NZ723766B2 - Pyrazole amide derivative - Google Patents

Pyrazole amide derivative

Info

Publication number
NZ723766B2
NZ723766B2 NZ723766A NZ72376615A NZ723766B2 NZ 723766 B2 NZ723766 B2 NZ 723766B2 NZ 723766 A NZ723766 A NZ 723766A NZ 72376615 A NZ72376615 A NZ 72376615A NZ 723766 B2 NZ723766 B2 NZ 723766B2
Authority
NZ
New Zealand
Prior art keywords
carbamoyl
trifluoromethyl
pyrazolyl
trans
oxoethyl
Prior art date
Application number
NZ723766A
Other versions
NZ723766A (en
Inventor
Hilary Plake Beck
Shon Keith Booker
Howard Bregman
Victor J Cee
Nagasree Chakka
Timothy D Cushing
Oleg Epstein
Brian M Fox
Meyer Stephanie Geuns
Xiaolin Hao
Original Assignee
Teijin Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teijin Pharma Limited filed Critical Teijin Pharma Limited
Priority claimed from PCT/JP2015/056584 external-priority patent/WO2015129926A1/en
Publication of NZ723766A publication Critical patent/NZ723766A/en
Publication of NZ723766B2 publication Critical patent/NZ723766B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Ā -Ā C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Ā -Ā C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Abstract

The present invention relates to compounds of formula (I) having a function of inhibiting RORĪ³ 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. eases, or cancer diseases.

Description

The present invention relates to compounds of formula (I) having a function of ting RORĪ³ 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, lic diseases, or cancer diseases.
NZ 723766 DESCRIPTION PYRAZOLE AMIDE DERIVATIVE Technical Field The present invention relates to novel compounds that modulate RORĪ³ activity, pharmaceutical composition, and use in treatment or prevention of autoimmune diseases, inflammatory diseases, lic diseases, or cancer diseases.
Background Art Retinoid-related orphan receptor gamma (RORĪ³) is a nuclear receptor that binds to DNA and regulates transcription (NPL 1). Two isoforms of RORĪ³ that differ only in the N- terminus are generated from the RORC gene; RORĪ³1 and RORĪ³t (also referred to as RORĪ³2) (NPL 2). RORĪ³ is used as a term to describe both isoforms of RORĪ³1 and RORĪ³t.
RORĪ³1 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 ts against high fat diet induced insulin resistance. Consequently, by inhibiting the function of RORĪ³1, insulin ance could be improved.
RORĪ³t is expressed ively in cells of the immune system (NPLs 4 and 5) and is a master regulator of a Th17 cell-related transcriptional network associated with autoimmune pathology. Th17 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 flammatory cytokine IL-17A. Th17 cells also express CCR6, which mediates ion to sites of inflammation, are maintained and expanded by IL- 23, through the IL-23 or (IL23R), and express other pro-inflammatory cytokines and ines, including IL- 17F, IL-21, IL-22, CCL20 and GM-CSF, which er promote recruitment of other inflammatory cell types, especially neutrophils, to mediate pathology at the target tissue. RORĪ³t is required for the differentiation of Th17 cells and directly and indirectly regulates expression of many of these pro-inflammatory mediators (NPL 6). RORĪ³-deficient mice have significantly reduced numbers of Th17 cells in vivo, lack the ability to produce IL-17A and other Th17-related cytokines ex vivo, and show resistance to ion of various e models such as EAE, dermatitis, enteritis and nephritis (NPLs 6, and 12 to 14). Therefore, by inhibiting the function of RORĪ³, development of various autoimmune diseases and inflammatory diseases, in which the Th17 cell-related cytokines are involved, could be suppressed. rmore, expression of RORĪ³t and the consequent expression of the Th17 elated transcriptional network has been observed in other immune cell types that may also be important in disease pathogenesis, namely CD8+ T cells, so called Tc17s, Ī³Ī“ T cells, natural killer T cells, innate lymphoid cells, natural killer cells, and mast cells (NPLs 7 and 8).
Th17 cell-related cytokines and chemokines have been implicated in the pathogenesis of various human autoimmune and matory diseases including multiple sis, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, cystic is, asthma, chronic obstructive pulmonary disease, emphysema, lung fibrosis, systemic erythematodes, vasculitis, Wegener granuloma, polymyalgia rheumatica, giant cell arteritis, arteriosclerosis, autoimmune myositis, uveitis, dry eye, matory bowel disease, alcoholinduced hepatitis, non-alcoholic hepatitis, primary biliary cirrhosis, viral hepatitis and type 1 diabetes.
(NPLs 9 to 11).
RORĪ³t is known to possess an inhibitory effect on the umorigenic activity of Th9 cells, a subtype of helper T cells (NPL 15). In the RORĪ³-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 RORĪ³, the function of Th9 cells is activated and formation of melanoma and other malignant tumors can be suppressed.
From the evidence described above, a RORĪ³ modulator can be expected to show therapeutic or preventive benefit in treatment of; metabolic diseases such as diabetes; for autoimmune diseases or matory diseases and; for melanoma and other cancer diseases.
Citation List Non Patent Literature NPL 1: Gigure, Endocrine. Reviews. 20: 689-725, 1999 NPL 2: , Nucl. . Signal. 7: e003, 2009 NPL 3: Meissburger et al., EMBO Mol. Med. 3: 637- 651, 2011 NPL 4: Hirose et al., m. Biophys. Res. Commun. : 1976-1983, 1994 NPL 5: Eberl and Littman., 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, NPL 9: Miossec et al., Nature Reviews Drug Discovery 11: 763-776,2012 NPL 10: ich 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 . 122: 2252-2256, 2012 NPL 13: Buonocore et al., Nature 464: 1371-1375, NPL 14: Steinmetz et al., J. Am. Soc. Nephrol. 22: 472-483, 2011 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 RORĪ³ activity; and/or to at least provide the public with a useful choice.
Solution to Problem The present inventors conducted diligent research in order to achieve the above-described object and, as a result, found a novel nd represented by formula (I) or a ceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof having a function of inhibiting RORĪ³ activity. That is, the t invention provides as follows. (1) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: R1 is selected from F, Cl, Br, a C1 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 lkyl 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, -CO2H, -SO3H, -CONH2, -SO2NH2, a (C1 to C6 alkoxy)carbonyl group tuted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 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 (C1 to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)sulfonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups; R6 and R7 are independently ed from H, F, -OH, -NH2, -CN, a C1 to C6 alkyl group tuted by 0, 1, 2 or 3 Rb groups and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rb groups; R3 is selected from H, F, Cl, -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)(C1 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 (C1 to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re , a (C6 to C10 aryl)(C1 to C3 alkyl) group tuted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 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 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)(C1 to C3 alkyl) group tuted 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 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 bicycloalkyl)(C1 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 , and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; R5 is ed from a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 Ri groups, a 5- to 10-membered aryl group substituted by 0, 1, 2, 3, or 4 Ri groups, a C3 to C8 cycloalkyl group tuted 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 C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh groups, and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rh ; or R8 and R9 er 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 C1 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 Rf groups, a C6 to C10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 Rf groups,a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 l)(C1 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 cycloalkyl group tuted 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)(C1 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 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 , 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 C9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or Rg groups, and a (C6 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg ; R14 is independently selected from H and a C1 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 lkene ring tuted 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 ; Rm is independently selected from H, F, Cl, -CH3 and -CF3; Rg and Rj are , independently selected from F, Cl, a C1 to C6 alkyl group, -OH, -CN, -NH2, -NO2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3, a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 Rl groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 Rl groups and an oxo group; Rf and Ri are are independently selected from F, Cl, Br, - OH, -CN, -NO2, -CO2H, a C1 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 C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 lkyloxy group substituted by 0, 1, 2 or 3 Rk groups, -SH, a C1 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 (C1 to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 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 C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rk groups, -NH2, a 1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups and a di(C1 to C6 alkyl)amino group tuted by 0, 1, 2 or 3 Rk groups; and Ra, Rb, Rc, Re, Rh, Rk and Rl are independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, - CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 amino group, -CF3 and an oxo group. (2) The compound according to section 1 or pharmaceutically acceptable salt thereof, wherein Y is selected from formula , formula (II-b), formula (II-c) and formula (II-d): (II-a), (II-b), (II-c) or , 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 (II-a): . (4) The compound according to section 2 or pharmaceutically acceptable salt f, wherein Y is a group represented by a (II-d): (II-d) and n is 2. (5) The compound ing to any one of sections 1 to 4 or pharmaceutically acceptable salt thereof, wherein R3 is (6) The compound according to any one of sections 1 to 5 or pharmaceutically acceptable salt f, wherein R2 is -CO2H or a ycarbonylmethyl 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 R12 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 nd according to any one of sections 1 to 8 or pharmaceutically acceptable salt thereof, wherein R1 is -CF3, -CF2H or Cl. (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 Ri groups or a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 Ri groups. (11) The compound according to any one of sections 1 to or pharmaceutically acceptable salt thereof, wherein R4 is a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Re groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 lkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg , 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 spiroalkyl)(C1 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups or a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups. (12) Use of a compound according to any one of sections 1 to 11 or pharmaceutically acceptable salt thereof, in the manufacture of a ment for treating or ting a e, 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 ing to any one of sections 1 to 11 or ceutically acceptable salt thereof.
Also described is a method of treating or preventing a e using a nd 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, matory bowel disease or asthma.
Certain statements that appear below are broader than what appears in the statements of the invention above.
These statements are provided in the interests of providing the reader with a better understanding of the invention and its practice. The reader is directed to the accompanying claim set which s the scope of the invention.
Advantageous Effects of Invention The present invention provides a novel compound having excellent ty of inhibiting RORĪ³ and a method for producing the same. Further, the compound of the present invention or a ceutically acceptable salt thereof is useful as a therapeutic agent or a preventive agent for autoimmune es, 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 es (especially malignant melanoma), or the like.
Description of Embodiments In the following, terms used either independently or in ation in the present ption will be explained. Unless particularly described, explanation of each substituent shall be common to each position. In on, when any variable substituent (for example, Rj and the like) is present in respective arbitrary constituent elements (for e, Rf, Ri, 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 ally 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 t 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 cycloalkyl)(C1 to C3 alkyl) group" in R4 is represented by group wherein "a C1 to C3 alkyl group" is bonded to nitrogen in a (I) and "a C3 to C8 cycloalkyl group" and "a C1 to C3 alkyl group" are bonded.
Additionally, the number situated to the right of carbon indicates the number of the carbon. For example, "C1 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 C1 to C4 alkyl group" means alkyl groups having 1 to 4 carbon among those defined by "C1 to C4 alkyl group". Treatment of the number of carbons in other groups is the same.
In the present invention, "a C1 to C6 alkyl group" means a saturated linear or branched aliphatic arbon group having 1 to 6 carbons. For example, there may be mentioned a methyl group, an ethyl group, a yl group, a l group, a n-pentyl group, a nhexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl 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 methylbutyl 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 C1 to C4 alkyl group" means a saturated linear or branched aliphatic arbon 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 tyl 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 ion, "a C1 to C3 alkyl group" means a ted linear or branched aliphatic hydrocarbon group having 1 to 3 s. For example, there may be mentioned a methyl group, an ethyl group, a yl 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-methylpropenyl group, a 2-methylpropenyl group, a nyl group, a 3-butenyl group, a 2-pentenyl group, a 3-penten- 1-yl group, a 4-pentenyl group, a 5-hexenyl group, a 4-hexenyl group, a 3-hexenyl group, a 2-hexen yl group, a 3-methylbutenyl group, a 3-methyl pentenyl group, a 3-methylpentenyl group, a 4- methylpentenyl group, a 4-methylpentenyl group, a 2-methylpentenyl group, and the like.
In the present ion, "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-propynyl group, a 2-propynyl group, a 2-butyn yl group, a 3-butynyl group, a 2-pentynyl group, a ynyl group, a 4-pentynyl group, a 5-hexyn yl group, a 4-hexynyl group, a 3-hexynyl group, a 2-hexynyl group, and the like.
In the t invention, "a C1 to C6 alkylene group" means a bivalent group formed by removing hydrogen from "a C1 to C6 alkyl group". For example, there may be mentioned methylene, ethylene, propylene, butylene, ene, hexylene, and the like. The C1 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 ned vinylene, propenylene, 1-butenylene, 2- butenylene, 1-pentenyene, 2-pentenyene, 1-hexenyene, 2- ene, 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 ned a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
In the present ion, "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 o[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-1H-indenyl group, a bicyclo[3.2.2]nonanyl group, a o[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[1.1.1]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 o[4.2.0]octanyl group, a bicyclo[4.1.1]octanyl group, a bicyclo[5.1.0]octanyl group, an octahydro-1H-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 t invention, "spiroalkyl group" means a group consisting of two lkyl moieties that have exactly one atom in common. "A C6 to C9 spiroalkyl group" means a lkyl group having 6 to 9 carbons. For e, 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 group, 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)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a (C6 to C9 spiroalkyl) group" at arbitrary position. For e, 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 ary 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 entenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, and the like.
In the present invention, "a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 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 cycloalkenyl)(C1 to C3 alkyl) group" means a group obtained by tuting "a C1 to C3 alkyl group" with "a C3 to C8 cycloalkenyl group" at arbitrary position. For example, there may be mentioned a cyclopropenylmethyl group, a cyclopropenylethyl 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 ion, "a (C2 to C6 l)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a C2 to C6 alkenyl group" at arbitrary position. For example, there may be mentioned a enyl group, an 1-methylpropenyl group, a 2- methylpropenyl group, a 2-butenyl group, a 3-buten- 1-yl group, a 2-pentenyl group, a 3-pentenyl group, a 4-penytenyl group, a 5-hexenyl group, a 4-hexen- 1-yl group, a 3-hexenyl group, a 2-hexenyl group, an 1-methylbutenyl group, an 1-ethylbutenyl group, a 2-methylbutenyl group, a 3-methylbuten- 1-yl group, a ylpentenyl group, a 3-methyl pentenyl group, a 3-ethylpentenyl group, a 4- methylpentenyl group, a 4-methylpentenyl group, a 2-methylpentenyl group, and the like.
In the present invention, "a (C2 to C6 l)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a C2 to C6 alkynyl group" at arbitrary position. For example, there may be mentioned a 2-propynyl group, an 1-methylpropynyl group, an lpropynyl group, a 2-butynyl group, an 1-methylbutynyl group, an 1-ethylbutynyl group, a 3-butynyl group, an 1-methylbutynyl group, an 1-ethylbutynyl group, a 2-pentynyl group, an 1-methylpentynyl group, a 3-pentynyl group, an ylpentynyl group, a 4-pentynyl group, a 5-hexynyl group, a 4-hexynyl group, a 3- hexynyl group, a 2-hexynyl group, and the like.
In the present invention, "a C1 to C6 alkoxy group" means a group obtained by substituting an oxy group with "a C1 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 oxy 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 (C1 to C6 alkoxy)(C2 to C4 alkyl)" means a group obtained by substituting "a C2 to C4 alkyl group" with "a C1 to C6 alkoxy group" or, in other words, a group obtained by replacing one carbon of a C4 to C11 alkyl group with one oxygen at arbitrary ally possible on. For example, there may be mentioned a methoxyethyl group, an ethoxyethyl group, a oxyethyl 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-ethylpropyloxyethyl group, an 1,1-dimethylpropyloxyethyl group, an 1,2- dimethylpropyloxyethyl group, a neopentyloxyethyl group, a xyethyl group, a 4-methylpentyloxyethyl group, a 3-methylpentyloxyethyl group, a ylpentyloxyethyl group, an ylpentyloxyethyl group, a 3,3- dimethylbutyloxyethyl group, a 2,2-dimethylbutyloxyethyl group, an 1,1-dimethylbutyloxyethyl 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 secbutyloxypropyl group, a tert-butyloxypropyl group, an isopentyloxypropyl group, a 2-methylbutyloxypropyl group, a 3-methylbutyloxypropyl group, an lpropyloxypropyl group, an 1,1-dimethylpropyloxypropyl group, an 1,2- dimethylpropyloxypropyl group, a neopentyloxypropyl group, a xypropyl 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 lbutyloxypropyl 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 ylpentyloxybutyl group, a ylpentyloxybutyl group, an 1-methylpentyloxybutyl group, a 3,3- dimethylbutyloxybutyl group, a methylbutyloxybutyl 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 C1 to C6 alkylthio group" means a group obtained by substituting a thio group with "a C1 to C6 alkyl group". For example, there may be mentioned a thio group, an hio 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 . 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 (C1 to C6 alkyl)carbonyl group" means a group obtained by substituting a yl group with "a C1 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 (C1 to C6 alkoxy)carbonyl group" means a group obtained by substituting a carbonyl group with "a C1 to C6 alkoxy group". For example, there may be mentioned a methoxycarbonyl group, an ethoxycarbonyl group, a npropoxycarbonyl group, an isopropoxycarbonyl group, a nbutoxycarbonyl group, an isobutoxycarbonyl group, a secbutoxycarbonyl group, a tert-butoxycarbonyl group, a n- pentoxycarbonyl group, an isopentoxycarbonyl group, a 2- methylbutoxycarbonyl group, a 3-methylbutoxycarbonyl group, an 1-ethylpropoxycarbonyl group, an 1,1- dimethylpropoxycarbonyl group, an 1,2- dimethylpropoxycarbonyl group, a toxycarbonyl group, a 4-methylpentoxycarbonyl group, a 3- pentoxycarbonyl, a 2-methylpentoxycarbonyl group, an 1-methylpentoxycarbonyl group, a 3,3- ylbutoxycarbonyl group, a 2,2- dimethylbutoxycarbonyl group, an 1,1- dimethylbutoxycarbonyl group, an 1,2- ylbutoxycarbonyl group, an 1,3- ylbutoxycarbonyl 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(C1 to C6 alkyl)amino group" means a group obtained by substituting an amino group with "a C1 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 secbutylamino group, a tert-butylamino group, a pentylamino group, a hexylamino group, and the like.
In the present ion, "a di(C1 to C6 alkyl)amino group" means a group obtained by substituting an amino group with two of the same or different "a C1 to C6 alkyl group". For e, there may be mentioned a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, a di(secbutyl )amino group, a di(tert-butyl)amino group, a dipentylamino group, a dihexylamino group, and the like.
In the present invention, "a (C1 to C6 alkyl)aminocarbonyl group" means a group obtained by substituting a carbonyl group with "a (C1 to C6 alkyl)amino group". For example, there may be mentioned a aminocarbonyl group, an minocarbonyl group, a propylaminocarbonyl group, an pylaminocarbonyl group, a butylaminocarbonyl group, an isobutylaminocarbonyl group, a tylaminocarbonyl group, a tert-butylaminocarbonyl group, a pentylaminocarbonyl group, a hexylaminocarbonyl group, and the like.
In the t invention, "a C1 to C6 alkylsulfonyl group" means a group obtained by substituting a sulfonyl group with "a C1 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 C1 to C6 alkylaminosulfonyl group" means a group obtained by substituting a yl group with "a mono(C1 to C6 alkyl)amino group". For example, there may be mentioned a methylaminosulfonyl group, an ethylaminosulfonyl group, a aminosulfonyl group, an isopropylaminosulfonyl group, a butylaminosulfonyl group, an isobutylaminosulfonyl group, a sec-butylaminosulfonyl group, a tert-butylaminosulfonyl group, a pentylaminosulfonyl group, a minosulfonyl group, and the like.
In the present invention, "a (hydroxycarbonyl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a (hydroxycarbonyl) group" at ary position. For example, there may be mentioned a hydroxycarbonylmethyl group, a (1-hydroxycarbonyl)ethyl group, a (2-hydroxycarbonyl)ethyl group, a (3- hydroxycarbonyl)propyl group, an a (2- hydroxycarbonyl)propyl group, a roxycarbonyl)propyl group, a (1-hydroxycarbonyl)(1-methyl)ethyl group, and the like.
In the present invention, "a (C1 to C6 alkoxy)carbonyl(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a (C1 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 (1-methoxycarbonyl)propyl group, a hoxycarbonyl)(1-methyl)ethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group, an (3-ethoxycarbonyl)propyl group, an (2- ethoxycarbonyl)propyl group, an (1-ethoxycarbonyl)propyl group, an (1-ethoxycarbonyl)(1-methyl)ethyl group , and the like.
In the present invention, "a (C1 to C6 alkyl)sulfonyl(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a (C1 to C6 alkyl)sulfonyl group" at ary position.
For example, there may be mentioned a methlsulfonyl methyl group, a methylsulfonylethyl group, a (3- sulfonyl)propyl group, a (2-methylsulfonyl)propyl group, a (1-methylsulfonyl)propyl group, a (1- methylsulfonyl)(1-methyl)ethyl group, an ethylsulfonylmethyl group, an ethylsulfonylethyl group, an (3-ethylsulfonyl)propyl group, an (2- ethylsulfonyl)propyl group, an (1-ethylsulfonyl)propyl group, an (1-ethylsulfonyl)(1-methyl)ethyl group , and the like.
In the t invention, "a C6 to C10 aryl group" means an ic 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 l 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 C6 to 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 ion, "a (C6 to C10 aryl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a C6 to C10 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 ic cyclic group having aromaticity, wherein the heterocyclic group contains 1 to 5 atoms selected from oxygen, sulfur and en. 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 can be formed and can exist chemically stably.
As such "a 5- to 10-membered heteroaryl group", for example, there may be ned a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyridazinyl group, a furyl group, a thienyl group, a e group, a pyrazolyl group, an 1,3-dioxaindanyl group, an isoxazolyl group, an isothiazolyl group, a uranyl 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 ion, "a (5- to bered heteroaryl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 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 ydropyranyl group, a tetrahydrothienyl group, a morpholyl group, and the like.
In the present invention, "a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a 3- to 8-membered heterocycloalkyl . For example, there may be mentioned a piperidylmethyl group, a ydrofuranylmethyl group, a tetrahydropyranylmethyl group, a tetrahydrothienylmethyl group, a morpholinoethyl group, a oxetanylmethyl 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 piro[2.5]octaneyl group, and the like.
In the present invention, "a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a C5 to C9 bicycloalkyl group" at arbitrary position. For e, there may be mentioned a bicyclo[1.1.1]pentanyl methyl group, a bicyclo[3.1.0]hexanyl methyl group, a o[3.1.0]hexanyl ethyl group, a bicyclo[2.2.0]hexanyl methyl group, a bicyclo[2.2.0]hexanyl ethyl group, a bicyclo[2.1.1]hexanyl methyl group, a o[2.1.1]hexanyl ethyl group, a bicyclo[3.2.0]heptanyl methyl group, a bicyclo[3.2.0]heptanyl ethyl group, a o[2.2.1]heptanyl methyl group, a bicyclo[2.2.1]heptanyl ethyl group, a bicyclo[3.1.1]heptanyl methyl group, a bicyclo[4.1.0]heptanyl methyl group, an octahydropentalenyl methyl group, a o[2.2.2]octanyl methyl group, a bicyclo[3.2.1]octanyl methyl group, a bicyclo[4.2.0]octanyl methyl group, a bicyclo[4.1.1]octanyl methyl group, a bicyclo[5.1.0]octanyl methyl group, an octahydro-1H- indenyl methyl group, a bicyclo[3.2.2]nonanyl methyl group, a bicyclo[3.3.1]nonanyl methyl group, a bicyclo[4.2.1]nonanyl 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 ed 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)(C1 to C3 alkyl) group" means a group obtained by substituting "a C1 to C3 alkyl group" with "a C6 to C9 heterobicycloalkyl group" at ary 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 C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups", when the C1 to C6 alkyl group is substituted by a plurality of Ra groups, each Ra group can be selected independently and the C1 to C6 alkyl group can be substituted by the same Ra groups or by different Ra . In addition, meaning of other expressions such as "a C1 to C6 alkyl group tuted 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: In the formula (I), R1 is selected from F, Cl, Br, a C1 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 ed from F, C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
The "a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups" in R1 is preferably C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Ra groups, and more preferable is a oromethyl 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 Cl, a C1 to C4 alkyl group substituted by 0, 1, 2 or 3 Ra groups or a cyclopropyl group tuted by 0, 1, 2 or 3 Ra groups, and more preferable is a trifluoromethyl group, a difluoromethyl group or Cl.
In the formula (I), Y is a C4 to C6 cycloalkyl group, a C6 to C9 oalkyl group or a C6 to C9 spiroalkyl group, all of which are tuted by a R2 group, 0 or 1 R6 group and 0, 1, 2 or 3 R7 groups; wherein R2 is selected from -OH, -CO2H, -SO3H, -CONH2, - SO2NH2, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)aminocarbonyl group tuted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 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 (C1 to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)sulfonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C1 to C3 alkyl) group tuted by 0, 1, 2 or 3 Rc groups; R6 and R7 are independently selected from H, F, -OH, -NH2, -CN, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rb groups; wherein Rband Rc are , independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 amino group, a di(C1 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 group, all of which are substituted by a R2 group, 0 or 1 R6 group and 0, 1, 2 or 3 R7 " in Y is preferably a group represented by formula , formula (II-b), formula (II-c) or formula (II-d): (II-a), (II-b), (II-c) or (II-d), wherein: k is 0, 1 or 2; and n is 1, 2 or 3.
In the case of the group represented by formula (II- a), formula (II-b), formula (II-c) or formula (II-d), Y is ably a group represented by formula (II-a), formula (II-c) or formula (II-d); and more preferably a group represented by formula (II-a) or formula .
The variable, n, is preferably 2 in a group represented by formula (II-d).
R2 in Y is preferably -CO2H, -SO3H, , -SO2NH2, a (C1 to C2 alkyl)aminocarbonyl group substituted by 0 or 1 Rc groups, a C1 to C2 alkylsulfonyl group substituted by 0 or 1 Rc groups, a C1 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 -CO2H or a hydroxycarbonylmethyl group substituted by 0, 1 or 2 Rc groups.
R6 in Y is ably H or a C1 to C4 alkyl group without Rb group, and more preferable is H, a methyl group or an ethyl group.
R7 in Y is preferably H or a C1 to C2 alkyl group without Rb group, and more preferable is H or a methyl group.
In the formula (I), R3 is selected from H, F, Cl, - CH3 and -CF3. R 3 is preferably H.
In the formula (I), R4 is selected from a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re , a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 l)(C1 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 lkyl 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 5Rg 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a 3- to ered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, 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 Rg , 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 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 Rg groups; wherein Re isindependently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group; Rf is independently selected from F, Cl, Br, -OH, -CN, - NO2, -CO2H, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 l group tuted 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 C1 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 , -SH, a C1 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 (C1 to C6 carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group tuted by 0, 1, 2 or 3 Rk groups, a C1 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(C1 to C6 alkyl)amino group tuted by 0, 1, 2 or 3 Rk groups; wherein, Rk is independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group; Rg is is independently selected from F, Cl, a C1 to C6 alkyl group, -OH, -CN, -NH2, -NO2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 amino group, -CF3, a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 Rl groups, a C2 to C6 lene group substituted by 0, 1, 2 or 3 Rl groups and an oxo group; wherein Rl is independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
The "a C1 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 alkenyl)(C1 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)(C1 to C3 alkyl) and more preferably a 3-methyl butenyl group.
The "a (C2 to C6 alkynyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5Re groups" in R4 is ably one having 4 to 8 carbons in (C2 to C6 l)(C1 to C3 alkyl) and more preferably a 4,4- dimethylpentynyl group.
The "a (C1 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 (C1 to C6 alkoxy)(C2 to C4 alkyl), more preferably a C1 to C4 alkoxyethyl group tuted by 0, 1, 2 or 3 alkyl groups, and even more preferably a methyl methoxyethyl group or a 2-(tert-butoxy)ethyl group.
The "a (C6 to C10 aryl)(C1 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 Rf's; more preferably a benzyl group substituted by 1, 2 or 3 groups selected from F and Cl, or a unsubstituted benzyl group; and even more preferable is a 4- fluorobenzyl group, a 3,5-difluorobenzyl group or a 4- uoromethyl)benzyl group.
The "a (5- to 10-membered heteroaryl)(C1 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 tuted by 0, 1, 2, 3, 4 or 5 Rg 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 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg 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 (1- fluorocyclopentyl)methyl group, a (3,3- dimethylcyclobutyl)methyl group, a (1- methylcyclobutyl)methyl group, a (1- (trifluoromethyl)cyclobutyl)methyl group, a (1- (trifluoromethyl)cyclopropyl)methyl group or a (1- methylcyclopropyl)methyl group.
The "a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups" in R4 is preferably a 3- to 6-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg .
The "a (3- to 8-membered cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg 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 tetrahydrofuranylmethyl group substituted by 1, 2 or 3 groups selected from F, a C1 to C4 alkyl group and a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 Rl .
The "a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg 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]octanyl group, a spiro[3.5]nonanyl group, a spiro[3.3]heptanyl group or a spiro[3.3]heptanyl group.
The "a (C6 to C9 spiroalkyl)(C1 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]octanylmethyl group substituted by 0, 1, 2 or 3 Rg groups or a spiro[2.3]hexanylmethyl group substituted by 0, 1, 2 or 3 Rg groups; and even more preferable is a spiro[2.5]octanylmethyl group, (5- -spiro[2.3]hexan)ylmethyl group or spiro[2.3]hexanylmethyl 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 Rg groups.
The "a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups" in R4 is preferably a C6 to C8 bicycloalkyl ring tuted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a o[3.1.0]hexanyl group substituted by 0, 1, 2 or 3 Rg ; and even more preferable is a 6,6-dimethylbicyclo[3.1.0]hexanyl group.
The "a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg " in R4 is preferably a C5 to C7 bicycloalkyl methyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; more preferably a (bicyclo[1.1.1]pentanyl)methyl group substituted by 0, 1, 2 or 3 Rg groups or a (bicyclo[2.2.1]heptanyl)methyl group substituted by 0, 1, 2 or 3 Rg groups; and even more preferable is a (4- methylbicyclo[2.2.1]heptanyl)methyl group or (bicyclo[1.1.1]pentanyl)methyl group.
The "a (C6 to C9 heterobicycloalkyl)(C1 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]heptanyl)methyl group substituted by 0, 1, 2 or 3 Rg groups; and, even more able is (4-methyloxabicyclo[2.2.1]heptan yl)methyl group or (7-oxabicyclo[2.2.1]heptanyl)methyl group.
In the formula (I), R5 is ed from a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 Ri groups, a - to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 Ri , 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 Ri is ndently selected from F, Cl, Br, -OH, -CN, -NO2, -CO2H, a C1 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 , a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk , a C3 to C8 cycloalkyloxy group tuted by 0, 1, 2 or 3 Rk groups, -SH, a C1 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 (C1 to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkoxy)carbonyl group tuted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk , a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a C1 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(C1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups; Rj isindependently selected from F, Cl, a C1 to C6 alkyl group, -OH, -CN, -NH2, -NO2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 amino group, -CF3, a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 Rl , a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 Rl groups and an oxo group; wherein, when Rj is a divalent group of a C1 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 Rl are independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
The "a C6 to C10 aryl group substituted by 0, 1, 2, 3, or 4 Ri groups" in R5 is preferably a phenyl group substituted by 2 to 4 groups selected from -OH, -NH2, Cl, F, -CN, -CF3, -OCF3, -OCF2H, a methyl group, a cyclopropyl group and a methoxy group; and more able is a 2,6- rophenyl group, a 2,6-dichlorofluorophenyl group, a 2,6-dichloromethylphenyl group, a 2,4,6- trichlorophenyl group, a 2-chlorofluorophenyl group or a 2,6-dichlorofluorophenyl group.
The "a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 Ri groups" in R5 is preferably a pyridyl group substituted by 2 to 3 groups selected from -OH, -NH2, Cl, F, -CN, -CF3, a methyl group, and a methoxy group; and more preferable is a 3,5- dichloropyridinyl group, a 3-chloromethoxypyridin- 4-yl group, a 3-chlorofluoropyridinyl group or a 2,4-dichloromethylpyridinyl group.
On the whole, R5 is preferably a phenyl group optionally substituted by 2, 3 or 4 Ri groups or a 6- membered heteroaryl group ally substituted by 2 or 3 Ri .
In the formula (I), R8 and R9 are independently selected from H, F, -OH, -NH2, a C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh groups, and a C1 to C6 alkoxy group tuted 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 C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
The "a C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh " in R8 and R9 is preferably methyl group substituted by 0, 1, 2 or 3 Rh groups.
The "a C1 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 Rh 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 -CR13R14-CRmRm- or -CR13R14-CRmRm-CRmRm- to form a pyrrolidine ring.
R13 is selected from H, a C1 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 Rf groups, a C6 to C10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (C2 to C6 alkenyl)(C1 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 (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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf , a (5- to 10-membered heteroaryl)(C1 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 Rg groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 , 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)(C1 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 tuted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group tuted 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, (C6 to C9 heterobicycloalkyl) group substituted by 0, 1, 2, 3, 4 or Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; R14 is selected from H and a C1 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 tuted 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, Cl, -CH3 and -CF3; wherein Rg is selected from F, Cl, a C1 to C6 alkyl group, -OH, -CN, -NH2, -NO2, -CO2H, a C1 to C6 alkoxy group, a 1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3, a C1 to C6 ne group substituted by 0, 1, 2 or 3 Rl groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 Rl groups and an oxo group; Rf is independently ed from F, Cl, Br, -OH, -CN, - NO2, -CO2H, a C1 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 , 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 , a C1 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 C1 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 (C1 to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 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 C1 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(C1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups; and Re and Rk are, independently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, -NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 amino group, -CF3 and an oxo group.
Preferably R12 is H; or R4 and R12 together are -CH2- CR13R14-CH2- to form a idine ring, more preferably R12 is H.
R13 is preferably a C1 to C6 alkyl group, a C6 to C10 aryl group, a C6 to C10 aryloxy group, a (C6 to C10 aryl)(C1 to C3 alkyl) group, or a C3 to C8 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, Rg, Rh, Ri, Rj, Rk, Rl, Rm is preferably one where respective preferable components described above are combined; and more preferably one where components described above as more able are combined.
In another embodiment, in conjunction with any above or below embodiments, R1 is a C1 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 C1 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 ments, R2 is CO2H.
In another embodiment, in conjunction with any above or below embodiments, Y is selected from formula (II-a), formula (II-b), formula (II-c) and formula (II-d): (II-a), (II-b), (II-c) and (II-d), wherein, 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 (II-a) and a (II-d); (II-a), or (II-d); wherein in k is 0, 1 or 2; and n is 1, 2 or 3.
In another ment, in conjunction with any above or below ments, Y is ed from formula (II-a) and formula (II-d); (II-a), or (II-d); wherein in k is 0; and n 2.
In another ment, in conjunction with any above or below embodiments, Y is .
In another embodiment, in conjunction with any above or below embodiments, Y is .
In another embodiment, in conjunction with any above or below embodiments, R6 is selected from F, -OH, -NH2, -CN, a C1 to C6 alkyl group tuted by 0, 1, 2 or 3 Rb groups and a C1 to C6 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 C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rb.
In another ment, in conjunction with any above or below ments, R6 is CH3.
In another embodiment, in conjunction with any above or below embodiments, R7 is independently selected from H, F and a C1 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, -CO2H, -SO3H, -CONH2 and -SO2NH2.
In another embodiment, in ction 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 C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Re groups, a (C6 to C10 C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf , a C3 to C8 cycloalkyl 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 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 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 Rg groups or a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg .
In another embodiment, in conjunction with any above or below embodiments, R4 is a C1 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 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf .
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)(C1 to C3 alkyl) group tuted 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 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another embodiment, in ction with any above or below embodiments, R4 is a (C5 to C9 bicycloalkyl)(C1 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 ments, R4 is a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
In another ment, 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, R8 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 Ri .
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 Ri groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is a 5- to bered heteroaryl group substituted by 0, 1, 2, 3, or 4 Ri groups.
In another embodiment, in conjunction with any above or below embodiments, R5 is a 6-membered heteroaryl group tuted by 0, 1, 2, 3, or 4 Ri groups.
In r embodiment, in conjunction with any above or below embodiments, R5 is pyridyl substituted by 0, 1, 2, 3, or 4 Ri 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-CR13R14- CH2- to form a pyrrolidine ring.
In another ment, in conjunction with any above or below embodiments, R14 is selected from H and CH3.In r 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 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.
In another embodiment, in conjunction with any above or below embodiments, R13 is selected from a C1 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 Rf groups, a C6 to C10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (C2 to C6 alkenyl)(C1 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 tuted by 0, 1, 2, 3, 4 or 5 Re groups, a (C1 to C6 alkoxy)(C2 to C4 alkyl) group tuted by 0, 1, 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered aryl)(C1 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 Rg groups, a C3 to C8 lkenyl 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 lkenyl)(C1 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 Rg groups, a (C6 to C9 lkyl)(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 C6 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 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 ments, 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 ented by formula (I) forms acid on salts. r, 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- yethanesulfonate, a p-toluenesufonate, a benzenesulfonate, an ethane-1,2-disulfonate ion, a 1,5- alenedisulfonate ion, a naphthalenesulfonate 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-hydroxynaphthoate, and the like. As the salts with bases, there are ned 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 mine 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 s (E-, Z-, cis-, and trans-forms), s due to the ce of chiral carbons (R- and S-forms, Ī±- and Ī²- urations, enantiomers, and diastereomers), optically active substances with optical rotation (D-, L-, d-, and l-forms), tautomers, polar nds obtained by tographic separation (a highly-polar compound and a lowly-polar compound), equilibrium compounds, rotamers, mixtures of these compounds in an arbitrary ratio, c mixtures, and the like.
The present invention also includes various deuterated forms of the compounds represented by a (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 lents 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. In this ication where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
The term ā€˜comprisingā€™ as used in this ication and claims means sting at least in part ofā€™. When interpreting statements in this ication and claims which includes the ā€˜comprisingā€™, other features besides the es prefaced by this term in each statement can also be present. Related terms such as ā€˜compriseā€™ and ā€˜comprisedā€™ are to be interpreted in similar manner.
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 cturing technology that the functional group may be ted with an appropriate protecting group or a group that can be easily converted to a functional group in the process of using a raw al and an ediate 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 c 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 an intended compound.
Among compound represented by formula (I) in the present ion, a compound (I-1) can be prepared, for example, by the following method: (wherein, R8 and R9 are independently H; F; a hydroxyl group; an amino group; a C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh groups; a C1 to C6 alkoxy group tuted by 0, 1, 2 or 3 Rh ; 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 nd (2).
The reactive derivative of the compound (1) means a reactive derivative of a carboxyl group, and for e, 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 on 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.), lent methods thereto or a combination of these methods and the conventional method. Namely, the present reaction can be carried out by using a sation agent that is well known to a person skilled in the art, or an ester activation , 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- ohexylcarbodiimide, 1-methylbromopyridinium iodide, N,N'-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N,N'-disuccinimidyl carbonate, N,N'-disuccinimidyl oxalate, 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride, benzotriazolyl-oxy-tris(pyrrolidinol)phosphonium hexafluorophosphate, 2-(1H-benzotriazolyl)-1,1,3,3- tetramethyluronium hexafluorophosphate, orbornene- 2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3- tetramethyluronium tetrafluoroborate, bromotris (pyrrolidino)phosphonium hexafluorophosphate, ethyl chloroformate, yl chloroformate, or 2-(7-aza-1H- benzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and the like. Above all, for e, thionyl chloride, oxalyl chloride, 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride or 2-(7- aza-1H-benzotriazolyl)-1,1,3,3-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 amideforming 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 lent of the compound (1), and preferably 0.1 equivalents to 10 equivalents.
A base used es, for e, tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N- methylpyrrolidine, N-methylpiperidine, N,N- dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene, 1,5- azabicyclo[4.3.0]nonene, and the like; aromatic amines such as pyridine, 4- dimethylaminopyridine, picoline, ne, quinoline, or isoquinoline, and the like.
Above all, ry aliphatic amine and the like are preferable, and triethylamine or N,N- diisopropylethylamine and the like are in particular preferable.
The amount of the base used varies ing 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), ably 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, r, 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 t include ydrofuran, acetonitrile, N,N-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 ature is generally 0Ā°C to the boiling point temperature of the solvent, and preferably room temperature to 80Ā°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 nd (I-1) obtained in such a manner can be isolated and ed by an isolation and purification method that is well known to a person skilled in the art (e.g., tration, 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 ied).
Moreover, among all the compounds represented formula (I) in the present invention, compounds (I-2) and (I-3) can be ed, for example, by the following method: (wherein, other symbols have the same meanings as described above.) (Step 2) The present step is a method for producing a compound (I-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 tional method.
The nd (I-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 (I-3) by subjecting the nd (I-2) to an oxidation on.
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 MnO2 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 t used is generally 1 equivalent to 10 lents with respect to 1 equivalent of the compound (I-2), preferably 1 equivalent to 4 lents.
The on in the present step is generally carried out in an inactive solvent. As the ve solvent, for example, tetrahydrofuran, itrile, N,N- dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, and the like; or es 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 -78Ā°C to the boiling point temperature of the solvent, and preferably -20Ā°C to room temperature.
The compound (I-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 ably protected in 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 ted by referring to the method in previously mentioned cting Groups in Organic Synthesis (the third edition, 1999)".
Moreover, among compounds represented by formula (I) in the present invention, a compound (I-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: (wherein, Rpro is a protecting group. Other symbols have the same meanings as described ) A compound represented by formula (a) can be synthesized according to a method well known to a person d in the art.
A compound represented by formula (c) can be synthesized ing to a method well known to a person skilled in the art.
(Step A) The t 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,N-dimethylformamide l acetal, N,N- dimethylformamide diisopropyl acetal, or the like can be used instead of N,N-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 on solvent used is not in particular limited as far as it is inert to the reaction, and specifically includes, for example, ol, ethanol, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or mixtures thereof.
The reaction time is lly 0.5 hours to 96 hours, and preferably 1 hour to 24 hours.
The reaction temperature is generally 0Ā°C to the boiling point temperature of the solvent, and preferably room temperature to 160Ā°C.
The compound (b) obtained in such a manner can be ted to a next step with or without isolation and purification by an isolation and cation 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 hydrazino group represented by formula (c).
The amount of the compound (c) used is generally 0.5 lents 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 ide, 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 t used is not in particular limited as far as it is inert to the reaction.
Specifically, examples include, methanol, ethanol, npropanol , n-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, 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 0Ā°C to the boiling point ature of the solvent, and ably room ature to 100Ā°C.
The compound (d) obtained in such a manner can be subjected to a next step with or without ion and purification by an ion and purification method that is well known to a person skilled in the art.
(Step C) The t step is a method for producing a compound (1-a) by eliminating the protecting group Rpro of the nd (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 tional method.
For example, when the protecting group is a benzyl group, the benzyl group can be ated 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 R8 and R9 are H can be synthesized, for example, by the following method: (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 nd (g) by reacting an organic lithium compound (e) with ne oxide (f).
The amount of ethylene oxide (f) used is generally 0.1 equivalents to 10 equivalents with t to 1 lent of the compound (e), and preferably 0.5 equivalents to 3 equivalents.
The on 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, ne, ane, 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 ature is generally -78Ā°C to the boiling point temperature of the solvent, and preferably -78Ā°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 t step can be carried out according to s 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 ium catalyst and the like; a reduction method using sodium dride; and the like.
For example, the reduction method using phosphine can be carried out using triphenylphosphine and water in a t 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 es thereof.
The amount of triphenylphosphine used is generally 1 lent 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 0Ā°C to the boiling point ature 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 lents to 10 equivalents with respect to 1 equivalent of the compound (i), and preferably 0.3 equivalents to 5 lents.
The on 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 0Ā°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 ion and purification method that is well known to a person skilled in the art.
A group represented by formula: (wherein, each symbol has the same meanings as described above) corresponds to the R4.
Moreover, among the compounds (2) used to prepare the compounds in the present invention, a compound (2-b) wherein either R8 or R9 is F and the other is H can be sized, for example, by the ing method: (wherein, each symbol has the same meanings as bed 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 (l) by reacting the nd (k) with hylsilyl 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 , zinc bromide, and the like.
The fluorinating agent used includes, for example, (N,N-diethylamino)sulfur trifluoride, bis(2- methoxyethyl)aminosulfur trifluoride, 1,1,2,2- tetrafluoroethyl-N,N- dimethylamine, and the like.
The amount of fluorinating agent used is lly 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 lly 30 minutes to 48 hours, and preferably, 1 hour to 24 hours.
The reaction temperature is generally 0Ā°C to the boiling point temperature of the solvent.
The compound (l) obtained in such a manner can be ted to a next step with or without ion and purification by an isolation and purification method that is well known to a person d in the art.
(Step I) The present step is a method for producing a compound (m) by subjecting the compound (l) to a reduction reaction of the cyano group.
The reducing agents used include, for e, lithium aluminium hydride, sodium bis(2- methoxyethoxy)aluminumhydride, a -tetrahydrofuran complex, and the like.
The amount of the reducing agent used is generally 1 to10 equivalents with respect to 1 equivalent of the compound (l).
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 0Ā°C to the boiling point temperature of the solvent.
The compound (m) obtained in such a manner can be ted to a next step with or without ion 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 d 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 cation method that is well known to a person skilled in the art.
Moreover, among the nds (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: (n) OH ORpro R5 TBSO TBSO R5 R5 Step K Step L Step M (e) (o) (p) ORpro ORpro (s) R4 ORpro HO O HN R5 R5 R5 Step N Step O (q) (r) (3-P) (wherein, Rpro is a protecting group. Other symbols have the same meanings as described above.) A compound ented 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 nd (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 ting 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 ned "Protecting Groups in Organic Synthesis (the third edition, , an equivalent method thereto, or a combination of these s and the conventional method.
The compound (p) obtained in such a manner can be subjected to a next step with or without isolation and cation by an isolation and purification method that is well known to a person skilled in the art.
(Step M) The t 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 d 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 ation of these methods and the conventional method.
The compound (r) obtained in such a manner can be subjected to a next step with or t 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 ng the compound (r) with a compound (s) in the presence of a ng 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 ion 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 e the compounds in the present ion, a compound (2-c) n both R8 and R9 are F can be synthesized, for example, by the following method: (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 sized 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 ably 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, itrile, 1,4- dioxane, dimethyl sulfoxide, N,N-dimethylformamide, and the like.
The reaction time is generally 30 minutes to 48 hours.
The on temperature is generally room temperature to the boiling point temperature of the 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 nd (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 ng the compound (w) or a ve derivative thereof with a compound (s).
The reaction in the t 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 cation 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) ed 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 es a e of these ers and s, and isolated ones.
Furthermore, described is a ceutically acceptable prodrug of the compound represented by formula (I). The term "pharmaceutically acceptable prodrug" means a nd producing a compound represented by formula (I) by solvolysis or conversion to CO2H, 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), "Iyakuhin 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 g of the corresponding compound of formula (I) which has CO2H, 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, oric acid, carbonic acid, and the like; lower alkyl sulfonic acids such as methanesulfonic acid, sulfonic acid, and the like; arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like; organic acids such as formic acid, acetic acid, nic 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, m, 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 l knowledge in the technical field in the The compound represented by formula (I) and the ceutically 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 RORĪ³ inhibitory activity and can be used as a RORĪ³ inhibitor that is clinically applicable to treat or prevent RORĪ³ ated diseases and symptoms. Among RORĪ³ related diseases, the compound of the present invention is useful as a eutic agent or preventive agent for, in particular, es selected from auto immune disease and inflammatory disease (e.g., le sclerosis, chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic tis, inflammatory bowel disease (e.g., Crohn's disease), and asthma), metabolic disease (especially, diabetes), and cancer (especially, malignant melanoma).
Moreover, the term ntion" 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 nd of the t invention or administration this to individuals who have already developed diseases or symptoms. Accordingly, a procedure of administration to individuals who have already ped es 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 ing 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 ition 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, eral administration es subcutaneous injection, intravenous injection, uscular injection, intraperitoneal ion, 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, es, 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 ic 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 stered in single or multiple times daily for adult in a range of 0.01 mg to 1000 mg, although the dosage is ent depending on the conditions of the patient, body weight, types of the compound, administration route, and the like. iations Ac acetyl aq. aqueous Bn benzyl Boc utoxycarbonyl BuOH butanol Bzl benzyl cat. catalytic conc. concentrated DAST ethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undecene DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetoamide DMAP 4-(N,N-dimethylamino)pyridine DMF methylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide Et2O dietylether EtOAc ethyl acetate EtOH ethanol HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate LDA litium diisopropylamide MeOH ol Ms methanesulfonyl ) 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 sed from vendors (for example, h, Wako Junyaku, Tokyo Kasei, Fluka, Sigma, and the like) and used without further cation.
The structure of the novel compound isolated was confirmed by and/or mass spectrometry using single quadrupole instrumentation ed 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, 6, CD3CN or CDCl3) was measured, the chemical shift (Ī“: ppm) and coupling constant (J: Hz) are shown. In addition, the ing abbreviations ent 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 oscopy (LC/MS) is. 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 AcquityUPLCTM-SQD Column: Acquity UPLCTM BEH C18 1.7 Ī¼m 2.1 mm Ɨ 50 mm UV: PDA detection (254 nm) CAD:CORONATM ULTRA detector Column temperature: 40 Ā°C ES voltage: 3.0 kV(capillary) Cone voltage: 30 V Gradient conditions: ts: A: H2O/MeCN = 95/5 0.05% TFA B: H2O/MeCN = 5/95 0.05% TFA Flow rate: 0.6 mL/min Gradients: 0.01 to 0.20 min, Solvent B: 2%, t A: 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 ement Condition (LC/MS method A): LC Mass spectrometer: Agilent Technologies Corporation 1260 INFINITYTM HPLC-6130MSD Column: Phenomenex GeminiTM C18 A110 3 Ī¼m 4.6 mm Ɨ 30 mm UV: PDA detection (254 nm) Column temperature: 40 Ā°C ary voltage: 3.5 kV Frag mentor voltage: 70 V Gradient conditions: Solvents: A: H2O/MeCN = 95/5 0.05% TFA B: H2O/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: zu Corporation LCMS-2010 EV Column: Shim-packTM XR-ODII 2.0 mm Ɨ 75 mm UV: PDA detection (254 nm) Flow rate: 0.4 mL/min Column temperature: 40 Ā°C Detection voltage: 1.20 kV Gradient conditions: Solvents: A: H2O/MeCN = 90/5 0.1% HCO2H B: H2O/MeCN = 10/95 0.1% HCO2H Flow rate: 0.4 mL/min Gradients: 0.01 to 0.50 min, Solvent B: 10%, Solvent A: 0.50 to 2.0 min, Solvent B: 10% to 95%, t 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, t B: 10%, Solvent A: 90% [Reference example A1] Step 1: 1-(3,5-dichloropyridinyl)nitroethanol (A1- 1) To a solution of 3,5-dichloro necarboxyaldehyde (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 HCl (7 mL) and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgSO4. After the t was removed, the residue was purified by column chromatography on silica gel to give compound A1-1 (2.8 g, 90%) as a white solid.
Step 2: 3,5-dichloro(2-nitro ((triethylsilyl)oxy)ethyl)pyridine (A1-2) To a solution of compound A1-1 (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 e was quenched with water and extracted with EtOAc.
The organic layer was washed with brine x 2 and dried over MgSO4. After the solvent was d, the residue was purified by column chromatography on silica gel to give compound A1-2 (4.1 g, 98%) as a colorless oil.
Step 3: -dichloropyridinyl) ((triethylsilyl)oxy)ethanamine (A1-3) Compound A1-2 (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 e was purified by column tography on silica gel to give compound A1-3 (1.9 g, 50%) as a white solid.
Step 4: 2-(3,5-dichloropyridinyl)-N-(4-fluorobenzyl)- 2-((triethylsilyl)oxy)ethanamine (A1) To a solution of compound A1-3 (2.8 g, 11.9 mmol) in toluene (6 mL) and MeOH (6 mL) was added 4- fluorobenzaldehyde (360 Ī¼L, 3.4 mmol), and the mixture was stirred at 70 Ā°C for 2 h. The reaction mixture was cooled to 0 Ā°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 ed with water and extracted with EtOAc.
The organic layer was washed with brine x 2 and anhydrous Na2SO4. After the solvent was removed, the residue was purified by column tography on silica gel to give compound A1 (1.2 g, 88%) as a colorless oil.
[Reference example A12] Step 1: 4-(methoxymethylene)-1,1-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, .94 mmol) in THF (20 mL) at -78 Ā°C and stirred for 10 min at the same temperature and then stirred for 2.5 h at room ature. The reaction e was cooled down to -78 Ā°C, a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at -78 Ā°C.
The reaction e was allowed to warm to room temperature and stirred at room temperature for overnight. The reaction mixture was quenched with sat.
NaHCO3 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 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 (A12-2) 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 e was ed with sat.
NaHCO3 aq. (10 mL) and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude compound A12-2 as pale yellow oil. The crude product was used for next step without purification.
Step 3: 2-(3,5-dichloropyridinyl)-N-((4,4- dimethylcyclohexyl)methyl) ((triethylsilyl)oxy)ethanamine (A12) Crude A12-2 (52 mg) and amine A1-3 (100 mg, 311.2 mmol) was added to a solution of MeOH (1 mL) and toluene (1 mL) and d at 80 Ā°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 e at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with sat. NaHCO3 aq. (10 mL) and extracted with EtOAc (50 mL). The c layer was washed with sat. NaHCO3 aq. and brine, dried over anhydrous Na2SO4, 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 trating zone 20 x 4 cm, 20% EtOAc/hexane as eluent) to provide compound A12 (58.6 mg, 42%) as pale yellow oil. 1H NMR (CDCl3, 400 MHz): Ī“ 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, 1H), 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). ence example A31] Step 1: 1-(2,6-dichlorofluorophenyl)nitroethanol (A31-1) A mixture of 2,6-dichlorofluorobenzaldehyde (10.0 g, 51.8 mmol), nitromethane (2 mL) and K2CO3 (3.57 g, 25.9 mmol) was stirred at room ature for 2 h. The reaction e 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 Na2SO4, and trated 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: (1-(2,6-dichlorofluorophenyl) 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 e 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 Na2SO4, and concentrated under reduced pressure. The residue was purified by column tography (silica gel, 0-10% EtOAc/hexane as eluent) to provide compound A31-2 (32.8 g, 74%) as colorless gum. 1H NMR (CDCl3, 400 MHz): Ī“ 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-dichlorofluorophenyl) ((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 NH4Cl (21.8 g, 407.6 mmol).
The e was stirred at 70 Ā°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 re. 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 Na2SO4, and concentrated under reduced pressure. The residue was ed by column chromatography (silica gel, 5% MeOH/DCM as eluent) to provide nd A31-3 (13.0 g, 94%) as colorless oil. 1H NMR , 400 MHz): Ī“ 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-dichlorofluorophenyl)-N-(3,5- difluorobenzyl)((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 ion (monitored by TLC), solid NaBH4 (4.9 g, 133.1 mmol) was added in portions at 0 Ā°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 Na2SO4, and concentrated under reduced pressure.
The e was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A31 (30.0 g, 70%) as colorless gum.
[Reference example A35] Step 1: 2,6-dichloroiodobenzaldehyde (A35-1) To a stirred solution of 1,3-dichloroiodobenzene (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 Ā°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 Ā°C and stirred for 3 h.
The reaction e was quenched with saturated NH4Cl (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 ous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% hexane as eluent) to afford compound A35-1 (1.4 g, 32%) as colorless oil.
Step 2: 1-(2,6-dichloroiodophenyl)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 K2CO3 (0.23 g, 2.0 mmol) in CH3NO2 (10 mL) using a r procedure to that described in nce example A1, step 1.
Step 3: (1-(2,6-dichloroiodophenyl) 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 A1, step Step 4: 2-(2,6-dichloroiodophenyl) ((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 NH4Cl (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-dichloroiodophenyl)-N-((3,5- difluorophenyl)((triethylsilyl)oxy)methyl)ethanamine (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 e A31, step4.
Step 6: tert-butyl (2-(2,6-dichloroiodophenyl) ((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl)carbamate (A35-6) To a stirred on of compound A35-5 (1.87 g, 3.26 mmol) in DCM/water (4:1, 20 mL) was added NaHCO3 (0.55 g, 6.5 mmol) and (Boc)2O (1.07 g, 4.9 mmol) in DCM (8 mL) at 0 Ā°C. The e was stirred at room temperature for 2 h. The reaction e 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 Na2SO4 and concentrated under reduced pressure to get compound A35-6 (2.47 g, crude) as a colorless gum.
Step 7: tert-butyl 6-dichlorocyanophenyl) ((triethylsilyl)oxy)ethyl)(3,5-difluorobenzyl)carbamate 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 Ā°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 Na2SO4 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(2-((3,5-difluorobenzyl)amino) 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 HCl (5 mL) and the mixture was stirred at 80 Ā°C for overnight. The reaction mixture was quenched with water (50 mL) and basified with % NaOH solution up to pH 9 and extracted with EtOAc (2 x 30 mL). The combined c layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced re. The crude t 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] Step 1: 4-methylthiophenecarboxylic acid (A56-1) To a stirred solution of 3-bromomethylthiophene (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 Ā°C se over a period of 15 min and the mixture was stirred at -78 Ā°C for 30 min. The CO2 (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 Ā°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 c layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 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-dimethylthiophenecarboxylic 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 Ā°C for 10 min. The mixture was d at -78 Ā°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 Ā°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 s NH4Cl and ted with EtOAc (2x25 mL). The ed organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under d 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-dimethylthiophenyl)methanol (A56-3) To a stirred solution of compound A56-2 (246 mg, 1.5 mmol) in THF (3 mL) was added BH3Ā·THF (1 M in THF, 5.5 mL, .5 mmol) dropwise at 0 Ā°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 NaHCO3 and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (2x10 mL), dried over ous Na2SO4 and concentrated under d pressure. The residue was purified by column chromatography (silica gel, 25% hexane as eluent) to provide compound A56-3 (201 mg, 90%) as a colorless gum.
Step 4: 2,4-dimethylthiophenecarbaldehyde (A56-4) To a d 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 Ā°C and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 and NaHCO3, and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4, 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: -dimethylthiophenyl)nitroethanol (A56-5) A mixture of compound A56-4 (133 mg, 0.95 mmol), nitromethane (2 mL) and K2CO3 (50 mg, 0.36 mmol) was d at room ature 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 Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 40% EtOAc/hexane as eluent) to provide nd A56- (80 mg, 42%) as a yellow gum.
Step 6: (1-(2,4-dimethylthiophenyl) nitroethoxy)triethylsilane (A56-6) To a stirred solution of nd A56-5 (235 mg, 1.17 mmol) in DMF (4 mL) were added ole (238 mg, 3.5 mmol) and TES-Cl (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 , 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-dimethylthiophenyl) ((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 NH4Cl (407 mg, 7.6 mmol).
The mixture was stirred at 70 Ā°C for 45 min. Upon completion, the reaction e 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 Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography a gel, 5% MeOH/DCM as eluent) to provide compound A56-7 (192 mg, 88%) as a yellow gum.
Step 8: N-(3,5-difluorobenzyl)(2,4-dimethylthiophen yl)((triethylsilyl)oxy)ethanamine (A56) To a stirred solution of nd 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 ored by TLC), solid NaBH4 (51 mg, 1.3 mmol) was added in portions at 0 Ā°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 mL), dried over ous Na2SO4, and concentrated under reduced re. 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 (CDCl3, 300 MHz): Ī“ 6.90-6.77 (m, 3H), 6.7160 (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).
[Reference example A57] Step 1: 2,6-dichloro(methylthio)benzaldehyde (A57-1) 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 Ā°C and stirred for 1 h at the same temperature. A on of DMF (0.6 mL, 7.7 mmol) in THF (3 mL) was added slowly at -78 Ā°C and stirred for 1 h.
The reaction mixture was quenched with saturated NH4Cl aq. (50 mL) and extracted with EtOAc (2 x 30 mL). The combined c layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as ) to afford compound A57-1 (1.4 g, 99%) as colorless oil.
Step 2: 1-(2,6-dichloro(methylthio)phenyl) nitroethanol ) 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 K2CO3 (0.13 g, 0.92 mmol) in CH3NO2 (5 mL) using a similar procedure to that described in reference example A1, step 1.
Step 3: (1-(2,6-dichloro(methylthio)phenyl) 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 A1, step Step 4: 2-(2,6-dichloro(methylthio)phenyl) ((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 NH4Cl (1.34 g, .3 mmol) in EtOH/water (4:1, 20 mL) using a r procedure to that described in reference example A31, step 3.
Step 5: 2-(2,6-dichloro(methylthio)phenyl)-N-(3,5- robenzyl)((triethylsilyl)oxy)ethanamine (A57) nd A57 (0.73 g, 55%) was obtained as a colorless gum from the on of compound A57-4 (0.98 g, 2.69 mmol), fluorobenzaldehyde (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 (CDCl3, 300 MHz): Ī“ 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] 3,5-Dichloro(2-((3,5-difluorobenzyl)amino) hydroxyethyl)benzamide (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 Ā°C. The mixture was allowed to warm to room temperature while stirring continued for 4 h. The reaction mixture was acidified with HCl (1 M, 6 mL) and extracted with EtOAc (3Ɨ10 mL). The ed organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound A58 (60 mg, 47%) as a yellow solid. LCMS (APCI): 391 (M+H)+.
[Reference example A59] Ethyl 3,5-dichloro(2-((3,5-difluorobenzyl)amino) hydroxyethyl)benzoate (A59) To a stirred on of compound A35-7 (0.2 g, 0.3 mmol) in EtOH (5 mL) was added conc. HCl (5 mL) and the mixture was stirred at reflux for overnight. The reaction mixture was quenched with water (50 mL) and ed 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 Na2SO4 and concentrated under d pressure.
The crude product was purified by column chromatography (silica gel, 30% hexane as eluent) to afford compound A59 (0.1 g, 92%) as a white solid.
[Reference example A66] Step 1: 4,4-dimethylpentynal (A66-1) To a stirred solution of 3,3-dimethylbutanyl (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 Ā°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 Ā°C and the reaction mixture was allowed to warm to room temperature for overnight. The reaction mixture was quenched with saturated NH4Cl (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 nd A66-1. The crude product was used for next step without purification.
Step 2: N-(2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-4,4-dimethylpentynamine (A66) Compound A66 (76.1 mg, 36.6%) was obtained as a pale yellow oil from the reaction of compound A1-3 (160 mg, 0.5 mmol), compound A66-1 (80 mg, 0.726 mmol), NaBH4 (120 mg) and MgSO4 (100mg) in MeOH (6 mL) and DCM (3mL) using a similar ure to that described in reference example A31, step 4. 1H NMR (CDCl3, 400 MHz): Ī“ 8.43 (s, 2H), .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] Step 1: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- aldehyde (A75-1) To a stirred suspension of NaH (274 mg, 11.4 mmol) in DMF (20 mL) was added solution of 1H-pyrazole carbaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) dropwise at 0 Ā°C and the e was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 Ā°C and SEM-Cl (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 ted with EtOAc (3 x 20 mL).
The combined organic layers were washed water (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as ) to provide compound A75-1 (350 mg, 29%) as colorless gum.
Step 2: 2-nitro(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolyl)ethanol ) Compound A75-2 (428 mg, 64%) was obtained as yellow gum from the reaction of compound A75-1 (350 mg, 1.54 mmol), CH3NO2 (1 mL) and K2CO3 (85 mg, 0.616 mol) using a similar procedure to that described in nce example A1, step 2.
Step 3: 3-(2-nitro((triethylsilyl)oxy)ethyl)((2- (trimethylsilyl)ethoxy)methyl)-1H-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 ole (303 mg, 4.47 mmol) using a similar procedure to that described in reference example A1, step 3.
Step 4: 2-((triethylsilyl)oxy)(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl)ethanamine (A75-4) Compound A75-4 (600 mg, crude) was ed as colorless gum from the reaction of compound A75-3 (604 mg, 1.51 mmol), Fe powder (843 mg, 15.1 mmol) and NH4Cl (806 mg, 15.1 mmol) using a similar procedure to that described in reference example A31, step 3.
Step 5: N-(3,5-difluorobenzyl)((triethylsilyl)oxy) (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol 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 ure to that described in reference example A31, step 4. 1H NMR (CDCl3, 300 MHz): Ī“ 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 e A84] Step 1: 2-(2-chloronitrophenyl) ((trimethylsilyl)oxy)acetonitrile (A84-1) To a stirred solution of 2-chloro 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 on 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 Na2SO4 and concentrated under reduced pressure to get compound A84-1 (1.0 g, 67%) as a brown color oil.
Step 2: 2-(2-chloronitrophenyl) ((trimethylsilyl)oxy)ethanamine To a stirred solution of compound A84-1 (0.85 g, 3.0 mmol) in THF (15 mL) was added BH3Ā·THF (1.0 M in THF, 17.9 mL, 17.88 mmol) and stirred at room temperature for 16 h.
The reaction e was quenched with MeOH and extracted with EtOAc (2 x 30 mL). The ed organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get compound A84-2 (0.65 g, 75%) as a brown color gum.
Step 3: 1-(2-chloronitrophenyl)((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 (CDCl3, 300 MHz): Ī“ .29 (m, 3H), .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] Step 1: (5S)(((tetrahydro-2H-pyran yl)oxy)methyl)dihydrofuran-2(3H)-one (A92-1) To a d solution of (S) (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 enesulfonate (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 ed organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, 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)methyl((tetrahydro-2H-pyran )hexane-2,5-diol (A92-2) To a stirred solution of nd A92-1 (5.85 g, 29.1 mmol) in THF (50 mL) was added methyl ium bromide (3.0 M in Et2O, 22.4 mL, 67.2 mmol) dropwise at 0 Ā°C for 10 min and the mixture was stirred at 0 Ā°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 NH4Cl and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under d pressure. The residue was purified by column tography (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-dimethyltetrahydrofuranyl)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 ed 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 35% EtOAc/hexane as ) to provide compound A92-3 (330 mg, 57%) as a colorless Step 4: (S)-(5,5-dimethyltetrahydrofuranyl)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 Ā°C. The mixture was stirred at 0 Ā°C for 30 min. The mixture was d 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 Na2SO4 and concentrated under reduced re. The residue was purified by column chromatography (silica gel, 35% EtOAc/hexane as eluent) to provide nd A92-4 (310 mg, 64%) as a colorless gum.
Step 5: 2-(3,5-dichloropyridinyl)-N-(((S)-5,5- dimethyltetrahydrofuranyl)methyl) ((triethylsilyl)oxy)ethanamine (A92) A e of compound A92-4 (140 mg, 0.67 mmol), compound A1-3 (216 mg, 0.67 mmol), Na2CO3 (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 Ā°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 c layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% MeOH/DCM as eluent) to e compound A92 (40 mg, 14%) as a colorless gum.
[Reference example A93] Step 1: 1-(2-chloromethoxyphenyl)nitroethanol (A93- Compound A93-1 (1.35 g, crude) was obtained as a colorless oil from the reaction of 2-chloro ybenzaldehyde (1.0 g, 5.88 mmol) and K2CO3 (0.3 g, 2.2 mmol) in CH3NO2 (10 mL) using a similar procedure to that described in reference example A1, step 1.
Step 2: (1-(2-chloromethoxyphenyl) nitroethoxy)triethylsilane ) 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 A1, step Step 3: 2-(2-chloromethoxyphenyl) ((triethylsilyl)oxy)ethanamine (A93-3) nd A93-3 (1.6 g, 84%) was obtained as a ess oil from the reaction of compound A93-2 (2.14 g, 6.2 mmol), Fe (3.48 g, 62.0 mmol) and NH4Cl (3.3 g, 62.0 mmol) in EtOH/water (4:1, 20 mL) using a similar procedure to that described in reference e A1, step 3.
Step 4: 2-(2-chloromethoxyphenyl)-N-(3,5- difluorobenzyl)((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 r procedure to that described in reference example A1, step 4. 1H NMR (CDCl3, 300 MHz): Ī“ 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] Step 1: (S)-(5-oxotetrahydrofuranyl)methyl 4- methylbenzenesulfonate (A94-1) To a stirred solution of (S) (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 Ā°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 c layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% hexane as eluent) to provide compound A94-1 (4.06 g, 87%) as a white solid.
Step 2: (R)-(5,5-dimethyltetrahydrofuranyl)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) se at -78 Ā°C for 10 min and the mixture was stirred at -78 Ā°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 Na2SO4 and trated under reduced pressure. The residue was purified by column chromatography (silica gel, 35% hexane as eluent) to provide compound A94-2 (220 mg, 28%) as a colorless Step 3: ,5-dimethyltetrahydrofuranyl)methyl esulfonate (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-dichloropyridinyl)-N-(((R)-5,5- dimethyltetrahydrofuranyl)methyl) ((triethylsilyl)oxy)ethanamine (A94) nd A94 (32 mg, 8%) was obtained as a colorless gum from the on of compound A94-3 (200 mg, 0.96 mmol), compound A1-3 (247 mg, 0.77 mmol) and Na2CO3 (508 mg, 4.8 mmol) in isopropanol (3.0 mL) using a similar procedure to that described in reference e A92, step 5.
[Reference example A103] Step 1: N-methoxy-N-methyl (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)ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol) and N,O- 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 e was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to provide compound A103-1 (164 mg, 85%) as a pale yellow oil.
Step 2: 1-(trifluoromethyl)cyclopropanecarbaldehyde (A103-2) To a d solution of compound A103-1 (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 Ā°C under nitrogen atmosphere. After 0.5 h, the mixture was allowed to warm to 0 Ā°C and stirred for 0.5 h. The reaction mixture was quenched with sat. KHSO4 aq. (10 mL) and ted 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-dichloropyridinyl) ((triethylsilyl)oxy)-N-((1- (trifluoromethyl)cyclopropyl)methyl)ethanamine (A103) Compound A1-3 (0.20 g, 0.622 mmol) was dissolved in DCM solution ning compound A103-2. MgSO4 (0.2 g) was added to this solution and the e 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 ted c layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silicagel column chromatography eluting with 20% EtOAc in heptane to give compound A103 (87 mg, 32%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) Ī“: 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 A111] Step 1: 2,6-dichloromethylbenzoic acid (A111-1) To a stirred solution of 1,3-dichloromethylbenzene (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 Ā°C dropwise over a period of 10 min and mixture was stirred at -78 Ā°C for 30 min. A dry-ice was added to the reaction mixture slowly and the mixture was stirred at the same ature for min. Thereafter, the reaction mixture was slowly warmed to room temperature, ed with 6 M HCl (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 Na2SO4 and concentrated under d pressure to get compound A111-1 (1.1 g, 44%) as a white solid.
Step 2: 2,6-dichloroformylbenzoic acid (A111-2) To a stirred solution of compound A111-1 (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 ature and evaporated the solvent. To the residue, EtOAc (10 mL) was added and the obtained solids were filtered through Buckner . The filtrate was ated and the crude product was dissolved in EtOH (20 mL) and heated to 50 Ā°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 HCl (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 Na2SO4 and concentrated under reduced pressure to get compound A111-2 (1.6 g, crude) as a brown oil.
Step 3: methyl 2,6-dichloroformylbenzoate (A111-3) To a stirred solution of compound A111-2 (1.1 g, 5.0 mmol) in DMF (10 mL) was added K2CO3 (1.0 g, 7.5 mmol) at 0 Ā°C ed by slow addition of MeI (0.94 mL, 15.0 mmol) and the reaction mixture was stirred at the same temperature for 30 min. Then reaction e 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 Na2SO4 and concentrated under reduced pressure. The residue was ed by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A111-3 (0.59 g, 50%) as a white solid.
Step 4: methyl 2,6-dichloro(difluoromethyl)benzoate (A111-4) To a stirred solution of compound A111-3 (0.36 g, 1.5 mmol) in DCM (10 mL) was added DAST (0.37 mL, 2.8 mmol) at -78 Ā°C se followed by a drop addition of MeOH and the reaction was stirred at the same temperature for 15 min and t to 0 Ā°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 NaHCO3 (20 mL) at 0 Ā°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 Na2SO4 and concentrated under reduced pressure to get compound A111-4 (0.37g, 94%) as a colorless oil.
Step 5: (2,6-dichloro(difluoromethyl)phenyl)methanol (A111-5) To a d solution of compound A111-4 (1.44 g, .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 Ā°C dropwise for min and brought to 0 Ā°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 HCl (20 mL) at 0 Ā°C and stirred for 20 min and ted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced re to get compound A111-5 (0.59 g, 45%) as a colorless oil.
Step 6: 2,6-dichloro(difluoromethyl)benzaldehyde (A111-6) Compound A111-6 (0.38 g, 65%) was obtained as a colorless oil from the on of compound A111-5 (0.59 g, 2.46 mmol) and artin 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(difluoromethyl)phenyl) ((trimethylsilyl)oxy)acetonitrile (A111-7) To a stirred solution of compound A111-6 (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 ature and stirred for 1 h. The on 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 Na2SO4 and concentrated under reduced pressure to get compound A111-7 (0.53 g, 97%) as a yellow solid.
Step 8 2-(2,6-dichloro(difluoromethyl)phenyl) ((trimethylsilyl)oxy)ethanamine (A111-8) To a stirred solution of compound A111-7 (0.53 g, 1.6 mmol) in THF (10 mL) was added BH3Ā·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 Na2SO4 and concentrated under reduced pressure to get compound A111-8 (0.5 g, crude) as a yellow oil.
Step 9: 1-(2,6-dichloro(difluoromethyl)phenyl) ((3,5-difluorobenzyl)amino)ethanol (A111) Compound A111 (0.21 g, 36%) was obtained as a colorless gum from the reaction of compound A111-8 (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. 1H NMR (CDCl3, 400 MHz): Ī“ 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 A112] Step 1: roxymethyl)methylcyclohexanol (A112-1) 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 Et2O, 7.8 mL, 23.4 mmol) dropwise at 0 Ā°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 NH4Cl and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over ous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 80% EtOAc/hexane as eluent) to provide compound A112-1 (300 mg, 27%) as a white solid.
Step 2: oxymethylcyclohexanecarbaldehyde (A112- Compound A112-2 (49 mg, crude) was obtained as a yellow foam from the reaction of compound A112-1 (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 e A56, step 4.
Step 3: 4-(((2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)amino)methyl) methylcyclohexanol (A112) To a d on of compound A112-2 (49 mg, 0.34 mmol) in DCM (15 mL) was added compound A1-3 (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 NaHCO3 (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 Na2SO4 and concentrated under reduced re. The residue was ed by column chromatography (silica gel, 5% MeOH/DCM as eluent) to provide compound A112 (58 mg, 37% over two steps) as a yellow gum. ence example A118] N-(2-bromobenzyl)(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethanamine (A118) nd A118 (1.2 g, 79%) was obtained as a colorless oil from the reaction of compound A1-3 (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 A1, step 4. 1H NMR (CDCl3, 400 MHz): Ī“ 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), .86 (m, 9H), 0.58-0.51 (m, 6H).
[Reference example A119] Step 1: 1,3-dibromo-2,2-dimethylpropane (A119-1) To a stirred solution of triphenylphosphine (26.2 g, 0.1 mol) in CH3CN (50 mL) was added a on of bromine (5.13 mL, 0.10 mol) in CH3CN (30 mL) dropwise at 0 Ā°C. 2,2-Dimethylpropane-1,3-diol (5.1 g, 0.05 mol) was added in portion to the reaction and the reaction mixture was d at 90 Ā°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 te 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 trated under d pressure to provide compound A119-1 (6.5 g, 59%) as brown oil.
Step 2: dipentyl 3,3-dimethylcyclobutane-1,1- 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 Ā°C to get a clear solution. The on mixture was heated to 70 Ā°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 Ā°C and compound A119-1 (5.0 g, 21 mmol) was added dropwise over a period of 10 min. The reaction mixture was heated at 130 Ā°C for 4 h. The solvent was removed under vacuum at 100 Ā°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 A119-2 (6 g, crude) as brown oil. The crude product was used for next step without purification.
Step 3: 3,3-dimethylcyclobutane-1,1-dicarboxylic acid (A119-3) To a solution of compound A119-2 (6 g, crude) in EtOH/water (60 mL, 2:1) was added KOH on (40% s solution, 10 mL) and the reaction mixture was stirred at 100 Ā°C for 4 h. After removing the solvent under reduced pressure, the e 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 Na2SO4 and concentrated under reduced pressure to provide compound A119-3 (2.5 g, crude) as brown olid gum. The crude product was used for next step without purification.
Step 4: 3,3-dimethylcyclobutanecarboxylic acid (A119-4) Compound A119-3 (2.5 g, crude) was heated neat at 200 Ā°C for 2 h to provide compound A119-4 (900 mg, crude) as light brown gum.
Step 5: (3,3-dimethylcyclobutyl)methanol (A119-5) To a stirred suspension of LiAlH4 (534 mg, 14.0 mmol) in THF (20 mL) was added a solution of compound A119-4 (900 mg, 7.0 mmol) in THF (10 mL) at 0 Ā°C and the mixture was stirred at the same ature for 3 h. The reaction mixture was quenched with water (3 mL) and 20% aqueous NaOH (3 mL) and stirred at room temperature for 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as ) to e compound A119-5 (160 mg, 20%) as light yellow oil.
Step 6: 3,3-dimethylcyclobutanecarbaldehyde (A119-6) To a stirred solution of compound A119-5 (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 on mixture was diluted with DCM (10 mL) and quenched with aqueous Na2S2O8 (5 mL) and NaHCO3 on (5 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over ous Na2SO4 and concentrated under reduced pressure to provide compound A119-6 (150 mg, quant.) as yellow oil. The crude product was used for next step without purification.
Step 7: 2-(3,5-dichloropyridinyl)-N-((3,3- dimethylcyclobutyl)methyl) ((triethylsilyl)oxy)ethanamine (A119) The mixture of nd A119-6 (150 mg, 1.33 mmol) and compound A1-3 (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 c layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The e was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound A119 (190 mg, 36%) as yellow gum. 1H NMR (CDCl3, 400 MHz): Ī“ 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).
[Reference example A122] Step 1: ethyl 4-methylenecyclohexanecarboxylate (A122-1) Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a d solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0 Ā°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 Ā°C and stirred for 2 h from 0 Ā°C to room temperature. The reaction was quenched with saturated NH4Cl aq. and extracted with hexane. The collected organic layer was dried over MgSO4 and concentrated under reduced re. The solvent (100 mL, hexane/Et2O = 5/1) was added to the residue and stirred for 30 min. The sion was filtrated. The filtrate was concentrated under reduced pressure. The e was purified by silicagel chromatography (5% EtOAc/hexane as eluent) to provide compound A122-1 (1.478 g, 73%) as a ess oil.
Step 2: ethyl 1-(bromomethyl) methylenecyclohexanecarboxylate (A122-2) n-BuLi (2.6 M in hexane, 2.5 mL, 6.6 mmoL) was added dropwisely to a solution of ropylamine (0.93 mL, 6.6 mmol) in THF (20 mL) at -78 Ā°C and stirred for 30 min at the same temperature. Hexamethylphosphoramide (4 mL) was added to the reaction e and stirred for 20 min at the same temperature. A solution of compound A122-1 (1.01 g, 6 mmol) in THF (5 mL) was added and d 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 NH4Cl aq., brine, dried over MgSO4 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]heptanecarboxylate (A122-3) To a stirred solution of compound A122-2 (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 Ā°C for 1 h. The on mixture was cooled down and concentrated under d 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 Na2SO4 and concentrated under reduced re. The e was purified by silicagel chromatography (10% EtOAc/hexane as ) to provide compound A122-3 (501 mg, 92%) as a colorless oil.
Step 4: 4-methylbicyclo[2.2.1]heptanecarboxylic acid (A122-4) To a stirred on of compound A122-3 (500 mg, 2.74 mmol) in ater (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 Ā°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 HCl to pH 1 and extracted with DCM. The organic layers were dried over MgSO4 and concentrated under d 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 carboxamide (A122-5) To a mixture of compound A122-4 (302 mg, 1.96mmol), 1-hydroxybenzotrizole monohydrate (460 mg, 3 mmol), 1-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride (466 mg, 3 mmol) and N,O-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 ature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc.
The collected organic layer was washed with saturated NH4Cl aq., brine, dried over MgSO4 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 ess oil.
Step 6: 4-methylbicyclo[2.2.1]heptanecarbaldehyde (A122-6) To a solution of compound A122-5 (271 mg, 1.37 mmol) in Et2O (5 mL) was added a suspension of LiAlH4 (52 mg, 1.37 mmol) in Et2O (2 mL) at 0 Ā°C and stirred for 45 min at the same temperature. The reaction mixture was quenched with saturated KHSO4 aq. (5 mL) at 0 Ā°C and stirred for 30 min at room temperature and extracted with Et2O. The organic layer was dried with MgSO4 and concentrated under reduced pressure to provide compound A122-6 (163 mg, 86%) as a colorless oil. The crude product was used for next step without purification.
Step 7: 2-(3,5-dichloropyridinyl)-N-((4- methylbicyclo[2.2.1]heptanyl)methyl) ((triethylsilyl)oxy)ethanamine (A122) Compound A122 (177 mg, 80%) was ed as a pale yellow oil from the reaction of compound A1-3 (160 mg, 0.50 mmol), compound A122-6 (82 mg, 0.59 mmol), NaBH4 (120 mg) and MgSO4 ) in MeOH (4 mL) and DCM (3mL) using a similar procedure to that described in reference example A31, step 4. 1H NMR (CDCl3, 400 MHz): Ī“ 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).
[Reference example A124] Step 1: ethyl cyclopentanecarboxylate (A124-1) To a solution of entanecarboxylate (1.14 g, 10 mmol) in EtOH (5mL) was added H2SO4 (0.1 mL) at room ature. The mixture was allowed to warm to 80 Ā°C and stirred at the same temperature for 3.5 h. The on mixture was cooled down to room temperature and poured into saturated NaHCO3 aq. (40 mL). The mixture was stirred at room ature for 30 min and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide compound A124-1 (1.01 g, 71%) as a pale yellow oil. The crude product was used for next step without purification.
Step 2: ethyl 1-fluorocyclopentanecarboxylate (A124-2) n-BuLi (2.6 M in hexane, 4.0 mL, 10.5 mmoL) was added dropwisely to a on of diisopropylamine (1.55 mL, 11 mmol) in THF (40 mL) at -78 Ā°C and stirred for 30 min at the same temperature. A solution of compound A124-1 (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 e was allowed to warm to 0 Ā°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 NH4Cl aq. and extracted with EtOAc. The collected organic layer was concentrated under reduced pressure. The residue was purified by silicagel tography (10% EtOAc/hexane as eluent) to provide compound A124-2 (911 m g, 81%) as a yellow oil.
Step 3: 1-fluorocyclopentanecarboxylic acid (A124-3) To a stirred solution of compound A124-2 (910 mg, .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 t was removed under reduced re. The residue was acidified with 2 M aqueous HCl to pH 1 and ted with EtOAc. The organic layer was dried over MgSO4 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 (A124-4) To a mixture of compound A124-3 (709 mg, 5.37 mmol), 1-hydroxybenzotrizole (986 mg, 6.44 mmol), 1-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride (1.0 g, 6.44 mmol) and N,O-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 HCl (30 mL) and extracted with EtOAc. The collected organic layer was washed with water, brine, dried over MgSO4 and concentrated under reduced re. The residue was purified by silicagel chromatography (20% EtOAc/hexane as eluent) to provide compound A124-4 (543 mg, 58%) as a yellow oil.
Step 5: 1-fluorocyclopentanecarbaldehyde (A124-5) To a on of compound A124-4 (140 mg, 0.8 mmol) in Et2O (20 mL) was added LiAlH4 (33 mg, 0.88 mmol) at 0 Ā°C and stirred for 5 h at the same temperature. The on mixture was quenched with saturated KHSO4 aq. (5 mL) at 0 Ā°C and extracted with Et2O. The ed organic layer was dried over MgSO4 and concentrated under reduced pressure to provide compound A124-5. The crude product was used for next step t purification.
Step 6: 2-(3,5-dichloropyridinyl)-N-((1- fluorocyclopentyl)methyl) ((triethylsilyl)oxy)ethanamine (A124) Compound A124 (207 mg, 68%) was ed from the reaction of compound A1-3 (233 mg, 0.73 mmol), compound A124-5 (93 mg, 0.8 mmol), NaBH(OAc)3 (231 mg, 1.09 mmol), MgSO4 (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 (CDCl3, 400 MHz): Ī“ 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).
[Reference example A141] Step 1: 3-methylenecyclobutanecarboxylic acid 1) To a stirred solution of KOH (10 g, 178 mmol) in water (15 mL) and EtOH (15 mL) was added 3- methylenecyclobutanecarbonitrile (3.92 g, 42 mmol) at room temperature for 10 min. The mixture was allowed to warm to 90 Ā°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 Ā°C. The mixture was acidified with 6 M aqueous HCl to pH 1 and ted with DCM. The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide compound A141-1 (4.65 g, 98%) as a colorless oil.
The t 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 Ā°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 re. The residue was purified by silicagel chromatography (20% DCM/hexane as eluent) to provide nd A141-2 (3.8 g, 73%) as a colorless oil.
Step 3: methyl spiro[2.3]hexanecarboxylate (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) se at 0 Ā°C for 30 min. A on of diiodomethane (3.7 mL, 46 mmol) in DCM (50 mL) was added dropwise at 0 Ā°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 e was allowed to warm to room temperature for overnight. The reaction mixture was quenched with saturated NH4Cl aq. (200 mL) and extracted with DCM. The collected organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (20% EtOAc/hexane as eluent) to provide compound A141-3 (1.77 g, 63%) as a colorless oil.
Step 4: spiro[2.3]hexanecarboxylic 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 nd A141-3 (1.76 g, 12.6 mmol) at room temperature.
The mixture was stirred at room temperature for 40 min.
The on mixture was concentrated under reduced pressure to ca. 20 mL of solution. The solution was acidified with 6 M aqueous HCl to pH 1 and ted with DCM. The organic layer was dried over MgSO4 and concentrated under reduced pressure to e compound A141-4 (1.51 g, 95%) as a colorless oil. The product was used for next step without futher purification.
Step 5: oxy-N-methylspiro[2.3]hexanecarboxamide (A141-5) To a mixture of compound A141-4 (1.51 mg, 12.0 mmol), 1-hydroxybenzotrizole monohydrate (2.30 g, 15 mmol), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (2.33 g, 15 mmol) and N,O- 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 HCl aq. (100 mL), water, saturated Na2CO3 aq. (2 x 100 mL), brine, dried over MgSO4 and concentrated under reduced pressure. The residue was ed by silicagel chromatography (75% EtOAc/hexane as eluent) to e compound A141-5 (1.72 g, 84%) as a colorless oil.
Step 6: 2.3]hexanecarbaldehyde (A141-6) To a solution of compound A141-5 (677 mg, 4 mmol) in Et2O (15 mL) was added a suspension of LiAlH4 (152 mg, 4 mmol) in Et2O (5 mL) at 0 Ā°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 Ā°C and ted with Et2O. The ed organic layer was dried with MgSO4 and concentrated under reduced pressure to provide compound A141-6 (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 ylmethyl)((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)((triethylsilyl)oxy)ethanamine (248 mg, 0.7 mmol), compound A141-6 (100 mg, 0.91 mmol), NaBH4 (212 mg) and MgSO4 (100mg) 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 (CDCl3, 400 MHz): Ī“ 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, [Reference example A194] 1-(2,6-dichlorofluorophenyl)(((1- (trifluoromethyl)cyclopropyl)methyl)amino)ethanol Step 1: -dichlorofluorophenyl) ((trimethylsilyl)oxy)acetonitrile To a 200 ml RBF was charged with solution of 2,6- dichlorofluorobenzaldehyde (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 a gel, eluent: 0% to 30% EtOAc/heptane) to provide 2-(2,6- dichlorofluorophenyl) ((trimethylsilyl)oxy)acetonitrile (1.435 g, 4.91 mmol, 41.4 % yield) as colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ .42 (m, 1 H); 7.12-7.24 (m, 1 H); .30 (m, 1 H); 0.12-0.33 (m, 9 H).
Step 2: 2-(2,6-dichlorofluorophenyl) ((trimethylsilyl)oxy)acetaldehyde To a 100 mL three-necked RBF were added -dichloro- 3-fluorophenyl)((trimethylsilyl)oxy)acetonitrile (0.50 g, 1.711 mmol) and DCM (9 ml). The reaction mixture was purged with nitrogen and cooled to -64 Ā°C. Under a en here, diisobutylaluminum hydride, 1.0 M solution in hexane (2.6 ml, 2.6 mmol) was added dropwise.
The mixture was stirred at -64 Ā°C. After 2 h, the reaction was ed. While maintaining temp <-65 Ā°C, MeOH (1.4 ml, 34.2 mmol) was carefully added dropwise to the reaction mixture followed by ted 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 MgSO4, and concentrated to afford 2-(2,6- rofluorophenyl) ethylsilyl)oxy)acetaldehyde as a colorless oil (0.517 g, crude).
Step 3: 1-(2,6-dichlorofluorophenyl)(((1- (trifluoromethyl)cyclopropyl)methyl)amino)ethanol To a solution of crude 2-(2,6-dichloro fluorophenyl)((trimethylsilyl)oxy)acetaldehyde (0.258 g, 0.874 mmol) in MeCN (9 ml) was added (1- (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 NaHCO3 solution and stirred for 30 min. It was extracted with DCM (2x5 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, 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 NaHCO3 and extracted with DCM. The combined c layer was dried over anhydrous MgSO4 and concentrated under reduced pressure.
The crude material was ed by column chromatography (silica gel, eluent : 0% to 50% EtOAc/heptane) to provide 1-(2,6-dichlorofluorophenyl)(((1- (trifluoromethyl)cyclopropyl)methyl)amino)ethanol (116 mg, 0.335 mmol, 38.3% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 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., 1H), 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-dichlorofluorophenyl)-N-((1- methylcyclopropyl)methyl) ((triethylsilyl)oxy)ethanamine A mixture of 1-methylcyclopropanecarbaldehyde (31.6 mg, 0.375 mmol) and 2-(2,6-dichlorofluorophenyl) ((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 ns and the mixture was d 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 fluorophenyl)-N-((1-methylcyclopropyl)methyl) ((triethylsilyl)oxy)ethanamine (111 mg, 0.273 mmol, 72.8% yield). 1H NMR (500 MHz, CDCl3) Ī“ 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-((1-methylcyclopropyl)methyl) ((triethylsilyl)oxy)ethanamine To a mixture of 1-methylcyclopropanecarbaldehyde (32.8 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6- dichlorophenyl)((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by Ac)3 (124 mg, 0.585 mmol).
After 45 min, this was quenched with sat. aq. NaHCO3. 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-((1- methylcyclopropyl)methyl) thylsilyl)oxy)ethanamine (95 mg, 0.245 mmol, 62.7 %yield). 1H NMR (500 MHz, CDCl3) Ī“ 7.28-7.30 (m, 2H), 7.12-7.16 (m, 1H), 5.65 (br. s., 1H), 3.37-3.44 (m, 1H), 2.82-2.90 (m, 1H), 2.69 (br. s., 1H), 2.48 (d, J=11.86 Hz, 1H), 1.60 (br. s., 1H), 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 A259] Step 1: 2-(2,6-dichlorophenyl) ((trimethylsilyl)oxy)acetonitrile A 100 ml RBF was charged with solution of 2,6- robenzaldehyde (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 t 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% EtOAc in heptane to afford 2-(2,6- dichlorophenyl)((trimethylsilyl)oxy)acetonitrile (3.01 g, 38%).
Step 2: 2-(2,6-dichlorophenyl) ((trimethylsilyl)oxy)acetaldehyde.
To a solution of 2-(2,6-dichlorophenyl) ((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 Ā°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 EtOAc (20 ml). The organic layer was separated and washed with brine, filtered through celite pad and concentrated to obtain 2-(2,6-dichlorophenyl) ((trimethylsilyl)oxy)acetaldehyde (1.34 g, 97%) as a white solid.
Step 3: 2-(2,6-dichlorophenyl)-N-((1- (trifluoromethyl)cyclopropyl)methyl) ((trimethylsilyl)oxy)ethanamine.
To a solution of crude 2-(2,6-dichlorophenyl) ethylsilyl)oxy)acetaldehyde (0.35 g, 1.263 mmol) in DCM (6.31 ml) was added (1- uoromethyl)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 NH4Cl solution and diluted with DCM (50 mL). Organic layer was passed through phase seperator and concentrated to obtain 2-(2,6-dichlorophenyl)-N-((1- (trifluoromethyl)cyclopropyl)methyl) ((trimethylsilyl)oxy)ethanamine (0.378 g, 70%) as light yellow oil. This was used in next step without r purification.
[Reference e A260] 2-(2,6-dichlorophenyl)-N-((1-methylcyclobutyl)methyl) ((triethylsilyl)oxy)ethanamine To a mixture of 1-methylcyclobutanecarbaldehyde (38.3 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6- dichlorophenyl)((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by Ac)3 (124 mg, 0.585 mmol).
After 45 min, this was quenched with sat. aq. . 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-((1- methylcyclobutyl)methyl)((triethylsilyl)oxy)ethanamine (89 mg, 0.221 mmol, 56.7% yield). 1H NMR (500 MHz, CDCl3) Ī“ 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 yl)methyl)((triethylsilyl)oxy)ethanamine Spiro[2.3]hexanecarbaldehyde (300 mg, 2.72 mmol) and N-ethyl-N-isopropylpropanamine (546 Ī¼l, 3.13 mmol) were combined in MeCN (5 mL) and trimethylsilyl trifluoromethanesulfonate (517 Ī¼l, 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 on was d and sonicated for an additional 30 min. 2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethanamine (785 mg, 2.451 mmol) and AcOH (187 Ī¼l, 3.27 mmol) were added. The solution was stirred for 30 min and Ac)3 (1154 mg, 5.45 mmol) was added and the solution was stirred for an additional 2 h.
The solution was quenched with saturated NaHCO3, the aqueous layer was extracted with ethyl aceate and the combined organic layers were washed with brine and dried over anhydrous Na2SO4, 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 yl)methyl)((triethylsilyl)oxy)ethanamine (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]octanylmethyl) ((triethylsilyl)oxy)ethanamine To a on of 2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 Ī¼l) was added spiro[2.5]octanecarbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 Ī¼l, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for ght. 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 Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give 2-(2,6-dichlorophenyl)-N- (spiro[2.5]octanylmethyl) ((triethylsilyl)oxy)ethanamine.
[Reference example A275] N-(2-(3-chloroquinolinyl) thylsilyl)oxy)ethyl)-2,2-dimethylpropanamine Step 1: 3-chloroquinolin-4(1H)-one (A275-1) A mixture of 4-hydroxyquinoline (5.33 g, 36.7 mmol) in AcOH (184 mL) was treated with rosuccinimide (6.37 g, 47.7 mmol) and the yellow homogeneous mixture was stirred and heated at 60 Ā°C. After 3 h, the mixture was cooled to room temperature and concentrated in vacuo.
Saturated aqueous NaHCO3 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(1H)-one (A275-1) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 12.28 (1H, br. s.), 8.40 (1H, d, J=6.5 Hz), 8.15 (1H, dd, J=8.2, 1.4 Hz), 7.65-7.73 (1H, m), .63 (1H, m), 7.39 (1H, ddd, J=8.1, 6.9, 1.2 Hz); LCMS (ESI) m/z 180.1 (M+H)+.
Step 2: 4-bromochloroquinoline (A275-2) To a cooled suspension of 3-chloroquinolin-4(1H)-one (A275-1) (5.15 g, 28.7 mmol) in DMF (43.4 mL) at 0 Ā°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 Ā°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 Ā°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-bromochloroquinoline (A275-2) as offwhite solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.96 (1H, s), 8.20 (1H, dd, J=8.2, 1.6 Hz), 8.12 (1H, 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 ]+.
Step 3: roquinolinecarbaldehyde (A275-3) A flask was charged with 4-bromochloroquinoline (A275-2) (1.00 g, 4.12 mmol) and THF (16.5 mL) under nitrogen, and the solution was cooled to -78 Ā°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 Ā°C for 1 hour. To the mixture was added DMF (1.60 mL, 20.6 mmol) se, and the e was d to warm to room temperature. After 4 h, the mixture was quenched with saturated aqueous NH4Cl (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 c extract was dried over MgSO4. 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 REDISEPTM 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- chloroquinolinecarbaldehyde (A275-3) as brown solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 10.74 (1H, s), 9.10 (1H, s), 8.68-8.73 (1H, m), 8.15 (1H, dd, J=8.5, 0.9 Hz), 7.79- 7.92 (2H, m); LCMS (ESI) m/z 192.1 (M+H)+.
Steps 4: 1-(3-chloroquinolinyl)nitroethanol (A275- To a brown clear solution of 3-chloroquinoline 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 neous mixture was d at room temperature. After 4 h, the on 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 Na2SO4. The solution was filtered, trated in vacuo, and dried under high vacuum to give 1-(3-chloroquinolinyl)nitroethanol (A275-4) as a brown solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.88-8.93 (1H, m), 8.73 (1H, dd, J=8.6, 0.8 Hz), 8.08 (1H, dd, J=8.4, 1.0 Hz), 7.82 (1H, ddd, J=8.4, 6.9, 1.5 Hz), 7.72 (1H, ddd, J=8.5, 6.9, 1.4 Hz), 6.91 (1H, dd, J=4.5, 1.0 Hz), 6.26 (1H, ddd, J=10.0, 4.6, 3.6 Hz), 5.03-5.12 (1H, m), 4.94-5.01 (1H, m); LC-MS (ESI) m/z 253.1 (M+H)+.
Step 5: 3-chloro(2-nitro ((triethylsilyl)oxy)ethyl)quinoline (A275-5) To a brown clear solution of 1-(3-chloroquinolin yl)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 Na2SO4. The solution was filtered and trated 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(2-nitro ((triethylsilyl)oxy)ethyl)quinoline (A275-5). 1H NMR (400 MHz, DMSO-d6) Ī“ 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- .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: hloroquinolinyl) ((triethylsilyl)oxy)ethanamine (A275-6) To a clear yellow solution of ro(2-nitro ((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 d and heated at 60 Ā°C. After 4 h, the mixture was cooled to room temperature and filtered through a celite pad and washed the pad with MeOH (3 Ɨ 30 mL). The combined filtrates were concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The e (pH ~4.0) was washed with saturated aqueous NaHCO3 (1 x 50 mL), water (1 x 50 mL), and brine (1 x 50 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and dried under high vacuum to give 2-(3- chloroquinolinyl)((triethylsilyl)oxy)ethanamine (A275-6) as a yellow syrup. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.84 (1H, s), 8.72 (1H, d, J=8.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.76 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.64 (1H, ddd, J=8.5, 7.0, 1.3 Hz), 5.52 (1H, dd, J=7.6, 5.5 Hz), 3.16 (1H, dd, J=13.0, 7.9 Hz), 2.88 (1H, dd, J=13.0, .4 Hz), 1.74 (1H, 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-chloroquinolinyl) ((triethylsilyl)oxy)ethyl)-2,2-dimethylpropanamine (A275) To a yellow clear solution of 2-(3-chloroquinolin yl)((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 t was washed with saturated NaCl (1 x 50 mL) and dried over . 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 tography through a REDISEPTM 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- quinolinyl)((triethylsilyl)oxy)ethyl)-2,2- dimethylpropanamine (A275) as colorless syrup. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.84 (1H, s), 8.75 (1H, d, J=7.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.77 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.61-7.68 (1H, m), 5.70 (1H, dd, J=7.7, 5.0 Hz), 3.26 (1H, dd, J=12.6, 8.1 Hz), 2.85 (1H, dd, J=12.6, 5.0 Hz), 2.23-2.39 (2H, m), 1.72 (1H, 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-dichloropyridinyl)-N-((5-methyltetrahydrofuran- 2-yl)methyl)((triethylsilyl)oxy)ethanamine To a clear solution of yltetrahydrofuranmethanol in DCM was added artin 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- ropyridinyl)((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 Na2S2O3 and saturated NaHCO3. The reaction mixture was extracted with DCM. The organic extract was dried over Na2SO4. 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 e to provide 2- (3,5-dichloropyridinyl)-N-((5-methyltetrahydrofuran yl)methyl)((triethylsilyl)oxy)ethanamine (A281) as a light-yellow syrup. 1H NMR (300 MHz, DMSO-d6) Ī“ 8.58 (2H, s), 5.34-5.46 (1H, m), 3.71-3.90 (2H, m), 3.10 (1H, dt, , 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), 1.11 (3H, t, J=6.3 Hz), .89 (9H, m), 0.40- 0.62 (6H, m); LCMS (ESI) m/z 419.1 (M+H)+.
[Reference example A294] N-(2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2- dimethylpropanamine 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 e was stirred at room temperature. After 15 min, to the dark clear mixture was added N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) and the mixture was stirred at room temperature. After 18 h, the reaction mixture was d with EtOAc (100 mL) and washed with 1 N HCl (2 x 100 mL), and sat. NaCl (5 x 100 mL) and dried over Na2SO4. 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- oro-N-methoxy-N,2,2-trimethylpropanamide 3 g, .4 mmol, 79% yield) as yellow liquid. 1H NMR (300 MHz, CDCl3) Ī“ 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: 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 Et2O (25.3 ml, 25.3 mmol) at 0 Ā°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, .3 mmol) in Et2O (47.7 ml) dropwise over 35 min at 0 Ā°C.
After the completion of the addition, the reaction mixture was further stirred at 0 Ā°C. After 2 h, the mixture was carefully ed at 0 Ā°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 Et2O (50 mL), treated with Na2SO4 and then filtered through a Celite pad, washed with Et2O (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, CDCl3) Ī“ 9.69 (1H, d, J=1.4 Hz), 1.31 (6H, s).
Step 3: N-(2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2- dimethylpropanamine (A294) To a yellow clear mixture of 2-(3,5-dichloropyridin- 4-yl)((triethylsilyl)oxy)ethanamine (3.57 g, 11.11 mmol) in DCM (37.0 mL) was added trifluoro-2,2- dimethylpropanal (11.11 mmol) in DCM ed 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 NaHCO3 (100 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The c extract was dried over Na2SO4. 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 ed by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to provide N-(2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2- dimethylpropanamine (A294) (3.4393 g, 7.72 mmol, 69.5% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ 8.44 (2H, s), 5.48 (1H, dd, J=7.7, 4.4 Hz), 3.27 (1H, dd, J=12.3, 8.4 Hz), .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 es described above: ā€”128- ā€”\,SiJ HOā€™CI HO'CI H 0 Cl N N | | /N /N Cl Cl A3 A4 oā€™CI H 0ā€™ Cl O'CI O'CI O'CI ā€”130- F ā€”\.5'1 F ā€”\Si~/ Cl OMe A43 A44 F ā€”\51 ā€”\3.1 OMe Cl A46 A48 A,SiJ A> H 0 Cl 0ā€™S Cl M90 H KN \ A50 A51 ā€”\SiJ ā€”\s-J N/l H 0 Cl H 0 Cl \ N N Cl Cl F A53 A54 F ā€”\Ā§iā€”/ ā€”\ F 3:1 mo C. m 0 C.
A60 A61 _\SIā€”/ _\SIā€”/ /N H 0 Cl / H 0 Cl \ N \ N \ \ l | /N /N Cl Cl A62 A63 A64 F ā€”\ā€™31 F ā€”\siJ F ā€”\siJ H o o OMe o OMe F QĀ»... F F QĀ»... NJDCICl N\)jĀ©MeO N\):Ā©\Cl Cl A65 A67 A69 ā€”\ ā€”\ F ā€”\Ā§i_/ ,SiJ ,SiJ Qā€œ Ā° H 0 CI H O OMe _ā€œ |\ _ ā€™N Cl Cl Cl A70 A71 A72 F ā€”\Ā§i_/ _\,SiJ F _\SiJ QH O OMe Owl-I 0 Cl QH 0 Cl N N N \ F \ /N Boc MeO Cl / N Cl N OMe A73 A74 A76 ā€”\,SiJ F ļ¬‚,SiJ ā€”\SiJ H 0 Cl QH O CF3 >|//, H 0 CI ļ¬r! Ndji: N |\ F \ /N /N Cl Cl Cl A77 A79 A80 ā€”\,SiJ F ā€”\$1 _\ 0 ,SiJ N N N |\ F \ /N / N Cl Cl OCF3 Cl A81 A82 A83 F ļ¬S Ā§i_/ F _\Siā€”/ F ā€”\Siā€”ā€”/ O Ole H 0 o FQH \N leo N/ 0le Nā€™J / A85 A87 A88 F F Si Si Si H O H O Cl H O Cl F N N Cl CF3 N Cl Cl A89 A90 A95 Si F Si MeO Si O Cl H O NO2 H H O NO2 N N N F A96 A97 A98 Si Si Si H O Cl F N H O OMe H O Cl O N N N Cl OCF3 N Cl Cl A99 A100 A101 Si Si Si H O Cl N H O Cl H O N N N N OMe N Cl Cl Cl CF3 A102 A104 A105 Si Si Si H O Cl N H O Cl H O Cl N N O N N N N H N Cl Cl Cl A106 A107 A108 Si Si Si H O Cl H O Cl N O O H Cl O N N N S N H N N N Cl Cl Cl A109 A110 A113 ā€”\SiJ 0 Cl CI CI ā€”\,SiJ H 0 CI A170 A171 ā€”136- ā€”\,Si1 ā€”\,s-J 8g X KNO Cl H o F H 0 \ 9 /N /N CI CI A173 A174 A175 ā€”\,s-J ā€”\,SiJ H 0 Cl H 0 Cl 0500 u Cl F Cl F A177 A178 ā€”\Si1 ā€”\5'1 H 0 Cl H 0 Cl F ā€WI: CI F WUCI A180 A181 ā€”\Siā€”/ ā€”\__/ ,S' H (5 CI F H 0 CI N /N o CI F/J\F A183 A184 reference reference ure structure example example A185 #NAME? A192 #NAME? A186 #NAME? A193 #NAME? A187 #NAME? A194 #NAME? A188 #NAME? A195 #NAME? A189 #NAME? A196 #NAME? A190 #NAME? A197 #NAME? A191 #NAME? A198 #NAME? reference reference ure structure example example A199 #NAME? A206 #NAME? A200 #NAME? A207 #NAME? A201 #NAME? A208 #NAME? A202 #NAME? A209 #NAME? A203 #NAME? A210 #NAME? A204 #NAME? A211 #NAME? A205 #NAME? A212 #NAME? reference nce structure structure example example A213 #NAME? A220 #NAME? A214 #NAME? A221 #NAME? A215 #NAME? A222 #NAME? A216 #NAME? A223 #NAME? A217 #NAME? A224 #NAME? A218 #NAME? A225 #NAME? A219 #NAME? A226 #NAME? reference nce structure structure example example A227 #NAME? A234 #NAME? A228 #NAME? A235 #NAME? A229 #NAME? A236 #NAME? A230 #NAME? A237 #NAME? A231 #NAME? A238 #NAME? A232 #NAME? A239 #NAME? A233 #NAME? A240 #NAME? reference nce structure structure example example A241 #NAME? A248 #NAME? A242 #NAME? A249 #NAME? A243 #NAME? A250 #NAME? A244 #NAME? A251 #NAME? A245 #NAME? A252 #NAME? A246 #NAME? A253 #NAME? A247 #NAME? A254 #NAME? reference reference ure structure example example A255 #NAME? A262 #NAME? A256 #NAME? A263 #NAME? A257 #NAME? A264 #NAME? A258 #NAME? A265 #NAME? A259 #NAME? A266 #NAME? A260 #NAME? A267 #NAME? A261 #NAME? A268 #NAME? reference reference structure structure e example A269 #NAME? A276 #NAME? A270 #NAME? A277 #NAME? A271 #NAME? A278 #NAME? A272 #NAME? A279 #NAME? A273 #NAME? A280 #NAME? A274 #NAME? A281 #NAME? A275 #NAME? A282 #NAME? reference reference structure ure example example A283 #NAME? A290 #NAME? A284 #NAME? A291 #NAME? A285 #NAME? A292 #NAME? A286 #NAME? A293 #NAME? A287 #NAME? A294 #NAME? A288 #NAME? A295 #NAME? A289 #NAME? A296 #NAME? reference reference structure structure e example A297 #NAME? A304 #NAME? A298 #NAME? A305 #NAME? A299 #NAME? A306 #NAME? A300 #NAME? A307 #NAME? A301 #NAME? A308 #NAME? A302 #NAME? A309 #NAME? A303 #NAME? A310 #NAME? reference reference structure structure e example A311 #NAME? A318 #NAME? A312 #NAME? A313 #NAME? A314 #NAME? A315 #NAME? A316 #NAME? A317 #NAME? [Reference example B1] Step 1: 2-(3,5-dichloropyridinyl)ethanol (B1-1) 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 Ā°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 d to warm to room temperature gradually and stirred for 1 h at room temperature. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The c layer was washed with brine (2 times) and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound B1-1(3.1 g, 60%) as a yellow solid.
Step 2: 4-(2-azidoethyl)-3,5-dichloropyridine (B1-2) To a solution of compound B1-1 (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 Ā°C. The on mixture was allowed to warm to room temperature gradually and stirred at room ature 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 MgSO4.
After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound B1-2 (2.4 g, 68%) as a yellow oil.
Step 3: 2-(3,5-dichloropyridinyl)ethanamine (B1-3) To a solution of compound B1-2 (2.4 g, 11.1 mmol) in THF (25 mL) was added triphenylphosphine (2.9 g, 22.1 mmol) at 0 Ā°C. The mixture was d at room temperature for 2 h, and then water (2.5 mL) was added.
The reaction mixture was allowed to warm to room temperature lly and stirred at room temperature for 22 h. The reaction mixture was quenched by adding 2 M aqueous HCl (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 MgSO4.
Drying the solution under high vacuum yielded compound B1-3 (1.9 g, 90%) as a white solid.
Step 4: 2-(3,5-dichloropyridinyl)-N-(4- fluorobenzyl)ethanamine (B1) To a solution of nd B1-3 (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 ature for 3 h. The reaction mixture was cooled to 0 Ā°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 MgSO4. After the solvent was removed, the residue was purified by column tography on silica gel to give compound B1 (3.4 g, 75%) as a pale yellow solid.
[Reference example B2] Step 1: 1,3-dichlorofluoro(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 HCl (20 mL) at room ature and the mixture was stirred at reflux for overnight. The reaction mixture was neutralized with % 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% hexane as eluent) to provide compound B2-1 (0.22 g, 18%) as a ess oil.
Step 2: 2-(2,6-dichlorofluorophenyl)ethanamine (B2-2) To a stirred on 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 ing hylsilane 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 Ā°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 Na2SO4 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: -dichlorofluorophenyl)-N-(3,5- difluorobenzyl)ethanamine (B2) Compound B2 (0.21 g, 69%) was ed 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 B1, step 4. 1H NMR (CDCl3, 300 MHz): Ī“ 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] Step 1: 2-(3,5-dichloropyridinyl)acetaldehyde (B3-1) Compound B1-1 (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% Na2S2O3, the organic layer was washed with saturated NaHCO3 dried with anhydrous Na2SO4 and concentrated. The product was purified by silica gel column chromatography (40 g column) using 0-100 % EtOAc in e 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-dichloropyridinyl)ethyl)-2,2- dimethylpropanamine (B3) Compound B3-1 (0.65 g, 3.42 mmol) was dissolved in DCM (17 ml) under inert atmosphere, then 2,2- dimethylpropanamine (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 ml of saturated NaHCO3 and d for 45 min. The organic layer was ted and trated. The t 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] Step 1: 1-(3,5-dichloropyridinyl)((3,5- difluorobenzyl)amino)ethanol (B13-1) To a stirred solution of 2-(3,5-dichloropyridin yl)-N-(3,5-difluorobenzyl) ((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 Ā°C, and the mixture was allowed to warm up from 0 Ā°C to room temperature while stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2Ɨ20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure to provide nd B13-1 (0.2 g, crude) as brown color gum.
Step 2: tert-butyl (2-(3,5-dichloropyridinyl) hydroxyethyl)(3,5-difluorobenzyl)carbamate (B13-2) To a stirred solution of nd B13-1 (0.2 g, 0.6 mmol) in DCM/water (4:1, 5 mL) were added NaHCO3 (0.1 g, 1.2 mmol) and (Boc) 2O (0.19 g, 0.9 mmol) in DCM (2 mL) at 0 Ā°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 c layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column tography (silica gel, 20% EtOAc/hexane as eluent) to provide compound B13-2 (0.17 g, 65%) as a colorless Step 3: tert-butyl (2-(3,5-dichloropyridinyl) methoxyethyl)(3,5-difluorobenzyl)carbamate (B13-3) 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 MeI (44 Ī¼L, 0.7 mmol) at 0 Ā°C. The mixture was stirred at room temperature for 2 h. The reaction e 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column tography (silica gel, 10% EtOAc/hexane as eluent) to provide compound B13-3 (0.11 g, 99%) as a ess oil.
Step 4: tert-butyl 2-(3,5-dichloropyridinyl)-N-(3,5- difluorobenzyl)methoxyethanamine (B13) To a stirred solution of nd 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. t was evaporated under reduced pressure to provide compound B13-3 (0.1 g, 48%) as a white solid. 1H NMR (CDCl3, 300 MHz): Ī“ 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 B15] Step 1: 3,5-dichloroiodopyridine (B15-1) To a stirred on of 3,5-dichloropyridine (3.0 g, 20.4 mmol) in THF (15 mL) was added LDA (2.0 M solution in THF/heptane/ethylbenzene, 12.14 mL, 24.4 mmol) dropwise at 0 Ā°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 e. Upon tion 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 c layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound B15-1 (3.2 g, 57%) as a yellow gum.
Step 2: ethyl(3,5-dichloropyridinyl)-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 Ā°C for 16 h. The on mixture was cooled to room temperature and quenched with saturated NH4Cl 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% hexane as ) to provide compound B15-2 (315 mg, 60%) as yellowish brown gum.
Step 3: 2-(3,5-dichloropyridinyl)-2,2-difluoroethanol (B15-3) To a stirred solution of compound B15-2 (315 mg, 1.16 mmol) in EtOH (10 mL) was added solid NaBH4 (16.2 mg, 1.74 mmol) in portions at 0 Ā°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 ous Na2SO4 and concentrated under reduced re. The residue was purified by column chromatography (silica gel, 55% EtOAc/hexane as eluent) to provide compound B15-3 (180 mg, 44%) as a ess gum.
Step 4: 4-(2-azido-1,1-difluoroethyl)-3,5- ropyridine (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 Ā°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 Na2SO4, 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-dichloropyridinyl)-2,2- difluoroethanamine (B15-5) To a stirred solution of compound B15-4 (80 mg, 0.31 mmol) in EtOAc (2 mL) were added P (0.47 mL, 0.47 mmol) and H2O (0.5 mL). The e 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 Na2SO4, and concentrated under reduced pressure to provide compound B15-5 (60 mg) as a yellow gum. The crude e was used for next step without purification.
Step 6: 2-(3,5-dichloropyridinyl)-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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as ) to provide compound B15 (66 mg, 38%) as a white solid. 1H NMR (CDCl3, 300 MHz): Ī“ 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)+.
[Reference example B19] Step 1: (E)chloro(2-nitrovinyl)-1H-indole (B19-1) A e of 4-chloroindolecarbaldehyde (314 mg, 1.75 mmol) and ammonium acetate (404 mg, 5.25 mmol) in nitromethane (6 mL) was stirred at 100 Ā°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 MgSO4 and concentrated under reduced pressure. The crude material was purified by silicagel column chromatography (50-100% EtOAc/heptane) to give nd B19-1 (224 mg, 58%) as an orange solid.
Step 2: 2-(4-chloro-1H-indolyl)ethanamine (B19-2) A on of compound B19-1 (1.46 g, 6.56 mmol) in THF (25 mL) was added to a stirred slurry of lithium aluminum e (995 mg, 26.2 mmol) in THF (50 mL) at room ature. 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 usly 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 MgSO4, filtered and concentrated under reduced pressure to give compound B19-2 (1.02 g, 80%) as a dark red syrup.
Step 3: (1R,3r,5S)-N-(2-(4-chloro-1H-indolyl)ethyl)- 6,6-dimethylbicyclo[3.1.0]hexanamine (B19) Compound B19 (22 mg, 14%) was obtained from the reaction of nd B19-2 (100 mg, 0.514 mmol), compound C22-5 (128 mg, 1.03 mmol), NaBH(OAc)3 (326 mg, 1.54 mmol) and AcOH (0.108 mL, 2.05 mmol) in DCM (2 mL) using a similar procedure to that bed in reference example A31, step4. 1H NMR (CDCl3, 400 MHz) Ī“: 8.09 (1H, br s), 7.26-7.22 (1H, m), 7.07-7.05 (3H, m), .47 (1H, 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).
[Reference example B50] 3,5-dichloro(((2R)isopropylpyrrolidin yl)methyl)pyridine (B50) Step 1: (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol- (3H)-one The reaction was ed with a Dean-Stark then 2,2-dimethoxypropane (17.09 mL, 139 mmol) was added to a stirred mixture of (R)-(-)(hydroxymethyl) pyrrolidinone (5.353 g, 46.5 mmol) and p-toluenesulfonic acid drate (0.126 g, 0.662 mmol) in toluene (100 mL). The reaction mixture was refluxed for 1.5 h and d to stir at room ature overnight. Solvent was evaporated to afford (R)-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (7.22 g, 100% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 4.18 (tt, J=8.8, 6.2 Hz, 1H), 4.00 (dd, J=8.1, .8 Hz, 1H), 3.40 (t, J=8.6 Hz, 1H), 2.69 (ddd, J=16.4, 12.1, 8.6 Hz, 1H), 2.33 (dd, J=16.3, 9.1 Hz, 1H), 2.02- 2.11 (m, 1H), 1.73 (tt, J=12.1, 8.9 Hz, 1H), 1.53 (s, 3H), 1.33 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Step 2: (7aR)(2-hydroxypropanyl)-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one To a solution of 3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.68 g, 43.0 mmol) in THF (100 mL) cooled to -78 Ā°C, was added lithium diisopropylamide, 2.0 M solution in ptane/ethylbenzene (43.0 mL, 86 mmol) and stirred at -78 Ā°C for 1 h. The resulting mixture was treated with acetone,99.8%, extra dry, acroseal (6.32 mL, 86 mmol) at -78 Ā°C and then allowed to warm up to room temperature for 16 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (2 x 200 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide (7aR)(2-hydroxypropanyl)- 3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.088 g, 28.5 mmol, 66.3% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) Ī“ 4.50 (s, 1H), 4.07 - 4.18 (m, 1H), 3.98 (dd, J=8.0, 5.7 Hz, 1H), 3.32 - 3.35 (m, 1H), 2.50 - 2.56 (m, 1H), 2.22 (ddd, J=13.4, 7.2, 2.0 Hz, 1H), 1.83 (ddd, J=13.3, 10.4, 7.6 Hz, 1H), 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: (R)-3,3-dimethyl(propan ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one To a solution of (7aR)(2-hydroxypropanyl)-3,3- dimethyltetrahydropyrrolo -[1,2-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 Ā°C for 1 h. The resulting mixture was d 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 MgSO4, ed and concentrated to provide crude (R)-3,3- dimethyl(propanylidene)tetrahydropyrrolo[1,2- 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: (R)(hydroxymethyl)(propan ylidene)pyrrolidinone To a solution of (R)-3,3-dimethyl(propan ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.63 g, 23.73 mmol) in MeOH (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.451 g, 2.373 mmol) and then heated at 60 Ā°C for 45 min. The solvent was evaporated and the crude material was absorbed onto a plug of silica gel and was purified by tography through a PTM pre-packed silica gel column (80 g), eluting with a gradient of 0% to 10% MeOH in DCM to give (R)(hydroxymethyl)(propanylidene)pyrrolidin one (2.223 g, 14.32 mmol, 60.4% yield) as an yellow solid. 1H NMR (400 MHz, CDCl3) Ī“ 6.60 (br. s., 1H), 3.74 (td, J=8.0, 3.9 Hz, 1H), 3.67 (dd, J=11.1, 3.6 Hz, 1H), 3.44 (dd, J=11.1, 7.3 Hz, 1H), 2.75-2.86 (m, 1H), 2.81 (dd, J=16.5, 8.7 Hz, 1H), .43 (m, 1H), 2.23 (s, 3H), 1.77 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Step 5: (5R)(hydroxymethyl)isopropylpyrrolidin one A mixture of (R)(hydroxymethyl)(propan e)pyrrolidinone (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 (5R)(hydroxymethyl)isopropylpyrrolidinone (2.251 g, 14.32 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) Ī“ 6.56-6.71 (m, 1H), 3.64-3.80 (m, 2H), 3.37-3.53 (m, 1H), 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=12.7, .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: ((2R)isopropylpyrrolidinyl)methanol To a solution of (5R)(hydroxymethyl) isopropylpyrrolidinone (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 ature dropwise slowly. The resulting mixture was then refluxed at 75 Ā°C for 2 h. Additional m 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 Ā°C. The reaction was quenched by adding ted aqueous solution of Rochelle's salt. The reaction mixture was stirred usly for 1 h and the layers were separated.
The aqueous layer was extracted with EtOAc twice and the organics were ed, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 4-isopropylpyrrolidinyl)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:(3aR)isopropyltetrahydro-3H-pyrrolo[1,2- c][1,2,3]oxathiazole 1,1-dioxide A solution of ((2R)isopropylpyrrolidin yl)methanol (1.639 g, 11.44 mmol) and triethylamine (3.18 mL, 22.89 mmol) in DCM (100 mL) was cooled to -78 Ā°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, tograph through a REDISEPTM pre-packed a gel column (40 g), eluting with a gradient of 0% to 10% MeOH (with 2 M NH3) in DCM to give (3aR)isopropyltetrahydro-3H- pyrrolo[1,2-c][1,2,3]oxathiazole oxide (211.9 mg, 1.032 mmol, 9 %yield) as light yellow oil. m/z (ESI, +ve) 206 (M+H).
Step 8: 3,5-dichloro(((2R)isopropylpyrrolidin yl)methyl)pyridine To a solution of 3,5-dichloropyridine (228 mg, 1.542 mmol) in THF (2.6 mL) at -78 Ā°C was added m diisopropylamide, 2.0 M heptane/THF/ethylbenzene (0.976 mL, 1.953 mmol) dropwise. After stirring for 45 min, a solution of (3aR)isopropyltetrahydro-3H-pyrrolo[1,2- c][1,2,3]oxathiazole 1,1-dioxide (211 mg, 1.028 mmol) in THF (3.0 mL) was added dropwise at -78 Ā°C. The resulting mixture was allowed to warm to room temperature and then stirred for 3 h. After evaporation of the solvent, the ing brown solid was treated with 2 N HCl (3 mL) and EtOH (3 mL) and heated at 80 Ā°C for 2 h. The reaction mixture was concentrated to remove the EtOH. The resulting mixture was d 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 h a REDISEPTM 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(((2R) isopropylpyrrolidinyl)methyl)pyridine (102 mg, 0.373 mmol, 36.3% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) Ī“ 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-diallylpyrrolidin hyl)pyridine Step 1: (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol- (3H)-one To a stirred suspension of (R)-(-) (hydroxymethyl)pyrrolidinone (2.20 g, 19.11 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[1,2-c]oxazol-5(3H)-one (3.04 g, 19.59 mmol, 103% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 4.27 (tt, J=6.01, 9.00 Hz, 1H), 4.09 (dd, J=5.65, 8.24 Hz, 1H), .50 (m, 1H), 2.81 (ddd, , 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- yltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one To a solution of (R)-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (2.55 g, 16.43 mmol) in THF (54.8 ml) cooled to -78 Ā°C, was added lithium ropylamide (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 Ā°C prior addition of lithium diisopropylamide (14.79 ml, 29.6 mmol). The mixture was stirred at -78 Ā°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. NH4Cl 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 ed by chromatography through a REDISEPTM pre-packed silica gel column (80 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide 6-diallyl-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (3.31 g, 14.07 mmol, 86% yield) as light-yellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 5.66-5.90 (m, 2H), 5.06-5.19 (m, 4H), 4.01- 4.11 (m, 2H), 3.29-3.38 (m, 1H), 2.32-2.48 (m, 2H), 2.20- 2.29 (m, 1H), 2.12 (dd, J=8.97, 13.79 Hz, 1H), 1.86-1.98 (m, 1H), 1.73-1.84 (m, 1H), 1.65 (s, 3H), 1.46 (s, 3H).
Step 3: (R)-3,3-diallyl(hydroxymethyl)pyrrolidinone To a solution of (R)-6,6-diallyl-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (0.75 g, 3.19 mmol) in MeOH (12 ml) was added p-toluenesulfonic acid drate (0.061 g, 0.319 mmol). The resulting mixture was heated at reflux for 2 h. TLC showed complete conversion. t was evaporated and the crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEPTM pre-packed silica gel column (12 g), eluting with a nt of 0% to 6% MeOH in DCM, to provide 3-diallyl (hydroxymethyl)pyrrolidinone (0.62 g, 3.18 mmol, 100% yield) as white oil. 1H NMR (400 MHz, CDCl3) Ī“ 6.68 (br. s., 1H), .86 (m, 2H), 5.06-5.20 (m, 4H), 3.62-3.74 (m, 2H), 3.36-3.45 (m, 1H), 2.37 (ddd, J=6.45, 11.86, 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, 1H), 1.69 (dd, J=7.44, 13.40 Hz, 1H).
Step 4: (R)-(4,4-diallylpyrrolidinyl)methanol To a solution of (R)-3,3-diallyl (hydroxymethyl)pyrrolidinone (0.43 g, 2.202 mmol) in THF (5.51 ml) cooled to 0 Ā°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 Ā°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 trated to afford (R)-(4,4- diallylpyrrolidinyl)methanol (0.34 g, 1.876 mmol, 85% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ 5.72- .88 (m, 2H), 5.00-5.17 (m, 4H), 3.49-3.59 (m, 1H), 3.30- 3.46 (m, 2H), 2.79 (d, J=11.30 Hz, 1H), 2.67 (d, 5 Hz, 1H), .19 (m, 4H), 1.72 (dd, J=6.97, 13.04 Hz, 1H), 1.22-1.39 (m, 1H).
Step 5: (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2- c][1,2,3]oxathiazole 1,1-dioxide A solution of ylamine (2.460 ml, 17.65 mmol) and (R)-(4,4-diallylpyrrolidinyl)methanol (1.60 g, 8.83 mmol) in DCM (44.1 ml) was cooled to -78 Ā°C. To this mixture was added sulfuryl chloride (0.859 ml, 10.59 mmol) in DCM (44 mL) dropwise in 1 h. The on was ined at this temperature for 3 h, then allowed to warm to room temperature and stirred overnight. The mixture was washed with aq. 1 N HCl (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 REDISEPTM 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[1,2-c][1,2,3]oxathiazole 1,1-dioxide (0.66 g, 2.71 mmol, 30.7% yield) as lightyellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 5.71-5.86 (m, 2H), 5.10-5.20 (m, 4H), 4.57 (dd, J=6.63, 8.76 Hz, 1H), 4.24- 4.36 (m, 1H), 4.19 (dd, J=4.66, 8.76 Hz, 1H), 3.21-3.32 (m, 2H), 2.19-2.29 (m, 4H), .18 (m, 1H), 1.57-1.63 (m, 1H).
Step 6: (R)-3,5-dichloro((4,4-diallylpyrrolidin yl)methyl)pyridine To a solution of 3,5-dichloropyridine (1.069 g, 7.22 mmol) in THF (12.04 ml) at -78 Ā°C was added lithium ropylamide, 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[1,2- c][1,2,3]oxathiazole 1,1-dioxide (1.172 g, 4.82 mmol) in THF (10 mL) was aded dropwise at -78 Ā°C and the mixture was d 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 HCl (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 ts were dried, evaporated and ed by chromatography through a PTM 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- diallylpyrrolidinyl)methyl)pyridine (0.70 g, 2.249 mmol, 46.7% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 8.46 (s, 2H), 5.66-5.86 (m, 2H), 5.03-5.18 (m, 4H), 3.59-3.72 (m, 1H), 3.25 (d, J=7.15 Hz, 1H), 2.97 (d, J=11.51 Hz, 1H), 2.82 (d, 1 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)((3,5-dichloropyridinyl)methyl) azaspiro[4.4]nonene A mixture (R)-3,5-dichloro((4,4- lpyrrolidinyl)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 Ā°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 NH3Ā·MeOH in DCM, to e (R)((3,5- dichloropyridinyl)methyl)azaspiro[4.4]nonene (1.0 g, 3.53 mmol, 35.5% yield) as dark-brown oil. 1H NMR (400 MHz, CDCl3) Ī“ 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 (m, 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)((3,5-dichloropyridinyl)methyl) azaspiro[4.4]nonene A e of (R)((3,5-dichloropyridin yl)methyl)azaspiro[4.4]nonene (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 hloro product (~ 4:1). The crude material was ed onto a plug of silica gel and purified by chromatography through a REDISEPTM pre-packed silica gel column (12 g), eluting with a gradient of 5% to 50% 1 M NH3Ā·MeOH in DCM, to provide (R)((3,5-dichloropyridinyl)methyl) azaspiro[4.4]nonane (0.053 g, 0.186 mmol, 58.5% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) Ī“ 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, 1H); LCMS (ESI) m/z 285.0 (M+H)+.
The following secondary amines were ed using similar procedure in reference examples disclibed above. -l67- CI CI 21 CI j: CI B10 B11 B12 B16 B17 B20 B21 reference reference ure structure example example B27 #NAME? B34 #NAME? B28 #NAME? B35 #NAME? B29 #NAME? B36 #NAME? B30 #NAME? B37 #NAME? B31 #NAME? B38 #NAME? B32 #NAME? B39 #NAME? B33 #NAME? B40 #NAME? reference reference structure structure e example B41 #NAME? B48 #NAME? B42 #NAME? B49 #NAME? B43 #NAME? B50 #NAME? B44 #NAME? B51 #NAME? B45 #NAME? B52 #NAME? B46 #NAME? B53 #NAME? B47 #NAME? B54 #NAME? reference reference structure ure example example B55 #NAME? B62 #NAME? B56 #NAME? B63 #NAME? B57 #NAME? B64 #NAME? B58 #NAME? B65 #NAME? B59 #NAME? B66 #NAME? B60 #NAME? B67 #NAME? B61 #NAME? B68 #NAME? reference structure example B69 #NAME? B70 #NAME? [Reference example C1] 2,6-dichlorofluorophenyl) ((triethylsilyl)oxy)ethyl)-4,4-dimethylcyclohexanamine 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 d at room temperature for 17 h, then quenched with 0.5 M NaOH aq. (10 mL) and extracted with EtOAc (2 Ɨ 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was ed by silicagel column chromatography (eluent : 5% to 30% EtOAc/hexane) to yield compound C1 (122 mg, 86%) as colorless syrup.
[Reference example C22] Step 1: (1S,3R,4R,6R)bromo-3,7,7- trimethylbicyclo[4.1.0]heptanol (C22-1) A suspension of (+)carene (4.09 g, 30 mmol), CaCO3 (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 Et2O (100 mL). The organic layer was washed with water (3 x 50 mL), saturated 3 aq. (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide nd C22-1 (4.53 g, 65%) as a white solid.
Step 2: 1-((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 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 Et2O. The organic layer was washed with water, dried over MgSO4 and concentrated under d pressure to provide compound C22-2 (2.86 g, 99%) as a pale yellow oil. The crude product was used for next step t purification.
Step 3: (1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexanyl acetate (C22-3) To a on 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 Ā°C and d at room temperature for h. The reaction e was quenched with 0.2 M aqueous NaOH and extracted with DCM (80 mL and 2 x 50 mL). The ted organic layers were washed with saturated NaHCO3 aq., water and brine, dried over MgSO4 and trated 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: (1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexanol (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 d at room temperature for 2.5 h. The mixture was diluted with water and ted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine, dried over MgSO4 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]hexanone (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% Na2S2O3 and extracted with Et2O (30 mL). The organic layer was washed with saturated NaHCO3 aq. twice, dried over MgSO4 and concentrated under reduced re to provide nd C22-5 (261 mg, quant.) as a colorless gum. The crude product was used for next step without purification.
Step 6: (1R,3r,5S)-N-(2-(2,6-dichlorofluorophenyl) thylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (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 (CDCl3, 400 MHz): Ī“ 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, 1H), 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] Step 1: 1-(2,6-dichloromethylphenyl)nitroethanol (C45-1) Compound C45-1 (1.25 g, 96%) was obtained as a colorless gum from the on of 2,6-dichloro benzaldehyde (1.0 g, 5.3 mmol) and K2CO3 (0.28 g, 2.0 mmol) in CH3NO2 (10 mL) using a similar procedure to that described in example A1, step 2.
Step 2: (1-(2,6-dichloromethylphenyl) 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 ure to that described in reference example A1, step Step 3: 2-(2,6-dichloromethylphenyl) ((triethylsilyl)oxy)ethanamine ) nd 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 NH4Cl (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: (1R,3r,5S)-N-(2-(2,6-dichloromethylphenyl) ((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (C45) Compound C45 (75 mg, 44%) was obtained from the on 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 (CDCl3, 400 MHz) Ī“: 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).
[Reference example C46] Step 1: 1-(2,6-dichlorophenyl)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 K2CO3 (0.15 g, 1.08 mmol) in CH3NO2 (10 mL) using a similar procedure to that described in nce example A1, step 2.
Step 2: (1-(2,6-dichlorophenyl) nitroethoxy)triethylsilane (C46-2) nd 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 bed in reference example A1, step Step 3: 2-(2,6-dichlorophenyl) ((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 NH4Cl (1.51 g, 28.4 mmol) in EtOH/water (4:1, 20 mL) using a similar ure to that described in reference example A31, step 3.
Stepp 4: (1R,3r,5S)-N-(2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (C46) Compound C46 (94 mg, 78%) was obtained from the reaction of nd 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. 1H NMR (CDCl3, 400 MHz) Ī“: 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 (11H, m), 0.60-0.45 (6H, m).
[Reference e C80] (1R,3r,5S)-N-(2-(2,6-dichlorofluorophenyl) ((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine Cl OH Si Cl O HN Cl Step 1 NO2 Step 2 Step 3 NH2 OSiEt3 O F Cl Cl Cl Cl F Step 1: 1-(2,6-dichlorofluorophenyl)nitroethanol In a ed 100 mL RBF, freshly ground potassium carbonate (0.486 g, 3.51 mmol) was added to a solution of 2,6-dichlorofluorobenzaldehyde (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 Na2SO4 and concentrated under reduced pressure to give 1- (2,6-dichlorofluorophenyl)nitroethanol (2.97 g, 11.69 mmol, 100% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 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, .1 Hz, 1 H), 4.57 (dd, J=13.3, 3.4 Hz, 1 H), 3.20 (br. s., 1 H).
Step 2: -dichlorofluorophenyl) ((triethylsilyl)oxy)ethanamine To a 100 mL three-necked RBF were added (1-(2,6- dichlorofluorophenyl)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 en and was heated to 60 Ā°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 . 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 d pressure. It was diluted with 50 mL of EtOAc, washed with water, brine, dried over anhydrous MgSO4, and concentrated to give 2-(2,6-dichlorofluorophenyl) ((triethylsilyl)oxy)ethanamine hydrochloride as an offwhite solid. The HCl salt was dissolved with 50 mL of DCM. The suspension was basicified w/ satd' aq NaHCO3 (pH=9). The organic layer was separated, washed with brine, dried over ous MgSO4, and concentrated to give 2-(2,6-dichlorofluorophenyl) thylsilyl)oxy)ethanamine (2.73 g, 8.07 mmol, 82% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) Ī“ 7.23-7.29 (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, 1H), 0.83-0.93 (m, 9H), 0.46-0.61 (m, 6H); LCMS: 338.2 [M+H]+.
Step 3: (1R,3r,5S)-N-(2-(2,6-dichlorofluorophenyl) ((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (1R,5S)-6,6-dimethylbicyclo[3.1.0]hexanone (0.181 g, 1.457 mmol) and 2-(2,6-dichlorofluorophenyl) ((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 ed with saturated . 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 on was then filtered h a pad of celite. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to afford a yellow oil. The crude material was purified by column chromatography ( silica gel, eluent : 0% to 10% EtOAc / heptane) to provide (1R,3r,5S)-N-(2-(2,6-dichlorofluorophenyl) ((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (414 mg, 0.927 mmol, 63.6% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ 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), .59 (m, 6 H); LCMS: 446.2 [M+H]+.
The following secondary amines were prepared using similar ure in reference examples disclibed above. -l79- ā€”l80- 1.1 iSiJ H 0 Cl H 0 Cl MN N \ \ I I /N /N C| C| C24 C25 1.1 53:1 H 0 Cl H 0 Cl 7(7N \ | NC2CfN \ 0 /N /N Cl Cl C27 C28 ā€”\Slā€”/ ā€”\ISiā€”/ H 0 Cl H 0 Cl 0ā€˜ā€œ P ā€™N 0ā€ P F3C\ C| F3C Cl C30 C31 ism ism H 0 Cl H O CF3 #1ā€w ļ¬‚WI:Cl Cl Cl C33 C34 / ā€”\ISIā€˜/ H 0 CI H O OMe Ā£jwiĀ©gCI #931:Cl C36 C37 H O 0M6 #3 c. Q3. -l8l- Hoā€™CI Hoā€™CI N N C64 C66 Si Si Si H O H O H O N N N Cl MeO F3C C67 C68 C69 Si Si Si H O H O H O N N N N S Cl Cl Cl C70 C71 C72 Si Si H O Cl N H O H O N N N N O N C73 C74 C75 H HN F Si H O N H O N N N N N Cl Cl N C76 C77 C78 reference nce structure structure example example C80 #NAME? C87 #NAME? C81 #NAME? C88 #NAME? C82 #NAME? C89 #NAME? C83 #NAME? C90 #NAME? C84 #NAME? C85 #NAME? C86 #NAME? [Reference example D1] Step 1: tert-butyl 2-(trans4- (ethoxycarbonyl)cyclohexyl)hydrazinecarboxylate (D1-1) To a on 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 Ā°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 Na2CO3 solution and extracted with DCM. The DCM extracts were washed with brine x 2 and dried over MgSO4. After the solvent was removed, the e was purified by column chromatography on silica gel to give compound D1-1 (3.0 g, 36%) as a white solid.
Step 2: ethyl transhydrazinylcyclohexanecarboxylate hydrochloride (D1-2) To a on of compound D1-1 in EtOH (25 mL) was added 4 M HCl (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 D1-2 (2.8 g, ) as a white solid.
Step 3: benzyl 4,4,4-trifluorooxobutanoate (D1-3) To a solution of ethyl 4,4,4-trifluoro 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 Ā°C by using Dean-Stark for 5 h, and then the reaction mixture was cooled to 0 Ā°C. Drying the solution under high vacuum yielded compound D1-3 (21.2 g, quant.) as a colorless oil, which was used to the next step without further purification.
Step 4: benzyl 2-((dimethylamino)methylene)-4,4,4- trifluorooxobutanoate (D1-4) To a on of compound D1-3 (21.2 g, 92.3 mmol) and AcOH (10.6 mL, 184.7 mmol) in THF (100 mL) was added N,N-dimethylformamide diisopropyl acetal (38.6 mL, 184.7 mmol) dropwise over 25 min, and the e was stirred at room temperature for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine x 2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound D1-4 (17.1 g, 91%) as a yellow oil.
Step 5: benzyl 1-(trans(ethoxycarbonyl)cyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate (D1-5) To a solution of compound D1-2 (2.8 g, 10.5 mmol) in EtOH (50 mL) were added DIPEA (3.2mL, 12.6 mmol) and nd D1-4 (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 MgSO4. After the solvent was removed, the residue was purified by column tography on silica gel to give compound D1-5 (3.5 g, 78%) as a colorless oil.
Step 6: 1-(trans(ethoxycarbonyl)cyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid (D1) Compound D1-5 (3.5 g, 8.2 mmol) and 10% Pd on carbon (300 mg) in EtOAc (40 mL) was hydrogenated in H2 here (1 atm) at room temperature for 25 h. The on mixture was filtered through a pad of celite and washed with EtOAc. Drying the solution under high vacuum yielded compound D1 (2.6 g, 95%) as a white solid.
[Reference example D2] Step 1: ethyl-1,4-dioxaspiro[4.5]decanecarboxylate (D2-1) The mixture of ethyloxocyclohexanecarboxylate (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 t 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 (CDCl3, 400 MHz): Ī“ 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: ethylmethyl-1,4-dioxaspiro[4.5]decane carboxylate (D2-2) To a stirred solution of nd 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 Ā°C over a period of 15 min. The mixture was stirred at -78 Ā°C for 30 min. A solution of thane (2.23 mL, 35.74 mmol) in THF (1 mL) was added to the mixture dropwise, and the whole was stirred at -78 Ā°C for min. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated s NH4Cl and ted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was ed by column chromatography (silica gel, 2% EtOAc/hexane as eluent) to provide compound D2-2 (2.7 g, 50%) as colorless oil. 1H NMR , 400 MHz): Ī“ 4.14 (q, J = 7.2 Hz, 2H), 3.93 (s, 4H), .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, 3H).
Step 3: ethylmethyloxocyclohexanecarboxylate (D2-3) To a solution of nd 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 Na2SO4 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 (CDCl3, 400 MHz): Ī“ 4.22 (q, J = 7.0 Hz, 2H), 2.47- 2.38 (m, 4H), 2.34-2.30 (m, 2H), .64 (m, 2H), 1.31- 1.29 (m, 6H).
Step 4: tert-butyl(trans(ethoxycarbonyl) 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 Ā°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 ued 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 Na2SO4 and trated under reduced re. 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 transhydrazinyl methylcyclohexanecarboxylate hydrochloride (D2-5) To a solution of compound D2-4 (36.0 g, 120.0 mmol) in EtOH (100 mL) was added HCl (4 M in 1,4-dioxane, 350 mL) dropwise at 0 Ā°C, and the whole was stirred at room temperature for 18 h. The t was removed under reduced pressure and residue was triturated with Et2O to get compound D2-5 (31.0 g, 95%) as white solid. The crude product was used in the next step without cation. 1H NMR , 400 MHz): Ī“ 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(trans(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole 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) se and the mixture was stirred at room ature for 5 min. A solution of compound D1-4 (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 Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 15% EtOAc/hexane as ) to provide compound D2-6 (20.0 g, 40%) as brown gum. 1H NMR (CDCl3, 400 MHz): Ī“ 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(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid (D2) A e of compound D2-6 (20.0 g, 45.6 mmol) and % Pd on carbon (10.0 g, 50% by weight) in MeOH (200 mL) was stirred under H2 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 e compound D2 (13.0 g, 82%) as white solid. 1H NMR (CDCl3, 300 MHz): Ī“ 8.03 (s, 1H), 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).
[Reference example D19] Step 1: 1,4-dioxaspiro[4.5]decanylmethanol (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 Ā°C and the reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was cooled to 0 Ā°C, quenched with water (7 mL) and 6 M NaOH (7 mL) and stirred at room temperature for 20 min. Na2SO4 (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 ess oil. The crude t 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 Na2SO4 and concentrated under reduced pressure to obtain nd D19-2 (7.5 g, 51%) as colorless gum.
Step 3: tert-butyl 2-(trans (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 d 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 ed with water (50 mL) and extracted with EtOAc (2 x 50 mL). The ed organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was ed 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: (transhydrazinylcyclohexyl)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: ethylamino(trans (hydroxymethyl)cyclohexyl)-1H-pyrazolecarboxylate (D19-5) To a solution of nd D19-4 (720 mg, 3.31 mmol) in EtOH (20 mL) were added ethylcyanoethoxyacrylate (448 mg, 2.65 mmol) and NaOAc (571 mg, 6.96 mmol) and the mixture was stirred at 70 Ā°C for 18 h. The solvent was removed under reduced pressure, the e was ded in water (20 mL) and extracted with EtOAc (3 x 20 mL).
The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 30% CH3CN/water as eluent) to provide compound D19-5 (320 mg, 37%) as reddish brown solid.
Step 6: ethylchloro(trans (hydroxymethyl)cyclohexyl)-1H-pyrazolecarboxylate (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) se at 0 Ā°C. A solution of compound D19-5 (200 mg, 0.749 mmol) in CH3CN (4 mL) was added dropwise to above mixture at 0 Ā°C and stirred at the same temperature for 5 min. The mixture was stirred at room temperature for 30 min and at 70 Ā°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 Na2SO4 and trated under reduced pressure. The residue was ed 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(5-chloro(ethoxycarbonyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid (D19-7) To a suspension of H5IO6 (159 mg, 0.698 mmol) in CH3CN was added CrO3 (0.6 mg, 0.0061 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0 Ā°C and a solution of nd D19-6 (100 mg, 0.349 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30 min. The organic t was removed under reduced pressure, e was suspended in water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure to provide compound D19-7 (105 mg, quant) as an off-white solid.
Step 8: ethyl(trans(tertbutoxycarbonyl )cyclohexyl)chloro-1H-pyrazole ylate (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 Ā°C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column tography (C18 silica gel, 90% CH3CN/water as ) to provide compound D19-8 (70 mg, 56%) as colorless gum.
Step 9: 1-(trans(tert-butoxycarbonyl)cyclohexyl) chloro-1H-pyrazolecarboxylic acid (D19) 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 KHSO4 to pH 4 and extracted with EtOAc (3 x 10 mL) to provide compound D19 (62 mg, 90%) as white solid. 1H NMR , 300 MHz): Ī“ 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] Step 1: benzyl 3-cyclopropyloxopropanoate (D20-1) A mixture of ethyl 3-cyclopropyloxopropanoate (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 d under reduced pressure to provide nd D20-1 (5.2 g, crude) as a brown oil.
Step 2: benzyl 2-(cyclopropanecarbonyl) (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 Ā°C for 13 h. The on mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined c layers were washed with water (25 mL), brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to provide compound D20-2 (1.2 g, crude) as a yellowish brown gum.
Step 3: benzyl 5-cyclopropyl(trans (ethoxycarbonyl)cyclohexyl)-1H-pyrazolecarboxylate (D20-3) To a solution of compound D1-2 (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 ature for 4 h.
The on 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography a gel, 20% EtOAc/hexane as ) to provide compound D20-3 (425 mg, impure) as yellow gum.
Step 4: 5-cyclopropyl(trans (ethoxycarbonyl)cyclohexyl)-1H-pyrazolecarboxylic 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 EtOAc (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] Step 1: ethyl l-1,4-dioxaspiro[4.5]decane 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) se at -78 Ā°C for 5 min. The mixture was stirred at -78 Ā°C for min before the addition of EtBr (1.09 mL, 14.7 mmol).
The reaction mixture was stirred at -78 Ā°C for 1 h. The mixture was d to warm to room temperature and d at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and trated under reduced pressure. The residue was purified by column tography (silica gel, 20% EtOAc/hexane as eluent) to provide compound D22-1 (2.07 g, 87%) as a colorless Step 2: ethyl 1-ethyloxocyclohexanecarboxylate (D22-2) To a stirred solution of compound D22-1 (2.07 g, 8.54 mmol) in acetone (60 mL) was added aqueous HCl (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 ed with aqueous NaHCO3 solution and extracted with DCM (2 x mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was ed 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(ethoxycarbonyl) 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 transethyl hydrazinylcyclohexanecarboxylate hloride (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 HCl (4 M in 1,4-dioxane, 8.3 mL, 33.4 mmol) using a similar procedure to that described in nce example D2, step 5.
Step 5: benzyl 1-(trans(ethoxycarbonyl) ethylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (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 D1-4 (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 Step 6: ns(ethoxycarbonyl)ethylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic 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. ence example D26] Step 1: benzyl-4,4-difluorooxobutanoate (D26-1) Compound D26-1 (7.5 mg, crude) was obtained as a yellow oil from the reaction of ethyl-4,4-difluoro oxobutanoate (5 g, 0.12 mmol) and BnOH (3.25 g, 30.0 mmol) in toluene (50 mL) using a r procedure to that described in reference example D1, step 3.
Step 2: benzyl((dimethylamino)methylene)-4,4-difluoro- 3-oxobutanoate ) 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), ylformamide 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 D1, step 4.
Step 3: benzyl(difluoromethyl)-trans ycarbonyl)cyclohexyl)-1H-pyrazolecarboxylate (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, .28 mmol), compound D1-2 (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 nce example D1, step Step 4: 5-(difluoromethyl)-trans (ethoxycarbonyl)cyclohexyl)-1H-pyrazolecarboxylic 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 D1, step 6.
LCMS (APCI): 317 (M+H)+.
[Reference example D27] Step 1: benzyl 2-((dimethylamino)methylene) oxobutanoate (D27-1) To a stirred benzyl utanoate (1.1 g, 5.7 mmol), dimethylformamide ylacetal (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 d pressure and the residue was azeotroped with toluene (3 x 10 mL) to e compound D27-1 as a brown oil (1.4 g, quant.).
Step 2: benzyl 1-((trans(ethoxycarbonyl)cyclohexyl) methyl-1H-pyrazolecarboxylate (D27-2) To a solution of compound D1-2 (1.12 g, 4.3 mmol) in EtOH (10 mL) was added DIPEA (1.2 mL, 6.7 mmol) dropwise.
The mixture was d 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 ted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide nd D27- 2 (0.78 g, 54%) as a white solid.
Step 3: 1-((trans(ethoxycarbonyl)cyclohexyl)methyl- 1H-pyrazolecarboxylic 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, % 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 Na2SO4 and concentrated under d 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, 6): Ī“ 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] Step 1: 1,5-di-tert-butyl 3-ethyl 3-acetylpentane-1,3,5- tricarboxylate (D28-1) To a stirred solution of ethyl 3-oxobutanoate (45 g, 345 mmol) and Triton-B (40%, weight% on in water, 1.08 mg, 6.90 mmol) in tert-BuOH (54 mL) was added tertbutyl acrylate (100.72 g, 691 mmol) dropwise over a period of 30 min under N2 atmosphere. The on was d 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 EtOAc (2 x 50 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to e compound D28-1 (140 g, quant) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): Ī“ 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(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 Ā°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: ethylacetyloxocyclohexanecarboxylate (D28- 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 Ā°C for 2 h. The solvent was removed under reduced pressure, the residue was suspended in water (200 mL) and ted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was ed by silica gel column chromatography (14% EtOAc/hexane as eluent) to provide compound D28-3 (11 g, 17%) as brown gum. 1H NMR (CDCl3, 400 MHz): Ī“ 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)oxobicyclo[2.2.2]octane- oxylate (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 e was cooled to room temperature. HCl (3 M, 250 mL) was added to the on mixture, and the whole was d 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc/hexane as eluent) to provide nd D28-4 (30 g, 85%) as an off-white solid. 1H NMR (CDCl3, 400 MHz): Ī“ 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(benzylamino) hydroxybicyclo[2.2.2]octanecarboxylate ) To a d 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 Ā°C. The whole was stirred at room temperature for 30 min. The mixture was ed with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined c layers were washed with water (150 mL), brine (150 mL), dried over Na2SO4 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(benzylamino) ylsulfonyl)oxy)bicyclo[2.2.2]octanecarboxylate (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 Ā°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 Na2SO4 and concentrated under reduced pressure to provide compound D28-6 (14 g, crude).
The crude t was used in the next step without purification.
Step 7: ethyl(benzylamino)bicyclo[2.2.2]octene carboxylate (D28-7) To a stirred solution of compound D28-6 (17.6 g, 46.3 mol) and NaI (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 Ā°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 Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 50% hexane as ) to provide compound D28- 7 (8 g, 61%, over two steps) as an off-white solid. 1H NMR (CDCl3, 400 MHz): Ī“ 7.36-7.32 (m, 5H), 6.44 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 8.8 Hz, 1H), 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: ethylaminobicyclo[2.2.2]octanecarboxylate (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, % 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 te was concentrated under reduced pressure to provide compound D28-8 (5.2 g, 94%) as a colorless gum. 1H NMR , 400 MHz): Ī“ 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, 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)-1,2-oxaziridine ylate (D28-10, mixture of cis- and trans- isomer) To a stirred solution of compound D28-9 (13 g, 1.67 mmol) in CHCl3 (220 mL) was added a pre-cooled solution of K2CO3 (50 g) in water (400 mL) at 0 Ā°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 d at 0 Ā°C for 50 min. The on mixture was ted to ten such cycles. The combined organic layer was separated, washed with water (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 45-50% CH3CN/water as eluent) to provide compound D28-10 (1.3 g, 14% over two steps) as a white solid. 1H NMR (CDCl3, 400 MHz, mixture of cis- and ): Ī“ 7.73-7.58 (m, 6.5H), .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 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 d for 3 h at 0 Ā°C. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide nd D28-11 (0.6 g, 50%) as a white solid.
Step 12: ethylhydrazinylbicyclo [2.2.2] octane carboxylate hydrochloride (D28-12) A mixture of compound D28-11 (0.6 g, 1.92 mmol) and 4 M HCl in dioxane (4.80 mL, 19.2 mmol) was stirred at room temperature for 18 h. The solvent was d 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)(trifluoromethyl)-1H-pyrazolecarboxylate (D28- 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 on of nd D1-4 (0.64 g, 2.15 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was ed with water (20 mL) and extracted with EtOAc (2 x 20 mL).
The combined c layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and trated 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 (CDCl3, 400 MHz): Ī“ 7.81-7.80 (s, 1H), 7.39-7.25 (m, 5H), 5.29 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), .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]octanyl)- -(trifluoromethyl)-1H-pyrazolecarboxylic 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 d 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. 1H NMR (CDCl3, 400 MHz): Ī“ 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).
[Reference e D30] Step 1: benzyl(difluoromethyl)-trans (ethoxycarbonyl)methylcyclohexyl)-1H-pyrazole carboxylate (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 ure to that described in reference example D1, step . 1H NMR (CDCl3, 400 MHz): Ī“ 7.94 (s, 1H), 7.40-7.35 (m, 6H), 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 2: 1-trans(ethoxycarbonyl)cyclohexyl (trifluoromethyl)-1H-pyrazolecarboxylic acid (D30) Compound D30 (1.19 g, 79%) was ed as a white solid from the reaction of compound D30-1 (1.91 g, 4.54 mmol) and 5% Pd on carbon (200 mg, 10% by weight) in EtOH (30 mL) using a similar procedure to that described in reference example D1, step 6. 1H NMR (CDCl3, 300 MHz): Ī“ 8.03 (s, 1H), 7.51 (t, J = 51.6 Hz), 4.4-4.42 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.2-2.25 (m, 2H), 1.88-1.92 (m, 6H), 1.35 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H).
[Reference example D33] Step 1: Ethyl 5-amino(trans(ethoxycarbonyl) methylcyclohexyl)-1H-pyrazolecarboxylate (D33-1) To a solution of ethyl oethoxyacrylate (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 , 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(trans(ethoxycarbonyl) methylcyclohexyl)-1H-pyrazolecarboxylate ) To a stirred mixture of copper (I) chloride (0.77 g, 7.8 mmol) in CH3CN (10 mL) at 0 Ā°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 e at the same temperature. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1 h and at 60 Ā°C for another 1 h.
The reaction mixture was quenched with 6 M HCl (10 mL) at 0 Ā°C and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as ) to provide compound D33-2 (0.3 g, 37%) as a colourless Step 3: 5-chloro(trans(ethoxycarbonyl) methylcyclohexyl)-1H-pyrazolecarboxylic 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 e pH was adjusted to 3 and extracted with EtOAc (2 x 200 mL). The ed organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The e was purified by reverse phase column chromatography (C18 silica gel, 80% CH3CN/water as eluent) to provide compound D33 (0.4 g, 55%) as an offwhite solid.
[Reference example D41] 1-((1S,3R,4S)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid Step 1: (1S,2R)-ethyl 2-methyl 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-methyloxocyclohexenecarboxylate (23.65 ml, 140 mmol) and 5 N hydrochloric acid (1.679 ml, 8.40 mmol) were added into the reaction e. The atmosphere of the flask was degassed, and then filled with hydrogen (50 psi). The mixture was d to stir under hydrogenation conditions 30 min. The progress of the on was monitored by LC/MS and TLC (50% EtOAc/hexane; potassium permanganate stain), which suggested reaction tion. 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 (1S,2R)-ethyl 2-methyloxocyclohexanecarboxylate (18.277 g, 99 mmol, 70.9% yield) (Racemic) as lightyellow oil. 1H NMR (400 MHz, CDCl3) Ī“ 4.19 (dtt, 2H), 2.85 (td, J=4.25, 8.31 Hz, 1H), .58 (m, 4H), 2.31 (ddd, J=6.06, 8.75, 14.72 Hz, 1H), .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: (1S,2R)-ethyl 2-methyl oxocyclohexanecarboxylate (Chiral) (1S,2R)-ethyl 2-methyloxocyclohexanecarboxylate (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 : % EtOH in Heptane Flow Rate : 400 ml/min. ion : 220 nm, 300 nm. This purification method provided peak 1 (1S,2R)-ethyl 2-methyloxocyclohexanecarboxylate (>98% ee) as ess oil. 1H NMR (400 MHz, CDCl3) Ī“ 4.19 (ddquin, 2H), 2.85 (td, J=4.25, 8.31 Hz, 1H), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.16, 8.66, 14.72 Hz, 1H), 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 (1R,2S)-ethyl 2- methyloxocyclohexanecarboxylate (>95% ee) as colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ 4.19 (ddquin, 2H), 2.85 (td, J=4.13, 8.36 Hz, 1H), .58 (m, 4H), 2.31 (ddd, J=6.16, 8.66, 14.72 Hz, 1H), 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-((1S,3R,4S)(ethoxycarbonyl) methylcyclohexyl) hydrazinecarboxylate To a 500-mL 3-neck round-bottomed flask was added (1S,2R)-ethyl 2-methyloxocyclohexanecarboxylate (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 Ā°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 e was allowed to stir under inert here 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. NaHCO3 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 Na2SO4, filtered and concentrated uo. 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 e tert-butyl ,3R,4S) (ethoxycarbonyl)methylcyclohexyl) hydrazinecarboxylate (8.512 g, 28.3 mmol, 52.2% yield) (Peak 1; Cis) 1H NMR (400 MHz, CDCl3) Ī“ 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, , 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 tertbutyl 2-((1S,3R,4S)(ethoxycarbonyl) methylcyclohexyl) hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans) 1H NMR (400 MHz, DMSO- d6) Ī“ 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: (1S,2R,4S)-ethyl 4-hydrazinyl methylcyclohexanecarboxylate hydrochloride To a 250-mL round-bottomed flask was added tertbutyl 2-((1S,3R,4S)(ethoxycarbonyl) cyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol) in EtOH (56.5 ml). Then hydrogen de, 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 o.
This gave (1S,2R,4S)-ethyl 4-hydrazinyl methylcyclohexanecarboxylate hloride (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-((1S,3R,4S)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate To a 250-mL round-bottomed flask was added (1S,2R,4S)-ethyl 4-hydrazinyl 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-trifluorooxobutanoate (5.09 g, 16.90 mmol) in EtOH (84 ml) was added se 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 ng material remaining. The on 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-((1S,3R,4S)(ethoxycarbonyl) cyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (5.631 g, 12.84 mmol, 76% yield) as lightyellow oil. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.14 (s, 1H), .45 (m, 5H), 5.30 (s, 2H), 4.55-4.65 (m, 1H), 4.02- 4.15 (m, 2H), 2.65 (td, J=4.50, 11.54 Hz, 1H), 2.13 (dt, , 12.42 Hz, 1H), 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: 1-((1S,3R,4S)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole 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 1-((1S,3R,4S)(ethoxycarbonyl) cyclohexyl)(trifluoromethyl)-1H-pyrazole ylate (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 en gas (3x). The reaction was stirred vigourously under hydrogenation (35 psi) conditions for 2.5 h. The ss 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 tion and the solids were rinsed with hexane. This gave 1-((1S,3R,4S) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic acid (3.810 g, 10.94 mmol, 85% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 7.91- 8.21 (m, 1H), 4.47-4.69 (m, 1H), 4.01-4.16 (m, 2H), 2.56- 2.70 (m, 1H), 2.12 (dt, , 12.37 Hz, 1H), 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] 1-((1R,3R,4R)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid compound with 1-((1S,3S,4S)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid (1:1) (D43) Step 1: tert-butyl 2-((1R,3R,4R)(ethoxycarbonyl) cyclohexyl)hydrazinecarboxylate compound with tert- butyl 2-((1S,3S,4S)(ethoxycarbonyl) methylcyclohexyl)hydrazinecarboxylate (1:1) (D43-1) To a homogeneous racemic mixture of (1R,2R)-ethyl 2- methyloxocyclohexanecarboxylate compound with (1S,2S)- ethyl 2-methyloxocyclohexanecarboxylate (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, Rf of 1,4-trans-desired product=0.25. The reaction mixture was poured into saturated aqueous NaHCO3 solution (150 mL). The reaction e was extracted with DCM (2 x 100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude al as a colorless oil. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography g 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-((1R,3S,4S) (ethoxycarbonyl)methylcyclohexyl)hydrazinecarboxylate nd with tert-butyl 2-((1S,3R,4R) (ethoxycarbonyl)methylcyclohexyl)hydrazinecarboxylate (1:1) (1.4418 g, 4.80 mmol, 55.3% yield) as light-yellow syrup : 1H NMR (300 MHz, CDCl3) Ī“ 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): d product (Rf =0.25 at 30% of EtOAc in Hexane) tert-butyl 2- ((1R,3R,4R)(ethoxycarbonyl) methylcyclohexyl)hydrazinecarboxylate compound with tert- butyl 2-((1S,3S,4S)(ethoxycarbonyl) methylcyclohexyl)hydrazinecarboxylate (1:1) (D43-1) (0.5467 g, 1.820 mmol, 20.96% yield) as off-white syrupy solid. 1H NMR (300 MHz, CDCl3) Ī“ 6.05 (1H, br. s.), 4.06- 4.23 (2H, m), 2.81-2.99 (1H, m), 1.65-2.07 (5H, m), 1.39- 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 +.
[NOTE]: The second fraction was used in Step 2.
Step 2: (1R,2R,4R)-ethyl 4-hydrazinyl methylcyclohexanecarboxylate compound with (1S,2S,4S)- ethyl azinylmethylcyclohexanecarboxylate (1:1) dihydrochloride (D43-2) To a mixture of tert-butyl 2-((1R,3R,4R) (ethoxycarbonyl)methylcyclohexyl)hydrazinecarboxylate compound with tert-butyl 2-((1S,3S,4S) (ethoxycarbonyl)methylcyclohexyl)hydrazinecarboxylate (1:1) ) (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 e), 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 (1R,2R,4R)-ethyl 4-hydrazinyl methylcyclohexanecarboxylate compound with (1S,2S,4S)- ethyl 4-hydrazinylmethylcyclohexanecarboxylate (1:1) dihydrochloride ) as light-yellow solid. 1H NMR (300 MHz, DMSO-d6) Ī“ 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-((1R,3R,4R)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate compound with benzyl 1-((1S,3S,4S) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylate (1:1) (D43-3) To a mixture of (1R,2R,4R)-ethyl 4-hydrazinyl methylcyclohexanecarboxylate compound with (1S,2S,4S)- ethyl 4-hydrazinylmethylcyclohexanecarboxylate (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-trifluorooxobutanoate (0.526 g, 1.745 mmol) in EtOH (5 mL). The clear brown e was d at room temperature. After 15 h, LC-MS (ESI) showed that the reaction wasa complete, the desired product (m/z 439.1 (M+1)) 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 Na2SO4. The solution was filtered and concentrated in vacuo to give the crude al 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 1- ((1R,3R,4R)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate nd with benzyl ,3S,4S)(ethoxycarbonyl) cyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (1:1) (D43-3) (0.4258 g, 0.971 mmol, 55.7% yield) as yellow syrup: 1H NMR (300 MHz, DMSO-d6) Ī“ 8.06- 8.17 (1H, m), .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: 1-((1R,3R,4R)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid compound with 1-((1S,3S,4S) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic acid (1:1) (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 1- ((1R,3R,4R)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate compound with benzyl 1-((1S,3S,4S)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (1:1) (D43-3) (0.4258 g, 0.971 mmol) 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 d vigourously under hydrogenation (33 psi) at 21 Ā°C. After 3 h, LCMS (ESI) showed that the reaction was complete. The reaction e was purged with nitrgen gas for 30 min.
The mixture was ed through a pad of celite and the filter cake was rinsed with EtOAc. The filtrate was concentrated in vacuo to give 1-((1R,3R,4R) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- azolecarboxylic acid compound with 1- ((1S,3S,4S)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid (1:1) (D43) (0.3224 g, 0.926 mmol, 95% yield) as light-yellow solid: 1H NMR (300 MHz, DMSO-d6) Ī“ 13.14 (1H, br. s.), 8.01 (1H, s), 4.40-4.59 (1H, m), 4.10 (2H, q, J=7.0 Hz), 1.48-2.16 (8H, m), 1.20 (3H, t, J=7.1 Hz), 0.89 (3H, d, J=6.0 Hz); LCMS (ESI) m/z 349.1 (M+H)+.
[Reference example D48] 1-((3aS,5R,7aS)-3a-(methoxycarbonyl)octahydro-1H-inden yl)(trifluoromethyl)-1H-pyrazolecarboxylic acid Step 1: methyl 2-oxo(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 Ā°C for 24 h. The reaction was brought to room ature, diluted with EtOAc, washed with sat. NH4Cl, dried over , filtered, concentrated and chromatographed on silica gel using 0- 50% heptane/EtOAc to afford a colorless oil as methyl 2- oxo(3-oxobutyl)cyclopentanecarboxylate (2.0 g, 9.42 mmol, 67.0% yield).
Step 2: methyl 5-(pyrrolidinyl)-2,6,7,7a-tetrahydro- 1H-indene-7a-carboxylate A solution of methyl 2-oxo(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 trated. The residue was dissolved in EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to afford a sh oil as methyl 5-(pyrrolidinyl)-2,6,7,7a-tetrahydro-1H-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-1H-indene-3acarboxylate 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. NH4Cl, sat.
NaHCO3, brine, dried over Na2SO4, filtered, trated and tographed on silica gel using 0-30% heptane/EtOAc to afford methyl 6-oxo-2,3,3a,4,5,6- hexahydro-1H-indene-3a-carboxylate (1.32 g, 6.80 mmol, 48.3% yield) as a bright yellow oil. MS m/z=195.2 [M+H]+.
Step 4: (3aS,7aR)-methyl ctahydro-1H-indene-3a- carboxylate To a stirred solution of methyl 6-oxo-2,3,3a,4,5,6- hexahydro-1H-indene-3a-carboxylate (1.32 g, 6.80 mmol) in EtOH (30 mL) was added palladium, 10 wt.%(dry basis) on activated carbon, wet, a type e101 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-1H-indene-3a- ylate (0.278 g, 1.417 mmol, 20.84% yield) and (3aS,7aS)-methyl 6-oxooctahydro-1H-indene-3a-carboxylate (0.394 g, 2.008 mmol, 29.5% yield) as colorless oil. MS m/z=181.2 [M+H]+.
Steps 5 through 8. 1-((3aS,5R,7aS)-3a- (methoxycarbonyl)octahydro-1H-indenyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid was ed from (3aS,7aR)-methyl 6-oxooctahydro-1H-indene- 3a-carboxylate using similar procedures as in e D22. MS m/z=361.2 [M+H]+.
[Example D55] trans(4-(Ethoxycarbonyl)-3,3-dimethylcyclohexyl) (trifluoromethyl)-1H-pyrazole carboxylic acid (racemic mixture) O O O O O HN O HN O O + step 1 step 2 NH O NH O EtO EtO EtO EtO (racemic mixture) NMe2 O N O N O NH2.HCl N N NH + O OBn OBn EtO OH step 3 step 4 EtO step 5 EtO F3C O F3C CF3 O O (racemic mixture) (racemic e) Step 1: Ethyl 2,2-dimethyloxocyclohexanecarboxylate (racemic mixture) Methyllithium (170 mL of a 1.6 M solution with Et2O, 260 mmol) was added to a stirring mixture of copper (I) iodide (25 g, 130 mmol) and Et2O (130 mL), at -40 Ā°C under a nitrogen here. After stirring for 10 min at -40 Ā°C, ethyl 2-methyloxocyclohexenecarboxylate (12 g, 66 mmol) was added. After stirring for 30 min at -40 Ā°C, the reaction mixture was allowed to warm to -20 Ā°C.
After stirring for 90 min at -20 Ā°C, saturated aqueous ammonium chloride and EtOAc were added tially, the mixture was partitioned between more ted aqueous ammonium de and EtOAc, the layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (2Ɨ) and brine, dried (Na2SO4), 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 ted to flash tography on silica gel (gradient elution; 19:1 to 9:1 hexane-EtOAc) to give ethyl 2,2-dimethyl oxocyclohexanecarboxylate (8.9 g, 68% yield; racemic mixture) as a clear yellow oil.
Step 2: tert-Butyl trans4-(ethoxycarbonyl)-3,3- dimethylcyclohexyl)hydrazinecarboxylate (racemic mixture) Ac)3 (29 g, 140 mmol) was added to a stirring solution of ethyl 2,2-dimethyl 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 NaHCO3, the mixture was stirred for 60 min, partitioned n EtOAc and more saturated aqueous NaHCO3, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and the filtrate was trated 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-EtOAc) to give tert-butyl trans4-(ethoxycarbonyl)-3,3- dimethylcyclohexyl)hydrazinecarboxylate (0.79 g, 5.6% yield; racemic e) as a clear ess oil.
Step 3: Ethyl transhydrazinyl-2,2- dimethylcyclohexanecarboxylate hydrochloride ic 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 trans4-(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 e was heated at 60 Ā°C. After stirring for 3 h at 60 Ā°C, the reaction mixture was allowed to cool to room temperature and then concentrated under d pressure to give ethyl transhydrazinyl- methylcyclohexanecarboxylate hydrochloride (0.63 g, 100% yield; c mixture) as an off-white solid.
Step 4: Benzyl trans4-(ethoxycarbonyl)-3,3- dimethylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate ic mixture) A solution of (Z)-benzyl 2- ((dimethylamino)methylene)-4,4,4-trifluorooxobutanoate (0.76 g, 2.5 mmol) and EtOH (2.4 mL) was added to a ng solution of ethyl transhydrazinyl-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 d pressure, the residue was partitioned n EtOAc and saturated aqueous NaHCO3, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHCO3 and brine, dried (Na2SO4), 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 les were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (19:1 hexane-EtOAc) to give benzyl 1(ethoxycarbonyl)-3,3- dimethylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (0.76 g, 67% yield; racemic mixture) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) Ī“ 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(4-(Ethoxycarbonyl)-3,3-dimethylcyclohexyl) (trifluoromethyl)-1H-pyrazole carboxylic acid (racemic mixture) A stirring mixture of benzyl trans4- (ethoxycarbonyl)-3,3-dimethylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate (0.76 g, 1.7 mmol, from Step 4; racemic mixture), palladium (0) (10 wt. % dry basis, wet) on ted carbon (0.18 g, 0.17 mmol), EtOAc (4.2 mL), and EtOH (4.2 mL) was exposed to gaseous hydrogen (33 psi). After ng for 2 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give trans(4- (ethoxycarbonyl)-3,3-dimethylcyclohexyl) (trifluoromethyl)-1H-pyrazole carboxylic acid (0.59 g, 97% yield; racemic mixture) as a colorless solid. LCMS (ESI): 363.0 (M+H)+.
[Reference example D60] 1-(((+/-)-cis)allylcyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxylic acid as a racemate (D60) O Step 1 HN Step 2 NH HCl O NH2 HCl N N N N Step 3 OEt Step 4 OH F O F O F F F F Step 1: tert-butyl 2-(((+/-)cis) allylcyclohexyl)hydrazinecarboxylate as a racemate To a on of tert-butyl carbazate (0.966 g, 7.31 mmol), 2-allylcyclohexanone (1.00 g, 7.24 mmol), and AcOH (1.00 ml, 17.47 mmol) at 0 Ā°C was added NaBH(OAc)3 (4.60 g, 21.71 mmol) and the ew was stirred at room temperature overnight. The reaction mixture was added slowly to a saturated aqueous solution of Na2CO3. The layers were separated and the aqueous layer was extracted with DCM twice. The cs were pooled, washed with brine, dried over Na2SO4, 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 trated in vacuo to provide tert-butyl 2-(((+/-)cis)allylcyclohexyl)hydrazinecarboxylate as a Step 2: (((+/-)cis)allylcyclohexyl)hydrazine dihydrochloride as a racemate 4 M HCl in dioxane (11.79 ml, 47.2 mmol) was added to a solution of tert-butyl 2-(((+/-)cis) allylcyclohexyl)hydrazinecarboxylate as a te (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)allylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate as a racemate A solution of (Z)-ethyl 2- ((dimethylamino)methylene)-4,4,4-trifluorooxobutanoate (1.073 g, 4.49 mmol) in EtOH (11 mL) was added slowly to a solution of )cis)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 ature. After 6 h, the reaction e was concentrated in vacuo, diluted with water and extracted with EtOAc twice. The ed organic layers were washed with brine, dried over Na2SO4, 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)allylcyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxylate as a racemate as a pale yellow Step 4: 1-(((+/-)-cis)allylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid as a racemate A solution of lithium hydroxide hydrate (1.265 g, .2 mmol) in water was added to a solution of ethyl 1- (((+/-)cis)allylcyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxylate 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 HCl and the e was stirred vigorously for 30 min. The resulting precipitate was collected by vacuum filtration to provide 1-(((+/-)-cis)- 2-allylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid as a racemate (D60) as a white solid. ence example D68 (cis and trans)] 1-((1r,4r)(2-ethoxyoxoethyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid and 1- s)(2-ethoxyoxoethyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic acid Step 1: ethyl ethyl-1,4-dioxaspiro[4.5]decan yl)acetate To a solution of CuI (5.8 g, 30 mmol, 3.24 eq) in Et2O (100 mL) maintained under N2 at 0 Ā°C was added a solution of 3.0 M MeLi (21.3 mL, 64 mmol, 6.8 eq) in dimethoxyethane dropwise. The ing solution was stirred at 0 Ā°C for 10 min and the ether solvent was removed from the reaction under vacuum (120 torr) at 0 Ā°C.
DCM (100 mL) was then added to the e and the reaction was cooled to -78 Ā°C. TMSCl (4.4 mL, 35 mmol, 3.7 eq) was added followed by ethyl 2-(1,4- dioxaspiro[4.5]decanylidene)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 NH4Cl 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 ethyl-1,4-dioxaspiro[4.5]decanyl)acetate (1.6 g, 6.60 mmol, 70.2% yield) as a colorless liquid: 1H NMR (500 MHz, CDCl3) Ī“ 1.07 (s, 3H), 1.19-1.33 (m, 3H), 1.49-1.67 (m, 8H), 2.27 (s, 2H), 3.94 (s, 4H), .16 (m, 2H).
Step 2: ethyl ethyloxocyclohexyl)acetate Water (0.5 mL) was added to a stirring solution of ethyl 2-(8-methyl-1,4-dioxaspiro[4.5]decanyl)acetate (1.6 g, 6.60 mmol) and formic acid (10 mL) at room ature. Analysis of the reaction mixture by LCMS indicated that the ng material was consumed and the desired product had formed. The on 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 (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid ethyl 2-(1-methyloxocyclohexyl)acetate (1.6 g, 8.07 mmol, 86% yield): 1H NMR (500 MHz, CDCl3) Ī“ 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-ethoxyoxoethyl) methylcyclohexyl)hydrazinecarboxylate Ethyl 2-(1-methyloxocyclohexyl)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 NaHCO3 solution, and the mixture was ted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium e, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:EtOAc, 100%-35%) to give utyl 2-(4-(2-ethoxyoxoethyl) 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-hydrazinylmethylcyclohexyl)acetate hloride tert-Butyl 2-(4-(2-ethoxyoxoethyl) methylcyclohexyl)hydrazinecarboxylate (1.7 g, 5.41 mmol) in EtOH (5 mL) was added HCl (4 M in 1,4-dioxane, 10 mL) dropwise at 0 Ā°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-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate A solution of (Z)-benzyl 2- ((dimethylamino)methylene)-4,4,4-trifluorooxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl 2-(4-hydrazinyl cyclohexyl)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 al oil was purified using a 40 g REDISEPTM Gold SiO2 column g with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and concentrated in vacuo to provide benzyl 1- ethoxyoxoethyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS = 453.4 (M+H)+.
Step 6: ,4r)(2-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid and 1-((1s,4s)(2-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid Benzyl 1-(4-(2-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylate (2.1 g, 4.64 mmol) was ved in EtOH (10 mL) and EtOAc (10 mL) and added to wet Pd/C (10%, 210 mg) in a re flask under N2 . The reaction mixture was equipped with a pressure gauge and one arm was ted 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 h 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 CO2, 10% co-solvent at 180 g/min.
Temp. = 29Ā°C, Outlet pressure = 100 bar, Wavelength = 230 nm. Injected 0.5 mL of 1,500 mg sample dissolved in 20 mL 1:1 MeOH: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 1-((1r,4r)(2-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid (600 mg, 1.656 mmol, 35.7% yield): 1H NMR (500 MHz, CD2Cl2) Ī“ 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: 1-((1s,4s)(2-ethoxyoxoethyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid (700 mg, 1.932 mmol, 41.6% yield): 1H NMR (500 MHz, CDCl3) Ī“ 1.09 (s, 3H), 1.25-1.28 (m, 3H), 1.33- 1.43 (m, 2H), 1.82-1.88 (m, 4H), 2.17-2.32 (m, 2H), 2.47 (s, 2H), 4.12-4.17 (m, 2H), 4.35 (tt, J=11.7, 3.9 Hz, 1H), 6.72 (br. s, 1H), 7.98 (s, 1H). LCMS = 363.4 (M+H)+.
The following pyrazole carboxylic acids were ed using similar procedure in reference examples described above.
O N O F N O N N N N EtO OH EtO OH MeO OH F3C O F3C O F3C O D3 D4 D5 O N O N N N N TBSO N MeO OH EtO OH OH F3C O F O F3C F O D6 D7 D8 N N MeO2S N MeO2S N MeO N OH OH N F3C O F3C O F3C O D9 D10 D11 TBSO N TBSO N MeO N N N N MeO OH MeO OH O F3C O O F3C F3C O D12 D13 D14 BocHN N BocHN N NC N N N N MeO OH MeO OH MeO OH O F3C O O F3C O O F3C O D15 D16 D17 NC N O N O N N N N MeO OH EtO OH EtO OH O F3C O O TBSO O D18 D21 D23 O N O N O N EtO OH N N EtO OH EtO OH O BocHN O F3C O D24 D25 D29 F3C 0 NC 0 032 D34 O .\\\ 2 0 g N o N EtO*0 w H)c / 0ā€œ / OH 0 0 D35 D36 037 EtO ~ F >;LWOH 0 F30 0 reference reference structure ure example example D40 #NAME? D46 #NAME? D40b #NAME? D47 #NAME? D41 #NAME? D48 #NAME? D42 #NAME? D49 #NAME? D43 #NAME? D50 #NAME? D44 #NAME? D51 #NAME? D45 #NAME? D52 #NAME? reference reference structure structure e example D53 #NAME? D60 #NAME? D54 #NAME? D61 #NAME? D55 #NAME? D62 #NAME? D56 #NAME? D63 #NAME? D57 #NAME? D64 #NAME? D58 #NAME? D65 #NAME? D59 #NAME? D66 #NAME? reference structure example D67 #NAME? D68 #NAME? D69 #NAME? D70 #NAME? D71 #NAME? D72 #NAME? le 1] trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-(triethylsilyloxy)ethyl)(4-fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (1-1) To a mixture of acid D1 (6.22 g, 18.6 mmol) and amine A1 (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 ed with water (200 mL) and ted with EtOAc (2Ɨ100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford compound 1-1 (15 g, crude) as a brown gum.
Step 2: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(4-fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 Ā°C, and the mixture was d to warm up from 0 Ā°C to room temperature while stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2Ɨ150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography a gel, eluent: 70% hexane) to provide nd 1-2 (9.9 g, 84% over two steps) as a yellow-brown gum. 1H NMR (CDCl3) rotomers present Ī“ 8.42 and 8.38 (2H, 2xs); 7.57 and 7.53 (1H, 2xs); 7.41-7.35 and 7.14-7.09 (4H, 2xm); 5.61-5.45 (1H, m); 5.10-4.50 (3H, m); 4.25-3.90 (4H, m); 3.31-3.15 (1H, m); .16 (6H, m); 1.65-1.51 (2H, m); 1.28-1.23 (3H, m); LCMS: 631 (M+H)+.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(4-fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 ature for 3 h. The reaction mixture was quenched with NaHCO3 (50 mL, sat. aq.) and Na2S2O3 (50 mL, sat. aq.), then ted with DCM (2Ɨ150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: % EtOAc/hexane) to yield compound 1-3 (9.12 g, 92%) as a white solid. 1H NMR (CDCl3) rs present Ī“ 8.74 and 8.67 (2H, 2xs); 7.85 and 7.79 (1H, 2xs); 7.30-7.26 (1H, m); 7.41-7.37 and 7.22-7.15 (3H, 2xm); 4.73-4.51 (4H, m); 4.27-4.21 (1H, m); 4.07 (2H, q, J = 7.2 Hz); 2.50-2.48 (1H, 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-((2-(3,5-dichloropyridinyl) oxoethyl)(4-fluorobenzyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)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 Ā°C. The mixture was allowed to warm to room temperature while ng continued for 4 h. The reaction mixture was acidified with HCl (1 M, 60 mL) and extracted with EtOAc (3Ɨ100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced re to provide the compound of example 1 (8.0 g, 94%) as a white solid. 1H NMR (CDCl3) rotomers present Ī“ 8.53 and 8.47 (2H, 2xs); 7.69 and 7.60 (1H, 2xs); 7.31-7.28 (1H, m); 7.16-7.12 (1H, 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 (1H, m); 2.78 (1H, 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-((2-(2,6-dichlorofluorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichloro fluorophenyl)((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)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 ytic 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 se 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 Ā°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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-10% EtOAc/hexane as eluent) to provide nd 2-1 (27.0 g, 91%) as a colorless gum. 1H NMR (CDCl3) rotomers present Ī“ 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 .50-5.47 (1H, 2xm); .29 (2H, m); 4.18-4.12 and 3.30-3.26 (4H, 2xm); 3.87-3.81 (1H, m); .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-((2-(2,6-dichloro fluorophenyl)hydroxyethyl)(3,5- robenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)methylcyclohexanecarboxylate (2-2) Compound 2-2 was prepared using a similar procedure to that described in example 1, step 2.
Step 3: ethyl 4-(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)(3,5-difluorobenzyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (2-3) Compound 2-3 was prepared using a similar procedure to that described in example 1, step 3.
Step 4: trans(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (2) The compound of example 2 was prepared using a similar procedure to that described in example 1, step 4. 1H NMR (CDCl3) rotomers present Ī“ 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-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen- 3-yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid Step 1 and 2: ethyl trans(4-((3,5-difluorobenzyl)(2- (2,4-dimethylthiophenyl)hydroxyethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (3-2) To a mixture of acid D1 (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 Na2SO4 and concentrated under reduced re to e 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 d at the same temperature for 1 h. The reaction mixture was quenched with saturated s NaHCO3 solution and extracted with EtOAc (2x20 mL). The organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound 3-2 (290 mg, 97%) as a colorless gum.
Step 3: ethyl trans(4-((3,5-difluorobenzyl)(2-(2,4- dimethylthiophenyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (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 Ā°C and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated s Na2S2O3 and NaHCO3, and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was ed by column tography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 3-3 (220 mg, 78%) as a colorless gum.
Step 4: 4-(4-((3,5-difluorobenzyl)(2-(2,4- dimethylthiophenyl)oxoethyl)carbamoyl) uoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (3) To a solution of compound 3-3 (220 mg, 0.37 mmol) in EtOH (1 mL), THF (1 mL) and H2O (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 HCl (pH was ed 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 Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 56% CH3CN as ) to provide the compound of example 3 (56 mg, 26%) as a white solid. 1H NMR (DMSO-d6) rotamers present Ī“ 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-((2-(2,6-dichloro(methylsulfonyl)phenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(2,6-dichloro (methylthio)phenyl)((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylate (4-1) Compound 4-1 (0.44 g, crude) was ed as a brown color gum from the on of amine A57 (0.26 g, 0.52 mmol), acid D1 (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-((2-(2,6-dichloro (methylthio)phenyl)hydroxyethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- yclohexanecarboxylate (4-2) nd 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-((2-(2,6-dichloro (methylthio)phenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-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 ure to that described in e 1.
Step 4: ethyl trans(4-((2-(2,6-dichloro (methylsulfonyl)phenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-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 Na2SO4 and concentrated under d 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-((2-(2,6-dichloro (methylsulfonyl)phenyl)oxoethyl)(3,5- robenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-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 Ī“ 12.21 (1H, brs); 8.10 and 8.03 (2H, 2xs); 7.88 and 7.86 (1H, 2xs); .14 (1H, 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 (1H, m); 3.37 and 3.32 (3H, 2xs); 2.35-2.29 (1H, m); 2.07-2.02 (2H, m); 1.98-1.90 (4H, m); 1.60-1.49 (2H, m); LCMS : 696 (M+H)+.
[Example 5] N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-(3,5- difluorobenzyl)(trans(hydroxycarbamoyl)cyclohexyl)- fluoromethyl)-1H-pyrazolecarboxamide Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylate (5-1) Compound 5-1 (633 mg, crude) was obtained as a brown gum from the reaction of acid D1, amine A18 (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-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl) uoromethyl)-1H-pyrazolyl)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 ure to that described in e 1. LCMS: 649 (M+H)+.
Step 3: trans(4-((2-(3,5-dichloropyridinyl) yethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 LiOHĀ·H2O (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: 1-(trans(((tert- butyldimethylsilyl)oxy)carbamoyl)cyclohexyl)-N-(2-(3,5- dichloropyridinyl)hydroxyethyl)-N-(3,5- difluorobenzyl)(trifluoromethyl)-1H-pyrazole carboxamide (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), t-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: 1-(trans(((tertbutyldimethylsilyl )oxy)carbamoyl)cyclohexyl)-N-(2-(3,5- dichloropyridinyl)oxoethyl)-N-(3,5-difluorobenzyl)- -(trifluoromethyl)-1H-pyrazolecarboxamide (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 bed in example 1. LCMS: 748 (M+H)+.
Step 6: N-(2-(3,5-dichloropyridinyl)oxoethyl)-N- (3,5-difluorobenzyl)(trans (hydroxycarbamoyl)cyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxamide (5) To a d on 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 ed with MeOH (2 mL) and extracted with EtOAc (2 x 20 mL).
The combined organic layers were washed with brine (2 x mL), dried over Na2SO4 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 (CDCl3) rotamers present Ī“ 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-dichloropyridinyl)oxoethyl)-N-(3,5- difluorobenzyl)(trans(methoxycarbamoyl)cyclohexyl)- -(trifluoromethyl)-1H-pyrazolecarboxamide Step 1: N-(2-(3,5-dichloropyridinyl)hydroxyethyl)- N-(3,5-difluorobenzyl)(trans (methoxycarbamoyl)cyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxamide (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 ted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 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-dichloropyridinyl)oxoethyl)-N- (3,5-difluorobenzyl)(trans (methoxycarbamoyl)cyclohexyl)(trifluoromethyl)-1H- pyrazolecarboxamide (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 inane (85 mg, 0.19 mmol) in DCM (5.0 mL) using a similar ure to that described in example 1. 1H NMR (CDCl3) rotamers present Ī“ 8.54 and 8.48 (2H, 2xs); 8.07 (1H, brs); 7.64 and 7.60 (1H, 2xs); .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-((3,5-difluorobenzyl)(2-(2-hydroxy methoxyphenyl)oxoethyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((3,5-difluorobenzyl)(2-(2,6- dimethoxyphenyl)((triethylsilyl)oxy)ethyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazol 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 D1 (0.1 g, 0.3 mmol), HATU (0.13 g, 0.35 mmol) and DIPEA (76 Ī¼L, 0.44 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl trans(4-((3,5-difluorobenzyl)(2-(2,6- dimethoxyphenyl)hydroxyethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 4-(4-((3,5-difluorobenzyl)(2-(2,6- oxyphenyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 artin 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-((3,5-difluorobenzyl)(2-(2- hydroxymethoxyphenyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (7-4) To a stirred on 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 ature and the mixture was stirred for 16 h. Solvent was evaporated under reduced re and the ed 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 Step 5: trans(4-((3,5-difluorobenzyl)(2-(2-hydroxy methoxyphenyl)oxoethyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)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 Ī“ 11.81 (1H, brs); 10.89 (1H, brs); 7.76 and 7.64 (1H, 2xs); 7.42-7.23 (1H, 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-((3,5-difluorobenzyl)(2-oxo(1H-pyrazol yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid Step 1: ethyl 4-(4-((3,5-difluorobenzyl)(2- ((triethylsilyl)oxy)(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylate (8-1) Compound 8-1 (34 mg, ) was obtained as a colorless gum from the reaction of amine A75 (40 mg, 0.080 mmol), acid D1 (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-((3,5-difluorobenzyl)(2-hydroxy- 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 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-((3,5-difluorobenzyl)(2-oxo (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylate (8-3) Compound 8-3 (40 mg, 50%) was obtained as an offwhite solid from the on 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 e 1.
Step 4: trans(4-((3,5-difluorobenzyl)(2-oxo(1H- pyrazolyl)ethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid (8) To a stirred solution of compound 8-3 (75 mg, 0.107 mmol) in 1,4-dioxane (2 mL) was added HCl (12 M, 0.5 mL).
The mixture was stirred at 80 Ā°C for 2 h. The t 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 e phase column chromatography (C18 silica gel, 70% CH3CN/water as eluent) to provide the nd of example 8 (10 mg, 16%) as a white solid. 1H NMR (CD3OD) rotamers present Ī“ 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)+. le 9] 4-(4-((3,5-difluorobenzyl)(2-(2,6-dihydroxyphenyl) oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((3,5-difluorobenzyl)(2-(2- hydroxymethoxyphenyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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) se, 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)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 on mixture was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 55% water/CH3CN as eluent) to provide the nd of example 9 (3 mg, 6%) as a white solid. 1H NMR (DMSO-d6) rs present Ī“ 11.91 (1H, brs); 7.79 and 7.61 (1H, 2xs); .88 (4H, m); 6.36-6.02 (2H, m); 4.89-4.13 (5H, m); 2.29-2.22 (1H, m); 2.05-1.83 (6H, m); 1.55-1.46 (2H, m); LCMS (ESI): 582 (M+H)+.
[Example 10] trans(4-((2-(3,5-dichloropyridinyl)-2,2- difluoroethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2,2-difluoroethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (10-1) To a mixture of acid D1 (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 Ā°C and stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated KHPO4 solution (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 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: 4-(4-((2-(3,5-dichloropyridinyl)-2,2- difluoroethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (10) The compound of example 10 (11 mg, 46%) was ed as a white solid from the on 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 H2O (0.2 mL) using a similar procedure to that described in example 1. 1H NMR (DMSO- d6) rotamers present Ī“ 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); .77 (6H, m); 1.61-1.44 (2H, m); LCMS (APCI): 641 (M+H)+.
[Example 11] trans(4-((2-(2-aminochlorophenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2-chloronitrophenyl) hydroxyethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 D1 (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-((2-(2-chloronitrophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (11-2) nd 11-2 (0.28 g, 70%) was obtained as a ess 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 ure to that described in example 1.
Step 3: ethyl trans(4-((2-(2-aminochlorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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-((2-(2-aminochlorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (11) The nd of e 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. 1H NMR (DMSO-d6) rotamers present Ī“ 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-((3,5-difluorobenzyl)(2-oxo(2,4,6- trihydroxypyrimidinyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid Step 1: ethyl 4-(4-((3,5-difluorobenzyl)(2- ((triethylsilyl)oxy)(2,4,6-tris(benzyloxy)pyrimidin yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 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 D1 (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 r procedure to that described in example 1.
Step 2: ethyl trans(4-((3,5-difluorobenzyl)(2-hydroxy- ,6-tris(benzyloxy)pyrimidinyl)ethyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazol 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-((3,5-difluorobenzyl)(2-oxo (2,4,6-tris(benzyloxy)pyrimidinyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 inane (0.29 g, 0.7 mmol) in DCM (10 mL) using a r procedure to that described in example 1.
Step 4: trans(4-((3,5-difluorobenzyl)(2-oxo(2,4,6- roxypyrimidinyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 HCl (5 mL) at room temperature and the mixture was stirred at 80 Ā°C for 2 h.
% NaOH solution was added to the reaction mixture up to pH 5 and extracted with EtOAc (2 x 30 mL). The ed organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 75% water/CH3CN as eluent) to provide the compound of example 12 (8 mg, 12%) as a white solid. 1H NMR (DMSO-d6) rotamers present Ī“ 7.78 and 7.72 (1H, 2xs); 7.18-6.89 (3H, m); 4.92-4.56 (4H, m); .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] 4-(4-((2-(2-acetamidochlorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(2-acetamido chlorophenyl)oxoethyl)(3,5-difluorobenzyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol 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 Ī¼L, 0.08 mmol) at 0 Ā°C and stirred for 2 h.
The reaction mixture was ed 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 Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to e compound 13-1 (50 mg, quant.) as a yellow solid.
Step 2: trans(4-((2-(2-acetamidochlorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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. 1H NMR (DMSO-d6) rotamers present Ī“ 10.10 and 9.74 (1H, 2xs), 7.80 and 7.78 (1H, 2xs); 7.59-6.91 (6H, m); .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-((2-(3,5-dichloropyridinyl) oxoethyl)(((S)-5,5-dimethylTHFyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)(((S)-5,5-dimethylTHF yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylate (14-1) Compound 14-1 (42 mg, 61%) was obtained as a yellow foam from the reaction of acid D1 (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 ure to that described in example 1. LCMS (APCI): 749 (M+H)+.
Step 2: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(((S)-5,5-dimethylTHF yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 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 r procedure to that described in example 1.
LCMS (APCI): 635 (M+H)+.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(((S)-5,5-dimethylTHFyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol 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 inane (29 mg, 0.069 mmol) in DCM (4.0 mL) using a similar ure to that described in example 1.
LCMS (APCI): 633 (M+H)+.
Step 4: 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)(((S)-5,5-dimethylTHFyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 LiOHĀ·H2O (8 mg, 0.19 mmol) in HF/H2O (4 mL, 1:1:0.5) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present Ī“ 12.16 (1H, 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-((2-(2-chlorohydroxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(2-chloromethoxyphenyl)- 2-((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-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 D1 (0.17 g, 0.52 mmol), HATU (0.23 g, 0.62 mmol) and DIPEA (0.133 mL, 0.78 mmol) in DMF (10 mL) using a similar procedure to that bed in example 1.
Step 2: ethyl trans(4-((2-(2-chloromethoxyphenyl)- 2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 4-(4-((2-(2-chloromethoxyphenyl)- 2-oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (15-3) Compound 15-3 (0.25 g, 70%) was obtained as a white solid from the reaction of nd 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-((2-(2-chlorohydroxyphenyl)- 2-oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (15-4) To a stirred solution of nd 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 d for 16 h. Solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography a gel, 30% EtOAc/hexane as eluent) to provide compound 15-4 (85 mg, 35%) as a yellow oil.
Step 5: trans(4-((2-(2-chlorohydroxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (15) The nd 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. 1H NMR (DMSO-d6) rotamers t Ī“ 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-((2-(3,5-dichloropyridinyl) oxoethyl)(((R)-5,5-dimethylTHFyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid Step 1: ethyl 4-(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)(((R)-5,5-dimethylTHF yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylate (16-1) nd 16-1 (29 mg, 52%) was obtained as a colorless gum from the reaction of acid D1 (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 r procedure to that described in example 1.
LCMS (APCI): 749 (M+H)+.
Step 2: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(((R)-5,5-dimethylTHF yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 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-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(((R)-5,5-dimethylTHFyl)methyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylate (16-3) Compound 16-3 (23 mg, crude) was obtained as a ess 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-((2-(3,5-dichloropyridinyl) oxoethyl)(((R)-5,5-dimethylTHFyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (16) The compound of e 16 (8.5 mg, 39%) was obtained as a white solid from the reaction of compound 16-3 (23 mg, crude) and LiOHĀ·H2O (12 mg, 0.29 mmol) in MeOH/THF/H2O (4 mL, 1:1:0.5) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers present Ī“ 12.19 (1H, brs), 8.79 and 8.72 (2H, 2xs); 7.84 and 7.69 (1H, 2xs); 5.01-4.76 (2H, m); 4.27-3.80 (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 17] trans(5-cyclopropyl((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-1H-pyrazol lohexanecarboxylic acid Step 1: ethyl 4-(5-cyclopropyl((2-(3,5- dichloropyridinyl)((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)-1H-pyrazol yl)cyclohexanecarboxylate (17-1) Compound 17-1 (130 mg, crude) was ed 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(5-cyclopropyl((2-(3,5- dichloropyridinyl)hydroxyethyl)(3,5- robenzyl)carbamoyl)-1H-pyrazol 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(5-cyclopropyl((2-(3,5- dichloropyridinyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)-1H-pyrazol yl)cyclohexanecarboxylate (17-3) Compound 17-3 (60 mg, 75%) was obtained as an te 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: 4-(5-cyclopropyl((2-(3,5- dichloropyridinyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)-1H-pyrazol 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 r ure to that described in example 1. 1H NMR (DMSO-d6) rotamers present Ī“ 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] 4-(4-((2-(2,6-dichloro(difluoromethyl)phenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(2,6-dichloro (difluoromethyl)phenyl)hydroxyethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-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 A111 (0.10 g, 0.26 mmol), acid D1 (87 mg, 0.26 mmol), HATU (0.12 g, 0.31 mmol) and DIPEA (67 Ī¼L, 0.39 mmol) in DMF (5 mL) using a similar procedure to that described in example 1.
Step 2: ethyl trans(4-((2-(2,6-dichloro (difluoromethyl)phenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylate (18-2) Compound 18-2 (0.12 g, 67%) was obtained as a ess 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 ure to that described in example 1.
Step 3: trans(4-((2-(2,6-dichloro (difluoromethyl)phenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-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 to that described in example 1. 1H NMR (DMSO-d6) rotamers t Ī“ 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); .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-((2-(3,5-dichloropyridinyl)oxoethyl)((4- hydroxymethylcyclohexyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)((4-hydroxy methylcyclohexyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylate (19-1) Compound 19-1 (72 mg, crude) was obtained as a colorless gum from the reaction of acid D1 (44 mg, 0.129 mmol), amine A112 (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 bed in example 1.
Step 2: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)((4-hydroxy methylcyclohexyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)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-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((4-hydroxy methylcyclohexyl)methyl)carbamoyl)(trifluoromethyl)- azolyl)cyclohexanecarboxylate (19-3) Compound 19-3 (45 mg, crude) was obtained as a colorless gum from the reaction of nd 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-((2-(3,5-dichloropyridinyl) oxoethyl)((4-hydroxy methylcyclohexyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylic acid (19) The compound of example 19 (16 mg, 38%) was obtained as a white solid from the on of compound 19-3 (45 mg, 0.069 mmol) and LiOHĀ·H2O (18 mg, 0.41 mmol) in EtOH/THF/H2O (4 mL, 1:1:0.5) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers t Ī“ 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] 4-(4-((2-(3,5-Dichloropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (difluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- iethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(difluoromethyl)-1H-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 A18 (105 mg, 0.31 mmol), 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-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(3,5-difluorobenzyl)carbamoyl) (difluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (20-2) Compound 20-2 (101 mg, 91%) was obtained as an offwhite 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-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(3,5-difluorobenzyl)carbamoyl) (difluoromethyl)-1H-pyrazolyl)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 ure to that described in example 2.
Step 4: trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (difluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (20) To a solution of compound 20-3 (106 mg, 0.17 mmol) in dioxane (6 mL) was added 6 M HCl (6 mL) and heated at 80 Ā°C for 16 h. The reaction mixture was cooled to room temperature, added H2O and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 75% CH3CN /water as eluent) to provide the compound of example 20 (36 mg, 62%) as a white solid. 1H NMR d6) rotamers present Ī“ 8.76 and 8.69 (2H, 2xs); 7.77 and 7.67 (1H, 2xs); 7.45-7.00 (4H, m); 4.91-4.70 (4H, m); 4.36-4.29 (1H, m); 2.31-2.24 (1H, m); 2.06-2.02 (2H, m); 1.94-1.89 (4H, m); 1.56-1.45 (2H, m); LCMS (ESI): 599 (M+H)+. le 21] 4-(4-((2-(2-aminochloropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl 4-(4-((2-(2-azidochloropyridin yl)oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (21-1) To a stirred solution of ethyl trans(4-((2-(2,4- dichloropyridinyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylate (100 mg, 0.15 mmol) in DMF (5 mL) was added NaN3 (50 mg, 0.7 mmol) and the mixture was d 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 Na2SO4 and trated 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-((2-(2-aminochloropyridin yl)oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (21-2) To a stirred on 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 Ā°C and e was stirred at room temperature for 2 h. H2O (0.06 mL) was added to the reaction mixture at 0 Ā°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-((2-(2-aminochloropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (21) To a stirred on 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 on mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL), acidified with 0.5 M HCl (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 Na2SO4 and concentrated under d pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 70% water as eluent) to provide the compound of example 21 (25 mg, 66%) as a white solid. 1H NMR (DMSO-d6) rotamers present Ī“ 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] 4-(4-((2-cyanobenzyl)(2-(3,5-dichloropyridinyl)- 2-oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-bromobenzyl)(2-(3,5- dichloropyridinyl) ((triethylsilyl)oxy)ethyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylate (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 D1 (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 r ure to that described in example 1.
Step 2: ethyl trans(4-((2-bromobenzyl)(2-(3,5- dichloropyridinyl)hydroxyethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (22-2) Compound 22-2 (175 mg, 73%) was obtained as an offwhite solid from the on 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-((2-bromobenzyl)(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylate (22-3) Compound 22-3 (150 mg, 86%) was ed as an offwhite solid from the on 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-((2-cyanobenzyl)(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 Ā°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 Na2SO4 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-((2-cyanobenzyl)(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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 H2O (1 mL) using a similar procedure to that described in example 1. 1H NMR (DMSO-d6) rotamers t Ī“ 8.56-8.50 (2H, m); 7.91 (2H, brs); 7.94 (1H, s); 7.54-7.42 and 7.17 (3H, m and s); 7.08 (1H, s); 5.62-5.58 and 4.64-4.59 (1H, 2xm); 4.33-4.17 (1H, m); 2.39-2.33 (1H, m); 2.10-1.93 (7H, m); LCMS (APCI): 608 (M+H)+.
[Example 23] trans(4-((2-(3,5-dichloropyridinyl) yl)((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic Step 1: ethyl 4-(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)((3,3- dimethylcyclobutyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylate (23-1) Compound 23-1 (180 mg, crude) was obtained as a yellow gum from the reaction of amine A119 (190 mg, 0.455 mmol), acid D1 (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 bed in example 2.
Step 2: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)((3,3- dimethylcyclobutyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylate (23-2) nd 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 ure to that described in example 1.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)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-((2-(3,5-dichloropyridinyl) oxoethyl)((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid (23) The nd 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 ure to that described in example 1. 1H NMR (CD3OD) rotamers present Ī“ 8.65 and 8.58 (2H, 2xs); 7.74 and 7.57 (1H, 2xs); 4.81 and 4.63 (2H, 2xs); 4.36-4.24 (1H, 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); .56 (3H, m); 1.37- 1.29 (1H, m); 1.15-0.93 (6H, m); LCMS (APCI): 591 (M+H)+.
[Example 186] trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid Step 1: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (186-1) nd 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-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate ) 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 ure to that described in example 1.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)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-((2-(3,5-Dichloropyridinyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 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 bed in example 1. 1H NMR (CDCl3) rotamers present Ī“ 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 (1H, 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-dichloropyridinyl)oxoethyl)-(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid Step 1: ethyl 4-(4-((2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)bicyclo[2.2.2]octane carboxylate (233-1) nd 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-dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)bicyclo[2.2.2]octanecarboxylate (233- 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-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)bicyclo[2.2.2]octanecarboxylate (233-3) nd 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 r procedure to that described in example 1.
Step 4: 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid (233) The compound of example 233 (27 mg, 51%) was ed 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 ) rotamers present Ī“ 8.57 and 8.50 (2H, 2xs); 7.64 and 7.49 (1H, 2xs); 4.84 and 4.50 (2H, 2xs); 3.61-3.26 (2H, m); 2.32-2.22 (6H, m); 2.08-2.04 (6H, m); 1.01 and 0.85 (9H, 2xs); LCMS (ESI) : 589.2 (M+H)+.
[Example 276] trans(5-chloro((2-(3,5-dichloropyridinyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl)pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(5-chloro((2-(3,5- dichloropyridinyl) ((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl)-1H- pyrazolyl)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(5-chloro((2-(3,5- dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)-1H-pyrazolyl) cyclohexanecarboxylate (276-2) Compound 276-2 (160 mg, 88%, over 2 steps) was ed as white solid from the on 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 bed in example 1.
Step 3: ethyl trans(5-chloro((2-(3,5- dichloropyridinyl)oxoethyl)(neopentyl)carbamoyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate (276-3) Compound 276-3 (130 mg, 81%) was obtained as an offwhite 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(5-chloro((2-(3,5-dichloropyridin yl)oxoethyl)-(2,2-dimethylpropyl)carbamoyl)pyrazol yl)methylcyclohexanecarboxylic 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 Ī“ 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); .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-((2-(2,6-dichloromethylphenyl) yl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichloro methylphenyl)((triethylsilyl)oxy)ethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (277-1) Compound 277-1 was obtained from the on 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-((2-(2,6-dichloro methylphenyl)hydroxyethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (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 e 1.
Step 3: ethyl trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (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, mol) 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: 4-(4-((2-(2,6-dichloromethylphenyl) ((triethylsilyl)oxy)ethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (277) The compound of example 277 (58 mg, 75%) was obtained as a white solid from the on 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. 1H NMR (CDCl3) rotamers present Ī“ 7.69 and 7.54 (1H, 2xs); 7.16 and 7.08 (2H, 2xs); 5.10-5.00 and 4.36-4.14 (2H, 2xm); 4.59 and 4.39 (2H, 2xs); 2.35 and 2.31 (3H, 2xs); 2.31-1.85 (10H, 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-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (278-1) Compound 278-1 was obtained from the on 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-((2-(2,6-dichlorophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (278-2) nd 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.
Step 3: ethyl trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylate (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-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (278) The compound of example 278 (35 mg, 44%) was ed 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 described in example 1. 1H NMR (CDCl3) rotamers present Ī“ 7.70 and 7.55 (1H, 2xs); .26 (3H, m); 5.10-5.00 and 4.37-4.15 (2H, 2xm); 4.61 and 4.42 (2H, 2xs); 2.31-1.87 (10H, 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-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-(trifluoromethyl)cyclopropyl)methyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid Step 1: ethyl 4-(4-((2-(3,5-dichloropyridinyl)- 2-((triethylsilyl)oxy)ethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (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-((2-(3,5-dichloropyridinyl)- 2-hydroxyethyl)((1- uoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (330-2) Compound 330-2 (37 mg, 58% over 2 steps) was ed as a colorless oil from the reaction of nd 330-1 (crude) and TBAF (0.098 mL, 0.098 mmol, 1 M in THF) in THF (1 mL) using a similar ure to that described in example 1.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (330-3) Compound 330-3 (31 mg, 83%) was 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-((2-(3,5-dichloropyridinyl) oxoethyl)-((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane ylic 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. 1H NMR (CDCl3) rotamers present Ī“ 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); .06 (4H, m); LCMS (ESI) : 629.2 (M+H)+.
[Example 343] trans(4-((2-(4-chloro-1H-indolyl)ethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(4-chloro-1H-indol yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (343-1) Compound 343-1 (42 mg, 91%) was obtained as a yellow gum from the reaction of amine B19 (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 DMF (1 mL) using a similar procedure to that described in example 1.
Step 2: trans(4-((2-(4-chloro-1H-indol yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (343) The compound of e 343 (31 mg, 78%) was obtained as a white solid from the reaction of nd 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 ure to that described in example 1. 1H NMR (CDCl3) rotamers present Ī“ 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 (8H, m); 1.70-1.60 (2H, m); 1.41 and 1.39 (3H, 2xs); .85 (10H, m); LCMS (ESI) : 606.0 (M+H)+.
[Example 361 and 362] trans(4-(((2R)(2,6-dichlorofluorophenyl) hydroxyethyl)-(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid or trans(4-(((2S)(2,6-dichloro fluorophenyl)hydroxyethyl)-(4,4- ylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichloro fluorophenyl)((triethylsilyl)oxy)ethyl)(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (361-1) Compound 361-1 was obtained from the reaction of amine C1 (89 mg, 0.199 mmol), acid D2 (60 mg, 0.172mmol), 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-((2-(2,6-dichloro methylphenyl)hydroxyethyl)(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)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 4-(4-(((S)(2,6-dichloro methylphenyl)hydroxyethyl)(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate and ethyl trans(4-(((R)(2,6-dichloromethylphenyl) hydroxyethyl)(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (361-3 and 362-1) Compound 361-2 (100 mg, 0.151 mmol) was ed by chiral HPLC (250 x 20 mm DAICEL CHIRALPAKTM IA 5 Ī¼m 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-(((2R)(2,6-dichloro fluorophenyl)hydroxyethyl)-(4,4- ylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid or trans (4-(((2S)(2,6-dichlorofluorophenyl) hydroxyethyl)-(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 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: 4-(4-(((2R)(2,6-dichlorofluorophenyl) yethyl)-(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid or 4-(4-(((2S)(2,6-dichloro fluorophenyl)hydroxyethyl)-(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic 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. 1H NMR (CDCl3) rotamers present Ī“ 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); .64 and 4.09-4.02 (1H, 2xm); 4.30-4.20 (1H, 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-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[25]octylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid Step 1 and Step 2: ethyl trans(4-((2-(2,6- dichlorophenyl)hydroxyethyl)(spiro[2.5]octan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylate To a solution of 1-((trans)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic 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]octanylmethyl) ((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 ature. 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 Na2SO4. The on 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-((2-(2,6- dichlorophenyl)hydroxyethyl)(spiro[2.5]octan ylmethyl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylate (0.0815 g, 0.124 mmol, 27.4% yield) a colorless gum.
Step 3: ethyl 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[2.5]octanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a solution of ethyl trans(4-((2-(2,6- dichlorophenyl)hydroxyethyl)(spiro[2.5]octan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylate 5 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 Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL). The on mixture was extracted with DCM (2 x 100 mL). The organic extract was dried over Na2SO4. 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-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[2.5]octanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylate (0.0685 g, 0.104 mmol, 84% yield) as a colorless syrup.
Step 4: trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[25]octylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid To a solution of ethyl trans(4-((2-(2,6- dichlorophenyl)oxoethyl)(spiro[2.5]octan ylmethyl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- ylcyclohexanecarboxylate (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 Ā°C overnight. The THF and MeOH were d in vacuo and the turbid solution was diluted with water (3 mL) to provide a clear solution. 1 M HCl was added to adjust the pH to 1. The mixture was stirred for 30 min before collecting the precipitate by vacuum filtration to e a white solid. The solid was purified by silica gel column tography eluting with a gradient of 0% to 5% MeOH in DCM to provide Example 569 7 g, 0.073 mmol, 69.7% yield) as white solid. 1H NMR (400 MHz, CD3OD) Ī“ 7.40-7.79 (4H, m), 5.30-5.54 (1H, m), 4.87 (1H, 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), 1.54-1.98 (10H, m), 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] trans(4-(((2R)((3,5-dichloropyridinyl)methyl)- 4,4-dimethylpyrrolidinyl) carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ed according to WO patent: 2013004290A1.
To a stirred suspension of (R)-(-)(hydroxymethyl) pyrrolidinone (Sigma Aldrich Chemical Company, St. Louis, MO, 5.36 g, 46.5 mmol) and p-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 methoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 36 h. The solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as an orange waxy solid. MS (ESI) 156.1 [M + H]+. The crude material was taken to the next step without further purification.
Step 2: ed according to WO patent: WO2013004290A1.
To a on of (R)-3,3-dimethyltetrahydropyrrolo[1,2- c]oxazol-5(3H)-one (3.50 g, 22.55 mmol) in THF (75 mL) cooled to -78 Ā°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 Ā°C prior addition of lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, .30 mL, 40.6 mmol). The e was stirred at -78 Ā°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 MgSO4, filtered and trated to provide crude (R)-3,3,6,6 tetramethyltetrahydropyrrolo[1,2-c]oxazol- (3H)-one as an orange tar. MS (ESI) 184.1 [M + H]+.
Step 3: Prepared according to WO patent: 2013004290. To a on of (R)-3,3,6,6- tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.13 g, 22.54 mmol) in MeOH (90 mL) was added ptoluenesulfonic 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 tography on an ISCO CombiflashTM RF (40 g Grace Reverlis column, using a gradient of 0-20% MeOH in DCM) affording (R) (hydroxymethyl)-3,3-dimethylpyrrolidinone (2.91 g, .31 mmol, 90% yield) as a white semi-solid. MS (ESI) 144.1 [M + H]+.
Step 4: Prepared ing to US : 20070032433A1.
To a on of (R)(hydroxymethyl)-3,3- dimethylpyrrolidinone (2.91 g, 20.30 mmol) in THF (50.8 mL) cooled to 0 Ā°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 e (2.0 M on in THF, 12.18 mL, 24.36 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0 Ā°C in an ice bath prior to addition of water (3.67 mL) followed by 15% s 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 (R)-(4,4- dimethylpyrrolidinyl)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 (R)-(4,4-dimethylpyrrolidinyl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to -78 Ā°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 ined at this temperature for ~ 3 h, d to warm to room temperature and stirred overnight (16 h). The mixture was washed with aqueous 1 N HCl (30 mL x 2), brine (40 mL), dried over MgSO4, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was ed onto a plug of silica gel and purified by chromatography on an ISCO CombiflashTM RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (R)-5,5-dimethyltetrahydro-3H- pyrrolo[1,2-c][1,2,3]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, .38 mmol) in THF (9.0 mL) at -78 Ā°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 (R)-5,5-dimethyltetrahydro-3H- pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (686 mg, 3.59 mmol) in THF (9.0 mL) was added se at -78 Ā°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 d with hot (80 Ā°C) 2 N HCl (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 CombiflashTM RF (25 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording (R)-3,5-dichloro((4,4-dimethylpyrrolidin yl)methyl)pyridine (748 mg, 2.89 mmol, 80% yield) as an orange oil. MS (ESI) 259.1, 261.0 [M + H]+.
Step 7: 1-((1r,4r)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole ylic acid (445 mg, 1.28 mmol) was treated with DCM (8 mL) and three drops of DMF, cooled to 0 Ā°C in an ice bath and treated with oxalyl de (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 y evaporator) and the crude acid chloride was treated with DCM (10 mL), cooled in an ice bath and treated with (R)-3,5-dichloro((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 t was evaporated and the crude al was ed onto a plug of silica gel and purified by chromatography on an ISCO CombiflashTM RF (40 g Thomson SingleStep column, using a gradient of 0-40% EtOAc in heptane) to provide (1R,4r)-ethyl 4-(4-((R)((3,5-dichloropyridin yl)methyl)-4,4-dimethylpyrrolidinecarbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (489 mg, 0.83 mmol, 68% yield) as a light yellow amorphous solid after drying in a vacuum oven over 48hrs at 40 Ā°C. MS (ESI) 589.3/591.2 [M + H]+.
Step 8: To a mixture of (1R,4r)-ethyl 4-(4-((R)((3,5- dichloropyridinyl)methyl)-4,4-dimethylpyrrolidine carbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (464 mg, 0.787 mmol) in THF (3.9 mL) and MeOH (3.9 mL) was added m 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 re (rotary evaporator) and the s on was acidified with 1 N HCl leading to the ion of a precipitate. The mixture was extracted with EtOAc (2 x 40 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO CombiflashTM RF (40 g Thomson SingleStep column, using a gradient of 0-8% MeOH in DCM) ing (1R,4r)(4-((R)((3,5- dichloropyridinyl)methyl)-4,4-dimethylpyrrolidine carbonyl)(trifluoromethyl)-1H-pyrazolyl) 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-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1 and Step 2: ethyl trans(4-((2-(3,5- dichloropyridinyl)hydroxyethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate To a ly cloudy solution of 1-((1r,4r) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic acid (1.0102 g, 2.90 mmol) in DCM (29.0 ml) was added oxalyl de (0.307 ml, 3.63 mmol) followed by DMF (1 drop) and the light-yellow slightly cloudy reaction mixture was d at room temperature. After 3 h, the mixture was concentrated in vacuo to give ethyl trans(4-(chlorocarbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate as light-yellow syrup. To the residue was added a solution of N-(2-(3,5- dichloropyridinyl)((triethylsilyl)oxy)ethyl)-3,3,3- trifluoro-2,2-dimethylpropanamine (1.292 g, 2.90 mmol) in THF (29.0 ml) followed by DIPEA (2.021 ml, 11.60 mmol) and the mixture was stirred at room temperature. After 19 h, LCMS (ESI) showed that ethyl 4-(4-((2-(3,5- dichloropyridinyl)((triethylsilyl)oxy)ethyl)(3,3,3- trifluoro-2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate 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 . 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 4-(4-((2-(3,5- ropyridinyl)hydroxyethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (1.6938 g, 2.56 mmol, 88% yield) as a white gummy solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 8.46-8.63 (2H, m), 7.71-7.83 (1H, m), 6.11 (1H, d, J=4.1 Hz), .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 l peak sets due to diastereomers and rotamers; LCMS (ESI) m/z 661.1 (M+H)+.
Step 3: ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)methylcyclohexanecarboxylate To a clear solution of ethyl trans(4-((2-(3,5- dichloropyridinyl)hydroxyethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate 6 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 Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL). The reaction mixture was extracted with DCM (2 x 100 mL). The c extract was dried over Na2SO4. 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 nt of 0% to 30% EtOAc in heptane to provide ethyl trans(4-((2-(3,5- dichloropyridinyl)oxoethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-methylcyclohexanecarboxylate (1.5825 g, 2.400 mmol, 94% yield) as a white gummy solid. 1H NMR (400 MHz, CDCl3) Ī“ 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: 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid To a clear mixture of ethyl trans(4-((2-(3,5- dichloropyridinyl)oxoethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)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 e. The yellow cloudy mixture was stirred and heated at 60 Ā°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 5 g, 2.210 mmol, 93% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 12.27 (1H, br. s.), 8.58-8.83 (2H, m), 7.75-8.02 (1H, m), .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] (1r,4r)(4-((2-(2,6-dichlorophenyl)oxoethyl)((5- spiro[2.3]hexanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichloro fluorophenyl)((triethylsilyl)oxy)ethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)methylcyclohexanecarboxylate 1-((1r,4r)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic 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 ts 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 (1s,4s)-ethyl 4- (4-(chlorocarbonyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylate. 2-(2,6-dichlorophenyl)- N-((5-fluorospiro[2.3]hexanyl)methyl) thylsilyl)oxy)ethanamine (150 mg, 0.347 mmol) was dissolved in 2 ml of DCM and (1s,4s)-ethyl 4-(4- (chlorocarbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (127 mg, 0.347 mmol) dissolved in 2 ml of DCM was added, followed by triethylamine (242 Ī¼l, 1.734 mmol). The solution was stirred for 1 h and was concentrated to afford crude (1r,4r)-ethyl (2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate (265 mg, 0.347 mmol, 100% yield).
Step 2: (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate To a stirred solution of (1r,4r)-ethyl 4-(4-((2- (2,6-dichlorophenyl)((triethylsilyl)oxy)ethyl)((5- fluorospiro[2.3]hexanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (265 mg, 0.347 mmol) in 2 ml of THF was added TBAF (695 Ī¼l, 0.695 mmol), and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over ous Na2SO4 and concentrated under reduced pressure to afford crude (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate (225 mg, 0.347 mmol, 100% yield). MS m/z =648 [M+H]+.
Step 3: (1r,4r)-ethyl (2-(2,6-dichlorophenyl) oxoethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol methylcyclohexanecarboxylate (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate (225 mg, 0.347 mmol) was ved in 10 ml of DCM and Dess-Martin ane (184 mg, 0.434 mmol) was added. The solution was stirred for 1 h. The solution was quenched with 5% Na2S2O3, washed with saturated NaHCO3, dried with Na2SO4 and trated. The product was purified via silica gel column chromatography (40 g column) using 0-100 % EtOAc in heptane to afford )-ethyl 4-(4-((2-(2,6- dichlorophenyl)oxoethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate (140 mg, 0.217 mmol, 62.4% yield). MS m/z =646 .
Step 4: (1r,4r)(4-((2-(2,6-dichlorophenyl) oxoethyl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylic acid (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) yl)((5-fluorospiro[2.3]hexan yl)methyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)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 Ā°C for 3 h. The solution was made acidic with 6 N HCl and diluted with water. The product was ted with EtOAc, dried with Na2SO4, filtered and concentrated to afford (1r,4r)(4-((2- (2,6-dichlorophenyl)oxoethyl)((5- fluorospiro[2.3]hexanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (115mg, 0.186 mmol, 86% yield). 1H NMR (400 MHz, CD3OD, mixture of rotamers) Ī“ 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-((2-(2,6-dichlorofluorophenyl) oxoethyl)((1-methylcyclopropyl)methyl) carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichloro phenyl)((triethylsilyl)oxy)ethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate 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-((2-(2,6-dichloro fluorophenyl)hydroxyethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate This nd was prepared using similar ure described for examples 1, step 2 without chromatography purification. LCMS (ESI) m/z 623.9 .
Step 3: ethyl trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate This compound was prepared using similar procedure described for examples 1, step 3. 1H NMR (500 MHz, CDCl3) rotamers present Ī“ 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-((2-(2,6-dichlorofluorophenyl) oxoethyl)((1-methylcyclopropyl)methyl) carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid This compound was ed as a white solid using similar procedures described for example 1, step 4. 1H NMR (500 MHz, DMSO-d6) rotamers present Ī“ 12.29 (s, 1H), 7.52-7.82 (m, 3H), 5.17 and 4.87 (2xs, 1H), 4.69 (s, 1H), .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), .57 (m, 1H), 0.23-0.38 (m, 3H); LCMS (ESI) m/z 592.1 (M+H)+.
[Example 729] Step 1: (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) ((trimethylsilyl)oxy)ethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylate.
To a solution of 2-(2,6-dichlorophenyl)-N-((1- (trifluoromethyl)cyclopropyl)methyl) ((trimethylsilyl)oxy)ethanamine (0.15 g, 0.375 mmol) in DCM (3 mL) was added ethyl 4-(4-(chlorocarbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (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:EtOAc (0-50%) to obtain (1r,4r)-ethyl 4-(4-((2- (2,6-dichlorophenyl)((trimethylsilyl)oxy)ethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (0.177 g, 0.242 mmol, 65%) as clear oil.
Step 2 : )-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a solution of (1r,4r)-ethyl 4-(4-((2-(2,6- dichlorophenyl)((trimethylsilyl)oxy)ethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (0.177 g, 0.242 mmol) in 2- Me-THF (0.808 ml) was added tetra-n-butylammonium fluoride (0.291 ml, 0.291 mmol) The mixture was stirred at ambient temperature for 1h. The reaction e was ed with saturated s NH4Cl (1 mL) and diluted with EtOAc (50 mL) and water (20 mL). The organic layer was concentrated under reduced pressure to afford (1r,4r)-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) 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 Na2S2O3 (5 mL) ed by saturated NaHCO3 (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 )-ethyl 4-(4-((2-(2,6-dichlorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (0.13 g, 82%) as amorphous white solid.
Step 3: )(4-((2-(2,6-dichlorophenyl) oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
To a solution of (1r,4r)-ethyl 4-(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylate (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 Ā°C for 1 h. Reaction mixture was acidified with 2 N HCl to pH 2 and ted with EtOAc (2 x 30 mL). Organic layer was dried on anhydrous Na2SO4 filtered and concentrated to obtain (1r,4r)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (0.1g, 75%) as amorphous white solid. 1H NMR Ī“ (DMSO-d6) rotamers present 12.22 (1H, brs); 9.79 (1H, 2xs); 7.69 and 7.67 (1H, 2xs); 7.55 and 7.54 (1H, 2xs); 7.46 and 7.44 (1H, 2xs); 5.19 (1H, m); 4.30-4.20 (2H, m); 3.78 (2H, m); .20 (2H, m); 2.18-1.98 (3H, m); 1.88-1.47 (8H, m); 1.24 and 1.23 (3H, 2xs) LCMS (ESI): 628.0 (M+H)+.
[Example 759] trans(4-((2-(2,6-dichlorophenyl)oxoethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylic acid Step 1: trans-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((1-methylcyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a solution of 1-(trans(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole ylic acid (2.88 g, 8.27 mmol) in DCM thionyl de (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 oC 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) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (2.87 g, 95% yield) which was used without further cation. To a solution of 2-(2,6-dichlorophenyl)-N-((1-methylcyclopropyl)methyl) ((triethylsilyl)oxy)ethanamine (95 mg, 0.245 mmol) in DCM (1.2 ml) was added DIPEA (85 Ī¼l, 0.489 mmol) and transethyl 4-(4-(chlorocarbonyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (90 mg, 0.245 mmol). After 45 min, TBAF (1 M solution in THF) (905 Ī¼l, 0.905 mmol) was added. After 2 h, 1 M aq. HCl 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.
NaHCO3, dried with Na2SO4 and concentrated to provide crude trans-ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((1-methylcyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (206 mg) which was used t purification in the next step.
Step 2: trans-ethyl 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)((1-methylcyclopropyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a solution of trans-ethyl (2-(2,6- dichlorophenyl)hydroxyethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate (206 mg, 0.341 mmol) in DCM (3.5 ml) was added Dess-Martin inane (217 mg, 0.511 mmol). After 40 min 1 M aq.
Na2S2O3 and sat. aq. NaHCO3 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)oxoethyl)((1- cyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate (100 mg, 0.166 mmol, 48.7% yield).
Step 3: trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1-methylcyclopropyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid To a mixture of trans-ethyl 4-(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)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 Ā°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. HCl. The mixture was stirred for 15 min, precipitated solid was filtered, washed with waterand dried in vacuo to afford trans(4- ((2-(2,6-dichlorophenyl)oxoethyl)((1- methylcyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylic acid (82 mg, 0.143 mmol, 86% yield). 1H NMR (400 MHz, 6) mixture of rotamers and keto-enol tautomers Ī“ 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), .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, 1H), 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-((2-(2,6-dichlorophenyl)oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)(trifluoromethyl)- azolyl)methylcyclohexanecarboxylic acid Step 1: ethyl trans(4-((2-(2,6-dichlorophenyl) ((triethylsilyl)oxy)ethyl)((1- methylcyclobutyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate This compound was prepared using similar procedure described for example 1, step 1 without chromatography purification.
Step 2: ethyl 4-(4-((2-(2,6-dichlorophenyl) hydroxyethyl)((1-methylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate This nd 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-((2-(2,6-dichlorophenyl) oxoethyl)((1-methylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate This compound was prepared using similar procedure bed for example 1, step 3. 1H NMR (500 MHz, DMSO-d6) rotamers present Ī“ 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-((2-(2,6-dichlorophenyl) oxoethyl)((1-methylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid This compound was obtained as a white solid using similar procedure described for example 1, step 4. 1H NMR (500 MHz, 6) rotamers present Ī“ 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), .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 .
[Example 785] (1S,4S)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylic acid Step 1: Ethyl trans(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylate (racemic mixture).
Oxalyl chloride (64 Ī¼L, 0.72 mmol) and DMF (1 drop) were added sequentially to a ng solution of trans- 1-(4-(ethoxycarbonyl)-3,3-dimethylcyclohexyl) (trifluoromethyl)-1H-pyrazole 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-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-2,2-dimethylpropanamine (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 n EtOAc and saturated aqueous NaHCO3, the layers were ted, the organic material was washed sequentially with saturated aqueous NaHCO3 (2Ɨ) and brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The e was dissolved with DCM (5.5 mL) and the ing 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 ted aqueous NaHCO3, the layers were separated, the organic material was washed sequentially with ted aqueous NaHCO3 and brine, dried (Na2SO4), ed, 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 re. The residue was subjected to flash chromatography on silica gel (gradient elution; 9:1 to 4:1 hexane-EtOAc) to give ethyl trans(4-((2-(3,5- dichloropyridinyl)oxoethyl)(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)-2,2-dimethylcyclohexanecarboxylate (0.27 g, 80% overall yield; racemic e) as a colorless solid.
Step 2: Ethyl (1S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylate.
Ethyl trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylate (0.22 g, from Step 1; racemic mixture) was resolved using preparative high- performance liquid chromatography LPAKTM AD-H column from Chiral Technologies, Inc., West Chester, PA (250 mm x 30 mm, 5 Ī¼m 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 (1R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- ylcyclohexanecarboxylate (0.10 g) as a colorless solid. Peak 2: Ethyl (1S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylate (0.098 g) as a ess solid.
Step 3: (1S,4S)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-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 (1S,4S)(4- ((2-(3,5-dichloropyridinyl)oxoethyl)(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-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 Ā°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 Et2O, 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 d re to give (1S,4S)(4-((2-(3,5-dichloro nyl)oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylic acid (0.082 g, 88% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) major rotamer/tautomer xylic acid proton not observed) Ī“ 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), .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 (1R,4R)-ethyl ester from Step 2 example 785.
[Example 807]: made in the same manner as example 754.
[Example 791] (4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexyl)acetic acid Steps 1 and 2: 2-((1r,4r)(4-((2-(3,5-dichloropyridin- 4-yl)hydroxyethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetate Steps 1 and 2 were conducted in a similar manner to Example 1 to give ethyl 2-((1r,4r)(4-((2-(3,5- dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexyl)acetate.
Step 3: ethyl 2-((1r,4r)(4-((2-(3,5- dichloropyridinyl)oxoethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetate To a solution of ethyl 2-((1r,4r)(4-((2-(3,5- ropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)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 NaHCO3 (5 mL, sat. aq.) and 3 (5 mL, sat. aq.), then extracted with CH2Cl2 (2Ɨ15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced re. The residue was purified by column chromatography (24 g Gold, 0% -50% EtOAc/Hexane) to yield pure white solid as ethyl 2- ((1r,4r)(4-((2-(3,5-dichloropyridinyl) yl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexyl)acetate (85.5 mg, 0.138 mmol, 63.7% yield). LCMS = 618 (M+H)+.
Step 4: (trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetic acid.
To solution of ethyl 2-((1r,4r)(4-((2-(3,5- dichloropyridinyl)oxoethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) 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. t 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-((1r,4r)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- lyl)methylcyclohexyl)acetic acid (82 mg, 0.139 mmol, 100% yield) as mixture of tautomers. 1H NMR (500 MHz, DMSO-d6) Ī“ 0.90-1.01 (m, 9H) 1.05-1.14 (m, 3H) .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 (M+H)+.
[Example 795] O N HO N Cl F3C O trans(4-(((2S,4S)((3,5-dichloro pyridinyl)carbonyl)phenoxypyrrolidinyl) carbonyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was prepared according to example 822 using (2S,4S)-Bocphenoxy-pyrrolidinecarboxylic acid (Chem Impex Int'l, Wood Dale, IL, 2.07 g, 6.74 mmol). The mixture of epimers was ted using prepartory SFC under the ing conditions. Step 1: Preparative SFC: OX-H (5 um, 21 mm x 25 cm), Organic modifier: 15% MeOH. F=70 ml/min, T=40 Ā°C, BPR=100 bar, 220 nm. P=151 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 um, 21 mm x 25 cm), Organic modifier: 25% MeOH. F=70 ml/min, T=40 Ā°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: ing Peak 1 collection.
OX-H (5 um, 21 mm x 25 cm) Organic modifier: 25% MeOH. F=70 ml/min, T=40 Ā°C, BPR=100 bar, 220 nm. P=165 bar. All sample ved 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] O N HO N Cl F3C O trans(4-(((2R,4S)((3,5-dichloro pyridinyl)carbonyl)phenoxypyrrolidinyl) carbonyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was ed (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] trans(4-(((2S,4R)((3,5-dichloro pyridinyl)carbonyl)phenoxypyrrolidinyl) carbonyl)- fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was isolated (6.7 mg, 10.48 Ī¼mol, 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 g peak under the separation ions described above for example 795.
[Example 798] (1r,4r)(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid F3C O N CF3 O N HN N Step 1 N EtO Step 2 N OH Cl EtO F3C O F3C O Cl Cl HO F F O N O N CF3 CF3 N N N Step 3 N EtO HO Cl Cl F3C F3C O O O O Cl Cl F F Step 1: )-ethyl 4-(4-((2-(2,6-dichloro phenyl)hydroxyethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a solution of 1-(2,6-dichlorofluorophenyl) (((1-(trifluoromethyl)cyclopropyl)methyl)amino)ethanol (116 mg, 0.335 mmol) and (1r,4r)-ethyl 4-(4- (chlorocarbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (147 mg, 0.402 mmol) in DCM (2.3 mL) was added DIPEA (117 Ī¼l, 0.670 mmol). The reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The ed c layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a light-yellow oil. The crude material was purified by column chromatography (silica gel, eluent: % to 70% EtOAc/heptane), to provide (1r,4r)-ethyl 4-(4- ((2-(2,6-dichlorofluorophenyl)hydroxyethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (150 mg, 0.222 mmol, 66.2% yield) as a white solid. LCMS: 675.9 (M+H)+.
Step 2: (1r,4r)-ethyl 4-(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate A mixture of (1r,4r)-ethyl 4-(4-((2-(2,6-dichloro fluorophenyl)hydroxyethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (150 mg, 0.222 mmol), TEMPO (3.46 mg, 0.022 mmol), DCM (2.2 mL) and 1 M aq NaHCO3 (554 Ī¼l, 0.554 mmol) was d at 0 Ā°C. Then sodium hypochlorite, 5.65-6% (1.5 ml, 1.1 mmol) was added slowly. After 1 h, the reaction was ed with saturated aqueous Na2S2O3 at 0 Ā°C and extracted with DCM (10 mL). The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure to afford colorless residue. The crude material was purified by column chromatography (silica gel, eluent : 0% to 40% EtOAc/heptane) to provide (1r,4r)-ethyl 4-(4-((2-(2,6- dichlorofluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (113 mg, 0.168 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) Ī“ 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), .97 (m, 6H), 1.34-1.39 (m, 3H), 1.25- 1.31 (m, 3H), 1.07 (d, J=6.4 Hz, 4H); LCMS: M+H]+.
Step 3: (1r,4r)(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid To a mixture of (1r,4r)-ethyl (2-(2,6- dichlorofluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) 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 Ī¼l, 0.838 mmol). The reaction mixture was heated to 50 Ā°C for 2 h. It was concentrated, cooled to 0 Ā°C and acidified with 1 N aqueous HCl solution. The white solid was ted, washed with water and dried under reduced pressure to provide (1r,4r)(4-((2-(2,6- dichlorofluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (86 mg, 0.133 mmol, 79% yield). 1H NMR (400 MHz, DMSO-d6) Ī“ 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] (1S,2S,4S)(4-((2-(3,5-dichloropyridinyl) yl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1 and Step 2: (1S,2S,4S)-ethyl 4-(4-((2-(3,5- dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- azolyl)methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer To a light-yellow clear solution of 1-((1S,3S,4S) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic acid with its ,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 (1S,2S,4S)-ethyl 4-(4- ocarbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer as brown syrupy solid. To the residue was added a on of N-(2-(3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)-2,2-dimethylpropanamine (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 (1S,2S,4S)-ethyl 4-(4-((2- (3,5-dichloropyridinyl) ((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer was formed: LCMS (ESI) m/z 721.1 (M+H)+.
To the reaction mixture was added TBAF on, 1.0 M in THF (3.59 ml, 3.59 mmol). After 1 hour, the reaction e was diluted with water (30 mL) and brine (30 mL).
The on mixture was extracted with EtOAc (2 x 50 mL). The organic extract was washed with satd NaCl (1 x 100 mL) and dried over . The solution was filtered and concentrated in vacuo to give the crude material as a orange syrup. The crude material was ed 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 (1S,2S,4S)-ethyl 4-(4-((2-(3,5- dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer (0.4742 g, 0.781 mmol, 87% yield) as off-white syrupy solid: 1H NMR (300 MHz, DMSO-d6) Ī“ 8.44- 8.63 (2H, m), 7.57-7.71 (1H, m), 6.01 (1H, d, J=4.4 Hz), .28 (1H, dt, J=9.0, 4.5 Hz), 4.32 (1H, d, J=7.2 Hz), 4.11 (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: (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin yl)oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate To a light-yellow clear solution of (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridinyl) hydroxyethyl)(neopentyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate with its (1R,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 ature. After 2 h, the mixture was quenched with saturated aqueous NaHCO3 (30 mL) and saturated aqueous 3 (30 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2SO4. 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 (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate with its ,4R)-isomer (0.437 g, 0.722 mmol, 93% yield) : 1H NMR (400 MHz, CDCl3) Ī“ 8.46-8.61 (2H, m), 7.51-7.74 (1H, m), 4.49-4.92 (2H, m), .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: ,4R)-ethyl 4-(4-((2- (3,5-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (0.1588 g, 0.262 mmol, 33.9% yield) as white solid: 1H NMR (300 MHz, DMSO-d6) Ī“ 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: ,4S)-ethyl 4-(4-((2- (3,5-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- lyl)methylcyclohexanecarboxylate (0.1526 g, 0.252 mmol, 32.6% yield) as white solid: 1H NMR (300 MHz, DMSO-d6) Ī“ 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: (1S,2S,4S)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2-dimethylpropyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
To a mixture of the racemic e of (1S,2S,4S)- ethyl 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)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 Ā°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 ed to ~3.0 with 2 N HCl and the resulting precipitate was ted 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, DMSO-d6) Ī“ 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 (1H, 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 chemisty was arbitrarily assigned as (1S,2S,4S).
[Example 822] trans(4-(((2R,4S)cyclohexyl((3,5-dichloro pyridinyl)carbonyl)pyrrolidinyl) carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: )-Boccyclohexyl-pyrrolidinecarboxylic acid (Chem Impex Int'l, Wood Dale, IL, 997 mg, 3.35 mmol) was treated with DCM (25 mL) followed by 1,1'- 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 N,O-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 NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4-cyclohexyl (methoxy(methyl)carbamoyl)pyrrolidinecarboxylate (1.14 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: (2S,4S)-tert-butyl 4-cyclohexyl (methoxy(methyl)carbamoyl)pyrrolidinecarboxylate (1.14 g, 3.35 mmol) was treated with THF (20 mL), cooled to 0 Ā°C in an ice bath and then treated with lithium aluminum hydride (1.0M solution in THF, 3.35 mL, 3.35 mmol) slowly dropwise over 3 min. The on was then stirred at 0 Ā°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 MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4- cyclohexylformylpyrrolidinecarboxylate 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-butyl 4-cyclohexyl formylpyrrolidinecarboxylate (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 NH4Cl and extracted, washed with brine, dried over MgSO4, filtered and trated affording a mixture of crude (2S,4S)-tert-butyl 4-cyclohexylformylpyrrolidine carboxylate and (2R,4S)-tert-butyl ohexyl formylpyrrolidinecarboxylate (470 mg, 1.67 mmol, 99% yield) as a clear, ess viscous oil. MS (ESI) 304.1 [M + Na]+.
Step 4: Lithium ropylamide (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 Ā°C and stirred at this temperature for 1 h. (2S,4S)-tert-butyl 4-cyclohexyl formylpyrrolidinecarboxylate (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 ed with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2 x 50 mL) and the organic layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and trated. The crude product was purified on an ISCO lashTM RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2S,4S)- utyl 4-cyclohexyl((S)-(3,5-dichloropyridin yl)(hydroxy)methyl)pyrrolidinecarboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1,453.1 [M + Na]+.
Step 5: (2S,4S)-tert-butyl 4-cyclohexyl((S)-(3,5- dichloropyridinyl)(hydroxy)methyl)pyrrolidine carboxylate (1.20 g, 2.79 mmol) and its epimer at C2 of the idine was treated with DCM (10 mL) and TFA (7 mL, 91 mmol) and allowed to stir at room temperature for 1.5 h. The on mixture was concentrated on the rotovap and the crude e purified on an ISCO CombiflashTM RF (40 g Grace Reveleris , using a gradient of 0-20% 2M NH3/MeOH in DCM) affording (S)- ((2S,4S)cyclohexylpyrrolidinyl)(3,5- dichloropyridinyl)methanol 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 + H]+.
Step 6: Oxalyl chloride (0.22 mL, 2.55 mmol) was added to a solution of 1-((1r,4r)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic 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 d 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 Ā°C. The stirring solution was then treated with (S)-((2S,4S)cyclohexylpyrrolidin yl)(3,5-dichloropyridinyl)methanol 2,2,2- trifluoroacetate (755 mg, 1.70 mmol) and DIPEA (0.89 mL, .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 CombiflashTM RF (40 g Grace Reveleris column, using a gradient of 0-100% EtOAc in heptane) affording (1S,4r)-ethyl 4-(4-((2S,4S)cyclohexyl((S)-(3,5- dichloropyridinyl)(hydroxy)methyl)pyrrolidine carbonyl)(trifluoromethyl)-1H-pyrazolyl) 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 (1R,4r)-ethyl 4-(4-((2R,4S)cyclohexyl((R)-(3,5- dichloropyridinyl)(hydroxy)methyl)pyrrolidine carbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (640 mg, 0.97 mmol) as a mixture with its epimer at C2 of the pyrrolidine were treated with DCM (10 mL) and d to stir at room temperature for 3 h. The reaction was treated with a saturated solution of NaHCO3 and solid sodium metabisulfite. The reaction mixture was then extracted with DCM (2 x 75 mL), dried over MgSO4, filtered and concentrated affording crude t as a light orange foam. This residue was purified on an ISCO CombiflashTM RF (25 g Grace Reverlis column, using a gradient of 0-70% EtOAc in heptane) affording (1R,4r)-ethyl 4-(4-((2R,4S)- ohexyl(3,5-dichloroisonicotinoyl)pyrrolidine yl)(trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylate (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: (1S,4r)-ethyl 4-(4-((2S,4S)cyclohexyl(3,5- roisonicotinoyl)pyrrolidinecarbonyl) (trifluoromethyl)-1H-pyrazolyl) 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 on, 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 HCl 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 MgSO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO CombiflashTM RF (25 g n SingleStep column, using a gradient of 0-100% [10% MeOH in DCM] in DCM) ing a mixture of two products epimeric at C2 of the pyrrolidine. This al was subjected to separation on a preparatory SFC using the following conditions: OX column 21, 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 Ā°C, BPR=100 bar, 220 nm. P=165 bar, all sample (416 mg) dissolved in 8 mL of MeOH, ~ 52 , 1.0 mL inj. affording trans(4- (((2R,4S)cyclohexyl((3,5-dichloro pyridinyl)carbonyl)pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) 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] trans(4-(((2S,4S)cyclohexyl((3,5-dichloro pyridinyl)carbonyl)pyrrolidinyl) carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was isolated (291 mg, 0.46 mmol, 67% yield) as a light yellow amorphous solid following atory SFC tion 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.
[Example 827] trans(4-(((2S,4R)((3,5-dichloro pyridinyl)carbonyl)phenylpyrrolidinyl) carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid The title compound was prepared according to example 822 using (2S,4R)(tert-butoxycarbonyl) phenylpyrrolidinecarboxylic 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 ions. Column: CHIRALPAKTM AZ-H (Reversed) (250 x 21 mm, 5 Ī¼m), Mobile Phase: 82:18 (A:B), A: Liquid CO2, B: EtOH. Flow Rate: 70 mL/min.
Column/Oven temp.: 40 Ā°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 tion conditions bed above.
[Example 828] trans(4-(((2R,4R)((3,5-dichloro pyridinyl)carbonyl)phenylpyrrolidinyl) carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title nd 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 g peak under the separation conditions described above for example 827.
[Example 845] (1S,2R,4S)(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
Step 1: ,4S)-ethyl 4-(4-((2-(2,6-dichloro fluorophenyl)hydroxyethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate.
To a solution of (1R,3r,5S)-N-(2-(2,6-dichloro fluorophenyl)((triethylsilyl)oxy)ethyl)-6,6- dimethylbicyclo[3.1.0]hexanamine (97 mg, 0.217 mmol) and (1S,2R,4S)-ethyl 4-(4-(chlorocarbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (96 mg, 0.261 mmol) in DCM (0.8 mL) was added DIPEA (76 Ī¼l, 0.434 mmol). The reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM (3x10 mL). The c layer was combined, dried over anhydrous MgSO4, 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 Ī¼l, 0.434 mmol). The mixture was stirred at room temperature for 0.5 h. It was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a lightyellow oil. The crude material was purified by column chromatography (silica gel, t: 0% to 40% EtOAc/heptane) to provide ,4S)-ethyl 4-(4-((2-(2,6- dichlorofluorophenyl)hydroxyethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (96 mg, 0.145 mmol, 66.7% yield) as a white solid. LCMS: 662.1[M+H]+ Step 2: (1S,2R,4S)-ethyl 4-(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (1S,2R,4S)-ethyl (2-(2,6-dichloro fluorophenyl)hydroxyethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (96 mg, 0.145 mmol) was ved 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% Na2S2O3, washed with saturated NaHCO3, dried with anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (silica gel, eluent: 0-40% EtOAc / e) to afford (1S,2R,4S)-ethyl 4-(4- ((2-(2,6-dichlorofluorophenyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (90 mg, 0.136 mmol, 94% yield) as a viscous white oil.
LCMS 660.0 [M+H]+.
Step 3: (1S,2R,4S)(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
To a mixture of (1S,2R,4S)-ethyl 4-(4-((2-(2,6- dichlorofluorophenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (90 mg, 0.136 mmol) in MeOH (0.34 mL) and THF (0.34 mL) (1:1 ratio) was added 2 N aq.
NaOH (0.34mL, 0.68 mmol). The reaction e was heated to 50 Ā°C for 3 h. It was concentrated, cooled to 0 Ā°C and acidified with 1 N aqueous HCl. The white solid was collected, washed with water and dried under reduced pressure to provide (1S,2R,4S)(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (58 mg, 0.092 mmol, 67.3% yield). 1H NMR (500 MHz, DMSO-d6) Ī“ 12.18 (br. s., 1H), 7.87-7.56 (m, 2H), 7.40-7.51 (m, 1H), 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-((2-(3,5-dichloropyridinyl) yl)((1s,4s)oxabicyclo[221]hept ylmethyl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid Step 1 and Step 2: ethyl trans(4-(((1s,4S) oxabicyclo[2.2.1]heptanylmethyl)(2-(3,5- dichloropyridinyl)hydroxyethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate.
To a clear solution of 1-((1r,4r) ycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic 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 (1r,4r)-ethyl 4-(4-(chlorocarbonyl)(trifluoromethyl)-1H-pyrazol methylcyclohexanecarboxylate as light-yellow syrup.
To the e was added a solution of N-((1s,4s) oxabicyclo[2.2.1]heptanylmethyl)(3,5- dichloropyridinyl)((triethylsilyl)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-(((1s,4S) oxabicyclo[2.2.1]heptanylmethyl)(2-(3,5- dichloropyridinyl) ((triethylsilyl)oxy)ethyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)methylcyclohexanecarboxylate was formed: LCMS (ESI) m/z 761.2 (M+H)+. To the reaction e 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 . 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 e ethyl trans(4-(((1s,4S)oxabicyclo[2.2.1]heptan ylmethyl)(2-(3,5-dichloropyridinyl) hydroxyethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylate (0.1083 g, 0.167 mmol, 48.1% yield) as ess syrupy solid: 1H NMR (400 MHz, DMSO-d6) Ī“ 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-(((1s,4S) oxabicyclo[2.2.1]heptanylmethyl)(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate To a clear solution of ethyl trans(4-(((1s,4S) oxabicyclo[2.2.1]heptanylmethyl)(2-(3,5- dichloropyridinyl)hydroxyethyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate 5 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 Na2S2O3 (30 mL) and saturated aqueous NaHCO3 (30 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2SO4. 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 e ethyl trans(4-(((1s,4S)oxabicyclo[2.2.1]heptan ylmethyl)(2-(3,5-dichloropyridinyl) oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- ylcyclohexanecarboxylate (0.0841 g, 0.130 mmol, 83% yield) as colorless syrup. 1H NMR (400 MHz, CDCl3) Ī“ 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-((2-(3,5-dichloropyridinyl) oxoethyl)((1s,4s)oxabicyclo[221]hept ylmethyl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid To clear solution of ethyl trans(4-(((1s,4S) oxabicyclo[2.2.1]heptanylmethyl)(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate 6 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 neous mixture was stirred and heated at 60 Ā°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) Ī“ 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 .
[Example 872] trans(4-((2-(3,5-dichloromethoxy pyridinyl)ethyl)(2,2-dimethylpropyl) carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was ed from N-(2-(3,5- dichloromethoxypyridinyl)ethyl)-2,2-dimethylpropan- 1-amine and 1-((1r,4r)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid by procedures similar to those described in e 545. MS (ESI) 593.2, 595.1 [M + H]+.
[Example 879] (1S,2S,4S)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1 and Step2: (1R,2R,4R)-ethyl 4-(4-((2-(3,5- dichloropyridinyl)hydroxyethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate compound with (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin yl)hydroxyethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 2-methylcyclohexanecarboxylate (1:1) To a slightly cloudy mixture of 1-((1R,3R,4R) (ethoxycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic acid compound with 1- ((1S,3S,4S)(ethoxycarbonyl)methylcyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxylic 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 DMF (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 ,4R)-ethyl 4-(4- (chlorocarbonyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate nd with (1S,2S,4S)- ethyl 4-(4-(chlorocarbonyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (1:1) as light-yellow syrup.
To the yellow syrup was added a solution of N-(2- ichloropyridinyl)((triethylsilyl)oxy)ethyl)- 3,3,3-trifluoro-2,2-dimethylpropanamine (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 d at room temperature. After 4 h, LCMS (ESI) showed that the intermediate (1S,2S,4S)-ethyl 4-(4-((2-(3,5- dichloropyridinyl)((triethylsilyl)oxy)ethyl)(3,3,3- trifluoro-2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate 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 d 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 Na2SO4. 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 (1R,2R,4R)-ethyl 4-(4- ((2-(3,5-dichloropyridinyl)hydroxyethyl)(3,3,3- trifluoro-2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate nd with ,4S)- ethyl 4-(4-((2-(3,5-dichloropyridinyl) hydroxyethyl)(3,3,3-trifluoro-2,2- ylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)methylcyclohexanecarboxylate (1:1) (0.4648 g, 0.351 mmol, 82% yield) as ess syrup: 1H NMR (400 MHz, DMSO-d6) Ī“ 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), .31 (12H, m), (diastereomers and rotamers); LCMS (ESI) m/z 661.1 (M+H)+.
Step 3: (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin yl)oxoethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)methylcyclohexanecarboxylate To a clear solution of (1R,2R,4R)-ethyl 4-(4-((2- ichloropyridinyl)hydroxyethyl)(3,3,3- trifluoro-2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate compound with (1S,2S,4S)- ethyl 4-(4-((2-(3,5-dichloropyridinyl) hydroxyethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)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 d at room temperature. After 14 h, the mixture was quenched with saturated aqueous Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL). The reaction mixture was extracted with DCM (2 x 50 mL). The organic extract was dried over Na2SO4. 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 (1R,2R,4R)-ethyl 4-(4-((2-(3,5- dichloropyridinyl)oxoethyl)(3,3,3-trifluoro-2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 2-methylcyclohexanecarboxylate compound with (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (1:1) (0.3795 g, 0.288 mmol, 83% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) Ī“ 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 e was ted by SFC to give two fractions where the stereochemisty of each fraction was arily assigned.
First peak on SFC IA column: ,4R)-ethyl 4-(4-((2- (3,5-dichloropyridinyl)oxoethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (0.1371 g, 0.208 mmol, 43.4% yield) as white solid: 1H NMR (400 MHz, CDCl3) Ī“ 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.), .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: (1S,2S,4S)-ethyl 4-(4-((2- (3,5-dichloropyridinyl)oxoethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate 7 g, 0.219 mmol, 45.8% yield) as white powder: 1H NMR (400 MHz, CDCl3) Ī“ 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), .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, J=6.1 Hz), rotamers present; LCMS (ESI) m/z 659.0 (M+H)+.
Step 4: (1S,2S,4S)(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid To a clear solution of (1S,2S,4S)-ethyl 4-(4-((2- (3,5-dichloropyridinyl)oxoethyl)(3,3,3-trifluoro- 2,2-dimethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)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 Ā°C. After 4 h, the reaction mixture was concentrated in vacuo to remove THF and EtOH.
The ing 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) Ī“ 12.18 (1H, br. s.), 8.59-8.86 (2H, m), 7.73- 8.02 (1H, m), .49 (2H, m), 4.33 (1H, 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 (1S,2S,4S).
[Example 885] trans(4-((2-(3,5-dichlorooxo-1,2-dihydro nyl)ethyl)(2,2-dimethylpropyl) carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
The title compound was ed 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]+.
[Example 886] (1S,2R,4S)(4-((2-(3,5-dichlorooxo-1,2-dihydro pyridinyl)ethyl)(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid Step 1: Oxalyl chloride (2.0M in DCM, 0.52 mL, 1.03 mmol) was added to a solution of 1-((1S,3R,4S) ycarbonyl)methylcyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxylic 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 e was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was treated with DCM (2.0 mL) and cooled to 0 Ā°C.
The stirring solution was then treated with 3,5- dichloromethoxypyridinyl)ethyl)-2,2-dimethylpropan- 1-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 d pressure (rotary evaporator) and the crude residue was purified on an ISCO CombiflashTM RF (25 g Grace Reveleris column, using a gradient of 0-50% EtOAc in heptane) affording (1S,2R,4S)-ethyl 4-(4-((2-(3,5- romethoxypyridin yl)ethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylate (350 mg, 0.56 mmol, 82% yield) as a white crystalline solid. MS (ESI) 621.2, 623.2 [M + H]+.
Step 2: (1S,2R,4S)-ethyl (2-(3,5-dichloro methoxypyridinyl)ethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylate (109 mg, 0.175 mmol) was treated with aqueous hydrochloric acid (5.0 N, 3.00 mL, .00 mmol) and hydrochloric acid (4.0 N in 1,4-dioxane, 3.00 mL, 12.00 mmol), fitted with a reflux condenser and heated to 120 Ā°C for 3 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary ator) and the crude residue was purified on a Gilson (GeminiTM Phenomenex; 30 x 150 mm, 5 u, using a gradient of 10-95% A/CH3CN in 0.1%TFA/water), concentrated in a genevac ght affording (1S,2R,4S)- 4-(4-((2-(3,5-dichlorooxo-1,2-dihydropyridin yl)ethyl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)methylcyclohexanecarboxylic acid (57 mg, 0.098 mmol, 56% yield) as a white amorphous solid. MS (ESI) 579.0, 581.2 [M + H]+.
[Example 887] (1S,2R,4S)(4-((2-(3,5-dichloromethoxy pyridinyl)ethyl)(2,2-dimethylpropyl) carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid The title compound was prepared from N-(2-(3,5- dichloromethoxypyridinyl)ethyl)-2,2-dimethylpropan- 1-amine and 1-((1S,3R,4S)(ethoxycarbonyl) methylcyclohexyl)(trifluoromethyl)-1H-pyrazole carboxylic acid by ures similar to those described in example 872. MS (ESI) 593.2, 595.1 [M + H]+.
The following examples were synthesized similar procedures described above. example structure 4ā€”(4-((2-(3,5-dichIoropyridinā€”4ā€”y|)ethy|)(4- o o fluorobenzyl)ca rbamoyl)(trifluoromethy|)- HOVON/EYNVYEā€˜' FF 0 \ N 1H-pyrazoI-l-y|)cyc|ohexanecarboxylic acid F Cl cis(4-((2-(3,5-dichloropyridiny|) oxoethyl)(4-fluorobenzyl)ca rbamoy|) (trifluoromethyl)-1H-pyrazoI-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(isobutyl)ca rbamoyl)ā€”5- (trifluoromethyI)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid transā€”4-(4-((2-(3,5ā€”dichloropyridin-4ā€”yl) oxoethyl)(neopentyl)carbamoyl)ā€”5- (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans-4ā€”(4-((cyc|obuty|methy|)(2ā€”(3,5- dichloropyridinyl)oxoethy|)ca l)- -(trifluoromethyl)-1H-pyrazo| yl)cyclohexaneca rboxylic acid trans(4-((cyclopenty|methyl)(2-(3,5- dichloropyridinyl)ā€”2-oxoethy|)ca rbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexaneca ic acid M)" p.. 4-(4-((cyc|ohexy|methyl)(2-(3,5- HOH Hļ¬‚ā€ dichloropyridinyl)oxoethyl)ca l)- FFF ā€˜3on 5-(trifluoromethyl)-1H-pyrazo|ā€”1- yl)cyclohexanecarboxylic acid Cl / N example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethyl)((lā€” 31 methylcyclopropy|)methy|)carbamoy|) (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)(isopentyl)carbamoyl) uoromethyl)-1H-pyrazoI-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3-dimethy|buty|)ca rbamoyl)ā€”5- (trifluoromethyI)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid transā€”4-(4-((2-cyclopropylethyl)(2-(3,5- ' ropyridinyl)ā€”2-oxoethy|)carbamoyl)ā€” 34 ' -(trifluoromethyl)-1H-pyrazol yl)cyclohexaneca rboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- yl)(3-methylbutenyl)carbamoyl)- yā€ . -(trifluoromethyl)-1H-pyrazo| yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)((4,4- 36 dimethylcyclohexyl)methyl)carbamoyl)-5ā€” (trifluoromethyI)-1H-pyrazol-lyl )cyclohexaneca rboxylic acid trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethyl)(spirolz.5]octan y|methyl)carbamoy|)(trif|uoromethy|)-1H- pyrazoI-l-yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) y|)(((S)-tetra hyd rofu ran yl)methyl)ca rbamoyl)(trifluoromethyl)-1H- pyrazol-l-yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)(((R)-tetra hydrofu ra n y|)methyl)carbamoyl)(trif|uoromethyl)ā€”1H- pyrazol-l-yl)cyclohexaneca rboxylic acid trans(4-(benzyl(2-(3,5-dichloropyridin y|)-2ā€”oxoethy|)carbamoyl)ā€”5- (trifluoromethyI)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid transā€”4-(4-((4-ch|orobenzy|)(2ā€”(3,5- clichloropyridinyl)oxoethy|)ca rbamoyl)ā€” -(trifluoromethyl)-1H-pyrazol yl)cyclohexaneca rboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- oxoethyl)(3,S-difluorobenzyl)carbamoy|) (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethy|)(2,3-dif|uorobenzy|)carbamoy|) uoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethy|)(3,4-difluorobenzyl)carbamoy|) uoromethyI)-1H-pyrazoI-l- yl)cyclohexaneca rboxylic acid example structure trans(4-((2-(3,5-dichloropyridinyl) oxoethy|)(2,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazoI-l- y|)cyc|ohexanecarboxylic acid 'N trans(4-((2-(3,5-dichloropyridinyl)ā€”2- " y|)(fura nā€”2-ylmethy|)carbamoyI)ā€”5- (trifluoromethy|)-1H-pyrazoI-l- |ohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl) ā€™- oxoethyl)(fura nylmethy|)ca rbamoy|) (trifluoromethyI)-1H-pyrazoI-l- y|)cyc|ohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- " oxoethyl)(pyrazinylmethyl)carbamoyl)ā€”5- (trifluoromethyl)ā€”1H-pyrazoIā€”l- y|)cyc|ohexanecarboxylic acid trans(4-((2ā€”(3-ch|oromethylpyridin-4ā€” y|)-2ā€”oxoethy|)(3,5- difluorobenzy|)ca rbamoy|) (trifluoromethyl)ā€”1H-pyrazoIā€”l- y|)cyc|ohexanecarboxylic acid trans(4-((2-(3-chlorofluoropyridiny|)- 2-oxoethy|)(3,5-difluorobenzyl)carbamoyl) 50 ' (trifluoromethy|)-1H-pyrazoI-l- y|)cyc|ohexanecarboxylic acid 4-(4-((3,5-difluorobenzyl)(2-(3,5- ' difluoropyridinyl)oxoethyl)carbamoyl)- 51 " -(trifluoromethyl)-1H-pyrazol y|)cyc|ohexanecarboxylic acid example structure ā€”ļ¬_ trans(4-((3,5-difluorobenzyl)(2-(3,5- dimethylpyridiny|)oxoethy|)ca l)ā€” -(trifluoromethyl)-1H-pyrazol |ohexaneca rboxylic acid trans(4-((2-(2,6ā€”dichloropheny|) oxoethy|)(3,S-difluorobenzyl)carbamoy|) (trifluoromethyl)-1H-pyrazoI-l- |ohexaneca rboxylic acid trans(4-((2-(2-ch|oromethoxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoy|) (trifluoromethyI)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid transā€”4-(4-((2-(2,6ā€”dichloro-4ā€”fluorophenyl)ā€” ā€˜ 2-oxoethyl)(3,5ā€”difluorobenzyl)carbamoyl)ā€”5- 55 \)-- ., (trifluoromethy|)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid transā€”4ā€”(4-((3,5ā€”dif|uorobenzy|)(2-oxoā€”2- (2,4,6-trichlorophenyl)ethyl)ca rbamoyI) uoromethy|)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid trans(4-((2-(2,6-dichloroā€”4- (trifluoromethyl)phenyI)oxoethyl)(3,5- 57 difluorobenzyl)ca rbamoyl)-5ā€” (trifluoromethyI)-1H-pyrazol-lyl )cyc|ohexaneca rboxylic acid trans(4-((2-(2,6-dichlorocyanophenyl)ā€” 2-oxoethy|)(3,5-difluorobenzy|)carbamoyl) (trifluoromethyI)-1H-pyrazoI-l- yl)cyc|ohexaneca rboxylic acid example structure trans(4-((2-(3,5-dichlorophenyl) >ā€˜m ā€™ oxoethy|)(3,5-dif|uorobenzyl)carbamoy|) (trifluoromethy|)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid 4-(4-((3,5-difluorobenzyl)(2-(3,5- Y ' difluorophenyl)oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazoI-l- |ohexaneca rboxylic acid trans(4-((2-(2-chlorofluoropheny|) yl)(3,5-difluorobenzyl)carbamoy|) (trifluoromethyI)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid transā€”4-(4-((3,5ā€”dif|uorobenzy|)(2-oxo .. (pyridin-4ā€”yl)ethy|)carbamoyl) 62 ā€˜ (trifluoromethy|)-1H-pyrazol-l- F yl)cyc|ohexaneca rboxylic acid trans-4ā€”(4-((3,5ā€”difluorobenzyl)(2-(2,4- u dimethylfu ranyl)oxoethy|)carbamoyl) (trifluoromethy|)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid trans(4-((3,5-difluorobenzyl)(2-(3,5- ā€˜N dimethylisoxazoly|) 64 " Jļ¬r oxoethyl)carbamoyl)(trifluoromethy|)-1H- pyrazoI-l-yl)cyclohexaneca rboxylic acid trans(4-((2-cyclohexyloxoethyl)(3,5- ā€˜i difluorobenzyl)ca rbamoyl) (trifluoromethyI)-1H-pyrazoI-l- yl)cyc|ohexaneca rboxylic acid structure trans(4-((2-(2,6-dichloroā€”4- cyclopropylphenyl)ā€”2-oxoethy|)(3,5- 66 difluorobenzyl)ca rbamoyl) (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)(3,5- 67 robenzy|)ca rbamoyl)ā€”5- (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid 4-(4-((2-(2-ch|oroethynylphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoy|) (trifluoromethyI)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid transā€”4-(4-((3,5ā€”difluorobenzyl)(2-(4ā€” hydroxyphenyl)oxoethyl)ca rbamoyl)ā€”5- uoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid trans(4-((2-(2,6-dich|oro hydroxyphenyl)oxoethyl)(3,5- difluorobenzy|)ca rbamoyl) (trifluoromethyl)ā€”1H-pyrazoIā€”l- yl)cyclohexaneca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethy|)((tetra hyd ro-2H-pyran hyl)ca rbamoy|)(trif|uoromethyl)-1H- pyrazoI-l-yl)cyclohexaneca rboxylic acid ONO" 'N ā€˜ trans(4-((cyc|opropy|methy|)(2-(3,5- .. ,ā€˜N 72 Hļ¬n/N' a dichloropyridinyl)oxoethyl)ca rbamoyl)- p F 001:6 -(trifluoromethyl)-1H-pyrazo|ā€”1- CI / N yl)cyclohexanecarboxylic acid ā€”347ā€” example structure ā€”E_ Oy'ONā€™Nā€˜ X trans(4-((2-(3,5-dichloropyridinyl) HO H c. oxoethy|)(2-fluoro F14%ā€0 F F o methylpropyl)carbamoy|)(trifluoromethy|)- CI 1H-pyrazoly|)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)(2-methoxy methylpropyl)carbamoy|)(trif|uoromethy|)- 1H-pyrazol-l-y|)cyclohexanecarboxylic acid Hoyiiā€™Oigļ¬‚0 ,N\ (k; trans(4-((2-(3,5-dichloropyridinyl) Cl oxoethyl)(2,2,2-trifluoroethy|)carbamoyl)ā€”5- F o (trifluoromethyI)-1H-pyrazol-l- F F o \ I/N yl)cyc|ohexanecarboxylicacid transā€”4-(4-((2-(3,5ā€”dichloropyridin-4ā€”yl) oxoethyl)(pyridinylmethy|)ca rbamoyl)ā€”5- (trifluoromethy|)-1H-pyrazol-l- yl)cyc|ohexaneca rboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- oxoethyl)(4-fluorobenzyl)ca rbamoyI) uoromethy|)-1 H-pyrazoI-l-yI) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethy|)(3,5-dif|uorobenzy|)carbamoy|) (trifluoromethy|)-1H-pyrazol-l-y|) cyclohexanecarboxylic acid 4-(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethyl)(4-fluorobenzy|)ca rbamoy|) (trifluoromethyI)-1H-pyrazol-l-yI) methylcyclohexanecarboxylic acid example structure trans(4-((2-(3,5-dichloropyridinyl) .\ā€˜ oxoethyl)(4-fluorobenzy|)ca l)ā€”5- 80 L_ (trifluoromethy|)-1H-pyrazol-l-y|) fluorocyclohexanecarboxylic acid cis(4-((2-(3,5-dichloropyridiny|) " oxoethyl)(4-fluorobenzyl)ca rbamoy|) (trifluoromethyI)-1H-pyrazol-l-yl) fluorocyclohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl) z yl)(4ā€”fluorobenzy|)ca rbamoyl)ā€”5ā€” (trifluoromethyI)-1H-pyrazol-l- y|)cyc|obutanecarboxylic acid cisā€”3ā€”(4ā€”((2-(3,5-dichloropyridinā€”4-y|) oxoethyl)(4ā€”fluorobenzyl)carbamoyl)ā€”5- 83 ,, (trifluoromethy|)-1H-pyrazol-l- y|)cyc|obutanecarboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- y. oxoethyl)(4-fluorobenzyl)ca rbamoyl)ā€”5-(1,1- difluoroethyl)-1H-pyrazo|ā€”1ā€” y|)cyclohexaneca rboxylic acid N-(2-(3,5-dichloropyridinyl)oxoethy|)-N- ' (3,5-difluorobenzyl)(trans hydroxycyclohexyl)(trifluoromethyl)-1H- Iecarboxamide N-(2-(3,5-dichloropyridiny|)oxoethyl)-N- IS: . 9 (4-fluorobenzyl)(cis (methylsulfony|)cyc|ohexy|) (trifluoromethyI)-1H-pyrazoIecarboxamide example structure N-(2-(3,5-dichloropyridiny|)oxoethy|)-N- " (4-fluorobenzyl)ā€”1-(trans (methylsuIfony|)cyclohexyl) (trifluoromethyl)ā€”1H-pyrazoleā€”4-carboxamide 1-(transcarbamoylcyclohexyl)-N-(2-(3,5- y I. ā€œa ropyridinyl)oxoethyI)-N-(4- fluorobenzyl)ā€”5-(trifluoromethyl)ā€”1H- pyrazolecarboxamide N-(2-(3,5-dichloropyridiny|)oxoethy|)-N- (4-fluorobenzyl)ā€”1-(trans((2- hydroxyethyl)ca rbamoyl)cyc|ohexyl) uoromethyl)ā€”1H-pyrazolecarboxamide transā€”4-(4-((2-(3,5ā€”dichloropyridin-4ā€”yl) y. ' hydroxyethy|)(4-f|uorobenzyl)carbamoyl) (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid transā€”4ā€”(4-((2ā€”(2,6-dichlorophenyl)ā€”2- " fluoroethyl)(4-fluorobenzyl)ca rbamoyI) 91 :, (trifluoromethy|)-1H-pyrazol-l- yl)cyclohexaneca rboxylic acid (15,3S)(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-((4- 92 fluorophenyl)methyl)ca rbamoyl)ā€”5ā€” (trifluoromethy|)pyrazo|y|)cyclopenta ne carboxylic acid (1R,3$)(4-((2-(3,5-dichloropyridiny|) oxoethyl)ā€”((4ā€” 93 fluorophenyl)methyl)carbamoyl)ā€”5- uoromethyl)pyrazoly|)cyclopentane-l- carboxylic acid example structure trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethyI)-(2,2-dimethylpropy|)ca rbamoy|)- -(trifluoromethyl)pyrazol-l-yl) methylcyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- yl)-(2-((2-methylpropan y|)oxy)ethy|)carbamoyl)ā€”5- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(2,6-dichlorophenyl)-2,2- difluoroethyl)ā€”((4- fluoropheny|)methyl)ca rbamoyI) (trifluoromethy|)pyrazoly|)cyclohexane-lā€” carboxylic acid 4ā€”(4-((2ā€”(4-carbamoyIā€”2,6- clich|oropheny|)oxoethy|)-((3,5- difluorophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans-4ā€”(2-((1ā€”(4-carboxycyclohexy|)ā€”5- (trifluoromethy|)pyrazo|ecarbonyI)-((3,5- difluorophenyl)methy|)amino)acetyl)ā€”3,5- dichlorobenzoic acid trans(4-((2-(2-chlorophenyl)oxoethyl)- ((3,5ā€”difluoropheny|)methyl)carbamoyl)ā€”5- (trifluoromethy|)pyrazoly|)cyclohexane-l- carboxylic acid trans(4-(2-(2,6-dich|oropheny|)propyl-((4- pheny|)methyl)carbamoyl) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”l- carboxylic acid e structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((4,4ā€” 101 difluorocyclohexy|)methyl)ca I) (trifluoromethyl)pyrazo|-1ā€”y|)cyclohexaneā€”lcarboxylic trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-((1- 102 methylcyclohexy|)methyl)carbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(pyridiny|methyl)ca l)ā€”5- (trifluoromethyl)pyrazoly|)cyclohexane-l- carboxylic acid transā€”4-(4-((2-(3,5ā€”dichloropyridin-4ā€”yl) yl)-(pyridinylmethyl)ca rbamoy|) (trifluoromethy|)pyrazo|y|)cyclohexane-l- carboxylic acid cis(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((4- fluorophenyl)methyl)carbamoy|) (trifluoromethyl)pyrazol-1ā€”y|)-1ā€” hydroxycyclohexane-l-ca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-((4- 106 fluorophenyl)methyl)ca rbamoyl)ā€”5ā€” (trifluoromethyl)pyrazoly|) hydroxycyclohexane-lā€”ca rboxylic acid trans(4-((2-(2,5-dichlorophenyl)ā€”2- oxoethyl)ā€”((3,5- 107 difluorophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid example structure trans(4-(2-(2,6-dichlorophenyl)propyl- ((3,5-difluoropheny|)methyl)carbamoyl)ā€”5- (trifluoromethyl)pyrazo|y|)cyclohexa ne carboxylic acid 4-(4-((2-(3,5-dichloropyridinyl)ā€”2- methoxyethyl)-((3,5- 109 difluorophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(4,4-dimethy|pent ynyl)carbamoy|)-S-(trifluoromethy|)pyrazol yl)cyclohexane-lā€”carboxylic acid trans-4ā€”(4-((3,5-difluorophenyl)methyI-(Z- (2,6-dimethoxyphenyl)ā€”2- 111 oxoethy|)carbamoyI)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((2-(2,4-dichloro methoxyphenyl)oxoethy|)-((3,5- rophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-cyclopentyloxoethy|)-((3,5- difluorophenyl)methy|)ca rbamoy|) (trifluoromethy|)pyrazoly|)cyclohexane-l- carboxylic acid o trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- 114 Nā€™N\ \X oxoethyl)-((2$)-3,3-dimethy|butan F o yl)carbamoyl)ā€”5-(trif|uoromethyl)pyrazol F F 0 /N y|)cyclohexanecarboxylic acid example structure trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((2R)-3,3-dimethy|butan yl)ca rbamoyI)(trifluoromethyl)pyrazol y|)cyclohexane-lā€”carboxylic acid cis(4-((2-(3,5-dichloropyridiny|)ā€”2- oxoethy|)-((4- 116 fluoropheny|)methyl)carbamoyl)ā€”5- (trifluoromethyl)pyrazoly|) aminocyclohexane-l-carboxylic acid cis(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((4- pheny|)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- aminocyclohexane-l-carboxylic acid trans-4ā€”(4-((2ā€”(2,6-dichlorophenyl) methylpropyl)-((3,5- 118 rophenyl)methy|)carbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((3,5-difluorophenyl)methyI-(Z- (3,5ā€”dimethoxypyridinyl) oxoethy|)carbamoy|)-S- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-(2-(2,6-dichloro-4ā€” fluorophenyl)ethyl-((3,5- 120 difluorophenyl)methyl)ca l)ā€”5ā€” (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethyl)-(piperidinylmethyl)carbamoyl)- S-(trifluoromethyl)pyrazoI-l-y|)cyclohexane- 1-ca rboxylic acid example structure trans(4-((3,5-difluorophenyl)methyl-(Z- imethyIā€”6-oxo-1H-pyridinyl)ā€”2- oxoethy|)carbamoy|)-S- (trifluoromethyl)pyrazo|-1ā€”y|)cyclohexaneā€”lcarboxylic trans(4-(l-adamantylmethyI-(Z-(3,5- dichloropyridinyl)oxoethyl)ca rbamoy|)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-((2-(2-ch|oro (trifluoromethyl)phenyI)oxoethyl)-((3,5- difluorophenyl)methyl)ca rbamoyI) uoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans-4ā€”(4-((3ā€”tert-butylcyclobutyl)methyl-(2- (3,5-dichloropyridinyl)ā€”2- oxoethy|)carbamoy|)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid tran5(4-((3-tert-butylcyclobutyl)methyl-(2- (3,5-dichloropyridiny|) y|)carbamoy|)-S- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(2,6-dichloroā€”4- (trifluoromethoxy)phenyI)oxoethy|)-((3,5- difluorophenyl)methyl)ca rbamoyl)ā€”5ā€” (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic o R!ā€œ trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)ā€”((4ā€” H0wNJL (g122%" c. fluoropheny|)methyl)carbamoyl)ā€”5- F 0 01b F F (trifluoromethyl)pyrazoly|) C. cyanocyclohexane-lā€”carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((4ā€” 129 fluorophenyl)methy|)ca rbamoyI) (trifluoromethyl)pyrazo|-1ā€”y|) cyanocyclohexane-1ā€”carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-((6,6-dimethy|oxan 130 y|)methyl)carbamoyI) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((3-tert-butylcyclobutyl)-(2-(3,5- _ clichloropyridinyl)oxoethy|)ca rbamoyl)ā€” 131 ā€˜ S-(trifluoromethyl)pyrazol-l-yl)cyclohexane- 1-carboxylic acid transā€”4-(4-((3-tertā€”butylcyclobutyl)-(2-(3,5- .. dichloropyridinyl)ā€”2-oxoethy|)carbamoyl)ā€” 132 _ -(trifluoromethyl)pyrazol-l-y|)cyclohexane- 1-ca rboxylic acid trans(4-((3,5-difluorophenyl)methyl-(Z- (4,6ā€”dimethylpyrimidinā€”S-yl) oxoethy|)carbamoy|)-S- uoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((3,5-difiuorophenyl)methyl-(Z- (2,4-dimethylpyridiny|) 134 yl)carbamoyl)ā€”S- (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic trans(5-chloro((2-(3,5-dichloropyridin oxoethyl)-((3,5- difluorophenyl)methy|)carbamoyl)pyrazol y|)cyclohexanecarboxylic acid e ure trans(4-((2-(2-chloro-4ā€” uoromethyl)phenyI)oxoethyl)-((3,5- difluorophenyl)methyl)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans(4-((2-(2,6-dichloromethylphenyl)- 2-oxoethyl)-((3,S- rophenyl)methy|)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-(((2R)(2,6-dichlorophenyI) fluoroethyl)ā€”((3,S- difluorophenyl)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-(((ZS)(2,6-dich|oropheny|) fluoroethyl)ā€”((3,5- difluorophenyl)methyl)ca rbamoy|) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((3-(2,2- dimethylpropyl)cyclobutyl)methyl)carbamoyl) (trifluoromethy|)pyrazol-l-yl)cyclohexane- 1-carboxylic acid oxoethy|)-((4- 0 KG/OH trans(4-((2-(3,5-dichloropyridinyl)ā€”2- 5H ,N\ N/ N hydroxyphenyl)methy|)carbamoyl)ā€”5- Ho\)H1<:>ā€˜ F (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” F F 00:15| / N carboxylic acid trans(4-((2-(2-aminophenyl)ā€”2-oxoethy|)- 0 SHM F ((3,5-difluorophenyl)methyl)carbamoyl) HoVON/ H .
NH: (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”l- F o F F o carboxylic acid example structure trans(4-((2-(2-amino-5ā€”methylphenyl)ā€”2ā€” oxoethy|)ā€”((3,5- 143 difluorophenyl)methyl)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans(4-((2-(2,6-dichloro uoromethyl)phenyl)oxoethy|)-(2-((2- 144 methylpropan-Z-yl)oxy)ethy|)carbamoy|)ā€”5- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3-chloro-S-hydroxypyridin y|)oxoethy|)-((4- fluoropheny|)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid transā€”4ā€”(4-((2-(2,6-dichlorophenyl) ā€œK ' -- yl)-(pyrimidiny|methyl)carbamoyl)ā€” -(trifluoromethyl)pyrazol-l-y|)cyclohexane- 1-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((2- H yphenyl)methyl)ca rbamoyl) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(5-tert-butyl((2-(3,5- dichloropyridiny|)oxoethy|)-((3,5- difluorophenyl)methyl)ca rbamoyl)pyrazol y|)cyclohexane-lā€”carboxylic acid trans(4-((2-(2,6-dichloro (trifluoromethy|)phenyl)ā€”2-oxoethyl)ā€”(2-((2ā€” 149 methylpropan-Z-yl)oxy)ethyl)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexaneā€”l-carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((1ā€” 150 uoromethy|)cyc|opropy|)methyl)carbamo yl)(trifluoromethy|)pyrazol yl)cyclohexane-lā€”carboxylic acid trans(4-((2-(2,6ā€”dichloropheny|) oxoethyl)-(pyridazinylmethyl)ca rbamoyl)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-((2-(3-ch|oro (trifluoromethyl)pyridiny|)oxoethyl)- difluorophenyl)methyl)carbamoyl) (trifluoromethy|)pyrazoly|)cyclohexane-lā€” carboxylic acid trans-4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4-y|) s oxoethyl)ā€”((3- 153 " hydroxypheny|)methyl)carbamoyl) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((1-methy|piperidin yl)methyl)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- yl)-(3-((2-methy|propan 155 yl)oxy)cyclobutyl)ca rbamoy|)ā€”S- (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)ā€”((3,5- 156 difluorophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazoly|) ethylcyclohexanecarboxylic acid example structure ā€”ļ¬_ trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethyl)ā€”(((ZS)ā€”5-oxopyrro|idinā€”2ā€” 157 yl)methy|)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazo|-1ā€”y|)cyclohexaneā€”lcarboxylic trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-(((2R)oxopyrrolidin 158 yl)methy|)carbamoyI) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((3,5ā€” 159 " difluorophenyl)methyl)ca rbamoyI) (hydroxymethyl)pyrazol-l-yl)cyc|ohexane carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((1-methy|ā€”7- 1,. oxabicyclo[2.2.1]heptanā€”4- yl)methy|)carbamoy|) uoromethy|)pyrazoly|)cyclohexane-lā€” carbox lic acid trans(4-((2-(3,5-dichloropyridinyl) ,N oxoethyl)ā€”((1S,2R)ā€”2- 161 phenylcyclopropyl)ca rbamoyI) (trifluoromethyl)pyrazoly|)cyclohexa ne ylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((3,5ā€” difluorophenyl)methyl)ca rbamoyl)propan- 2-y|pyrazoly|)cyc|ohexanecarboxylic acid trans(5-(aminomethyl)((2-(3,5- dichloropyridinyl)oxoethyl)-((3,5- difluorophenyl)methy|)carbamoyl)pyrazol y|)cyclohexanecarboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((3,5ā€” 164 difluorophenyl)methyl)ca rbamoyI) methylpyrazoI-lā€”yl)cyclohexa ne-l-carboxylic 4-(4-((4-ch|oro-1,3-thiazolyl)methyl- (2-(3,5-dichloropyridiny|) 165 oxoethyl)carbamoy|)ā€”5ā€” (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid 4-(4-((2-(3,S-dichloropyridinyl) oxoethyl)ā€”((4- fluoropheny|)methyl)ca rbamoyI) (trifluoromethy|)pyrazol yl)bicyclo[2.2.2]octanecarboxy|ic acid trans-4ā€”(4-((2ā€”chIoro-1,3-thiazol-4ā€”yl)methyl- (2-(3,5-dichloropyridiny|) 167 Ā»" y|)carbamoyI)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((5-ch|oro-1,3-thiazolyl)methyl- N (2-(3,5-dichloropyridinā€”4-yl)ā€”2- y. . , oxoethy|)carbamoy|)-S- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-(4,4- 169 dimethylcyclohexyl)carbamoy|)-S- (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic trans(4-((3-cyanophenyl)methy|ā€”(2-(3,5- dichloropyridinyl)oxoethyl)ca rbamoyl)- S-(trifluoromethyl)pyrazoI-l-y|)cyclohexane- 1-ca rboxylic acid example structure trans(4-((4-cyanophenyl)methyl-(2-(3,5- dichloropyridinyl)ā€”2-oxoethy|)ca l)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-((1-acetylazetidiny|)-(2ā€”(3,5- dichloropyridinyl)oxoethyl)ca rbamoyl)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(1-(2,2- y. I dimethylpropanoyl)azetidiny|)ca rbamoyl)- -(trifluoromethyl)pyrazol-lā€”y|)cyclohexane- 1-ca rboxylic acid _N transā€”4-(4-(cyclohexyIā€”(Z-(3,5-dichloropyridin- " 4-yl)ā€”2-oxoethyl)carbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|)cyclohexane-l- carboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- V" oxoethy|)-(4,4-difluorocyclohexyl)ca rbamoyl)- -(trifluoromethyl)pyrazol-l-y|)cyclohexane- 1-ca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-(3-((2-methy|propan 176 yl)oxy)cyclobutyl)ca rbamoy|)ā€”S- (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic 4-(4-((2-(3,5ā€”dichloropyridiny|)ā€”2- 0ā€˜5 6 L (Q/ oxoethyl)ā€”((4ā€” 177 H0 c. fluoropheny|)methyl)carbamoyl)ā€”5- F 0 F F o \ uoromethyl)pyrazol O yl)bicyc|o[2.2.1]heptane-l-carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((3,5ā€” difluorophenyl)methyl)ca rbamoyI) oromethyl)pyrazo|ā€”1-y|)ā€”1ā€” methylcyclohexane-1ā€”carboxylic acid trans(4-((2ā€”(2-ch|oro-4,6-difluorophenyl)- 2-oxoethyl)-((3,S- difluorophenyl)methy|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(2,3-dihydro-lH-inden-Z- yl)ca rbamoyI)(trif|uoromethyl)pyrazol yl)cyclohexane-lā€”carboxylic acid transā€”4-(4-((2-(3,5ā€”dichloropyridin-4ā€”yl) oxoethy|)-(oxan-4ā€”yl)carbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|)cyclohexane-l- carboxylic acid transā€”4ā€”(4-((2ā€”(3,5-dichloropyridinā€”4ā€”yl)ā€”2- oxoethyl)-spiro[2.5]octanylcarbamoy|) uoromethy|)pyrazoly|)cyclohexane-lā€” carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-((1$)-3,3- ylcyclopenty|)ca rbamoyI)ā€”5ā€” (trifluoromethyl)pyrazoly|)cyclohexane-lcarboxylic trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)ā€”((1S)-3,3- dimethylcyclopentyl)ca rbamoyl) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid example structure ā€”ļ¬_ trans(4-(cyclopentyl-(Z-(3,5- dichloropyridinyl)ā€”2-oxoethy|)ca rbamoy|)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-(1-cyc|openty|ethyi-(2-(3,5- ropyridinyl)oxoethyl)ca rbamoy|)- -(trifluoromethyl)pyrazoI-l-yl)cyclohexane- 1-ca rboxylic acid trans(4-((2-(3-chloro-S-methoxypyridin y|)oxoethy|)-((4- fluoropheny|)methyl)ca I) (trifluoromethy|)pyrazo|y|)cyclohexa ne carboxylic acid transā€”4-(4-((4,4ā€”dimethylcyclohexylH2ā€”oxo- 2-(2,4,6-trichIorophenyl)ethyl)ca rbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|)cyclohexane-l- carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethyI)-(4,4ā€” dimethylcyclohexy|)carbamoy|)-S- (trifluoromethyl)pyrazol-1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid trans(4-((4,4-dimethylcyclohexyl)-(2-oxo- 2-(2,4,6-trichIorophenyl)ethyl)ca rbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((1-methy|ā€”4- o[2.2.1]heptanyl)methy|)carbamoyl) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid example structure trans(4-((2-(2,6-dichloroā€”4-fluorophenyl)ā€” 2ā€”oxoethy|)-((1-methyl 193 bicyclo[2.2.1]heptanyl)methyl)carbamoyl) uoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethy|)-((1- 194 fluorocyclopentyl)methyl)carbamoy|) uoromethyl)pyrazoly|)cyclohexa ne carboxylic acid 4-(4-((2-(4-chloro-Z-oxo-lH-pyridin y|)oxoethy|)-((4- fluoropheny|)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexa ne ylic acid trans(4-((2ā€”(3,5-dichloropyridinyl) oxoethyl)ā€”(4,4- Ā§\~ ' 196 dimethylcyclohexyl)carbamoyI)-S- (difluoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethyI)ā€”((3,5- 1H difluorophenyl)methy|)ca rbamoy|) (difluorom ethyl)pyrazolyl) methylcyclohexane-l-carboxylic acid ā€™N trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(oxo|any|)carbamoy|) (trifluoromethy|)pyrazoly|)cyclohexane-l- carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)ā€”((1R,3r,5$)ā€”6,6-dimethy|ā€”3- 199 bicyc|o[3.1.0]hexa ny|)ca rbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexaneā€”l-carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”(spiro[2.3]hexan 200 yl)carbamoy|)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans(4-((2-(3,5-dichloro-1ā€”m ethylpyrazol- 4-y|)oxoethyI)-((3,S- 201 difluorophenyl)methy|)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- ~N 2-oxoethy|)-(spiro[2.3]hexan 202 " ylmethy|)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(2,6-dichloroā€”4-fluorophenyl)- 2-oxoethyI)-(3-(2,2- 203 ' ., dimethylpropyl)cyclobutyl)ca l) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”(1-spiro[2.3]hexan ylethyl)ca l) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-(3,3- 205 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” carboxylic acid 4-(4-((2-(2,6-dichloromethylpheny|)- 2-oxoethy|)-(4,4-dimethy|pent ynyl)carbamoy|)(trif|uoromethy|)pyrazol y|)methylcyclohexane-l-carboxylic acid example structure trans(4-(4,4-dimethylpent-Z-ynyl-(Z-oxo-Z- (2,4,6-trichlorophenyl)ethy|)ca rbamoy|) (trifluoromethyl)pyrazo|y|) trans(4-((2-(3,5-dichloropyridiny|) oxoethyl)-(5,5-dimethyloxolan y|)ca rbamoyl)ā€”5-(trif|uoromethyl)pyrazol y|)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro-1H-pyrazoIyl)- 'N 2-oxoethy|)-((3,5- 209 " " difluorophenyl)methyl)ca rbamoyI) 3T (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((3ā€”cyanomethylcyclopentyl)-(2- (3,5-dichloropyridinyI) 210 " e oxoethy|)carbamoy|)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexaneā€”lā€” carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) yl)-((1R,3r,5$)-6,6ā€”dimethyl-3ā€” 211 A " o[3.1.0]hexa ny|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-(4- 212 (trifluoromethy|)cyc|ohexyl)ca rbamoyl)ā€”5ā€” (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” ylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-(4- 213 (trifluoromethy|)cyc|ohexy|)ca rbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid e structure trans(4-((2-(2-ch|oromethoxyphenyl) oxoethyl)-(4,4-dimethy|pent ynyl)carbamoyl)(trifluoromethyl)pyrazol y|)methylcyclohexane-lā€”carboxylic acid trans(4-(3-bicyclo[2.2.1]hepta nyl-(2-(3,5- dichloropyridinyl)oxoethyl)ca l)- S-(trifluoromethyl)pyrazoI-l-yl)cyc|ohexanel-carboxylic trans(4-((2-(3,5-dichloro-1,2-thiazo|y|)- 2-oxoethy|)-((3,5- difluorophenyl)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-l- carboxylic acid trans(4-((2ā€”(2-ch|oro (trifluoromethyl)phenyl)oxoethyl)-(4,4- dimethylpent-Z-yny|)ca rbamoyI)-S- (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans-4ā€”(4-((2ā€”(2,6-dichloroā€”4-fluorophenyl)- thyl)-(4,4-dimethy|pent ynyl)carbamoy|)(trif|uoromethy|)pyrazol yl)-1ā€”methylcyclohexane-1ā€”carboxylic acid trans(4-(((1R,3r,SS)-6,6-dimethyl bicyclo[3.1.0]hexa nyl)ā€”(2ā€”oxo(2,4,6- trichloropheny|)ethyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)ā€”((4,4- dimethyicyclohexyl)methyl)carbamoy|) (trifluoromethyl)pyrazoly|) p methylcyclohexaneā€”l-carboxylic acid example structure trans(4-(2,2-dimethylpropyI-(Z-oxo-Z- (2,4,6-trichlorophenyl)ethy|)ca rbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexanecarboxylic acid 4-(4-((2-(2-chloro (trifluoromethyl)phenyl)ā€”2-oxoethyl)- ((1R,3r,5$)-6,6-dimethy|ā€”3- bicyclo[3.1.0]hexany|)carbamoy|) uoromethyl)pyrazoly|) meth lc clohexane-l-carbox lic acid transā€”4-(4-((2-(3,5-dichloropyridin-4ā€”yl)ā€”2ā€” yl)ā€”((1R)ā€”3,3ā€” dimethylcyclopenty|)ca l)ā€”5- (trifluoromethy|)pyrazoly|)cyclohexane-l- carboxylic acid trans(4-((2-(2,6-dichloroā€”4-fluorophenyl)ā€” - 2-oxoethyI)-((1- 224 fluorocyclopenty|)methy|)carbamoyl)ā€”5- (trifluoromethyl)pyrazolyl) methylcyclohexane-1ā€”carboxylic acid trans(4-((1-fluorocyclopentyl)methyI-(Z- oxo(2,4,6- ). I, trichIorophenyl)ethy|)carbamoy|) (trifluoromethyl)pyrazol-1ā€”y|)ā€”1ā€” methylcyclohexane-l-carboxylic acid trans(4-((2-(2,6-dichloromethylpheny|)- 2-oxoethy|)-((1-methyl oxabicyclo[2.2.1]heptan yl)methyl)carbamoyI) (trifluoromethyl)pyrazol-1ā€”y|)ā€”1ā€” methylcyclohexane-l-carboxvlic acid trans(4-((2-(2,6-dichloromethylphenyl)- 2-oxoethy|)-(4,4- 227 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazol-1ā€”y|)ā€”1ā€” methylcyclohexane-l-carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethy|)ā€”((4- 228 fluorophenyl)methyl)ca rbamoyl)ā€”5ā€”(2,2,2- trifluoroethyl)pyrazoI-l-yl)cyclohexane-lcarboxylic trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- y|)-(4,4- 229 dimethylcyclohexy|)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid 4-(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)ā€”(4,4- ylcyclohexyl)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1- yl)bicyclo[2.2.2]octanecarboxy|ic acid 4ā€”(4-((4,4-dimethylcyclohexyI)ā€”(2-oxo ā€™ (2,4,6-trichlorophenyl)ethy|)ca rbamoyl)ā€”5ā€” (trifluoromethy|)pyrazo| yl)bicyclo[2.2.2]octanecarboxylic acid trans(4-((2-(2-chloromethoxyphenyl) oxoethyl)-((1R,3r,5$)-6,6ā€”dimethyl-3ā€” bicyc|o(3.1.0)hexa ny|)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid trans(4-((2-oxo(2,4,6- trichlorophenyl)ethyl)-(spiro[2.3]hexan-Sā€” 234 ylmethyl)carbamoyl)-S- uoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2-ch|oro (trifluoromethy|)phenyl)ā€”2-oxoethyl)ā€” 235 (spiro[2.3]hexanylmethyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazoly|) methylcyclohexaneā€”l-carboxylic acid example structure 4-(4-((2-(2,6-dichloromethylphenyI)-2ā€” oxoethyl)ā€”(4,4- 236 ylcyclohexyl)ca rbamoyl)-S- (trifluoromethy|)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid (2-(2,6-dichIoromethylpheny|) oxoethyl)-((3,3- 237 climethylcyclobuty|)methyl)carbamoyI) (trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid transā€”4-(4-((2-(2,6-dichloromethylphenyl)ā€” 2-oxoethyI)-((3,3- ylcyclobutyl)methyl)carbamoyl)ā€”S- (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((4,4ā€”dimethylcyclohexyl)methyl- } (2-oxo(2,4,6- 239 "H trichlorophenyl)ethy|)carbamoyI)ā€”5- (trifluoromethyl)pyrazolyl) methylcyclohexane-1ā€”carboxylic acid 4-(4-((2-(2,6-dich|orof|uoropheny|)ā€”2- oxoethyl)-((1R,3r,SS)-6,6ā€”dimethyl-3ā€” / bicyc|o[3.1.0]hexa ny|)ca rbamoy|) uoromethyl)pyrazol yl)bicyc|o(2.2.2)octanecarboxylic acid 4-(4-(((1R,3r,5$)-6,6-dimethyl bicyc|o[3.1.0]hexa ny|)-(2-oxo(2,4,6- 241 trichlorophenyl)ethyl)carbamoy|) (trifluoromethy|)pyrazol y|)bicyc|o(2.2.2)octanecarboxylic acid 4-(4-((2-(2-chIoro(trifluoromethyl)phenyl)- 2-oxoethy|)-(4,4- 242 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octaneā€”1-carboxylic acid ā€”371ā€” example structure 4-(4-((2-(2ā€”ch|oromethoxyphenyl)ā€”2- y|)ā€”(4,4- 243 dimethylcyclohexyl)carbamoy|) (trifluoromethy|)pyrazol yl)bicyclo[Z.2.2]octane-1ā€”carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethy|)-((1-methy|ā€”7- oxabicyclo[2.2.1]heptan yl)methyl)carbamoy|)ā€”5- (trifluoromethy|)pyrazolyl) meth lc clohexane-l-carbox lic acid 4-(4-((2-(2,6-dich|orof|uorophenyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl)ā€”5- (trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid 4ā€”(4-(2,2-dimethylpropyI-(Z-oxo-Zā€”(2,4,6- trichloropheny|)ethyl)carbamoy|)ā€”5- (trifluoromethy|)pyrazo| yl)bicyclo[Z.2.2]octanecarboxylic acid 4-(4-((2-(2-chloro(trifluoromethyl)phenyl)- 2-oxoethyI)ā€”((1R,3r,5$)-6,6-dimethy|ā€”3- bicyc|o[3.1.0]hexa ny|)ca rbamoy|) (trifluoromethyl)pyrazol yl)bicyclo[Z.2.2]octanecarboxylic acid 4-(4-((2-(2ā€”ch|oromethoxyphenyl)ā€”2- yl)-((1R,3r,5$)ā€”6,6-dimethy| 248 bicyc|o[3.1.0]hexa ny|)ca l)ā€”5ā€” (trifluoromethyl)pyrazo| yl)bicyclo[Z.2.2]octane-1ā€”carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)ā€”((3,3- 249 dimethylcyclobuty|)methy|)carbamoyl)ā€”5- (trifluoromethyl)pyrazoly|) F methylcyclohexaneā€”l-carboxylic acid ā€”372ā€” example structure trans(4-((3,3ā€”dimethylcyclobutyl)methylā€” (2-oxo(2,4,6- 250 trichlorophenyl)ethyl)carbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2-chloro (trifluoromethyl)phenyl)oxoethy|)-((3,3- 251 dimethylcyclobuty|)methyl)carbamoyI) (trifluoromethyl)pyrazoly|) cyclohexane-l-carboxylic acid trans(4-((2-(2-ch|oromethoxyphenyl) oxoethyl)-((3,3- ylcyclobutyl)methyl)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid , \ transā€”4ā€”(4-((2-(2-ch|oro-6ā€”methoxyphenyl)ā€”2- oxoethyl)-(2,2-dimethylpropyl)carbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(4-((2-(2-chloro (trifluoromethyl)phenyl)oxoethyl)-(4,4ā€” dimethylcyclohexy|)carbamoy|)-S- (trifluoromethyl)pyrazo|ā€”1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid trans(4-((2-(2-chloro-6ā€”methoxyphenyl)ā€”2- oxoethyl)-(4,4ā€” 255 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid 4-(4-((3,3-dimethylcyclobutyl)methyl-(Z-oxoā€” ,6-trichIorophenyl)ethyl)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1- yl)bicyclo[2.2.2]octanecarboxylic acid example ure 4-(4-((2-(2ā€”ch|oromethoxyphenyl)ā€”2- oxoethy|)-((3,3- 257 dimethylcyclobutyl)methyl)carbamoyl)-S- (trifluoromethy|)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid 4-(4-((2ā€”(2-ch|oro(trifluoromethyl)phenyl)- 2-oxoethy|)-((3,3- 258 climethylcyclobuty|)methyl)carbamoyI) (trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid transā€”4-(4-((2-(2-chloro-6ā€”methoxyphenyl)ā€”2- oxoethy|)ā€”((4,4ā€” ylcyclohexyl)methyl)carbamoyl) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((1-methy|ā€”7- N oxabicyclo[2.2.1]heptanyl)methyI-(2-oxo- 3Ā» " 260 2-(2,4,6-trichIorophenyl)ethyl)ca rbamoyI)ā€”S- (trifluoromethyl)pyrazolyl) methylcyclohexane-1ā€”carboxylic acid 4-(4-((2-(2,6-dichIoromethylphenyl) oxoethyl)ā€”((1-methy|ā€”7- oxabicyclo[2.2.1]heptan hyl)carbamoy|)ā€”5- (trifluoromethy|)pyrazol | bic clo 2.2.2 octane-l-carbox Iic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”(7-oxabicyclo[2.2.1]heptan 262 ylmethyl)carbamoyl)-S- (trifluoromethy|)pyrazoly|)cyclohexane-lā€” carboxylic acid 4-(4-((2-(2-chloro(trifluoromethyl)pheny|)- 2-oxoethy|)-(2,2-dimethylpropyl)carbamoy|)- -(trifluoromethyl)pyrazoI-l- y|)bicyc|o[2.2.2]octanecarboxylic acid ā€”374ā€” structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- oxoethyl)ā€”((1R,3r,5$)-6,6-dimethyl 264 bicyclo[3.1.0]hexa nyl)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazo|ā€”1-y|)cyclohexane-lā€” carboxylic acid trans(4-((2-(2-chloro (trifluoromethyl)phenyl)oxoethy|)-(2,2- 265 dimethyipropyl)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid 4-(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)-((3,3- dimethylcyclobutyl)methyl)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1- yl)bicyclo[2.2.2]octanecarboxy|ic acid trans(4-((2ā€”(3,5-dichloropyridinyl) yl)ā€”((1-methy|ā€”4- bicyclo[2.2.1]heptanyl)methyl)carbamoyl) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(4-chloro-2,6-dimethylphenyl)- 2-oxoethyI)ā€”((3,5- difluorophenyl)methy|)ca rbamoy|) uoromethyl)pyrazoly|)cyclohexa ne carboxylic acid 4-(4-((2-(2-chloro-4,6-dimethylphenyl)ā€” 2-oxoethy|)ā€”((3,5- 269 difluorophenyl)methy|)ca rbamoyl)ā€”5ā€” (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” carboxylic acid Ć©ā€˜F trans(4-((2-(2-ch|oro (trifluoromethyl)phenyl)ā€”2-oxoethyl)ā€”((1ā€” 270 =H:f\l\n/N.\ FFF fluorocyclopentyl)methyl)carbamoy|)-5ā€” F uoromethyl)pyrazoly|) CI methylcyclohexaneā€”l-carboxylic acid example structure 4-(4-((2-(2,6-dich|orofluorophenyl)ā€”2- oxoethy|)ā€”((1- 271 fluorocyclopentyl)methyl)carbamoy|)ā€”5- (trifluoromethy|)pyrazol yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid trans(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethy|)-((1- 272 fluorocyclopentyl)methyl)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid 4-(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)ā€”(4,4- dimethylcyclohexyl)carbamoyl)-S- (difluoromethy|)pyrazol yl)bicyclo[2.2.2]octanecarboxy|ic acid 4-(4-((2ā€”(2,6-dichloroā€”4-fluorophenyl)- . 2-oxoethy|)-((1-methyl 274 " bicyclo[2.2.1]heptanyl)methyl)carbamoyl) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((1-methyI bicyclo[2.2.1]heptanyl)methylā€”(Z-oxo-Z- (2,4,6-trich|oropheny|)ethy|)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid trans(4-((2-(2-chloro-4,6-dimethylphenyl)ā€” thy|)ā€”(4,4- 279 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(4-ch|oroā€”2,6-dimethylphenyl)- 2-oxoethyl)ā€”(4,4ā€” 280 dimethylcyclohexy|)carbamoyl)ā€”5- (trifluoromethyl)pyrazoly|) C. methylcyclohexaneā€”l-carboxylic acid example structure ā€”ļ¬_ trans(4-((2-(2,6-dichlorophenyl)ā€”2- oxoethy|)ā€”((1- 281 fluorocyclopentyl)methyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazo|ā€”1-y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2,6-dichloromethylphenyl)- 2-oxoethyl)-((1- 282 fluorocyclopentyl)methyl)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((2-(2,6-dichlorophenyl) yl)ā€”(4,4- dimethylcyclohexyl)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid , transā€”4ā€”(4-((2-(2,6-dichlorophenyl) " oxoethyl)-(2,2-dimethylpropyl)carbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethy|)ā€”((1-methy| oxabicyclo[2.2.1]heptan y|)methyl)carbamoy|) (trifluoromethyl)pyrazol-1ā€”y|)-1ā€” meth lc clohexane-lā€”carbox lic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”(2,2-dimethylbutyl)ca rbamoyl) uoromethyl)pyrazoly|) cyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-pentanylcarbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid ā€”377ā€” example structure ā€”ļ¬_ 4-(4-((2-(3,S-dichloropyridinyl) oxoethyl)ā€”(2,2-dimethylbuty|)ca rbamoyl)ā€”5- (trifluoromethy|)pyrazo| yl)bicyclo[2.2.2]octanecarboxylic acid 1-methyl(4-(2-oxaspiro[3.5]nonan yl-(Z-oxo-Z-(2,4,6- 289 trichlorophenyl)ethyl)carbamoy|) (trifluoromethyl)pyrazoly|)cyclohexa ne carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethy|)-(4,4- dimethylcyclohexyl)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclobutane-l- carboxylic acid cis(4-((2-(2,6-dichlorofluoropheny|) oxoethyl)ā€”(4,4- dimethylcyclohexyl)carbamoyI)-S- (trifluoromethyl)pyrazo|ā€”1-y|)cyclobutane-l- carboxylic acid trans(4-((2-(2,6-dichlorofluorophenyl)- thyI)ā€”(2-((2-methylpropan-Zā€” yl)oxy)ethy|)carbamoyI) (trifluoromethyl)pyrazo|ā€”1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid transmethylā€”4-(4-(2ā€”((2-methylpropan yl)oxy)ethy|ā€”(2ā€”oxoā€”2-(2,4,6- 293 trichloropheny|)ethyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” carboxylic acid oĀ» @ā€” 'ā€\ Kā€˜< trans(4-((2-(3-chlorof|uoropyridinyl)ā€” " 2N 2-oxoethy|)-(2,2-dimethylpropy|)ca l)- FF F 00 5-(trifluoromethyl)pyrazol-l-y|) methylcyclohexane-l-carboxylic acid example structure trans(4-((2-(2,6-dichlorofluorophenyl)- 2-oxoethy|)-(1-methylpiperidin yl)ca rbamoyl)(trifluoromethyl)pyrazol y|)methylcyclohexane-lā€”carboxylic acid trans(4-((2-(2,6ā€”dichlorofluorophenyl)- 2-oxoethy|)-(1-propanylpiperidin y|)ca rbamoyl)ā€”5-(trif|uoromethyl)pyrazol y|)methylcyclohexane-l-carboxylic acid trans(4-((2-(2-chlorofluoropheny|) oxoethyl)-(2,2-dimethylpropyl)carbamoyl)ā€”5- uoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid (1-fluorocyclopentyl)methyl-(2-oxo-2ā€” (2,4,6-trichlorophenyl)ethy|)ca l)ā€”5ā€” (trifluoromethy|)pyrazo| yl)bicyclo[2.2.2]octanecarboxylic acid 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”((1- fluorocyclopentyl)methyl)carbamoyI) (trifluoromethyl)pyrazol y|)bicyclo[2.2.2]octanecarboxylic acid 4-(4-((2-(2,6-dichloromethylphenyI)-2ā€” oxoethy|)-((1- 300 fluorocyclopentyl)methyl)carbamoyI)ā€”5- (trifluoromethyl)pyrazo| yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid cis(4-((2-(2,6-dichlorofluoropheny|) oxoethy|)-(4,4- 301 dimethylcyclohexy|)carbamoyl)ā€”5- (trifluoromethyl)pyrazoly|) methylcyclohexaneā€”l-carboxylic acid example structure trans(4-((2-(2,6-dichlorofluorophenyl)- thy|)-(2,2-dimethylbuty|)carbamoy|) (trifluoromethyl)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)-(8-methyI 303 azabicyclo[3.2.1]octany|)ca rbamoy|) (trifluoromethyl)pyrazoly|) cyclohexane-l-carboxylic acid trans(4-(8-azabicyclo[3.2.1]octanyl-(2- (2,6-dichlorofluoropheny|) oxoethy|)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(2,6-dichloroā€”4-fluorophenyl)- 2-oxoethyI)-(8-propanyI 305 ā€˜ azabicyclo[3.2.1]octany|)carbamoyl) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans-4ā€”(4-(2,2-dimethylbutyI-(Z-oxo-Z- >ā€˜~- ' ., (2,4,6-trichlorophenyl)ethyl)ca rbamoyI) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2-chloro-6ā€”cyano phenyI)ā€”2-oxoethy|)ā€”((3,5- 307 difluorophenyl)methyl)ca rbamoyl)ā€”5ā€” (trifluoromethyl)pyrazo|y|)cyclohexane-lā€” carboxylic acid 4-(4-(2,2ā€”dimethylbutyI-(Z-oxo-Z-(2,4,6- trichlorophenyl)ethyl)carbamoyI) (trifluoromethyl)pyrazo|ā€”1- yl)bicyclo[2.2.2]octanecarboxylic acid example structure 4-(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)ā€”(2,2-dimethylbuty|)ca l)ā€”5- (trifluoromethy|)pyrazo| yclo[2.2.2]octanecarboxylic acid trans(5-cyano((2-(3,5-dichloropyridin y|)oxoethy|)-(2,2- dimethylpropy|)carbamoyl)pyrazo|ā€”1-y|)ā€”1ā€” cyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(1,2,2,6,6-pentamethylpiperidin y|)ca rbamoyl)(trif|uoromethyl)pyrazol y|)methylcyclohexane-l-carboxylic acid transā€”4ā€”(4-((2-(3,5-dichloropyridinā€”4ā€”yl)ā€”2- ,. I \ -' oxoethyl)ā€”(4-methylpentanā€”2-y|)carbamoyl)- -(trifluoromethyl)pyrazol-l-y|) methylcyclohexane-l-carboxylic acid trans-4ā€”(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethyl)ā€”(1-methoxypropan y|)ca rbamoy|)(trif|uoromethyl)pyrazo|ā€”1- yl)-1ā€”methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(3-methylbutenyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((2-(3-chloromethoxypyridin y|)-2ā€”oxoethy|)ā€”(2,2- 315 dimethyipropyl)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclohexaneā€”l-carboxylic acid example structure ā€”ļ¬_ 4-(4-((2-(3,5-dichloropyridin-4ā€”y|)-2ā€” oxoethy|)ā€”((1- 316 methylcyclopropy|)methy|)carbamoyl) (trifluoromethy|)pyrazol yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid 4-(4-((2-(2,6ā€”dich|oropheny|)ā€”2-oxoethy|)ā€” (2,2-dimethylpropy|)ca rbamoyl) (trifluoromethyl)pyrazo|ā€”1- yl)bicyclo[2.2.2]octanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-(2-((2-methy|propan H yl)oxy)ethy|)carbamoyl) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(3,5-dichloropyridinyl) , oxoethyl)ā€”(1-(2- 319 methylpropyl)cyclopropy|)carbamoy|)-S- (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5$)ā€”6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazol yclo[2.2.2]octanecarboxylic acid 4-(4-((2-(2,6-dichloromethylphenyI)-2ā€” yl)((1R,3r,5$)ā€”6,6ā€” 321 dimethylbicyclo[3.1.0]hexanyl)ca |)- -(trifluoromethyl)-1H-pyrazo| yl)bicyclo[2.2.2]octane-1ā€”carboxylic acid 4-(4-((2-(3,Sā€”dichloropyridiny|)ā€”2- ( V oxoethyl)-((2,2,3,3- 322 H0O>_Ā®\N,N\72%ā€ c. tetramethylcyclopropyl)methy|)carbamoyl)ā€”5- F 0 F o \ (trifluoromethyl)pyrazol F | /N y|)bicyclo[2.2.2]octanecarboxylic acid example ure ā€”ļ¬_ trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”(6,6-dimethyloxanyl)carbamoy|)- -(trifluoromethyl)pyrazol-l-yl) methylcyclohexane-l-carboxylic acid 4-(4-((2-(3,5-dichloropyridinyl) oxoethy|)-((1- 324 hydroxycyclopentyl)methy|)ca rbamoyl) (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((2,2,3,3- tetra methylcyclopropyl)methyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(3,5-dichloropyridinyl) .. oxoethyl)ā€”(2-f|uoro 326 methylpropyl)carbamoyI) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid 4-(4-((2-(3,5-dichloropyridinyl) oxoethyl)ā€”(2-fluoroā€”2- methylpropyl)carbamoyI) (trifluoromethyl)pyrazol y|)bicyc|o[2.2.2]octanecarboxylic acid trans(4-(2,2-dimethy|propyl-(Z-(lH-indol- 3-yl)ethyl)carbamoy|)ā€”5- (trifluoromethyl)pyrazoly|) methylcyclohexane-l-carboxylic acid F F 4-(4-((2-(3,Sā€”dichloropyridiny|)ā€”2- 0 2% ā€0%:ZQYN,N\ oxoethyl)-((1- G (trifluoromethy|)cyc|opropy|)methy|)carbamo F O F F o11ā€˜? (trifluoromethyl)pyrazol / N y|)bicyc|o[2.2.2]octanecarboxylic acid structure trans(4ā€”(((1R,2S)ā€”2-tertā€”buty|cyclopropyl)- (2-(3,5ā€”dich|oropyridin-4ā€”y|) 331 oxoethy|)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1ā€”yl)ā€”1- methylcyclohexaneā€”l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethy|)-(1-((2-methy|propan 332 y|)oxy)propanyl)ca rbamoy|) (trifluoromethyl)pyrazo|yl) methylcyclohexaneā€”l-carboxylic acid 4-(4-((2-(3-chloro-S-fluoropyridinyl)- 2-oxoethyl)((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazoI-1ā€”yl) methylcyclohexanecarboxylic acid trans-4ā€”(4ā€”(2ā€”(4-chloro-1H-indo|ā€”3-y|)ethy|ā€” (2,2-dimethylpropyl)carbamoyl)ā€”5- (trifluoromethyl)pyrazo|yl) methylcyclohexaneā€”l-carboxylic acid 4-(4-((2-(3-chIoro-S-fluoropyridinyl) oxoethyl)((1R,3r,5$)-6,6ā€” dimethylbicyclo[3.1.0]hexany|)carbamoy|)- ā€”(trifluoromethyl)-1H-pyrazol-l- y|)bicyclo(2.2.2)octaneca rboxylic acid trans-4ā€”(4-((2-(2-chloro-6ā€”methoxyphenyl)ā€”2- hydroxyethyl)-(4,4ā€” 336 dimethylcyclohexyl)carbamoyl) uoromethyl)pyrazo|ā€”1ā€”yl) methylcyclohexaneā€”1-carboxylic acid $0ā€œ trans(4-((2-(3-ch|orofluoropyridiny|)ā€” .l 'Ā¢.N 9ā€œ 337 HO Hļ¬N 2-oxoethyl)-(2,2-dimethylbuty|)carbamoyl) FFF 00 uoromethyl)pyrazolyl) methylcyclohexanecarboxylic acid example ure trans(4-((4,4-dimethylcyclohexyI)-(2-(3,5- dimethyl-lH-pyrazoIyl)ethy|)ca rbamoyl)ā€”5- (trifluoromethyl)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)-(4,4- 339 dimethylcyclohexy|)carbamoy|) (trifluoromethyl)pyrazoly|) methylcyclobutane-l-carboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((15,ZS)propan ylcyclopropyl)ca rbamoyI) (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid trans(4-((2ā€”(2-ch|oromethoxyphenyI) hydroxyethy|)((1R,3r,SS)-6,6- 341 dimethylbicyclol3.1.0]hexany|)carbamoyl)- -(trifluoromethyl)ā€”1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloromethoxyphenyl) [N hydroxyethy|)((1R,3r,SS)-6,6- 342 A dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazol-1ā€”y|)-1ā€” methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloropyridinyl)ā€”2- oxoethyl)-((3-((2-methylpropanā€”Z- 344 yl)oxy)cyclobutyl)methyl)carbamoyl)ā€”5- uoromethyl)pyrazoly|) methylcyclohexane-1ā€”carboxylic acid 4-(5-ch|oro((2-(2,6-dichloro fluorophenyl)oxoethyl)-(4,4- climethylcyclohexyl)carbamoy|)pyrazolyl)- l-methylcyclohexane-l-carboxylic acid example structure trans(4-((2-(3,5-dichloropyridinā€”4-yl)ā€”2- yl)ā€”((1$,2R)propan 346 ylcyclopropyl)ca rbamoy|) (trifluoromethyl)pyrazo|ā€”1-y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2ā€”(2,6-dichlorofluorophenyl)- 2-oxoethyl)-(4,4- 347 dimethylcyclohexy|)carbamoy|)propan zolyl)methylcyclohexane carboxylic acid trans(4-(2-tert-butylsulfanylethyl-(Z-(2,6- dichlorofluoropheny|)ā€”2- oxoethy|)carbamoyl)-S- (trifluoromethyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid transā€”4ā€”(4-(2-(4ā€”ch|oroā€”1H-indol-3ā€”yl)ethy|ā€” Ā° ā€˜ \ ' (4,4ā€”dimethylcyclohexyl)carbamoyl)ā€”5- (trifluoromethy|)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(4-(2-tert-butylsu|fony|ethy|-(2-(2,6- dichlorofluorophenyI) oxoethyl)carbamoy|)-S- (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-(2-tert-buty|sulfinylethyI-(Z-(2,6- sJ< dichlorofluorophenyI) '6 oxoethy|)carbamoy|)-S- 351 N o (trifluoromethyl)pyrazoly|) F 0 methylcyclohexane-l-carboxylic acid 0 F o m x trans(4-((2-(4-chloro-1H-indo|ā€”3-y|) CI oxoethyl)-(2,2-dimethylpropyl)carbamoyl) 352 HoĀ»~"<:>ā€™%~F 0 luoromethyl)pyrazo|ā€”1-y|)ā€”1- F F O N methylcyclohexane-l-carboxylic acid example structure trans(4-((2-(2,6-dichloroā€”4-fluorophenyl)ā€” 2ā€”oxoethy|)-(2-(3-fluoropiperidin-lā€” 353 y|)ethy|)carbamoyl) (trifluoromethyl)pyrazo|ā€”1-y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(2-ch|orof|uorophenyl)ā€”2- hydroxyethyl)((lR,3r,SS)-6,6- 354 dimethyibicyclo[3.1.0]hexanyl)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid 4-(4-((2-(2-chlorofluorophenyI) hydroxyethyl)((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)ā€”1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-(((2R)(2ā€”ch|oro .,_ methoxyphenyl)ā€”2-hydroxyethyl)-(2,2- 356 dimethylpropyl)carbamoy|) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-(((ZS)(2-chloro methoxyphenyl)ā€”2ā€”hyd roxyethyl)-(2,2ā€” dimethylpropyl)carbamoy|) (trifluoromethyl)pyrazo|ā€”1ā€”y|)-1ā€” methylcyclohexane-l-carboxylic acid trans(5-ch|oro((2-(2,6-dich|oropheny|)- 2-oxoethy|)-(2,2- dimethylpropyl)ca l)pyrazolyl) methylcyclohexane-l-carboxylic acid trans(5-ch|oro((2-(2,6-dichloro methylphenyl)oxoethyl)-(2,2- dimethylpropy|)carbamoyl)pyrazo|ā€”1-y|)ā€”1- methylcyclohexane-l-carboxylic acid example structure trans(4-(2-(4-chloro-Z-methyl-1H-indol yl-(2,2-dimethylpropy|)ca rbamoy|) (trifluoromethyl)pyrazo|y|) methylcyclohexane-l-carboxylic acid trans(5-ch|oro((2-(2,6-dichlorophenyl)ā€” 2-oxoethyl)((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- 1H-pyrazoIyl)-l- cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -methyl-1H-pyrazoIy|) cyclohexanecarboxylic acid trans(4-((2ā€”(2,6-dichloroā€”4-methylphenyl)- 2-oxoethyl)((1R,3r,5$)ā€”6,6- dimethylbicyclo[3.1.0]hexany|)ca rbamoyl)- -methyI-1H-pyrazoI-l-yl) methylcyclohexanecarboxylic acid trans(S-ch|oro((2-(2,6-dich|oro methylpheny|)oxoethy|)((1R,3r,5$)ā€”6,6ā€” dimethylbicyclo[3.1.0]hexany|)carbamoy|)- 1H-pyrazoIā€”1-yl) methylcyclohexanecarboxylic acid trans(5-ch|oro-4ā€”((2-(3,5-dichloropyridin y|)oxoethy|)((1R,3r,SS)-6,6ā€” dimethylbicyclo[3.1.0]hexanyl)ca rbamoyl)- 1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(4-((2-(2-ch|oropheny|)ā€”2- hydroxyethyl)((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid example structure 4-(4-((2-(2-chloropheny|) hydroxyethyl)((1R,3r,SS)-6,6- 369 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- ā€”(trifluoromethyl)-1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-(((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexanyl)(2-hydroxy- 370 ethoxypheny|)ethy|)carbamoy|) (trifluoromethy|)-1H-pyrazol-l-y|) methylcyclohexanecarboxylic acid 4-(4-(((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexanyl)(2-hydroxy- 371 ~ '1 2-(2-methoxyphenyl)ethyl)carbamoyl) (trifluoromethyI)-1H-pyrazol-l-yl) .14 methylcyclohexanecarboxylic acid trans(4-(((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)(2-hydroxy- , 2-(2- 372 __ (trifluoromethyl)pheny|)ethyl)carbamoyl) s (trifluoromethyI)-1H-pyrazol-l-yI) meth lc clohexanecarbox Iic acid trans(4-(((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)(2-hydroxy- ā€œ 2-(2- 373 " (trifluoromethy|)pheny|)ethyl)carbamoy|) (trifluoromethy|)-1H-pyrazolā€”l-yl)ā€”1- meth lc clohexanecarbox Iic acid trans(5-chloro-4ā€”((2ā€”(2-chloroā€”6- methoxyphenyl)-2ā€”hyd roxyethy|)((1R,3r,SS)ā€” 374 6,6ā€”dimethylbicyclol3.1.0]hexa nā€”3- y|)carbamoyI)ā€”1H-pyrazoI-l-yl) methylcyclohexanecarboxylic acid trans(5-ch|oro((2-(2-chloro methoxyphenyl)ā€”2ā€”hyd roxyethy|)((1R,3r,SS)- 375 6,6-dimethylbicyc|o[3.1.0]hexan yl)carbamoyl)ā€”1H-pyrazoI-l-yI)ā€”1- methylcyclohexanecarboxylic acid example structure trans(4-((2-(4-chloro-1H-indazoI y|)ethyl)((1R,3r,5$)ā€”6,6- 376 ylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- -(trifluoromethyl)-1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4ā€”((2-(4-ch|oro-1Hā€”indo| yl)propyl)((1R,3r,5$)-6,6- 377 dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid ā€™N trans(5-chloro((2-(3,5-dichloropyridin " y|)-2ā€”oxoethy|)ā€”((1- methylcyclopropyl)methy|)carbamoyl)pyrazo| y|)methy|cyc|ohexaneca rboxylic acid trans(4-((2ā€”(3-ch|oromethylpyridin .. y|)oxoethy|)ā€”(2,2- 379 dimethylpropyl)ca rbamoyI) (trifluoromethy|)pyrazo|y|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(4-chloro-lH-pyrrolo(2,3- c)pyridinyl)ethyl)((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- fluoromethyl)-1H-pyrazol-1ā€”y|)-1ā€” methylcyclohexanecarboxylic acid ā€˜N trans(5-ch|oro((2-(3,5-dichIoropyridin oxoethy|)-((3,3- dimethylcyclobuty|)methyl)carbamoyl)pyrazo |y|)methylcyclohexaneā€”1-ca rboxylic acid trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)-((3,3ā€” 382 dimethylcyclobuty|)methy|)carbamoyl)ā€”5- methylpyrazol-l-yl)methylcyclohexane-l- carboxylic acid example structure transā€”4-(4-((2-(3-chloro-5ā€”fluoropyridin-4ā€”yl)ā€” 2-hyd roxyethyl)((1R,3r,5$)-6,6- 383 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- ā€”(trifluoromethyl)-1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid 4-(4-((2-(3-ch|orof|uoropyridinyl)ā€” 2-hyd roxyethyl)((1R,3r,55)-6,6- 384 dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(5-cyclopropyl((2-(2,6- dich|oropheny|)ā€”2-oxoethyl)((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- 1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(5-chloro((2-(3,5-dichloropyridin - y|)oxoethy|)-((1-methy|ā€”7- 386 yclo[2.2.1]hepta n y|)methyl)ca rba yrazoly|) methylcyclohexane-1ā€”carboxylic acid trans(4-((2-(3-chloromethylpyridin yl)ā€”2ā€”oxoethy|)((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazol-1ā€”y|)-1ā€” methylcyclohexanecarboxylic acid trans(5-ch|oro-4ā€”((2-(3,5-dichloropyridin-4ā€” y|)-2ā€”oxoethy|)-((1- 388 (trifluoromethy|)cyc|opropyl)methy|)carbamo yl)pyrazoIā€”l-yI)methylcyclohexaneā€”lcarboxylic trans(5-chloro((2-(2,6-dich|oropheny|)- 2-oxoethy|)-(4,4- dimethylcyclohexyl)carbamoyl)pyrazo|ā€”1-y|)ā€” 1-methylcyclohexane-l-carboxylic acid example structure trans(4-((2-(3-chloropyridin-Zā€”y|) hydroxyethyl)((1R,3r,5$)-6,6- 390 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- -(trifluoromethyl)-1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-((2-(3-chloropyridiny|) hydroxyethyl)((1R,3r,SS)-6,6- 391 dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- fluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(4-((2-(4-ch|oromethyl-1H-indol y|)ethy|)((1R,3r,SS)-6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)ā€”1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-((2ā€”(2-chlorophenyl) hydroxypropyl)((1R,3r,SS)-6,6- 393 ' dimethylbicyclo[3.1.0]hexany|)carbamoyl)- fluoromethyl)ā€”1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans-4ā€”(4-((2-(3,5ā€”dichloropyridinyl)ā€”2- oxoethyl)-(2-ethy|f|uorobuty|)ca rbamoyl)ā€” -(trifluoromethyl)pyrazol-l-y|) cyclohexane-1ā€”carboxylic acid trans(5-ch|oro((2-(3,5-dichIoropyridin y|)ā€”2-oxoethy|)-(2-ethy| fluorobutyl)carbamoyl)pyrazolyl) methylcyclohexane-l-carboxylic acid trans(4-((2-(3-ch|orothiopheny|) hydroxyethyl)((1R,3r,SS)-6,6- 396 dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid example structure transā€”4-(4-((2-(3-chlorothiophenyl)ā€”2- hydroxyethyl)((1R,3r,SS)-6,6- 397 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- ā€”(trifluoromethyl)-1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-((2-(3-chloropyridiny|) oxoethyl)((1R,3r,5$)-6,6- 398 dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro-6ā€” (difluoromethoxy)phenyl) hydroxyethy|)((1R,3r,5$)ā€”6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazol-1ā€”y|)-1ā€” meth lc clohexanecarbox Iic acid trans(4-((2-(2-ch|oro (difluoromethoxy)pheny|)ā€”2- ' oxoethyl)((1R,3r,5$)ā€”6,6- dimethylbicyclo[3.1.0]hexany|)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) meth lc anecarbox Iic acid trans(4-(((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexanyl)(2-hydroxy- 2-(pyridiny|)ethyl)carbamoy|) uoromethyI)-1H-pyrazolā€”l-yl)ā€”1- methylcyclohexanecarboxylic acid trans(4-((2-(3-chloropyridin-Z-y|) hydroxyethyI)ā€”(2,2ā€” 402 ylpropy|)carbamoy|)-5ā€” (trifluoromethyl)pyrazol-1ā€”y|) methylcyclohexane-lā€”carboxylic acid trans(4-((2-(3-ch|oropyridiny|) hydroxyethyl)-(2,2ā€” 403 dimethylpropy|)carbamoy|) (trifluoromethyl)pyrazoly|)ā€”1- methylcyclohexaneā€”l-carboxylic acid example structure transā€”4-(4-((2-(2,6-dichlorophenyl)ā€”2- oxoethyl)((1R,3r,5$)-6,6ā€” 404 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- ā€”(l-fluorocyclopropyl)-1H-pyrazo|y|)ā€”1- methylcyclohexanecarboxylic acid trans(4-((2ā€”(7-ch|oro-1H-benzo(d)imidazo|ā€” thy|)((1R,3r,5$)-6,6- 405 ylbicyclo[3.1.0]hexanyl)carbamoy|)- -(trifluoromethyl)-1H-pyrazoly|) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro (difluoromethoxy)pheny|)oxoethy|)-(2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazo|ā€”1-y|) methylcyclohexane-l-carboxylic acid trans(4-((2-(5-ch|oromethylpyrimidin hydroxyethyl)((1R,3r,SS)-6,6- ā€™ ,ā€˜ 407 V'ā€œ dimethylbicyclo[3.1.0]hexany|)carbamoyl)- -(trifluoromethyl)ā€”1H-pyrazo|ā€”1-y|) methylcyclohexanecarboxylic acid trans(4-((2-(5-chloropyrimidinyl) hydroxyethyl)((1R,3r,SS)-6,6- 408 ' dimethylbicyclo[3.1.0]hexany|)carbamoy|)- O 5-(trifluoromethyl)-1H-pyrazol-1ā€”y|)-1ā€” methylcyclohexanecarboxylic acid trans(4-((2-amino-Z-(Zā€”chloro-S- fluorophenyl)ethy|)((1R,3r,SS)-6,6- 409 dimethylbicyclo[3.1.0]hexan-3ā€”yl)carbamoyl)- -(trifluoromethyl)-1Hā€”pyrazo|y|) methylcyclohexanecarboxylic acid trans(4-(((1R,3r,5$)-6,6- dimethylbicyclo[3.1.0]hexan-3ā€”yl)(2-hydroxyā€” 410 2-(3-methylpyrazinyl)ethy|)carbamoyl)ā€”5- (trifluoromethy|)-1H-pyrazol-l-y|) methylcyclohexanecarboxylic acid example structure trans(4-((2-(2-ch|orothiophenyl) hydroxyethy|)((1R,3r,5$)ā€”6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoy|)- fluoromethy|)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(2-(3,S-dich|oropyridinyl)ethy|ā€” ((4-fluoropheny|)methy|)ca rbamoyl)-3,5- bis(trif|uoromethy|)pyrazoI-l-yl)cyclohexane- 1-carboxylic acid example structure name trans(4-((4-chlorobenzyl)(2-(2- chlorophenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(2,6- dichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((4-chlorobenzyl)(2- phenylethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(1H- indolyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(2,4- dichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((4-chlorobenzyl)(2-(2,4- dimethylphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(1H- 4-yl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(1H- indolyl)ethyl)carbamoyl) uoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(1H- indolyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(2- methylphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(2,6- dichloro 510 methylphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)ethyl)((1- 511 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)ethyl)(2,2- 512 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(2- methyl-1H-indolyl)ethyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(2,6- ro 514 methylphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)ethyl)(2,2- 515 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(4,4- 516 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(2,2- 517 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl) oxoethyl)(spiro[2.5]oct ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 519 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((3,3- 520 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((3,3- 521 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(3,5- difluoro (trifluoromethyl)benzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6- dichlorophenyl)ethyl)(2,2- 523 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((2R)(2,6- dichlorophenyl)hydroxyethyl)(2,2- 524 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(4,4- 525 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6- dichlorophenyl)ethyl)(4- 526 (trifluoromethyl)benzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)(4- 527 (trifluoromethyl)benzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(4- 528 (trifluoromethyl)benzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((2R/S)(2,6-dichloro methylphenyl)methoxyethyl)(2,2- 529 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((2S)(2,6-dichloro methylphenyl)methoxyethyl)(2,2- 530 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((2R)(2,6-dichloro methylphenyl)methoxyethyl)(2,2- 531 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((4,4- 532 dimethylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(2,6- romethylphenyl) 533 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6- dichlorophenyl)ethyl)(4,4- 534 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((4,4- 535 dimethylcyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(trans(2- propanyl)cyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(2,6- dichloromethylphenyl) 537 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3-chloroquinolinyl)- thyl)(2,2- 538 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3-chloroquinolinyl)- 2-oxoethyl)(4- 539 fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(2,6- dichlorofluorophenyl) 541 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)(2,2- 542 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((4-chlorobenzyl)(2-(2,4- dichloromethylpyridinyl) 543 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((4-chlorobenzyl)(2-(4,6- dimethyloxo-1(2H)- 544 pyridinyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(2,2- 545 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)ethyl)((4,4- 546 dimethylcyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(2,2- 547 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(4,4-dimethylpentyn- 548 1-yl)carbamoyl)(trifluoromethyl)-1H - pyrazolyl)cyclohexanecarboxylic trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 549 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(4,4- 550 ylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(((2S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((3,3- 553 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(((1R)-2,2- 554 dimethylcyclopropyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R,3s,5S)-6,6- dimethylbicyclo[3.1.0]hex bamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic trans(4-((2-(3,5-dichloro nyl)ethyl)((3,3- 556 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)ethyl)((1- 557 methylcyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R,3r,5S)-6,6- ylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((3,3- 559 dimethylcyclobutyl)methyl)carbamoyl) - fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 560 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((4,4- 561 dimethylcyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 562 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 563 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 564 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichloro methylphenyl) oxoethyl)(spiro[2.3]hex yl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[2.3]hex 566 ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[2.3]hex 567 ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(2,2- 568 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[2.5]oct 569 ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4R)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 570 ylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 571 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 572 dimethylcyclobutyl)methyl)carbamoyl) - fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R)(2,6- dichlorophenyl)hydroxyethyl)(2,2- 573 dimethylpropyl)carbamoyl) uoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((2S)(2,6- dichlorophenyl)hydroxyethyl)(2,2- 574 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)(4,4- 575 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-(((3R)((3,5-dichloro pyridinyl)methyl)azaspiro[4.4]non- 576 7-enyl)carbonyl)(trifluoromethyl)- 1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 577 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)-2,2- 578 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro yphenyl)oxoethyl)(4,4- 579 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)((3,3- 580 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)((3,3- 581 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((3R)((3,5-dichloro pyridinyl)methyl)azaspiro[4.4]non- 582 2-yl)carbonyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl) oxoethyl)(spiro[2.3]hex ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)((1- 584 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2-bromophenyl) oxoethyl)((3,3- 585 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid N-(2-(3,5-dichloropyridinyl) oxoethyl)-N-(2,2-dimethylpropyl) 586 S)(2-propenyl)cyclohexyl) - fluoromethyl)-1H-pyrazole carboxamide trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3- 587 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 588 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-bromophenyl) oxoethyl)((3,3- 589 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)((1- 590 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 591 methylcyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((cyclopentylmethyl)(2-(3,5- dichloropyridinyl) 592 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 593 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((3,3- 594 difluorocyclobutyl)methyl)carbamoyl)- fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro fluorophenyl)oxoethyl)((3,3- 595 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2-chlorofluorophenyl)- 2-oxoethyl)((3,3- 596 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid cis(4-((2-(2,6-difluorophenyl) oxoethyl)((3,3- 597 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-difluorophenyl) oxoethyl)((3,3- 598 dimethylcyclobutyl)methyl)carbamoyl) - fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)(3,3- 599 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)(3,3- 600 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2R)-4,4-dimethyl 601 oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((3,3- dimethylcyclobutyl)methyl)(2-(2- fluoromethoxyphenyl) oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1- 603 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid trans(4-((2-(2-cyanophenyl) oxoethyl)((3,3- 604 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6- dichlorophenyl)ethyl)((2R)hydroxy- 605 4,4-dimethylpentanyl)carbamoyl)-5 - (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 606 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((4,4-dimethylcyclohexyl)(2 - (2-fluoromethoxyphenyl) 607 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((1- fluorocyclopentyl)methyl)(2-(2-fluoro- 6-methoxyphenyl) oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloro pyridinyl)ethyl)((1- 609 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- lyl)cyclohexanecarboxylic trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1- 611 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((1r,4r) methylbicyclo[2.2.1]hept yl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[3.3]hept 613 yl)carbamoyl)(trifluoromethyl)-1H- lyl)cyclohexanecarboxylic trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R,5R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) yl)(((1r,4r) methylbicyclo[2.2.1]hept yl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R)-2,2- 616 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)-2,2- 617 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R)((3,5-dichloro pyridinyl)methyl)-4,4-di(2-propen 618 yl)pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[2.4]hept 619 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[2.4]hept 620 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloro pyridinyl)ethyl)((1R)-spiro[3.3]hept 621 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic trans(4-((3-cyanomethylbutyl)(2- (2,6-dichlorophenyl) 622 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)-2,2- 623 ylcyclopropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[2.4]hept 624 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[2.4]hept 625 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[3.4]oct 626 bamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-spiro[3.4]oct 627 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2R)-4,4-dimethyl 628 oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2S)-4,4-dimethyl 629 oxetanyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 630 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 631 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,6-dichlorophenyl) oxoethyl)(spiro[3.3]hept 632 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)oxoethyl)(spiro[3.3]hept-2 - 633 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((1R)-2,2- 634 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((1S)-2,2- 635 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-2,2- 636 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-2,2- 637 dimethylcyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 638 methoxycyclopentyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-spiro[3.3]hept 639 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid (4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-spiro[3.3]hept 640 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic trans(4-((2-(2,6-dichlorophenyl) yl)((1S)-spiro[3.3]hept 641 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[3.3]hept 642 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic trans(4-((2-(2-chloro fluorophenyl)oxoethyl)((1- 643 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 644 diethylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)oxoethyl)((1- 645 methoxycyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((1- 646 methoxycyclopentyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)-2,2- 647 ylcyclopropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R)-2,2- 648 dimethylcyclopropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[3.4]oct 649 bamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-spiro[3.4]oct 650 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1S)-spiro[2.4]hept 651 yl)carbamoyl)(trifluoromethyl)-1H- lyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R)-spiro[2.4]hept 652 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((8S)oxaspiro[3.5]non 653 yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((8R)oxaspiro[3.5]non 654 yl)carbamoyl)(trifluoromethyl)-1H- lyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R)-5,5- dimethyltetrahydro l)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)-2,2- 656 dimethylcyclopropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2-chloro fluorophenyl)oxoethyl)(2,2- 657 dimethylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro fluorophenyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid ((1S,2R)(4-((2-(3,5-dichloro nyl)oxoethyl)(2,2- 659 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol lohexyl)acetic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid ,4R)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 662 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 663 ylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(2,6- dichlorofluorophenyl) 664 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 665 fluorocyclohexyl)methyl)carbamoyl)-5 - (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 666 fluorocyclohexyl)methyl)carbamoyl)-5 - (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)((1- 667 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid (4-((2-(2,6-dichlorophenyl) oxoethyl)((3,3- 668 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclobutyl)acetic acid (cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((3,3- 669 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazol yl)cyclobutyl)acetic acid (4-((2-(2,6-dichlorophenyl) oxoethyl)(2,2- 670 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- 671 methylcyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((3,3- 672 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((3-methyl 675 oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((3-methyl- 676 3-oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid trans(4-((1S,2R,4R)- o[2.2.1]heptyl(2-(3,5- dichloropyridinyl) oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((1S,2S,4R)- o[2.2.1]heptyl(2-(2,6- dichloromethylphenyl) oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(((2R)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)ethyl)(((2R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)ethyl)(((2S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid ,4R)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 683 dimethylcyclobutyl)methyl)carbamoyl) - fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,2S,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((3,3- 684 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R)-4,4- dimethyl oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S)-4,4- dimethyl oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)(2,2- 687 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R)((3,5-dichloro pyridinyl)methyl)-4,4-dimethyl 688 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(cis(2- methyl yl)cyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- 690 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- 691 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3-trifluoro- 692 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro-4,6-dimethyl- 3-pyridinyl)oxoethyl)(2,2- 693 dimethylpropyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclobutylmethyl)(2-(2,6- dichlorofluorophenyl) 694 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((cyclopropylmethyl)(2-(2,6 - dichlorofluorophenyl) 695 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- 696 methylcyclohexyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2,2-dimethylpropyl)(2- oxo(2,3,5-trichloro 697 pyridinyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((cyclopentylmethyl)(2-(2,6- dichlorofluorophenyl) 698 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(cis(2-methyl- 699 2-propanyl)cyclobutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3- 700 methylbutyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-(((2R,4R)((3,5-dichloro- 4-pyridinyl)methyl)(2-propanyl) 701 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro-4,6-dimethyl- 3-pyridinyl)oxoethyl)(3,5- 702 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)((1- 703 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(3- 704 butyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R,5S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S,5R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclopropylmethyl)(2-(2,6 - dichloromethylphenyl) 707 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,3r,5S,6s)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1R,3r,5S)-6,6- 708 ylbicyclo[3.1.0]hexyl)carbamoyl)- 3-(trifluoromethyl)-1H-pyrazol yl)bicyclo[3.1.0]hexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 709 methylcyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclopropylmethyl)(2-(3,5 - dichloropyridinyl) 710 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 711 methylcyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((5- fluorospiro[2.3]hex hyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((5-fluorospiro[2.3]hex 713 yl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) cyclohexanecarboxylic acid trans(4-((2-(3,5-dichloromethyl- 4-pyridinyl)oxoethyl)(2,2- 715 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- 716 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 717 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclopentylmethyl)(2-(2,6- dichloromethylphenyl) 718 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 719 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid (cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(2,2- 720 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1S)- 721 spiro[3.3]heptyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1R)- 722 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(((2S)-4,4- dimethyl oxetanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(((2R)-4,4- dimethyl oxetanyl)methyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(((2S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(((2R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2S)methyltetrahydro 727 furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2R)methyltetrahydro 728 furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)ca rbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 730 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro phenyl)oxoethyl)((1- 731 methylcyclobutyl)methyl)carbamoyl)- fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)(4,4- 732 dimethylcyclohexyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclobutylmethyl)(2-(2,6- dichloromethylphenyl) 733 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((cyclobutylmethyl)(2-(3,5- dichloropyridinyl) 734 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((cyclohexylmethyl)(2-(3,5- dichloropyridinyl) 735 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 736 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid ,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 737 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 738 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,2S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 739 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)(2,2- 740 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid trans(4-((2-(2-chloro fluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)ca rbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 742 ethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((1S)-2,2- 743 dimethylcyclopropyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 744 yclobutyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2,6-dichloro phenyl)oxoethyl)(((1R)-2,2- 745 dimethylcyclopropyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid 4-(4-(((2R,4S)((3,5-dichloro- 4-pyridinyl)methyl)(2-propanyl) 746 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R,4R)((3,5-dichloro- 4-pyridinyl)methyl)(2-propanyl) 747 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)- 748 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R)- 749 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1R,3r,5S)- 750 6,6-dimethylbicyclo[3.1.0]hex bamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexyl)acetic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)((1- 751 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(3-methylbutyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro methoxypyridinyl)oxoethyl)(2,2- 753 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 754 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,5- 755 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid (1S,2R,4S)(4-((2-(3,5-dichloro nyl)oxoethyl)((3,3- 756 dimethylcyclobutyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chloro-4,6-dimethyl- 3-pyridinyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloromethyl- 4-pyridinyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex bamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1- 759 methylcyclopropyl)methyl)carbamoyl) - fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) yl)((1- 760 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,4-dichloromethyl pyridinyl)oxoethyl)(3,5- 761 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid 4-(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)(3,5- 762 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)(2,2- 764 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,3r,5S,6r)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3- methylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)bicyclo[3.1.0]hexanecarboxylic (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3- 766 oropropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,2S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3- 767 trifluoropropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloromethyl- 4-pyridinyl)oxoethyl)(3,5- 768 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid (1R,3r,5S,6s)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- fluorocyclopentyl)methyl)carbamoyl)- fluoromethyl)-1H-pyrazol yl)bicyclo[3.1.0]hexanecarboxylic (1R,3r,5S,6s)(4-((2-(3,5-dichloro-4 - pyridinyl)oxoethyl)(2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)bicyclo[3.1.0]hexanecarboxylic (4r)(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(2,2- 771 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)spiro[3.3]heptanecarboxylic acid (S)((1R,3S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1R,3r,5S)-6,6- 772 dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclobutyl)propanoic acid (1R,2S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S)-5,5- dimethyltetrahydro l)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 775 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid trans(4-((2-cyclopropylethyl)(2-(3,5 - dichloropyridinyl) 776 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-cyclopropylethyl)(2-(2,6 - dichloromethylphenyl) 777 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 4-(4-((2-(2-chlorofluoro methylphenyl)oxoethyl)((1- 778 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- dinyl)oxoethyl)(2-((2-methyl- 779 2-propanyl)oxy)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid 2-(trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,5- 780 difluorobenzyl)carbamoyl) uoromethyl)-1H-pyrazol yl)cyclohexyl)propanoic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- 781 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 782 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro methylphenyl)oxoethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 784 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylic acid (1S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 785 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-2,2- dimethylcyclohexanecarboxylic acid 2-(cis(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,5- 786 robenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)propanoic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl) yl)((1R,3r,5S)-6,6- 787 dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 788 methylcyclopropyl)methyl)carbamoyl) - -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,5- 789 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetic acid (cis(4-((2-(3,5-dichloropyridinyl)- 2-oxoethyl)(3,5- 790 difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 791 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexyl)acetic acid (cis(4-((2-(3,5-dichloropyridinyl)- thyl)(2,2- 792 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexyl)acetic acid (1R,2R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 793 dimethylpropyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)(2,2- 794 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2S,4S)((3,5-dichloro- 4-pyridinyl)carbonyl)phenoxy 795 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid trans(4-(((2R,4S)((3,5-dichloro- 4-pyridinyl)carbonyl)phenoxy 796 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2S,4R)((3,5-dichloro- 4-pyridinyl)carbonyl)phenoxy 797 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)ca l)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- (trifluoromethyl)cyclobutyl)methyl)car bamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro nyl)oxoethyl)((1- (fluoromethyl)cyclobutyl)methyl)carba moyl)(trifluoromethyl)-1H-pyrazol-1 - yl)methylcyclohexanecarboxylic trans(4-((cyclohexylmethyl)(2-(2,4- dichloromethylpyridinyl) 801 oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro nyl)oxoethyl)(3,3,3-trifluoro- 802 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3- 803 methylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)(3- 804 methylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chlorofluoro phenyl)oxoethyl)(((2S) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2-chlorofluoro methylphenyl)oxoethyl)(((2R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid )(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl)- 2,2-dimethylcyclohexanecarboxylic trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((2R)-tetrahydro- 808 2-furanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-(((3R)((3,5- dichloropyridinyl)methyl) 809 azaspiro[4.4]nonenyl)carbonyl)- fluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 810 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)ca rbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid (1R,2R,4R)(4-((2-(3,5-dichloro nyl)oxoethyl)(2,2- 812 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 813 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)(((2R) methyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)(((2S) tetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1S)- 816 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1R)- 817 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((1S)-2,2- 818 rocyclopropyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((1R)-2,2- 819 difluorocyclopropyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((2R)-tetrahydro- 820 2-furanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) yl)(((2R)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R,4S)cyclohexyl ((3,5-dichloropyridinyl)carbonyl) 822 idinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2S,4S)cyclohexyl ((3,5-dichloropyridinyl)carbonyl) 823 idinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl)- 2,2-dimethylcyclohexanecarboxylic )(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl)- 2,2-dimethylcyclohexanecarboxylic (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(((2R)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2S,4R)((3,5-dichloro- 4-pyridinyl)carbonyl)phenyl 827 pyrrolidinyl)carbonyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R,4R)((3,5-dichloro- 4-pyridinyl)carbonyl)phenyl 828 pyrrolidinyl)carbonyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2-fluoro 829 methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- (trifluoromethyl)cyclopropyl)methyl)ca rbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)(2-fluoro- 831 2-methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(2-fluoro 832 methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid cis(4-((2-(2,4-dichloromethyl pyridinyl)oxoethyl)((4,4- 833 dimethylcyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid cis(4-((cyclohexylmethyl)(2-(2,4- dichloromethylpyridinyl) 834 yl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid trans(4-((2-(2,4-dichloromethyl- 3-pyridinyl)oxoethyl)((4,4- 835 ylcyclohexyl)methyl)carbamoyl )(trifluoromethyl)-1H-pyrazolyl)- ylcyclohexanecarboxylic acid (4R/S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 836 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)spiro[3.3]heptanecarboxylic acid (4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 837 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)spiro[3.3]heptanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2S)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(((2R)-5,5- dimethyltetrahydro furanyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-(((2R)(3,5-dichloro pyridinyl)hydroxyethyl)((1- 840 fluorocyclopropyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid N-(2-(3,5-dichloropyridinyl) yl)-N-(2,2-dimethylpropyl) ((methylsulfonyl)methyl)cyclohexyl) (trifluoromethyl)-1H-pyrazole carboxamide (1R,3S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 842 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (1S,3S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 843 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1- 844 methoxycyclopropyl)methyl)carbamo yl)(trifluoromethyl)-1H-pyrazolyl)- 1-methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6-dichloro fluorophenyl)oxoethyl)((1R,3r,5S)- 6,6-dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl) methylcyclohexanecarboxylic acid (cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6- 846 dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclobutyl)acetic acid -(4-((2-(3,5-dichloropyridinyl) - 2-oxoethyl)(2-fluoro 847 methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)spiro[3.3]heptanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- dichlorophenyl)oxoethyl)((1S)- 848 spiro[3.3]heptyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(2,6- rophenyl)oxoethyl)((1R)- 849 spiro[3.3]heptyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2-ethoxy 850 methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(spiro[2.5]oct 851 ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid ,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(spiro[2.5]oct 852 ylmethyl)carbamoyl) uoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1s,4s) oxabicyclo[2.2.1]hept ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((bicyclo[1.1.1]pent ylmethyl)(2-(3,5-dichloropyridinyl)- 854 2-oxoethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,3R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 855 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (1S,3S,4R)(4-((2-(3,5-dichloro nyl)oxoethyl)(2,2- 856 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (1R,3R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 857 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6- 858 dimethylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- lyl)cyclobutyl)acetic acid (cis(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6- 859 ylbicyclo[3.1.0]hex yl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclobutyl)acetic acid (1R,3r,6R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 860 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)spiro[2.5]octanecarboxylic acid (1S,2S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 861 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,2- dimethylcyclohexanecarboxylic acid (1S,2S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 862 ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,2- dimethylcyclohexanecarboxylic acid trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((3,3-difluoro 863 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3-trifluoro- 864 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,4R)(4-((2-(2,6-dichlorophenyl)- 2-oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl)- 2,2-dimethylcyclohexanecarboxylic (1S,4S)(4-((2-(2,6-dichlorophenyl)- 2-oxoethyl)((1- methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazolyl)- 2,2-dimethylcyclohexanecarboxylic (1S,2S,4S)(4-((2-(3,5-dichloro nyl)oxoethyl)((1s,4s) oxabicyclo[2.2.1]hept ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,3R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) fluoro methylcyclohexanecarboxylic acid (1R,3S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) fluoro cyclohexanecarboxylic acid (1R,3S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- ylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) fluoro methylcyclohexanecarboxylic acid (3aR,6R,7aR)(4-((2-(3,5- dichloropyridinyl)oxoethyl)((2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)octahydro-1H-indene-3a-carboxylic trans(4-((2-(3,5-dichloro methoxypyridinyl)ethyl)(2,2- 872 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 873 dimethylpropyl)carbamoyl) uoromethyl)-1H-pyrazolyl)-1,2- dimethylcyclohexanecarboxylic acid (1R,2R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 874 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,2- dimethylcyclohexanecarboxylic acid ,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3-trifluoro- 875 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (3aS,6S,7aS)(4-((2-(3,5- dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)octahydro-1H-indene-3a-carboxylic (3aR,6R,7aR)(4-((2-(3,5- dichloropyridinyl) oxoethyl)(neopentyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)octahydro-1H-indene-3a-carboxylic (1R,2R,4R)(4-((2-(3,5-dichloro nyl)oxoethyl)(3,3,3-trifluoro- 878 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2S,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3-trifluoro- 879 2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1R,2R,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1s,4s) oxabicyclo[2.2.1]hept ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid ,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)((1s,4s) oxabicyclo[2.2.1]hept ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,3R,4S)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 882 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (1R,3S,4R)(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(2,2- 883 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)-1,3- dimethylcyclohexanecarboxylic acid (trans(4-((2-(3,5-dichloro pyridinyl)oxoethyl)(3,3,3-trifluoro- 884 methylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid trans(4-((2-(3,5-dichlorooxo-1,2- opyridinyl)ethyl)(2,2- 885 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro oxo-1,2-dihydropyridinyl)ethyl)(2,2- 886 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (1S,2R,4S)(4-((2-(3,5-dichloro methoxypyridinyl)ethyl)(2,2- 887 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid (trans(4-((2-(2,6-dichloro methoxyphenyl)oxoethyl)((1- 888 fluorocyclopentyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid (trans(4-((2-(2,6-dichloro yphenyl)oxoethyl)(4- 889 fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazol yl)cyclohexyl)acetic acid (4-((2-(2,6-dichloro methylphenyl)oxoethyl)((1- 890 methylcyclobutyl)methyl)carbamoyl)- -(trifluoromethyl)-1H-pyrazol lohexyl)acetic acid trans(4-((2-(2,6-dichloro methoxyphenyl) oxoethyl)(spiro[3.5]non ylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(6,8- dichloro[1,2,4]triazolo[1,5-a]pyridin yl)ethyl)(2,2- dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid trans(4-((2-(2,6-dichlorophenyl) oxoethyl)(3,3,3-trifluoro-2,2- 893 dimethylpropyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid The results of high performance liquid tography mass spectroscopy (LC/MS) analysis for the above examples were shown in the following tables. e Exact Mass Obs. Mass example Exact Mass Obs. Mass 24 586.1 587.1 60 585.1 586 600.1 601.2 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 65 555.2 554 588.2 569.1 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 70 633.1 634 560.1 561.2 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 e 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 e Exact Mass Obs. Mass example Exact Mass Obs. Mass 168 623.0 624 205 602.2 603.3 169 602.2 603.1 206 613.2 614.2 170 607.1 608 207 633.1 634.2 171 607.1 608 208 590.1 591.2 172 589.1 590.0 209 607.1 608.2 173 631.2 632.1 210 599.1 600.2 174 574.1 575.1 211 600.2 601.3 175 610.1 611.0 212 642.1 643.2 176 618.2 619.1 213 642.1 643.2 177 612.1 613.0 214 595.2 596.3 178 614.1 615 215 586.1 587 179 619.1 620 216 624.0 625 180 608.1 609.0 217 633.2 634.3 181 576.1 577.0 218 617.1 618.3 182 600.2 601.1 219 647.1 648.2 183 588.2 589 220 647.2 648.3 184 588.2 589.2 221 609.1 610.2 185 560.1 561.2 222 647.2 648.3 187 588.2 589.2 223 588.2 589.3 188 596.1 597.1 224 623.1 624.2 189 635.1 636.0 225 639.1 640.2 190 633.2 634.3 226 643.2 645 191 649.1 650.2 227 629.2 630 192 614.2 615.3 228 614.1 615 193 631.2 632.2 229 616.2 617.3 194 592.1 593.2 230 645.2 646.3 195 582.1 583.2 231 661.1 662.2 196 598.2 597 232 609.2 610.3 197 631.1 632.2 234 633.1 634.2 198 562.1 563.2 235 633.2 634.3 199 631.2 632.3 236 641.2 642 200 586.1 587.2 237 627.2 628 201 621.1 622.2 238 615.2 616 202 617.1 618.2 239 663.2 664.3 203 647.2 648.3 240 643.2 644.3 204 600.2 601.3 241 659.1 660.2 e 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 e 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 e 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 e 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 27 606.1 637 573.1403 574 606 592.1625 593 637 573.1403 574 607 595.266 596.2 638 618.1617 619 e 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 e 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 e Exact Mass Obs. Mass example Exact Mass Obs. Mass 772 599.2 600 809 584.2 585.2 773 618.2 619.1 810 606.1 607 774 618.2 619.1 810 606.1 607 775 588.2 587.9 811 627.1 628 776 574.1 575.2 812 576.2 577.1 777 587.2 588 813 576.2 577.1 778 585.2 586.2 814 621.1 622.2 779 620.2 619.8 815 621.1 622.2 780 646.1 645.7 816 600.2 601.2 781 587.2 589 817 600.2 601.2 782 588.2 590 818 596.1 597 783 631.2 632.0 819 596.1 597 784 590.2 591 820 590.1 591.2 785 590.2 591 821 617.2 618.2 786 646.1 646.3 822 628.2 629.1,631.1 787 613.2 614.2 823 628.2 629.1,631.1 788 574.1 575.2 824 602.2 604 789 646.1 646.3 825 602.2 604 790 646.1 645.5 826 618.2 619.1 791 590.2 590 827 622.1 623.0,625.0 792 590.2 590 828 622.1 623.0,625.0 793 576.2 577.1 829 580.1 581.2 794 575.2 577 830 628.1 629.2, 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 e 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 As for the examples, the results of spectrum were shown in the following tables. example Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.69 and 7.59 (1H, 2xs); 7.31-7.28 (1H, m); 7.16- 7.12 (1H, m); .02 (2H, m); 4.83 and 4.65 (2H, 2xs); 4.61 and 4.30 (2H, 2xs), 4.27-4.21 (1H, m); 2.78 (1H, m); 2.44-2.40 (2H, m); 2.26-2.15 (2H, m); .86 (2H, m); 1.74-1.67 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.63 and 7.55 (2H, 2xs); 4.77 and 4.44 (2H, 2xs); 26 4.28-4.19 (1H, m); 3.44(1H, d, J = 6.8Hz) and 3.21(1H, d, J = 7.6Hz); 2.52-2.42 (1H, m); 2.26-2.23 (2H, m); 2.14- 2.03 (4H, m); .59 (1H, m); 0.99 and 0.84 (6H, 2xd, J = 6.6Hz) Ī“ (400 MHz, CDCl3) rotomers present 8.57 and 8.50 (2H, 2xs); 7.71 and 7.56 (2H, 2xs); 4.87 and 4.53 (2H, 2xs); 27 4.25-4.19 (1H, m); 3.43-3.34 (2H, m); 2.49-2.43 (1H, m); 2.26-2.23 (2H, m); 2.10-2.03 (4H, m); 1.70-1.59 (2H, m); 1.01 and 0.85 (9H, 2xs) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.50 (2H, 2xs); 7.64 and 7.54 (2H, 2xs); 4.71 and 4.40 (2H, 2xs); 28 4.28-4.17 (1H, m); 3.66 and 3.40 (2H, 2xd, J = ; 2.71-2.42 (2H, m); 2.27-2.22 (2H, m); 2.15-1.99 (6H, m); .52 (6H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.63 and 7.55 (1H, 2xs); 4.79 and 4.46 (2H, 2xs); 29 4.30-4.18 (1H, m); 3.57 and 3.32 (2H, 2xd, J = 7.8Hz); .42 (1H, m); 2.27-2.22 (2H, m); 2.13-2.04 (4H, m); 1.78-1.49 (9H, m); 1.31-1.27 (1H, m); 1.07-1.03 (1H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.62 and 7.55 (1H, 2xs); 4.76 and 4.44 (2H, 2xs); 4.28-4.19 (1H, m); 3.45 and 3.22 (2H, 2xd, J = 7.8Hz); 2.51-2.42 (1H, m); 2.27-2.23 (2H, m); 2.14-2.03 (4H, m); 1.75-1.64 (9H, m); 1.54-1.46 (1H, m); 1.16-1.10 (1H, m); 1.07-1.01 (1H, m); 0.77-0.71 (1H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.62 and 7.55 (1H, 2xs); 4.95 and 4.60 (2H, 2xs); 31 4.30-4.22 (1H, m); 3.57 and 3.34 (2H, 2xs); 2.52-2.43 (1H, 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) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.65 and 7.55 (1H, 2xs); 4.74 and 4.42 (2H, 2xs); 32 4.30-4.17 (1H, m); 3.61 and 3.34 (2H, 2xt, J = 7.7Hz); 2.50-2.43 (1H, m); .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) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.52 (2H, 2xs); 7.65 and 7.54 (1H, 2xs); 4.74 and 4.41 (2H, 2xs); 33 4.30-4.20 (1H, m); 3.62-3.58 and 3.33-3.29 (2H, 2xm); .43 (1H, m); .23 (2H, m); 2.12-2.04 (4H, m); 1.72-1.62 (2H, m); .51 and 1.42-1.38 (2H, 2xm); 0.97 and 0.76 (9H, 2xs) Ī“ (400 MHz, CDCl3) rotomers present 8.56 and 8.49 (2H, 2xs); 7.63 and 7.55 (1H, 2xs); 5.19-5.16 and 5.10-5.06 (1H, 1xm); 4.29-4.27 and 3.99-3.97 (2H, 2xm); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); .03 (4H, m); 1.72 and 1.52 (3H, 2xs); 1.70-1.63 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.63 and 7.55 (1H, 2xs); 4.76 and 4.44 (2H, 2xs); 36 4.28-4.17 (1H, m); 3.49 and 3.26 (2H, 2xd, J = 6.8Hz); 2.51-2.42 (1H, m); 2.27-2.23 (2H, m); 2.14-2.03 (4H, m); 1.71-0.97 (11H, m); 0.90-0.78 (6H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.64 and 7.55 (1H, 2xs); 4.77 and 4.45 (2H, 2xs); 37 .19 (1H, m); 3.51 and 3.28 (2H, 2xd, J = 6.8Hz); 2.51-2.43 (1H, m); 2.27-2.23 (2H, m); 2.14-2.03 (4H, m); 1.73-1.54 (7H, m); 1.27-1.18 (1H, m); 0.98-0.84 (3H, m), 0.30-0.10 (4H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.52 and 8.45 (2H, 2xs); 7.69 and 7.60 (1H, 2xs); 7.37-7.29 (4H, m); 7.17- 40 7.15 (1H, m); 4.87 and 4.66 (2H, 2xs); 4.64 and 4.30 (2H, 2xs); 4.30-4.21 (1H, m); 2.49-2.42 (1H, m); 2.25-2.22 (2H, m); 2.09-2.04 (4H, m); 1.71-1.64 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.68 and 7.60 (1H, 2xs); 7.33 (2H, d, J = 8.3Hz); 41 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 (1H, m); 2.50-2.42 (1H, m); 2.27-2.23 (2H, m); 2.11-2.03 (4H, m); 1.70-1.59 (2H, Ī“ (400 MHz, CDCl3) rotomers present 8.55 and 8.49 (2H, 2xs); 7.66 and 7.61 (1H, 2xs); .69 (3H, m); 4.83 and 42 4.70 (2H, 2xs); 4.62 and 4.34 (2H, 2xs); 4.28-4.21 (1H, m); 2.49-2.43 (1H, m); 2.27-2.23 (2H, m); 2.10-2.04 (4H, m); 1.71-1.60 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.54 and 8.48 (2H, 2xs); 7.67 and 7.59 (1H, 2xs); .21, 7.15-7.70 and 43 6.93-6.89 (3H, 3xm); 4.92 and 4.71 (2H, 2xs); 4.71 and 4.42 (2H, 2xs); 4.28-4.18 (1H, m); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); 2.12-2.03 (4H, m); 1.71-1.59 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.54 and 8.48 (2H, 2xs); 7.67 and 7.60 (1H, 2xs); 7.19-7.12 and .89 44 (3H, 2xm); 4.80 and 4.67 (2H, 2xs); 4.60 and 4.32 (2H, 2xs); 4.27-4.19 (1H, m); 2.49-2.42 (1H, m); 2.26-2.23 (2H, m); 2.11-2.04 (4H, m); 1.70-1.63 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.55 and 8.48 (2H, 2xs); 7.68 and 7.60 (1H, 2xs); 7.19-7.14, .95 and 45 6.82-6.78 (3H, 3xm); 4.87 and 4.73 (2H, 2xs); 4.66 and 4.42 (2H, 2xs); 4.28-4.19 (1H, m); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); 2.13-2.03 (4H, m); 1.70-1.60 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.56 and 8.49 (2H, 2xs); 7.78 and 7.75 (1H, 2xs); 7.39 (1H, m); 6.35 (1H, m); 46 6.33-6.32 and 6.22-6.21 (1H, 2xm); 4.84 and 4.73 (2H, 2xs); 4.56 and 4.44 (2H, 2xs); 4.33-4.19 (1H, m); 2.50- 2.42 (1H, m); 2.27-2.23 (2H, m); 2.14-2.03 (4H, m); 1.73- 1.62 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.55 and 8.49 (2H, 2xs); 7.70 and 7.58 (1H, 2xs); 7.41-7.33 (2H, m); 6.40 and 47 6.26 (1H, 2xs); 4.70 (2H, s); 4.46 and 4.35 (2H, 2xs); 4.32-4.18 (1H, m); 2.50-2.42 (1H, m); 2.27-2.23 (2H, m); 2.14-2.03 (4H, m); 1.72-1.59 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.76-8.36 (5H, m); 7.71 48 and 7.60 (1H, 2xs); 4.94 and 4.85 (2H, 2xs); 4.74 and 4.66 (2H, 2xs); 4.26-4.18 (1H, m); 2.49-2.42 (1H, m); 2.25-2.22 (2H, m); 2.11-2.03 (4H, m); 1.70-1.59 (2H, m) Ī“ (400 MHz, DMSO-d6) rs t 12.16 (1H, brs); 8.56-8.51 and 8.49-8.43 (2H, 2xm); 7.88 and 7.82 (1H, 49 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 (1H, m); 2.33-2.29 (1H, m); 2.28 and 1.83 (3H, 2xs); 2.07-2.03 (2H, m); .91 (4H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 8.78 and 8.71 (1H, 2xs); 8.69 and 8.62 (1H, 2xs); 7.81 and 7.78 (1H, 2xs); 50 7.18-6.90 (3H, m); 4.84 and 4.81 (2H, 2xs); 4.70 and 4.59 (2H, 2xs); 4.23-4.14 (1H, m); 2.33-2.26 (1H, m); 2.09-2.02 (2H, m); 1.99-1.90 (4H, m); .46 (2H, m) Ī“ (400 MHz, 6) rotamers present 12.20 (1H, brs); 8.72 and 8.66 (2H, 2xs); 7.74 and 7.72 (1H, 2xs); 7.18-7.10 51 (1H, 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 (1H, m); 2.33-2.27 (1H, m); 2.09-1.92 (6H, m); 1.55-1.49 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.31 and 8.24 (2H, 2xs); 7.67 and 7.63 (1H, 2xs); 6.83-6.72 (3H, m); 4.84 and 52 4.63 (2H, 2xs); 4.47 and 4.20 (2H, 2xs); 4.27-4.25 (1H, m); 2.49-2.43 (1H, m); 2.27-2.23 (2H, m); 2.23 and 1.86 (6H, 2xs); 2.11-2.06 (4H, m); 1.68-1.64 (2H, m) Ī“ (400 MHz, 6) rotamers present 12.20 (1H, brs); 7.86 and 7.84 (1H, 2xs); 7.57-7.49 (3H, m); 7.19-7.13 (1H, m); 53 7.11-7.08 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 (1H, m); 2.34- 2.27 (1H, m); 2.06-2.03 (2H, m); 1.98-1.92 (4H, m); 1.58- 1.50 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 7.75 (1H, s); 7.47-7.38 (1H, m); 7.18-6.88 (5H, m); 4.71 and 54 4.67 (2H, 2xs); 4.53 and 4.52 (2H, 2xs); 4.25-4.23 (1H, m); 3.77 and 3.67 (3H, 2xs); 2.34-2.28 (1H, m); 2.06-1.90 (6H, m); 1.59-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 12.20 (1H, brs); 7.86 and 7.84 (1H, 2xs); 7.68 and 7.62 (2H, 2xd, J=8.4 Hz); 55 .91 (3H, m); 4.80 and 4.71 (2H, 2xs); 4.65 and 4.55 (2H, 2xs); 4.26-4.21 (1H, m); 2.35-2.28 (1H, m); 2.07-2.06 (2H, m); 1.97-1.92 (4H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.86 and 7.84 (1H, 2xs); 7.84 and 7.76 (2H, 2xs); 7.19-6.91 (3H, m); 4.80 and 56 4.71 (2H, 2xs); 4.65 and 4.56 (2H, 2xs); 4.27-4.17 (1H, m); 2.34-2.27 (1H, m); 2.06-2.02 (2H, m); 1.97-1.91 (4H, m); 1.59-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.18 (1H, brs); 8.08 and 8.02 (2H, 2xs); 7.88 and 7.85 (1H, 2xs); 7.19-6.92 57 (3H, m); 4.84 and 4.72 (2H, 2xs); 4.68 and 4.57 (2H, 2xs); 4.27-4.18 (1H, m); 2.35-2.27 (1H, m); 2.07-2.03 (2H, m); 1.98-1.93 (4H, m); 1.60-1.51 (2H, m) Ī“ (400 MHz, CD3CN) rotamers present 7.88-7.68 (3H, m); 58 7.02-6.86 (3H, m); 4.79 and 4.76 (2H, 2xs); 4.62 and 4.56 (2H, 2xs); 4.35-4.29 (1H, m); 2.47-2.40 (1H, m); 2.17-2.12 (2H, m); 2.08-2.02 (4H, m); 1.67-1.62 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 8.04-7.87 (3H, m); 7.75 and 7.52 (1H, 2xs); .10 (1H, 59 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 (1H, m); 2.32- 2.25 (1H, m); .98 (2H, m); 1.95-1.81 (4H, m); 1.55- 1.47 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 7.77-7.51 (4H, m); 7.17-7.07 (1H, m); 7.05 and 6.89 (2H, 60 2xd, J=1.6 Hz); 5.07 and 4.93 (2H, 2xs); 4.68 and 4.57 (2H, 2xs); 4.18-4.17 (1H, m); 2.29-2.25 (1H, m); 2.05-1.98 (2H, m); 1.95-1.81 (4H, m); 1.53-1.47 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.76-7.72 and 7.38- 7.34 (1H, 2xm); 7.58 and 7.50 (1H, 2xs); 7.18-7.02 (2H, 61 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 (1H, m); 2.45-2.41 (1H, m); 2.24-2.21 (2H, m); 2.10-2.02 (4H, m); 1.66-1.62 (2H, m) Ī“ (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 62 Hz); 7.76 and 7.55 (1H, 2xs); 7.15-7.10 (1H, 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); .15 (1H, m); .21 (1H, m); 2.04-1.79 (6H, m); 1.53-1.45 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.10 (1H, brs); 7.74 and 7.61 (1H, 2xs); 7.40 and 7.34 (1H, 2xs); 7.16-6.88 63 (3H, m); 4.74 and 4.68 (2H, 2xs); 4.55 and 4.53 (2H, 2xs); 4.21-4.12 (1H, m); 2.56 and 2.39 (3H, 2xs); 2.33-2.21 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 7.73 and 7.62 (1H, 2xs); .89 (3H, m); 4.81 and 4.67 (2H, 64 2xs); 4.61 and 4.55 (2H, 2xs); 4.20-4.11 (1H, m); 2.73 and 2.49 (3H, 2xs); 2.39 and 2.28 (3H, 2xs); .17 (1H, m); 2.02-1.99 (2H, m); 1.96-1.85 (4H, m); 1.53-1.43 (2H, Ī“ (400 MHz, CDCl3) rotamers present 7.57 and 7.40 (1H, 2xs); 6.78-6.65 (3H, m); 4.69 and 4.49 (2H, 2xs); 4.27 and 65 3.95 (2H, 2xs); 4.25-4.21 (1H, m); 2.47-2.37 (2H, m); .21 (2H, m); 2.09-2.03 (4H, m); 1.86-1.77 (2H, m); .60 (4H, m); 1.51-1.26 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 7.83 and 7.82 (1H, 2xs); 7.28 and 7.21 (2H, 2xs); 7.18-7.12 (1H, m); 7.07 and 66 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 (1H, m); 2.28-2.21 (1H, m); 2.04-2.01 (2H, m); 1.99-1.89 (5H, m); 1.54-1.50 (2H, m); 1.04-0.96 (2H, m); 0.82-0.74 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 7.84 and 7.82 (1H, 2xs); 7.18-7.09 (3H, m); 7.08 and 6.91 (2H, 67 2xd, J=1.6 Hz); 4.78 and 4.70 (2H, 2xs); 4.61 and 4.54 (2H, 2xs); 4.26-4.20 (1H, m); 3.83 and 3.78 (3H, 2xs); 2.33-2.27 (1H, m); 2.05-2.02 (2H, m); 1.97-1.91 (4H, m); 1.58-1.50 (2H, m) Ī“ (400 MHz, 6) rotamers t 7.98 (1H, s); 7.76- 7.74 (1H, m); 7.52-7.50 (1H, m); 7.45-7.41 (1H, m); 7.12- 68 7.05 (3H, m); 6.70 (1H, s); 5.10-4.76 (4H, m); 4.23-4.19 (1H, m); 2.27-2.21 (1H, m); 2.01-1.98 (2H, m); 1.91-1.85 (4H, m); 1.55-1.44 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.92-7.90 and 7.75- 7.73 (2H, 2xm); 7.75 and 7.49 (1H, 2xs); 7.15-7.08 (1H, 69 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 (1H, m); 2.29-2.23 (1H, m); 2.04-1.96 (2H, m); 1.91-1.83 (4H, m); 1.53-1.45 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.82 (1H, s); 7.18- 7.12 (1H, m); 7.07 and 6.90 (2H, 2xd, J=1.6 Hz); 6.85 and 70 6.75 (2H, 2xs); 4.75 and 4.68 (2H, 2xs); 4.58 and 4.53 (2H, 2xs); 4.25-4.19 (1H, m); 2.30-2.26 (1H, m); .02 (2H, m); 1.96-1.90 (4H, m); 1.58-1.48 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.59 and 8.52 (2H, 2xs); 7.64 and 7.55 (1H, 2xs); 4.76 and 4.45 (2H, 2xs); 71 4.28-4.19 (1H, 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 (1H, m); 1.16-1.06 (1H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.58 and 8.51 (2H, 2xs); 7.64 and 7.56 (1H, 2xs); 4.91 and 4.57 (2H, 2xs); 72 4.31-4.18 (1H, m); 3.54 and 3.26 (2H, d, J = 6.9 Hz); 2.50-2.43 (1H, 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 (1H, 2xm); .56 (2H, m); 0.36-0.32 (1H, m); 0.15-0.10 (1H, m) Ī“ (400 MHz, CDCl3) rotomers t 8.57 and 8.50 (2H, 2xs); 7.66 and 7.56 (1H, 2xs); 5.00 and 4.68 (2H, 2xs); 73 4.27-4.19 (1H, m); 3.83-3.57 (2H, m); 2.50-2.42 (1H, 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) Ī“ (400 MHz, CDCl3) rotomers present 8.56 and 8.48 (2H, 2xs); 7.66 and 7.54 (1H, 2xs); 5.12 and 4.82 (2H, 2xs); 74 4.27-4.18 (1H, m); 3.46 and 3.13 (2H, 2xs); 3.17(3H, s); 2.49-2.43 (1H, m); .23 (2H, m); 2.12-2.03 (4H, m); .59 (2H, m); 1.22 and 1.04 (6H, 2xs) Ī“ (400 MHz, CDCl3) rotomers present 8.60 and 8.53 (2H, 75 2xs); 7.66 and 7.57 (1H, 2xs); 4.94 and 4.62 (2H, 2xs); 4.30-4.22 (2H, m); 4.04-3.98 (1H, m); 2.51-2.43 (1H, m); 2.27-2.24 (2H, m); 2.14-2.05 (4H, m); 1.71-1.62 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.62 (2J, d, J = 5.2 Hz); 8.54 and 8.48 (2H, 2xs); 7.65 and 7.62 (1H, 2xs); 76 7.25 and 7.13 (2H, 2xd, J = 5.2 Hz); 4.86 and 4.70 (2H, 2xs); 4.66 and 4.34 (2H, 2xs); 4.27-4.22 (1H, m); 2.49- 2.42 (1H, m); 2.27-2.24 (2H, m); 2.10-2.05 (4H, m); 1.71- 1.61 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.70 and 7.61 (1H, 2xs); 7.31-7.25 (1H, m); 7.16- 77 7.13 (1H, m);7.07-7.03 (2H, m); 4.83 and 4.65 (2H, 2xs);4.62 and 4.30 (2H, 2xs); 4.30-4.19 (1H, m); 2.26- 2.16 (2H, m); 1.94-1.86 (6H, m); 1.40 (3H, s) Ī“ (400 MHz, CDCl3) rotomers present 8.55 and 8.49 (2H, 2xs); 7.66 and 7.62 (1H, 2xs); 6.85-6.69 (3H, m); 4.83 and 78 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) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.68 and 7.59 (1H, 2xs); .26 (1H, m); 7.15- 79 7.12 (1H, m); 7.06-7.02 (2H, m); 4.83 and 4.65 (2H, 2xs); 4.61 and 4.30 (2H, 2xs); 4.25-4.17 (1H, m); 2.43-2.40 (2H, m); 2.19-2.11 (2H, m); 1.97-1.88 (2H, m); 1.41-1.34 (2H, m); 1.31 (3H, s) Ī“ (400 MHz, CDCl3) rotomers t 8.53 and 8.48 (2H, 2xs); 7.73 and 7.64 (1H, 2xs); .27 (1H, m); 7.17- 80 7.13 (1H, m); 7.07-7.03 (2H, m); 4.83 and 4.65 (2H, 2xs); 4.62 and 4.30 (2H, 2xs); 4.58-4.51 (1H, m); 2.67-2.56 (2H, m); 2.25-2.14 (4H, m); 2.02-1.93 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.54 and 8.48 (2H, 2xs); 7.72 and 7.63 (1H, 2xs); 7.31-7.27 (1H, m); 7.17- 81 7.13 (1H, m); 7.07-7.03 (2H, m); 4.83 and 4.65 (2H, 2xs); 4.62 and 4.30 (2H, 2xs); 4.41-4.34 (1H, m); 2.46-2.38 (2H, m); 2.33-2.27 (2H, m); .94 (4H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.74 and 7.66 (1H, 2xs); 7.30-7.27 (1H, m); 7.16- 82 7.13 (1H, m); 7.07-7.02 (2H, m); 5.26-5.14 (1H, m); 4.83 and 4.64 (2H, 2xs); 4.61 and 4.29 (2H, 2xs); 3.34-3.27 (1H, m); 3.10-2.98 (2H, m); 2.86-2.77 (2H, m) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.74 and 7.65 (1H, 2xs); 7.30-7.26 (1H, m); 7.16- 83 7.12 (1H, m); 7.07-7.02 (2H, m); 4.90-4.82 (1H, m); 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) Ī“ (400 MHz, CDCl3) rotomers present 8.53 and 8.47 (2H, 2xs); 7.58 and 7.48 (1H, 2xs); 7.31-7.28 (1H, m); 7.19- 84 7.15 (1H, m); 7.07-7.02 (2H, m); 4.82 and 4.66 (2H, 2xs); 4.64 and 4.40 (2H, 2xs); .30 (1H, m); 2.50-2.42 (1H, m); 2.24-2.03 (9H, m), 1.71-1.59 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 8.77 and 8.70 (2H, 2xs); 7.87 and 7.83 (1H, 2xs); 7.20-7.14 (1H, m); 7.10 and 85 6.92 (2H, 2xd, J=1.6 Hz); 4.86 and 4.72 (2H, 2xs); 4.72 and 4.57 (2H, 2xs); 4.51-4.49 (1H, m); 4.26-4.21 (1H, m); 3.87 (1H, brs); 2.32-2.29 (2H, m); 1.81-1.78 (2H, m); 1.60-1.58 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.48 (2H, 2xs); 7.69 and 7.60 (1H, 2xs); 7.31-7.26 (1H, m); 7.16- 86 7.13 (1H, 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 (1H, m); 3.04-2.97 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.47 (2H, 2xs); 7.70 and 7.61 (1H, 2xs); 7.30-7.26 (1H, m); 7.16- 87 7.12 (1H, m); .03 (2H, m); 4.82 and 4.65 (2H, 2xs); 4.60 and 4.29 (2H, 2xs); 4.33-4.23 (1H, m); 3.01-2.93 (1H, m); 2.90 (3H, s); 2.44-2.41 (2H, m); .09 (4H, m); 1.87-1.76 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.47 (2H, 2xs); 7.69 and 7.60 (1H, 2xs); 7.30-7.26 (1H, m); 7.16- 88 7.12 (1H, 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 (1H, m); 2.30-2.24 (1H, m); 2.14 -2.03 (6H, m); 1.77- 1.67 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.52 and 8.47 (2H, 2xs); 7.68 and 7.59 (1H, 2xs); 7.30-7.26 (1H, m); 7.16- 89 7.12 (1H, m); 7.06-7.02 (2H, m); 5.93 (1H, t, J = 5.9Hz); 4.82 and 4.64 (2H, 2xs); 4.60 and 4.29 (2H, 2xs); 4.29- 4.23 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 8.43 and 8.39 (2H, 2xs); 7.59 and 7.55 (1H, 2xs); 7.38-7.35 and .12 (2H, 2xm); 7.07-7.02 (2H, m); 5.60-5.45 (1H, m); 5.08- 90 5.04, 4.75-4.71 and 3.98-3.88 (1H, 3xm); 4.60-4.54 (2H, m); .21 (1H, m); 3.32-3.20 (1H, m); 2.48-2.42 (1H, m); 2.25 -2.22 (2H, m); 2.10-2.04 (4H, m); 1.70-1.60 (2H, Ī“ (400 MHz, CDCl3) rotamers present 7.58 and 7.52 (1H, 2xs); 7.38-7.31 (2H, m); 7.26-7.17 (2H, m); 7.12-7.00 (3H, 91 m); 6.53 and 6.13 (1H, 2xddd, J = 47.5, 9.8, 3.2Hz); 5.40, 4.80, 4.63 and 4.58 (2H, 4xd J = ); 4.25-3.92 and 3.34-3.22 (3H, 2xm); 2.49-2.43 (1H, m); 2.26 -2.22 (2H, m); 1.70-1.59 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.47 (2H, 2xs); 7.67 and 7.59 (1H, 2xs); .26 (1H, m); 7.16- 92 7.13 (1H, m); 7.07-7.02 (2H, m); .93 (1H, m); 4.83 and 4.64 (2H, 2xs); 4.61 and 4.29 (2H, 2xs), 3.35-3.27 (1H, m); 2.50-2.25 (4H, m); 2.23-2.09 (1H, m); 2.04-1.95 (1H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.48 (2H, 2xs); 7.71 and 7.62 (1H, 2xs); 7.31-7.26 (1H, m); 7.16- 93 7.13 (1H, m); 7.07-7.02 (2H, m); 4.94-4.78 (2H, m); 4.65 (1H, s); 4.61 and 4.30 (2H, 2xs); 3.08-3.00 (1H, m); 2.58- 2.50 (2H, m); 2.26-2.12 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.73 and 7.57 (1H, 2xs); 7.13 and 7.06 (2H, 2xd, J=7.8 Hz); 4.88 and 4.51 94 (2H, 2xs); 4.24-4.16 (1H, m); 3.52-3.32 (2H, m); 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 2xs); 7.68 and 7.54 (1H, 2xs); 4.94 and 4.74 (2H, 2xs); 95 4.28-4.19 (1H, m); 3.77-3.74 (1H, m); 3.63 (1H, t, J=4.9 Hz); 3.53 (1H, t, J=5.4 Hz); 3.41 (1H, t, J=5.4 Hz); 2.50- 2.42 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.39-7.22 (5H, m); 7.10-7.01 (3H, m); 5.03 and 4.74 (2H, 2xs); 4.32 and 3.85 96 (2H, 2xt, J=13.6 Hz); .16 (1H, m); 2.49-2.42 (1H, m); 2.25-2.23 (2H, m); 2.09-2.04 (4H, m); 1.69-1.59 (2H, Ī“ (400 MHz, DMSO-d6) rotamers present 8.23-8.17 (1H, m); 7.98 and 7.91 (2H, 2xs); 7.87 and 7.84 (1H, 2xs); 7.77- 97 7.75 (1H, m); 7.19-7.13 (1H, m); 7.12-7.08 and 6.93-6.91 (2H, m); 4.84 and 4.72 (2H, 2xs); 4.68 and 4.57 (2H, 2xs); .17 (1H, m); 2.34-2.25 (1H, m); 2.07-2.01 (2H, m); .90 (4H, m); 1.59-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.16 (1H, brs); 7.95-7.85 (3H, m); 7.19-7.13 (1H, m); 7.12-7.08 and 6.94- 98 6.91 (2H, m); 4.84 and 4.72 (2H, 2xs); 4.69 and 4.57 (2H, 2xs); 4.28-4.17 (1H, m); 2.37-2.28 (1H, m); 2.07-2.02 (2H, m); 1.98-1.90 (4H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.17 (1H, brs); 7.81-7.41 (5H, m); 7.17-6.88 (3H, m); 4.88 and 4.83 (2H, 99 2xs); 4.72 and 4.60 (2H, 2xs); 4.25-4.12 (1H, m); 2.30- 2.23 (1H, m); 2.05-2.00 (2H, m); 1.97-1.88 (4H, m); 1.56- 1.46 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.39-7.30 (3H, m); 100 .97 (5H, m); .46 (6H, m); 2.49-2.40 (1H, m); 2.26-2.20 (2H, m); .03 (4H, m); 1.70-1.60 (2H, m); 1.46 and 1.28 (3H, 2xd, J=7.3 Hz) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.52 (2H, 101 2xs); 7.63 and 7.55 (1H, 2xs); 4.74 and 4.44 (2H, 2xs); 4.28-4.17 (1H, m); 3.49 and 3.30 (2H, 2xd, J=6.7 Hz); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); 2.13-1.35 (15H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 2xs); 7.72 and 7.56 (1H, 2xs); 4.86 and 4.54 (2H, 2xs); 102 4.27-4.17 (1H, m); 3.45-3.35 (2H, m); 2.50-2.42 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58-8.47 (3H, m); 7.76-7.47 (2H, m); 7.26-7.11 (2H, m); 4.94 and 4.82 (2H, 103 2xs); 4.71 and 4.65 (2H, 2xs); 4.27-4.18 (1H, m); 2.48- 2.42 (1H, m); 2.25-2.22 (2H, m); 2.09-2.05 (4H, m); 1.71- 1.57 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present .44 (2H, m); 8.54 and 8.49 (2H, 2xs); 7.97-7.93 (1H, m); 7.71 and 7.61 (1H, 104 2xs); 7.52-7.34 (1H, m); 4.89 and 4.68 (2H, 2xs); 4.68 and 4.39 (2H, 2xs); 4.28-4.18 (1H, m); 2.49-2.43 (1H, m); 2.26-2.23 (2H, m); 2.12-2.03 (4H, m); 1.71-1.60 (2H, m) Ī“ (400 MHz, CDCl3) rotamers t 8.53 and 8.47 (2H, 2xs); 7.71 and 7.62 (1H, 2xs); .26 (1H, m); 7.16- 105 7.13 (1H, m); 7.07-7.02 (2H, m); 4.83 and 4.65 (2H, 2xs); 4.62 and 4.30 (2H, 2xs); 4.36-4.28 (1H, m); 2.50-2.46 (2H, m); 2.10-1.88 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.47 (2H, 2xs); 7.92 and 7.80 (1H, 2xs); 7.31-7.26 (1H, m); 7.17- 106 7.14 (1H, m); 7.07-7.03 (2H, m); 4.84 and 4.65 (2H, 2xs); 4.62 and 4.31 (2H, 2xs); 4.49-4.39 (1H, m); 2.43-2.31 (4H, m); 2.11-2.03 (2H, m); 1.84-1.75 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.14 (1H, brs); 7.90-7.53 (4H, m); 7.17-6.86 (3H, m); 4.90 and 4.86 (2H, 107 2xs); 4.72 and 4.60 (2H, 2xs); .12 (1H, m); 2.34- 2.26 (1H, m); 2.05-2.01 (2H, m); .89 (4H, m); 1.58- 1.46 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.15 (1H, brs); 108 7.58-6.70 (7H, m); 4.88-3.62 (6H, m); 2.35-2.29 (1H, m); 2.09-1.86 (6H, m); 1.59-1.45 (2H, m); 1.40 and 1.22 (3H, 2xd, J=7.0 Hz) Ī“ (400 MHz, DMSO-d6) rotamers present 8.62 and 8.53 (2H, 109 2xs); 7.81 and 7.68 (1H, 2xs); 7.21-6.81 (3H, m); 5.32- 3.40 (6H, m); 3.18 and 2.93 (3H, 2xs); 2.34-2.26 (1H, m); 2.08-1.90 (6H, m); 1.60-1.47 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.52 (2H, 2xs); 7.73 and 7.56 (1H, 2xs); 4.89 and 4.63 (2H, 2xs); 110 4.49 and 4.14 (2H, 2xs); 4.32-4.20 (1H, m); 2.50-2.43 (1H, m); 2.27-2.24 (2H, m); 2.14-2.04 (4H, m); 1.72-1.62 (2H, m); 1.20 (9H, s) Ī“ (400 MHz, DMSO-d6) rotamers t 7.73 and 7.63 (1H, 2xs); 7.39-7.30 (1H, m); 7.19-6.85 (3H, m); 6.71 and 6.64 111 (2H, 2xd, J=8.4 Hz); 4.64-4.38 (4H, m); 4.27-4.15 (1H, m); 3.70 and 3.62 (6H, 2xs); .23 (1H, m); 2.09-1.90 (6H, m); 1.58-1.47 (2H, m) Ī“ (400 MHz, CD3OD) rotamers present 7.71 and 7.62 (1H, 112 2xs); 7.12-6.80 (5H, m); 4.76-4.47 (4H, m); 4.34-4.26 (1H, m); 3.82 and 3.74 (3H, 2xs); 2.42-2.35 (1H, m); 2.19-2.03 (6H, m); .56 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.57 and 7.41 (1H, 2xs); .65 (3H, m); 4.70 and 4.50 (2H, 2xs); 4.28- 113 3.95 (3H, m); 2.92-2.84 and .58 (1H, 2xm); 2.47-2.40 (1H, m); 2.24-2.21 (2H, m); 2.09-2.03 (4H, m); 1.85-1.42 (10H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 2xs); 7.68 and 7.54 (1H, 2xs); 5.02 and 4.62 (1H, 2xd, 114 J=19.0 Hz); 4.48 and 4.33 (1H, 2xd, J=19.0 Hz); 4.31-4.19 (1H, m); 3.80 (1H, q, J=7.0 Hz); 2.51-2.42 (1H, m); 2.27- 2.24 (2H, m); 2.12-2.04 (4H, m); 1.72-1.62 (2H, m); 1.30 and 1.22 (3H, 2xd, J=7.0 Hz); 0.99 and 0.88 (9H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 2xs); 7.68 and 7.54 (1H, 2xs); 5.02 and 4.62 (1H, 2xd, 115 J=19.0 Hz); 4.48 and 4.33 (1H, 2xd, J=19.0 Hz); 4.31-4.20 (1H, m); 3.80 (1H, q, J=7.0 Hz); 2.50-2.43 (1H, m); 2.27- 2.23 (2H, m); 2.12-2.04 (4H, m); 1.69-1.63 (2H, m); 1.30 and 1.22 (3H, 2xd, J=7.0 Hz); 0.99 and 0.88 (9H, 2xs) Ī“ (400 MHz, DMSO-d6) rotamers present 8.74 and 8.67 (2H, 2xs); 7.83 and 7.77 (1H, 2xs); 7.40-7.11 (4H, m); 6.80 116 (2H, brs); 4.73 and 4.67 (2H, 2xs); 4.59 and 4.50 (2H, 2xs); 4.15-4.09 (1H, m); 2.56-2.49 (2H, m); 2.14-2.11 (2H, m); 1.76-1.72 (2H, m); 1.48-1.42 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 8.74 and 8.67 (2H, 117 2xs); 7.87 and 7.81 (1H, 2xs); 7.65 (2H, brs); 7.40-7.13 (4H, m); 4.72 and 4.68 (2H, 2xs); 4.59 and 4.51 (2H, 2xs); 4.27-4.21 (1H, m); .07 (4H, m); 1.81-1.78 (4H, m) Ī“ (400 MHz, CD3OD) rotamers present 7.59 (1H, s); 7.38 and 7.33 (2H, 2xd, J=8.0 Hz); 7.17 (1H, t, J =8.0 Hz); 6.83- 118 6.78 (1H, 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 (1H, m); 2.17-1.84 (9H, m); .54 (4H, m); 1.30-1.28 (2H, Ī“ (400 MHz, CDCl3) rotamers present 8.07 and 8.02 (2H, 119 2xs); 7.63 and 7.53 (1H, 2xs); 6.85-6.67 (3H, m); 4.81- 4.21 (5H, m); 3.89 and 3.83 (6H, 2xs); 2.48-2.42 (1H, m); 2.25-2.22 (2H, m); 2.11-2.06 (4H, m); 1.71-1.60 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.81 and 7.79 (1H, 2xs); 7.50 and 7.44 (2H, 2xd, J=8.6 Hz); 7.21-6.83 (3H, 120 m); 4.80 and 4.52 (2H, 2xs); 4.27-4.15 (1H, m); 3.62-2.89 (4H, m); 2.34-2.24 (1H, m); 2.07-1.88 (6H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 9.33-8.95 (2H, m); 121 8.81-8.64 (2H, m); 8.11 and 7.91 (1H, 2xs); 5.32-4.59 (4H, m); .18 (1H, m); 3.67-3.25 (3H, m); 2.87-2.79 (1H, m); 2.34-2.28 (1H, m); 2.05-1.43 (13H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 11.61 (1H, brs); 7.79 and 7.75 (1H, 2xs); 7.16-7.07 (2H, m); 6.89 (1H, d, J=6.4 122 Hz); 6.04 and 5.97 (1H, 2xs); 4.67 and 4.62 (2H, 2xs); 4.59 and 4.58 (2H, 2xs); 4.24-4.13 (1H, m); 2.26-2.18 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 123 2xs); 7.70 and 7.56 (1H, 2xs); 4.84 and 4.50 (2H, 2xs); 4.29-4.19 (1H, m); 3.40-3.12 (2H, m); 2.49-2.42 (1H, m); 2.26-2.23 (2H, m); 2.13-1.94 (6H, m); 1.74-1.36 (15H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.93-7.68 (4H, m); 124 .90 (3H, m); 4.88-4.14 (5H, m); 2.34-2.26 (1H, m); 2.09-1.88 (6H, m); .49 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57-8.50 (2H, m); 125 7.65-7.53 (1H, m); 4.72-4.42 (2H, m); 4.30-4.18 (1H, m); 3.78-3.32 (2H, m); 2.51-1.19 (15H, m); 0.82-0.69 (9H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57-8.50 (2H, m); 126 .53 (1H, m); 4.73-4.42 (2H, m); 4.30-4.19 (1H, m); 3.78-3.32 (2H, m); 2.48-1.19 (15H, m); 0.82-0.69 (9H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.16 (1H, brs); 127 7.86-7.74 (3H, m); 7.19-6.91 (3H, m); .56 (4H, m); .17 (1H, m); 2.35-2.27 (1H, m); 2.07-1.92 (6H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.54 and 8.48 (2H, 2xs); 7.73 and 7.63 (1H, 2xs); 7.31-7.26 (1H, m); 7.14- 129 7.03 (3H, m); 4.83 and 4.65 (2H, 2xs); 4.62 and 4.31 (2H, 2xs); .23 (1H, m); 2.60-2.41 (4H, m); 2.17-2.01 (4H, Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.51 (2H, 2xs); 7.66 and 7.54 (1H, 2xs); 4.83-4.45 (2H, m); 4.29- 130 4.17 (1H, m); 3.73-3.21 (4H, m); 2.50-2.41 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.60-8.50 (2H, m); 131 7.65-7.54 (1H, m); 4.80-4.46 (2H, m); 4.31-3.99 (2H, m); 2.51-2.43 (1H, m); 2.27-1.93 (9H, m); 1.81-1.56 (4H, m); 0.89-0.76 (9H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.60-8.50 (2H, m); 132 .54 (1H, m); 4.86-4.46 (2H, m); 4.31-3.98 (2H, m); 2.50-2.44 (1H, m); 2.27-1.99 (9H, m); 1.82-1.62 (4H, m); 0.89-0.76 (9H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.98 and 8.93 (1H, 133 2xs); 7.66 and 7.63 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 8.37 and 8.31 (1H, 2xd, J=5.1 Hz); 7.89 and 7.81 (1H, 2xs); 7.18-6.92 (4H, 134 m); 4.75-4.61 (4H, m); 4.27-4.14 (1H, m); 2.37 and 2.22 (3H, 2xs); 2.33-2.25 (1H, m); 2.06-1.87 (6H, m); 1.89 and 1.73 (3H, 2xs); 1.58-1.46 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.52 (2H, s); 7.62 (1H, 135 s); 6.86-6.74 (3H, m); 4.79 (2H, s); 4.67 and 4.49 (2H, 2xs); 4.35-4.30 (1H, m); 2.47-2.41 (1H, m); 2.26-2.23 (2H, m); 2.07-1.93 (4H, m); 1.72-1.62 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers t .72 (4H, m); 136 7.17-6.87 (3H, m); 4.88-4.62 (4H, m); 4.26-4.12 (1H, m); 2.33-2.24 (1H, m); 2.05-1.89 (6H, m); 1.57-1.47 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.85 and 7.83 (1H, 137 2xs); 7.42 and 7.25 (2H, 2xd, J=0.7 Hz); 7.18-6.90 (3H, m); 4.79-4.55 (4H, m); 4.27-4.16 (1H, m); 2.34-2.28 (4H, m); 2.07-1.90 (6H, m); 1.59-1.48 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.57 and 7.55 (1H, 2xs); 7.35-7.18 (3H, m); 6.92 and 6.65 (2H, 2xd, J=5.7 138 Hz); 6.78-6.72 (1H, m); 6.61-6.46 and 6.19-6.04 (1H, 2xm); .01-4.62 (2H, m); 4.27-4.15 (2H, m); 4.02-3.93 and 3.39- 3.26 (1H, 2xm); 2.28-2.18 (2H, m); 1.96-1.90 (6H, m); 1.42 and 1.39 (3H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 7.57 and 7.55 (1H, 2xs); 7.35-7.18 (3H, m); 6.92 and 6.65 (2H, 2xd, J=6.1 139 Hz); 6.78-6.72 (1H, m); 6.61-6.46 and 6.19-6.04 (1H, 2xm); .01-4.62 (2H, m); 4.27-4.15 (2H, m); 4.02-3.93 and 3.39- 3.26 (1H, 2xm); 2.26-2.19 (2H, m); 1.96-1.90 (6H, m); 1.42 and 1.39 (3H, 2xs) Ī“ (400 MHz, DMSO-d6) rotamers present 9.45 (1H, brs); 8.74 and 8.68 (2H, 2xs); 7.86 and 7.74 (1H, 2xs); 7.13 and 6.98 141 (2H, 2xd, J=8.5 Hz); 6.75-6.69 (2H, m); 4.66 and 4.58 (2H, 2xs); 4.50 and 4.39 (2H, 2xs); 4.27-4.19 (1H, m); 2.34- 2.27 (1H, m); 2.07-1.90 (6H, m); .48 (2H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.16 (1H, brs); 7.82-7.79 and 7.52-7.50 (1H, 2xm); 7.75 and 7.50 (1H, 142 2xs); 7.30-6.87 (6H, m); 6.80-6.74 (1H, m); 6.57-6.52 and 6.45-6.41 (1H, 2xm); 4.98 and 4.76 (2H, 2xs); 4.66 and 4.55 (2H, 2xs); 4.21-4.12 (1H, 2xm); 2.33-2.19 (1H, m); 2.05-1.77 (6H, m); .42 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.16 (1H, brs); 7.75 and 7.48 (1H, 2xs); 7.62 and 7.32 (1H, 2xs); 7.16-6.86 143 (6H, m); 6.73-6.67 (1H, m); 4.97 and 4.75 (2H, 2xs); 4.65 and 4.55 (2H, 2xs); 4.22-4.11 (1H, m); .22 (1H, m); 2.19 and 2.09 (3H, 2xs); 2.05-1.78 (6H, m); 1.56-1.42 (2H, Ī“ (400 MHz, CDCl3) rotamers present 7.69-7.52 (3H, m); 4.97 144 and 4.73 (2H, 2xs); .18 (1H, m); .40 (4H, m); 2.49-2.43 (1H, 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) Ī“ (400 MHz, CDCl3) rs present 8.36 (1H, s); 8.18 (1H, 145 s); 7.63 (1H, s) , 7.26-7.06 (4H, m); 4.76-4.54 (4H, m); 4.30-4.25 (1H, m); 2.49-2.42 (1H, m); 2.26-2.23 (2H, m); 2.12-2.05 (4H, m); 1.68-1.58 (2H, m) Ī“ (400 MHz, DMSO-d6) rs present 9.11 and 9.08 (1H, 2xs); 8.82 and 8.60 (2H, 2xs); 7.94 and 7.88 (1H, 2xs); 146 7.59-7.46 (3H, m); 4.87 and 4.78 (2H, 2xs); 4.74 and 4.61 (2H, 2xs); 4.26-4.19 (1H, m); 2.35-2.27 (1H, m); 2.07-1.88 (6H, m); 1.59-1.48 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.17 (1H, brs); 9.68 (1H, brs); 8.74 and 8.68 (2H, 2xs); 7.76 and 7.75 (1H, 147 2xs); 7.20-7.08 and 6.92-6.71 (4H, m); .45 (4H, m); 4.27-4.19 (1H, m); 2.34-2.26 (1H, m); 2.07-1.90 (6H, m); 1.59-1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.11 (1H, brs); 8.75 and 8.70 (2H, 2xs); 7.36 and 7.26 (1H, 2xs); 7.20-7.14 148 (1H, m); 7.08-7.06 and 6.98-6.95 (2H, 2xm); 5.00-4.50 (4H, m); 4.37-4.31 (1H, m); .24 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.69-7.52 (3H, m); 4.97 149 and 4.74 (2H, 2xs); 4.29-4.19 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 8.59 and 8.52 (2H, 2xs); 7.64 and 7.52 (1H, 2xs); 4.94 and 4.57 (2H, 2xs); 150 4.28-4.19 (1H, m); 3.84 and 3.73 (2H, 2xs); 2.49-2.43 (1H, m); 2.26-2.23 (2H, m); .03 (4H, m); 1.73-1.60 (2H, m); 1.10-1.06 (4H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.12 (1H, brs); 9.26-9.25 and 9.05-9.04 (1H, 2xm); 9.21-9.20 and 9.16-9.15 151 (1H, 2xm); 7.92 and 7.85 (1H, 2xs); 7.66-7.46 (4H, m); 4.85 and 4.78 (2H, 2xs); 4.75 and 4.63 (2H, 2xs); 4.28- 4.17 (1H, m); 2.33-2.26 (1H, m); .02 (2H, m); 1.97- 1.90 (4H, m); 1.59-1.48 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.18 (1H, brs); 9.09-8.98 (1H, m); 8.68-8.63 (1H, m); 7.75 and 7.70 (1H, 152 2xs); 7.18-7.10 (1H, m); 7.08-7.06 (1H, m); 6.94-6.91 (1H, m); 5.02 and 4.96 (2H, 2xs); 4.73 and 4.60 (2H, 2xs); 4.24-4.13 (1H, m); 2.33-2.22 (1H, m); 2.05-1.99 (2H, m); 1.94-1.86 (4H, m); 1.56-1.45 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.07 (1H, brs); 9.50 (1H, brs); 8.74 and 8.68 (2H, 2xs); 7.82 and 7.75 (1H, 153 2xs); 7.17-7.10 (1H, m); 6.79-6.58 (3H, m); 4.70 and 4.61 (2H, 2xs); 4.53 and 4.43 (2H, 2xs); 4.28-4.21 (1H, m); 2.35-2.26 (1H, m); 2.07-2.03 (2H, m); 1.98-1.91 (4H, m); 1.60-1.48 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.50 (2H, 2xs); 7.65 and 7.54 (1H, 2xs); 4.83 and 4.54 (2H, 2xs); 155 .46 and 3.75-3.68 (1H, 2xm); 4.30-4.21 (1H, m); 3.96-3.87 (1H, 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) Ī“ (400 MHz, 6) rotamers present 12.40 (1H, brs); 8.77 and 8.70 (2H, 2xs); 7.84 and 7.80 (1H, 2xs); 7.19-7.08 and 156 6.92-6.90 (3H, m); 4.85-4.56 (4H, m); 4.27-4.14 (1H, m); 2.20-2.17 (2H, m); .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 Ī“ (400 MHz, DMSO-d6) rs present 12.15 (1H, brs); 8.81 157 and 8.74 (2H, 2xs); 7.85-7.74 (2H, m); 4.95-4.76 (2H, m); 4.26-4.19 (1H, m); 3.88-3.25 (3H, m); 2.34-1.73 (11H, m); .49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.17 (1H, brs); 8.81 158 and 8.74 (2H, 2xs); 7.85-7.74 (2H, m); 4.93-4.76 (2H, m); 4.26-4.19 (1H, m); 3.86-3.25 (3H, m); 2.35-1.73 (11H, m); 1.59-1.49 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.55 and 8.52 (2H, 159 2xs); 7.56 and 7.43 (1H, 2xs); 6.86-6.77 (3H, m); 4.91- 4.67 (6H, m); 4.32-4.23 (1H, m); 2.48-2.42 (1H, m); 2.25- 2.22 (2H, m); 2.07-1.99 (4H, m); 1.72-1.61 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.55 and 8.48 (2H, 2xs); 7.64 and 7.56 (1H, 2xs); 5.09 and 4.80 (2H, 2xs); 160 4.28-4.18 (1H, m); 3.96 and 3.75 (2H, 2xs); 2.50-2.42 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.48 (2H, 2xs); 7.67 and 7.59 (1H, 2xs); 7.19-7.13 (3H, m); 6.73 161 (2H, d, J=6.8 Hz); 4.93 and 4.72 (2H, 2xd, J=18.8 Hz); 4.12-4.04 (1H, m); 3.50 (1H, brs); 3.18-3.14 (1H, m); 2.43-2.37 (1H, m); 2.21-2.07 (4H, m); 1.92-1.52 (4H, m); 1.35-1.30 (1H, m); 1.14-1.09 (1H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.50 (2H, brs); 7.43 (1H, s); 6.90-6.72 (3H, m); 4.79-4.72 (2H, m); 4.68 and 162 4.59 (2H, 2xs); 4.15-4.08 (1H, m); 3.35-3.25 (1H, m); 2.50-2.43 (1H, m); 2.25-2.22 (2H, m); .90 (6H, m); 1.40-1.38 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.17 (1H, brs); 8.71 164 (2H, s); 7.57-6.99 (4H, m); 5.00-4.68 (4H, m); 4.20-4.12 (1H, m); 2.38-2.21 (4H, m); 2.02-1.95 (2H, m); .80 (4H, m); 1.59-1.48 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 12.16 (1H, brs); 9.12 (1H, s); 8.78 and 8.72 (2H, 2xs); 7.86 and 7.77 (1H, 2xs); 165 4.97 and 4.84 (2H, 2xs); 4.77 and 4.74 (2H, 2xs); 4.25- 4.18 (1H, m); 2.28-2.22 (1H, m); 2.05-1.90 (6H, m); 1.57- 1.48 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.52 and 8.47 (2H, 2xs); 7.63 and 7.54 (1H, 2xs); 7.30-7.26 (1H, m); 7.16- 166 7.13 (1H, 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); .04 (6H, Ī“ (400 MHz, DMSO-d6) rotamers present 12.19 (1H, brs); 8.77 167 and 8.71 (2H, 2xs); 7.88 and 7.80 (1H, 2xs); 7.62 and 7.54 (1H, 2xs); 4.80-4.52 (4H, m); 4.28-4.20 (1H, m); 2.34-2.28 (1H, m); 2.07-1.92 (6H, m); .49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.25 (1H, brs); 8.78 168 and 8.71 (2H, 2xs); 7.81-7.77 (2H, m); 5.03-4.81 (4H, m); 4.26-4.19 (1H, m); 2.32-2.24 (1H, m); 2.06-1.93 (6H, m); 1.57-1.48 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 169 2xs); 7.65 and 7.55 (1H, 2xs); .18 (4H, m); 2.51- 2.42 (1H, m); 2.27-2.24 (2H, m); 2.15-2.03 (4H, m); 1.73- 1.42 (9H, m); 1.14-1.07 (1H, m); 0.94-0.87 (6H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.10 (1H, brs); 8.76 and 8.69 (2H, 2xs); 7.87-7.52 (5H, m); 4.84 and 4.75 (2H, 170 2xs); 4.72 and 4.60 (2H, 2xs); 4.28-4.17 (1H, m); 2.36- 2.26 (1H, m); 2.07-2.02 (2H, m); 1.98-1.91 (4H, m); 1.60- 1.49 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.14 (1H, brs); 8.75 and 8.69 (2H, 2xs); 7.87-7.80 (3H, m); 7.56 and 7.41 (2H, 171 2xd, J=8.3 Hz); 4.80 and 4.78 (2H, 2xs); 4.69 and 4.63 (2H, 2xs); 4.28-4.18 (1H, m); 2.36-2.26 (1H, m); .02 (2H, m); 1.98-1.90 (4H, m); 1.60-1.49 (2H, m) Ī“ (400 MHz, CDCl3) rs present 8.61 and 8.53 (2H, 2xs); 7.66 and 7.57 (1H, 2xs); 5.03-4.93 (1H, m); 4.80- 172 4.72 (1H, m); 4.63-3.99 (6H, m); 2.51-2.43 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.61 and 8.52 (2H, 173 2xs); 7.65 and 7.57 (1H, 2xs); 5.00-4.19 (8H, m); 2.50- 2.43 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); 7.65 and 7.55 (1H, 2xs); 4.62 and 4.42 (2H, 2xs); 174 .18 (1H, m); 3.55-3.50 (1H, m); .41 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.51 (2H, 175 2xs); 7.67 and 7.56 (1H, 2xs); 4.86-4.78 and 3.74-3.66 (1H, 2xm); 4.63 and 4.43 (2H, 2xs); 4.32-4.17 (1H, m); 2.53-2.42 (1H, m); 2.28-1.59 (16H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.53 and 8.47 (2H, 2xs); 7.64 and 7.55 (1H, 2xs); 7.32-7.26 (1H, m); 7.17- 177 7.13 (1H, m); 7.07-7.02 (2H, m); 4.83 and 4.64 (2H, 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) Ī“ (400 MHz, CDCl3) rotamers t 8.56-8.51 (2H, m); 7.56-7.46 (1H, m); 7.12-6.76 (4H, m); 4.82-4.78 (2H, m); 178 4.67-4.57 (2H, m); 4.53-4.38 (1H, m); 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) Ī“ (400 MHz, DMSO-d6) rs present 12.16 (1H, brs); 7.79 and 7.78 (1H, 2xs); 7.56-7.45 (2H, m); .88 (3H, m); 179 4.78 and 4.73 (2H, 2xs); 4.69 and 4.56 (2H, 2xs); 4.26- 4.14 (1H, m); 2.33-2.26 (1H, m); 2.09-1.90 (6H, m); 1.58- 1.46 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.50 and 8.42 (2H, 2xs); 7.72 and 7.58 (1H, 2xs); 7.23-7.15 (4H, m); 5.62- 180 5.54 and 4.80-4.72 (1H, 2xm); 4.58 and 4.42 (2H, 2xs); 4.31-4.23 (1H, m); 3.42-3.02 (m, 4H); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); 2.14-2.03 (4H, m); 1.71-1.61 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.51 (2H, 2xs); 7.66 and 7.56 (1H, 2xs); 4.99-4.91 and 3.84-3.76 181 (1H, 2xm); 4.65 and 4.45 (2H, 2xs); 4.33-4.17 (1H, m); 4.08-3.98 (2H, m); 3.59-3.53 and .22 (2H, 2xm); 2.52-2.41 (1H, m); 2.28-2.22 (2H, m); 2.16-2.03 (4H, m); 1.82-1.59 (6H, m) Ī“ (400 MHz, CDCl3) rs present 8.58 and 8.50 (2H, 2xs); 7.66 and 7.56 (1H, 2xs); 4.76-4.67 and 3.62-3.56 182 (1H, 2xm); 4.67 and 4.46 (2H, 2xs); 4.31-4.19 (1H, m); .42 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); 7.66 and 7.55 (1H, 2xs); 5.23-5.14 and 4.31-4.18 183 (2H, m); 4.65-4.42 (2H, m); 2.51-2.43 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 8.58 and 8.50 (2H, 185 2xs); 7.66 and 7.56 (1H, 2xs); 5.01-4.95 and 4.17-4.09 (1H, 2xm); 4.58 and 4.42 (2H, 2xs); 4.30-4.17 (1H, m); 2.51-2.42 (1H, m); 2.27-2.23 (2H, m); 2.14-1.50 (14H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 187 2xs); 7.65 and 7.56 (1H, 2xs); 4.95-4.17 and 3.57-3.50 (4H, m); .43 (1H, m); 2.27-2.24 (2H, m); 2.15-2.03 (4H, m); 1.94-0.98 (14H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.65 and 7.55 (1H, 2xs); 7.39 and 7.31 (2H, 2xs); 4.66 and 4.42 (2H, 2xs); 189 4.61-4.52 and 3.49-3.43 (1H, 2xm); 4.31-4.14 (1H, m); 2.51-2.42 (1H, m); 2.27-2.22 (2H, m); 2.15-2.02 (4H, m); 1.72-1.40 (9H, m); 1.13-1.05 (1H, m); .87 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.67 and 7.56 (1H, 2xs); 7.14 and 7.06 (2H, 2xd, J=8.1 Hz); 4.67 and 4.43 190 (2H, 2xs); 4.61-4.53 and 3.52-3.44 (1H, 2xm); 4.30-4.15 (1H, m); 2.29-2.14 (2H, m); 1.99-1.85 (6H, m); 1.65-1.39 (10H, m); .06 (1H, m); 0.94-0.87 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.66 and 7.56 (1H, 2xs); 7.39 and 7.31 (2H, 2xs); 4.66 and 4.43 (2H, 2xs); 191 4.61-4.53 and 3.52-3.44 (1H, 2xm); 4.30-4.15 (1H, m); 2.29-2.14 (2H, m); .86 (6H, m); 1.65-1.40 (10H, m); 1.13-1.02 (1H, m); 0.94-0.87 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 192 2xs); 7.66 and 7.55 (1H, 2xs); 4.81 and 4.47 (2H, 2xs); 4.28-4.17 (1H, m); 3.71-3.59 (2H, m); 2.50-2.42 (1H, m); 2.26-2.23 (2H, m); .03 (4H, m); 1.72-1.06 (15H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.52 (1H, 193 2xs); 7.14-7.05 (2H, m); 4.82 and 4.45 (2H, 2xs); 4.27- 4.17 (1H, m); 3.70-3.57 (2H, m); 2.46-2.42 (1H, m); 2.25- 2.22 (2H, m); 2.12-2.02 (4H, m); 1.78-1.05 (15H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 194 2xs); 7.67 and 7.56 (1H, 2xs); 5.00 and 4.69 (2H, 2xs); 4.29-4.19 (1H, m); 3.98-3.70 (2H, m); 2.50-2.42 (1H, m); 2.27-2.23 (2H, m); .03 (4H, m); 1.94-1.52 (10H, m) Ī“ (400 MHz, CDCl3) 12.80 (1H, brs); 7.52 (1H, s); 7.33 (1H, d, J=7.1 Hz); 7.26-7.23 (2H, m); 7.03-7.00 (2H, m); 6.46 195 (1H, d, J=7.1 Hz); 4.79 (2H, s); 4.43 (2H, s); 4.26-4.19 (1H, m); .32 (1H, m); 2.23-2.19 (2H, m); 2.14-2.09 (4H, m); 1.60-1.53 (2H, m) Ī“ (400 MHz, DMSO- d6) 8.80 and 8.73 (2H, 2xs); 7.72 and 7.59 (1H, 2xs); 7.37-7.04 (1H, m); 4.78 (2H, s); .24 196 and 3.72-3.64 (2H, m); 2.21-2.15 (2H, m); 2.04-1.91 (2H, m); 1.83-1.23 (11H, m); 1.15-1.10 (4H, m); 0.91-0.84 (6H, Ī“ (400 MHz, CDCl3) rotamers present 7.57-6.77 (7H, m); 197 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); 7.67 and 7.55 (1H, 2xs); 5.38-5.33 and 4.52-4.47 198 (1H, 2xm); 4.73 and 4.58 (2H, 2xs); 4.31-4.17 (1H, m); 4.10-4.03 (1H, m); 3.91-3.84 (1H, m); 3.79-3.52 (2H, m); 2.51-2.43 (1H, m); 2.28-1.91 (6H, m); 1.73-1.59 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.53 (1H, 199 2xs); 7.12 and 7.05 (2H, 2xd, J=8.0 Hz); 5.09-4.99 and .15 (4H, m); .89 (10H, m); 1.42 and 1.39 (3H, 2xs); 1.30-1.24 (2H, m); 1.07-0.96 (8H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.51 (2H, 2xs); 7.67 and 7.54 (1H, 2xs); 4.73 and 4.43 (2H, 2xs); 200 .16 (1H, m); 3.79 and 3.59 (2H, 2xd, J=7.7 Hz); 2.85-2.77 and 2.64-2.57 (1H, 2xm); 2.51-2.42 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 7.63 and 7.44 (1H, 2xs); 6.82-6.69 (3H, m); 4.78 and 4.75 (2H, 2xs); 4.57 and 201 4.41 (2H, 2xs); 4.28-4.19 (1H, m); 3.85 and 3.83 (3H, 2xs); 2.49-2.38 (1H, m); 2.24-2.21 (2H, m); 2.09-1.97 (4H, m); 1.69-1.59 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.69 and 7.55 (1H, 2xs); 7.14-7.06 (2H, m); 4.75 and 4.41 (2H, 2xs); 4.30- 202 4.16 (1H, m); 3.79 and 3.58 (2H, 2xd, J=7.6 Hz); 2.86-2.78 and 2.65-2.57 (1H, 2xm); 2.54-2.12 (4H, m); 2.05-1.84 (7H, m); 1.66-1.58 (1H, m); 1.42 and 1.40 (3H, 2xs); 0.42-0.16 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); .55 (1H, 2xs); 5.01-4.94 and .88 (1H, 204 2xm); 4.78-4.73 and 4.39-4.15 (3H, m); 2.55-2.40 (2H, 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 (3H, m); 0.43-0.22 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); 7.65 and 7.55 (1H, 2xs); 4.88-4.81 and 3.76-3.69 205 (1H, 2xm); 4.65-4.40 (2H, m); 4.30-4.20 (1H, m); 2.51-2.44 (1H, m); 2.27-2.24 (2H, m); .04 (4H, m); 1.87-0.65 (16H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.74 and 7.58 (1H, 2xs); 7.17 and 7.10 (2H, 2xs); 4.91 and 4.60 (2H, 2xs); 206 4.48 and 4.13 (2H, 2xs); 4.31-4.18 (1H, m); 2.37 and 2.33 (3H, 2xs); .17 (2H, m); 1.97-1.83 (6H, m); 1.41 and 1.40 (3H, 2xs); 1.20 and 1.19 (9H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 7.73 and 7.57 (1H, 2xs); 7.39 and 7.32 (2H, 2xs); 4.90 and 4.60 (2H, 2xs); 207 4.48 and 4.13 (2H, 2xs); 4.31-4.18 (1H, m); 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 208 2xs); 7.65 and 7.54 (1H, 2xs); 4.70-4.47 (3H, m); 4.31- 4.18 (1H, m); 4.07-3.76 (2H, m); 2.51-2.45 (1H, m); 2.28- 2.05 (7H, m); 1.75-1.62 (3H, m); 1.36-1.13 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.51 (2H, 210 2xs); 7.65 and 7.55 (1H, 2xs); 4.77-4.19 (4H, m); 2.48- 1.89 (13H, m); .39 (5H, m) (cis-, trans- mixture in AreaB) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.51 (2H, 2xs); 7.63 and 7.53 (1H, 2xs); 5.13-5.05 and .11 211 (1H, 2xm); 4.60 and 4.43 (2H, 2xs); 4.29-4.21 (1H, m); 2.50-2.43 (1H, m); 2.26-2.23 (2H, m); 2.11-2.02 (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) Ī“ (400 MHz, CDCl3) rs present 8.58 and 8.49 (2H, 212 2xs); 7.66 and 7.55 (1H, 2xs); 4.81-4.75 and 3.65-3.56 (1H, 2xm); 4.63 and 4.42 (2H, 2xs); 4.31-4.16 (1H, m); 2.51-2.03 (8H, m); 1.84-1.43 (10H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.51 (2H, 2xs); 7.65 and 7.55 (1H, 2xs); 4.60 and 4.41 (2H, 2xs); 213 4.60-4.54 and 3.62-3.55 (1H, 2xm); 4.32-4.16 (1H, m); 2.52-2.42 (1H, m); 2.28-2.24 (2H, m); 2.18-1.91 (6H, m); 1.73-1.21 (9H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.70 and 7.55 (1H, 2xs); 7.34-7.23 (1H, m); 7.03-6.79 (2H, m); 4.86 and 4.54 214 (2H, 2xs); 4.45 and 4.10 (2H, 2xs); 4.27-4.23 (1H, 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) Ī“ (400 MHz, DMSO-d6) 12.22 (1H, brs); 8.79-8.60 (2H, m); 7.85-7..69 (1H, m); 5.19-4.78 (2H, m); 4.50-4.39 and 4.09- 215 4.02 (1H, 2xm); 4.27-4.18 (1H, m); 2.67-2.57 (1H, m); 2.33-2.26 (1H, m); 2.23-2.19 (1H, m); 2.07-1.90 (6H, m); 1.59-1.16 (10H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.61 and 7.50 (1H, 216 2xs); .71 (3H, m); 4.80 and 4.73 (2H, 2xs); 4.60 and 4.48 (2H, 2xs); 4.29-4.19 (1H, m); 2.49-2.42 (1H, m); 2.25-2.22 (2H, m); 2.10-2.02 (4H, m); 1.70-1.59 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.75-7.49 (4H, m); 4.98 217 and 4.66 (2H, 2xs); 4.47 and 4.13 (2H, 2xs); 4.31-4.20 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 7.74 and 7.58 (1H, 2xs); 7.14 and 7.07 (2H, 2xd, J=8.0 Hz); 4.90 and 4.61 218 (2H, 2xs); 4.48 and 4.14 (2H, 2xs); 4.31-4.19 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 7.68 and 7.53 (1H, 219 2xs); 7.38 and 7.30 (2H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.65 and 7.56 (1H, 2xs); 7.13 and 7.07 (2H, 2xd, J=8.1 Hz); 4.77 and 4.42 220 (2H, 2xs); 4.29-4.17 (1H, m); 3.50-3.47 and 3.26-3.25 (2H, 2xm); 2.28-2.14 (2H, m); 1.96-1.85 (6H, m); 1.57-1.05 (11H, m); 0.96-0.78 (7H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.73 and 7.57 (1H, 2xs); 7.38 and 7.31 (2H, 2xs); 4.87 and 4.50 (2H, 2xs); 221 .15 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 7.69-7.49 (4H, m); 222 4.61-4.15 (4H, m); 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, Ī“ (400 MHz, CDCl3) rotamers present 7.69 and 7.57 (1H, 224 2xs); 7.12 and 7.05 (2H, 2xd, J=8.0 Hz); 5.01 and 4.67 (2H, 2xs); 4.25-4.17 (1H, m); 4.07-3.70 (2H, m); 2.25-2.15 (2H, m); .71 (14H, m); 1.41 and 1.40 (3H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.56 (1H, 225 2xs); 7.37 and 7.30 (2H, 2xs); 5.01 and 4.66 (2H, 2xs); 4.25-4.17 (1H, 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) Ī“ (400 MHz, CD3CN) rotamers present 7.55 and 7.46 (1H, 2xs); 7.20 and 7.12 (2H, 2xs); 4.91 and 4.67 (2H, 2xs); 226 4.22-4.16 (1H, m); 3.80 and 3.62 (2H, 2xs); 2.26 and 2.21 (3H, 2xs); 1.82-1.33 (16H, m); 1.27 and 1.25 (3H, 2xs); 1.23 and 1.21 (3H, 2xs) Ī“ (400 MHz, CD3OD) rotamers present 7.76 and 7.59 (1H, 2xs); 7.33 and 7.25 (2H, 2xs); 4.75 and 4.63 (2H, 2xs); 227 .28 (1H, m); 4.30-4.23 and 3.52-3.47 (1H, 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 (1H, m); 0.95-0.86 (6H, Ī“ (400 MHz, DMSO-d6) rotamers present 12.07 (1H, brs); 8.72 and 8.61 (2H, 2xs); 7.66 and 7.63 (1H, 2xs); 7.38-7.17 228 (4H, m); 4.73-4.67 (4H, m); 4.43-4.36 (1H, m); 4.26-4.08 (2H, m); 2.33-2.25 (1H, m); 2.03-1.76 (6H, m); 1.61-1.51 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.50 (2H, 2xs); 7.66 and 7.56 (1H, 2xs); 4.66 and 4.45 (2H, 2xs); 229 4.64-4.56 and .46 (1H, 2xm); 4.31-4.17 (1H, m); 2.29-2.16 (2H, m); 1.99-1.86 (6H, m); 1.63-1.27 (10H, m); 1.15-1.07 (1H, m); 0.95-0.88 (6H, m) Ī“ (400 MHz, CDCl3) rotamers t 7.59 and 7.50 (1H, 2xs); 7.14 and 7.06 (2H, 2xd, J=8.0 Hz); 4.65 and 4.40 230 (2H, 2xs); 4.61-4.53 and .38 (1H, 2xm); 2.33-2.18 (6H, m); 2.09-2.03 (6H, m); 1.64-1.39 (7H, m); 1.12-1.02 (1H, m); 0.93-0.86 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.59 and 7.50 (1H, 2xs); 7.39 and 7.31 (2H, 2xs); 4.64 and 4.39 (2H, 2xs); 231 4.61-4.53 and 3.46-3.38 (1H, 2xm); 2.33-2.21 (6H, m); 2.09-2.02 (6H, m); 1.63-1.39 (7H, m); 1.12-1.04 (1H, m); 0.93-0.86 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.55 (1H, 2xs); 7.38 and 7.32 (2H, 2xs); 4.74 and 4.41 (2H, 2xs); 234 4.30-4.16 (1H, m); 3.78 and 3.58 (2H, 2xd, J=7.8 Hz); 2.85-2.78 and .57 (1H, 2xm); 2.28-2.12 (4H, m); 2.02-1.85 (7H, m); 1.66-1.61 (1H, m); 1.42 and 1.39 (3H, 2xs); 0.43-0.16 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.71-7.48 (4H, m); 4.84 and 4.49 (2H, 2xs); 4.31-4.17 (1H, m); 3.83-3.59 (2H, m); 235 2.86-2.78 and 2.62-2.55 (1H, 2xm); 2.28-2.10 (4H, m); 2.01-1.87 (7H, m); 1.64-1.59 (1H, m); 1.42 and 1.41 (3H, 2xs); 0.43-0.16 (4H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.30 (1H, brs); 7.77 and 7.54 (1H, 2xs); 7.45 and 7.38 (2H, 2xs); 4.68 and 4.58 236 (2H, 2xs); 4.32-4.26 (1H, m); 2.36 and 2.30 (3H, 2xs); .18 (2H, m); 2.14-2.10 (4H, m); 1.94-1.88 (6H, m); 1.72-1.59 (2H, m); .24 (m, 5H); 1.00-0.92 (1H, m); 0.98-0.80 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 12.25 (1H, brs); 7.76 and 7.54 (1H, 2xs); 7.44 and 7.38 (2H, 2xs); 4.70 and 4.50 237 (2H, 2xs); 3.50-3.25 (2H, m); 2.59-2.53 and 2.45-2.37 (1H, 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); .87 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.66 and 7.55 (1H, 2xs); 7.16 and 7.09 (2H, 2xs); 4.74 and 4.38 (2H, 2xs); 238 4.31-4.15 (1H, m); 3.65 and 3.40 (2H, 2xd, J=7.1 Hz); .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) Ī“ (400 MHz, CDCl3) rotamers present 7.65 and 7.56 (1H, 2xs); 7.38 and 7.31 (2H, 2xs); 4.77 and 4.41 (2H, 2xs); 239 4.30-4.16 (1H, 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 (11H, m); 0.96-0.78 (7H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.61 and 7.46 (1H, 2xs); 7.12 and 7.05 (2H, 2xd, J=7.6 Hz); 5.09-4.99 and 240 4.31-4.21 (1H, 2xm); 4.57 and 4.35 (2H, 2xs); 2.34-2.21 (6H, m); 2.09-2.03 (6H, m); 1.94-1.87 and 1.40-1.33 (2H, m); .22 (2H, m); 1.09-0.95 (8H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.60 and 7.46 (1H, 2xs); 7.37 and 7.30 (2H, 2xs); 5.08-4.99 and 4.30-4.21 241 (1H, 2xm); 4.56 and 4.35 (2H, 2xs); 2.33-2.20 (6H, m); 2.09-2.02 (6H, m); 1.93-1.86 and .33 (2H, m); 1.28- 1.21 (2H, m); 1.10-0.95 (8H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.68-7.47 (4H, m); 4.71 242 and 4.48 (2H, 2xs); 4.31-4.22 and 3.46-3.39 (1H, 2xm); 2.33-2.24 (6H, m); 2.11-2.03 (6H, m); 1.87-1.77 (1H, m); 1.67-1.34 (6H, m); 1.11-1.03 (1H, m); 0.93-0.86 (6H, m) Ī“ (400 MHz, CDCl3) rs present 7.61 and 7.52 (1H, 2xs); .23 (1H, m); 7.04-6.80 (2H, m); 4.64 and 4.33 243 (2H, 2xs); 4.63-4.56 and 3.43-3.35 (1H, 2xm); 3.86 and 3.76 (3H, 2xs); 2.33-2.22 (6H, m); .02 (6H, m); 1.62-1.38 (7H, m); 1.11-1.04 (1H, m); 0.94-0.86 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.66 and 7.57 (1H, 244 2xs); 7.11 and 7.04 (2H, 2xd, J=8.1 Hz); 5.09 and 4.77 (2H, 2xs); 4.29-4.18 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.66 and 7.49 (1H, 245 2xs); 7.13 and 7.06 (2H, 2xd, J=8.1 Hz); 4.86 and 4.48 (2H, 2xs); 3.79-3.25 (2H, m); .21 (6H, m); 2.07-2.03 (6H, m); 1.01 and 0.84 (9H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 7.66 and 7.49 (1H, 246 2xs); 7.38 and 7.31 (2H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.66-7.47 (4H, m); 4.60 247 and 4.42 (2H, 2xs); 4.31-4.18 (1H, m); 2.34-2.22 (6H, m); 2.09-2.02 (6H, m); 1.92-1.83 (2H, m); 1.29-0.95 (10H, m) Ī“ (400 MHz, CDCl3) 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 248 4.28-4.19 (1H, 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 (1H, m); 1.33-1.24 (2H, m); 1.10-0.93 (8H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.66 and 7.54 (1H, 2xs); 7.13 and 7.07 (2H, 2xd, J=8.0 Hz); 4.72 and 4.39 249 (2H, 2xs); 4.29-4.16 (1H, m); 3.64 and 3.40 (2H, 2xd, J=7.6 Hz); 2.63-2.55 and 2.44-2.36 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.65 and 7.54 (1H, 2xs); 7.38 and 7.31 (2H, 2xs); 4.71 and 4.38 (2H, 2xs); 250 4.29-4.17 (1H, m); 3.64 and 3.40 (2H, 2xd, J=7.6 Hz); 2.62-2.54 and 2.43-2.35 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.68-7.48 (4H, m); 4.82 and 4.46 (2H, 2xs); 4.27-4.17 (1H, m); 3.66-3.39 (2H, m); 251 2.63-2.55 and 2.41-2.33 (1H, 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); .93 (6H, m) Ī“ (400 MHz, CDCl3) rotamers t 7.62 and 7.53 (1H, 2xs); 7.33-7.26 (1H, m); 7.03-6.79 (2H, m); 4.71 and 4.35 (2H, 2xs); 4.29-4.18 (1H, m); 3.86 and 3.76 (3H, 2xs); 252 3.64 and 3.37 (2H, 2xd, J=7.3 Hz); 2.63-2.55 and 2.44-2.36 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.70 and 7.55 (1H, 2xs); 7.33-7.25 (1H, m); 7.03-6.78 (2H, m); 4.86 and 4.46 253 (2H, 2xs); 4.24-4.18 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present .47 (4H, m); 4.73 254 and 4.51 (2H, 2xs); 4.27-4.17 and 3.52-3.44 (2H, 2xm); 2.26-2.21 (2H, m); .78 (7H, m); 1.68-1.40 (9H, m); 1.12-1.04 (1H, m); .86 (6H, m) Ī“ (400 MHz, CDCl3) rs present 7.68 and 7.58 (1H, 2xs); 7.32-7.25 (1H, m); 7.04-6.80 (2H, m); 4.66 and 4.36 255 (2H, 2xs); 4.62-4.58 and .42 (1H, 2xm); 4.29-4.15 (1H, m); 3.87 and 3.77 (3H, 2xs); 2.28-2.16 (2H, m); 1.98- 1.86 (6H, m); 1.66-1.39 (10H, m); 1.13-1.05 (1H, m); 0.94- 0.87 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.57 and 7.47 (1H, 2xs); 7.38 and 7.31 (2H, 2xs); 4.70 and 4.35 (2H, 2xs); 256 3.62-3.34 (2H, m); 2.62-2.54 and 2.43-2.35 (1H, 2xm); .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) Ī“ (400 MHz, CDCl3) rotamers present 7.54 and 7.45 (1H, 2xs); 7.32-7.26 (1H, m); 7.03-6.78 (2H, m); 4.70 and 4.32 257 (2H, 2xs); 3.86 and 3.75 (3H, 2xs); .32 (2H, m); 2.63-2.55 and 2.44-2.36 (1H, 2xm); 2.32-2.22 (6H, m); 2.08-2.02 (6H, m); .79 (2H, m); 1.63-1.58 and 1.36- 1.31 (2H, 2xm); 1.14-0.95 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.67-7.48 (4H, m); 4.81 258 and 4.44 (2H, 2xs); 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) Ī“ (400 MHz, CDCl3) rotamers present 7.61 and 7.55 (1H, 2xs); 7.33-7.26 (1H, m); 7.03-6.78 (2H, m); 4.76 and 4.38 259 (2H, 2xs); 4.28-4.18 (1H, m); 3.86 and 3.75 (3H, 2xs); 3.48 and 3.23 (2H, 2xd, J=7.1 Hz); 2.27-2.16 (2H, m); 1.95-1.87 (6H, m); .05 (11H, m); 0.96-0.78 (7H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.65 and 7.57 (1H, 260 2xs); 7.36 and 7.29 (2H, 2xs); 5.08 and 4.76 (2H, 2xs); 4.29-4.17 (1H, m); 3.96 and 3.75 (2H, 2xs); 2.25-2.14 (2H, m); 1.95-1.84 (6H, m); .39 (14H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 7.71 and 7.61 (1H, 2xs); 7.42 and 7.37 (2H, 2xs); 4.92 and 4.70 261 (2H, 2xs); 3.83 and 3.61 (2H, 2xs); 2.35 and 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) Ī“ (400 MHz, DMSO-d6) rotamers t 11.97 (1H, brs); 8.77 and 8.70 (2H, 2xs); 7.81 and 7.71 (1H, 2xs); 4.95 and 4.82 262 (2H, 2xs); 4.48-4.42 (1H, m); 4.27-4.19 (1H, m); 3.87 and 3.71 (2H, 2xs); 2.34-2.26 (1H, m); 2.07-1.90 (6H, m); 1.67-1.30 (10H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 2xs); 7.66 and 7.52 (1H, 2xs); 5.14-5.04 and 4.37-4.16 264 (2H, m); 4.57 and 4.40 (2H, 2xs); 2.52-2.44 (1H, m); 2.28- 2.25 (2H, m); 2.17-2.02 (4H, m); 1.96-1.89 (1H, m); 1.73- 1.62 (2H, m,); 1.36-0.96 (11H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.78 and 7.48 (4H, m); 265 4.97 and 4.60 (2H, 2xs); 4.24-4.18 (1H, m); .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) Ī“ (400 MHz, CDCl3) rotamers t 7.58 and 7.47 (1H, 2xs); 7.13 and 7.06 (2H, 2xd, J=8.0 Hz); 4.71 and 4.36 266 (2H, 2xs); 3.70-3.35 (2H, m); .55 and 2.43-2.35 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 267 2xs); 7.67 and 7.56 (1H, 2xs); 4.81 and 4.47 (2H, 2xs); 4.29-4.18 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.23 (1H, brs); 7.90 and 7.81 (1H, 2xs); 7.19-7.09 (4H, m); 6.93-6.91 (1H, m); 268 4.72-4.59 (4H, m); .13 (1H, m); 2.33-2.29 (1H, 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) Ī“ (300 MHz, DMSO-d6) rotamers t 12.15 (1H, brs); 7.85 269 and 7.81 (1H, 2xs); 7.17-6.91 (5H, m); 4.71-4.58 (4H, m); 4.28-4.13 (1H, m); 2.34-2.23 (4H, m); 2.22 and 1.77 (3H, 2xs); .90 (6H, m); .47 (2H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.65-7.47 (4H, m); 5.11 270 and 4.75 (2H, 2xs); 4.25-4.19 (1H, m); 4.02-3.70 (2H, m); 2.28-2.18 (2H, m); 1.95-1.73 (14H, m); 1.41 (3H, s) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 272 2xs); 7.67 and 7.56 (1H, 2xs); 5.00 and 4.69 (2H, 2xs); .19 (1H, m); 3.98-3.92 (2H, m); 2.28-2.16 (2H, m); 1.95-1.74 (14H, m); 1.41 (3H, s) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.56 (1H, 275 2xs); 7.38 and 7.31 (2H, 2xs); 4.82 and 4.44 (2H, 2xs); 4.29-4.17 (1H, 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) Ī“ (300 MHz, DMSO-d6) rotamers present 12.22 (1H, brs); 7.85 and 7.68 (1H, 2xs); 7.22 and 7.15 (1H, 2xs); 7.11 and 7.05 279 (1H, 2xs); 4.61 and 4.59 (2H, 2xs); 4.32-4.17 and 3.39- 3.30 (2H, 2xm); 2.30-1.98 (7H, m); .58 (9H, m); 1.50-1.31 (4H, m); 1.25 and 1.22 (3H, 2xs); 1.04-0.82 (8H, Ī“ (400 MHz, CD3OD) rotamers present 7.76 and 7.62 (1H, 280 2xs); 7.13 and 7.07 (2H, 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 (11H, m); 0.95-0.86 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.70 and 7.58 (1H, 281 2xs); 7.36-7.23 (3H, m); 5.05 and 4.69 (2H, 2xs); 4.25- 4.18 (1H, m); 4.00-3.95 (2H, m); 2.26-2.16 (2H, m); 1.94- 1.73 (14H, m); 1.40 (3H, s) Ī“ (400 MHz, CDCl3) rotamers present 7.69 and 7.58 (1H, 2xs); 7.15 and 7.07 (2H, 2xs); 5.02 and 4.66 (2H, 2xs); 282 .17 (1H, m); 3.98-3.70 (2H, m); 2.35 and 2.32 (3H, 2xs); 2.25-2.15 (2H, m); 1.94-1.73 (14H, m); 1.41 and 1.40 (3H, 2xs) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.58 (1H, 2xs); 7.38-7.23 (3H, m); 4.70 and 4.46 (2H, 2xs); 4.61- 283 4.53 and 3.52-3.44 (1H, 2xm); 4.30-4.15 (1H, m); 2.29-2.16 (2H, m); 1.98-1.86 (6H, m); 1.68-1.40 (10H, m); 1.13-1.06 (1H, m); .87 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.75 and 7.59 (1H, 2xs); 7.36-7.23 (3H, m); 4.92 and 4.53 (2H, 2xs); 4.24- 284 4.16 (1H, 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, Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 2xs); 7.65 and 7.57 (1H, 2xs); 4.64-4.57 and 3.55-3.48 287 (1H, 2xm); 4.54 and 4.35 (2H, 2xs); 4.30-4.21 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.24 (1H, brs); 8.78 288 and 8.72 (2H, 2xs); 7.65 and 7.62 (1H, 2xs); 4.82 and 4.66 (2H, 2xs); 3.49-3.22 (2H, m); 2.15-2.11 (6H, m); .89 (6H, m); 1.30-1.24 (2H, m); 0.89-0.72 (9H, m) Ī“ (400 MHz, CDCl3) rs present 7.66 and 7.55 (1H, 289 2xs); 7.39 and 7.31 (2H, 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 (1H, m); 1.45-1.28 (6H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.47 (1H, brs); 7.91 and 7.76 (1H, 2xs); 7.72 and 7.65 (2H, 2xd, J=8.6 Hz); 290 5.14-4.98 (1H, m); 4.73 and 4.65 (2H, 2xs); 4.34-4.28 and 3.43-3.38 (1H, 2xm); 3.17-3.09 (1H, 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 (1H, m); 0.91-0.81 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.38 (1H, brs); 7.89 and 7.75 (1H, 2xs); 7.72 and 7.66 (2H, 2xd, J=8.6 Hz); 291 4.98-4.85 (1H, m); 4.72 and 4.64 (2H, 2xs); 4.35-4.28 and 3.43-3.37 (1H, 2xm); 3.02-2.96 (1H, m); 2.81-2.59 (4H, m); 1.70-1.60 (2H, m); .27 (5H, m); 1.07-1.00 (1H, m); 0.91-0.82 (6H, m) Ī“ (400 MHz, CD3OD) rotamers present 7.81 and 7.59 (1H, 2xs); 7.40 and 7.34 (2H, 2xd, J=8.6 Hz); 4.96 and 4.78 292 (2H, 2xs); 4.35-4.25 (1H, m); 3.72-3.63 and 3.51-3.46 (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) Ī“ (400 MHz, CD3OD) rotamers present 7.81 and 7.59 (1H, 2xs); 7.61and 7.55 (2H, 2xs); 4.96 and 4.78 (2H, 2xs); 293 4.36-4.26 (1H, m); 3.72-3.63 and 3.52-3.45 (4H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.54-8.44 (2H, m); 7.61 294 and 7.51 (1H, 2xs); 4.71 and 4.54 (2H, 2xs); 4.27-4.19 (1H, m); 3.40-3.33 (2H, m); .17 (2H, m); 1.94-1.87 (6H, m); 1.41 and 1.40 (3H, 2xs); 1.01 and 0.86 (9H, 2xs) Ī“ (400 MHz, CD3OD) rotamers present 7.81 and 7.63 (1H, 2xs); 7.41 and 7.34 (2H, 2xd, J=6.3 Hz); .93 (4H, 295 m); 3.31-3.12 (2H, m); 2.99-2.94 (1H, m); 2.80-2.68 (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) Ī“ (400 MHz, DMSO-d6) rotamers present 7.88-7.69 (3H, m); 296 4.69-4.19 (4H, m); 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); .90 (6H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.64 and 7.52 (1H, 2xs); 7.39-6.99 (3H, m); 4.78 and 4.53 (2H, 2xs); 4.25- 297 4.18 (1H, m); .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, Ī“ (400 MHz, CDCl3) rotamers present 7.61 and 7.49 (1H, 298 2xs); 7.37 and 7.30 (2H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.56 and 8.49 (2H, 299 2xs); 7.60 and 7.49 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.62 and 7.50 (1H, 300 2xs); 7.15 and 7.07 (2H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.40 (1H, brs); 7.80 and 7.63 (1H, 2xs); 7.71 and 7.67 (2H, 2xd, J=8.6 Hz); 301 4.72 and 4.65 (2H, 2xs); 4.34-4.17 (2H, m); 2.20-2.14 (2H, m); 2.03-1.62 (6H, m); 1.48-1.24 (7H, m); 1.14 and 1.12 (3H, 2xs); 1.02-0.95 (1H, m); 0.90-0.81 (6H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 12.26 (1H, brs); 7.88 and 7.75 (1H, 2xs); 7.70 and 7.65 (2H, 2xd, J=8.5 Hz); 302 4.81 and 4.63 (2H, 2xs); .20 (1H, m); 3.82-3.75 and 3.38-3.23 (2H, 2xm); 2.09-1.98 (2H, m); 1.87-1.72 (6H, m); .15 (5H, m); 0.87-0.70 (9H, m) Ī“ (400 MHz, DMSO-d6) rs present 12.26 (1H, brs); 9.41 and 9.14 (1H, 2xbrs); 7.89 and 7.76 (1H, 2xs); 7.75 and 7.69 (2H, 2xd, J=8.6 Hz); .73 (2.5H, m); 4.36-4.31 303 (0.5H, m); 4.26-4.20 (1H, 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) Ī“ (400 MHz, CD3OD) rotamers present 7.82 and 7.62 (1H, 2xs); 7.43 and 7.37 (2H, 2xd, J=8.0 Hz); 4.79 and 4.70 304 (2H, 2xs); 4.45-4.36 (1H, m); .25 (1H, m); 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) Ī“ (400 MHz, CD3OD) rotamers present 7.66 and 7.63 (1H, 2xs); 7.37 and 7.29 (2H, 2xd, J=8.2 Hz); 4.77 and 4.72 305 (2H, 2xs); 4.29-4.17 (4H, m); 3.26-3.20 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 7.94-7.72 (3H, m); 306 4.80 and 4.63 (2H, 2xs); 4.16-4.09 (1H, m); .20 (2H, m); .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) Ī“ (400 MHz, DMSO-d6) 12.11 (1H, brs); 8.32 (2H, s); 7.49 (1H, s); 7.37 (1H, s); 7.18-7.13 (2H, m); 7.10-7.03 (2H, 307 m); 5.13 (1H, d, J=15.7 Hz); 4.30 (1H, d, J=15.7 Hz); 4.16-4.08 (1H, m); 2.28 (3H, s); .18 (1H, m); 2.00- 1.82 (4H, m); 1.75-1.69 (2H, m); 1.52-1.40 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 7.84 and 7.79 (2H, 308 2xs); 7.64 and 7.61 (1H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 7.80-7.61 (3H, m); 309 4.79 and 4.59 (2H, 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, Ī“ (400 MHz, DMSO-d6) rotamers present 12.30 (1H, brs); 8.78 and 8.73 (2H, 2xs); 8.13 and 8.04 (1H, 2xs); 4.86 (2H, s); 310 4.50-4.43 (1H, m); 3.41-3.28 (2H, m); 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) Ī“ (400 MHz, CD3OD) rotamers present 8.65 and 8.58 (2H, 2xs); 7.79 and 7.61 (1H, 2xs); 4.95-4.88 and .91 312 (1H, 2xm); 4.80-4.63 (2H, m); 4.37-4.25 (1H, m); .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 (1H, m); 1.23 and 1.21 (3H, 2xs); 0.99-0.93 (3H, m); 0.75 and 0.73 (3H, 2xs) Ī“ (400 MHz, 6) rotamers present 12.21 (1H, brs); 8.80 and 8.72 (2H, 2xs); 7.81 and 7.70 (1H, 2xs); 4.88-4.57 313 (2.5H, m); 4.31-4.21 (1H, m); 3.96-3.91 (0.5H, 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.27 (1H, brs); 8.79 and 8.72 (2H, 2xs); 7.85 and 7.75 (1H, 2xs); 5.17-5.11 314 (1H, m); 4.75 and 4.60 (2H, 2xs); 4.30-4.22 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers t 8.33-8.23 (2H, m); 7.68 and 7.53 (1H, 2xs); 4.80 and 4.47 (2H, 2xs); 4.24-4.19 315 (1H, m); 3.98 and 3.88 (3H, 2xs); 3.41-3.31 (2H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.51 (2H, 316 2xs); 7.54 and 7.48 (1H, 2xs); 4.94 and 4.58 (2H, 2xs); 3.55-3.30 (2H, m); 2.33-2.23 (6H, m); .05 (6H, m); 1.09 and 0.98 (3H, 2xs); 0.49-0.34 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 7.68 and 7.51 (2H, 317 2xs); 7.37-7.25 (3H, m); 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) Ī“ (400 MHz, CDCl3) rotamers present 7.71 and 7.60 (1H, 2xs); 7.37-7.27 (2H, m); 4.96 and 4.72 (2H, 2xs); 4.29- 318 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, Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.50 (2H, 319 2xs); 7.71 and 7.52 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.62 and 7.48 (1H, 320 2xs); .26 (3H, m); 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) Ī“ (400 MHz, CDCl3) rotamers t 7.62 and 7.47 (1H, 2xs); 7.16 and 7.08 (2H, 2xs); 5.11-5.01 and 4.30-4.21 321 (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) Ī“ (400 MHz, CDCl3) rs present 8.58 and 8.51 (2H, 2xs); 7.55 and 7.48 (1H, 2xs); 4.74 and 4.45 (2H, 2xs); 322 3.68 (1H, brs); 3.32 (1H, d, J=5.9 Hz); 2.31-2.23 (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) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.51 (2H, 2xs); 7.64 and 7.55 (1H, 2xs); 4.76 and 4.48 (2H, 2xs); 325 4.29-4.18 (1H, m); 3.68 and 3.37 (2H, 2xd, J=6.5 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 326 2xs); 7.67 and 7.57 (1H, 2xs); 5.00 and 4.68 (2H, 2xs); 4.26-4.20 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 327 2xs); 7.59 and 7.50 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.59 and 8.52 (2H, 329 2xs); 7.56 and 7.46 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.50 (2H, 2xs); 7.75 and 7.55 (1H, 2xs); 4.78 and 4.45 (2H, 2xs); 331 4.29-4.24 (1H, m); 2.83-2.79 (1H, m); 2.28-2.20 (2H, m); 1.95-1.90 (6H, m); 1.42 (3H, s); 1.04-0.99 (1H, m); 0.95 and 0.70 (9H, 2xs); 0.64-0.55 (2H, m) Ī“ (400 MHz, DMSO-d6) rotamers t 12.27 (1H, brs); 8.80 and 8.73 (2H, 2xs); 7.81 and 7.66 (1H, 2xs); 4.89-4.57 332 (2.5H, m); 4.30-4.21 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.54-8.44 (2H, m); 7.64 333 and 7.49 (1H, 2xs); 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) Ī“ (400 MHz, CDCl3) rs present 8.54-8.44 (2H, m); 7.62 337 and 7.50 (1H, 2xs); 4.71 and 4.53 (2H, 2xs); 4.26-4.19 (1H, m); 3.41 and 3.34 (2H, 2xs); .16 (2H, m); 1.94- 1.86 (6H, m); 1.40-1.14 (5H, m); 0.95-0.68 (9H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.11 (2H, brs); 7.89 and 7.80 (1H, 2xs); 4.29-4.23 (1H, m); 4.17-4.09 (1H, m); 338 3.26-3.16 (1H, m); .00 (1H, m); 2.57-2.53 (1H, m); 2.36-2.32 (1H, m); 2.15 (3H, s); .05 (2H, m); 1.88- 1.64 (11H, m); 1.58-1.55 (1H, m); .30 (4H, m); 1.24 (3H, s); 1.00-0.82 (7H, m) Ī“ (400 MHz, CD3OD) rotamers present 7.79 and 7.64 (1H, 2xs); 7.40 and 7.34 (2H, 2xd, J=8.5 Hz); 5.15-5.00 (1H, 339 m); 4.77 and 4.64 (2H, 2xs); 4.44-4.36 and 3.55-3.47 (1H, 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 (1H, m); 0.94-0.86 (6H, Ī“ (400 MHz, 6) rs present 12.27 (1H, brs); 8.81 and 8.73 (2H, 2xs); 7.95 and 7.73 (1H, 2xs); 4.88-4.56 340 (2H, m); 4.31-4.20 (1H, m); 2.71-2.60 (1H, m); 2.15-2.05 (2H, m); 1.90-1.75 (6H, m); 1.24 and 1.22 (3H, 2xs); 1.08- 1.07 (1H, m); 0.92-0.76 (2H, m); 0.67-0.59 (6H, m); 0.52- 0.48 (1H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.24 (1H, brs); 7.69 341 and 7.52 (1H, 2xs); 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.24 (1H, brs); 7.69 342 and 7.52 (1H, 2xs); 7.26-6.90 (3H, m); 5.47-4.96 (2H, m); 4.34-3.96 (2H, m); 3.79-3.50 (4H, m); .88 (23H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.25 (1H, brs); 7.77 345 and 7.65 (3H, m); 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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.19 (1H, brs); 8.81 and 8.74 (2H, 2xs); 8.09 and 7.73 (1H, 2xs); 4.96-4.56 346 (2H, m); 4.31-4.23 (1H, m); 3.22-3.04 (1H, m); 2.17-2.03 (2H, m); 1.88-1.73 (6H, m); 1.24 and 1.22 (3H, 2xs); 1.19- 1.07 (1H, m); 0.99-0.48 (9H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.29 (1H, brs); 7.96 and 7.73 (1H, 2xs); 7.73 and 7.68 (2H, 2xd, J=8.6 Hz); 348 4.86 and 4.74 (2H, 2xs); 4.32-4.21 (1H, m); 3.57-3.53 and .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) Ī“ (400 MHz, DMSO-d6) rotamers present 12.28 (1H, brs); 8.02 and 7.73 (1H, 2xs); 7.74 and 7.68 (2H, 2xd, J=8.8 Hz); 350 4.93 and 4.79 (2H, 2xs); .22 (1H, m); 3.89-3.85 and 3.70-3.66 (2H, 2xm); 3.42-3.38 and 3.35-3.31 (2H, 2xm); 2.11-2.00 (2H, m); .73 (6H, m); 1.33-1.22 (12H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.28 (1H, brs); 7.95 and 7.74 (1H, 2xs); 7.73 and 7.67 (2H, 2xd, J=8.6 Hz); 351 4.91-4.70 (2H, m); 4.31-4.21 (1H, m); .64 (2H, m); .64 (2H, m); 2.11-1.99 (2H, m); 1.87-1.72 (6H, m); 1.23 and 1.22 (3H, 2xs); 1.17 and 1.10 (9H, 2xs) Ī“ (400 MHz, DMSO-d6) rotamers present 12.28-12.23 (1H, m); 8.56 and 8.23 (1H, 2xd, J=2.0 Hz); 7.85 and 7.50 (1H, 352 2xs); 7.46-7.40 and 7.26-7.13 (3H, 2xm); 4.83 and 4.65 (2H, 2xs); 4.27-4.07 (1H, 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) Ī“ (300 MHz, 6) rotamers present 12.24 (1H, brs); 7.80 358 and 7.73 (1H, 2xs); 7.58-7.51 (3H, m); 4.84 and 4.72 (2H, 2xs); 4.34-4.27 (1H, m); 1.98-1.72 (8H, m); 1.21 (3H, s); 0.95 and 0.74 (9H, 2xs) Ī“ (300 MHz, DMSO-d6) rotamers present 12.30 (1H, brs); 7.79 359 and 7.72 (1H, 2xs); 7.43 and 7.38 (2H, 2xs); 4.82 and 4.68 (2H, 2xs); 4.36-4.27 (1H, m); 2.31 (3H, s); 2.02-1.72 (8H, m); 1.21 (3H, s); 0.95 and 0.74 (9H, 2xs) Ī“ (400 MHz, DMSO-d6) rotamers present 12.42 (1H, brs); 11.20 and 11.13 (1H, 2xs); 7.77 and 7.63 (1H, 2xs); 7.24- 360 7.17 (1H, m); 6.96-6.85 (2H, m); 4.25-4.20 (1H, m); 3.64- 3.42 (4H, m); .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) Ī“ (400 MHz, DMSO-d6) rs present 12.23 (1H, brs); 363 7.83-7.29 (4H, m); 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 (8H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.20 (1H, brs); 364 7.55-7.28 (4H, m); 4.62-4.55 (3H, m); 4.25-4.15 (1H, 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) Ī“ (300 MHz, DMSO-d6) rotamers present 12.19 (1H, brs); 365 7.51-7.33 (3H, m); 4.64-4.57 (3H, m); 4.16-4.05 (1H, m); .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) Ī“ (300 MHz, DMSO-d6) rotamers present 12.23 (1H, brs); 366 7.80-7.41 (3H, m); 4.59-4.34 (4H, m); 2.33 (3H, s); 2.07- 1.76 (10H, m); 1.31-1.21 (5H, m); 1.05-0.94 (8H, m) Ī“ (400 MHz, DMSO-d6) rotamers present 12.23 (1H, brs); 8.77 367 and 8.61 (2H, 2xs); 7.83 and 7.68 (1H, 2xs); 4.65-4.36 (4H, m); .78 (10H, m); 1.30-1.21 (5H, m); 1.05-0.95 (8H, m) Ī“ (400 MHz, CDCl3) rotamers t 8.57 and 8.51 (2H, 2xs); 7.69 and 7.62 (1H, 2xs); 4.96 and 4.72 (2H, 2xs); 378 4.35-4.27 (1H, m); 3.57 and 3.48 (2H, 2xs); 2.18-2.12 (2H, m); 1.95-1.84 (6H, m); 1.40 (3H, s); 1.13 and 0.96 (3H, 2xs); .39 (4H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.48-8.35 (2H, m); 7.70 and 7.58 (1H, 2xs); 4.76 and 4.51 (2H, 2xs); 4.28-4.19 379 (1H, m); 3.43-3.35 (2H, m); 2.40 and 1.90 (3H, 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) Ī“ (400 MHz, CDCl3) rotamers present 8.56 and 8.53 (2H, 381 2xs); 7.68 and 7.59 (1H, 2xs); 4.70 and 4.54 (2H, 2xs); 4.32-4.27 (1H, m); .56 (2H, m); 2.59-2.45 (1H, m); 2.17-2.11 (2H, m); .88 (8H, m); 1.39-0.96 (11H, m) Ī“ (400 MHz, CDCl3) 8.55 (2H, s); 7.56 (1H, s); 4.68 (2H, 382 s); 4.06-3.99 (1H, m); 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 (11H, m) Ī“ (300 MHz, CD3OD) rotamers present 8.43-8.33 (2H, m); 7.65 383 and 7.52 (2H, 2xs); 5.63-5.59 and 5.23-5.21 (1H, 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) Ī“ (400 MHz, CDCl3) 8.53 (1H, s); 8.46 (1H, s); 7.67 (1H, 387 s); 4.51 (2H, s); 4.38-4.26 (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); .97 (8H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.58 and 8.52 (2H, 388 2xs); 7.70 and 7.60 (1H, 2xs); 4.93 and 4.70 (2H, 2xs); 4.33-4.25 (1H, 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) Ī“ (400 MHz, CDCl3) rotamers present 7.71 and 7.61 (1H, 2xs); 7.37-7.27 (3H, m); 4.72 and 4.57 (2H, 2xs); 4.57- 389 4.49 and 3.87-3.81 (1H, 2xm); 4.38-4.21 (1H, m); 2.20-2.11 (2H, m); .83 (6H, m); 1.70-1.40 (10H, m); 1.27-1.23 (1H, m); 0.94-0.90 (6H, m) Ī“ (300 MHz, DMSO-d6) rs present 12.19 (1H, brs); 8.56-8.46 (1H, m); 7.91-7.85 (1H, m); 7.74 and 7.63 (1H, 390 2xs); 7.40-7.35 (1H, m); 5.53-5.44 and 4.98-4.93 (2H, 2xm); 4.29-3.98 (2H, m); 3.61-3.49 (1H, m); 2.13-1.73 (10H, m); 1.56-1.37 (1H, m); 1.23-0.82 (12H, m) Ī“ (300 MHz, DMSO-d6) rotamers present 12.24 (1H, brs); 11.19 and 11.14 (1H, 2xs); 7.83 and 7.66 (1H, 2xs); 7.24- 392 7.16 (1H, 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 (11H, m); 1.31-1.10 (6H, m); 0.99-0.88 (6H, m) Ī“ (400 MHz, CDCl3) 8.06 (1H, d, J=7.3 Hz); 7.52 (1H, s); 7.35-7.20 (3H, m); 5.91 (1H, s); .23 (1H, m); 4.16- 393 4.06 (1H, m); 3.99 (1H, d, J=14.4 Hz); 3.89 (1H, d, J=14.4Hz); 2.28-2.17 (2H, m); 1.96-1.22 (14H, m); 1.10- 0.83 (10H, m) Ī“ (400 MHz, CDCl3) rotamers present 8.57 and 8.49 (2H, 2xs); 7.69 and 7.57 (1H, 2xs); 5.00 and 4.69 (2H, 2xs); 394 4.25-4.20 (1H, m); 3.85-3.61 (2H, m); 2.26-2.16 (2H, m); .86 (6H, m); 1.76-1.41 (7H, m); 0.96 and 0.74 (6H, 2xt, J=7.6 Hz) Ī“ (400 MHz, CDCl3) rotamers present 8.56 and 8.50 (2H, 2xs); 7.71 and 7.64 (1H, 2xs); 5.01 and 4.79 (2H, 2xs); 395 4.30-4.25 (1H, m); 3.86-3.72 (2H, m); 2.18-2.08 (2H, m); 1.95-1.83 (6H, m); .39 (7H, m); 0.96 and 0.74 (6H, 2xt, J=7.3 Hz) Ī“ (400 MHz, DMSO-d6) rotamers present 12.26 (1H, brs); 7.75 and 7.60 (1H, 2xs); 7.60 and 7.54 (1H, 2xd, J=5.1 Hz); 396 6.99 and 6.93 (1H, 2xd, J=5.1 Hz); 6.31 and 6.08 (1H, 2xs); 5.40-5.36 and 4.82-4.80 (1H, 2xm); 4.30-4.01 (2H, m); 3.39-3.18 (2H, m); 2.07-1.70 (10H, m); 1.53-1.44 (1H, m); 1.28-0.84 (12H, m) Ī“ (400 MHz, CDCl3) rotamers t 8.55 and 8.46 (1H, 2xd, J=3.2 Hz); 7.84-7.79 (1H, m); 7.66 and 7.50 (1H, 2xs); 398 7.43-7.40 (1H, 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, Ī“ (300 MHz, DMSO-d6) rotamers present 12.27 (1H, brs); 8.54-8.52 and 8.41-8.39 (1H, 2xm); 7.83-7.23 (4H, m); 401 5.75-5.60 (1H, m); 5.00-4.96 and 4.64-4.59 (1H, 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 (1H, m); 1.23-0.82 (12H, m) Ī“ (400 MHz, CD3OD) rotamers present 8.55 and 8.48 (1H, 2xdd, J=4.6, 1.5 Hz); 7.87 and 7.79 (1H, 2xdd, J=8.1, 1.5 Hz); 7.68 and 7.65 (1H, 2xs); 7.36 and 7.33 (1H, 2xdd, 402 J=8.1, 4.6 Hz); 5.64-5.61 and 5.17-5.14 (1H, 2xm); 4.32- 4.27 (1H, 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, Ī“ (400 MHz, 6) 12.27 (1H, brs); 7.66-7.37 (4H, m); 404 4.76-4.37 (4H, m); 2.10-1.74 (10H, m); 1.51-1.45 (3H, m); 1.34-0.91 (14H, m) Ī“ (400 MHz, CD3OD) rotamers present 7.77 and 7.60 (1H, 2xs); 7.53-7.21(3H, m); 7.15-6.75 (1H, m); 4.83 and 4.63 406 (2H, 2xs); .26 (1H, m); 3.41-3.36 (2H, m); 2.26-2.14 (2H, m); .84 (6H, m); 1.35 and 1.34 (3H, 2xs); 1.01 and 0.85 (9H, 2xs) Ī“ (500 MHz, DMSO-d6) 12.19 (1H, br. s.), 7.75 (0.3H, s), 7.58 (0.7H, s), 7.34-7.48 (4H, m), 7.13-7.33 (4H, m), 4.78 500 (1.4H, s), 4.42 (0.6H, s), 4.15-4.28 (1H, m), 3.29-3.60 (2H, m), 2.94-3.00 (0.6H, m), 2.78-2.83 (1.4H, m), 2.25- 2.39 (1H, m), 1.89-2.10 (6H, m), 1.46-1.60 (2H, m) Ī“ (400 MHz, DMSO-d6) 12.18 (1H, br. s.), 7.79 (0.3H, s), 7.74 (0.7H, s), 7.34-7.47 (5H, m), 7.15-7.30 (2H, m), 4.78 501 (1.6H, s), 4.47 (0.4H, s), 4.14-4.29 (1H, m), 3.24-3.56 (2H, m), 3.15-3.20 (0.4H, m), 2.91-2.99 (1.6H, m), 2.25- 2.38 (1H, m), .10 (6H, m), 1.45-1.63 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.17 (1H, br. s.), 7.68 (0.3H, s), 7.53 (0.7H, s), 7.42-7.45 (1H, m), 7.36-7.40 (2H, m), 7.28-7.32 (1H, m), .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), .26 (1H, 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, z), 2.24-2.37 (1H, m), 1.86-2.09 (6H, m), 1.46- 1.591 (2H, m) Ī“ (400 MHz, DMSO-d6) 12.18 (1H, br. s.), 10.97 (1H, br. s.), 7.68 (0.4H, s), 7.57 (0.6H, s), 7.36-7.47 (4.4H, m), 7.25-7.28 (1H, m), 7.21 (0.4H, br. s), 7.11-7.15 (0.6H, 503 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), 6.32-6.38 (1H, m), 4.74 (1.2H, s), 4.36 (0.8H, s), 4.13-4.29 (1H, m), .60 (0.8H, m), 3.23-3.37 (1.2H, m), 2.74-2.93 (2H, m), 2.25-2.38 (1H, m), 1.38-2.10 (6H, m), 1.45-1.61 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.18 (1H, 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, 504 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), .26 (1H, m), 3.57 (0.7H, t, J=7.5Hz), 3.27-3.35 (1.3H, m), 2.95 (0.7H, t, z), 2.81 (1.3H, t, J=7.8Hz), 2.25-2.38 (1H, m), 1.87-2.09 (6H, m), 1.46-1.59 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.18 (1H, br. s.), 7.74 (0.3H, s), 7.68 (0.7H, s), .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), 505 4.77 (1.4H, s), 4.43 (0.6H, s), 4.14-4.28 (1H, 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 (1H, 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) Ī“ (500 MHz, DMSO-d6) 12.18 (1H, s), 11.05 (1H, 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), 506 6.48-6.50 (0.3H, m), 5.78-5.80 (0.7H, m), 4.79 (1.4H, s), 4.38 (0.6H, s), 4.15-4.27 (1H, 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 (1H, m), 1.89-2.11 (6H, m), 1.46-1.59 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.18 (1H, br. s.), 10.82 (1H, 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 (1H, m), 6.94-7.08 (2H, 507 m), 6.89 (0.7H, d, J=8.3Hz), 6.84 (0.7H, t, J=7.6), 4.77 (1.4H, s), 4.42 (0.6H, s), 4.16-4.28 (1H, 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 (1H, m), 1.88-2.10 (6H, m), 1.47-1.59 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.16 (1H, br. S.), 11.07 (0.4H, s), .96 (0.6H, 1 (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), 508 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), 4.32 (0.8H, s), 4.12-4.21 (1H, 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), .34 (1H, m), .07 (2H, m), 1.85-1.97 (4H, m), .58 (2H, m) Ī“ (500 MHz, DMSO-d6) 12.17 (1H, 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), 4.44 509 (0.6H, s), 4.15-4.28 (1H, m), 3.43-3.49 (0.6H, m), 3.17- 3.23 (1.4H, m), 2.79-2.84 (0.6H, m), .69 (1.4H, m), 2.28-2.37 (1H, m), 2.25 (1H, s), 1.89-2.092 (6H, m), 1.83 (2H, s), 1.48-1.60 (2H, m) Ī“ (500 MHz, 6) 12.21 (1H, br. s.), 7.74 (0.2H, s), 7.70 (0.8H, s), 7.32 (0.4H, s), 7.24 (1.6H, s), 4.17-4.27 510 (1H, 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, z), 2.91 (1.6H, t, J=8.1Hz), 2.21-2.38 (4H, m), .10 (6H, m), 1.45- 1.82 (8H, m), 0.90-1.25 (5H, m) Ī“ (500 MHz, DMSO-d6) 12.20 (1H, br. s.), 7.79-7.83 (1H, m), 511 7.24 (2H, s), 4.20-4.28 (1H, m), 3.36-3.47 (2H, m), 2.89 (2H, t, J=7.8Hz), 2.27-2.37 (1H, m), 2.23 (3H, s), 1.89- 2.10 (7H, m), 1.21-1.61 (13H, m), 0.93 (3H, s) Ī“ (500 MHz, DMSO-d6) 12.17 (1H, br. s.), 7.78 (1H, s), 7.24 512 (2H, s), 4.20-4.28 (1H, m), 3.29-3.42 (4H, m), 2.88 (2H, t, J=8.1Hz), 2.29-2.32 (1H, m), 2.23 (3H, s), 1.90-2.10 (6H, m), 1.55 (2H, qd, J=12.6, , 0.95 (9H, s) Ī“ (500 MHz, DMSO-d6) 12.18 (1H, br. s.), 10.74 (1H, 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 , m), 6.77-6.84 513 (1.5H, m), 4.82 (1.5H, s), 4.44 (0.5H, s), 4.15-4.28 (1H, 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), .38 (1H, m), 2.28 (0.75, s), 1.89-2.10 (8.25H, m), 1.48-1.61 (2H, m) Ī“ (500 MHz, 6) 12.26 (1H, 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 (1H, m), 3.52-3.57 (0.4H, m), 3.37 (1.6H, d, J=7.3Hz), 514 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, Ī“ (500 MHz, 6) 12.26 (1H, br. s.), 7.81 (1H, s), 7.24 515 (2H, s), 4.23-4.30 (1H, 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) Ī“ (400 MHz, CDCl3) 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.), 4.49-4.64 516 (1H, m), 4.35-4.49 (1H, m), 4.07-4.35 (1H, m), 3.36-3.58 (1H, 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), 1.37-1.53 (3H, m), 1.01-1.15 (1H, m), 0.83-0.97 (6H, m) Ī“ (400 MHz, CDCl3) 7.57-7.62 (1H, m), 7.09-7.16 (2H, m), 517 5.48 ( 0.6H, s) 4.51 (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) Ī“ (400 MHz, CDCl3) 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), 518 4.12-4.33 (1H, m), 3.50-3.53 (1.3H, m), 3.19-3.34 (0.7H, m), 2.42-2.49 (1H, 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) Ī“ (400 MHz, CDCl3) 7.54-7.64 (1H, m), 7.19-7.08 (2H, m), 519 4.52 (2H, s), 4.12-4.30 (1H, m), 3.50 (2H, s), 2.46-2.50 (1H, 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) Ī“ (400 MHz, CDCl3) 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 (1H, 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), .74 (4H, m), 1.14-1.11 (6H, m) Ī“ (400 MHz, CDCl3) 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- 521 4.32 (1H, m), 3.61-3.74 (1.2H, m), 3.33-3.43 (0.8H, 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) Ī“ (400 MHz, CDCl3) 7.67 -7.63 (1H, m), 7.16 -7.09 (2H, m), 522 .86 (2H, m), 4.84 (2H, s), 4.35 (2H, s), 4.16-4.30 (1H, m), 2.40-2.52 (1H, m), 2.37-2.23 (5H, m), 2.11-2.05 (4H, m.), 1.53-1.74 (2H, m) Ī“ (400 MHz, DMSO-d6) 12.16 (br. s., 1H) 7.75 (s, 1H) 7.35- 523 7.44 (m, 2H) .30 (m, 1H) 4.25 (d, J=6.06Hz, 1H) 3.35-3.44 (m, 4H) 2.86-3.00 (m, 2H) 2.24-2.41 (m, 1H) 1.87-2.12 (m, 6H) 1.44-1.65 (m, 2H) 0.95 (s, 9H) Ī“ (400 MHz, CDCl3) 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), 524 .17 (1H, m), 3.30-3.59 (1H, m), 2.37-2.56 (1H, m), 2.25 (2H, d, Hz), .16 (3H, m), 1.52-1.76 (4H, m), 1.02 (8H, s), 0.84 (1H, s) Ī“ (400 MHz, CDCl3) 7.68 (1H, s), 7.54-7.60 (1H, m), 7.28 (3H, s), 4.66-4.81 (1H, m), 4.51-4.64 (1H, m), 4.47 (1H, 525 s), 4.17-4.34 (1H, m), 3.36-3.57 (1H, m), 2.36-2.58 (1H, m), 2.08-2.33 (4H, m), 1.53-1.80 (6H, m), 1.36-1.50 (3H, m), 1.03-1.17 (1H, m), 0.78-0.99 (6H, m) Ī“ (400 MHz, DMSO-d6) 12.18 (br. s., 1H) 7.56-7.81 (m, 5H) 7.36 (s, 2H) 7.20-7.30 (m, 1H) 4.88 (s, 1.6H) 4.60 (s, 526 0.4H) 4.08-4.33 (m, 1H) 3.50-3.66 (m, 0.4H) 3.34-3.30 (m, 1.6H ) .25 (m, 0.4H) 2.87-3.04 (m, 1.6H) 2.22-2.41 (m, 1H) 1.64-2.13 (m, 4H) 1.40-1.63 (m, 2H) 1.20-1.31 (m, Ī“ (400 MHz, CDCl3) 7.55-7.74 (m, 2H) 7.45 (d, J=8.22Hz, 1H) 527 7.18-7.34 (m, 5H) 4.93 (br. s., 1H) 4.72 (d, J=2.74Hz, 1H) 4.32-4.21 (m, 2H) 2.46 (t, J=12.13Hz, 1H) 2.24 (d, J=13.11Hz, 2H) 2.06-2.13 (m, 5H) 1.53-1.78 (m, 2H) Ī“ (400 MHz, CDCl3) 7.57-7.72 (3H, m), 7.48-7.55 (0.5H, m), 7.44 (0.9H, d, J=8.1Hz), 7.27-7.32 (1H, m), 7.10-7.17 528 (0.7H, m), 7.06 (0.9H, s), 4.87-5.08 (1H, m), 4.71 (1H, 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) Ī“ (400 MHz, CDCl3) 7.49 (0.2H, s), 7.44 (0.8H, s), 7.16 (0.4H, s), .11 (1.6H, m), 5.14-5.18 (0.2H, m), 5.04- 529 5.07 (0.8H, m), 4.01-4.29 (1H, m), 3.71-3.76 (1H, m), 3.35-3.55 (1H, m), 3.14 (3H, s), 2.39-2.55 (1H, m), 2.20- 2.34 (6H, m), .14 (4H, m), 1.57-1.75 (3H, m), 1.02 (8H, s), 0.81 (1H, s) Ī“ (400 MHz, CDCl3) 7.39-7.53 (1H, m), 6.97-7.19 (2H, m), .53 (.1H, m), 4.94-5.11 (0.9H, m), 4.16-4.31 (1H, 530 m), .15 (1H, m), .81 (1H, m), 3.18-3.54 (2H, m), 3.13 (3H, s), 2.37-2.52 (1H, m), 2.27 (5H, s), 2.00- 2.13 (4H, m), 1.46-1.77 (2H, m), 1.01 (8H, s), 0.80 (1H, Ī“ (400 MHz, CDCl3) 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, 531 4.1Hz), 4.15-4.29 (1H, m), 4.08 (1H, dd, , 9.4Hz), 3.74 (1H, 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 (1H, s) Ī“ (400 MHz, CDCl3) 7.66 (s, 0.4H), 7.57 (s, 0.6H), 7.17 (s, 0.8H). 7.10 (s, 1.2H), 4.80 (s, 0.8H), 4.42 (s, 1.2H), 532 4.14-4.33 (m, 1H), 3.47-3.55 (m, 1.2H), .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) Ī“ (400 MHz, DMSO-d6) 7.81 (0.3H, s), 7.70 (0.7H, s), 7.45 533 (0.6H, s), 7.38 (1.4H, s), 4.77 (0.6H, s), 4.37 (1.4H, s), 4.17-4.32 (1H, m), 2.36 (0.9H,s), 2.30 (2.1H, s), 1.98- 2.17 (2H, m), 1.46-1.90 (12H, m) Ī“ (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, 1H), 1.88-2.11 (m, 6H), 2.27-2.38 (m, 1H), 2.50-2.57 (m , 1H), 2.90-2.98 (m, 1H), 534 .15 (m, 3H), 3.44-3.51 (m, 1H), 4.15-4.29 (m, 2H), .83 (m, 1H), 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, 1H) Ī“ (400 MHz, DMSO-d6) 7.82 (s, 0.2H), 7.69 (s, 0.8H), 7.47 (s, 0.4H). 7.40 (s, 1.6H), 4.78 (s, 0.4H), 4.59 (s, 1.6H), 535 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), .29 (m, 5H), 0.67-0.95 (m, 6H) Ī“ (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), 536 4.06-4.44 (m, 2.5H), 4.58-4.88 (m, 3H), 7.39 (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) Ī“ (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), 537 4.37 (1.4H, s), 4.16-4.32 (1H, m), 3.07-3.37 (1H, m), 2.43-2.69 (1H, m), 2.24-2.38 (4H, m), 1.85-2.11 (6H, m), 1.45-1.76 (7H, m), 0.85-1.27 (5H, m) Ī“ (400 MHz, DMSO-d6) 12.26 (1H, s), 8.88-9.04 (1H, m), 538 7.10-8.22 (5H, m), 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), .29 (3H, m), 0.78-1.03 (9H, m) Ī“ (400 MHz, DMSO-d6) 12.19 (1H, br. s.), 8.81-9.01 (1H, m), 539 8.12 (1H, dd, J=16.7, 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) Ī“ (400 MHz, CD3OD) .70 (2H, m), 2.04-2.24 (6H, m), 541 2.39-2.47 (1H, m), 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) Ī“ (400 MHz, CD3OD) 1.02-1.08 (9H, m), 1.57-1.69 (2H, m), 542 2.01-2.23 (6H, m), 2.41 (1H, tt, J=12.23, 3.52Hz), 2.50- 2.56 (3H, m), .35 (1H, m), 4.72 (2H, s), 7.44 (1H, s), 7.61-7.64 (1H, m) Ī“ (500 MHz, CDCl3) 7.61 (s, 1H), 7.53 (s, 1), 7.24-7.27 (m, 2H), 7.17-7.20 (m, 2H), 7.11 (s, 1H), .05 (m, 2H), 543 4.75 (br, s, 2H), 4.60 (s, 1H), 4.54 (s, 1H), 4.12-4.25 (m, 4H), 2.17-2.47 (m, 5H), 1.63-2.02 (m, 3H), 1.56-1.58 (m, 2H) Ī“ (400 MHz, DMSO-d6) 1.89-2.06 (12H, m), 2.27-2.33 (1H, m), 2.27-2.32 (1H, m), 2.36 (1H, s), 3.29-3.34 (1H, m), 3.57 544 (1H, t, J=7.04Hz), 3.91-3.95 (1H, m), 4.09-4.14 (1H, m), 4.46 (1H, s), 4.72 (1H, s), 5.89 (1H, s), 5.97 (1H, d, J=5.67Hz), 6.06 (1H, s), 7.10 (1H, d, J=7.49Hz), 7.34-7.44 (4H, m), 7.73 (1H, s) Ī“ (400 MHz, DMSO-d6) 12.06-12.33 (m, 1H), 8.72 (s, 2H), 7.75 (s, 1H), 4.71 (s, 2H), 4.40 (br. s., 1H), 3.28 (s, 739 2H), 2.13 (d, J=4.11Hz, 1H), 1.97 (br. s., 1H), 1.91 (br. s., 1H), 1.69-1.86 (m, 3H), 0.88-1.01 (m, 13H), 0.77 (s, le 900] ROR gamma Reporter Gene Assay Luciferase reporter gene assay was used to assess inhibition of RORĪ³ transcriptional activity.
ROR gamma expression vector was prepared by inserting the ligand g domain of human ROR gamma (amino acid 247-497 of Genbank Accession NO. 001523) 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 ga) containing the constitutive CMV promoter and the renilla luciferase.
For preparing transfection reagent/DNA e, 1 Ī¼g pM-ROR gamma, 1 Ī¼g pGL4 5xUAS, 625 pg pRL-CMV and 6.25 Ī¼L FuGENETM HD transfection reagent (Promega) were mixed in 0.25 mL OPTI-MEMTM (Life technologies) at room ature. At the same time, Negative control DNA e was prepared by using 1 Ī¼g pM empty vector instead of pM-ROR gamma plasmid. After a n minute incubation, 0.25 mL of transfection reagent/DNA e was added to 1,000,000 of HEK293T cells (ATCC) in 5 mL of OPTI-MEMTM containing 10% Charcoal Stripped Fetal Bovine Serum.
Transfected cells were seeded onto 384 well plate (10 Ī¼L/well) and the 7.5 nL of test compounds were added to the wells in 8 concentrations ranging from 3.5 nM to .5 Ī¼M. 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 37Ā°C, 5% CO2 in a cell culture incubator, the Dual-GloTM 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 e 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 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 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 8.08 134 6.61 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 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 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 7.33 70 < 5.00 110 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 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 e 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 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 6.75 400 7.54 [Example 901] ROR gamma Coactivator Peptide tment AlphascreenTM Assay AlphascreenTM 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 RORĪ³ binding to the vator GRIP1 was established using AlphascreenTM technology. The ction 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 or and a e containing a coactivator protein LXXLL nuclear receptor binding motif.
For the RORĪ³ uct used in the coactivator recruitment assay, nucleotides corresponding to the ligand g domain (LBD) of wild type human RORĪ³ (amino acids 262-518 of Genbank Accession No. NM_005060.3) were cloned into the pET24 expression vector (Novagen), downstream of in-frame N-terminal 6xHis and Flag tag sequences. Recombinant 6xHis:Flag-tagged human BD protein was expressed in E.coli ) and purified by affinity chromatography on a nickel Sepharose column, ed by anion exchange chromatography.
A 4x assay mixture of 6xHis:Flag-tagged human RORĪ³- LBD with the agonist ligand 7-Ī²-hydroxycholesterol was prepared in assay buffer (50 mM HEPES pH 7.4, BSA 0.05%, 150 mM NaCl, 5 mM MgCl2, 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 e of nickel e AlphascreenTM acceptor beads (PerkinElmer) and streptavidin AlphascreenTM 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 s, 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 nds were robotically dispensed directly into assay plates containing assay buffer to a 4x final test concentration. ing compound addition, the 6xHis:Flag-tagged human RORĪ³-LBD plus 7-Ī²-hydroxycholesterol assay mixture, biotinylated vator peptide and detection mixture were added. Final assay conditions were 5nM 6xHis:Flagtagged human RORĪ³-LBD, 30 nM 7-Ī²-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 ature plates were read on and EnvisionTM plate reader (PerkinElmer).
Data was plotted and pIC50 values were calculated using the Genedata ScreenerTM data analysis suite (Genedata).
The results are shown in the following tables. example result e 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 e 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 e result example result example result 813 8.22 852 6.05 891 7.81 814 8.04 853 7.77 892 6.52 815 7.89 854 8.33 893 8.65 816 8.35 855 8.24 817 7.19 856 7.17 818 8.14 857 7.47 819 7.30 858 8.70 820 7.00 859 8.22 821 8.01 860 7.94 822 5.23 861 8.32 823 5.04 862 7.42 824 7.54 863 8.19 825 8.86 864 8.53 826 7.73 865 8.11 827 - 866 8.65 828 - 867 7.61 829 8.02 868 8.34 830 8.57 869 7.86 831 8.58 870 6.24 832 8.41 871 8.30 833 8.23 872 7.01 834 8.00 873 8.28 835 6.60 874 8.11 836 7.51 875 7.93 837 8.43 876 8.21 838 7.86 877 8.21 839 8.14 878 8.41 840 6.62 879 8.53 841 6.71 880 7.79 842 6.51 881 7.61 843 8.23 882 6.19 844 7.52 883 6.15 845 8.84 884 8.74 846 8.62 885 6.13 847 7.66 886 6.33 848 8.88 887 7.79 849 8.06 888 8.49 850 7.89 889 8.69 851 - 890 9.15

Claims (17)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 5 wherein: R1 is selected from F, Cl, Br, a C1 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 10 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, -CO2H, -SO3H, -CONH2, - SO2NH2, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 15 1, 2 or 3 Rc , a (C1 to C6 alkyl)aminocarbonyl group tuted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylaminosulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a xycarbonyl)(C1 to C3 alkyl) group 20 substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)sulfonyl(C1 to C3 alkyl) group tuted by 0, 1, 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 25 1, 2 or 3 Rc groups; R6 and R7 are independently selected from H, F, -OH, -NH2, -CN, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rb groups; 30 R3 is ed from H, F, Cl, -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)(C1 to C3 alkyl) group tuted by 0, 1, 2, 3, 4 or 5 Re , a (C2 to C6 alkynyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C1 5 to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 10 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)(C1 to C3 alkyl) group substituted 15 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 tuted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 20 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 25 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 heterobicycloalkyl group tuted 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 Rg groups; 30 R5 is selected from a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 Ri groups, a 5- to 10-membered aryl group substituted by 0, 1, 2, 3, or 4 Ri , a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5Rj , a C3 to C8 cycloalkenyl group 35 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 ndently selected from H, F, -OH, -NH2, a C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh groups, and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rh groups; or R8 and R9 together form an oxo group or 5 a thioxo group; R12 is H; or R4 and R12 together are -CR13R14- CRmRm- or -CR13R14-CRmRm-CRmRm- to form a pyrrolidine ring; R13 is selected from H, a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a C6 to C10 10 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 Rf groups,a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 l)(C1 to C3 alkyl) group tuted by 0, 1, 2, 3, 15 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)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf , a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, 20 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)(C1 to C3 alkyl) group 25 tuted 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 30 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 C6 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg 35 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 C9 bicycloalkyl 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 Rg groups; R14 is independently selected from H and a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups; 5 or R13 and R14 er form a C3 to C8 cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups, C3 to C8 cycloalkene ring tuted 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; 10 Rm is ndently selected from H, F, Cl, -CH3 and -CF3; Rg and Rj are , ndently selected from F, Cl, a C1 to C6 alkyl group, -OH, -CN, -NH2, -NO2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 15 to C6 alkyl)amino group, -CF3, a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 Rl groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 Rl groups and an oxo group; Rf and Ri are are independently selected from F, Cl, 20 Br, -OH, -CN, -NO2, -CO2H, a C1 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 25 groups, a C1 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 C1 to C6 alkylthio group substituted by 0, 1, 2 or 3 Rk , a C3 to C8 cycloalkylthio group substituted by 0, 1, 2 or 3 Rk 30 groups, a (C1 to C6 carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 )carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group 35 substituted by 0, 1, 2 or 3 Rk groups, a C1 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(C1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups; and Ra, Rb, Rc, Re, Rh, Rk and Rl are ndently selected from F, a C1 to C4 alkyl group, -OH, -CN, -NO2, - 5 NH2, -CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, -CF3 and an oxo group.
2. The compound according to claim 1 or pharmaceutically acceptable salt thereof, n Y is 10 selected from formula (II-a), formula (II-b), formula (II-c) and formula (II-d): (II-a), (II-b), (II-c) or (II-d), wherein: 15 k is 0, 1 or 2; and n is 1, 2 or 3.
3. The compound according to claim 2 or pharmaceutically acceptable salt f, wherein Y is a group represented by formula (II-a): 20 (II-a).
4. The compound according to claim 2 or pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula (II-d): (II-d) 25 and n is 2.
5. The compound according to any one of claims 1 to 4 or ceutically able salt thereof, wherein R3 is H.
6. The compound according to any one of claims 1 to 5 or pharmaceutically able salt thereof, n R2 is -CO2H or a hydroxycarbonylmethyl group substituted 5 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 10 to 7 or pharmaceutically acceptable salt thereof, wherein R8 and R9 together form an oxo group or both R8 and R9 are
9. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt thereof, wherein 15 R1 is -CF3, -CF2H or Cl.
10. The nd according to any one of claims 1 to 9 or pharmaceutically acceptable salt thereof, wherein R5 is a C6 to C10 aryl group tuted by 0, 1, 2, 3, 4 or 5 Ri groups or a 5- to 10-membered heteroaryl group 20 substituted by 0, 1, 2, 3, or 4 Ri groups.
11. The compound according to any one of claims 1 to 10 or pharmaceutically acceptable salt thereof, wherein R4 is a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Re groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group 25 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 Rg 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 30 groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg , a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg , a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups or a (C6 to C9 35 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups.
12. A compound according to claim 1, wherein the compound is ed from the group consisting of: (1R,3S)(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclopentanecarboxylic 5 acid; (1S,3S)(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclopentanecarboxylic acid; 10 1-(transcarbamoylcyclohexyl)-N-(2-(3,5- dichloropyridinyl)oxoethyl)-N-(4-fluorobenzyl) uoromethyl)-1H-pyrazolecarboxamide; 4-(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexanyl)- (2-oxo(2,4,6-trichlorophenyl)ethyl)carbamoyl) 15 (trifluoromethyl)pyrazolyl)bicyclo(2.2.2)octane carboxylic acid; (1-fluorocyclopentyl)methyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane 20 carboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-((1- fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 25 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo(2.2.2)octane carboxylic acid; 30 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-((3,3- dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-(2,2- 35 dimethylbutyl)carbamoyl)(trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 5 1-yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)-(4,4- dimethylcyclohexyl)carbamoyl)(difluoromethyl)pyrazol- 1-yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichloromethylphenyl)oxoethyl)-((1- 10 fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2,6-dichloromethylphenyl)oxoethyl)-((1- methyloxabicyclo[2.2.1]heptanyl)methyl)carbamoyl)- 15 5-(trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2,6-dichloromethylphenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazol 20 yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichloromethylphenyl)oxoethyl)-((3,3- dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 25 4-(4-((2-(2,6-dichloromethylphenyl)oxoethyl)-(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- icyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(2,6-dichlorophenyl)oxoethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) 30 (trifluoromethyl)-1H-pyrazolyl)bicyclo[2.2.2]octane ylic acid; 4-(4-((2-(2,6-dichlorophenyl)oxoethyl)-(2,2- ylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid; 35 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-((3,3-dimethylcyclobutyl)methyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane 10 carboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 15 4-(4-((2-(2-chloromethoxyphenyl)oxoethyl)- ((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 20 4-(4-((2-(2-chloromethoxyphenyl)oxoethyl)-((3,3- dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(2-chloromethoxyphenyl)oxoethyl)-(4,4- 25 ylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((1- (trifluoromethyl)cyclopropyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane 30 ylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((1- fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 35 (2-(3,5-dichloropyridinyl)oxoethyl)-((1- methylcyclopropyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((2,2,3,3-tetramethylcyclopropyl)methyl)carbamoyl) uoromethyl)pyrazolyl)bicyclo[2.2.2]octane 5 carboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((4- fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 10 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((4- fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.1]heptane carboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2,2- 15 ylbutyl)carbamoyl)(trifluoromethyl)pyrazol yl)bicyclo[2.2.2]octanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2- fluoromethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane 20 carboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)ethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol lohexanecarboxylic acid; 4-(4-((2-(3-chlorofluoropyridinyl) 25 oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)bicyclo(2.2.2)octanecarboxylic acid; 4-(4-((3,3-dimethylcyclobutyl)methyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane carboxylic acid; 4-(4-((4,4-dimethylcyclohexyl)-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane 35 carboxylic acid; 4-(4-(2,2-dimethylbutyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane ylic acid; 4-(4-(2,2-dimethylpropyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)bicyclo[2.2.2]octane ylic acid; cis(4-(2-(2,6-dichlorofluorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclobutanecarboxylic 10 acid; cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol lobutanecarboxylic acid; cis(4-(2-(2,6-dichlorofluorophenyl)oxoethyl)- 15 (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((4- fluorophenyl)methyl)carbamoyl) 20 (trifluoromethyl)pyrazolyl)hydroxycyclohexane carboxylic acid; cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((4- fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)aminocyclohexane 25 carboxylic acid; cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)-((4- fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)aminocyclohexane carboxylic acid; 30 cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; cis(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 35 yl)fluorocyclohexanecarboxylic acid; N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-((3,5- difluorophenyl)methyl)(trans xycarbamoyl)cyclohexyl) (trifluoromethyl)pyrazolecarboxamide; N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-((3,5- difluorophenyl)methyl)(trans 5 (methoxycarbamoyl)cyclohexyl) (trifluoromethyl)pyrazolecarboxamide; 3,5-dichloropyridinyl)oxoethyl)-N-(3,5- difluorobenzyl)(transhydroxycyclohexyl) uoromethyl)-1H-pyrazolecarboxamide; 10 N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-(4- fluorobenzyl)(cis(methylsulfonyl)cyclohexyl) (trifluoromethyl)-1H-pyrazolecarboxamide; N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-(4- fluorobenzyl)(trans(methylsulfonyl)cyclohexyl) 15 (trifluoromethyl)-1H-pyrazolecarboxamide; N-(2-(3,5-dichloropyridinyl)oxoethyl)-N-(4- fluorobenzyl)(trans((2- hydroxyethyl)carbamoyl)cyclohexyl)(trifluoromethyl)- 1H-pyrazolecarboxamide; 20 transmethyl(4-(2-((2-methylpropanyl)oxy)ethyl- (2-oxo(2,4,6-trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; transmethyl(4-(2-oxaspiro[3.5]nonanyl-(2-oxo 25 (2,4,6-trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)cyclobutanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclobutane 35 carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclobutanecarboxylic acid; trans(2-((1-(4-carboxycyclohexyl) (trifluoromethyl)pyrazolecarbonyl)-((3,5- difluorophenyl)methyl)amino)acetyl)-3,5-dichlorobenzoic 5 acid; trans(4-(((1R,2S)tert-butylcyclopropyl)-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 10 4-(4-(((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)(2-hydroxy(2-methoxyphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 20 3-yl)(2-hydroxy(2-methoxyphenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)(2-hydroxy(2- 25 (trifluoromethyl)phenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)(2-hydroxy(2- 30 (trifluoromethyl)phenyl)ethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)(2-hydroxy(pyridinyl)ethyl)carbamoyl) 35 (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid; trans(4-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 2-hydroxy(3-methylpyrazinyl)ethyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-(((2R)(2,6-dichlorophenyl)fluoroethyl)- 5 ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(((2R)(2-chloromethoxyphenyl) hydroxyethyl)-(2,2-dimethylpropyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(((2S)(2,6-dichlorophenyl)fluoroethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 15 ylic acid; trans(4-(((2S)(2-chloromethoxyphenyl) hydroxyethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 20 trans(4-((1-acetylazetidinyl)-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((1-fluorocyclopentyl)methyl-(2-oxo(2,4,6- 25 trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((1-methylbicyclo[2.2.1]heptanyl)methyl-(2- oxo(2,4,6-trichlorophenyl)ethyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((1-methyloxabicyclo[2.2.1]heptan yl)methyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) 35 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,4-dichloromethoxyphenyl) yl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,5-dichlorophenyl)oxoethyl)-((3,5- 5 difluorophenyl)methyl)carbamoyl) uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloro(difluoromethyl)phenyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloro(trifluoromethoxy)phenyl)- 2-oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 15 acid; trans(4-((2-(2,6-dichloro(trifluoromethyl)phenyl)- 2-oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 20 trans(4-((2-(2,6-dichloro(trifluoromethyl)phenyl)- 2-oxoethyl)-(2-((2-methylpropan yl)oxy)ethyl)carbamoyl)(trifluoromethyl)pyrazol lohexanecarboxylic acid; trans(4-((2-(2,6-dichloro(trifluoromethyl)phenyl)- 25 2-oxoethyl)-(2-((2-methylpropan yl)oxy)ethyl)carbamoyl)(trifluoromethyl)pyrazolyl)- 1-methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorocyanophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) 30 (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorocyclopropylphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((1-fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((1-methylbicyclo[2.2.1]heptanyl)methyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- thyloxabicyclo[2.2.1]heptan yl)methyl)carbamoyl)(trifluoromethyl)pyrazolyl) 10 methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((1-methylbicyclo[2.2.1]heptanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane ylic acid; 20 trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- 25 ((3,5-difluorophenyl)methyl)carbamoyl) (difluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- ((4,4-dimethylcyclohexyl)methyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (1-methylpiperidinyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 35 carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (1-propanylpiperidinyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (2-((2-methylpropanyl)oxy)ethyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)methylcyclohexane ylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (2-(3-fluoropiperidinyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 10 carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (2,2-dimethylbutyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (3-(2,2-dimethylpropyl)cyclobutyl)carbamoyl) 20 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) 25 methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- 35 imethylpentynyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl)propanylpyrazol- 1-yl)methylcyclohexanecarboxylic acid; 4-(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- 5 (8-methylazabicyclo[3.2.1]octanyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (8-propanylazabicyclo[3.2.1]octanyl)carbamoyl)- 10 5-(trifluoromethyl)pyrazol-1yl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichlorofluorophenyl)oxoethyl)- (spiro[2.3]hexanylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 15 carboxylic acid; trans(4-((2-(2,6-dichlorohydroxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 20 trans(4-((2-(2,6-dichloromethoxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- 25 ((1-fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- ((1-methyloxabicyclo[2.2.1]heptan 30 yl)methyl)carbamoyl)(trifluoromethyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)methyl-1H-pyrazolyl) 35 cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- ((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- (4,4-dimethylpentynyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 10 carboxylic acid; trans(4-((2-(2,6-dichloromethylphenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-((2-(2,6-dichlorophenyl)-2,2-difluoroethyl)- ((4-fluorophenyl)methyl)carbamoyl) uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl)fluoroethyl)(4- 20 fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl)methylpropyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 25 acid; trans(4-((2-(2,6-dichlorophenyl)oxoethyl)-((1- fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 30 trans(4-((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan bamoyl)methyl-1H-pyrazolyl) cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl) 35 oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(1-fluorocyclopropyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl)oxoethyl)-(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)methylcyclohexanecarboxylic acid; 4-(4-((2-(2,6-dichlorophenyl)oxoethyl)(3,5- 5 difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl)oxoethyl)-(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; 10 trans(4-((2-(2,6-dichlorophenyl)oxoethyl)- (pyridazinylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2,6-dichlorophenyl)oxoethyl)- 15 (pyrimidinylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-acetamidochlorophenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) 20 uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-aminochloropyridinyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 25 acid; trans(4-((2-(2-aminomethylphenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(2-aminochlorophenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-aminophenyl)oxoethyl)-((3,5- 35 difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-chloro(trifluoromethyl)phenyl) yl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 5 trans(4-((2-(2-chloro-4,6-difluorophenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-chloro-4,6-dimethylphenyl)oxoethyl)- 10 ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-chloro-4,6-dimethylphenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) 15 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chlorofluorophenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; 20 trans(4-((2-(2-chloro(difluoromethoxy)phenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chloro(difluoromethoxy)phenyl) 25 yl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloro(difluoromethoxy)phenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 30 yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(4,4-dimethylpentynyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloro(trifluoromethyl)phenyl) yl)-((1R,3r,5S)-6,6-dimethyl 5 bicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(spiro[2.3]hexanylmethyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 15 carboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 20 trans(4-((2-(2-chloro(trifluoromethyl)phenyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 4-(4-((2-(2-chloro(trifluoromethyl)phenyl) 25 oxoethyl)-((1-fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chlorocyanomethylphenyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(2-chloroethynylphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(2-chlorofluorophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chlorofluorophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 5 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid; trans(4-((2-(2-chlorofluorophenyl)oxoethyl)- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 10 carboxylic acid; trans(4-((2-(2-chlorohydroxyphenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 15 4-(4-((2-(2-chloromethoxyphenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chloromethoxyphenyl) 20 hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chloromethoxyphenyl) yethyl)-(4,4-dimethylcyclohexyl)carbamoyl) 25 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- ((1R,3r,5S)-6,6-dimethyl bicyclo(3.1.0)hexanyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- ((3,3-dimethylcyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 35 carboxylic acid; trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- ((4,4-dimethylcyclohexyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- imethylpropyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chloromethoxyphenyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 10 acid; trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- (4,4-dimethylpentynyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-((2-(2-chloromethoxyphenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(2-chlorophenyl) 20 hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; 4-(4-((2-(2-chlorophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 25 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chlorophenyl) hydroxypropyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) 30 (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(2-chlorophenyl)oxoethyl)-((3,5- rophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(2-chlorothiophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloro-1,2-thiazolyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloro-1H-pyrazolyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 10 acid; trans(4-((2-(3,5-dichloromethylpyrazolyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 15 trans(4-((2-(3,5-dichlorophenyl)oxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)-2,2- difluoroethyl)-((3,5-difluorophenyl)methyl)carbamoyl) 20 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) hydroxyethyl)(4-fluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 25 acid; trans(4-((2-(3,5-dichloropyridinyl) methoxyethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (((2R)-5,5-dimethyloxolanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 35 (((2R)oxopyrrolidinyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (((2S)-5,5-dimethyloxolanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 5 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (((2S)oxopyrrolidinyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 10 oxoethyl)(((R)-tetrahydrofuranyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(((S)-tetrahydrofuranyl)methyl)carbamoyl) 15 (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-(trifluoromethyl)cyclopropyl)methyl)carbamoyl) uoromethyl)pyrazolyl)cyclohexanecarboxylic 20 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 25 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-fluorocyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 30 ((1-hydroxycyclopentyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-methyloxabicyclo[2.2.1]heptan 35 yl)methyl)carbamoyl)(trifluoromethyl)pyrazol yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-methylbicyclo[2.2.1]heptanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 5 ((1-methylbicyclo[2.2.1]heptanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-methyloxabicyclo[2.2.1]heptan 10 yl)methyl)carbamoyl)(trifluoromethyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1-methylcyclohexyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 15 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)((1- cyclopropyl)methyl)carbamoyl)(trifluoromethyl)- 1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 20 ((1-methylpiperidinyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1R)-3,3-dimethylcyclopentyl)carbamoyl) 25 uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1R,3r,5S)-6,6-dimethyl bicyclo[3.1.0]hexanyl)carbamoyl) 35 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1S)-3,3-dimethylcyclopentyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 5 ((1S)-3,3-dimethylcyclopentyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1S,2R)phenylcyclopropyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((1S,2R)propanylcyclopropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 15 carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- S)propanylcyclopropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 20 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((2,2,3,3-tetramethylcyclopropyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane ylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 25 ((2-hydroxyphenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 3,3-dimethylbutanyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((2S)-3,3-dimethylbutanyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3-((2-methylpropan yl)oxy)cyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 5 ((3-(2,2-dimethylpropyl)cyclobutyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,3-dimethylcyclobutyl)methyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,3-dimethylcyclobutyl)methyl)carbamoyl) methylpyrazolyl)methylcyclohexanecarboxylic 15 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (difluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 20 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) uoromethyl)pyrazolyl)ethylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 25 ((3,5-difluorophenyl)methyl)carbamoyl) (hydroxymethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl)propan 30 ylpyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl)methylpyrazol lohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 35 ((3,5-difluorophenyl)methyl)carbamoyl) (difluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((3-hydroxyphenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 5 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4,4-difluorocyclohexyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 10 oxoethyl)((4,4-dimethylcyclohexyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-fluorophenyl)methyl)carbamoyl) 15 (trifluoromethyl)pyrazolyl)hydroxycyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyanocyclohexane 20 carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- uorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyanocyclohexane carboxylic acid; 25 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-fluorophenyl)methyl)carbamoyl)(2,2,2- trifluoroethyl)pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 30 droxymethylcyclohexyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- ((4-hydroxyphenyl)methyl)carbamoyl) 35 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- dimethyloxanyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 5 oxoethyl)((tetrahydro-2H-pyranyl)methyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(1- ((2-methylpropanyl)oxy)propanyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(1- (2,2-dimethylpropanoyl)azetidinyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 15 acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(1- (2-methylpropyl)cyclopropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 20 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (1,2,2,6,6-pentamethylpiperidinyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(1- 25 methoxypropanyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(1- spiro[2.3]hexanylethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 30 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2- ((2-methylpropanyl)oxy)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 35 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2- ((2-methylpropanyl)oxy)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,2,2-trifluoroethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 5 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (2,2-dimethylbutyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 10 oxoethyl)(2,3-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (2,3-dihydro-1H-indenyl)carbamoyl) 15 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(2,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic 20 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2- ethylfluorobutyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 25 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(2- fluoromethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(2- fluoromethylpropyl)carbamoyl) 30 (trifluoromethyl)pyrazolyl)methylcyclohexane ylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(2- methoxymethylpropyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; 35 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(3- thylpropanyl)oxy)cyclobutyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(3- ((2-methylpropanyl)oxy)cyclobutyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 5 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (3,3-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 10 trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3-dimethylbutyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 15 oxoethyl)(3,4-difluorobenzyl)carbamoyl) uoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) 20 (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) yl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) 25 methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(3- methylbutenyl)carbamoyl)(trifluoromethyl)pyrazol yl)methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(3- 30 methylbutenyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(4- (trifluoromethyl)cyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(4- (trifluoromethyl)cyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (4,4-difluorocyclohexyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (4,4-dimethylpentynyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 10 acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 15 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) oromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 20 (4,4-dimethylcyclohexyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- benzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol 25 yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- 30 fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)fluorocyclohexanecarboxylic acid; 35 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)(4- fluorobenzyl)carbamoyl)(1,1-difluoroethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(4- methylpentanyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 5 (5,5-dimethyloxolanyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (6,6-dimethyloxanyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)-(7- oxabicyclo[2.2.1]heptanylmethyl)carbamoyl) uoromethyl)pyrazolyl)cyclohexanecarboxylic 15 acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(furanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 20 trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(furanylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) 25 oxoethyl)(isobutyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) yl)(isopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(3,5-dichloropyridinyl) yl)(neopentyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (oxanyl)carbamoyl)(trifluoromethyl)pyrazol 35 yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (oxolanyl)carbamoyl)(trifluoromethyl)pyrazol yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (piperidinylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 5 acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(pyrazinylmethyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 10 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (pyridinylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- 15 inylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(pyridinylmethyl)carbamoyl) 20 (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- (spiro[2.3]hexanylmethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 25 acid; trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(spiro[2.5]octanylmethyl)carbamoyl) uoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- pentanylcarbamoyl)(trifluoromethyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- spiro[2.5]octanylcarbamoyl) 35 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3-chloro(trifluoromethyl)pyridin yl)oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3-chlorofluoropyridinyl) 5 hydroxyethyl) ((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3-chlorofluoropyridinyl) 10 hydroxyethyl) ((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3-chlorofluoropyridinyl) 15 oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan bamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3-chlorofluoropyridinyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl) 20 uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3-chlorofluoropyridinyl) oxoethyl)-(2,2-dimethylbutyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 25 ylic acid; trans(4-((2-(3-chlorofluoropyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; 30 trans(4-((2-(3-chlorohydroxypyridinyl) oxoethyl)-((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3-chloromethoxypyridinyl) 35 oxoethyl)-((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3-chloromethoxypyridinyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 5 trans(4-((2-(3-chloromethylpyridinyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan bamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; 4-(4-((2-(3-chloromethylpyridinyl) 10 oxoethyl)-(2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3-chloromethylpyridinyl) oxoethyl)(3,5-difluorobenzyl)carbamoyl) 15 (trifluoromethyl)-1H-pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(3-chloropyridinyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) 20 methylcyclohexanecarboxylic acid; trans(4-((2-(3-chloropyridinyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; 25 trans(4-((2-(3-chloropyridinyl)hydroxyethyl)- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3-chloropyridinyl)hydroxyethyl)- 30 (2,2-dimethylpropyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((2-(3-chloropyridinyl)oxoethyl) ((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 35 yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3-chlorothiophenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(3-chlorothiophenyl) 5 hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- arbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(4-carbamoyl-2,6-dichlorophenyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl) 10 uoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-(4-chloro-1H-indazol yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) 15 methylcyclohexanecarboxylic acid; trans(4-((2-(4-chloro-1H-indolyl)oxoethyl)-(2,2- dimethylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)methylcyclohexanecarboxylic acid; trans(4-((2-(4-chloro-1H-indol 20 yl)propyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(4-chloro-1H-pyrrolo(2,3-c)pyridin yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 25 yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; 4-(4-((2-(4-chloro-2,6-dimethylphenyl)oxoethyl)- ((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 30 acid; trans(4-((2-(4-chloro-2,6-dimethylphenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 35 trans(4-((2-(4-chloromethyl-1H-indol yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(4-chlorooxo-1H-pyridinyl) oxoethyl)-((4-fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 5 acid; trans(4-((2-(4-methylsulfoyl-2,6-dichlorophenyl) yl)-((3,5-difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 10 trans(4-((2-(5-chloromethylpyrimidinyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(5-chloropyrimidinyl) 15 hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 3-yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-(7-chloro-1H-benzo(d)imidazol yl)ethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 20 yl)carbamoyl)(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(4-((2-amino(2-chloro fluorophenyl)ethyl)((1R,3r,5S)-6,6- dimethylbicyclo[3.1.0]hexanyl)carbamoyl) 25 (trifluoromethyl)-1H-pyrazolyl) cyclohexanecarboxylic acid; trans(4-((2-chloro-1,3-thiazolyl)methyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 30 acid; trans(4-((2-cyanophenyl)methyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 35 4-(4-((2-cyclohexyloxoethyl)(3,5- difluorobenzyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((2-cyclopentyloxoethyl)-((3,5- difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 5 4-(4-((2-cyclopropylethyl)(2-(3,5-dichloropyridin- 4-yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((2-oxo(2,4,6-trichlorophenyl)ethyl)- (spiro[2.3]hexanylmethyl)carbamoyl) 10 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((3,3-dimethylcyclobutyl)methyl-(2-oxo (2,4,6-trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 15 carboxylic acid; trans(4-((3,5-difluorobenzyl)(2-(2,4-dimethylfuran yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorobenzyl)(2-(3,5-difluorophenyl)- 20 2-oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorobenzyl)(2-(3,5-difluoropyridin- 4-yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; 25 trans(4-((3,5-difluorobenzyl)(2-(3,5-dimethylisoxazol- 4-yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorobenzyl)(2-(3,5-dimethylpyridin- 2-oxoethyl)carbamoyl)(trifluoromethyl)-1H- 30 pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorobenzyl)(2-(4-hydroxyphenyl) oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; 4-(4-((3,5-difluorobenzyl)(2-oxo(2,4,6- 35 trichlorophenyl)ethyl)carbamoyl)(trifluoromethyl)-1H- pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorobenzyl)(2-oxo(pyridin yl)ethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorophenyl)methyl-(2-(2,4-dimethyl- 1H-pyridinyl)oxoethyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorophenyl)methyl-(2-(2,4- dimethylpyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 10 acid; trans(4-((3,5-difluorophenyl)methyl-(2-(2,4- dimethylthiophenyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 15 trans(4-((3,5-difluorophenyl)methyl-(2-(2,6- dihydroxyphenyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((3,5-difluorophenyl)methyl-(2-(2,6- 20 dimethoxyphenyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorophenyl)methyl-(2-(2-hydroxy methoxyphenyl)oxoethyl)carbamoyl) 25 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorophenyl)methyl-(2-(3,5- dimethoxypyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 30 acid; trans(4-((3,5-difluorophenyl)methyl-(2-(4,6- dimethylpyrimidinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 35 trans(4-((3,5-difluorophenyl)methyl-(2-oxo(1H- pyrazolyl)ethyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((3,5-difluorophenyl)methyl-(2-oxo(2,4,6- trihydroxypyrimidinyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 5 trans(4-((3-cyanomethylcyclopentyl)-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3-cyanophenyl)methyl-(2-(3,5- 10 dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 4-(4-((3-tert-butylcyclobutyl)-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) 15 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((3-tert-butylcyclobutyl)-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 20 acid; trans(4-((3-tert-butylcyclobutyl)methyl-(2-(3,5- ropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 25 trans(4-((3-tert-butylcyclobutyl)methyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((4,4-dimethylcyclohexyl)-(2-(3,5-dimethyl-1H- 30 pyrazolyl)ethyl)carbamoyl)(trifluoromethyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; trans(4-((4,4-dimethylcyclohexyl)-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 35 acid; trans(4-((4,4-dimethylcyclohexyl)-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-((4,4-dimethylcyclohexyl)methyl-(2-oxo (2,4,6-trichlorophenyl)ethyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 4-(4-((4-chloro-1,3-thiazolyl)methyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 10 acid; 4-(4-((4-chlorobenzyl)(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((4-cyanophenyl)methyl-(2-(3,5- 15 dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((5-chloro-1,3-thiazolyl)methyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) 20 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-((cyclobutylmethyl)(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; 25 4-(4-((cyclohexylmethyl)(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((cyclopentylmethyl)(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 30 1-yl)cyclohexanecarboxylic acid; trans(4-((cyclopropylmethyl)(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-(1-adamantylmethyl-(2-(3,5-dichloropyridin 35 yl)oxoethyl)carbamoyl)(trifluoromethyl)pyrazol yl)cyclohexanecarboxylic acid; trans(4-(1-cyclopentylethyl-(2-(3,5-dichloropyridin yl)oxoethyl)carbamoyl)(trifluoromethyl)pyrazol yl)cyclohexanecarboxylic acid; 4-(4-(2-(2,6-dichlorofluorophenyl)ethyl-((3,5- rophenyl)methyl)carbamoyl) 5 (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-(2-(2,6-dichlorophenyl)propyl-((3,5- difluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic 10 acid; trans(4-(2-(2,6-dichlorophenyl)propyl-((4- fluorophenyl)methyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; 15 trans(4-(2-(3,5-dichloropyridinyl)ethyl-((4- fluorophenyl)methyl)carbamoyl)-3,5- bis(trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-(2-(4-chloro-1H-indolyl)ethyl-(2,2- 20 dimethylpropyl)carbamoyl)(trifluoromethyl)pyrazol yl)methylcyclohexanecarboxylic acid; trans(4-(2-(4-chloro-1H-indolyl)ethyl-(4,4- dimethylcyclohexyl)carbamoyl)(trifluoromethyl)pyrazol- 1-methylcyclohexanecarboxylic acid; 25 trans(4-(2-(4-chloromethyl-1H-indolyl)ethyl- (2,2-dimethylpropyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(2,2-dimethylbutyl-(2-oxo(2,4,6- 30 trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(2,2-dimethylpropyl-(2-(1H-indol yl)ethyl)carbamoyl)(trifluoromethyl)pyrazolyl) 35 methylcyclohexanecarboxylic acid; trans(4-(2,2-dimethylpropyl-(2-oxo(2,4,6- trichlorophenyl)ethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 4-(4-(2-tert-butylsulfanylethyl-(2-(2,6-dichloro fluorophenyl)oxoethyl)carbamoyl) 5 uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(2-tert-butylsulfinylethyl-(2-(2,6-dichloro fluorophenyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane 10 carboxylic acid; trans(4-(2-tert-butylsulfonylethyl-(2-(2,6-dichloro fluorophenyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; 15 trans(4-(3-bicyclo[2.2.1]heptanyl-(2-(3,5- dichloropyridinyl)oxoethyl)carbamoyl) (trifluoromethyl)pyrazolyl)cyclohexanecarboxylic acid; trans(4-(4,4-dimethylpentynyl-(2-oxo(2,4,6- 20 trichlorophenyl)ethyl)carbamoyl) uoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(8-azabicyclo[3.2.1]octanyl-(2-(2,6- dichlorofluorophenyl)oxoethyl)carbamoyl) 25 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(4-(benzyl(2-(3,5-dichloropyridinyl) oxoethyl)carbamoyl)(trifluoromethyl)-1H-pyrazol yl)cyclohexanecarboxylic acid; 30 trans(4-(cyclohexyl-(2-(3,5-dichloropyridinyl) oxoethyl)carbamoyl)(trifluoromethyl)pyrazol yl)cyclohexanecarboxylic acid; trans(4-(cyclopentyl-(2-(3,5-dichloropyridinyl) oxoethyl)carbamoyl)(trifluoromethyl)pyrazol 35 yl)cyclohexanecarboxylic acid; trans(5-(aminomethyl)((2-(3,5-dichloropyridin yl)oxoethyl)-((3,5- difluorophenyl)methyl)carbamoyl)pyrazolyl)cyclohexane- 1-carboxylic acid; trans(5-chloro((2-(2,6-dichlorofluorophenyl) oxoethyl)-(4,4-dimethylcyclohexyl)carbamoyl)pyrazol 5 yl)methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2,6-dichloromethylphenyl) oxoethyl)-(2,2-dimethylpropyl)carbamoyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2,6-dichloromethylphenyl) 10 oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan 15 yl)carbamoyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2,6-dichlorophenyl)oxoethyl)- (2,2-dimethylpropyl)carbamoyl)pyrazolyl) cyclohexanecarboxylic acid; 20 trans(5-chloro((2-(2,6-dichlorophenyl)oxoethyl)- (4,4-dimethylcyclohexyl)carbamoyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2-chloromethoxyphenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- 25 3-yl)carbamoyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(2-chloromethoxyphenyl) hydroxyethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan- arbamoyl)-1H-pyrazolyl) 30 methylcyclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl)pyrazol- yclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) 35 oxoethyl)-((1-methylcyclopropyl)methyl)carbamoyl)pyrazol- 1-yl)methylcyclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) oxoethyl)-((3,3- dimethylcyclobutyl)methyl)carbamoyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) 5 oxoethyl)-((1-methyloxabicyclo[2.2.1]heptan yl)methyl)carbamoyl)pyrazolyl)methylcyclohexane carboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) oxoethyl)-((1- 10 (trifluoromethyl)cyclopropyl)methyl)carbamoyl)pyrazol yl)methylcyclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)-1H-pyrazolyl) 15 methylcyclohexanecarboxylic acid; trans(5-chloro((2-(3,5-dichloropyridinyl) yl)-(2-ethylfluorobutyl)carbamoyl)pyrazolyl)- 1-methylcyclohexanecarboxylic acid; trans(5-cyano((2-(3,5-dichloropyridinyl) 20 oxoethyl)-(2,2-dimethylpropyl)carbamoyl)pyrazolyl) methylcyclohexanecarboxylic acid; trans(5-cyclopropyl((2-(2,6-dichlorophenyl) oxoethyl)((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan yl)carbamoyl)-1H-pyrazolyl) 25 methylcyclohexanecarboxylic acid; 4-(5-cyclopropyl((2-(3,5-dichloropyridinyl)- 2-oxoethyl)-((3,5- difluorophenyl)methyl)carbamoyl)pyrazolyl)cyclohexane- 1-carboxylic acid; 30 trans(5-tert-butyl((2-(3,5-dichloropyridinyl) oxoethyl)-((3,5-difluorophenyl)methyl)carbamoyl)pyrazol- 1-yl)cyclohexanecarboxylic acid; trans(4-((2-(3,5-dichloropyridinyl)oxoethyl)- imethylpropyl)carbamoyl) 35 (trifluoromethyl)pyrazolyl)methylcyclohexane carboxylic acid; and trans(4-((2-(3,5-dichloropyridinyl) oxoethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazolyl) methylcyclohexanecarboxylic acid.
13. Use of a compound according to any one of 5 claims 1 to 12 or ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a e, wherein the disease is multiple sclerosis, c rheumatoid arthritis, ankylosing spondylitis, systemic erythematodes, psoriasis, psoriatic 10 arthritis, inflammatory bowel disease or asthma.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or pharmaceutically able salt thereof.
15. A compound according to any one of claims 1 to 15 12, substantially as herein described with nce to any example thereof.
16. A use according to claim 13, substantially as herein described with reference to any example thereof.
17. A pharmaceutical composition according to claim 20 14, substantially as herein described with reference to any example thereof.
NZ723766A 2014-02-28 2015-02-27 Pyrazole amide derivative NZ723766B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2014039880 2014-02-28
JP2014-039880 2014-02-28
PCT/JP2015/056584 WO2015129926A1 (en) 2014-02-28 2015-02-27 Pyrazole amide derivative

Publications (2)

Publication Number Publication Date
NZ723766A NZ723766A (en) 2022-03-25
NZ723766B2 true NZ723766B2 (en) 2022-06-28

Family

ID=

Similar Documents

Publication Publication Date Title
US9365522B2 (en) Pyrazole amide derivative
EP3740478B1 (en) Fused imidazole derivatives as il-17 modulators
CN109265400B (en) Arginine methyltransferase inhibitors and uses thereof
AU2007292155B2 (en) Imidazole derivative
EP3233837B1 (en) Tetrahydroquinoline sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t))
RU2655380C2 (en) Cycloalkyl nitrile pyrazolo pyridones as janus kinase inhibitors
EP4132650B1 (en) Difluorocyclohexyl derivatives as il-17 modulators
JP2016537369A (en) Substituted 4,5,6,7-tetrahydropyrazolo [1,5-A] pyrazine derivatives as casein kinase 1D / E inhibitors
EP3426243B1 (en) 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
TWI568737B (en) Substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine compounds as pde2 inhibitors
JP6322275B2 (en) N- (2-cyanoheterocyclyl) pyrazolopyridone as Janus kinase inhibitor
TW201514136A (en) Histone deacetylase inhibitors and compositions and methods of use thereof
JP2016514709A (en) Geminal-substituted cyanoethylpyrazolopyridone as a Janus kinase inhibitor
NZ723766B2 (en) Pyrazole amide derivative
WO2024073658A1 (en) Hydantoin modulators of cholesterol biosynthesis and their use for promoting remyelination
EP4423068A1 (en) Rxfp1 agonists
EA037845B1 (en) 4-hydroxy-2-phenyl-1,3-thiazol-5-yl methanone derivatives as trpm8 antagonists