
141
and 4.58 (2H, 2xs) ; 4.50 and 4.39 (2H, 2xs) ; 4.27-4.19 (IH, m) ; 2.34-2.27 (IH, m) ; 2.07-1.90 (6H, m) ; 1.59- 1.48 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 7.82-7.79 and 7.52-7.50 (IH, 2xm) ; 7.75 and 7.50 (IH, 2xs) ; 7.30-6.87 (6H, m) ; 6.80-6.74 (IH, m) ;
142 6.57-6.52 and 6.45-6.41 (IH, 2xm) ; 4.98 and 4.76 (2H, 2xs) ; 4.66 and 4.55 (2H, 2xs) ; 4.21-4.12 (IH, 2xm) ; 2.33-2.19 (IH, m) ; 2.05-1.77 (6H, m) ; 1.56-1.42 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 7.75 and 7.48 (IH, 2xs) ; 7.62 and 7.32 (IH, 2xs) ; 7.16-6.86 (6H, m) ; 6.73-6.67 (IH, m) ; 4.97 and 4.75 (2H,
143
2xs) ; 4.65 and 4.55 (2H, 2xs) ; 4.22-4.1 1 (IH, m) ; 2.33-2.22 (IH, m) ; 2.19 and 2.09 (3H, 2xs) ; 2.05-1.78 (6H, m) ; 1.56-1.42 (2H, m) δ (400 MHz, CDC13) rotamers present 7.69-7.52 (3H, m) ; 4.97 and 4.73 (2H, 2xs) ;
144 4.28-4.18 (IH, m) ; 3.94-3.40 (4H, m) ; 2.49-2.43 (IH, m) ; 2.25-2.22 (2H, m) ; 2.13-2.03 (4H, m) ; 1.70-1.62 (2H, m) ; 1.31-1.14 (9H, m) δ (400 MHz, CDCI3) rotamers present 8.36 (IH, s) ; 8.18 (IH, s) ; 7.63 (IH, s) ,
145 7.26-7.06 (4H, m) ; 4.76-4.54 (4H, m) ; 4.30-4.25 (IH, m) ; 2.49-2.42 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.05 (4H, m) ; 1.68-1.58 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 9.1 1 and 9.08 (IH, 2xs) ; 8.82 and 8.60 (2H, 2xs) ; 7.94 and 7.88 (IH, 2xs) ; 7.59-7.46 (3H, m) ; 4.87 and 4.78 (2H, 2xs) ; 4.74 and
146
4.61 (2H, 2xs) ; 4.26-4.19 (IH, m) ; 2.35-2.27 (IH, m) ; 2.07-1.88 (6H, m) ; 1.59-1.48 (2H. m) δ (400 MHz, DMSO-d6) rotamers present 12.17 (IH, brs) ; 9.68 (IH, brs) ; 8.74 and 8.68 (2H, 2xs) ; 7.76 and 7.75 (IH, 2xs) ; 7.20-7.08 and 6.92-6.71 (4H, m) ; 4.73-4.45
147
(4H, m) ; 4.27-4.19 (IH, m) ; 2.34-2.26 (IH, m) ; 2.07-1.90 (6H, m) ; 1.59-1.49 (2H, m) . δ (400 MHz, DMSO-d6) rotamers present 12.11 (IH, brs) ; 8.75 and 8.70 (2H, 2xs) ; 7.36 and 7.26 (IH, 2xs) ; 7.20-7.14 (IH, m) ; 7.08-7.06 and 6.98-6.95 (2H, 2xm) ;
148
5.00-4.50 (4H, m) ; 4.37-4.31 (IH, m) ; 2.31-2.24 (IH, m) ; 2.03-1.91 (4H, m) ; 1.87-1.78 (2H, m) ; 1.63-1.53 (2H, m) ; 1.38 and 1.33 (9H, 2xs) δ (400 MHz, CDClj) rotamers present 7.69-7.52 (3H, m) ; 4.97 and 4.74 (2H, 2xs) ;
149 4.29-4.19 (IH, m) ; 3.94-3.37 (4H, m) ; 2.25-2.15 (2H, m) ; 1.95-1.86 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.16 and 1.14 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.52 (2H, 2xs) ; 7:64 and 7.52 (IH, 2xs) ; 4.94 and 4.57 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 3.84 and 3.73 (2H, 2xs) ;
150
2.49-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.73-1.60 (2H, m) ; 1.10-1.06 (4H, m) δ (400 MHz, DMSO-d6) rotamers present 12.12 (IH, brs) ; 9.26-9.25 and 9.05-9.04 (IH, 2xm) ; 9.21-9.20 and 9.16-9.15 (IH, 2xm) ; 7.92 and 7.85 (IH, 2xs) ; 7.66-7.46
151
(4H, m) ; 4.85 and 4.78 (2H, 2xs) ; 4.75 and 4.63 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 2.33-2.26 (IH, m) ; 2.06-2.02 (2H, m) ; 1.97-1.90 (4H, m) ; 1.59-1.48 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.18 ( IH, brs) ; 9.09-8.98 ( IH, m) ; 8.68-8.63 (IH, m) ; 7.75 and 7.70 (IH, 2xs) ; 7.18-7.10 (IH, m) ; 7.08-7.06 (IH, m) ;
152
6.94-6.91 (IH, m) ; 5.02 and 4.96 (2H, 2xs) ; 4.73 and 4.60 (2H, 2xs) ; 4.24-4.13 (IH, m) ; 2.33-2.22 (IH, m) ; 2.05-1.99 (2H, m) ; 1.94-1.86 (4H, m) ; 1.56-1.45 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.07 (IH, brs) ; 9.50 (IH, brs) ; 8.74 and 8.68 (2H, 2xs) ; 7.82 and 7.75 (IH, 2xs) ; 7.17-7.10 (IH, m) ; 6.79-6.58 (3H, m) ; 4.70
153
and 4.61 (2H, 2xs) ; 4.53 and 4.43 (2H, 2xs) ; 4.28-4.21 ( IH, m) ; 2.35-2.26 (IH, m) ; 2.07-2.03 (2H, m) ; 1.98-1,91 (4H, m) ; 1.60-1.48 (2H, m) δ (400 MHz, CDC13) rotamers present 8.59 and 8.50 (2H, 2xs) ; 7.65 and 7.54 (IH, 2xs) ; 4.83 and 4.54 (2H, 2xs) ; 4.54-4.46 and 3.75-3.68 (IH, 2xm) ; 4.30-4.21 (IH,
155
m) ; 3.96-3.87 (IH, m) ; 2.74-2.72 and 2.51-2.40 (3H, m) ; 2.27-2.24 (2H, m) ; 2.14-2.00 (6H, m) ; 1.72-1.61 (2H, m) ; 1.18 and 1.12 (9H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.40 (IH, brs) ; 8.77 and 8.70 (2H, 2xs) ; 7.84 and 7.80 (IH, 2xs) ; 7.19-7.08 and 6.92-6.90 (3H, m) ; 4.85-4.56 (4H, m) ;
156
4.27-4.14 (IH, m) ; 2.20-2.17 (2H, m) ; 2.04-1.95 (2H, m) ; 1.78-1.75 (2H, m) ; 1.48-1.43 (2H, m) ; 1.33-1.24 (2H, m) ; 0.80 (3H, t, J=7.5 Hz) δ (400 MHz, DMSO-d6) rotamers present 12.15 (IH, brs) ; 8.81 and 8.74 (2H, 2xs) ;
157 7.85-7.74 (2H, m) ; 4.95-4.76 (2H, m) ; 4.26-4.19 (IH, m) ; 3.88-3.25 (3H, m) ; 2.34-1.73 (l lH, m) ; 1.59-1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.17 (IH, brs) ; 8.81 and 8.74 (2H, 2xs) ;
158 7.85-7.74 (2H, m) ; 4.93-4.76 (2H, m) ; 4.26-4.19 (IH, m) ; 3.86-3.25 (3H, m) ; 2.35-1.73 (1 IH, m) ; 1.59-1.49 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.55 and 8.52 (2H, '2xs) ; 7.56 and 7.43 (IH,
159 2xs) ; 6.86-6.77 (3H, m) ; 4.91-4.67 (6H, m) ; 4.32-4.23 (IH, m) ; 2.48-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.07-1.99 (4H, m) ; 1.72-1.61 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.55 and 8.48 (2H, 2xs) ; 7.64 and 7.56 (IH, 2xs) ; 5.09 and 4.80 (2H, 2xs) ; 4.28-4.18 (IH, m) ; 3.96 and 3.75 (2H, 2xs) ;
160
2.50-2.42 (IH, m) ; 2.26-2.23 (2H, m) ; 2.13-2.03 (4H, m) ; 1.69-1.42 (10H, m) ; 1.40 and 1.39 (3H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.48 (2H, 2xs) ; 7.67 and 7.59 (IH, 2xs) ; 7.19-7.13 (3H, m) ; 6.73 (2H, d, J=6.8 Hz) ; 4.93 and 4.72 (2H, 2xd, J=18.8
161
Hz) ; 4.12-4.04 (IH, m) ; 3.50 (IH, brs) ; 3.18-3.14 (IH, m) ; 2.43-2.37 (I H, m) ; 2.21-2.07 (4H, m) ; 1.92-1.52 (4H, m) ; 1.35-1.30 (IH, m) ; 1.14-1.09 (IH, m) δ (400 MHz, CDC13) rotamers present 8.50 (2H, brs) ; 7.43 (IH, s) ; 6.90-6.72 (3H,
162 m) ; 4.79-4.72 (2H, m) ; 4.68 and 4.59 (2H, 2xs) ; 4.15-4.08 (IH, m) ; 3.35-3.25 (IH, m) ; 2.50-2.43 (IH, m) ; 2.25-2.22 (2H, m) ; 2.10-1.90 (6H, m) ; 1.40-1.38 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.17 (IH, brs) ; 8.71 (2H, s) ; 7.57-6.99
164 (4H, m) ; 5.00-4.68 (4H, m) ; 4.20-4.12 (IH, m) ; 2.38-2.21 (4H, m) ; 2.02-1.95 (2H, ra) ; 1.86-1.80 (4H, m) · 1.59-1.48 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 9.12 (IH, s) ; 8.78 and 165 8.72 (2H, 2xs) ; 7.86 and 7.77 (IH, 2xs) ; 4.97 and 4.84 (2H, 2xs) ; 4.77 and 4.74 (2H,
2xs) ; 4.25-4.18 (IH, m) ; 2.28-2.22 (IH, m) ; 2.05-1.90 (6H, m) ; 1.57-1.48 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.52 and 8.47 (2H, 2xs) ; 7.63 and 7.54 (IH,
166 2xs) ; 7.30-7.26 (IH, m) ; 7.16-7.13 (IH, m) ; 7.07^7.00 (2H, m) ; 4.82 and 4.63 (2H,
2xs) ; 4.57 and 4.26 (2H, 2xs) ; 2.31-2.22 (6H, m) ; 2.07-2.04 (6H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.19 (IH, brs) ; 8.77 and 8.71 (2H, 2xs) ;
167 7.88 and 7.80 (IH, 2xs) ; 7.62 and 7.54 (IH, 2xs) ; 4.80-4.52 (4H, m) ; 4.28-4.20 (IH, m) ; 2.34-2.28 (IH, m) ; 2.07-1.92 (6H, m) ; 1.59-1.49 (2H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.25 (IH, brs) ; 8.78 and 8.71 (2H, 2xs) ;
168 7.81-7.77 (2H, m) ; 5.03-4.81 (4H, m) ; 4.26-4.19 (IH, m) ; 2.32-2.24 (IH, m) ;
2.06-1.93 (6H, m) ; 1.57-1.48 (2H, m)
δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.55 (IH,
169 2xs) ; 4.66-4.18 (4H, m) ; 2.51-2.42 (IH, m) ; 2.27-2.24 (2H, m) ; 2.15-2.03 (4H, m) ;
1.73-1.42 (9H, m) ; 1.14-1.07 (IH, m) ; 0.94-0.87 (6H, m)
δ (400 MHz, DMSO-d6) rotamers present 12.10 (IH, brs) ; 8.76 and 8.69 (2H, 2xs) ;
170 7.87-7.52 (5H, m) ; 4.84 and 4.75 (2H, 2xs) ; 4.72 and 4.60 (2H, 2xs) ; 4.28-4.17 (IH, m) ; 2.36-2.26 (IH, m) ; 2.07-2.02 (2H, m) ; 1.98-1.91 (4H, m) ; 1.60-1.49 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.14 (IH, brs) ; 8.75 and 8.69 (2H, 2xs) ; 7.87-7.80 (3H, m) ; 7.56 and 7.41 (2H, 2xd, J=8.3 Hz) ; 4.80 and 4.78 (2H, 2xs) ; 4.69
171
and 4.63 (2H, 2xs) ; 4.28-4.18 (IH, m) ; 2.36-2.26 (IH, m) ; 2.07-2.02 (2H, m) ; 1.98-1.90 (4H, m) ; 1.60-1.49 (2H, m) δ (400 MHz, CDC13) rotamers present 8.61 and 8.53 (2H, 2xs) ; 7.66 and 7.57 (IH,
172 2xs) ; 5.03-4.93 (IH, m) ; 4.80-4.72 (IH, m) ; 4.63-3.99 (6H, m) ; 2.51-2.43 (IH, m) ; 2.28-2.24 (2H, m) ; 2.14-2.04 (4H, m) ; 1.91 and 1.87 (3H, 2xs) ; 1.72-1.59 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.61 and 8.52 (2H, 2xs) ; 7.65 and 7.57 (IH,
173 2xs) ; 5.00-4.19 (8H, m) ; 2.50-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.14-2.04 (4H, m) ; 1.72-1.61 (2H, m) ; 1.23-1.17 (9H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.55 (IH, 2xs) ; 4.62 and 4.42 (2H, 2xs) ; 4.31-4.18 (IH, m) ; 3.55-3.50 (IH, m) ; 2.52-2.41
174
(IH, m) ; 2.27-2.23 (2H, m) ; 2.15-2.03 (4H, m) ; 1.88-1.30 (10H, m) ; 1.19-0.97 (2H, m) δ (400 MHz, CDC13) rotamers present 8.59 and 8.51 (2H, 2xs) ; 7.67 and 7.56 (IH,
175 2xs) ; 4.86-4.78 and 3.74-3.66 (IH, 2xm) ; 4.63 and 4.43 (2H, 2xs) ; 4.32-4.17 (IH, m) ; 2.53-2.42 (IH, m) ; 2.28-1.59 (16H, m) δ (400 MHz, CDCI3) rotamers present 8.53 and 8.47 (2H, 2xs) ; 7.64 and 7.55 (IH, 2xs) ; 7.32-7.26 (IH, m) ; 7.17-7.13 (IH, m).; 7.07-7.02 (2H, m) ; 4.83 and 4.64 (2H,
177
2xs) ; 4.60 and 4.29 (2H, 2xs) ; 2.57 and 2.53 (2H, 2xs) ; 2.33-2.25 (4H, m) ; 2.21-1.99 (2H, m) ; 1.95-1.88 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.56-8.51 (2H, m) ; 7.56-7.46 ( IH, m) ; 7.12-6.76 (4H, m) ; 4.82-4.78 (2H, m) ; 4.67-4.57 (2H, m) ; 4.53-4.38 (IH, m) ;
178
2.41-2.38 (2H, m) ; 2.18-2.08 (2H, m) ; 1.99-1.93 (2H, m) ; 1.43-1.36 (2H, m) ; 1.30 (3H, s) , δ (400 MHz, DMSO-d6) rotamers present 12.16 (IH, brs) ; 7.79 and 7.78 (IH, 2xs) ;
179 7.56-7.45 (2H, m) ; 7.18-6.88 (3H, m) ; 4.78 and 4.73 (2H, 2xs) ; 4.69 and 4.56 (2H, 2xs) ; 4.26-4.14 (IH, m) ; 2.33-2.26 (IH, m) ; 2.09-1.90 (6H, m) ; 1.58-1.46 (2H, m) δ (400 MHz, C.DCI3) rotamers present 8.50 and 8.42 (2H, 2xs) ; 7.72 and 7.58 (IH, 2xs) ; 7.23-7.15 (4H, m) ; 5.62-5.54 and 4.80-4.72 (IH, 2xm) ; 4.58 and 4.42 (2H,
180
2xs) ; 4.31-4.23 (IH, m) ; 3.42-3.02 (m, 4H) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.14-2.03 (4H, m) ; 1.71-1.61 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.51 (2H, 2xs) ; 7.66 and 7.56 (IH, 2xs) ; 4.99-4.91 and 3.84-3.76 (IH, 2xm) ; 4 65 and 4.45 (2H, 2xs) ; 4.33-4.17 (IH,
181
m) ; 4.08-3.98 (2H, m) ; 3.59-3.53 and 3.28-3.22 (2H, 2xm) ; 2.52-2.41 (IH, m) ; 2.28-2.22 (2H, m) ; 2.16-2.03 (4H, m) ; 1.82-1.59 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.66 and 7.56 (IH, 2xs) ; 4.76-4.67 and 3.62-3.56 (IH, 2xm) ; 4.67 and 4.46 (2H, 2xs) ; 4.31-4.19 (IH,
182
m) ; 2.51-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.17-1.96 (4H, m) ; 1.83-1.55 (8H, m) ; 0.94-0.86 (2H, m) ; 0.38-0.29 (2H, m) ; 0.19-0.15 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.66 and 7.55 (IH,
183 2xs) ; 5.23-5.14 and 4.31-4.18 (2H, m) ; 4.65-4.42 (2H, m) ; 2.51-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.14-2.03 (4H, m) ; 1.97-1.32 (8H, m) ; 1.08-0.87 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.66 and 7.56 (IH,
185 2xs) ; 5.01-4.95 and 4.17-4.09 (IH, 2xm) ; 4.58 and 4.42 (2H, 2xs) ; 4.30-4.17 (IH, m) ; 2.51-2.42.(1H, m) ; 2.27-2.23 (2H, m) ; 2.14-1.50 (14H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.56 (IH,
187 2xs) ; 4.95-4.17 and 3.57-3.50 (4H, m) ; 2.51-2.43 (IH, m) ; 2.27-2.24 (2H, m) ; 2.15-2.03 (4H, m) ; 1.94-0.98 (14H, m) δ (400 MHz, CDCI3) rotamers present 7.65 and 7.55 (IH, 2xs) ; 7.39 and 7.31 (2H, 2xs) ; 4.66 and 4.42 (2H, 2xs) ; 4.61-4.52 and 3.49-3.43 ( IH, 2xm) ; 4.31-4.14 (IH, m) ; 2.51-2.42 (IH, m) ; 2.27-2.22 (2H, m) ; 2.15-2.02 (4H, m) ; 1.72-1.40 (9H, m) ; 1.13-1.05 (IH, m) ; 0.94-0.87 (6H, m)
5 (400 MHz, CDCI3) rotamers present 7.67 and 7.56 (IH, 2xs) ; 7.14 and 7.06 (2H, 2xd, J=8.1 Hz) ; 4.67 and 4.43 (2H, 2xs) ; 4.61-4.53 and 3.52-3.44 (IH, 2xm) ;
4.30-4.15 (IH, m) ; 2.29-2.14 (2H, m) ; 1.99-1.85 (6H, m) ; 1.65-1.39 (10H, m) ; 1.13-1.06 (lH, m) ; 0.94-0.87 (6H, m)
δ (400 MHz, CDCI3) rotamers present 7.66 and 7.56 (IH, 2xs) ; 7.39 and 7.31 (2H, 2xs) ; 4.66 and 4.43 (2H, 2xs) ; 4.61-4.53 and 3.52-3.44 (IH, 2xm) ; 4.30-4.15 (IH, m) ; 2.29-2.14 (2H, m) ; 1.99-1.86 (6H, m) ; 1.65-1.40 (10H, m) ; 1.13-1.02 (IH, m) ; 0.94-0.87 (6H, m)
δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.66 and 7.55 (IH, 2xs) ; 4.81 and 4.47 (2H,.2xs) ; 4.28-4.17 (IH, m) ; 3.71-3.59 (2H, m) ; 2.50-2.42 (IH, m) ; 2.26-2.23 (2H, m) ; 2.12-2.03 (4H, m) ; 1.72-1.06 (15H, m)
δ (400 MHz, CDCI3) rotamers present 7.68 and 7.52 (IH, 2xs) ; 7.14-7.05 (2H, m) ; 4.82 and 4.45 (2H, 2xs) ; 4.27-4.17 (IH, m) ; 3.70-3.57 (2H, m) ; 2.46-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.12-2.02 (4H, m) ; 1.78-1.05 (15H, m)
δ (400 MHz, CDCI3) rotamers present 8.57 and 8.49 (2H, 2xs) ; 7.67 and 7.56 (IH, 2xs) ; 5.00 and 4.69 (2H, 2xs) ; 4.29-4.19 (IH, m) ; 3.98-3.70 (2H, m) ; 2.50-2.42 (IH, m) ; 2.27-2.23 (2H, m) ; 2.13-2.03 (4H, m) ; 1.94-1.52 (10H, m)
δ (400 MHz, CDCI3) 12.80 (IH, brs) ; 7.52 (IH, s) ; 7.33 ( IH, d, J=7.1 Hz) ;
7.26-7.23 (2H, m) ; 7.03-7.00 (2H, m) ; 6.46 (IH, d, J=7.1 Hz) ; 4.79 (2H, s) ; 4.43 (2H, s) ; 4.26-4.19 (I H, m) ; 2.39-2.32 ( IH, m) ; 2.23-2.19 (2H, m) ; 2.14-2.09 (4H, m) ; 1.60-1.53 (2H, m) δ (400 MHz, DMSO- d6) 8.80 and 8.73 (2H, 2xs) ; 7.72 and 7.59 (IH, 2xs) ; 7.37-7.04 (IH, m) ; 4.78 (2H, s) ; 4.39-4.24 and 3.72-3.64 (2H, m) ; 2.21-2.15 (2H, m) ;
2.04-1.91 (2H, m) ; 1.83-1.23 (1 IH, m) ; 1.15-1.10 (4H, m) ; 0.91-0.84 (6H, m)
8 (400 MHz, CDC13) rotamers present 7.57-6.77 (7H, m) ; 4.82-4.38 (5H, m) ;
2.41-2.37 (2H, m) ; 2.17-2.09 (2H, m) ; 1.98-1.91 (2H, m) ; 1.43-1.35 (2H, m) ; 1.30 (3H. s)
δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.67 and 7.55 (IH, 2xs) ; 5.38-5.33 and 4.52-4.47 (IH, 2xm) ; 4.73 and 4.58 (2H, 2xs) ; 4.31-4.17 (IH, m) ; 4.10-4.03 (IH, m) ; 3.91-3.84 (IH, m) ; 3.79-3.52 (2H, m) ; 2.51-2.43 (IH, m) ; 2.28-1.91 (6H, m) ; 1.73-1.59 (4H, m)
δ (400 MHz, CDCI3) rotamers present 7.68 and 7.53 (IH, 2xs) ; 7.12 and 7.05 (2H, 2xd, J=8.0 Hz) ; 5.09-4.99 and 4.58-4.15 (4H, m) ; 2.31-1.89 (10H, m) ; 1.42 and 1.39 (3H, 2xs) ; 1.30-1.24 (2H, m) ; 1.07-0.96 (8H, m)
δ (400 MHz, CDCI3) rotamers present 8.58 and 8.51 (2H, 2xs) ; 7.67 and 7.54 (IH, 2xs) ; 4.73 and 4.43 (2H, 2xs) ; 4.32-4.16 (IH, m) ; 3.79 and 3.59 (2H, 2xd, J=7.7 Hz) ; 2.85-2.77 and 2.64-2.57 (IH, 2xm) ; 2.51-2.42 (IH, m) ; 2.28-2.23 (2H, m) ; 2.19-1.97 (7H, m) ; 1.73-1.59 (3H, m) ; 0.42-0.17 (4H, m)
δ (400 MHz, CDCI3) rotamers present 7.63 and 7.44 (IH, 2xs) ; 6.82-6.69 (3H, m) ; 4.78 and 4.75 (2H, 2xs) ; 4.57 and 4.41 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 3.85 and 3.83 (3H, 2xs) ; 2.49-2.38 (IH, m) ; 2.24-2.21 (2H, m) ; 2.09-1.97 (4H, m) ; 1.69-1.59 (2H, m)
δ (400 MHz, CDCI3) rotamers present 7.69 and 7.55 (IH, 2xs) ; 7.14-7.06 (2H, m) ; 4.75 and 4.41 (2H, 2xs) ; 4.30-4.16 (IH, m) ; 3.79 and 3.58 (2H, 2xd, J=7.6 Hz) ; 2.86-2.78 and 2.65-2.57 (IH, 2xm) ; 2.54-2.12 (4H, m) ; 2.05-1.84 (7H, m) ;
1.66-1.58 (IH, m) ; 1.42 and 1.40 (3H, 2xs) ; 0.42-0.16 (4H, m) δ (400 MHz, CDC13) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.70-7.55 (IH, 2xs) ; 5.01-4.94 and 3.96-3.88 (IH, 2xm) ; 4.78-4.73 and 4.39-4.15 (3H, m) ; 2.55-2.40 (2H,
204
m) ; 2.28-2.23 (2H, m) ; 2.16-1.94 (7H, m) ; 1.82-1.78 and 1.71-1.67 (3H, m) ; 1.18- 1.15 (3 H, m) ; 0.43-0.22 (4H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.55 (IH,
205 2xs) ; 4.88-4.81 and 3.76-3.69 (IH, 2xm) ; 4.65-4.40 (2H, m) ; 4.30-4.20 (IH, m) ; 2.51-2.44 (IH, m) ; 2.27-2.24 (2H, m) ; 2.13-2.04 (4H, m) ; 1.87-0.65 ( 16H, m) δ (400 MHz, CDCI3) rotamers present 7.74 and 7.58 (IH, 2xs) ; 7.17 and 7.10 (2H, 2xs) ; 4.91 and 4.60 (2H, 2xs) ; 4.48 and 4.13 (2H, 2xs) ; 4.31-4.18 (IH, m) ; 2.37 and
206
2.33 (3H, 2xs) ; 2.28-2.17 (2H, m) ; 1.97-1.83 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.20 and 1.19 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.73 and 7.57 (IH, 2xs) ; 7.39 and 7.32 (2H, 2xs) ; 4.90 and 4.60 (2H, 2xs) ; 4.48 and 4.13 (2H, 2xs) ; 4.31-4.18 (IH, m) ;
207
2.28-2.15 (2H, m) ; 1.98-1.86 (6H, m) ; 1.41 and 1.39 (3H, 2xs) ; 1.20 and 1.19 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.54 (IH,
208 2xs) ; 4.70-4.47 (3H, m) ; 4.31-4.18 (IH, m) ; 4.07-3,76 (2H, m) ; 2.51-2.45 (IH, m) ; 2.28-2.05 (7H, m) ; 1.75-1.62 (3H, m) ; 1.36-1.13 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.51 (2H, 2xs) ; 7.65 and 7.55 (IH,
210 2xs) ; 4.77-4.19 (4H, m) ; 2.48-1.89 (13H, m) ; 1.75-1.39 (5H, m) (cis-, trans- mixture in AreaB) δ (4.00 MHz, CDCI3) rotamers present 8.59 and 8.51 (2H, 2xs) ; 7.63 and 7.53 (IH, 2xs) ; 5.13-5.05 and 4.19-4.11 (IH, 2xm) ; 4.60 and 4.43 (2H, 2xs) ; 4.29-4.21 (IH,
21 1
m) ; 2.50-2.43 (IH, m) ; 2.26-2.23 (2H, m) ; 2.1 1-2.02 (4H, m) ; 1.87-1.84 (4H, m) ; 1.72-1.59 (2H, m) ; 1.25-1.19 (2H, m) ; 0.98-0.68 (6H, m) δ (400 MHz, CDC13) rotamers present 8.58 and 8.49 (2H, 2xs) ; 7.66 and 7.55 (IH,
212 2xs) ; 4.81-4.75 and 3.65-3.56 (IH, 2xm) ; 4.63 and 4.42 (2H, 2xs) ; 4.31-4.16 (IH, m) ; 2.51-2.03 (8H, m) ; 1.84-1.43 (10H, m) δ (400 MHz, CDC13) rotamers present 8.59 and 8.51 (2H, 2xs) ; 7.65 and 7.55 (IH,
213 2xs) ; 4.60 and 4.41 (2H, 2xs) ; 4.60-4.54 and 3.62-3.55 (IH, 2xm) ; 4.32-4.16. (IH, m) ; 2.52-2.42 (IH, m) ; 2.28-2.24 (2H, m) ; 2.18-1.91 (6H, m) ; 1.73-1.21 (9H, m) δ (400 MHz, CDCI3) rotamers present 7.70 and 7.55 (IH, 2xs) ; 7.34-7.23 (IH, m) ; 7.03-6.79 (2H, m) ; 4.86 and 4.54 (2H, 2xs) ; 4.45 and 4.10 (2H, 2xs) ; 4.27-4.23 (IH,
214
m) ; 3.87 and 3.75 (3H, 2xs) ; 2.27-2.17 (2H, m) ; 1.98-1.87 (6H, m) ; 1.41-1.40 (3H, m) ; 1.19 (9H, s)
8 (400 MHz, DMSO-d6) 12.22 (IH, brs) ; 8.79-8.60 (2H, m) ; 7.85-7..69 (IH, m) ; 5.19-4.78 (2H, m) ; 4.50-4.39 and 4.09-4.02 (IH, 2xm) ; 4.27-4.18 (IH, m) ;
215
2.67-2.57 (IH, m) ; 2.33-2.26 (IH, m) ; 2.23-2.19 (IH, m) ; 2.07-1.90 (6H, m) ; 1.59-1.16 (10H, m) δ (400 MHz, CDCI3) rotamers present 7.61 and 7.50 (IH, 2xs) ; 6.84-6.71 (3H, m) ;
216 4.80 and 4.73 (2H, 2xs) ; 4.60 and 4.48 (2H, 2xs) ; 4.29-4.19 (IH, m) ; 2.49-2.42 (IH, m) ; 2.25-2.22 (2H, m) ; 2.10-2.02 (4H, m) ; 1.70-1.59 (2H, m) δ (400 MHz, CDCI3) rotamers present 7.75-7.49 (4H, m) ; 4.98 and 4.66 (2H, 2xs) ;
217 4.47 and 4.13 (2H, 2xs) ; 4.31-4.20 (IH, m) ; 2.29-2.18 (2H, m) ; 1.99-1.89 (6H, m) ; 1.42 and 1.41 (3H, 2xs) ; 1.20 and 1.19 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.74 and 7.58 (IH, 2xs) ; 7.14 and 7.07 (2H, 2xd, J=8.0 Hz) ; 4.90 and 4.61 (2H, 2xs) ; 4.48 and 4.14 (2H, 2xs) ; 4.31-4.19 (IH,
218
m) ; 2.28-2.16 (2H, m) ; 1.99-1.86 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.20 and 1.20 (9H, 2xs) δ (400 MHz, CDC13) rotamers present 7.68 and 7.53 (IH, 2xs) ; 7.38 and 7.30 (2H,
219 2xs) ; 5.08-4.98 and 4.36-4.14 (2H, m) ; 4.57 and 4.38 (2H, 2xs) ; 2.31-1.84 (10H, m) ; 1.42 and 1.39 (3H, 2xs) ; 1.35-1.24 (2H, m) ; 1.10-0.95 (8H, m) δ (400 MHz, CDCI3) rotamers present 7.65 and 7.56 (IH, 2xs) ; 7.13 and 7.07 (2H, 2xd, J=8.1 Hz) ; 4.77 and 4.42 (2H, 2xs) ; 4.29-4.17 (IH, m) ; 3.50-3.47 and 3.26-3.25
220
(2H, 2xm) ; 2.28-2.14 (2H, m) ; 1.96-1.85 (6H, m) ; 1.57-1.05 (1 1H, m) ; 0.96-0.78 (7H, m) δ (400 MHz, CDC13) rotamers present 7.73 and 7.57 (IH, 2xs) ; 7.38 and 7.31 (2H,
221 2xs) ; 4.87 and 4.50 (2H, 2xs) ; 4.25-4.15 (IH, m) ; 3.49-3.31 (2H, m) ; 2.25-2.14 (2H, m) ; 1.94-1.83 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.00 and 0.83 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.69-7.49 (4H, m) ; 4.61-4.15 (4H, m) ;
222 2.31-2.17 (2H, m) ; 1.99-1.87 (8H, m) ; 1.42 and 1.40 (3H, 2xs) ; 1.30-1.19 (2H, m) ; 1.07-0.95 (8H, m) δ (400 MHz, CDCI3) rotamers present 7.69 and 7.57 (IH, 2xs) ; 7.12 and 7.05 (2H,
224 2xd, J=8.0 Hz) ; 5.01 and 4.67 (2H, 2xs) ; 4.25-4.17 (IH, m) ; 4.07-3.70 (2H, m) ; 2.25-2.15 (2H, m) ; 1.94-1.71 (14H, m) ; 1.41 and 1.40 (3H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.68 and 7.56 (IH, 2xs) ; 7.37 and 7.30 (2H,
225 2xs) ; 5.01 and 4.66 (2H, 2xs) ; 4.25-4.17 (IH, m) ; 4.01-3.88 and 3.77-3.70 (2H, m) ; 2.25-2.15 (2H, m) ; 1.94-1.71 (14H, m) ; 1.41 and 1.40 (3H, 2xs) δ (400 MHz, CD3CN) rotamers present 7.55 and 7.46 (IH, 2xs) ; 7.20 and 7.12 (2H, 2xs) ; 4.91 and 4.67 (2H, 2xs) ; 4.22-4.16 (IH, m) ; 3.80 and 3.62 (2H, 2xs) ; 2.26 and
226
2.21 (3H, 2xs) ; 1.82-1.33 (16H, m) ; 1.27 and 1.25 (3H, 2xs) ; 1.23 and 1.21 (3H, 2xs) δ (400 MHz, CD3OD) rotamers present 7.76 and 7.59 (IH, 2xs) ; 7.33 and 7.25 (2H, 2xs) ; 4.75 and 4.63 (2H, 2xs) ; 4.43-4.28 (IH, m) ; 4.30-4.23 and 3.52-3.47 (IH,
227
2xm) ; 2.38 and 2.33 (3H, 2xs) ; 2.30-2.15 (2H, m) ; 1.98-1.38 (13H, m) ; 1.36 and 1.34 (3H, 2xs) ; 1.16-1.05 (IH, m) ; 0.95-0.86 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.07 (IH, brs) ; 8.72 and 8.61 (2H, 2xs) ;
228 7.66 and 7.63 (IH, 2xs) ; 7.38-7.17 (4H, m) ; 4.73-4.67 (4H, m) ; 4.43-4.36 (IH, m) ; 4.26-4.08 (2H, m) ; 2.33-2.25 (IH, m) ; 2.03-1.76 (6H, m) ; 1.61-1.51 (2H, m) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.50 (2H, 2xs) ; 7.66 and 7.56 (IH, 2xs) ; 4.66 and 4.45 (2H, 2xs) ; 4.64-4.56 and 3.54-3.46 (IH, 2xm) ; 4.31-4.17 (IH,
229
m) ; 2.29-2.16 (2H, m) ; 1.99-1.86 (6H, m) ; 1.63-1.27 ( 1 OH, m) ; 1.15-1.07 (IH, m) ; 0.95-0.88 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.59 and 7.50 (IH, 2xs) ; 7.14 and 7.06 (2H, 2xd, J=8.0 Hz) ; 4.65 and 4.40 (2H, 2xs) ; 4.61-4.53 and 3.46-3.38 (IH, 2xm) ;
230
2.33-2.18 (6H, m) ; 2.09-2.03 (6H, m) ; 1.64-1.39 (7H, m) ; 1.12-1.02 (IH, m) ; 0.93-0.86 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.59 and 7.50 (IH, 2xs) ; 7.39 and 7.31 (2H,
231 2xs) ; 4.64 and 4.39 (2H, 2xs) ; 4.61-4.53 and 3.46-3.38 (IH, 2xm) ; 2.33-2.21 (6H, m) ; 2.09-2.02 (6H, m) ; 1.63-1.39 (7H, m) ; 1.12-1.04 (IH, m) ; 0.93-0.86 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.68 and 7.55 (IH, 2xs) ; 7.38 and 7.32 (2H, 2xs) ; 4.74 and 4.41 (2H, 2xs) ; 4.30-4.16 (IH, m) ; 3.78 and 3.58 (2H, 2xd, J=7.8
234
Hz) ; 2.85-2.78 and 2.64-2.57 (lH, 2xm) ; 2.28-2.12 (4H, m) ; 2.02-1.85 (7H, m) ; 1.66-1.61 (lH, m) ; 1.42 and 1.39 (3H, 2xs) ; 0.43-0.16 (4H, m) δ (400 MHz, CDC13) rotamers present 7.71-7.48 (4H, m) ; 4.84 and 4.49 (2H, 2xs) ; 4.31-4.17 (IH, m) ; 3.83-3.59 (2H, m) ; 2.86-2.78 and 2.62-2.55 (IH, 2xm) ;
235
2.28-2.10 (4H, m) ; 2.01-1.87 (7H, m) ; 1.64-1.59 (IH, m) ; 1.42 and 1.41 (3H, 2xs) ; 0.43-0.16 (4H, m) δ (400 MHz, DMSO-d6) rotamers present 12.30 (IH, brs) ; 7.77 and 7.54 ( IH, 2xs) ; 7.45 and 7.38 (2H, 2xs) ; 4.68 and 4.58 (2H, 2xs) ; 4.32-4.26 (IH, m) ; 2.36 and 2.30
236
(3H, 2xs) ; 2.21-2.18 (2H, m) ; 2.14-2.10 (4H, m) ; 1.94-1.88 (6H, m) ; 1.72-1.59 (2H, m) ; 1.47-1.24 (m, 5H) ; 1.00-0.92 (lH, m) ; 0.98-0.80 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.25 (IH, brs) ; 7.76 and 7.54 (IH, 2xs) ; 7.44 and 7.38 (2H, 2xs) ; 4.70 and 4.50 (2H, 2xs) ; 3.50-3.25 (2H, m) ; 2.59-2.53 and
237
2.45-2.37 (IH, 2xm) ; 2.35 and 2,31 (3H, 2xs) ; 2.21-2.10 (6H, m) ; 1.94-1.88 (6H, m) ; 1.82-1.70 (2H, m) ; 1.59-1.54 and 1.27-1.22 (2H, 2xm) ; 1.10-0.87 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 7.66 and 7.55 (IH, 2xs) ; 7.16 and 7.09 (2H, 2xs) ; 4.74 and 4.38 (2H, 2xs) ; 4.31-4.15 (IH, m) ; 3.65 and 3.40 (2H, 2xd, J=7.1
238
Hz) ; 2.66-2.13 (6H, m) ; 1.97-1.78 (8H, m) ; 1.65-1.58 and 1.36-1.29 (2H, m) ; 1.42 and 1.40 (3H, 2xs) ; 1.14-0.93 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.65 and 7,56 (IH, 2xs) ; 7.38 and 7.31 (2H,
239 2xs) ; 4.77 and 4.41 (2H, 2xs) ; 4.30-4.16 (IH, m) ; 3.48 and 3.25 (2H, 2xd, J=7.0 Hz) ; 2.28-2.14 (2H, m) ; 1.96-1.84 (6H, m) ; 1.57-1.05 (1 IH, m) ; 0.96-0.78 (7H, m) δ (400 MHz, CDCI3) rotamers present 7.61 and 7.46 (IH, 2xs) ; 7.12 and 7.05 (2H, 2xd, J=7.6 Hz) ; 5.09-4.99 and 4.31-4.21 (IH, 2xm) ; 4.57 and 4.35 (2H, 2xs) ;
240
2.34-2.21 (6H, m) ; 2.09-2.03 (6H, m) ; 1.94-1.87 and 1.40-1.33 (2H, m) ; 1.29-1.22 (2H, m) ; 1.09-0.95 (8H, m) δ (400 MHz, CDC13) rotamers present 7.60 and 7.46 (IH, 2xs) ; 7.37 and 7.30 (2H, 2xs) ; 5.08-4.99 and 4.30-4.21 (IH, 2xm) ; 4.56 and 4.35 (2H, 2xs) ; 2.33-2.20 (6H,
241
m) ; 2.09-2.02 (6H, m) ; 1.93-1.86 and 1.39-1.33 (2H, m) ; 1.28-1.21 (2H, m) ; 1.10-0.95 (8H, m) δ (400 MHz, CDCI3) rotamers present 7.68-7.47 (4H, m) ; 4.71 and 4.48 (2H, 2xs) ;
242 4.31-4.22 and 3.46-3.39 (IH, 2xm) ; 2.33-2.24 (6H, m) ; 2.1 1-2.03 (6H, m) ; 1.87-1.77 (IH, m) ; 1.67-1.34 (6H, m) ; 1.1 1-1.03 (IH, m) ; 0.93-0.86 (6Ή, m) δ (400 MHz, CDCI3) rotamers present 7.61 and 7.52 (IH, 2xs) ; 7.32-7.23 (IH, m) ; 7.04-6.80 (2H, m) ; 4.64 and 4.33 (2H, 2xs) ; 4.63-4.56 and 3.43-3.35 (IH, 2xm) ;
243
3.86 and 3.76 (3H, 2xs) ; 2.33-2.22 (6H, m) ; 2.09-2.02 (6H, m) ; 1.62-1.38 (7H, m) ; 1.11-1.04 (IH, m) ; 0.94-0.86 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.66 and 7.57 (IH, 2xs) ; 7.1 1 and 7.04 (2H,
244 2xd, J=8.1 Hz) ; 5.09 and 4.77 (2H, 2xs) ; 4.29-4.18 (IH, m) ; 3.96-3.76 (2H, m) ; 2.21-2.14 (2H, m) ; 1.96-1.84 (6H, m) ; 1.68-1.39 (14H, m) δ (400 MHz, CDCI3) rotamers present 7.66 and 7.49 (IH, 2xs) ; 7.13 and 7.06 (2H,
245 2xd, J=8.1 Hz) ; 4.86 and 4.48 (2H, 2xs) ; 3.79-3.25 (2H, m) ; 2.31-2.21 (6H, m) ; 2.07-2.03 (6H, m) ; 1.01 and 0.84 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.66 and 7.49 (IH, 2xs) ; 7.38 and 7.31 (2H,
246 2xs) ; 4.86 and 4.48 (2H, 2xs) ; 3.75-3.25 (2H, m) ; 2.32-2.21 (6H, m) ; 2.07-2.03 (6H, m) ; 1.00 and 0.84 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.66-7.47 (4H, m) ; 4.60 and 4.42 (2H, 2xs) ;
247 4.31-4.18 (IH, m) ; 2.34-2.22 (6H, m) ; 2.09-2.02 (6H, m) ; 1.92-1.83 (2H, m) ; . 1.29-0.95 (1 OH, m) δ (400 MHz, CDC13) rotamers present 7.62 and 7.47 (1H, 2xs) ; 7.31-7.23 (1H, m) ; 7.03-6.78 (2H, m) ; 5.19-5.09 and 4.28-4.19 (IH, 2xm) ; 4.56 and 4.30 (2H, 2xs) ; 3.84 and 3.73 (3H, 2xs) ; 2.33-2.21 (6H, m) ; 2.09-2.01 (7H, m) ; 1.91-1.84 (IH, m) ; 1.33-1.24 (2H, m) ; 1.10-0.93 (8H, m)
5 (400 MHz, CDCI3) rotamers present 7.66 and 7.54 (IH, 2xs) ; 7.13 and 7.07 (2H, 2xd, J=8.0 Hz) ; 4.72 and 4.39 (2H, 2xs) ; 4.29-4.16 (IH, m) ; 3.64 and 3.40 (2H, 2xd, J=7.6 Hz) ; 2.63-2.55 and 2.44-2.36 (IH, 2xm) ; 2.25-2.14 (2H, m) ; 1.95-1.80 (8H, m) ; 1.64-1.58 and 1.35-1.30 (2H, 2xm) ; 1.42 and 1.39 (3H, 2xs) ; 1.14-0.93 (6H, m) δ (400 MHz, CDC13) rotamers present 7.65 and 7.54 (IH, 2xs) ; 7.38 and 7.31 (2H, 2xs) ; 4.71 and 4.38 (2H, 2xs) ; 4.29-4.17 (IH, m) ; 3.64 and 3.40 (2H, 2xd, J=7.6 Hz) ; 2.62-2.54 and 2.43-2.35 (IH, 2xm) ; 2.28-1.79 (10H, m) ; 1.63-1.58 and 1.34-1.29 (2H, 2xm) ; 1.41 and 1.39 (3H, 2xs) ; 1.14-0.93 (6H, m)
δ (400 MHz, CDCI3) rotamers present 7.68-7.48 (4H, m) ; 4.82 and 4.46 (2H, 2xs) ; 4.27-4.17 (IH, m) ; 3.66-3.39 (2H, m) ; 2.63-2.55 and 2.41-2.33 (IH, 2xm) ;
2.29-2.17 (2H, m) ; 1.95-1.76 (8H, m) ; 1.63-1.58 and 1.33-1.27 (2H, 2xm) ; 1.42 and 1.41 (3H, 2xs) ; 1.14-0.93 (6H, m)
δ (400 MHz, CDCI3) rotamers present 7.62 and 7.53 (IH, 2xs) ; 7.33-7.26 (IH, m) ; 7.03-6.79 (2H, m) ; 4.71 and 4.35 (2H, 2xs) ; 4.29-4.18 (IH, m) ; 3.86 and 3.76 (3H, 2xs) ; 3.64 and 3.37 (2H, 2xd, J=7.3 Hz) ; 2.63-2.55 and 2.44-2.36 (IH, 2xm) ;
2.26-2.14 (2H, m) ; 1.94-1.79 (8H, m) ; 1.63-1.58 and 1.35-1.30 (2H, 2xm) ; 1.41 and 1.39 (3H, 2xs) ; 1.14-0.94 (6H, m)
δ (400 MHz, CDCI3) rotamers present 7.70 and 7.55 (IH, 2xs) ; 7.33-7.25 (IH, m) ; 7.03-6.78 (2H, m) ; 4.86 and 4.46 (2H, 2xs) ; 4.24-4.18 (IH, m) ; 3.85 and 3.75 (3H, 2xs) ; 3.42 and 3.33 (2H, 2xs) ; 2.26-2.18 (2H, m) ; 1.93-1.87 (6H, m) ; 1.41 and 1.39 (3H, 2xs) ; 1.01 and 0.83 (9H, 2xs) δ (400 MHz, CDC13) rotamers present 7.68-7.47 (4H, m) ; 4.73 and 4.51 (2H, 2xs) ;
254 4.27-4.17 and 3.52-3.44 (2H, 2xm) ; 2.26-2.21 (2H, m) ; 1.98-L78 (7H, m) ; 1.68-1.40 (9H, m) ; 1.12-1.04 (IH, m) ; 0.94-0.86 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.68 and 7.58 (IH, 2xs) ; 7.32-7.25 (IH, m) ; 7.04-6.80 (2H, m) ; 4.66 and 4.36 (2H, 2xs) ; 4.62-4.58 and 3.48-3.42 (IH, 2xm) ;
255
4.29-4.15 (IH, m) ; 3.87 and 3.77 (3H, 2xs) ; 2.28-2.16 (2H, m) ; 1.98-1.86 (6H, m) ; 1.66-1.39 (lOH, m) ; 1.13-1.05 (IH, m) ; 0.94-0.87 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.57 and 7.47 (IH, 2xs) ; 7.38 and 7.31 (2H, 2xs) ; 4.70 and 4.35 (2H, 2xs) ; 3.62-3.34 (2H, m) ; 2.62-2.54 and 2.43-2.35 (IH,
256
2xm) ; 2.32-2.21 (6H, m)■ 2.08-2.02 (6H, m) ; 1.89-1.79 (2H, m) ; 1.63-1.58 and 1.35-1.30 (2H, 2xm) ; 1.14-0.94 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.54 and 7.45 (IH, 2xs) ; 7.32-7.26 (IH, m) ; 7.03-6.78 (2H, m) ; 4.70 and 4.32 (2H, 2xs) ; 3.86 and 3.75 (3H, 2xs) ; 3.63-3.32 (2H,
257
m) ; 2.63-2.55 and 2.44-2.36 (IH, 2xm) ; 2.32-2.22 (6H, m) ; 2.08-2.02 (6H, m) ; 1.90-1.79 (2H, m) ; 1.63-1.58 and 1.36-1.31 (2H, 2xm) ; 1.14-0.95 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.67-7.48 (4H, m) ; 4.81 and 4.44 (2H, 2xs) ;
258 3.93-3.13 (2H, m) ; 2.63-2.23 (7H, m) ; 2.09-2.03 (6H, m) ; 1.88-1.76 (2H, m) ; 1.63-1.58 and 1.33-1.28 (2H, 2xm) ; 1.14-0.94 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.61 and 7.55 (IH, 2xs) ; 7.33-7:26 (IH, m) ; 7.03-6.78 (2H, m) ; 4.76 and 4.38 (2H, 2xs) ; 4.28-4.18 (IH, m) ; 3.86 and 3.75 (3H,
259
2xs) ; 3.48 and 3.23 (2H, 2xd, J=7.1 Hz) ; 2.27-2.16 (2H, m) ; 1.95-1.87 (6H, m) ; 1.67-1.05 (11H, m) ; 0.96-0.78 (7H, m) δ (400 MHz, CDCI3) rotamers present 7.65 and 7.57 (IH, 2xs) ; 7.36 and 7.29 (2H,
260 2xs) ; 5.08 and 4.76 (2H, 2xs) ; 4.29-4.17 (IH, m) ; 3.96 and 3.7.5 (2H, 2xs) ; 2.25-2.14 (2H, m) ; 1.95-1.84 (6H, m) ; 1.68-1.39 (14H, m) δ (400 MHz, DMSO-dfi) rotamers present 12.20 (IH, brs) ; 7.71 and 7.61 (IH, 2xs) ; 7.42 and 7.37 (2H, 2xs) ; 4.92 and 4.70 (2H, 2xs) ; 3.83 and 3.61 (2H, 2xs) ; 2.35 and
261
2.30 (3H, 2xs) ; 2.21-2.12 (6H, m) ; 1.93-1.89 (6H, m) ; 1.69-1.50 (6H, m) ; 1.45-1.38 (2H, m) ; 1.34 and 1.31 (3H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 1 1.97 (IH, brs) ; 8.77 and 8.70 (2H,.2xs) ; 7.81 and 7.71 (IH, 2xs) ; 4.95 and 4.82 (2H, 2xs) ; 4.48-4.42 (IH, m) ; 4.27-4.19 (IH,
262
m) ; 3.87 and 3.71 (2H, 2xs) ; 2.34-2.26 (IH, m) ; 2.07-1.90 (6H, m) ; 1.67-1.30 (10H, m) δ (400 MHz, CDC13) rotamers present 8.57 and 8.49 (2H, 2xs) ; 7.66 and 7.52 (IH, 2xs) ; 5.14-5.04 and 4.37-4.16 (2H, m) ; 4.57 and 4.40 (2H, 2xs) ; 2.52-2.44 (IH, m) ;
264
2.28-2.25 (2H, m) ; 2.17-2.02 (4H, m) ; 1.96-1.89 (IH, m) ; 1.73-1.62 (2H, m,) ; 1.36-0.96 (l lH, m) δ (400 MHz, CDCI3) rotamers present 7.78 and 7.48 (4H, m) ; 4.97 and 4.60 (2H,
265 2xs) ; 4.24-4.18 (IH, m) ; 3.72-3.12 (2H, m) ; 2.27-2.19 (2H, m) ; 1.94-1.88 (6H, m) ; 1.41 and 1.25 (3H, 2xs) ; 1.00 and 0.82 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.58 and 7.47 (IH, 2xs) ; 7.13 and 7.06 (2H, 2xd, J=8.0 Hz) ; 4.71 and 4.36 (2H, 2xs) ; 3.70-3.35 (2H, m) ; 2.63-2.55 and 2.43-2.35
266
(IH, 2xm) ; 2.32-2.21 (6H, m) ; 2.08-2.02 (6H, m) ; 1.89-1.79 (2H, m) ; 1.63-1.58 and 1.36-1.30 (2H, 2xm) ; 1.14-0.94 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.67 and 7.56 (IH,
267, 2xs) ; 4.81 and 4.47 (2H, 2xs) ; 4.29-4.18 (IH, m) ; 3.72 and 3.59 (2H, 2xs) ; 2.28-2.15 (2H, m) ; 1.95-1.85 (6H, m) ; 1.67-1.06 (16H, m) δ (400 MHz, DMSO-d6) rotamers present 12.23 (IH, brs) ; 7.90 and 7.81 (IH, 2xs) ; 7.19-7.09 (4H, m) ; 6.93-6.91 (IH, m) ; 4.72-4.59 (4H, m) ; 4.27-4.13 (IH, m) ;
268
2.33-2.29 (IH, m) ; 2.19 (3H, s) ; 2.05-2.02 (2H, m) ; 1.96-1.90 (4H, m) ; 1.70 (3H, s) ; 1.58-1.46 (2H, m) δ (300 MHz, DMSO-d6) rotamers present 12.15 (IH, brs) ; 7.85 and 7.81 (IH, 2xs) ;
269 7.17-6.91 (5H, m) ; 4.71-4.58 (4H, m) ; 4.28-4.13 (IH, m) ; 2.34-2.23- (4H, m) ; 2.22 and 1.77 (3H, 2xs) ; 2.08-1.90 (6H, m) ; 1.60-1.47 (2H, m) δ (400 MHz, CDCI3) rotamers present 7.65-7.47 (4H, m) ; 5.1 1 and 4.75 (2H, 2xs) ;
270 4.25-4.19 (IH, m) ; 4.02-3.70 (2H, m) ; 2.28-2.18 (2H, m) ; 1.95-1.73 (14H, m) ; 1.41 (3H, s) δ (400 MHz, CDCI3) rotamers present 8.57 and 8.49 (2H, 2xs) ; 7.67 and 7.56 (IH,
272 2xs) ; 5.00 and 4.69 (2H, 2xs) ; 4.26-4.19 (IH, m) ; 3.98-3.92 (2H, m) ; 2.28-2.16 (2H, m) ; 1.95-1.74 (14H, m) ; 1.41 (3H, s) δ (400 MHz, CDCI3) rotamers present 7.68 and 7.56 (IH, 2xs) ; 7.38 and 7.3 1 (2H,
275 2xs) ; 4.82 and 4.44 (2H, 2xs) ; 4.29-4.17 (IH, m) ; 3.71 and 3.58 (2H, m) ; 2.24-2.14 (2H, m) ; 1.96-1.84 (6H, m) ; 1.66-1.05 (16H, s) δ (300 MHz, DMSO-dfi) rotamers present 12.22 (IH, brs) ; 7.85 and 7.68 (IH, 2xs) ; 7.22 and 7.15 (IH, 2xs) ; 7.1 1 and 7.05 (IH, 2xs) ; 4.61 and 4.59 (2H, 2xs) ; 4.32-4.17
279
and 3.39-3.30 (2H, 2xm) ; 2.30-1.98 (7H, m) ; 1.90-1.58 (9H, m) ; 1.50-1.31 (4H, m) ; 1.25 and 1.22 (3H, 2xs) ; 1.04-0.82 (8H, m) δ (400 MHz, CD3OD) rotamers present 7.76 and 7.62 (IH, 2xs) ; 7.13 and 7.07 (2H,
280 2xs) ; 4.61 and 4.54 (2H, 2xs) ; 4.35-4.27 and 3.57-3.45 (2H, 2xm) ; 2.36-2.20 (7H, m) ; 1.95-1.81 (7H, m) ; 1.77-1.07 (1 IH, m) ; 0.95-0.86 (6H, m) δ (400 MHz, CDC13) rotamers present 7.70 and 7.58 (IH, 2xs) ; 7.36-7.23 (3H, m) ;
281 5.05 and 4.69 (2H, 2xs) ; 4.25-4.18 (IH, m) ; 4.00-3.95 (2H, m) ; 2.26-2.16 (2H, m) ; 1.94-1.73 (14H, m) ; 1.40 (3H, s) δ (400 MHz, CDCI3) rotamers present 7.69 and 7.58 (IH, 2xs) ; 7.15 and 7.07 (2H,
282 2xs) ; 5.02 and 4.66 (2H, 2xs) ; 4.25-4.17 (IH, m) ; 3.98-3.70 (2H, m) ; 2.35 and 2.32 (3Ή, 2xs) ; 2.25-2.15 (2H, m) ; 1.94-1.73 (14H, m) ; 1.41 and 1.40 (3H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.68 and 7.58 (IH, 2xs) ; 7.38-7.23 (3H, m) ; 4.70 and 4.46 (2H, 2xs) ; 4.61-4.53 and 3.52-3.44 (IH, 2xm) ; 4.30-4.15 (IH, m) ;
283
2.29-2.16 (2H, m) ; 1.98-1.86 (6H, m) ; 1.68-1.40 (10H, m) ; 1.13-1.06 (IH, m) ; 0.94-0.87 (6H, m) δ (400 MHz, CDCI3) rotamers present 7.75 and 7.59 (IH, 2xs) ; 7.36-7.23 (3H, m) ;
284 4.92 and 4.53 (2H, 2xs) ; 4.24-4.16 (IH, m) ; 3.44-3.36 (2H, m) ; 2.25-2,15 (2H, m) ; 1.94-1.85 (6H, m) ; 1.42 and 1.40 (3H, 2xs) ; 1.01 and 0.84 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.65 and 7.57 (IH, 2xs) ; 4.64-4.57 and 3.55-3.48 (IH, 2xm) ; 4.54 and 4.35 (2H, 2xs) ; 4.30-4.21 (IH,
287
m) ; 2 28-2.18 (2H, m) ; 1.97-1.87 (6H, m) ; 1.62-1.49 (4H, m) ; 1.42 and 1.40 (3H, 2xs) ; 0.99 and 0.90 (6H, 2xt, J=7.5 Hz) δ (400 MHz, DMSO-d6) rotamers present 12:24 (IH, brs) ; 8.78 and 8.72 (2H, 2xs) ;
288 7.65 and 7.62 (IH, 2xs) ; 4.82 and 4.66 (2H, 2xs) ; 3.49-3.22 (2H, m) ; 2.15-2.1 1 (6H, m) ; 1.93- 1.89 (6H,,m) ; 1.30-1.24 (2H, m) ; 0.89-0.72 (9H, m) δ (400 MHz, CDCI3) rotamers present 7.66 and 7.55 (IH, 2xs) ; 7.39 and 7.31 (2H,
289 2xs) ; 4.57-4.52 (1.5H, m) ; 4.39-4.15 (6H, m) ; 3.53-3.48 (0.5H, m) ; 2.27-2.13 (4H, m) ; 1.95-1.75 (8H, m) ; 1.65-1.58 (IH, m) ; 1.45-1.28 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.47 (IH, brs) ; 7.91 and 7.76 (IH, 2xs) ; 7.72 and 7.65 (2H, 2xd, J=8.6 Hz) ; 5.14-4.98 (IH, m) ; 4.73 and 4.65 (2H, 2xs) ;
290 4.34-4.28 and 3.43-3.38 (IH, 2xm) ; 3.17-3.09 (IH, m) ; 2.92-2.75 (2H, m) ; 2.71-2.59 (2H, m) ; 1.71-1.61 (2H, m) ; 1.48-1.24 (5H, m) ; 1.06-1.00 (IH, m) ; 0.91-0.81 (6H, m) δ (400 MHz, DMSO-dg) rotamers present 12.38 (I H, brs) ; 7.89 and 7.75 (IH, 2xs) ; 7.72 and 7.66 (2H, 2xd, J=8.6 Hz) ; 4.98-4.85 (IH, m) ; 4.72 and 4.64 (2H, 2xs) ;
291
4.35-4.28 and 3.43-3.37 (IH, 2xm) ; 3.02-2.96 (IH, m) ; 2.81-2.59 (4H, m) ; 1.70-1.60 (2H, m) ; 1.48-1.27 (5H, m) ; 1.07-1.00 (IH, m) ; 0.91-0.82 (6H, m) δ (400 MHz, CD3OD) rotamers present 7.81 and 7.59 (IH, 2xs) ; 7.40 and 7.34 (2H, 2xd, J=8.6 Hz) ; 4.96 and 4.78 (2H, 2xs) ; 4.35-4.25 (IH, m) ; 3.72-3.63 and 3.51-3.46
292
(4H, 2xm) ; 2.31-2.13 (2H, m) ; 1.93-1.84 (6H, m) ; 1.35 and 1.33 (3H, 2xs) ; 1.19 and 1.16 (9H, 2xs) δ (400 MHz, CD3OD) rotamers present 7.81 and 7.59 (IH, 2xs) ; 7.61and 7.55 (2H, 2xs) ; 4.96 and 4.78 (2H, 2xs) ; 4.36-4.26 (IH, m) ; 3.72-3.63 and 3.52-3.45 (4H,
293
2xm) ; 2.35-2.13 (2H, m) ; 1.94-1.85 (6H, m) ; 1.36 and 1.34 (3H, 2xs) ; 1.19 and 1.16 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.54-8.44 (2H, m) ; 7.61 and 7.51 (IH, 2xs) ;
294 4.71 and 4.54 (2H, 2xs) ; 4.27-4.19 (IH, m) ; 3.40-3.33 (2H, m) ; 2.27-2.17 (2H, m) ; 1.94-1.87 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.01 and 0.86 (9H, 2xs)
8 (400 MHz, CD3OD) rotamers present 7.81 and 7.63 (IH, 2xs) ; 7.41 and 7.34 (2H, 2xd, J=6.3 Hz) ; 4.79-3.93 (4H, m) ; 3.31-3.12 (2H, m) ; 2.99-2.94 (IH, m) ; 2.80-2.68
295
(4H, m) ; 2.46-2.37 (2H, m) ; 2.28-2.15 (2H, m) ; 1.95-1.72 (8H, m) ; 1.32 and 1.30 . (3H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 7.88-7.69 (3H, m) ; 4.69-4.19 (4H, m) ;
296 3.12-2.73 (4H, m) ; 2.13-2.02 (3H, m) ; 1.91-1.65 (10H, m) ; 1.25 and 1.22 (3H, 2xs) ; 1.05-0.90 (6H, m) δ (400 MHz, CDC13) rotamers present 7.64 and 7.52 (IH, 2xs) ; 7.39-6.99 (3H, m) ;
297 4.78 and 4.53 (2H, 2xs) ; 4.25-4.18 (IH, m) ; 3.41-3.33 (2H, m) ; 2.26-2.16 (2H, m) ; 1.94-1.87 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.01 and 0.85 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.61 and 7.49 (IH, 2xs) ; 7.37 and 7.30 (2H,
298 2xs) ; 4.99 and 4.64 (2H, 2xs) ; 3.94-3.66 (2H, m) ; 2.31-2.22 (6H, m) ; 2.07-2.03 (6H, m) ; 1.93-1.73 (8H, m) δ (400 MHz, CDCI3) rotamers present 8.56 and 8.49 (2H, 2xs) ; 7.60 and 7.49 (IH,
299 2xs) ; 4.99 and 4.67 (2H, 2xs) ; 3.94-3.66 (2H, m) ; 2.31-2.23 (6H, m) ; 2.08-2.04 (6H, m) ; 1.99-1.74 (8H, m) δ (400 MHz, CDCI3) rotamers present 7.62 and 7.50 (IH, 2xs) ; 7.15 and 7.07 (2H,
300 2xs) ; 5.01 and 4.64 (2H, 2xs) ; 3.95-3.67 (2H, m) ; 2.35 and 2.32 (3H, 2xs) ; 2.26-2.22 (6H, m) ; 2.07-2.03 (6H, m) ; 1.94-1.73 (8H, m) δ (400 MHz, DMSO-d6) rotamers present 12.40 (IH, brs) ; 7.80 and 7.63 (IH, 2xs) ; 7.71 and 7.67 (2H, 2xd, J=8.6 Hz) ; 4.72 and 4.65 (2H, 2xs) ; 4.34-4.17 (2H, m) ;
301
2.20-2.14 (2H, rti) ; 2.03-1.62 (6H, m) ; 1.48-1.24 (7H, m) ; 1.14 and 1.12 (3H, 2xs) ; 1.02-0.95 (lH, m) ; 0.90-0.81 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.26 (IH, brs) ; 7.88 and 7.75 (IH, 2xs) ; 7.70 and 7.65 (2H, 2xd, J=8.5 Hz) ; 4.81 and 4.63 (2H, 2xs) ; 4.25-4.20 (IH, m) ;
302
3.82-3.75 and 3.38-3.23 (2H, 2xm) ; 2.09-1.98 (2H, m) ; 1.87-1.72 (6H, m) ; 1.30-1.15 (5H, m) ; 0.87-0.70 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 12.26 (IH, brs) ; 9.41 and 9.14 (IH, 2xbrs) ; 7.89 and 7.76 (IH, 2xs) ; 7.75 and 7.69 (2H, 2xd, J=8.6 Hz) ; 4.80-4.73 (2.5H, m) ;
303 4.36-4.31 (0.5H, m) ; 4.26-4.20 (IH, m) ; 3.90-3.88 and 3.81-3.78 (2H, 2xm) ; 2.63 and 2.56 (3H, 2xd, J=4.5 Hz) ; 2.49-2.42 (2H, m) ; 2.29-2.27 (2H, m) ; 2.14-1.63 (12H, m) ; 1.25 and 1.23 (3H, 2xs) δ (400 MHz, CD3OD) rotamers present 7.82 and 7.62 (IH, 2xs) ; 7.43 and 7.37 (2H, 2xd, J=8.0 Hz) ; 4.79 and 4.70 (2H, 2xs) ; 4.45-4.36 (IH, m) ; 4.30-4.25 (IH, m) ;
304
4.11-4.02 (2H, m) ; 2.64-2.48 (2H, m) ; 2.26-2.06 (8H, m) ; 1.99-1.74 (7H, m) ; 1.36 and 1.34 (3H, 2xs) δ (400 MHz, CD3OD) rotamers present 7.66 and 7.63 (IH, 2xs) ; 7.37 and 7.29 (2H,
305 2xd, J=8.2 Hz) ; 4.77 and 4.72 (2H, 2xs) ; 4.29-4.17 (4H, m) ; 3.26-3.20 (IH, m) ; . 2.79-2.71 (2H, m) ; 2.33-2.15 (8H, m) ; 1.95-1.82 (6H, m) ; 1.47-1.34 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 7.94-7.72 (3H, m) ; 4.80 and 4.63 (2H,
306 2xs) ; 4.16-4.09 (IH, m) ; 3.48-3.20 (2H, m) ; 2.07-1.96 (2H, m) ; 1.80-1.63 (6H, m) ; 1.29-1.22 (2H, m) ; 1.12 (3H, s) ; 0.87-0.69 (9H, m) δ (400 MHz, DMSO-d6) 12.11 (IH, brs) ; 8.32 (2H, s) ; 7.49 (IH, s) ; 7.37 (IH, s) ; 7.18-7.13 (2H, m) ; 7.10-7.03 (2H, m) ; 5,13 (IH, d, J=15.7 Hz) ; 4.30 (IH, d, J=15.7
307
Hz) ; 4.16-4.08 (IH, m) ; 2.28 (3H, s) ; 2.24-2.18 (IH, m) ; 2.00-1.82 (4H, m) ; 1.75-1.69 (2H, m) ; 1.52-1.40 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 7.84 and 7.79 (2H, 2xs) ; 7.64 and 7.61 (IH,
308 2xs) ; 4.79 and 4.59 (2H, 2xs) ; 3.50-3.32 (2H, m) ; 2.19-2.10 (6H, m) ; 1.92-1.88 (6H, m) ; 1.29-1.22 (2H, m) ; 0.88-0.71 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 7.80-7.61 (3H, m) ; 4.79 and 4.59 (2H,
309 2xs) ; 3.50-3.22 (2H, m) ; 2.18-2.10 (6H, m) ; 1.91-1.88 (6H, m) ; 1.29-1.23 (2H, m) ; 0.87-0.71 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 12.30 (IH, brs) ; 8.78 and 8.73 (2H, 2xs) ; 8.13 and 8.04 (IH, 2xs) ; 4.86 (2H, s) ; 4.50-4.43 (IH, m) ; 3.41-3.28 (2H, m) ;
310
2.04-1.95 (2H, m) ; 1.88-1.83 (4H, m) ; 1.74-1.71 (2H, m) ; 1.20 and 1.14 (3H, 2xs) ; 0.94 and 0.76 (9H, 2xs) δ (400 MHz, CD3OD) rotamers present 8.65 and 8.58 (2H, 2xs) ; 7.79 and 7.61 (IH, 2xs) ; 4.95-4.88 and 3.99-3.91 (IH, 2xm) ; 4.80-4.63 (2H, m) ; 4.37-4.25 (IH, m) ;
312 2.33-2.14 (2H, m) ; 1.93-1.85 (7H, m) ; 1.68-1.40 (2H, m) ; 1.36 and 1.34 (3H, 2xs) ; 1.32-1.27 (lH, m) ; 1.23 and 1.21 (3H, 2xs) ; 0.99-0.93 (3H, m) ; 0.75 and 0.73 (3H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.21 (IH, brs) ; 8.80 and 8.72 (2H, 2xs) ; 7.81 and 7.70 (IH, 2xs) ; 4.88-4.57 (2.5H, m) ; 4.31-4.21 (IH, m) ; 3.96-3.91 (0.5H,
313
m) ; 3.54-3.22 (2H, m) ; 3.25 and 3.16 (3H, 2xs) ; 2.15-2.01 (2H, m) ; 1.88-1.76 (6H, m) ; 1.24 and 1.23 (3H, 2xs) ; 1.16 and 1.08 (3H, 2xd, J=6.8 Hz) δ (400 MHz, DMSO-d6) rotamers present 12.27 (IH, brs) ; 8.79 and 8.72 (2H, 2xs) ; 7.85 and 7.75 (IH, 2xs) ; 5.17-5.1 1 (IH, m) ; 4.75 and 4.60 (2H, 2xs) ; 4.30-4.22 ( IH,
314
m) ; 4.11 and 3.86 (2H, 2xd, J=6.7 Hz) ; 2.14-2.01 (2H, m) ; 1.88-1.74 (6H, m) ; 1 .70 and 1.66 (3H, 2xs) ; 1.64 and 1.37 (3H, 2xs) ; 1.24 and 1.23 (3H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.33-8.23 (2H, m) ; 7.68 and 7.53 (IH, 2xs) ; 4.80 and 4.47 (2H, 2xs) ; 4.24-4.19 (IH, m) ; 3.98 and 3.88 (3H, 2xs) ; 3.41-3.31 (2H,
315
m) ; 2.27-2.16 (2H, m) ; 1.94-1.86 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.01 and 0.85 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.51 (2H, 2xs) ; 7.54 and 7.48 (IH,
316 2xs) ; 4.94 and 4.58 (2H, 2xs) ; 3.55-3.30 (2H, m) ; 2.33-2.23 (6H, m) ; 2.09-2.05 (6H, m) ; 1.09 and 0.98 (3H, 2xs) ; 0.49-0.34 (4H, m) δ (400 MHz, CDC13) rotamers present 7.68 and 7.51 (2H, 2xs) ; 7.37-7.25 (3H, m) ;
317 4.91 and 4,51 (2H, 2xs) ; 3.49-3.33 (2H, m) ; 2.32-2.22 (6H, m) ; 2.07-2.03 (6H, m) ; 1.01 and 0.84 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 7.71 and 7.60 (1H, 2xs) ; 7.37-7.27 (2H, m) ;
318 4.96 and 4.72 (2H, 2xs) ; 4.29-4.18 (1H, m) ; 3.77-3.40 (4H, m) ; 2.25-2.17 (2H, m) ; 1.93-1.87 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.16 and 1.15 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.50 (2H, 2xs) ; 7.71 and 7.52 (1H,
319 2xs) ; 5.19-5.15 and 4.53-4.15 (3H, m) ; 2.28-2.14 (2H, m) ; 1.95-1.55 (8H, m) ; 1.42-0.55 (14H, m) δ (400 MHz, CDCI3) rotamers present 7.62 and 7.48 (1H, 2xs) ; 7.36-7.26 (3H, m) ;
320 5.10-5.00 and 4.31-4.22 (1H, 2xm) ; 4.60 and 4.38 (2H, 2xs) ; 2.34-2.21 (6H, m) ; 2.09-1.88 (8H, m) ; 1.43-1.23 (2H, m) ; 1.08-0.95 (8H, m) δ (400 MHz, CDCI3) rotamers present 7.62 and 7.47 (1H, 2xs) ; 7.16 and 7.08 (2H,
321 2xs) ; 5.1 1-5.01 and 4.30-4.21 (1H, 2xm) ; 4.57 and 4.35 (2H, 2xs) ; 2.35-2.21 (9H, m) ; 2.09-2.02 (7H, m) ; 1.93-1.85 (1H, m) ; 1.40-1.23 (2H, m) ; 1.10-0.95 (8H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.51 (2H, 2xs) ; 7.55 and 7.48 (1H, 2xs) ; 4.74 and 4.45 (2H, 2xs) ; 3.68 (1H, brs) ; 3:32 (1H, d, J=5.9 Hz) ; 2.31-2.23
322
(6H, m) ; 2.08-2.05 (6H, m) ; 1.09 (3H, s) ; 1.05 (3H, s) ; 1.03 (3H, s) ; 0.80 (3H, s) ; 0.55-0.51 and 0.31-0.28 (1H, m) δ (400 MHz, CDCI3) rotamers present 8.58 and 8.51 (2H, 2xs) ; 7.64 and 7.55 (1H, 2xs) ; 4.76 and 4.48 (2H, 2xs) ; 4.29-4.18 (1H, m) ; 3.68 and 3.37 (2H, 2xd, J=6.5
325
Hz) ; 2.31-2.16 (2H, m) ; 1.95-1.86 (6H, m) ; 1.42 and 1.41 (3H, 2xs) ; 1.09 (3H, s) ; 1,06 (3H, s) ; 1.04 (3H, s) ; 0:80 (3H, s) ; 0.53 and 0.31 (1H, 2xt, J=6.5 Hz) δ (400 MHz, CDCls) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.67 and 7.57 (IH,
326 2xs) ; 5.00 and 4.68 (2H, 2xs) ; 4.26-4.20 (IH, m) ; 3.83-3.58 (2H, m) ; 2.26-2.16 (2H, m) ; 1.95-1.86 (6H, m) ; 1.46-1.23 (9H, m) δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.59 and 7.50 (IH,
327 2xs) ; 4.99 and 4.66 (2H, 2xs) ; 3.80-3.54 (2H, m) ; 2.32-2.23 (6H, m) ; 2.08-2.04 (6H, m) ; 1.46-1.26 (6H, m) δ (400 MHz, CDCI3) rotamers present 8.59 and 8.52 (2H, 2xs) ; 7.56 and 7.46 (IH,
329 2xs) ; 4.94 and 4.55 (2H, 2xs) ; 3.84 and 3.70 (2H, 2xs) ; 2.33-2.22 (6H, m) ; 2.08-2.04 (6H, m) ; 1.10-1.06 (4H, m) δ (400 MHz, CDCI3) rotamers present 8.57 and 8.50 (2H, 2xs) ; 7.75 and 7.55 (IH, 2xs) ; 4.78 and 4.45 (2H, 2xs) ; 4.29-4.24 (IH, m) ; 2.83-2.79 (IH, m) ; 2.28-2.20
331
(2H, m) ; 1.95-1.90 (6H, m) ; 1.42 (3H, s) ; 1.04-0.99 (IH, m) ; 0.95 and 0.70 (9H, 2xs) ; 0.64-0.55 (2H, m) δ (400 MHz, DMSO-d6) rotamers present 12.27 (IH, brs) ; 8.80 and 8.73 (2H, 2xs) ;
332 7.81 and 7.66 (IH, 2xs) ; 4.89-4.57 (2.5H, m) ; 4.30-4.21 (IH, m) ; 3.87-3.82 (0.5H, m) ; 3.50-3.18 (2H, m) ; 2.13-2.04 (2H, m) ; 1.88-1.75 (6H, m) ; 1.24-1.07 (15H, m) δ (400 MHz, CDCI3) rotamers present 8.54-8.44 (2H, m) ; 7.64 and 7.49 (IH, 2xs) ;
333 5.26-5.20 and 4.34-4.17 (2H, 2xm) ; 4.52 and 4.36 (2H, 2xs) ; 2.31-1.88 (10H, m) ; 1.42 and 1.40 (3H, 2xs) ; 1.27-1.12 (2H, m) ; 1.04-0.97 (8H, m) δ (400 MHz, CDCI3) rotamers present 8.54-8.44 (2H, m) ; 7.62 and 7.50 (IH, 2xs) ;
337 4.71 and 4.53 (2H, 2xs) ; 4.26-4.19 (IH, m) ; 3.41 and 3.34 (2H, 2xs) ; 2.26-2.16 (2H, m) ; 1.94-1.86 (6H, m) ; 1.40-1.14 (5H, m) ; 0.95-0.68 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 12.11 (2H, brs) ; 7.89 and 7.80 (IH, 2xs) ; 4.29-4.23 (IH, m) ; 4.17-4.09 (IH, m) ; 3.26-3.16 (IH, m) ; 3.04-3.00 (IH, m) ;
338
2.57-2.53 (IH, m) ; 2.36-2.32 (IH, m) ; 2.15 (3H, s) ; 2.13-2.05 (2H, m) ; 1.88-L64 (l lH, m) ; 1.58-1.55 (IH, m) ; 1.48-1.30 (4H, m) ; 1.24 (3H, s) ; 1.00-0.82 (7H, m) δ (400 MHz, CD3OD) rotamers present 7.79 and 7.64 (lH, 2xs) ; 7.40 and 7.34 (2H, 2xd, J=8.5 Hz) ; 5.15-5.00 (IH, m) ; 4.77 and 4.64 (2H, 2xs) ; 4.44-4.36 and 3.55-3.47
339
(IH, 2xm) ; 2.99-2.87 (2H, m) ; 2.73-2.58 (2H, m) ; 1.83-1.70 (2H, m) ; 1.63-1.37 (8H, m) ; 1.15-1.08 (IH, m) ; 0.94-0.86 (6H, m) δ (400 MHz, DMSO-dfi) rotamers present 12.27 (IH, brs) ; 8.81 and 8.73 (2H, 2xs) ; 7.95 and 7.73 (IH, 2xs) ; 4.88-4.56 (2H, m) ; 4.31-4.20 (IH, m) ; 2.71-2.60 (IH, m) ;
340
2.15-2,05 (2H, m) ; 1.90-1.75 (6H, m) ; 1.24 and 1.22 (3H, 2xs) ; 1.08-1.07 (IH, m) ; 0.92-0.76 (2H, m) ; 0.67-0.59 (6H, m) ; 0.52-0.48 (lH, m) δ (400 MHz, DMSO-d6) rotamers present 12.24 (IH, brs) ; 7.69 and 7.52 (IH, 2xs) ;
341 7.26-6.90 (3H, m) ; 5.47-4.96 (2H, m) ; 4.34-3.96 (2H, m) ; 3.79-3.50 (4H, m) ; 2.09-0.88 (23H, m) δ (400 MHz, DMSO-d6) rotamers present 12.24 (IH, brs) ; 7.69 and 7.52 (IH, 2xs) ;
342 7.26-6.90 (3H, m) ; 5.47-4.96 (2H, m) ; 4.34-3.96 (2H, m) ; 3.79-3.50 (4H, m) ; 2.09-0.88 (23H, m) δ (400 MHz, DMSO-d6) rotamers present 12.25 (IH, brs) ; 7.77 and 7.65 (3H, m) ;
345 4.70 (2H, s) ; 4.39-4.24 and 3.70-3.62 (2H, 2xm) ; 2.03-1.64 (10H, m) ; 1.51-1.09 (10H, m) ; 0.91-0.85 (6H, m) δ (400 MHz, DMSO-d6) rotamers present 12.19 (IH, brs) ; 8.81 and 8.74 (2H, 2xs) ; 8.09 and 7.73 (IH, 2xs) ; 4.96-4.56 (2H, m) ; 4.31-4.23 (IH, m) ; 3.22-3.04 (IH, m) ;
346
2.17-2.03 (2H, m) ; 1.88-1.73 (6H, m) ; 1.24 and 1.22 (3H, 2xs) ; 1.19-1.07 (IH, m) ; 0.99-0.48 (9H, m) δ (400 MHz, DMSO-d6) rotamers present 12.29 (IH, brs) ; 7.96 and 7.73 (IH, 2xs) ; 7.73 and 7.68 (2H, 2xd, J=8.6 Hz) ; 4.86 and 4.74 (2H, 2xs) ; 4.32-4.21 (IH, m) ;
348
3.57-3.53 and 3.39-3.35 (2H, 2xm) ; 2.76-2.72 and 2.63-2.59 (2H, 2xm) ; 2.13-1.99 (2H, m) ; 1.88-1.72 (6H, m) ; 1.30 and 1.09 (9H, 2xs) ; 1.23 and 1.22 (3H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.28 (IH, brs) ; 8.02 and 7.73 (IH, 2xs) ; 7.74 and 7.68 (2H, 2xd, J=8.8 Hz) ; 4.93 and 4.79 (2H, 2xs) ; 4.32-4.22 (IH, m) ;
350
3.89-3.85 and 3.70-3.66 (2H, 2xm) ; 3.42-3.38 and 3.35-3.31 (2H, 2xm) ; 2.1 1-2.00 (2H, m) ; 1.88-1.73 (6H, m) ; 1.33-1.22 (12H, m) δ (400 MHz, DMSO-d6) rotamers present 12.28 (IH, brs) ; 7.95 and 7.74 (IH, 2xs) ; 7.73 and 7.67 (2H, 2xd, J=8.6 Hz) ; 4.91-4.70 (2H, m) ; 4.31-4.21 (IH, m) ; 3.91-3.64
351
(2H, m) ; 2.98-2.64 (2H, m) ; 2.1 1-1.99 (2H, m) ; 1.87-1.72 (6H, m) ; 1.23 and 1.22 (3H, 2xs) ; 1.17 and 1.10 (9H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.28-12.23 (IH, m) ; 8.56 and 8.23 (IH, 2xd, J=2.0 Hz) ; 7.85 and 7.50 (IH, 2xs) ; 7.46-7.40 and 7.26-7.13 (3H, 2xm) ; 4.83
352
and 4.65 (2H, 2xs) ; 4.27-4.07 (IH, m) ; 3.41-3.28 (2H, m) ; 2.11-1.63 (8H, m) ; 1.23 and 1.13 (3H, 2xs) ; 0.96 and 0.77 (9H, 2xs) δ (300 MHz, DMSO-d6) rotamers present 12.24 (IH, brs) ; 7.80 and 7.73 (IH, 2xs) ;
358 7.58-7.51 (3H, m) ; 4.84 and 4.72 (2H, 2xs) ; 4.34-4.27 (IH, m) ; 1.98-1.72 (8H, m) ; 1.21 (3H, s) ; 0.95 and 0.74 (9H, 2xs) δ (300 MHz, DMSO-dg) rotamers present 12.30 (IH, brs) ; 7.79 and 7.72 (IH, 2xs) ;
359 7.43 and 7.38 (2H, 2xs) ; 4.82 and 4.68 (2H, 2xs) ; 4.36-4.27 (IH, m) ; 2.31 (3H, s) ; 2.02-1.72 (8H, m) ; 1.21 (3H, s) ; 0.95 and 0.74 (9H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.42 (IH, brs) ; 11.20 and 1 1.13 (1H, 2xs) ; 7.77 and 7.63 (IH, 2xs) ; 7.24-7.17 (IH, m) ; 6.96-6.85 (2H, m) ; 4.25-4.20
360
(IH, m) ; 3.64-3.42 (4H, m) ; 3.1 1-3.07 and 2.91-2.87 (2H, 2xm) ; 2.10-1.99 (5H, m) ; 1.87-1.75 (6H, m) ; 1.24 (3H, s) ; 0.95 and 0.74 (9H, 2xs) δ (400 MHz, DMSO-d6) rotamers present 12.23 (IH, brs) ; 7^83-7.29 (4H, m) ;
363 4.90-4.34 (4H, m) ; 1.93-1.76 (10H, m) ; 1.45-1.41 (2H, m) ; 1.22 (3H, s) ; 1.05-0.95 (811. m) δ (400 MHz, DMSO-d6) rotamers present 12.20 (IH, brs) ; 7.55-7.28 (4H, m) ;
364 4.62-4.55 (3H, m) ; 4.25-4.15 (IH, m) ; 2.33-2.30 (3H, m) ; 2.09-1.81 (6H, m) ; 1.73-1.71 (4H, m) ; 1.32-1.27 (2H, m) ; 1.22 (3H, s) ; 1.05-0.90 (8H, m) δ (300 MHz, DMSO-d6) rotamers present 12.19 (IH, brs) ; 7.51-7.33 (3H, m) ;
365 4.64-4.57 (3H, m) ; 4.16-4.05 (IH, m) ; 2.35-2.26 (5H, m) ; 2.02-1.81 (6H, m) ; 1.74-1.71 (4H, m) ; 1.38-1.31 (2H, m) } 1.22 (3H, s) ; 1.04-0.90 (8H, m) δ (300 MHz, DMSO-d6) rotamers present 12.23 (IH, brs) ; 7.80-7.41 (3H, m) ;
366 4.59-4.34 (4H, m) ; 2.33 (3H, s) ; 2.07-1.76 ( 1 OH, m) ; 1.31-1.21 (5H, m) ; 1.05-0.94 (811, m) δ (400 MHz, DMSO-d6) rotamers present 12.23 (IH, brs) ; 8.77 and 8.61 (2H, 2xs) ;
367 7.83 and 7.68 (IH, 2xs) ; 4.65-4.36 (4H, m) ; 1.97-1.78 (10H, m) ; 1.30-1.21 (5H, m) ; 1.05-0.95 (8H, m) δ (400 MHz, CDClj) rotamers present 8.57 and 8.51 (2H, 2xs) ; 7.69 and 7.62 (IH, 2xs) ; 4.96 and 4.72 (2H, 2xs) ; 4.35-4.27 (IH, m) ; 3.57 and 3.48 (2H, 2xs) ;
378
2.18-2.12 (2H, m) ; 1.95-1.84 (6H, m) ; 1.40 (3H, s) ; 1.13 and 0.96 (3H, 2xs) ; 0.49-0.39 (4H, m) δ (400 MHz, CDCI3) rotamers present 8.48-8.35 (2H, m) ; 7.70 and 7.58 (IH, 2xs) ; 4.76 and 4.51 (2H, 2xs) ; 4.28-4.19 (IH, m) ; 3.43-3.35 (2H, m) ; 2.40 and 1.90 (3H,
379
2xs) ; 2.28-2.16 (2H, m) ; 1.95-1.85 (6H, m) ; 1.41 and 1.40 (3H, 2xs) ; 1.01 and 0.86 (9H, 2xs) δ (400 MHz, CDCI3) rotamers present 8.56 and 8.53 (2H, 2xs) ; 7.68 and 7.59 (IH,
381 2xs) ; 4.70 and 4.54 (2H, 2xs) ; 4.32-4.27 (IH, m) ; 3.63-3.56 (2H, m) ; 2.59-2.45 (IH, m) ; 2.17-2.1 1 (2H, m) ; 1.94-1.88 (8H, m) ; 1.39-0.96 (11H, m) δ (400 MHz, CDCI3) 8.55 (2H, s) ; 7.56 (IH, s) ; 4.68 (2H, s) ; 4.06-3.99 (IH, m) ;
382 3.61 (2H, d, J=6.8 Hz) ; 2.57-2.40 (4H, m) ; 2.22-2.16 (2H, m) ; 1.94-1.82 (8H, m) ; 1.40-1.00 (l lH, m) δ (300 MHz, CD3OD) rotamers present 8.43-8.33 (2H, m) ; 7.65 and 7.52 (2H, 2xs) ;
383 5.63-5.59 and 5.23-5.21 (IH, 2xm) ; 4.54-4.12 (2H, m) ; 3.90-3.73 and 3.48-3.44 (2H, 2xm) ; 2.29-1.56 ( 12H, m) ; 1.35 (3H, s) ; 1.26-0.93 (8H, m) δ (400 MHz, CDCI3) 8.53 (IH, s) ; 8.46 (IH, s) ; 7.67 (IH, s) ; 4.51 (2H, s) ; 4.38-4.26
387 (2H, m) ; 2.49 (3H, s) ; 2.32-2.21 (2H, m) ; 2.01-1.94 (8H, m) ; 1.42 (3H, s) ; 1.30-1.24 (2H, m) ; 1.06-0.97 (8H, m) δ (400 MHz, CDGI3) rotamers present 8.58 and 8.52 (2H, 2xs) ; 7.70 and 7.60 (IH,
388 2xs) ; 4.93 and 4.70 (2H, 2xs) ; 4.33-4.25 (IH, m) ; 3.86 (2H, s) ; 2.18-2.08 (2H, m) ; 1.94-1.82 (6H, m) ; 1.39 (3H, s) ; 1.09-1.05 (4H, m) δ (400 MHz, CDCI3) rotamers present 7.71 and 7.61 (IH, 2xs) ; 7.37-7.27 (3H, m) ; 4.72 and 4.57 (2H, 2xs) ; 4.57-4.49 and 3.87-3.81 (IH, 2xm) ; 4.38-4.21 (IH, m) ;
389
2.20-2.1 1 (2H, m) ; 1.94-1.83 (6H, m) ; 1.70-1.40 (10H, m) ; 1.27-1.23 (IH, m) ; 0.94-0.90 (6H, m) δ (300 MHz, DMSO-d6) rotamers present 12.19 (IH, brs) ; 8.56-8.46 (IH, m) ;
7.91-7.85 (IH, m) ; 7.74 and 7.63 (IH, 2xs) ; 7.40-7.35 (IH, m) ; 5.53-5.44 and 4.98-4.93 (2H, 2xm) ; 4.29-3.98 (2H, m) ; 3.61-3.49 (IH, m) ; 2.13-1.73 (10H, m) ; 1.56-1.37 (IH, m) ; 1.23-0.82 (12H, m)
5 (300 MHz, DMSO-d6) rotamers present 12.24 ( 1 H, brs) ; 11.19 and 11.14 ( 1 H, 2xs) ; 7.83 and 7.66 (IH, 2xs) ; 7.24-7.16 (IH, m) ; 6.95-6.83 (2H, m) ; 4.47-4.00 (2H, m) ; 3.41-2.85 (4H, m) ; 2.50 and 2.41 (3H, 2xs) ; 2.12-1.66 (1 1H, m) ; 1.31-1.10 (6H, m) ; 0.99-0.88 (6H, m)
δ (400 MHz, CDC13) 8.06 (IH, d, J=7.3 Hz) ; 7.52 (IH, s) ; 7.35-7.20 (3H, m) ; 5.91 (1Ή, s) ; 4.30-4.23 (IH, m) ; 4.16-4.06 (IH, m) ; 3.99 (IH, d, J=14.4 Hz) ; 3.89 (IH, d, J=14.4Hz) ; 2.28-2.17 (2H, m) ; 1.96-1.22 (14H, m) ; 1.10-0.83 (10H, m) δ (400 MHz, CDC13) rotamers present 8.57 and 8.49 (2H, 2xs) ; 7.69 and 7.57 (IH, 2xs) ; 5.00 and 4.69 (2H, 2xs) ; 4.25-4.20 (IH, m) ; 3.85-3.61 (2H, m) ; 2.26-2.16 (2H, m) ; 1.95-1.86 (6H, m) ; 1.76-1.41 (7H, m) ; 0.96 and 0.74 (6H, 2xt, J=7.6 Hz) δ (400 MHz, CDC13) rotamers present 8.56 and 8.50 (2H, 2xs) ; 7.71 and 7.64 (IH, 2xs) ; 5.01 and 4.79 (2H, 2xs) ; 4.30-4.25 ( IH, m) ; 3.86-3.72 (2H, m) ; 2.18-2.08 (2H, m) ; 1.95-1.83 (6H, m) ; 1.78-1.39 (7H, m) ; 0.96 and 0.74 (6H, 2xt, J=7.3 Hz) δ (400 MHz, DMSO-de) rotamers present 12.26 (IH, brs) ; 7.75 and 7.60 (IH, 2xs) ; 7.60 and 7.54 (IH, 2xd, J=5.1 Hz) ; 6.99 and 6.93 (IH, 2xd, J=5.1 Hz) ; 6.31 and 6.08
v.
(IH, 2xs) ; 5.40-5.36 and 4.82-4.80 (IH, 2xm) ; 4.30-4.01 (2H, m) ; 3.39-3.18 (2H, m) ; 2.07-1.70 (10H, m) ; 1.53-1.44 (IH, m) ; 1.28-0.84 (12H, m)
δ (400 MHz, CDCI3) rotamers present 8.55 and 8,46 (IH, 2xd, J=3.2 Hz) ; 7.84-7.79 (IH, m) ; 7.66 and 7.50 (IH, 2xs) ; 7.43-7.40 (IH, m) ; 4.92 and 4.71 (2H, 2xs) ; 4.32-4.18 (2H, m) ; 2.28-1.87 (9H, m) ; 1.46-1.16 (6H, m) ; 1.06-0.94 (8H, m) δ (300 MHz, DMSO-dfi) rotamers present 12.27 (IH, brs) ; 8.54-8.52 and 8.41-8.39 (IH, 2xm) ; 7.83-7.23 (4H, m) ; 5.75-5.60 ( IH, m) ; 5.00-4.96 and 4.64-4.59 (IH,
401
2xm) ; 4.30-3.99 (2H, m) ; 3.64-3.31 (2H, m) ; 2.11-2.02 (2H, m) ; 1.88-1.74 (8H, m) ; 1.53-1.37 (IH, m) ; 1.23-0.82 (12H, m) δ (400 MHz, CD3OD) rotamers present 8.55 and 8.48 (IH, 2xdd, J=4.6, 1.5 Hz) ; 7.87 and 7.79 (IH, 2xdd, J=8.1, 1.5 Hz) ; 7.68 and 7.65 (IH, 2xs) ; 7.36 and 7.33 (IH,
402 2xdd, J=8.1, 4.6 Hz) ; 5.64-5.61 and 5.17-5.14 (IH, 2xm) ; 4.32-4.27 (IH, m) ; 4.07-3.33 (4H, m) ; 2.30-2.17 (2H, m) ; 1.91-1.89 (6H, m) ; 1.35 and 1.34 (3H, 2xs) ; 1.01 and 0.81 (9H, 2xs) δ (400 MHz, DMSO-d6) 12.27 (IH, brs) ; 7.66-7.37 (4H, m) ; 4.76-4.37 (4H, m) ;
404
2.10-1.74 (10H, m) ; 1.51-1.45 (3H, m) ; 1.34-0.91 (14H, m) δ (400 MHz, CD3OD) rotamers present 7.77 and 7.60 (IH, 2xs) ; 7.53-7.21(3H, m) ; 7.15-6.75 (IH, m) ; 4.83 and 4.63 (2H, 2xs) ; 4.31-4.26 (IH, m) ; 3.41-3.36 (2H, m) ;
406
2.26-2.14 (2H, m) ; 1.95-1.84 (6H, m) ; 1.35 and 1.34 (3H, 2xs) ; 1.01 and 0.85 (9H, 2xs) δ (500 MHz, DMSO-dfi) 12.19 (IH, br. s.), 7.75 (0.3H, s), 7.58 (0.7H, s), 7.34-7.48 (4H, m), 7:13-7.33 (4H, m), 4.78 (1.4H, s), 4.42 (0.6H, s), 4.15-4.28 (IH, m),
500
3.29-3.60 (2H, m), 2.94-3.00 (0.6H, m), 2.78-2.83 (1.4H, m), 2.25-2.39 (IH, m), 1.89-2.10 (6H, m), 1.46-1.60 (2H, m) δ (400 MHz, DMSO-d6) 12.18 (IH, br. s.), 7.79 (0.3H, s), 7.74 (0.7H, s), 7.34-7.47 (5H, m), 7.15-7.30 (2H, m), 4.78 (1.6H, s), 4.47.(0.4H, s), 4.14-4.29 (IH, m),
501
3.24-3.56 (2H, m), 3.15-3.20 (0.4H, m), 2.91-2.99 (1.6H, m), 2.25-2.38 (IH, m), 1.88-2.10 (6H, m), 1.45-1.63 (2H, m) δ (500 MHz, DMSO-d6) 12.17 (IH, br. s.), 7.68 (0.3H, s), 7.53 (0.7H, s), 7.42-7.45 (IH, m), 7.36-7.40 (2H, m), 7.28-7.32 (IH, m), 7.17-7.26 (3H, m), 7.14 (0.7H, d,
502 J=8.3Hz), 6.93 (1.3H, d, J=7.1Hz), 4.72 (1.3H, s), 4.38 (0.7H, s), 4.13-4.26 (ΊΗ, m), 3.55 (0.7H, dd, J=8.6, 6.8), 3.27 (1.3H, t, J=7.6Hz), 2.81-2.86 (0.7H, m), 2.72 (1.3H, t, J=7.7Hz), 2.24-2.37 (IH, m), 1.86-2.09 (6H, m), 1.46-1.591 (2H, m) δ (400 MHz, DMSO-d6) 12.18 (IH, br. s.), 10.97 (IH, br. s.), 7.68 (0.4H, s), 7.57 (0.6H, s), 7.36-7.47 (4.4H, m), 7.25-7.28 (IH, m), 7.21 (0.4H, br. s), 7.1 1-7.15 (0.6H, m), 6.98 (0.6H, s), 6.85 (0.4H, dd, J=8.0, 1.4Hz), 6.52 (0.6H, dd, J=8.0, 1.4Hz),
503
6.32-6.38 (IH, m), 4.74 (1.2H, s), 4.36 (0.8H, s), 4.13-4.29 (IH, m), 3.53-3.60 (0.8H, m), 3.23-3.37 (1.2H, m), 2.74-2.93 (2H, m), 2.25-2.38 (IH, m), 1.38-2.10 (6H, m), 1 .45- 1.61 (211, m) δ (500 MHz, DMSO-d6) 12.18 (IH, br. s.), 7.74 (0.3H, s), 7.66 (0.7H, s), 7.56 (0.3H, d, J=1.2Hz), 7.47 (0.7H, d, J=2.2Hz), 7.44 (1.4H, dt, J=2.4, 8.6Hz), 7.33-7.42 (3.6H, m), 7.25 (0.7H, d, J=8.3Hz), 7.14 (0.3H, d, J=8.3Hz), 4.77 (1.3H, s), 4.43 (0.7H, s),
504
4.13-4.26 (IH, m), 3.57 (0.7H, t, J=7.5Hz), 3.27-3.35 (1.3H, m), 2.95 (0.7H, t, J=7.8Hz), 2.81 (1.3H, t, J=7.8Hz), 2.25-2.38 (IH, m), 1.87-2.09 (6H, m), 1.46-1.59 (2H, m) δ (500 MHz, DMSO-d6) 12.18 (IH, br. s.), 7.74 (0.3H, s), 7.68.(0.7H, s), 7.37-7.46 (3H, m), 7.17 (0.7H, d, J=8.3Hz), 6.85-7.01 (2.6H, m), 6.77 (0.7H, d, J=8.3Hz), 4.77
505 (1.4H, s), 4.43 (0.6H, s), 4.14-4.28 (IH, m), 3.40-3.45 (0.6H, m), 3.12-3.19 (1.4H, m), 2.74-2.79 (0.6H, m), 2.58-2.64 (1.4H, m), 2.25-2.37 (IH, m), 2.19-2.22 (1.8H, m), 2.18 (2.1H, s), 1.89-2.09 (6H, m), 1.79 (2.1H, s), 1.47-1.60 (2H, m) δ (500 MHz, DMSO-d6) 12.18 (IH, s), 11.05 (IH, s), 7.70 (0.3H, s), 7.66 (0.7H, s), 7.19-7.47 (5.4H, m), 7.13 (0.6H, d, J=8.3Hz), 6.98-7.02 (0.3H, m), 6.92-6.96 (0.7H, m), 6.80 (0.3H, d, J=7.1Hz), 6.61 (0.7H, d, J=7.1Hz), 6.48-6.50 (0.3H, m), 5.78-5.80
506
(0.7H, m), 4.79 (1.4H, s), 4.38 (0.6H, s), 4.15-4.27 (IH, m), 3.58-3.63 (0.6H, m), 3.29-3.63 (1.4H, m), 3.06 (0.6H, dd, J=8.8, 6.8Hz), 2.88-2.94 (1.4H, m), 2.25-2.38 (IH, m), 1.89-2.1 1 (6H, m), 1.46-1.59 ~(2H, m) δ (500 MHz, DMSO-d6) 12.18 (IH, br. s.), 10.82 (IH, br. s.), 7.75 (0.7H, s), 7.70 (0.3H, s), 7.48 (0.3H, d, J=7.8Hz), 7.36-7.40 (3.3H, m), 7.33 (0.3H, d, J=8.1Hz), 7.29 0.7H, d, J=8.1Hz), 7.13-7.17 (IH, m), 6.94-7.08 (2H, m), 6.89 (0.7H, d, J=8.3Hz),
507
6.84 (O.7H, t, J=7.6), 4.77 (1.4H, s), 4.42 (0.6H, s), 4.16-4.28 (IH, m), 3.59 (0.6H, t, J=8.1Hz), 3.28-3.34 (1.4H, m), 2.95 (0.6H, t, J=7.8Hz), 2.82 (1.4H, t, J=8.1Hz), 2.25-2.37 (IH, m), 1.88-2.10 (6H, m), 1.47-1.59 (2H, m) δ (500 MHz, DMSO-d6) 12.16 (IH, br. S.), 11.07 (0.4H, s), 10.96 (0.6H, s),7.61 (0.4H, s), 7.28-7.44 (5.4H, m), 7.09 (0.6H, s), 6.86-7.02 (2H, m), 6.59 (0.6H, d, J=7.1Hz), 6.45 (0.4H, dd, J=2.8, 1.8Hz), 6.42 (0.6H, dd, J=2.8, 1.8Hz), 4.73 (1.2H, s),
508
4.32 (0.8H, s), 4.12-4.21 (IH, m), 3.65 (0.8H, t, J=7.3Hz), 3.30-3.40 (1.2H, m), 3.14 (0.8H, t, J=7.3Hz), 3.05 (1.2H, t, J=7.1Hz), 2.25-2.34 (IH, m), 2.00-2.07 (2H, m), 1.85-1.97 (4H, m), 1.46-1.58 (2H, m) δ (500 MHz, DMSO-d6) 12.17 (IH, s), 7.74 (0.3H, s), 7.64 (0.7H, s), 7.36-7.47 (3.3H, m), 7.15-7.19 (0.7H, m), 7.03-7.15 (3.3H, m), 6.89-6.92 (0.7H, m), 4.78 (1.4H, s),
509 4.44 (0.6H, s), 4.15-4.28 (IH, m), 3.43-3.49 (0.6H, m), 3.17-3.23 (1.4H, m), 2.79-2.84 (0.6H, m), 2.62-2.69 (1.4H, m), 2.28-2.37 (IH, m), 2.25 (IH, s), 1.89-2.092 (6H, m), 1.83 (2H, s), 1.48-1.60 (2H, m) δ (500 MHz, DMSO-d6) 12.21 (IH, br. s.), 7.74 (0.2H, s), 7.70 (0.8H, s), 7.32 (0.4H, s), 7.24 (1.6H, s), 4.17-4.27 (IH, m), 3.52-3.57 (0.4H, m), 3.24-3.41 (3.2H, m), 3.12 (0.4H, d, J=7.1Hz), 3.04 (0.4H, d, J=6.8Hz), 2.91 (1.6H, t, J=8.1Hz), 2.21-2.38 (4H, m), 1.90-2.10 (6H, m), 1.45-1.82 (8H, m), 0.90-1.25 (5H, m)
δ (500 MHz, DMSO-d6) 12.20 (IH, br. s.), 7.79-7.83 (IH, m), 7.24 (2H, s), 4.20-4.28 (IH, m), 3.36-3.47 (2H, m), 2.89 (2H, t, J=7.8Hz), 2.27-2.37 (IH, m), 2.23 (3H, s), 1.89-2.10 (7H, m), 1.21-1.61 (13H, m), 0.93 (3H, s)
δ (500 MHz, DMSO-d6) 12.17 (IH, br. s.), 7.78 (IH, s), 7.24 (2H, s), 4.20-4.28 (IH, m), 3.29-3.42 (4H, m), 2.88 (2H, t, J=8.1Hz), 2.29-2.32 (IH, m), 2.23 (3H, s), 1.90-2.10 (6H, m), 1.55 (2H, qd, J=12.6, 4.2Hz), 0.95 (9H, s)
δ (500 MHz, DMSO-d6) 12.18 (IH, br. s.), 10.69-10.74 (IH, m), 7.79 (0.75H, s), 7.63 (0.25H, s), 7.36-7.47 (4H, m), 7.15-7.23 (1.25H, m), 6.88-6.99 (1.25H, m), 6.77-6.84 (1.5H, m), 4.82 (1.5H, s), 4.44 (0.5H, s), 4.15-4.28 (IH, m), 3.32-3.47 (0.5H, m), 3.13-3.19 (1.5H, m), 2.83-2.88 (0.5H, m), 2.66-2.71 (1.5H, m), 2.30-2.38 (IH, m), 2.28 (0.75, s), 1.89-2.10 (8.25H, m), 1.48-1.61 (2H, m)
δ (500 MHz, DMSO-d6) 12.26 (IH, br. s.), 7.75 (0.2H, s), 7.73 (0.8H, s), 7.32 (0.4H, s), 7.24 (1.6H, s), 4.21-4.28 (IH, m), 3.52-3.57 (0.4H, m), 3.37 (1.6H, d, J=7.3Hz), 3.25-3.33 (1.6H, m), 3.10-3.15 (0.4H, m), 3.04 (0.4H, d, J=6.8Hz), 2.87-2.94 (1.6H, m), 2.28 (0.6H, s), 2.23 (2.4H, s), 2.03-2.13 (2H, m), 1.46-1.90 (12H, m), 0.91-1.27 (8H, m)
δ (500 MHz, DMSO-d6) 12.26 (IH, br. s.), 7.81 (IH, s), 7.24 (2H, s), 4.23-4.30 (IH, m), 3.29-3.40 (2H,m), 2.89 (2H, t, J=8.1Hz), 2.23 (3H, s), 2.04-2.15 (3H, m), 1.74-1.90 (7H, m), 1.25 (3H, s), 0.95 (9H, s) δ (400 MHz, CDCI3) 7.68 (0.4H, s), 7.55 (0.6H, s), 7.18 (0.8H, s), 7.09 (1.2H, s), 4.70 (1H, br. s.), 4.49-4.64 (1H, m), 4.35-4.49 (1H, m), 4.07-4.35 (1H, m), 3.36-3.58 ( 1H,
516
m), 2.39-2.53 (1H, m), 2.18-2.39 (4H, m), 1.98-2.18 (4H, m), 1.53-1.75 (6H, m), L37-1.53 (3H, m), 1.01-1.15 (1H, m), 0.83-0.97 (6H, m) δ (400 MHz, CDCI3) 7.57-7.62 (1H, m), 7.09-7.16 (2H, m), 5.48 ( 0.6H, s) 4.51
517 (1.4H, s) 4.18-4.24 (1H, m), 4.44-4.58 (1H, m), 2.39-2.54 (1H, m), 2.33 (6H, s), 1.98-2.17 (4H, m), 1.50- 1.81 (2H, m), 0.90-1.09 (9H, m) δ (400 MHz, CDCI3) 7.66 (0.3H, s), 7.57 (0.7H, s), 7.17 (0.7H, s), 7.08 (1.4H, s), 4.81 (0.7H, s), 4.43 (1.4H, s), 4.12-4.33 (IH, m), 3.50-3.53 (1.3H, m), 3.19-3.34 (0.7H, m),
518
2.42-2.49 (IH, m), 2.31-2.39 (3H, m), 2.19-2.29 (2H, m), 2.04-2.14 (4H, m.), 1.53-1.81 (7H, m), 1.18-1.35 (2H, m), 0.70-1.04 (2H, m), 0.08-0.35 (4H, m) δ (400 MHz, CDCI3) 7.54-7.64 (IH, m), 7.19-7.08 (2H, m), 4.52 (2H, s), 4.12-4.30
519 (IH, m), 3.50 (2H, s), 2.46-2.50 (IH, m), 2.20-2.37 (5H, m), 1.97-2.14 (4H, m), 1.12-1.75 (12H, m), 0.85-1.07 (3H, m) δ (400 MHz, CDCI3) 7.64-7.67 (0.3H, m), 7.55 (0.7H, s), 7.15-7.19 (0.7H, m), 7.10 (1.3H, s), 4.70-4.79 (0.8H, m), 4.39 (1.2H, s), 4.12-4.32 (IH, m), 3.60-3.70 (1.3H, m),
520 3.37-3.44 (0.7H, m), 2.60 (0.3H, dt, J=16.5, 8.4Hz), 2.40-2.51 (1.7H, m), 2.29-2.39 (3H, m), 2.19-2.29 (2H, m), 1.99-2.17 (4H, m), 1.77-1.93 (2H, m), 1.55-1.74 (4H, m), 1.14-1.1 1 (6H, m) δ (400 MHz, CDCI3) 7.66 (0.3H, s), 7.55 (0.7H, s), 7.28-7.39 (3H, m), 4.72-4.82 (0.8H, m), 4.42 (1.2H, s), 4.15-4.32 (IH, m), 3.61-3.74 (1.2H, m), 3.33-3.43 (O. ,
521
m), 2.54-2.68 (0.6H, m), 2.33-2.54 (1.4H, m), 2.19-2.31 (2H, m), 1.98-2.19 (4H, m), 1.76- 1.95 (2H, m), 1.54- 1.71 (4H, m), 1.26- 1.18 (6H, m) δ (400 MHz, CDC13) 7.67 -7.63 (IH, m), 7.16 -7.09 (2H, m), 7.02-6.86 (2H, m), 4.84
522 (2H, s), 4.35 (2H, s), 4.16-4.30 (IH, m), 2.40-2.52 (IH, m), 2.37-2.23 (5H, m), 2.1 1-2.05 (4H, m.), 1.53-1.74 (2H, m) δ (400 MHz, DMSO-d6) 12.16 (br. s., IH) 7.75 (s, IH) 7.35-7.44 (m, 2H) 7.21-7.30
523 (m, IH) 4.25 (d, J=6.06Hz, IH) 3.35-3.44 (m, 4H) 2.86-3.00 (m, 2H) 2.24-2.41 (m, IH) 1.87-2.12 (m, 6H) 1.44-1.65 (m, 2H) 0.95 (s, 9H) δ (400 MHz, CDCI3) 7.72-7.77 (0.2H, m), 7.58 (0.8H, s), 7.22-7.38 (3H, m), 4.93 (0.4H, br. s.), 4.54 (1.6H, s), 4.25-4.17 (IH, m), 3.30-3.59 (IH, m), 2.37-2.56 (IH, m),
524
2.25 (2H, d, J=13.5Hz), 1.94-2.16 (3H, m), 1.52-1.76 (4H, m), . 1.02 (8H, s), 0.84 (IH, s) δ (400 MHz, CDCI3) 7.68 (IH, s), 7.54-7.60 (IH, m), 7.28 (3H, s), 4.66-4.81 (IH, m), 4.51-4.64 (IH, m), 4.47 (IH, s), 4.17-4.34 (IH, m), 3.36-3.57 (IH, m), 2.36-2.58 ( IH,
525 ■
m), 2.08-2.33 (4H, m), 1.53-1.80 (6H, m), 1.36-1.50 (3H, m), 1.03-1.17 (IH, m), 0.78-0.99 (6H, m) δ (400 MHz, DMSO-d6) 12.18 (br. s., IH) 7.56-7.81 (m, 5H) 7.36 (s, 2H) 7.20-7.30 (m, IH) 4.88 (s, 1.6H) 4.60 (s, 0.4H) 4.08-4.33 (m, IH) 3.50-3.66 (m, 0.4H) 3.34-3.30
526
(m, 1.6H ) 3.14-3.25 (m, 0.4H) 2.87-3.04 (m, 1.6H) 2.22-2.41 (m, IH) 1.64,2.13 (m, 4H) 1.40-1.63 (m, 2H) 1.20-1.31 (m, 2H) δ (400 MHz, CDCI3) 7.55-7.74 (m, 2H) 7.45 (d, J=8.22Hz, IH) 7.18-7.34 (m, 5H)
527 4.93 (br. s., 1H) 4.72 (d, J=2.74Hz, IH) 4.32-4.21 (m, 2H) 2.46 (t, J=12.13Hz, IH) 2.24 (d, J=13.11Hz, 2H) 2.06-2.13 (m, 5H) 1.53-1.78 (m, 2H) δ (400 MHz, CDCI3) 7.57-7.72 (3H, m), 7.48-7.55 (0.5H, m), 7.44 (0.9H, d, J=8.1Hz),
528 7.27-7.32 (IH, m), 7.10-7.17 (0.7H, m), 7.06 (0.9H, s), 4.87-5.08 (IH, m), 4.71 (IH, s), 4.13-4.34 (2H, m), 2.19-2.54 (5H, m), 1.99-2.15 (4H, m), 1.53-1.73 (4H, m) δ (400 MHz, CDCI3) 7.49 (0.2H, s), 7.44 (0.8H, s), 7.16 (0.4H, s), 7.00-7.1 1 (1.6H, m), 5.14-5.18 (0.2H, m), 5.04-5.07 (0.8H, m), 4.01-4.29 (IH, m), 3.71-3.76 (IH, m),
529
3.35-3.55 (IH, m), 3.14 (3H, s), 2.39-2.55 (IH, m), 2.20-2.34 (6H, m), 2.00-2.14 (4H, m), 1.57-1.75 (3H, m), 1.02 (8H, s), 0.81 (IH, s) δ (400 MHz, CDC13) 7.39-7.53 (IH, m), 6.97-7.19 (2H, m), 5.42-5.53 (.IH, m), 4.94-5.1 1 (0.9H, m), 4.16-4.31 (IH, m),, 4.03-4.15 (IH, m), 3.64-3.81 (IH, m),
530
3.18-3.54 (2H, m), 3.13 (3H, s), 2.37-2.52 (IH, m), 2.27 (5H, s), 2.00-2.13 (4H, m), 1.46-1.77 (2H, m), 1.01 (8H, s), 0.80 (IH, s) δ (400 MHz, CDCI3) 7.48 (0.2H, s), 7.15 (0.8H, s), 7.04 (2H, br. s.), 5.45-5.52 (0.2H, m), 5.04 (0.8H, dd, J=9.6, 4.1Hz), 4.15-4.29 (IH, m), 4.08 (IH, dd, J=14.5, 9.4Hz),
531
3.74 (IH, d, J=12.1Hz), 3.19-3.48 (2H, m), 3.12 (3H, s), 2.01-2.51 (10H, m), 1.54-1.73 (2H, m), 1.00 (8H, s), 0.79 (lH, s) δ (400 MHz, CDCI3) 7.66 (s, 0.4H), 7.57 (s, 0.6H), 7.17 (s, 0.8H). 7.10 (s, 1.2H), 4.80
532 ' (s, 0.8H), 4.42 (s, 1.2H), 4.14-4.33 (m, IH), 3.47-3.55 (m, 1.2H), 3.24-3.29 (m, 0.8H), 2.14-2.40 (m, 5H), 1.85-2.00 (m, 5H), 1.05-1.73 (m, 13H), 0.76-1.00 (m, 6H) δ (400 MHz, DMSO-d5) 7.81 (0.3H, s), 7.70 (0.7H, s), 7.45 (0.6H, s), 7.38 (1.4H, s),
533 4.77 (0.6H, s), 4.37 (1.4H, s), 4.17-4.32 (IH, m), 2.36 (0.9H,s), 2.30 (2.1H, s), 1.98-2.17 (2H, m), 1.46-1.90 (12H, m) δ (400 MHz, DMSO-d6) 0.81-1.01 (m, 7H), 1.28-1.42 (m, 2H), 1.43-1.63 (m, 4H), 1.69-1.64 (m, IH), 1.88-2.1 1 (m, 6H), 2.27-2.38 (m, IH), 2.50-2.57 (m , IH),
534 2.90-2.98 (m, IH), 3.18-3.15 (m, 3H), 3.44-3.51 (m, IH), 4.15-4.29 (m, 2H), 7.24-7.83 (m, IH), 7.41 (d, J=7.8Hz, 1.3H), 7.49 (d, J=7.8Hz, 0.7H), 7.79 (s, 0.3H), 7.86 (s, 0.7H), 12.19 (br. s, IH) δ (400 MHz, DMSO-d6) 7.82 (s, 0.2H), 7.69 (s, 0.8H), 7.47 (s, 0.4H). 7.40 (s, 1.6H),
535 4.78 (s, 0.4H), 4.59 (s, 1.6H), 4.17-4.29 (m, 1H), 3.14-3.39 (m, 2H), 2.26-2.41 (m, 4H), 1.87-2.11 (m, 6H), 1.33-1.66 (m, 7H), 0.97-1.29 (m, 5H), 0.67-0.95 (m, 6H) , δ (400 MHz, DMSO-d6) 0.67-0.87 (m, 9H), 1.45-1.63 (m, 2H), 1.73-2.14 (m, 8H), 2.15-2.38 (m, 5H), 3.87-3.99 (m, 0.5H), 4.06-4.44 (m, 2.5H), 4.58-4.88 (m, 3 H), 7.39
536
(d, J = 3.9Hz, 1H), 7.47 (d, J = 3.9Hz, 1H), 7.70 (s, 0.5H), 7.78 (s, 0.25H), 7.80 (s, 0.25H), 12.24 (br. S, 1H) δ (400 MHz, DMSO-d6) 12.17 (1H, s), 7.80 (0.3H, s), 7.68 (0.7H, s), 7.45 (0.6H, s), 7.38 (1.4H, s), 4.77 (0.6H, s), 4.37 (1.4H, s), 4.16-4.32 (1H, m), 3.07-3.37 (1H, m),
537
2.43-2.69 (1H, m), 2.24-2.38 (4H, m), 1.85-2.1 1 (6H, m), 1.45-1.76 (7H, m), 0.85- 1.27 (511, m δ (400 MHz, DMSO-d6) 12.26 (1H, s), 8.88-9.04 (1H, m), 7.10-8.22 (5H, m),
538 4.81-4.92 (2H, m), 4.29 (1H, d, J=3.5Hz), 3.36 (2H, s), 2.05-2.20 (2H, m), 1.70-1.93 (6H, m), 1.22-1.29 (3H, m), 0.78-1.03 (9H, m) δ (400 MHz, DMSO-d6) 12.19 (1H, br. s.), 8.81-9.01 (1H, m), 8.12 (1 H, dd, J=16.7,
539 8.3Hz), 6.78-8.02 (8H, m), 4.56-4.87 (4H, m), 4.18-4.33 (1H, m), 2.25-2.41 (1H, m), 1.88-2.14 (6H, m), 1.45-1.66 (2H, m) δ (400 MHz, CD3OD) 1.62-1.70 (2H, m), 2.04-2.24 (6H, m), 2.39-2.47 (1H, m),
541 4.29-4.35 (1H, m), 4.57 (2H, s), 4.62-4.69 (2H, m), 7.24 (1H, d, J=8.04Hz), 7.35-7.45 (5H, m), 7.71 (1H, s) δ (400 MHz, CD3OD) 1.02-1.08 (9H, m), 1.57-1.69 (2H, m), 2.01-2.23 (6H, m), 2.41
542 (1H, tt, J=12.23, 3.52Hz), 2.50-2.56 (3H, m), 4.26-4.35 (1H, m), 4.72 (2H, s), 7.44 (1H, s), 7.61-7.64 (1H, m) δ (500 MHz, CDC13) 7.61 (s, IH), 7.53 (s, 1), 7.24-7.27 (m, 2H), 7.17-7.20 (m, 2H),
543 7.1 1 (s, \U), 7.01-7.05 (m, 2H), 4.75 (br, s, 2H), 4.60 (s, IH), 4.54 (s, IH), 4.12-4.25 (m, 4H), 2.17-2.47 (m, 5H), 1.63-2.02 (m, 3H), 1.56-1.58 (m, 2H) δ (400 MHz, DMSO-d6) 1.89-2.06 (12H, m), 2.27-2.33 (IH, m), 2.27-2.32 (IH, m), 2.36 (IH, s), 3.29-3.34 (IH, m), 3.57 (IH, t, J=7.04Hz), 3.91-3.95 (IH, m), 4.09-4.14
544
(IH, m), 4.46 (IH, s), 4.72 (IH, s), 5.89 (IH, s), 5.97 (IH, d, J=5.67Hz), 6.06 (IH, s), 7.10 (IH, d, J=7.49Hz), 7.34-7.44 (4H, m), 7.73 (IH, s) δ (400 MHz, DMSO-d6) 12.06-12.33 (m, IH), 8.72 (s, 2H), 7.75 (s, IH), 4.71 (s, 2H),
739 4.40 (br. s., IH), 3.28 (s, 2H), 2.13 (d, J=4.11Hz, IH), 1.97 (br. s., IH), 1.91 (br. s., IH), 1.69-1.86 (m, 3H), 0.88-1.01 (m, 13H), 0.77 (s, IH)
[Example 900]
RO gamma Reporter Gene Assay
Luciferase reporter gene assay was used to assess inhibition of RORy
transcriptional activity.
ROR gamma expression vector was prepared by inserting the ligand binding domain of human ROR gamma (amino acid 247-497 of Genbank Accession NO.
NM 001001523) adjacent to the yeast GAL4 transcription factor DNA binding domain in the expression vector pM (Clontech). The resulting expression vector pM-ROR gamma was used in transfection experiments together with the pGL4 luciferase reporter plasmid (Promega) containing five copies of the UAS GAL4 recognition site and pRL-CMV , plasmids (Promega) containing the constitutive CMV promoter and the renilla luciferase.
For preparing transfection reagent/DNA mixture, 1 μg pM-ROR gamma, 1 μg pGL4 5xUAS, 625 pg pRL-CMV and 6.25 μΐ. FuGENE™ HD transfection reagent (Promega) were mixed in 0.25 mL OPTI-MEM™ (Life technologies) at room temperature. At the same time, Negative control DNA mixture was prepared by using 1 μg pM empty vector instead of pM-ROR gamma plasmid. After a fifteen minute incubation, 0.25 mL of transfection reagent/DNA mixture was added to 1,000,000 of HEK293T cells (ATCC) in 5 mL of OPTI-MEM™ containing 10% Charcoal Stripped Fetal Bovine Serum.
Transfected cells were seeded onto 384 well plate (10 μΕΛνεΙΙ) and the 7.5 nL of test compounds were added to the wells in 8 concentrations ranging from 3.5 nM to 10.5 μΜ. The compounds were dissolved in 100% DMSO and the final concentration of DMSO in the assay was 0.075%.
After 24 h of incubation at 37°C, 5% C02 in a cell culture incubator, the
Dual-Glo™ Luciferase Assay System was used to detect activity according to the manufacturer's instructions (Promega, Cat. No.: E2920). Data was plotted and pIC50 values were calculated using the XLfit program (ID Business Solutions Ltd.). The results are shown in the following tables.
example result example result example result example result
1 7.62 41 7.53 81 7.03 121 < 5.00
2 8.12 42 7.35 82 7.09 122 < 5.00
3 < 5.00 43 7.47 83 5.78 123 8.31
4 6.42 44 7.83 84 6.97 124 7.75
5 6.68 45 7.23 85 5.83 125 6.49
6 7.06 46 6.40 86 6.79 126 6.04
7 5.34 47 6.99 87 6.85 127 5.69
8 < 5.00 48 < 5.00 88 7.06 128 < 5.00
9 < 5.00 49 7.39 89 5.86 129 5.06
10 7.59 50 7.15 90 6.30 130 6.76
11 7.42 51 5.39 91 8.36 131 7.08
12 5.43 52 6.61 92 6.81 132 7.18
13 7.03 53 7.79 93 6.24 133 5.46
14 7.12 54 7.15 94 ; 8.08 13 6.61
15 7.02 55 8.05 95 6.82 135 5.51
16 6.93 56 7.81 96 7.54 136 7.08
17 7.61 57 7.42 97 6.55 137 8.32
18 7.93 58 6.87 98 < 5.00 138 8.14
19 < 5.00 59 5.23 99 6.98 139 7.76
20 7.15 60 < 5.00 100 6.63 140 6.70
21 < 5.00 61 6.70 101 7.06 141 6.27
22 < 5.00 62 < 5.00 102 7.13 142 5.18
23 7.62 63 5.47 103 5.72 143 5.65
24 6.78 64 < 5.00 104 5.69 144 7.06
25 6.58 65 < 5.00 105 6.69 145 5.46
26 6.55 66 7.08 106 6.42 146 6.83
27 7.25 67 7.25 107 5.55 147 6.46
28 6.71 68 5.88 108 6.49 148 6.32
29 7.12 69 < 5.00 109 6.20 149 7.22
30 7.33 70 < 5.00 no ; 6.79 150 7.27
31 7.11 ; 71 5.68 111 6.45 151 5.09
32 7.09 72 5.88 112 7.21 152 5.55
33 6.95 73 6.19 113 5.34 153 6.68
34 5.87 74 6.58 114 5.64 154 < 5.00
35 6.95 75 6.50 115 6.80 155 5.29
36 6.93 76 5.77 116 < 5.00 156 5.99
37 7.73 77 7.47 117 5.45 157 < 5.00
38 5.81 78 8.00 118 5.76 158 < 5.00
39 < 5.00 79 6.68 119 5.82 159 < 5.00
40 7.25 80 6.18 120 7.73 160 7.61 example result example result example result example result
161 5.66 201 < 5.00 241 8.29 281 8.37
162 5.99 202 8.10 242 7.50 282 8.47
163 < 5.00 203 6.04 243 7.26 283 8.04
164 5.93 204 7.22 244 8.16 284 7.95
165 5.93 205 6.86 245 8.05 285 -
166 7.81 206 7.00 246 7.94 286 8.04
167 6.48 207 7.20 247 7.49 287 5.92
168 6.83 208 6.52 248 7.67 288 7.93
169 7.39 209 < 5.00 249 > 8.46 289 7.03
170 6.75 210 5.99 250 > 8.46 290 6.72
171 6.78 211 7.65 251 8.22 291 5.99
172 < 5.00 212 7.70 252 8.00 292 7.32
173 < 5.00 213 6.95 253 7.34 293 7.48
174 6.18 214 6.49 254 ; 7.73 294 7.31
175 6.22 215 7.49 255 7.26 295 5.25
176 5.59 216 < 5.98 256 8.22 296 < 4.98
177 6.85 217 6.66 257 1 7.70 297 7.18
178 5.36 218 6.47 258 8.18 298 7.89
179 7.28 219 8.31 259 6.93 299 7.68
180 6.95 220 6.98 260 8.22 300 7.62
181 < 5.00 221 8.53 261 8.34 301 6.73
182 7.18 ; 222 8.38 262 7.39 302 7.83
183 6.76 223 7.30 263 8.23 303 < 5.46
184 6.79 224 8.57 264 8.09 304 < 4.98
185 5.74 225 8.53 265 7.74 305 < 4.98
186 7.57 226 8.47 266 8.27 306 8.08
187 6.65 227 8.40 267 7.87 307 5.08
188 6.56 228 6.71 268 6.97 308 7.78
189 7.52 229 7.89 269 8.09 309 7.95
190 8.08 230 8.18 270 7.79 310 < 4.98
191 8.05 231 7.97 271 8.29 311 < 4.98
192 7.93 232 7.77 272 7.95 312 7.28
193 8.19 233 7.80 273 7.85 313 5.81
194 7.85 234 8.00 274 8.08 314 7.38
195 < 5.00 235 7.88 275 > 8.46 315 7.26
196 5.46 236 7.98 276 6.91 316 8.04
197 6.29 237 > 8.46 277 8.14 317 8.00
198 < 5.00 238 8.36 278 7.93 318 7.70
199 8.30 239 > 8.46 279 7.42 319 6.85
200 7.80 240 8.26 280 6.61 320 8.01 example result example result example result
321 7.93 361 5.92 401 5.55
322 8.09 362 7.24 402 4.98
323 6.42 363 7.88 403 5.76
324 6.42 364 7.34 404 7.65
325 7.97 365 7.51 405 4.98
326 6.99 366 7.82 406 7.30
327 7.01 367 7.52 407 6.32
328 5.53 368 6.72 408 6.48
329 7.83 369 5.91 409 6.11
330 7.62 ; 370 6.27 410 5.67
331 6.99 371 5.27 411 6.65
332 6.29 372 6.48 412 5.95
333 7.77 ; 373 5.47
334 7.25 374 6.18
335 7.91 375 6.97
336 6.84 . 376 6.51
337 7.20 377 6.36
338 6.26 378 7.13
339 7.08 379 7.10
340 6.91 380 7.08
341 6.12 381 7.00
342 7.34 382 6.59
343 7.50 383 7.40
344 5.80 384 6.46
345 7.58 : 385 7.73
346 6.96 386 6.85
347 6.06 387 7.16
348 6.81 388 7.14
349 7.10 389 7.53
350 5.94 390 6.48
351 5.14 391 6.85
352 5.39 392 7.54
353 6.75 393 5.34
354 6.29 394 7.69
355 7.66 395 7.04
356 6.99 396 6.05
357 5.00 397 7.21
358 7.21 398 6.17
359 7.58 399 7.06
360 C b. "/7bC /inUnU " 17.DHA. [Example 901]
ROR gamma Coactivator Peptide Recruitment Alphascreen™ Assay
Alphascreen™ is a bead-based amplified homogenous luminescent proximity assay that can be used for measuring the effect of compounds on protein-protein interactions. When biological interactions bring donor and acceptor beads into close proximity, reactive oxygen, generated upon laser excitation of the donor beads, initiates a luminescence/fluorescence cascade in the acceptor beads that leads to a highly amplified signal that can be measured as light in the 520-620 nm range. When the acceptor and donor beads are not in proximity, the reactive oxygen decays and only a very low background signal is generated.
An in vitro assay to assess inhibition of RORy binding to the coactivator GRIP1 was established using Alphascreen™ technology. The interaction between nuclear receptors (NR) and coactivator proteins is a key step in signal transduction from the receptor to the transcriptional machinery and can be measured in vitro using only the ligand binding domain of the nuclear receptor and a peptide containing a coactivator protein LXXLL nuclear receptor binding motif.
For the RORy construct used in the coactivator recruitment assay, nucleotides corresponding to the ligand binding domain (LBD) of wild type human RORy (amino acids 262-518 of Genbank Accession No. NM_005060.3) were cloned into the pET24 expression vector (Novagen), downstream of in-frame N-termihal 6xHis and Flag tag sequences. Recombinant 6xHis:Flag-tagged human RORy-LBD protein was expressed in E.coli (BL-21) and purified by affinity chromatography on a nickel Sepharose column, followed by anion exchange chromatography.
A 4x assay mixture of 6xHis:Flag-tagged human RORy-LBD with the agonist ligand 7-P-hydroxycholesterol was prepared in assay buffer (50 mM HEPES pH 7.4, BSA 0.05%, 150 n M NaCl, 5 niM MgC12, 1 mM DTT, 0.01% Tween-20). For control wells a 4x mixture of 6xHis:Flag-tagged human ROR gamma LBD alone was also prepared.
A 4x stock of biotinylated coactivator peptide containing the LXXLL motif from GRIP1 (Biotin-PKKKQNALLRYLLDKDDTKDI) was prepared in assay buffer.
A 4x detection mixture of nickel chelate Alphascreen™ acceptor beads
(PerkinElmer) and streptavidin Alphascreen™ donor beads (PerkinElmer) was prepared in assay buffer.
Compounds to be tested were arranged in a pre-dose 384-well mother plate serially diluted 1 in 2 over 22 columns, in 100% DMSO, at 40x the final test concentration, from a high concentration of 4 mM. DMSO with no compound was placed in control columns. The compounds were robotically dispensed directly into assay plates containing assay buffer to a 4x final test concentration.
Following compound addition, the 6xHis:Flag-tagged human RORy-LBD plus 7-P-hydroxycholesterol assay mixture, biotinylated coactivator peptide and detection mixture were added. Final assay conditions were 5nM 6xHis: Flag-tagged human
RORy-LBD, 30 nM 7-P-hydroxycholesterol, 50nM biotinylated coactivator peptide, 2.5 ug/ml nickel acceptor beads and 10 ug/ml streptavidin donor beads. The final concentration of DMSO in the assay was 2.5%.
After overnight incubation at room temperature plates were read on and
Envision™ plate reader (PerkinElmer).
Data was plotted and pIC50 values were calculated using the Genedata Screener™ data analysis suite (Genedata). The results are shown in the following tables. example result example result example result example result
500 7.82 539 7.05 579 8.37 618 7.98
501 8.42 541 8.50 580 8.30 619 8.11
502 6.56 542 7.10 581 8.46 620 7.41
503 6.45 543 8.48 582 7.64 621 6.52
504 8.16 544 5.44 583 8.62 622 6.64
505 8.23 545 8.31 584 8.24 623 7.07
506 7.16 546 7.95 585 7.16 624 6.99
507 7.49 547 7.71 586 6.48 625 8.13
508 6.12 548 7.93 587 7.17 626 8.55
509 7.94 549 8.76 588 8.48 627 7.19
510 8.75 550 7.67 589 7.37 628 7.57
511 8.73 552 6.48 590 6.76 629 7.34
512 8.14 553 8.56 591 8.68 630 8.40
513 7.48 554 8.15 592 8.17 631 8.00
514 8.72 555 - 593 7.48 632 8.40
515 8.33 556 8.62 594 7.13 633 8.09
516 8.22 557 8.55 595 8.25 634 6.06
517 7.60 558 8.61 596 6.82 635 6.49
518 8.58 559 8.15 597 5.62 636 6.88
519 8.29 560 6.53 598 6.94 637 6.14
520 8.60 561 - 599 7.86 638 7.81
521 8.73 562 8.43 600 6.10 639 7.24
522 8.68 563 6.69 601 7.37 640 6.11
523 8.06 564 8.38 602 6.76 641 8.67
524 7.11 565 7.74 603 7.31 642 7.62
525 8.23 566 8.51 604 5.18 643 8.37
526 8.23 567 8.62 605 6.82 644 8.40
527 8.08 568 8.47 606 8.35 645 7.86
528 8.38 569 5.17 607 6.98 646 6.53
529 7.20 570 7.73 608 6.91 647 6.44
530 7.29 571 8.90 609 7.02 648 7.49
531 5.97 572 8.33 610 7.91 649 8.74
532 8.13 573 7.10 611 8.22 650 8.10
533 8.83 574 5.59 612 7.40 651 7.27
534 8.10 575 7.77 613 6.96 652 8.36
535 8.88 576 7.46 614 7.27 653 7.15
536 8.02 577 7.93 615 7.31 654 6.45
537 8.65 578 7.00 616 7.47 655 7.57
538 6.95 617 6.93 656 6.73 example result example result example result example result
657 8.65 696 8.79 735 8.56 774 7.66
658 8.71 697 7.89 736 6.96 775 8.52
659 6.48 698 8.68 737 7.85 776 7.66
660 7.59 699 7.40 738 7.87 777 8.37
661 7.69 700 7.88 739 8.24 778 8.35
662 8.15 701 8.03 740 7.84 779 7.74
663 8.71 702 8.10 741 8.83 780 8.12
664 8.84 703 7.15 742 8.58 781 8.81
665 8.86 704 8.61 743 8.65 782 8.40
666 8.34 705 7.23 744 9.23 783 8.41
667 6.52 706 7.49 745 9.00 784 7.46
668 8.46 707 8.21 746 7.49 785 8.40
669 8.39 708 7.97 747 8.40 786 7.46
670 7.66 709 9.05 748 8.47 787 8.68
671 9.06 710 7.56 749 7.22 788 7.76
672 8.69 711 8.69 750 8.80 789 8.68
673 7.44 712 7.89 751 8.03 790 7.46
674 7.75 713 8.39 752 8.32 791 8.28
675 6.63 714 8.45 753 7.60 792 6.99
676 7.29 715 7.98 754 8.16 793 7.60
677 8.25 716 8.57 755 8.63 794 8.53
678 8.97 717 8.68 756 8.59 795 -
679 7.92 718 8.76 757 8.10 796 4.74
680 7.32 719 8.22 758 8.45 797 -
681 8.02 720 7.13 759 8.43 798 8.50
682 7.30 721 9.08 760 8.62 799 8.41
683 8.05 722 8.02 761 8.10 800 8.52
684 7.86 723 8.00 762 8.27 801 8.07
685 7.01 724 8.22 763 8.79 802 8.52
686 7.04 725 8.35 764 8.36 803 7.20
687 7.83 726 8.56 765 6.61 804 7.27
688 6.96 727 7.93 766 7.49 805 7.95
689 8.38 728 8.32 767 6.43 806 6.99
690 8.17 729 8.62 768 8.40 807 7.34
691 8.78 730 8.45 769 7.73 808 6.73
692 8.49 731 9.03 770 7.37 809 7.75
693 7.36 732 8.04 771 8.20 810 8.51
694 8.40 733 8.60 772 8\43 811 8.75
695 8.00 734 8.00 773 7.09 812 8.03
Figure imgf000534_0001

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000535_0001
wherein:
R1 is selected from F, CI, Br, a d to C6 alkyl group substituted by 0, 1 , 2 or 3 Ra groups and a C3 to C8 cycloalkyl group substituted by 0, 1 , 2 or 3 Ra groups;
Y is selected from a C4 to C6 cycloalkyl group, a C6 to C9 bicycloalkyl group and a C6 to
2 6
C9 spiroalkyl group, all of which are substituted by a R group, 0 or 1 R group and 0, 1 , 2 or 3 R7 groups;
R2 is selected from -OH, -C02H, -S03H, -CONH2, -S02NH2, a (Q to C6 alkoxy)carbonyl group substituted by 0, 1 , 2 or 3 Rc groups, a (C\ to C alkyl)aminocarbonyl group substituted by 0, 1 , 2 or 3 Rc groups, a Q to C6 alkylsulfonyl group substituted by 0, 1 , 2 or 3 Rc groups, a C\ to C6 alkylaminosulfonyl group substituted by 0, 1 , 2 or 3 Rc groups, a (hydroxycarbonylXd to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups, a (C\ to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups, a (Ci to C6 alkyl)sulfonyl(C! to C3 alkyl) group substituted by 0, 1 , 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C! to C3 alkyl) group substituted by 0, 1, 2 or 3 R° groups;
R6 and R7 are independently selected from H, F, -OH, -NH2, -CN, a Ci to C6 alkyl group substituted by 0, 1 , 2 or 3 R groups. and a C\ to C alkoxy group substituted by 0, 1 , 2 or 3 Rb groups; RJ is selected from H, F, CI, -CH3 and -CF3;
R4 is selected from a Ci to C6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C2 to C6 alkenyl)(d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynyl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C1.to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(d to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(Ci to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to C cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C3 to Cg cycloalkenyl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a 3- to 8-membered heterocycloalkyl group substituted by O, 1 , 2, 3, 4 or 5 Rg groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C5 to C9 bicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkylXCi to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups; ·
R5 is selected from a C6 to Ci0 aryl group substituted by 0, 1 , 2, 3, 4 or 5 R1 groups, a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R1 groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5RJ groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5RJ groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 RJ groups; R8 and R9 are independently selected from H, F, -OH, -NH2, a C\ to C3 alkyl group substituted by 0, 1 , 2 or 3 Rh groups, and a Ci to C6 alkoxy group substituted by 0, 1 , 2 or 3 R groups; or R and R together form an oxo group or a thioxo group;
R12 is H; or R4 and R12 together are -CRmRm-CR13R14-CRmRm- or -CR13R14-CRmRm- CRmRm- to form a pyrrolidine ring;
R13 is selected from H, a Ci to C6 alkyl group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a C6 to C[o aryl group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C6 to C10 aryloxy group substituted by 0, 1 , 2, 3, 4 or 5 R groups,a (C2 to C6 alkenyl)(C! to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C alkynylXQ to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (Cj to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(d to C3 alkyl) group
substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (5- to 10-membered heteroarylXQ to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C3 to C8 cycloalkenyl group substituted by 0, 1 , 2, 3, 4 or 5 R groups, a (C3 to C8 cycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a (C3 to C8 cycloalkenyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rs groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a (C6 to C9 spiroalkyl)(C! to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9
bicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(d to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups; R is independently selected from H and a C\ to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups; or R13 and R14 together form a C3 to C8 cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups, C3 to C8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups; Rm is independently selected from H, F, CI, -CH3 and -CF3;
Rg and Rj are , independently selected from F, CI, a C\ to C6 alkyl group, -OH, -CN, -NH2, -N02, -C02H, a Ci to C6 alkoxy group, a mono(Ci to C6 alkyl)amino group, a di(C! to C6 alkyl)amino group, -CF3, a Ci to C6 alkylene group substituted by 0, 1, 2 or 3 R1 groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 R1 groups and an oxo group;
Rf and R' are are independently selected from F, CI, Br, -OH, -CN, -N02, -C02H, a Q to C6 alkyl group substituted by 0, 1 , 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a Ci to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkyloxy group substituted by 0, 1, 2 or 3 Rk groups, -SH, a Q to C6 alkylthio group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkylthio group substituted by 0, 1, 2 or 3 Rk groups, a (d to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Ci to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (Q to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 R groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1 , 2 or 3 R groups, a d to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rk groups, -NH2, a mono(Ci to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups and a di(Cj to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups; and
Ra, Rb, Rc, Re, Rh, Rk and R1 are independently selected from F, a Ci to C4 alkyl group, -OH, -CN, -N02, -NH2, -C02H, a C\ to C6 alkoxy group, a mono(Ci to C6 alkyl)amino group, a di(C[ to C6 alkyl)amino group, -CF3 and an oxo group.
2. The compound according to claim 1 or pharmaceutically acceptable salt thereof, wherein Y is selected from formula Il-a), formula (Il-b), formula (II-c) and formula (Il-d):
Figure imgf000539_0001
wherein:
k is 0, 1 or 2;
and n is 1, 2 or 3.
3. The compound according to claim 2 or pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula (Il-a):
Figure imgf000539_0002
4. The compound according to claim 2 or pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula (Il-d):
Figure imgf000539_0003
(II-d)
and n is 2.
5. The compound according to any one of claims 1 to 4 or pharmaceutically acceptable salt thereof, wherein R is H.
6. The compound according to any one of claims 1 to 5 or pharmaceutically acceptable salt thereof, wherein R is -C02H or a hydroxycarbonylmethyl group substituted by 0, 1 or 2 Rc groups.
7. The compound according to any one of claims 1 to 6 or pharmaceutically acceptable salt thereof, wherein R12 is H.
8. The compound according to any one of claims 1 to 7 or pharmaceutically acceptable
o n S O
salt thereof, wherein R and R together form an oxo group or both R and R are H.
9. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt thereof, wherein R1 is -CF3, -CF2H or CI.
10. The compound according to any one of claims 1 to 9 or pharmaceutically acceptable salt thereof, wherein R5 is a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 R1 groups or a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 R' groups.
,
11. The compound according to any one of claims 1 to 10 or pharmaceutically acceptable salt thereof, wherein R4 is a C\ to C6 alkyl group substituted by 0, 1, 2 or 3 Re groups, a (C6 to C10 aryl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R groups, a C3 to C8 cycloalkyl group substituted by 0, 1 , 2, 3, 4 or 5 R8 groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a (C6 to C9 spiroalkyl) (d to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 R8 groups, a (C5 to C9 bicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 R8 groups or a (C6 to C9 heterobicycloalkyl)(Ci to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
12. A method of treating or preventing a disease using a compound according to any one of claims 1 to 11 or pharmaceutically acceptable salt thereof, wherein the disease is multiple sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic
erythematodes, psoriasis, psoriatic arthritis, inflammatory bowel disease or asthma.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or pharmaceutically acceptable salt thereof.
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US10633375B2 (en) 2016-08-31 2020-04-28 Jinagsu Hengrui Medicine Co., Ltd Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof
US11084808B2 (en) 2016-08-31 2021-08-10 Jiangsu Hengrui Medicine Co., Ltd. Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof
JP2019535784A (en) * 2016-12-15 2019-12-12 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Process for preparing BTK inhibitors
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AU2018332501B2 (en) * 2017-09-13 2023-09-21 Atrogi Ab Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia
CN115108980A (en) * 2022-06-22 2022-09-27 济南大学 Preparation method of 4-bit acylated derivative of 2-methylquinoline compound

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