WO2010059606A2 - Inhibitors of diacylglycerol acyltransferase - Google Patents

Inhibitors of diacylglycerol acyltransferase Download PDF

Info

Publication number
WO2010059606A2
WO2010059606A2 PCT/US2009/064747 US2009064747W WO2010059606A2 WO 2010059606 A2 WO2010059606 A2 WO 2010059606A2 US 2009064747 W US2009064747 W US 2009064747W WO 2010059606 A2 WO2010059606 A2 WO 2010059606A2
Authority
WO
WIPO (PCT)
Prior art keywords
moiety
independently selected
alkyl
another embodiment
formula
Prior art date
Application number
PCT/US2009/064747
Other languages
French (fr)
Other versions
WO2010059606A3 (en
Inventor
Pauline C. Ting
Robert G. Aslanian
Mary Ann Caplen
Jianhua Cao
David Won-Shik Kim
Hyunjin Kim
Rongze Kuang
Joe F. Lee
John H. Schwerdt
Heping Wu
Gang Zhou
Nicolas Zorn
Original Assignee
Schering Corporation
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 Schering Corporation filed Critical Schering Corporation
Priority to EP09752999A priority Critical patent/EP2346853A2/en
Priority to US13/129,830 priority patent/US20110224136A1/en
Priority to AU2009316790A priority patent/AU2009316790A1/en
Priority to MX2011005233A priority patent/MX2011005233A/en
Priority to CA2743723A priority patent/CA2743723A1/en
Priority to JP2011536592A priority patent/JP2012509275A/en
Priority to CN2009801549615A priority patent/CN102282138A/en
Publication of WO2010059606A2 publication Critical patent/WO2010059606A2/en
Publication of WO2010059606A3 publication Critical patent/WO2010059606A3/en

Links

Classifications

    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to certain heterocyclic compounds useful as diacylglycerol acyltransferase (“DGAT”) inhibitors, especially diacylglycerol acyltransferase 1 (“DGAT1”) inhibitors, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat or prevent various diseases including cardiovascular disease, dyslipidemia, obesity and diabetes (e.g., Type 2 diabetes).
  • DGAT diacylglycerol acyltransferase
  • DGAT1 diacylglycerol acyltransferase 1
  • Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets- Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270).
  • Diacylglycerol O-acyltransferase also known as diglyceride acyltransferase or DGAT
  • DGAT is a key enzyme in triglyceride synthesis.
  • DGAT catalyzes the final and rate-limiting step in the triacylglycerol synthesis from 1 ,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates.
  • DAG 1,2-diacylglycerol
  • DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, pp. 395-400).
  • DGAT1 and DGAT2 Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2 [see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, pp. 13018-13023, Lardizabal et al, Journal of Biological Chemistry (2001) 276, pp. 38862-38869 and Cases et al, Journal of Biological Chemistry (2001) 276, pp. 38870-38876]. Although both enzymes utilize the same substrates, there is no homology between DGAT1 and DGAT2. Both enzymes are widely expressed however some differences do exist in the relative abundance of expression in various tissues.
  • Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack et al, EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino- oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, pp. 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, pp. 1340-1346), substituted benzyl- phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, pp.
  • Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) pp. 1 125, 203-9), 2- bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, pp. 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, pp. 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, pp.
  • this invention discloses a compound, or pharmaceutically acceptable salts, solvates, ester or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the general formula I:
  • each A is independently selected from C(R 3 ) and N; or alternately the moiety:
  • X is independently selected from C(R 3 ), N, N(R 4 ), O and S, provided that no more than one X is S or O, and at least one X or one Y is N, O, or S;
  • Y is independently selected from C and N;
  • Z is a bond, N(R 4 ) or O;
  • L is either one of the three options (i), (ii) or (iii):
  • alkynyl H CH2 ) fQ -5 or i— Q -(CH 2 JtH , wherein Q is selected from the group consisting of -NH-, -N(R 11 )-, -O-, -S-, -C(O)-NH-, and - NH-C(O)-; t is 0, 1 , 2 or 3; R 11 is H or alkyl; and R 1 is selected from alkyl, aryl or cycloalkyl, wherein each of said alkyl, aryl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, haloalkoxy, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalky
  • W is selected from alkyl, alkenyl, alkynyl, ⁇ y 2h ⁇ ⁇ or
  • t is O, 1 , 2 or 3;
  • R 11 is H or alkyl; and
  • R 12 is a heterocycloalkyl containing 1-4 heteroatoms which can be the same or different and are independently selected from the group consisting of O, S and N, wherein said heterocycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cyclo
  • said heterocycloalkyl for R 12 in (ii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN,
  • said heterocycloalkyl for L in (iii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN, -OR C , -C(O)R C , -C(O)OR C , -C(O)N(R c )(R d ), -SF 5 , -OSF 5 , -Si(R c ) 3
  • R 3 is selected from the group of H, lower alkyl, hydroxy, halo, O-alkyl, O-haloalkyl, O-cycloalkyl, S-alkyl, S-haloalkyl, CN, CF 3 , -SF 5 , -OSF 5 , -Si(R c ) 3 , -SR C , cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, N-alkyl, N-haloalkyl, and N-cycloalkyl;
  • R 4 is selected from the group of H, lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl;
  • R 5 is selected from the group of lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl;
  • R 10 is (i) a 5-6-membered heterocyclyl ring having from 1 to 3 ring N atoms, (ii) an aryl ring, or (iii) a heteroaryl ring, wherein each of said heterocyclyl ring, aryl ring and heteroaryl ring is unsubstituted or optionally independently substituted, off of a ring N atom or a ring C atom, with one or more G moieties, wherein G is the same or different and is selected independently from:
  • R a is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each moiety being selected independently from the group consisting of O-haloalkyl, S-haloalkyl
  • R b is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;
  • R c is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl
  • R d is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein each of said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl in R b , R c , and R d can be unsubstituted or optionally independently substituted with 1 -2 substituents independently selected from halo, OH, NH 2 , CF 3 , CN, Oalkyl, NHalkyl, N(alkyl) 2 and Si(alkyl) 3 ; and t is 0, 1 , 2 or 3.
  • spirocyclyl refers to a cyclic group substituted off the same carbon atom. Some non-limiting examples would be:
  • bicyclic heterocyclyl refers to bicyclic compounds containing heteroatom as part of the ring atoms.
  • a non-limiting example would be:
  • COOH bioisostere is as defined in The Practice of Medicinal Chemistry, C. G. Wermuth Ed.; Academic Press: New York, 1996, p. 203.
  • Non-limiting examples of COOH bioisosteres include -SO 3 H, -S(O) 2 NHR 7 , -S(O) 2 NHC(O)R 7 , -CH 2 S(O) 2 R 7 , -C(O)NHS(O) 2 R 7 , -C(O)NHOH, -C(O)NHCN, -CH(CF 3 )OH, -C(CFa) 2 OH, -P(O)(OH) 2 and the groups listed below:
  • R 7 is selected from alkyl, aryl or heteroaryl.
  • this invention provides compositions comprising at least one compound of Formula I.
  • this invention provides pharmaceutical compositions comprising at least one compound of Formula I and at least one pharmaceutically acceptable carrier.
  • this invention provides a method of treating diabetes in a patient in need of such treatment using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
  • this invention provides a method of treating diabetes in a patient in need of such treatment, e.g., Type 2 diabetes, using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
  • this invention provides a method of treating metabolic syndrome in a patient in need of such treatment, using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
  • this invention provides a method of inhibiting DGAT using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
  • this invention provides a method of inhibiting DGAT1 using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
  • the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof.
  • the following embodiments are independent of each other; different such embodiments can be independently selected and combined in various combinations. Such combinations should be considered as part of the invention.
  • A is C(R 3 ). In another embodiment, A is N.
  • one A is N and the other A moieties are C(R 3 ).
  • one A is C(R 3 ) and the other A moieties are N.
  • two A moieties are N and the other two A moieties are C(R 3 ).
  • X is C(R 3 ).
  • X is N.
  • X is N(R 4 ).
  • X is O. In another embodiment, X is S.
  • At least one X is O.
  • At least one Y is N.
  • one X is O and one other X is N.
  • one X is O and one other X is S. In another embodiment, one X is O, one X is N and the other X is
  • Y is C.
  • Y is N.
  • R 1 when L is Option (i), R 1 is unsubstituted aryl. In another embodiment, when L is Option (i), R 1 is aryl substituted as previously described.
  • R 1 is unsubstituted alkyl.
  • R 1 when L is Option (i), R 1 is alkyl substituted as previously described. In another embodiment, when L is Option (i), R 1 is unsubstituted cycloalkyl.
  • R 1 is cycloalkyl substituted as previously described.
  • W is alkyl. In another embodiment, when L is Option (i), W is alkenyl.
  • Q is -NH-, -N(CH 3 )-, -O-, - S-, -C(O)-NH-, and -NH-C(O)-
  • Q is -C(O)-NH-.
  • W is alkenyl
  • Q is -NH-, -N(CH 3 )-, -O-, -S-, -C(O)-NH-, and -NH-C(O)-
  • Q is -C(O)-NH-.
  • R 12 when L is Option (ii), R 12 is heterocyclyl. In another embodiment, when L is Option (ii), R 12 is unsubstituted heterocyclyl.
  • R 12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is 3-7 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 when L is Option (ii), R 12 is pyrrolidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (ii), R 12 is piperidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is piperazinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 when L is Option (ii), R 12 is morpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (ii), R 12 is thiomorpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is azetidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is azepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is oxazepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • R 12 is the moiety:
  • R 12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is pyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is piperidinyl, wherein said piperidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is piperazinyl, wherein said piperazinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 when L is Option (ii), R 12 is morpholinyl, wherein said morpholinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 when L is Option (ii), R 12 is 4-8 membered heterocyclyl, containing 1 -3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is pyrrolidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is piperidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is piperazinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 12 is morpholinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is heterocyclyl.
  • L is optional (iii), L is unsubstituted heterocyclyl.
  • L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is 3-7 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is pyrrolidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is piperidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is optional (iii)
  • L is piperazinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L when L is Option (iii), L is morpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (iii), L is thiomorpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is azetidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L when L is Option (iii), L is azepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (iii), L is oxazepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
  • L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier.
  • L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is pyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is piperidinyl, wherein said piperidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is piperazinyl, wherein said piperazinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is morpholinyl, wherein said morpholinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is 4-8 membered heterocyclyl, containing 1 -3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier.
  • L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is pyrrolidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is piperidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is piperazinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • L is morpholinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
  • R 3 is H.
  • R 3 is lower alkyl. In another embodiment, R 3 is hydroxyl.
  • R 3 is -O-alkyl
  • R 3 is -CN.
  • R 3 is -CF 3 . In another embodiment, R 3 is -O- haloalkyl.
  • R 3 is -OSF 5
  • R 3 is -SF 5
  • R 4 is H.
  • R 4 is lower alkyl.
  • R 10 is a 5-6-membered heterocyclyl ring having from 1 to 3 ring N atoms, wherein said heterocyclyl ring is substituted, off of a ring N atom, with v/w ⁇ -C(O)-N(R b )-R a , wherein R a and R b are as previously described.
  • R 10 is a piperidinyl ring, wherein said piperidinyl ring is substituted, off of the ring N atom, with
  • R 10 is a piperazinyl ring, wherein said piperazinyl ring is substituted, off of a ring N atom, with * ⁇ /w--C(O)-N(R b )-R a , wherein R a and R b are as previously described.
  • R a is unsubstituted alkyl.
  • R a is alkyl substituted as previously described under formula I.
  • R a is unsubstituted aryl.
  • R a is aryl substituted as previously described under formula I.
  • R a is unsubstituted heteroaryl.
  • R a is heteroaryl substituted as previously described under formula I.
  • R a is unsubstituted cycloalkyl. In another embodiment, R a is cycloalkyl substituted as previously described under formula I.
  • R a is unsubstituted heterocyclyl.
  • R a is heterocyclyl substituted as previously described under formula I.
  • R b is H.
  • R b is lower alkyl
  • R 10 and R a are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and R 1 is unsubstituted aryl.
  • Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is alkyl.
  • R 10 and R a are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • Y are C, one A is N and the other A's are C, R 1 is aryl substituted as described previously under Formula I, and R 3 is alkyl.
  • R 10 and R a are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • R 10 is unsubstituted aryl.
  • R a and the other moieties are independently selected, R 10 and R a are as previously defined, one X is N, a second X is C(R 3 ), and the third X is O, both
  • Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is alkyl.
  • R 1 is unsubstituted aryl
  • R 3 is alkyl.
  • R a and the other moieties are independently selected, R 10 and R a are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • R 10 and R a are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • R a and the other moieties are independently selected, R 10 and R a are as previously defined, one X is N, a second X is C(R 3 ), and the third X is O, both
  • Y are C, one A is N and the other A's are C, R 1 is aryl substituted as described previously under Formula I, and R 3 is alkyl.
  • R 1 is aryl substituted as described previously under Formula I
  • R 3 is alkyl.
  • R a and the other moieties are independently selected, R 10 and R a are as previously defined, one X is N, a second X is C(R 3 ), and the third X is O, both
  • Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is haloalkyl.
  • R 1 is unsubstituted aryl
  • R 3 is haloalkyl.
  • R a and the other moieties are independently selected, R 10 and R a are as previously defined, one X is N, a second X is C(R 3 ), and the third X is O, both
  • Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is haloalkyl.
  • R 1 is unsubstituted aryl
  • R 3 is haloalkyl.
  • R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is -CN.
  • X, Y, L, W, Q, R 1 , A, R 10 , R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, R 1 is unsubstituted aryl, and R 3 is -CN.
  • Formula I wherein X, Y, L, W, Q, R 1 , A, R 10 ,
  • R a and the other moieties are independently selected, the moiety:
  • v ⁇ Y'V is one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R a and the other moieties are independently selected, the moiety:
  • V ⁇ . xx Y V ⁇ ⁇ is one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R a and the other moieties are independently selected, the moiety:
  • R a and the other moieties are independently selected, the moiety:
  • X x ⁇ is one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • one A is N and the other A's are C, and R 1 is aryl substituted as previously described under Formula I.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • X V is the moiety:
  • R 1 is unsubstituted aryl.
  • R 1 is uns instituted aryl.
  • R 1 is unsubstituted aryl.
  • T V V ⁇ . ⁇ x X V S ⁇ is the moiety: and R 1 is unsubstituted aryl.
  • v ⁇ Y'V is one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R a and the other moieties are independently selected, the moiety:
  • V ⁇ x V ⁇ is the moiety: and R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously under Formula I.
  • IS and R 1 is aryl substituted as described previously.
  • V 1 X V is the moiety:
  • R 1 is aryl substituted as described previously.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • X x ⁇ is the moiety:
  • R 1 is unsubstituted aryl.
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • one A is N and the other A's are C, and R 1 is unsubstituted aryl.
  • V o' ⁇ / one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • one A is N and the other A's are C, and R 1 is aryl substituted as previously described.
  • R 1 is unsubstituted aryl.
  • X x ⁇ is the moiety:
  • R 1 is unsubstituted aryl.
  • IS and R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • one A is N and the other A's are C, and R 1 is aryl substituted as described previously.
  • one A is N and the other A's are C, and R 1 is aryl substituted as previously described.
  • V is the moiety:
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R a and the other moieties are independently selected, the moiety:
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously.
  • R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted aryl.
  • V X ⁇ is
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • V Y ⁇ V IS the moiety:
  • R 1 is unsubstituted aryl.
  • R 1 is unsubstituted aryl.
  • R 1 is aryl substituted as described previously.
  • X x f is the moiety.
  • R 1 is aryl substituted as described previously.
  • X x ⁇ is the moiety:
  • R 1 is aryl substituted as described previously.
  • R 1 is aryl substituted as described previously under Formula I.
  • R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is alkyl substituted as described previously
  • Ra and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, R 1 is unsubstituted alkyl, and R 3 is haloalkyl.
  • one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • X x r is one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • X x ⁇ is one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • v- Y -V'V is one A is N and the other A's are C, and R 1 is alkyl substituted as described previously.
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • X x ⁇ is the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • X x f is the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • V Y ⁇ V is the moiety:
  • R 1 is unsubstituted alkyl.
  • X x f is one A is N and the other A's are C, and R 1 is alkyl substituted as described previously.
  • one A is N and the other A's are C, and R 1 is a ,lkyl substituted as previously described.
  • - ⁇ is the moiety:
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • X is the moiety:
  • R 1 is unsubstituted alkyl.
  • V Y ⁇ Y V is the moiety:
  • R 1 is unsubstituted alkyl.
  • V is the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • X x ⁇ is the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • X X S is the moiety: and R 1 is alkyl substituted as described previously.
  • R 1 is unsubstituted alkyl.
  • V Y ⁇ Y V is the moiety:
  • R 1 is unsubstituted alkyl.
  • V Y ⁇ V IS the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • V V ⁇ Y V is one A is N and the other A's are C, and R 1 is unsubstituted alkyl, R 10 is piperazinyl ring and R a is as previously described.
  • X x f is one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • one A is N and the other A's are C, and R 1 is unsubstituted alkyl.
  • one A is N and the other A's are C, and R 1 is alkyl substituted as previously described.
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • one A is N and the other A's are C, and R 1 is alkyl substituted as described previously.
  • one A is N and the other A's are C, and R 1 is alkyl substituted as previously described.
  • R 1 is alkyl substituted as previously described.
  • R a and the other moieties are independently selected, the moiety:
  • ⁇ v is the moiety:
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R 1 is alkyl substituted as described previously.
  • R a and the other moieties are independently selected, the moiety:
  • R 1 is alkyl substituted as described previously.
  • R 1 is unsubstituted alkyl.
  • V Y ⁇ Y V is the moiety:
  • R 1 is unsubstituted alkyl.
  • R 1 is unsubstituted alkyl.
  • R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, and R 1 is cycloalkyl substituted as described previously.
  • R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, R 1 is unsubstituted cycloalkyl, and R 3 is haloalkyl.
  • R a and the other moieties are independently selected, one X is N, a second X is C(R 3 ), and the third X is O, both Y are C, one A is N and the other A's are C, R 1 is unsubstituted cycloalkyl, R 3 is -CN.
  • X 'VY IS one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • V V ⁇ V IS one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • R a and the other moieties are independently selected, the moiety:
  • X x f is one A is N and the other A's are C, and R 1 is cycloalkyl substituted as previously described.
  • IS and R 1 is unsubstituted cycloalkyl.
  • Vv is and R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • X x r is the moiety:
  • R 1 is unsubstituted cycloalkyl.
  • X x f is the moiety:
  • R 1 is unsubstituted cycloalkyl.
  • V v ⁇ jl is the moiety:
  • R 1 is unsubstituted cycloalkyl.
  • V X" YN x x V ⁇ • is one A is N and the other A's are C, and R 1 is cycloalkyl substituted as described previously.
  • V- Y ⁇ V is one A is N and the other A's are C, and R 1 is cycloalkyl substituted as previously described.
  • V Y ⁇ V is the moiety:
  • R 1 is cycloalkyl substituted as described previously.
  • R 1 is cycloalkyl substituted as described previously.
  • R 1 is cycloalkyl substituted as described previously.
  • R 1 is cycloalkyl substituted as described previously.
  • IS and R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is cycloalkyl substituted as described previously.
  • R 1 is cycloalkyl substituted as described previously.
  • R 1 is cycloalkyl substituted as described previously.
  • X X / is the moiety: and R 1 is cycloalkyl substituted as described previously.
  • ⁇ SlV is the moiety:
  • R 1 is unsubstituted cycloalkyl.
  • a / is and R 1 is unsubstituted cycloalkyl.
  • V 1 IS the moiety:
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • R 1 is unsubstituted cycloalkyl.
  • v-Vv is one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • X-VV one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • X S is one A is N and the other A's are C, and R 1 is unsubstituted cycloalkyl.
  • one A is N and the other A's are C, R 1 is unsubstituted heterocyclyl, R 10 is piperazinyl ring and R a is as previously described.
  • one A is N and the other A's are C, R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as previously described under Formula I
  • R 10 is piperazinyl ring and R a is as previously described.
  • ⁇ x V is the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • X x f is the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • v Y -Y- Y v is the moiety.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • X x ⁇ is one A is N and the other A's are C, R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • v- Y V'V is one A is N and the other A's are C, R 1 is heterocyclyl substituted as previously described under Formula I, R 10 is piperidinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring and R a is as previously described.
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperazinyl ring and R a is as previously described.
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • V X ⁇ is the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • V Y ⁇ Y V is the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • X is the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperazinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperazinyl ring with -C(O)-N R a R b
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • V Y Y Y V IS the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl with -C(O)-NR a R b
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • one A is N and the other A's are C, R 1 is unsubstituted heterocyclyl, R 10 is piperazinyl ring and R a is as previously described.
  • X X r is one A is N and the other A's are C, R 1 is unsubstituted heterocyclyl, R 10 is piperazinyl ring and R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • % x ⁇ is one A is N and the other A's are C, R 1 is unsubstituted heterocyclyl, R 10 is piperidinyl ring and R a is as previously described.
  • V X YN x x Y" V ⁇ • is one A is N and the other A's are C, R 1 is unsubstituted heterocyclyl, R 10 is piperidinyl ring and R a is as previously described.
  • X x ⁇ is one A is N and the other A's are C, R 1 is heterocyclyl substituted as previously described under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • V x ⁇ is the moiety: -
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • X x ⁇ is one A is N and the other A's are C, R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as previously described under Formula I
  • R 10 is piperidinyl ring and R a is as previously described.
  • V Y ⁇ V is the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring and R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • ⁇ Y-V is the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I, R 10 is piperazinyl ring and R a is as previously described.
  • V Y ⁇ Y V IS the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • VVv is the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperazinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • ⁇ fV is the moiety:
  • R 1 is heterocyclyl substituted as described previously under Formula I
  • R 10 is piperazinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperidinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl ring with -C(O)-NR a R b
  • R a is as previously described.
  • X, Y, R 1 , W, Q, A, R 10 , R a and the other moieties are independently selected, the moiety:
  • v Y -V-V is the moiety:
  • R 1 is unsubstituted heterocyclyl
  • R 10 is piperazinyl with -C(O)-NR a R b
  • R a is as previously described.
  • ⁇ - x ⁇ is one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier.
  • vVv IS one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier.
  • one A is N and the other A's are C, and L is piperidinyl (unsubstituted, substituted and/or fused as described earlier).
  • L is piperazinyl (unsubstituted, or substituted and/or fused as described.
  • X x f is the moiety:
  • L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
  • vTv is the moiety:
  • L is pyrrolidinyl (unsubstituted, substituted and/or fused as described earlier).
  • L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • X x ⁇ is the moiety:
  • L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is piperidinyl (unsubstituted, substituted and/or fused as described earlier).
  • L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier).
  • V ⁇ - ⁇ 'V IS the moiety:
  • L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
  • X x ⁇ is the moiety:
  • X x ⁇ is the moiety.
  • L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier).
  • X x ⁇ is the moiety.
  • L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is azetidinyl (unsubstituted, or substituted and/or fused as described earlier).
  • L is thiomorpholinyl (unsubstituted, or substituted and/or fused as described earlier).
  • N. x S is one A is N and the other A's are C, and L is azepanyl (unsubstituted, or substituted and/or fused as described earlier).
  • v y IS one A is N and the other A's are C, and L is oxazepanyl (unsubstituted, or substituted and/or fused as described earlier), R 10 is piperazinyl ring and R a is as previously described.
  • Patient includes both humans and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • substituents include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridy
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexyl methyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen or "halo” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroa
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrol idone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S- oxide or S,S-dioxide.
  • heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (e.
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. It should be noted that in heteroatom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl” means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non- limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkoxyalkyl- means an alkyl-O-alkyl- group in which the alkyl group is as previously described.
  • suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, n-propoxyethyl, isopropoxyethyl and n- butoxymethyl.
  • the bond to the parent moiety is through the alkyl.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxyalkyl- means an aryl-O-alkyl- group in which the aryl and aryl groups are as previously described.
  • suitable aryloxyalkyl groups include phenoxymethyl and naphthoxyethyl. The bond to the parent moiety is through the alkyl.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthioalkyl- means an alkyl-S-alkyl- group in which the alkyl group is as previously described.
  • suitable alkylthioalkyl groups include methylthioethyl and ethylthiomethyl. The bond to the parent moiety is through the alkyl.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthioalkyl- means an aryl-S-alkyl- group in which the aryl group is as previously described.
  • suitable arylthioalkyl groups include phenylthioethyl and phenylthiomethyl. The bond to the parent moiety is through the alkyl.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • the present invention further includes the inventive compounds in their isolated form(s).
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • a functional group in a compound is termed "protected”
  • Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo Xo yield a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-CsJalkyl, (C 2 -C 12 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N)alkanoyloxymethyl, 1 -(alkanoyloxymethyl, 1 -(alkanoyloxymethyl, 1 -(
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 - C 6 )alkanoyloxymethyl, 1 -((CrC 6 )alkanoyloxy)ethyl, 1 -methyl-1 -((C 1 - C 6 )alkanoyloxy)ethyl, (CrC 6 )alkoxycarbonyloxymethyl, N-(C 1 - C 6 )alkoxycarbonylaminomethyl, succinoyl, (C r C 6 )alkanoyl, ⁇ -amino(C r
  • each ⁇ -arninoacyl group is independently selected from the naturally occurring L- amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (C r Cio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, — C(OY 2 ) Y 3 wherein Y 2 is (Ci-C 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (C 1 - C 6 )alkyl, amino(C r C 4 )alkyl or mono-N — or di-N,
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution- phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., (2004) 93(3). pp. 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., (2004) 5(1), article 12; and A. L. Bingham et al, Chem.
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci- 4 alkyl, or Ci -4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphoric acid
  • the compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
  • the compounds according to the invention have pharmacological properties.
  • the compounds of Formula I are inhibitors of DGAT, particularly DGAT1 , and can be useful for the therapeutic and/or prophylactic treatment of diseases that are modulated by DGAT, particularly by DGAT1 , such as, for example, metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), obesity and the like.
  • the invention also includes methods of treating diseases that are modulated by DGAT, particularly by DGAT1.
  • the invention also includes methods of treating metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), and obesity in a patient by administering at least one compound of Formula I to said patient.
  • Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose, or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Abnormal glucose homeostasis is associated with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. As such, the diabetic patient is at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • Insulin resistance is not associated with a diminished number of insulin receptors but rather to a post-insulin receptor binding defect that is not well understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • Type 2 diabetes which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat.
  • sulfonylureas e.g. tolbutamide and glipizide
  • meglitinide which stimulate the pancreatic [beta]-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues.
  • the biguanides are a class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. However, the biguanides can induce lactic acidosis and nausea/diarrhea.
  • the glitazones are a separate class of compounds with potential for the treatment of Type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR- gamma subtype.
  • PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones.
  • Newer PPAR agonists that are being tested for treatment of Type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.
  • New biochemical approaches include treatment with alpha- glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors.
  • alpha- glucosidase inhibitors e.g. acarbose
  • PTP-1 B protein tyrosine phosphatase-1 B
  • DPP-IV dipeptidyl peptidase-IV
  • compositions e.g., pharmaceutical compositions, comprising at least one compound of Formula I.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • Other carriers include Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof.
  • PEG polyethylene glycol
  • Cremophor/ethanol polyethylene glycol
  • Trappsol alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof.
  • Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • the therapeutic agents of the present invention are preferably formulated in pharmaceutical compositions and then, in accordance with the methods of the invention, administered to a subject, such as a human subject, in a variety of forms adapted to the chosen route of administration.
  • the therapeutic agents may be formulated for intravenous administration.
  • the formulations may, however, include those suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, or other parenteral administration (including subcutaneous, intramuscular, intrathecal, intraperitoneal and intratumoral, in addition to intravenous) administration.
  • Formulations suitable for parenteral administration conveniently include a sterile aqueous preparation of the active agent, or dispersions of sterile powders of the active agent, which are preferably isotonic with the blood of the recipient.
  • Parenteral administration of the therapeutic agents e.g., through an I. V. drip
  • Isotonic agents that can be included in the liquid preparation include sugars, buffers, and sodium chloride. Solutions of the active agents can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions of the active agent can be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, glycerol esters, and mixtures thereof.
  • the ultimate dosage form is sterile, lluid, and stable under the conditions of manufacture and storage.
  • the necessary fluidity can be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants.
  • Sterilization of a liquid preparation can be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization. Preferred methods for preparing powders include vacuum drying and freeze drying of the sterile injectible solutions.
  • antimicrobial agents for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Absorption of the active agents over a prolonged period can be achieved by including agents for delaying, for example, aluminum monostearate and gelatin.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes containing the first and/or second therapeutic agents, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught.
  • Such compositions and preparations may contain at least about 0.1 wt-% of the active agent.
  • the amounts of the therapeutic agents should be such that the dosage level will be effective to produce the desired result in the subject.
  • Nasal spray formulations include purified aqueous solutions of the active agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye. Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a natural or artificial flavoring agent.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose, or aspartame
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like.
  • a syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent.
  • the material used in preparing any unit dosage form is substantially nontoxic in the amounts employed.
  • the active agent may be incorporated into sustained-release preparations and devices.
  • the compound is administered orally, intraperitoneally, or intravenously or intrathecal ⁇ or some suitable combination(s) thereof.
  • the therapeutic agents described in the present disclosure can be administered to a subject alone or together (coadministered, optionally but not necessarily, in a single formulation) with other active agents as described herein, and are preferably administered with a pharmaceutically acceptable buffer.
  • the therapeutic agents can be combined with a variety of physiological acceptable carriers, additives for delivery to a subject, including a variety of diluents or excipients known to those of ordinary skill in the art.
  • isotonic saline is preferred.
  • a cream including a carrier such as dimethylsulfoxide (DMSO), or other agents typically found in topical creams that do not block or inhibit activity of the peptide, can be used.
  • DMSO dimethylsulfoxide
  • Other suitable carriers include, but are not limited to, alcohol, phosphate buffered saline, and other balanced salt solutions.
  • the formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • such methods include the step of bringing the therapeutic agent (i.e., the active agent) into association with a carrier that constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.
  • the methods of the invention include administering the therapeutic agents to a subject in an amount effective to produce the desired effect.
  • the therapeutic agents can be administered as a single dose or in multiple doses.
  • Useful dosages of the active agents can be determined by comparing their in vitro activity and the in vivo activity in animal models.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art.
  • the total daily dosage may be divided and administered in portions during the day as required.
  • the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • kits comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • compositions comprising at least one compound of Formula I and at least one other therapeutic agent in combination.
  • combination agents are described below.
  • the agents in the combination can be administered together as a joint administration (e.g., joint single pill), separately, one after the other in any order and the like as is well known in the art.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent that is not a Compound of Formula (I), wherein the amounts administered are together effective to treat or prevent a Condition.
  • the therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • the one or more Compounds of Formula (I) is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to novel heterocyclic compounds as diacylglycerol acyltransferase ("DGAT") inhibitors, pharmaceutical compositions comprising the heterocyclic compounds and the use of the compounds for treating or preventing a cardiovascular disease, a metabolic disorder, obesity or an obesity-related disorder, diabetes, dyslipidemia, a diabetic complication, impaired glucose tolerance or impaired fasting glucose. An illustrative compound of the invention is shown below.

Description

INHIBITORS OF DIACYLGLYCEROL ACYLTRANSFERASE
Field of the Invention
The present invention relates to certain heterocyclic compounds useful as diacylglycerol acyltransferase ("DGAT") inhibitors, especially diacylglycerol acyltransferase 1 ("DGAT1") inhibitors, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat or prevent various diseases including cardiovascular disease, dyslipidemia, obesity and diabetes (e.g., Type 2 diabetes).
Background of the Invention
There is a need for additional ways of treating diseases associated with metabolic syndrome such as, for example, dyslipidemia, cardiovascular disease, obesity and diabetes (e.g., Type 2 diabetes).
Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets- Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270).
Diacylglycerol O-acyltransferase, also known as diglyceride acyltransferase or DGAT, is a key enzyme in triglyceride synthesis. DGAT catalyzes the final and rate-limiting step in the triacylglycerol synthesis from 1 ,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates. Thus, DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, pp. 395-400).
Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2 [see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, pp. 13018-13023, Lardizabal et al, Journal of Biological Chemistry (2001) 276, pp. 38862-38869 and Cases et al, Journal of Biological Chemistry (2001) 276, pp. 38870-38876]. Although both enzymes utilize the same substrates, there is no homology between DGAT1 and DGAT2. Both enzymes are widely expressed however some differences do exist in the relative abundance of expression in various tissues.
Disorders or imbalances in triglyceride metabolism, both absorption as well as de novo synthesis, have been implicated in the pathogenesis of a variety of disease risks. These include obesity, insulin resistance syndrome, Type Il diabetes, dyslipidemia, metabolic syndrome (syndrome X) and coronary heart disease [see Kahn, Nature Genetics (2000) 25, pp. 6-7, Yanovski and Yanovski, New England Journal of Medicine (2002) 346, pp. 591-602, Lewis et al, Endocrine Reviews (2002) 23, pp. 201 , Brazil, Nature Reviews Drug Discovery (2002) 1 , pp. 408, Malloy and Kane, Advances in Internal Medicine (2001 ) 47, pp. 1 11 , Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270 and Yu and Ginsberg, Annals of Medicine (2004) 36, pp. 252-261]. Compounds that can decrease the synthesis of triglycerides from diacylglycerol by inhibiting or lowering the activity of the DGAT enzyme would be of value as therapeutic agents for the treatment of diseases associated with abnormal metabolism of triglycerides.
Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack et al, EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino- oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, pp. 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, pp. 1340-1346), substituted benzyl- phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, pp. 1433-1437, Goto et al, Chemistry and Pharmaceutical Bulletin (1996) 44, pp. 547-551 , lkeda et al, Thirteenth International Symposium on Athersclerosis (2003), abstract 2P-0401 , and Miyata et al, JP 2004067635), aryl alkyl acid derivatives (see Smith et al, WO2004100881 and US20040224997), furan and thiophene derivatives (see WO2004022551), pyrrolo[l,2b]pyridazine derivatives (see Fox et al, WO2005103907), and substituted sulfonamides (see Budd Haeberlein and Buckett, WO20050442500). Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) pp. 1 125, 203-9), 2- bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, pp. 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, pp. 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, pp. 42-7), isochromophilone, prenylflavonoids (see Chung et al, Planta Medica (2004) 70, V58-260), polyacetylenes (see Lee et al, Planta Medica (2004) 70, pp. 97-200), cochlioquinones (see Lee et al, Journal of Antibiotics (2003) 56, pp. 967-969), tanshinones (see Ko et al, Archives of Pharmaceutical Research (2002) 25, pp. 446-448), gemfibrozil (see Zhu et al, Atherosclerosis (2002) 164, pp. 221 -228), and substituted quinolones (see Ko et al, Planta Medica (2002) 68, pp. 1 131-1133). Also known to be modulators of DGAT activity are antisense oligonucleotides (see Monia and Graham, US20040185559). Particular mention is made to PCT publication WO 2007/060140
(published May 31 , 2007; applicant: F. Hoffmann-La Roche AG). Claim 1 therein discloses compounds of the formula:
Figure imgf000004_0001
wherein R1, R2, R3, R4, R5, Re and R7 are as described. Addiitonal publications include WO 2008 / 141976 (published May 13, 2008); US 2009 / 0093497 (published May 1 , 2009) and US 2009 / 0105273 (published May 1 , 2009). A need exists in the art, however, for additional DGAT inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, Type Il diabetes mellitus and metabolic syndrome.
Summary of the Invention
In an embodiment, this invention discloses a compound, or pharmaceutically acceptable salts, solvates, ester or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the general formula I:
Figure imgf000005_0001
I wherein: each A is independently selected from C(R3) and N; or alternately the moiety:
Figure imgf000005_0002
X is independently selected from C(R3), N, N(R4), O and S, provided that no more than one X is S or O, and at least one X or one Y is N, O, or S;
Y is independently selected from C and N;
Z is a bond, N(R4) or O;
L is either one of the three options (i), (ii) or (iii):
R1 W-
(i) *, wherein W is selected from alkyl, alkenyl,
alkynyl, HCH2)fQ-5 or i— Q-(CH2JtH , wherein Q is selected from the group consisting of -NH-, -N(R11)-, -O-, -S-, -C(O)-NH-, and - NH-C(O)-; t is 0, 1 , 2 or 3; R11 is H or alkyl; and R1 is selected from alkyl, aryl or cycloalkyl, wherein each of said alkyl, aryl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, haloalkoxy, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd,
-CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected; or
( ..i.i.) R12 w } 5
wherein W is selected from alkyl, alkenyl, alkynyl, < y 2h~~ or
i— Q (CH2)t— -| ^ Wherejn Q js selected from the group consisting of - NH-, -N(R11)-, -O-, -S-, -C(O)-NH-, and -NH-C(O)-; t is O, 1 , 2 or 3; R11 is H or alkyl; and R12 is a heterocycloalkyl containing 1-4 heteroatoms which can be the same or different and are independently selected from the group consisting of O, S and N, wherein said heterocycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd),
-CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb),
-CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected;
or alternatively, said heterocycloalkyl for R12 in (ii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN,
-ORC, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,
-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected;
or still alternatively, said heterocycloalkyl for R12 in (ii) can be fused with aryl, wherein each of said heterocycloalkyl and aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =O, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, P(O)(ORc)(ORd),
-N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected; or
(iii) L is a heterocycloalkyl containing 1-4 heteroatoms which can be the same or different and are independently selected from the group consisting of O, S and N, wherein said heterocycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd),
-N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected;
or alternatively, said heterocycloalkyl for L in (iii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN, -ORC, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd,
-P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -M(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected;
or still alternatively, said heterocycloalkyl for L in (iii) can be fused with aryl, wherein each of said heterocycloalkyl and aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =O, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd,
-CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected;
R3 is selected from the group of H, lower alkyl, hydroxy, halo, O-alkyl, O-haloalkyl, O-cycloalkyl, S-alkyl, S-haloalkyl, CN, CF3, -SF5, -OSF5, -Si(Rc)3, -SRC , cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, N-alkyl, N-haloalkyl, and N-cycloalkyl;
R4 is selected from the group of H, lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl;
R5 is selected from the group of lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl; and
R10 is (i) a 5-6-membered heterocyclyl ring having from 1 to 3 ring N atoms, (ii) an aryl ring, or (iii) a heteroaryl ring, wherein each of said heterocyclyl ring, aryl ring and heteroaryl ring is unsubstituted or optionally independently substituted, off of a ring N atom or a ring C atom, with one or more G moieties, wherein G is the same or different and is selected independently from:
>Λw-(CH2)rC(O)-N(Rb)-Ra;
Figure imgf000010_0001
ovw*-C(O)-(cycloalkyl)- -C(O)-N(Rb)-Ra; v/VTV/Vr -C(O)-(cycloalkyl)- -C(O)-OR 55.;
Figure imgf000010_0002
v/wvr-C(O)-(cycloalkyl)— C(O)-OH bioisostere; wherein Ra is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each moiety being selected independently from the group consisting of O-haloalkyl, S-haloalkyl, CN, NO2, CF3, cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, N-alkyl, N-haloalkyl, and N-cycloalkyl; alkyl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -ORC, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb),
-N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, and -S(O)2RC; wherein each Rb, Rc and Rd is independently selected;
Rb is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;
Rc is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; Rd is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein each of said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl in Rb, Rc, and Rd can be unsubstituted or optionally independently substituted with 1 -2 substituents independently selected from halo, OH, NH2, CF3, CN, Oalkyl, NHalkyl, N(alkyl)2 and Si(alkyl)3; and t is 0, 1 , 2 or 3.
The term "spirocyclyl" refers to a cyclic group substituted off the same carbon atom. Some non-limiting examples would be:
Figure imgf000011_0001
The term "oxo" refers to the moiety =C(O) substituted off the same carbon atom.
The term "bicyclic heterocyclyl" refers to bicyclic compounds containing heteroatom as part of the ring atoms. A non-limiting example would be:
Figure imgf000011_0002
with no limitation as to the position of the heteroatom.
The term "COOH bioisostere" is as defined in The Practice of Medicinal Chemistry, C. G. Wermuth Ed.; Academic Press: New York, 1996, p. 203. Non-limiting examples of COOH bioisosteres include -SO3H, -S(O)2NHR7, -S(O)2NHC(O)R7, -CH2S(O)2R7, -C(O)NHS(O)2R7, -C(O)NHOH, -C(O)NHCN, -CH(CF3)OH, -C(CFa)2OH, -P(O)(OH)2 and the groups listed below:
Figure imgf000012_0001
where R7 is selected from alkyl, aryl or heteroaryl.
When a disubstituted moiety is shown with v/vw on both sides, the attachment points are from left to right when looking at the parent formula, e.g. Formula I. Thus, for example, if the moiety:
Figure imgf000012_0002
in Formula I, it means that the pyrazine ring is attached to NH on the left hand side and R10 on the right hand side in Formula I. In another aspect, this invention provides compositions comprising at least one compound of Formula I.
In another aspect, this invention provides pharmaceutical compositions comprising at least one compound of Formula I and at least one pharmaceutically acceptable carrier.
In another aspect, this invention provides a method of treating diabetes in a patient in need of such treatment using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I. In another aspect, this invention provides a method of treating diabetes in a patient in need of such treatment, e.g., Type 2 diabetes, using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
In another aspect, this invention provides a method of treating metabolic syndrome in a patient in need of such treatment, using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
In another aspect, this invention provides a method of inhibiting DGAT using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
In another aspect, this invention provides a method of inhibiting DGAT1 using therapeutically effective amounts of at least one compound of Formula I, or of a composition comprising at least one compound of Formula I.
DESCRIPTION OF THE INVENTION
In an embodiment, the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof. The following embodiments (stated as "another embodiment") are independent of each other; different such embodiments can be independently selected and combined in various combinations. Such combinations should be considered as part of the invention.
In another embodiment, A is C(R3). In another embodiment, A is N.
In another embodiment, one A is N and the other A moieties are C(R3).
In another embodiment, one A is C(R3) and the other A moieties are N.
In another embodiment, two A moieties are N and the other two A moieties are C(R3).
In another embodiment, X is C(R3).
In another embodiment, X is N.
In another embodiment, X is N(R4).
In another embodiment, X is O. In another embodiment, X is S.
In another embodiment, at least one X is O.
In another embodiment, at least one Y is N.
In another embodiment, one X is O and one other X is N.
In another embodiment, one X is O and one other X is S. In another embodiment, one X is O, one X is N and the other X is
C(R3).
In another embodiment, Y is C.
In another embodiment, Y is N.
In another embodiment, when L is Option (i), R1 is unsubstituted aryl. In another embodiment, when L is Option (i), R1 is aryl substituted as previously described.
In another embodiment, when L is Option (i), R1 is unsubstituted alkyl.
In another embodiment, when L is Option (i), R1 is alkyl substituted as previously described. In another embodiment, when L is Option (i), R1 is unsubstituted cycloalkyl.
In another embodiment, when L is Option (i), R1 is cycloalkyl substituted as previously described.
In another embodiment, when L is Option (i), W is alkyl. In another embodiment, when L is Option (i), W is alkenyl.
In another embodiment, when L is Option (i), Q is -NH-, -N(CH3)-, -O-, - S-, -C(O)-NH-, and -NH-C(O)-
In another embodiment, when L is Option (i), Q is -NH-.
In another embodiment, when L is Option (i), Q is -N(CH3)-. In another embodiment, when L is Option (i), Q is -O-.
In another embodiment, when L is Option (i), Q is -S-.
In another embodiment, when L is Option (i), Q is -C(O)-NH-.
In another embodiment, when L is Option (i), Q is -NH-C(O)-. In another embodiment, when L is Option (ii), W is alkyl.
In another embodiment, when L is Option (ii), W is alkenyl.
In another embodiment, when L is Option (ii), Q is -NH-, -N(CH3)-, -O-, -S-, -C(O)-NH-, and -NH-C(O)-
In another embodiment, when L is Option (ii), Q is -NH-. In another embodiment, when L is Option (ii), Q is -N(CH3)-.
In another embodiment, when L is Option (ii), Q is -O-.
In another embodiment, when L is Option (ii), Q is -S-.
In another embodiment, when L is Option (ii), Q is -C(O)-NH-.
In another embodiment, when L is Option (ii), Q is -NH-C(O)-. In another embodiment, when L is Option (ii), t is 0.
In another embodiment, when L is Option (ii), t is 1.
In another embodiment, when L is Option (ii), t is 2.
In another embodiment, when L is Option (ii), t is 3.
In another embodiment, when L is Option (ii), R12 is heterocyclyl. In another embodiment, when L is Option (ii), R12 is unsubstituted heterocyclyl.
In another embodiment, when L is Option (ii), R12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is 3-7 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is pyrrolidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (ii), R12 is piperidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is piperazinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is morpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (ii), R12 is thiomorpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is azetidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is azepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is oxazepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (ii), R12 is the moiety:
Figure imgf000016_0001
In another embodiment, when L is Option (ii), R12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (ii), R12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is pyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is piperidinyl, wherein said piperidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is piperazinyl, wherein said piperazinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is morpholinyl, wherein said morpholinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (ii), R12 is 4-8 membered heterocyclyl, containing 1 -3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (ii), R12 is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (ii), R12 is pyrrolidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (ii), R12 is piperidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is piperazinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (ii), R12 is morpholinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (iii), L is heterocyclyl.
In another embodiment, when L is Option (iii), L is unsubstituted heterocyclyl.
In another embodiment, when L is Option (iii), L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is 3-7 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is pyrrolidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is piperidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is piperazinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is morpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (iii), L is thiomorpholinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is azetidinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
In another embodiment, when L is Option (iii), L is azepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier. In another embodiment, when L is Option (iii), L is oxazepinyl, wherein said heterocyclyl can be unsubstituted or optionally substituted, and/or fused as defined earlier.
Figure imgf000019_0001
In another embodiment, when L is Option (iii), L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (iii), L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is pyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (iii), L is piperidinyl, wherein said piperidinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is piperazinyl, wherein said piperazinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is morpholinyl, wherein said morpholinyl can be unsubstituted or optionally substituted as defined earlier, and is fused with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is 4-8 membered heterocyclyl, containing 1 -3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with an aryl wherein said aryl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is 4-8 membered heterocyclyl, containing 1-3 heteroatoms which can be the same or different and is independently selected from the group consisting of N, O and S, wherein said heterocyclyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is pyrrolidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is piperidinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, when L is Option (iii), L is piperazinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier. In another embodiment, when L is Option (iii), L is morpholinyl, wherein said pyrroldinyl is substituted with a phenyl wherein said phenyl can be unsubstituted or optionally substituted as defined earlier.
In another embodiment, R3 is H.
In another embodiment, R3 is lower alkyl. In another embodiment, R3 is hydroxyl.
In another embodiment, R3 is -O-alkyl.
In another embodiment, R3 is -CN.
In another embodiment, R3 is -CF3. In another embodiment, R3 is -O- haloalkyl.
In another embodiment, R3 is -OSF5
In another embodiment, R3 is -SF5
In another embodiment, R4 is H.
In another embodiment, R4 is lower alkyl. In another embodiment, R10 is a 5-6-membered heterocyclyl ring having from 1 to 3 ring N atoms, wherein said heterocyclyl ring is substituted, off of a ring N atom, with v/w\Λ-C(O)-N(Rb)-Ra, wherein Ra and Rb are as previously described.
In another embodiment, R10 is a piperidinyl ring, wherein said piperidinyl ring is substituted, off of the ring N atom, with
>^vwp-C(O)-N(Rb)-Ra, wherein Ra and Rb are as previously described.
In another embodiment, R10 is a piperazinyl ring, wherein said piperazinyl ring is substituted, off of a ring N atom, with *Λ/w--C(O)-N(Rb)-Ra , wherein Ra and Rb are as previously described. In another embodiment, Ra is unsubstituted alkyl.
In another embodiment, Ra is alkyl substituted as previously described under formula I.
In another embodiment, Ra is unsubstituted aryl.
In another embodiment, Ra is aryl substituted as previously described under formula I.
In another embodiment, Ra is unsubstituted heteroaryl.
In another embodiment, Ra is heteroaryl substituted as previously described under formula I.
In another embodiment, Ra is unsubstituted cycloalkyl. In another embodiment, Ra is cycloalkyl substituted as previously described under formula I.
In another embodiment, Ra is unsubstituted heterocyclyl.
In another embodiment, Ra is heterocyclyl substituted as previously described under formula I. In another embodiment, Rb is H.
In another embodiment, Rb is lower alkyl.
In another embodiment, in Formula I, the moiety:
Figure imgf000022_0001
In another embodiment, in Formula I, the moiety:
Figure imgf000022_0002
In another embodiment, in Formula I, the moiety:
Figure imgf000022_0003
In another embodiment, in Formula I, the moiety:
X X / ,s
Figure imgf000022_0004
In another embodiment, in Formula I, the moiety:
Figure imgf000022_0005
In another embodiment, in Formula I, the moiety:
X/YΫYV i is
Figure imgf000023_0001
In another embodiment, in Formula I, the moiety:
X X ^ IS
Figure imgf000023_0002
In another embodiment, in Formula I, the moiety: vVv is
Figure imgf000023_0003
In another embodiment, in Formula I, the moiety:
\ X ^ IS
Figure imgf000023_0004
In another embodiment, in Formula I, the moiety: is
Figure imgf000023_0005
In another embodiment, in Formula I, the moiety:
X X / IS
Figure imgf000023_0006
In another embodiment, in Formula I, the moiety:
Figure imgf000024_0001
In another embodiment, in Formula I, the moiety:
Figure imgf000024_0002
In another embodiment, in Formula I, the moiety:
Figure imgf000024_0003
In another embodiment, in Formula I, the moiety:
Figure imgf000024_0004
In another embodiment, in Formula I, the moiety:
Figure imgf000024_0005
In another embodiment, in Formula I, the moiety:
Figure imgf000025_0001
In another embodiment, in Formula I, the moiety:
Figure imgf000025_0002
I1 When L is Option (i):
In another embodiment of Formula I, wherein X, Y, L, W1 Q, R1, A, R10, Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is aryl substituted as described previously under Formula I, and R3 is alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is aryl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is aryl substituted as described previously under Formula I, and R3 is alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is haloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, R10 and Ra are as previously defined, one X is N, a second X is C(R3), and the third X is O, both
Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is haloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is -CN. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted aryl, and R3 is -CN. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
v^Y'V is
Figure imgf000027_0001
one A is N and the other A's are C, and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
V \. xx YV ^ ■ is
Figure imgf000027_0002
one A is N and the other A's are C, and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
v*ϊV , IS
Figure imgf000027_0003
one A is N and the other A's are C, and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000027_0004
one A is N and the other A's are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000028_0001
one A is N and the other A's are C, and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Y^
X /i< •'
^ *v ^ is
Figure imgf000028_0002
one A is N and the other A's are C, and R1 is aryl substituted as previously described under Formula I.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X / IS
Figure imgf000028_0003
the moiety:
Figure imgf000028_0004
and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X f |S
Figure imgf000029_0001
the moiety:
Figure imgf000029_0002
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X V is
Figure imgf000029_0003
the moiety:
Figure imgf000029_0004
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000029_0005
|S the moiety:
Figure imgf000030_0001
and R1 is uns instituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W1 Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X «** |S
Figure imgf000030_0002
the moiety:
Figure imgf000030_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
T V V \.^ x X V S ■ is
Figure imgf000030_0004
the moiety:
Figure imgf000031_0001
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v^Y'V is
Figure imgf000031_0002
one A is N and the other A's are C, and R1 is aryl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
X X S ,s
Figure imgf000031_0003
one A is N and the other A's are C, and R1 is aryl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V^x V ■ is
Figure imgf000031_0004
the moiety:
Figure imgf000032_0001
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X ^ is
Figure imgf000032_0002
the moiety:
Figure imgf000032_0003
and R1 is aryl substituted as described previously under Formula I.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000032_0004
the moiety:
Figure imgf000032_0005
IS
Figure imgf000033_0001
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V 1 X V is
Figure imgf000033_0002
the moiety:
Figure imgf000033_0003
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
^YV IS
the moiety:
Figure imgf000033_0004
and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V is
the moiety:
Figure imgf000034_0001
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000034_0002
the moiety:
Figure imgf000034_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000035_0001
the moiety:
Figure imgf000035_0002
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000035_0003
. the moiety:
Figure imgf000035_0004
. and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X / IS
Figure imgf000035_0005
the moiety:
Figure imgf000036_0001
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000036_0002
the moiety:
Figure imgf000036_0003
and 1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000036_0004
the moiety:
Figure imgf000036_0005
IS
Figure imgf000037_0001
. and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v X^^ X V / ■ is
Figure imgf000037_0002
the moiety:
Figure imgf000037_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X χ <* ιs
Figure imgf000037_0004
the moiety:
Figure imgf000037_0005
and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000038_0001
the moiety:
Figure imgf000038_0002
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000038_0003
the moiety:
Figure imgf000038_0004
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ |S
Figure imgf000039_0001
one A is N and the other A's are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000039_0002
one A is N and the other A's are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W1 Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000039_0003
one A is N and the other A's are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety: V is
Figure imgf000039_0004
one A is N and the other A's are C, and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y1 L, W, Q1 R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000039_0005
V o' \/ one A is N and the other A's are C, and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000040_0001
one A is N and the other A's are C, and R1 is aryl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000040_0002
the moiety:
Figure imgf000040_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f |S
Figure imgf000040_0004
the moiety:
Figure imgf000041_0001
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000041_0002
the moiety:
Figure imgf000041_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X χ ^ is
the moiety:
Figure imgf000041_0004
IS
Figure imgf000042_0001
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
^ x * is
Figure imgf000042_0002
the moiety:
Figure imgf000042_0003
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety.
Figure imgf000042_0004
and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000043_0001
one A is N and the other A's are C, and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000043_0002
one A is N and the other A's are C, and R1 is aryl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
χ-γ-χ- •V is
Figure imgf000043_0003
the moiety:
Figure imgf000043_0004
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety: ^ry IS
Figure imgf000044_0001
the moiety:
Figure imgf000044_0002
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
^Vv IS
Figure imgf000044_0003
the moiety:
Figure imgf000044_0004
and R1 is aryl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
Figure imgf000044_0005
N"-^CF3 the moiety:
Figure imgf000045_0001
and R1 is aryl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
the moiety:
Figure imgf000045_0002
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V X ^ is
the moiety:
Figure imgf000045_0003
Figure imgf000046_0001
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety.
the moiety:
Figure imgf000046_0002
and R1 is unsubstituted aryl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫV IS
Figure imgf000046_0003
the moiety:
Figure imgf000046_0004
and R1 is unsubstituted aryl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V is
the moiety:
Figure imgf000047_0001
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000047_0002
the moiety.
Figure imgf000047_0003
and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is the moiety:
Figure imgf000048_0001
. and R1 is aryl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety.
Figure imgf000048_0002
and R1 is aryl substituted as described previously under Formula I.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is alkyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is alkyl substituted as described previously
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted alkyl, and R3 is alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is alkyl substituted as described previously under Formula I, and R3 is alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted alkyl, and R3 is haloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted alkyl, and R3 is haloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted alkyl, and R3 is -CN.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted alkyl, and R3 is -CN.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
v-γ-ϊ-γv IS
Figure imgf000050_0001
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
vVv IS
Figure imgf000050_0002
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x r is
Figure imgf000050_0003
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000051_0001
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
v-Y-V'V is
Figure imgf000051_0002
one A is N and the other A's are C, and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X X S ,s
Figure imgf000051_0003
one A is N and the other A's are C, and R1 is alkyl substituted as previously described. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10,
Ra and the other moieties are independently selected, the moiety:
X x ^ is
the moiety:
Figure imgf000051_0004
is
Figure imgf000052_0001
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
\ x ^ |S
Figure imgf000052_0002
the moiety:
Figure imgf000052_0003
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000052_0004
the moiety:
Figure imgf000052_0005
and R1 is unsubstituted alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000053_0001
the moiety:
, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000053_0003
the moiety:
Figure imgf000053_0004
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫV is
Figure imgf000054_0001
the moiety:
Figure imgf000054_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000054_0003
one A is N and the other A's are C, and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000054_0004
one A is N and the other A's are C, and R1 is a ,lkyl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
-^ is
Figure imgf000055_0001
the moiety:
Figure imgf000055_0002
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1 , A, R10, Ra and the other moieties are independently selected, the moiety:
vY-V-v IS
Figure imgf000055_0003
the moiety:
Figure imgf000055_0004
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000055_0005
the moiety:
Figure imgf000056_0001
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X ^ |S
Figure imgf000056_0002
the moiety:
Figure imgf000056_0003
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X is
Figure imgf000056_0004
the moiety:
Figure imgf000056_0005
is
Figure imgf000057_0001
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫYV is
Figure imgf000057_0002
the moiety:
Figure imgf000057_0003
and R1 is unsubstituted alkyl.
In another embodiment of Formula i I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
V is
Figure imgf000057_0004
the moiety:
Figure imgf000057_0005
and R1 is unsubstituted alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000058_0001
the moiety:
Figure imgf000058_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
YrZ X X f |S
Figure imgf000058_0003
the moiety:
Figure imgf000058_0004
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
YrZ
X X S |S
Figure imgf000059_0001
the moiety:
SN
A / is
Figure imgf000059_0002
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000059_0003
the moiety:
Figure imgf000059_0004
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X S is
Figure imgf000059_0005
the moiety:
Figure imgf000060_0001
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v^ΫV IS
Figure imgf000060_0002
the moiety:
Figure imgf000060_0003
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
\. x ^ is
the moiety:
Figure imgf000060_0004
IS
Figure imgf000061_0001
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫYV is
Figure imgf000061_0002
the moiety:
Figure imgf000061_0003
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫV IS
Figure imgf000061_0004
the moiety:
Figure imgf000061_0005
and R1 is unsubstituted alkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VVΫYV is
Figure imgf000062_0001
one A is N and the other A's are C, and R1 is unsubstituted alkyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000062_0002
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000062_0003
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000062_0004
one A is N and the other A's are C, and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety: X X ^ is
Figure imgf000063_0001
one A is N and the other A's are C, and R1 is alkyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
X * ^ is
Figure imgf000063_0002
one A is N and the other A's are C, and R1 is alkyl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X-VV IS
Figure imgf000063_0003
the moiety:
Figure imgf000063_0004
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
1H. X S is
Figure imgf000064_0001
the moiety:
Figure imgf000064_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety.
Figure imgf000064_0003
\Λrv the moiety:
Figure imgf000064_0004
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X f |S
Figure imgf000064_0005
the moiety:
Figure imgf000065_0001
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety:
Figure imgf000065_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X ^ IS
Figure imgf000065_0003
the moiety:
^%
%*~V i :s
Figure imgf000066_0001
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000066_0002
one A is N and the other A's are C, and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000066_0003
one A is N and the other A's are C, and R1 is alkyl substituted as previously described. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
< v is
Figure imgf000066_0004
the moiety:
Figure imgf000066_0005
is
Figure imgf000067_0001
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y1 L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety:
Figure imgf000067_0002
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000067_0003
the moiety:
Figure imgf000067_0004
and R1 is alkyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
V is
the moiety:
Figure imgf000068_0001
and R1 is alkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
the moiety.
Figure imgf000068_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
}ft
VYΫYV is
Figure imgf000069_0001
the moiety:
Figure imgf000069_0002
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Λ, X S is
the moiety:
Figure imgf000069_0003
and R1 is unsubstituted alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is cycloalkyl substituted as described previously under Formula I, and R3 is alkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted cycloalkyl, and R3 is haloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted cycloalkyl, and R3 is haloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted cycloalkyl, and R3 is -CN. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted cycloalkyl, R3 is -CN.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X 'VY IS
Figure imgf000071_0001
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000071_0002
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VV¥V IS
Figure imgf000071_0003
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000072_0001
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
%rγγγv is
Figure imgf000072_0002
one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10,
Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000072_0003
one A is N and the other A's are C, and R1 is cycloalkyl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ IS
Figure imgf000072_0004
the moiety:
Figure imgf000072_0005
IS
Figure imgf000073_0001
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X r^ IS
Figure imgf000073_0002
the moiety:
Vv is
Figure imgf000073_0003
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety.
Figure imgf000073_0004
the moiety:
Vv is
Figure imgf000073_0005
and R1 is unsubstituted cycloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x r is
Figure imgf000074_0001
the moiety:
Figure imgf000074_0002
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000074_0003
the moiety:
Figure imgf000074_0004
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v vY.UVvχjl is
Figure imgf000075_0001
the moiety:
Figure imgf000075_0002
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V X"YN x x V ^ • is
Figure imgf000075_0003
one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V-YΫV is
Figure imgf000075_0004
one A is N and the other A's are C, and R1 is cycloalkyl substituted as previously described.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫV is
Figure imgf000076_0001
the moiety:
Figure imgf000076_0002
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000076_0003
X ΛJC the moiety:
Figure imgf000076_0004
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000076_0005
the moiety:
Figure imgf000077_0001
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v "\ y.
the moiety:
Figure imgf000077_0002
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000077_0003
the moiety:
Figure imgf000077_0004
IS
Figure imgf000078_0001
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000078_0002
the moiety.
Figure imgf000078_0003
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X r^ |S
the moiety:
Figure imgf000078_0004
and R1 is unsubstituted cycloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety.
Figure imgf000079_0001
the moiety:
Figure imgf000079_0002
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
x x ^ I IS
Figure imgf000079_0003
the moiety:
Figure imgf000079_0004
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
x-^'V i IS
Figure imgf000080_0001
the moiety:
Figure imgf000080_0002
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v*¥V IS
the moiety:
Figure imgf000080_0003
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X / is
Figure imgf000080_0004
the moiety:
Figure imgf000081_0001
and R1 is cycloalkyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
^SlV is
Figure imgf000081_0002
the moiety:
Figure imgf000081_0003
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000081_0004
the moiety:
A / is
Figure imgf000082_0001
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
V1 IS
Figure imgf000082_0002
the moiety:
Figure imgf000082_0003
and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X X !■*• js
Figure imgf000082_0004
the moiety:
Figure imgf000082_0005
and R1 is unsubstituted cycloalkyl. In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
v-Vv is
Figure imgf000083_0001
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X-VV
Figure imgf000083_0002
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
\. X S is
Figure imgf000083_0003
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety: V IS
Figure imgf000083_0004
one A is N and the other A's are C, and R1 is unsubstituted cycloalkyl.
In another embodiment of Formula I, wherein X, Y, L, W, Q, R1, A, R10, Ra and the other moieties are independently selected, the moiety: X x f is
Figure imgf000084_0001
one A is N and the other A's are C, and R1 is cycloalkyl substituted as described previously. M1 When L is Option fii):
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is alkyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R3 is alkyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected,, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is alkyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R3 is alkyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is haloalkyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is haloalkyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is -CN, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R3 is -CN, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000086_0001
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000086_0002
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X X / IS
Figure imgf000086_0003
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ IS
Figure imgf000087_0001
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000087_0002
one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
-^ is
Figure imgf000087_0003
one A is N and the other A's are C, R1 is heterocyclyl substituted as previously described under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
^ x V is
Figure imgf000087_0004
the moiety:
Figure imgf000088_0001
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000088_0002
the moiety:
Figure imgf000088_0003
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ |S
Figure imgf000088_0004
the moiety.
Figure imgf000088_0005
Figure imgf000089_0001
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x C |S
Figure imgf000089_0002
the moiety:
Figure imgf000089_0003
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000089_0004
the moiety:
Figure imgf000089_0005
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
vY-Y-Yv is
Figure imgf000090_0001
the moiety.
Figure imgf000090_0002
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000090_0003
one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
v-YV'V is
Figure imgf000090_0004
one A is N and the other A's are C, R1 is heterocyclyl substituted as previously described under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000091_0001
the moiety:
Figure imgf000091_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
x^srv is
O-irCF3 v /\\ Jl
V the moiety:
Figure imgf000091_0003
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000092_0001
the moiety:
Figure imgf000092_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
vΛ?V is
Figure imgf000092_0003
the moiety:
Figure imgf000092_0004
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000093_0001
the moiety:
Figure imgf000093_0002
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
V X ^ is
Figure imgf000093_0003
the moiety:
Figure imgf000093_0004
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000093_0005
is
Figure imgf000094_0001
the moiety:
Figure imgf000094_0002
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫYV is
Figure imgf000094_0003
the moiety:
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety.
X X / |S
Figure imgf000094_0005
the moiety:
Figure imgf000095_0001
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VyV'V „
Figure imgf000095_0002
the moiety:
Figure imgf000095_0003
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X is
Figure imgf000095_0004
the moiety:
Figure imgf000095_0005
is
Figure imgf000096_0001
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X X S IS
the moiety:
Figure imgf000096_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring with -C(O)-N RaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X V IS
Figure imgf000096_0003
the moiety:
Figure imgf000096_0004
3V R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000097_0001
the moiety:
Figure imgf000097_0002
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VYYYV IS
Figure imgf000097_0003
the moiety:
Figure imgf000097_0004
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring with -C(O)-NRaRb, and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000098_0001
the moiety:
Figure imgf000098_0002
R1 is unsubstituted heterocyclyl, R10 is piperazinyl with -C(O)-NRaRb, and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000098_0003
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X X r is
Figure imgf000098_0004
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
% x ^ is
Figure imgf000099_0001
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
V X YN x x Y"V ^ • is
Figure imgf000099_0002
one A is N and the other A's are C, R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
V %^YNX x YV ^ ■ is
Figure imgf000099_0003
one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I1 R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000099_0004
one A is N and the other A's are C, R1 is heterocyclyl substituted as previously described under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
vXΛv
V y IS
the moiety:
Figure imgf000100_0001
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
V x ^ is
Figure imgf000100_0002
the moiety: -
Figure imgf000100_0003
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
x^srv IS
the moiety:
Figure imgf000101_0001
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000101_0002
the moiety:
Figure imgf000101_0003
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety: the moiety:
Figure imgf000102_0001
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000102_0002
the moiety:
Figure imgf000102_0003
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000103_0001
one A is N and the other A's are C, R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
X X S ,s
Figure imgf000103_0002
one A is N and the other A's are C, R1 is heterocyclyl substituted as previously described under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫV is
Figure imgf000103_0003
the moiety:
Figure imgf000103_0004
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety: X X / |S
/CF3 vV V , the moiety:
Figure imgf000104_0001
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
^ x V is
the moiety:
Figure imgf000104_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
^Y-V is
Figure imgf000105_0001
the moiety:
Figure imgf000105_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VYΫYV IS
Figure imgf000105_0003
the moiety:
Figure imgf000105_0004
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000105_0005
the moiety:
Figure imgf000106_0001
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
-v is
Figure imgf000106_0002
the moiety:
Figure imgf000106_0003
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000106_0004
the moiety:
Figure imgf000107_0001
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
VVv is
Figure imgf000107_0002
the moiety:
Figure imgf000107_0003
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000107_0004
the moiety:
Figure imgf000107_0005
is
Figure imgf000108_0001
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety:
Figure imgf000108_0002
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
^fV is
Figure imgf000108_0003
the moiety:
Figure imgf000108_0004
R1 is heterocyclyl substituted as described previously under Formula I, R10 is piperazinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
V-^YV i IS
J-
VV v the moiety:
Figure imgf000109_0001
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
^ X x X V S ■ K IS
Figure imgf000109_0002
the moiety:
Figure imgf000109_0003
R1 is unsubstituted heterocyclyl, R10 is piperidinyl ring with -C(O)-NRaRb, and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000110_0001
the moiety:
Figure imgf000110_0002
R1 is unsubstituted heterocyclyl, R10 is piperazinyl ring with -C(O)-NRaRb, and Ra is as previously described. In another embodiment of Formula I, wherein X, Y, R1, W, Q, A, R10, Ra and the other moieties are independently selected, the moiety:
vY-V-V is
Figure imgf000110_0003
the moiety:
Figure imgf000110_0004
R1 is unsubstituted heterocyclyl, R10 is piperazinyl with -C(O)-NRaRb, and Ra is as previously described. ML When L is Option (Mi): In another embodiment, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and L is unsubstituted heterocyclyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and L is heterocyclyl substituted as described earlier.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted pyrrolidinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is pyrrolidinyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted piperidinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is piperidinyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted piperazinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and R1 is piperazinyl substituted as described previously.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted morpholinyl. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is morpholinyl substituted as described previously. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted pyrrolidinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is pyrrolidinyl as described.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted piperidinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is piperidinyl substituted as described.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted piperazinyl. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is piperazinyl as described earlier.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is unsubstituted morpholinyl.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is morpholinyl as described earlier
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
^- x ^ is
Figure imgf000113_0001
one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000113_0002
one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
vVv IS
Figure imgf000113_0003
one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ ιS
Figure imgf000114_0001
one A is N and the other A's are C, and L is heterocyclyl (unsubstituted, or substituted and/or fused as described earlier.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f |S
Figure imgf000114_0002
one A is N and the other A's are C, and L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000114_0003
one A is N and the other A's are C, and L is piperidinyl (unsubstituted, substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f ,s
Figure imgf000114_0004
the moiety:
Figure imgf000114_0005
is
Figure imgf000115_0001
L is piperazinyl (unsubstituted, or substituted and/or fused as described.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x f is
Figure imgf000115_0002
the moiety:
Figure imgf000115_0003
and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
vTv is
Figure imgf000115_0004
the moiety:
Figure imgf000115_0005
and L is pyrrolidinyl (unsubstituted, substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
the moiety:
Figure imgf000116_0001
and L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is P^rCF3
*&* , the moiety:
Figure imgf000116_0002
and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000117_0001
the moiety:
Figure imgf000117_0002
and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, R1, A, R10, Ra and the other moieties are independently selected, the moiety:
X x / |S
Figure imgf000117_0003
one A is N and the other A's are C, and L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x / |S
Figure imgf000117_0004
one A is N and the other A's are C, and L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ? is
the moiety:
Figure imgf000118_0001
and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X H x, ^ is
Figure imgf000118_0002
the moiety:
Figure imgf000118_0003
and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety: the moiety:
Figure imgf000119_0001
and L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
VYV IS
the moiety:
Figure imgf000119_0002
and L is piperidinyl (unsubstituted, substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Λ. X f is
Figure imgf000120_0001
the moiety:
Figure imgf000120_0002
and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Vγ-χ'V IS
Figure imgf000120_0003
the moiety:
Figure imgf000120_0004
and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000120_0005
the moiety:
Figure imgf000121_0001
and L is pyrrolidinyl (unsubstituted, substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000121_0002
the moiety.
Figure imgf000121_0003
and L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
vVv IS
Figure imgf000121_0004
the moiety:
Figure imgf000121_0005
Figure imgf000122_0001
and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
X x ^ is
Figure imgf000122_0002
the moiety.
Figure imgf000122_0003
, and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X1 Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
vYVv is
Figure imgf000122_0004
the moiety:
Figure imgf000122_0005
and L is pyrrolidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
v-v-Y-V IS
Figure imgf000123_0001
the moiety:
Figure imgf000123_0002
and L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
vγ T¥Tγ- V is
Figure imgf000123_0003
the moiety:
Figure imgf000123_0004
. and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000124_0001
the moiety:
Figure imgf000124_0002
and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000124_0003
the moiety:
Figure imgf000124_0004
and L is azetidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I1 wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
Figure imgf000125_0001
the moiety:
Figure imgf000125_0002
and L is thiomorpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
N. x S is
Figure imgf000125_0003
one A is N and the other A's are C, and L is azepanyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, the moiety:
v y IS
Figure imgf000125_0004
one A is N and the other A's are C, and L is oxazepanyl (unsubstituted, or substituted and/or fused as described earlier), R10 is piperazinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A moieties are C, and L is pyrrolidinyl (unsubstituted, substituted and/or fused as described earlier), R10 is piperidinyl ring and Ra is as previously described.
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and L is piperidinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is piperazinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, and L is morpholinyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is thiomorpholinyl (unsubstituted, substituted and/or fused as described earlier). In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, L is azetidinyl (unsubstituted, or substituted and/or fused as described earlier), and R3 is alkyl. In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C, and the third X is O, both Y are C, one A is N and the other A's are C, and L is azepanyl (unsubstituted, or substituted and/or fused as described earlier).
In another embodiment of Formula I, wherein X, Y, L, A, R10, Ra and the other moieties are independently selected, one X is N, a second X is C(R3), and the third X is O, both Y are C, one A is N and the other A's are C, L is oxazepanyl (unsubstituted, or substituted and/or fused as described earlier), and R3 is alkyl.
Non-limiting examples of the compounds of Formula I are shown below:
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Several of the above-noted compounds exhibited IC50 values less than 500 nM in the assay described later. Many compounds exhibited IC50 values less than 10O nM.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both humans and animals. "Mammal" means humans and other mammalian animals.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, pyridine, alkoxy, alkylthio, amino, oxime (e.g., =N-OH), -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexyl methyl, adamantylmethyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
"Halogen" or "halo" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH2) -C(=NH)-NH2, -C(=NH)-NH(alkyl), oxime (e.g., =N-OH), YiY2N-, Y^N-alkyl-, YiY2NC(O)-, Y1Y2NSO2- and -SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000135_0001
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like. "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrol idone:
Figure imgf000136_0001
"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S- oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000137_0001
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. It should be noted that in heteroatom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000137_0002
H there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000137_0003
are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non- limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Alkoxyalkyl-" means an alkyl-O-alkyl- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, n-propoxyethyl, isopropoxyethyl and n- butoxymethyl. The bond to the parent moiety is through the alkyl.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxyalkyl-" means an aryl-O-alkyl- group in which the aryl and aryl groups are as previously described. Non-limiting examples of suitable aryloxyalkyl groups include phenoxymethyl and naphthoxyethyl. The bond to the parent moiety is through the alkyl.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Alkylthioalkyl-" means an alkyl-S-alkyl- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthioalkyl groups include methylthioethyl and ethylthiomethyl. The bond to the parent moiety is through the alkyl.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Arylthioalkyl-" means an aryl-S-alkyl- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthioalkyl groups include phenylthioethyl and phenylthiomethyl. The bond to the parent moiety is through the alkyl.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
The present invention further includes the inventive compounds in their isolated form(s).
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo Xo yield a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-CsJalkyl, (C2-C12)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2- C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di (C1- C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl, and the like. Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1- C6)alkanoyloxymethyl, 1 -((CrC6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1- C6)alkanoyloxy)ethyl, (CrC6)alkoxycarbonyloxymethyl, N-(C1- C6)alkoxycarbonylaminomethyl, succinoyl, (CrC6)alkanoyl, α-amino(Cr
C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-arninoacyl group is independently selected from the naturally occurring L- amino acids, P(O)(OH)2, -P(O)(O(C1 -C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula I incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (CrCio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α- aminoacyl, -C(OH)C(O)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, — C(OY2) Y3 wherein Y2 is (Ci-C4) alkyl and Y3 is (CrC6)alkyl, carboxy (C1- C6)alkyl, amino(CrC4)alkyl or mono-N — or di-N,N-(CrC6)alkylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(Cr C6)alkylarnino morpholino, piperidin-1-yl or pyrrolidin-1 -yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution- phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., (2004) 93(3). pp. 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., (2004) 5(1), article 12; and A. L. Bingham et al, Chem. Commun., (2001) pp. 603-604. A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The term "effective" or 'therapeutically effective" is used herein, unless otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result or therapeutic effect as understood in the common knowledge of those skilled in the art.
The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66( 1 ) pp. 1 -19; P. Gould, International J. of Pharmaceutics (1986) (2001 ) 33 pp. 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci-4alkyl, or Ci-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci-2o alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
It is also possible that the compounds of Formula I may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36CI, respectively.
Certain isotopically-labelled compounds of Formula I (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
The compounds according to the invention have pharmacological properties. The compounds of Formula I are inhibitors of DGAT, particularly DGAT1 , and can be useful for the therapeutic and/or prophylactic treatment of diseases that are modulated by DGAT, particularly by DGAT1 , such as, for example, metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), obesity and the like.
The invention also includes methods of treating diseases that are modulated by DGAT, particularly by DGAT1.
The invention also includes methods of treating metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), and obesity in a patient by administering at least one compound of Formula I to said patient.
Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose, or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Abnormal glucose homeostasis is associated with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. As such, the diabetic patient is at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissue (muscle, liver and adipose tissue), and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not associated with a diminished number of insulin receptors but rather to a post-insulin receptor binding defect that is not well understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
The available treatments for Type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic [beta]-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides are a class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. However, the biguanides can induce lactic acidosis and nausea/diarrhea.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a separate class of compounds with potential for the treatment of Type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR- gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.
Additional methods of treating the disease are currently under investigation. New biochemical approaches include treatment with alpha- glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors.
Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type 2 diabetes.
The invention includes compositions, e.g., pharmaceutical compositions, comprising at least one compound of Formula I. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Other carriers include Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
The therapeutic agents of the present invention are preferably formulated in pharmaceutical compositions and then, in accordance with the methods of the invention, administered to a subject, such as a human subject, in a variety of forms adapted to the chosen route of administration. For example, the therapeutic agents may be formulated for intravenous administration. The formulations may, however, include those suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, or other parenteral administration (including subcutaneous, intramuscular, intrathecal, intraperitoneal and intratumoral, in addition to intravenous) administration.
Formulations suitable for parenteral administration conveniently include a sterile aqueous preparation of the active agent, or dispersions of sterile powders of the active agent, which are preferably isotonic with the blood of the recipient. Parenteral administration of the therapeutic agents (e.g., through an I. V. drip) is an additional form of administration. Isotonic agents that can be included in the liquid preparation include sugars, buffers, and sodium chloride. Solutions of the active agents can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions of the active agent can be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, glycerol esters, and mixtures thereof. The ultimate dosage form is sterile, lluid, and stable under the conditions of manufacture and storage. The necessary fluidity can be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants. Sterilization of a liquid preparation can be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization. Preferred methods for preparing powders include vacuum drying and freeze drying of the sterile injectible solutions. Subsequent microbial contamination can be prevented using various antimicrobial agents, for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Absorption of the active agents over a prolonged period can be achieved by including agents for delaying, for example, aluminum monostearate and gelatin. Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes containing the first and/or second therapeutic agents, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught. Such compositions and preparations may contain at least about 0.1 wt-% of the active agent. The amounts of the therapeutic agents should be such that the dosage level will be effective to produce the desired result in the subject. Nasal spray formulations include purified aqueous solutions of the active agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye. Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
The tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a natural or artificial flavoring agent. When the unit dosage form is a capsule, it may further contain a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like. A syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent. The material used in preparing any unit dosage form is substantially nontoxic in the amounts employed. The active agent may be incorporated into sustained-release preparations and devices.
Preferably the compound is administered orally, intraperitoneally, or intravenously or intrathecal^ or some suitable combination(s) thereof.
Methods of administering small molecule therapeutic agents are well- known in the art.
The therapeutic agents described in the present disclosure can be administered to a subject alone or together (coadministered, optionally but not necessarily, in a single formulation) with other active agents as described herein, and are preferably administered with a pharmaceutically acceptable buffer. The therapeutic agents can be combined with a variety of physiological acceptable carriers, additives for delivery to a subject, including a variety of diluents or excipients known to those of ordinary skill in the art. For example, for parenteral administration, isotonic saline is preferred. For topical administration, a cream, including a carrier such as dimethylsulfoxide (DMSO), or other agents typically found in topical creams that do not block or inhibit activity of the peptide, can be used. Other suitable carriers include, but are not limited to, alcohol, phosphate buffered saline, and other balanced salt solutions.
The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Preferably, such methods include the step of bringing the therapeutic agent (i.e., the active agent) into association with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations. The methods of the invention include administering the therapeutic agents to a subject in an amount effective to produce the desired effect. The therapeutic agents can be administered as a single dose or in multiple doses. Useful dosages of the active agents can be determined by comparing their in vitro activity and the in vivo activity in animal models. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Another aspect of the invention includes pharmaceutical compositions comprising at least one compound of Formula I and at least one other therapeutic agent in combination. Non-limiting examples of such combination agents are described below. The agents in the combination can be administered together as a joint administration (e.g., joint single pill), separately, one after the other in any order and the like as is well known in the art.
In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
COMBINATION THERAPY Accordingly, in one embodiment, the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent that is not a Compound of Formula (I), wherein the amounts administered are together effective to treat or prevent a Condition.
When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
In one embodiment, the one or more Compounds of Formula (I) is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
In another embodiment, the one or more Compounds of Formula (I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition. In another embodiment, the one or more Compounds of Formula (I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
In still another embodiment, the one or more Compounds of Formula (I) and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
In one embodiment, the one or more Compounds of Formula (I) and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration.
The one or more Compounds of Formula (I) and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
In one embodiment, the administration of one or more Compounds of Formula (I) and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
In one embodiment, when the patient is treated for diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose, the other therapeutic is an antidiabetic agent which is not a Compound of Formula I.
In another embodiment, the other therapeutic agent is an agent useful for reducing any potential side effect of a Compound of Formula I. Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
In one embodiment, the other therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the other therapeutic agent is used at its normally prescribed dosage. In another embodiment, the other therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
Examples of antidiabetic agents useful in the present methods for treating diabetes or a diabetic complication include a sulfonylurea; an insulin sensitizer (such as a PPAR agonist, a DPP-IV inhibitor, a PTP-1 B inhibitor and a glucokinase activator); a glucosidase inhibitor; an insulin secretagogue; a hepatic glucose output lowering agent; an anti-obesity agent; a meglitinide; an agent that slows or blocks the breakdown of starches and sugars in vivo; an histamine H3 receptor antagonist; a sodium glucose uptake transporter 2 (SGLT-2) inhibitor; a peptide that increases insulin production; and insulin or any insulin-containing composition.
In one embodiment, the antidiabetic agent is an insulin sensitizer or a sulfonylurea. Non-limiting examples of sulfonylureas include glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, gliclazide, glibenclamide and tolazamide.
Non-limiting examples of insulin sensitizers include PPAR activators, such as rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; DPP-IV inhibitors; PTP-1 B inhibitors; and α- glucokinase activators, such as miglitol, acarbose, and voglibose.
Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitagliptin (Januvia™, Merck), saxagliptin, denagliptin, vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), Bl-A and Bl-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCI (Janumet™, Merck).
Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku).
Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR.
Non-limiting examples of histamine H3 receptor antagonist agents include the following compound:
Figure imgf000156_0001
Non-limiting examples of insulin secretagogues include sulfonylurea and non-sulfonylurea drugs such as GLP-1 , a GLP-1 mimetic, exendin, GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenclamide, repaglinide and glimepiride. Non-limiting examples of GLP-1 mimetics useful in the present methods include Byetta-Exenatide, Liraglutide, CJC-1131 (ConjuChem, Exenatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
The term "insulin" as used herein, includes all pyridinones of insulin, including long acting and short acting forms of insulin.
Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
In one embodiment, the antidiabetic agent is an anti-obesity agent. Non-limiting examples of anti-obesity agents useful in the present methods for treating diabetes include a 5-HT2C agonist, such as lorcaserin; a neuropeptide Y antagonist; an MCR4 agonist; an MCH receptor antagonist; a protein hormone, such as leptin or adiponectin; an AMP kinase activator; and a lipase inhibitor, such as orlistat. Appetite suppressants are not considered to be within the scope of the anti-obesity agents useful in the present methods.
Non-limiting examples of meglitinides useful in the present methods for treating diabetes include repaglinide and nateglinide.
Non-limiting examples of insulin sensitizing agents include biguanides, such as metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCE™ from Bristol-Myers Squibb) and buformin; glitazones; and thiazolidinediones, such as rosiglitazone, rosiglitazone maleate (AVANDIA™ from GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOS™, from Takeda) ciglitazone and MCC-555 (Mitsubishi Chemical Co.)
In one embodiment, the insulin sensitizer is a thiazolidinedione.
In another embodiment, the insulin sensitizer is a biguanide.
In another embodiment, the insulin sensitizer is a DPP-IV inhibitor.
In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor. Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Alpha- glucosidase inhibitors help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. Non-limiting examples of suitable alpha-glucosidase inhibitors include acarbose; miglitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose. Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP-1) agonistic activity as disclosed in WO 00/07617 (incorporated herein by reference). Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Compound(s) of Formula (I) and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous. Generally, a total daily dosage of the one or more Compounds of Formula (I) and the additional therapeutic agent(s) can, when administered as combination therapy, range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration. In one embodiment, the dosage is from about 0.2 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
The compounds of the invention can be made according to the processes described below. The compounds of this invention are also exemplified in the examples below, which examples should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. General Methods
The general methods described in this paragraph were used unless stated otherwise in the examples below. All solvents and reagents were used as received. Proton NMR spectra were obtained using a Varian XL-400 (400 MHz) or a Bruker (500 MHz) instrument and were reported as parts per million (ppm) downfield from Me4Si. LCMS analysis was performed using a PE SCIEX API-150EX, single quadrupole mass spectrometer equipped with a Phenomenex column: Gemini C-18, 50 x 4.6 mm, 5 micron; mobile phase A: 0.05 % trifluoroacetic acid in water, B: 0.05% trifluoroacetic acid in CH3CN; gradient: 90 % A and 10 % B to 5 % A and 95 % B in 5 minutes. Flash column chromatography was performed using Teledyne lsco RediSep Normal Phase Columns. Preparative TLC was performed using Analtech Silica gel GF plates. Intermediate A-4 2-(1-Piperidinyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-4)
Figure imgf000160_0001
Step 1 : Ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1) To a suspension of urea (13.5 g) in DMF (50 ml_) was added ethyl 4,4,4- trifluoro-2-chloroacetoacetate (10 ml_) and the resulting reaction mixture was heated at 120 °C for 3 days. Then, the reaction mixture was cooled to RT and diluted with H2O (100 ml_). Then, the reaction mixture was stirred at 0 0C for 1 h. The resulting precipitate was filtered, washed with H2O and dried in vacuo to yield ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1 ) as a white powder (9.8 g, 74% yield). LCMS (ESI) [M+1]+ 225.1. Step 2: Ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) To a suspension of ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1) (9.8 g) in acetonitrile (100 ml_) at 0 °C was first added copper (II) bromide (11.8 g) then te/t-butylnitrite (13.8 ml_) slowly. The reaction mixture was warmed slowly from 0 °C to RT under a nitrogen atmosphere. After 4 h of stirring at RT, the reaction mixture was concentrated. The residue was suspended in EtOAc (200 ml_), washed with 1 N HCI (3 x 100 ml_), brine (1 x 100 rriL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (eluant: EtOAc and hexanes) to yield ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) as a colorless liquid (9.18 g, 73% yield). LCMS (ESI) [M+1]+ 288.2. Step 3: Ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A- 3) To a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (0.85 mL) in α,α,α-trifluorotoluene (10 mL) at RT was added piperidine (1.1 mL). The reaction mixture was heated at 120 0C for 20 min by microwave then cooled to RT and diluted with EtOAc (100 ml_). The organic solution was washed with H2O (2 x 100 ml_), sat. NH4CI (1 x 100 ml_), brine (1 x 100 ml_), dried over Na2SO4, filtered, and concentrated to give ethyl 2-(1 -piperidinyl)-4- trifluoromethyloxazole-5-carboxylate (A-3) as a yellow solid (1.28 g, 88% yield). LCMS (ESI) [M+1]+ 293.2.
Step 4: 2-(1-Piperidinyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-4) To a solution of ethyl 2-(1 -piperidinyl)-4-trilluoromethyloxazole-5-carboxylate (A-3) (1.28 g) in THF (20 ml_) at RT was added 1 N NaOH (20 ml_). The reaction mixture was stirred at RT for 3 h then diluted with H2O (100 mL) and 1 N NaOH (10 mL). The aqueous solution was washed with Et2O (2 x 100 mL) and then acidified to pH = 1 by addition of 1 N HCI and extracted with EtOAc (3 x 50 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated to yield 2-(1 -piperidinyl)-4-trifluoromethyloxazole-5- carboxylic acid (A-4) as a white solid (1.16 g, 100% yield). LCMS (ESI) [M+1]+ 265.1.
Intermediate A-5
2-(3,5-Dimethylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-5)
Figure imgf000161_0001
Intermediate A-5 was prepared by the general procedure for intermediate A-4, by using A-2 and 3,5-dimethylpiperidine as starting materials. MS (M+1 ): 293. Intermediate A-6 2-(3,3-Dimethylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid
(A-6)
Figure imgf000161_0002
Intermediate A-6 was prepared by the general procedure for intermediate A-4, by using A-2 and 3,3-dimethylpiperidine as starting materials. MS (M+1 ): 293. Intermediate A-7
2-(3-Methylpiperidin-1 -yl)-4-methyloxazole-5-carboxylic acid (A-7)
Figure imgf000162_0001
A-7
Intermediate A-7 was prepared by the general procedure for intermediate A-4, by using ethyl 4-methyl-2-chloroacetoacetate in step 1 and 3-methylpiperidine step 3. MS (M+1): 225. Intermediate A-9 2-(Cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylic acid (A-9)
Figure imgf000162_0002
Step 1 : Ethyl 2-(cyclohexylthio)-4-trif luoromethyloxazole-5-carboxylate (A-8)
To compound A-2 (300 mg, 1.04 mmol) in dry THF (8 ml_) was added cyclohexanethiol (242 mg, 2.08 mmol, 0.26 ml_) and potassium carbonate (288 mg, 2.08 mmol). The resulting reaction mixture was heated at 80 0C for 5 h then cooled to RT and concentrated. Water (15 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product ethyl 2- (cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylate (A-8) as a yellow oil (336 mg, 100% yield). MS (M+1 ): 324. Step 2: 2-(Cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylic acid (A-
9)
To compound A-8 (336 mg, 1.04 mmol) in THF (6 ml_) and water (2 ml_) was added lithium hydroxide (175 mg, 4.16 mmol). The resulting reaction mixture was stirred at RT for 20 h then concentrated. 1 N aqueous HCI (15 ml.) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product 2-(cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylic acid (A-9) as a yellow oil (307 mg, 100% yield). MS (M+1): 296. Intermediate A-10
2-(Cyclopentylthio)-4-tιϊf luoromethyloxazole-5-carboxylic acid (A-10)
Figure imgf000163_0001
Intermediate A-10 was prepared by the general procedure for intermediate A- 9, by using A-2 and cyclopentanethiol as starting materials. MS (M+1): 282. Intermediate A-13 2-(2(E)-Phenylethenyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-13)
Figure imgf000163_0002
Step 1 : Ethyl 2-(2(E)-phenylethenyl)-4-hydroxy-4- trif luoromethyloxazoline-5-carboxylate (A-11 )
To ethyl 4,4,4-trifluoro-2-chloroacetoacetate (20.0 g, 0.0916 mol) dissolved in dry THF (400 ml_) was added cinnamamide (16.16 g, 0.110 mol) and sodium bicarbonate (1 1.54 g, 0.137 mol). The resulting reaction mixture was heated at 80 0C for 16 h then cooled to RT and concentrated. Water (400 rriL) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product ethyl 2-(2(E)-phenylethenyl)-4-hydroxy-4-trifluoromethyloxazoline-5- carboxylate (A-11 ) as a yellow solid (26.79 g, 89% yield). MS (M+1): 330. Step 2: Ethyl 2-(2(E)-phenylethenyl)-4-trifluoromethyloxazole-5- carboxylate (A-12)
To compound A-11 (26.78 g, 0.0813 mol) suspended in CH2CI2 (100 ml_) and cooled to 0 0C was carefully added trifluoroacetic anhydride (100 ml_) then pyridine (10 ml_). The resulting reaction mixture was warmed slowly from 0 °C to RT over 2 h then stirred at RT for 16 h. The solution was concentrated, cooled to 0 0C, and 1 N NaOH (400 ml_) was added. The aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc - hexane) gave the product ethyl 2-(2(E)-phenylethenyl)-4- trifluoromethyloxazole-5-carboxylate (A-12) as a white solid (8.84 g, 35% yield). MS (M+1): 312.
Step 3: 2-(2(E)-Phenylethenyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-13)
Using the procedure for step 2 of intermediate A-9, the product 2-(2(E)- phenylethenyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-13) was obtained as a white solid MS (M+1): 284. Intermediate A-14
2-(Cyclopentyl(methyl)amino)-4-trifluoromethyloxazole-5-carboxylic acid (A-14)
Figure imgf000164_0001
A-14
Intermediate A-14 was prepared by the general procedure for intermediate A- 4, by using A-2 and N-methylcyclopentylamine as starting materials. MS (M+1): 279. Intermediate A-15 2-(Cyclohexyl(methyl)amino)-4-trifluoromethyloxazole-5-carboxylic acid (A-15)
Figure imgf000164_0002
A-15
Intermediate A-15 was prepared by the general procedure for intermediate A- 4, by using A-2 and N-methylcyclohexylamine as starting materials. MS (M+1): 293.
Intermediate A-16 2-(4-Phenylpiperidin-1 -yl)-4-trif luoromethyloxazole-5-carboxylic acid (A- 16)
Figure imgf000165_0001
Intermediate A-16 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-phenylpiperidine as starting materials. MS (M+1): 341.
Intermediate A-17
2-(3-Phenylpiperidin-1 -yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-
17)
Figure imgf000165_0002
A-17
Intermediate A-17 was prepared by the general procedure for intermediate A-
4, by using A-2 and 3-phenylpiperidine as starting materials. MS (M+1): 341. Intermediate A-18
2-(3-(Trifluoromethyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-18)
Figure imgf000165_0003
A-18
Intermediate A-18 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(trifluoromethyl)piperidine as starting materials. MS (M+1): 333. Intermediate A-19
2-(3-Fluoropiperidin-1 -yl)-4-trif luoromethyloxazole-5-carboxylic acid (A- 19)
Figure imgf000166_0001
A-19
Intermediate A-19 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-fluoropiperidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 283. Intermediate A-20
2-(3-Hydroxypiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-20)
Figure imgf000166_0002
Intermediate A-20 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-hydroxypiperidine as starting materials. MS (M+1): 281.
Intermediate A-21
2-(3-Methoxypiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-21)
Figure imgf000166_0003
A-21
Intermediate A-21 was prepared by the general procedure for intermediate A-
4, by using A-2 and 3-methoxypiperidine as starting materials. MS (M+1): 295.
Intermediate A-22 2-(3-Methoxypyrrolidin-1 -yl)-4-trif luoromethyloxazole-5-carboxylic acid
(A-22)
Figure imgf000167_0001
A-22
Intermediate A-22 was prepared by the general procedure for intermediate A-
4, by using A-2 and 3-methoxypyrrolidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 281.
Intermediate A-23
2-(3-Methylpyrrolidin-1 -yl)-4-trif luoromethy loxazole-5-carboxylic acid (A-
23)
Figure imgf000167_0002
A-23
Intermediate A-23 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-methylpyrrolidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 265. Intermediate A-24 2-(Pyrrolidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-24)
Figure imgf000167_0003
A-24
Intermediate A-24 was prepared by the general procedure for intermediate A-
4, by using A-2 and pyrrolidine as starting materials. LCMS (ESI) [M+1]+
251.1.
Intermediate A-27
2-Bromo-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (A-27)
Figure imgf000168_0001
Step 1 : 2-Bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-25)
LiOH-H2O (0.64 g, 15.25 mmol) was added to a solution of ethyl 2-bromo-4- trifluoromethyloxazole-5-carboxylate (A-2) (3.50 g, 12.2 mmol) in THF/H2O (20/5 m L) at 0 0C followed by stirring for 3 h at 0 0C. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 1 M HCI (16 mL) at 0 0C. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The product was dried in vacuo to yield 2-bromo-4- trifluoromethyloxazole-5-carboxylic acid (A-25) as a white solid (2.80 g, 88% yield).
Step 2: 2-Bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-26) To a solution of 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-25) (1.30 g, 5.0 mmol) in CH2CI2 (25 mL) was added oxalyl chloride (8.5 mL, 10.0 mmol) and DMF (0.019 mL), respectively, at RT under a nitrogen atmosphere. The reaction was stirred for 6 h at RT. The solvent was concentrated, and the residue was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5- carbonyl chloride (A-26) as yellow oil (1.30 g, 96% yield). Step 3: 2-Bromo-N-(6-(4-(2-f luorophenylcarbamoyl)piperazin-1 -yl)pyridin- 3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (A-27) A solution of 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-26) (0.255 g, 0.90 mmol) and 4-(5-aminopyridin-2-yl)-N-(2- fluorophenyl)piperazine-1 -carboxamide (B-5) (0.255 g, 0.81 mmol) in CH2CI2 (5 mL) was cooled to - 78 0C then triethyl amine (0.13 mL, 0.90 mmol) was added. The reaction mixture was stirred for 4 h while the temperature was warmed slowly up to RT. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0 - 30% EtOAc/hexane gradient) to yield 2-bromo-N-(6-(4-(2- fluorophenylcarbamoyOpiperazin-i-yOpyridin-S-yO^-CtrifluoromethyOoxazole- 5-carboxamide (A-27) (78 mg, 16% yield) as a yellow solid. LCMS (ESI) calcd for [M+1]+ for bromide (chloride) 558.3 (512.1 ), found 558.8 (513.0). Intermediate A-29
2-(2-Oxopyrrolidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxylic acid (A- 29)
ftΛΛγ o0Et *"""
Figure imgf000169_0001
'ΛAY o OH
A-2 A28 A-29
Step 1 : Ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxylate (A-28)
NaH (0.060 mg, 1.5 mmol) (60 %) was added to a solution of 2-oxopyrrolidine (0.13 g, 1.5 mmol) in DMF (5.0 mL) at - 78 0C followed by stirring for 15 mins at - 78 °C. Then ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate A-2 (0.29 g, 1.0 mmol) was added. The reaction mixture was stirred for 3 h while the temperature was slowly warmed to RT. The reaction mixture was purified by chromatography on a Prep Gilson HPLC to yield ethyl 2-(2-oxopyrrolidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-28) as a white solid (0.15 g, 34% yield). 1H NMR (500 MHz, CDCI3) δ 4.44 (m, 2H), 4.09 (t, 2H, J = 7.0 Hz), 2.69 (t, 2H1 J = 8.2 Hz), 2.28 (m, 2H), 2.42 (t, 3H, J = 7.3 Hz). Step 2: 2-(2-Oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-29)
LiOH-H2O (0.096 g, 2.28 mmol) was added to a solution of ethyl 2-(2- oxopyrrolidin-1-yl)-4-(trϊlϊuoromethyl)oxazole-5-carboxylate (A-28) (0.140 g, 0.48 mmol) in THF/CH3OH/H2O (2/2/0.5 mL) at RT followed by stirring overnight. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 2.5 mL of 1 M HCI. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The residue was dried in vacuo to yield 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A- 29) as a white solid (0.120 g, 95% yield). 1H NMR (500 MHz, CD3OD) δ 5.18 (br s, 1 H), 3.41 (t, 2H, J= 6.8 Hz), 2.42 (t, 2H, J= 7.2 Hz), 1.93 (m, 2H). Intermediate A-30
2-(2-Oxopiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A- 30)
Figure imgf000170_0001
Intermediate A-30 was prepared by the general procedure for intermediate A- 29, by using compound A-2 and 2-oxopiperidine as starting materials. Intermediate A-32 2-(1 -Piperidinyl)-4-trif luoromethylthiazole-5-carboxylic acid (A-32)
Figure imgf000170_0002
A-31 A-32
Step 1 : Ethyl 2-amino-4-trifluoromethylthiazole-5-carboxylate (A-31)
To a suspension of thiourea (3.3 g, 22.88 mmol) in EtOH (200 mL) was added ethyl 4,4,4-trifluoro-2-chloroacetoacetate (5 g, 22.88 mmol), and the resulting reaction mixture was heated at 80 °C for 24 h. Then, the reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by column chromatography to give ethyl 2-amino-4-trifluoromethylthiazole-5-carboxylate (A-31) as a colorless oil (5.98 g, 85% yield). 1H NMR (500 MHz, CDCI3) δ 4.32 (q, 2H, J= 7.0 Hz), 3.56 (m, 4H), 1.70 (m, 6H), 1.36 (t, 3H, J = 7.0 Hz); LCMS (ESI) [M+1]+ 309.3. Step 2: 2-(1-Piperidinyl)-4-trifluoromethylthiazole-5-carboxylic acid (A- 32)
Compound A-32 was prepared by the general procedure for step 2 of intermediate A-9 using compound A-31 as starting material. 1H NMR (500 MHz, CDCI3) δ 3.56 (m, 4H), 1.73 (m, 6H); LCMS (ESI) [M+1]+ 281.2. Intermediate A-33
2-(4-Phenylpiperidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid (A-33)
Figure imgf000171_0001
Intermediate A-33 was prepared by the general procedure for intermediate A- 4, by using thioamide with ethyl 4,4,4-trifluoro-2-chloroacetoacetate to form the thiazole ring and 4-phenylpiperidine as starting materials. MS (M+1): 357. Intermediate A-34
2-(3-Methylpyrrolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid (A-34)
Figure imgf000171_0002
A-34
Intermediate A-34 was prepared by the general procedure for intermediate A- 4, by using thioamide with ethyl 4,4,4-trifluoro-2-chloroacetoacetate to form the thiazole ring and 3-methylpyrrolidine as starting materials. MS (M+1): 281. Intermediate A-35 2-(Phenylthio)-4-trifluoromethyloxazole-5-carboxylic acid (A-35)
Figure imgf000171_0003
Intermediate A-35 was prepared by the general procedure for intermediate A- 9, by using A-2 and phenyl mercaptan as starting materials. MS (M+1 ): 290. Intermediate A-36 2-(Benzylthio)-4-trifluoromethyloxazole-5-carboxylic acid (A-36)
Figure imgf000171_0004
Intermediate A-36 was prepared by the general procedure for intermediate A- 9, by using A-2 and benzyl mercaptan as starting materials. MS (M+1): 304. Intermediate A-37 2-(Diethylamino)-4-trifluoromethyloxazole-5-carboxylic acid (A-37)
Figure imgf000172_0001
A-37
Intermediate A-37 was prepared by the general procedure for intermediate A- 4, by using A-2 and N,N-diethylamine as starting materials. MS (M+1): 253. Intermediate A-38
2-(4-(4-Fluorophenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-38)
Figure imgf000172_0002
Intermediate A-38 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-(4-fluorophenyl)piperidine as starting materials. MS
(M+1): 359.
Intermediate A-39
2-(4-(4-Methoxyphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-39)
Figure imgf000172_0003
Intermediate A-39 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-(4-methoxyphenyl)piperidine as starting materials. MS (M+1): 371. Intermediate A-40
2-(3-(4-Fluorophenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-40)
Figure imgf000173_0001
Intermediate A-40 was prepared by the general procedure for intermediate A-
4, by using A-2 and 3-(4-fluorophenyl)piperidine as starting materials. MS
(M+1): 359.
Intermediate A-41
2-(4-Propylpiperidin-1 -yl)-4-trif luoromethyloxazole-5-carboxylic acid (A-
41)
Figure imgf000173_0002
A-41
Intermediate A-41 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-propylpiperidine as starting materials. MS (M+1 ): 307. Intermediate A-42
2-(4-Trifluoromethylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-42)
Figure imgf000173_0003
Intermediate A-42 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-trifluoromethylpiperidine as starting materials. MS
(M+1): 333.
Intermediate A-43
2-(4-Benzylpiperidin-1 -yl)-4-trif luoromethyloxazole-5-carboxylic acid (A- 43)
Figure imgf000174_0001
Intermediate A-43 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-benzylpiperidine as starting materials. MS (M+1 ): 355. Intermediate A-44 2-(4-Methylpiperidin-1-yl)-4-trifluoromethyloxa2ole-5-carboxylic acid (A-
44)
Figure imgf000174_0002
Intermediate A-44 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-methylpiperidine as starting materials. MS (M+1 ): 279. Intermediate A-45
2-(3-(2-Fluorophenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-45)
Figure imgf000174_0003
Intermediate A-45 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(2-fluorophenyl)piperidine as starting materials. MS (M+1): 359. Intermediate A-46
2-(3-(3-Fluorophenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-46)
Figure imgf000174_0004
A-46 Intermediate A-46 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(3-fluorophenyl)piperidine as starting materials. MS (M+1): 359. Intermediate A-47 2-(3-(2-Methoxyphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-47)
Figure imgf000175_0001
Intermediate A-47 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(2-methoxyphenyl)piperidine as starting materials. MS (M+1): 371.
Intermediate A-48
2-(3-(4-Methoxyphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-48)
A-48 Intermediate A-48 was prepared by the general procedure for intermediate A-
4, by using A-2 and 3-(4-methoxyphenyl)piperidine as starting materials. MS
(M+1): 371.
Intermediate A-49
2-(3-(3-Methylphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-49)
Figure imgf000175_0003
Intermediate A-49 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(3-methylphenyl)piperidine as starting materials. MS (M+1): 355. Intermediate A-50 2-(3-(S)-Phenylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid
(A-50)
Figure imgf000176_0001
A-50 Intermediate A-50 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(S)-phenylpiperidine as starting materials. MS (M+1 ): 341.
Intermediate A-51
2-(3-Phenyl)pyrrolidin-1-yl)-4-tri1iuoromethyloxazole-5-carboxylic acid (A-51)
Figure imgf000176_0002
A-51
Intermediate A-51 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-phenylpyrrolidine as starting materials. MS (M+1 ): 327. Intermediate A-52 2-(3-(4-Methylphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-52)
Figure imgf000176_0003
Intermediate A-52 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(4-methylphenyl)piperidine as starting materials. MS (M+1): 355.
Intermediate A-53
2-(4-(2-Methoxyphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-53)
Figure imgf000177_0001
Intermediate A-53 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-(2-methoxyphenyl)piperidine as starting materials. MS (M+1): 371. Intermediate A-54
2-(3-(R)-Phenylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic acid (A-54)
Figure imgf000177_0002
A-54
Intermediate A-54 was prepared by the general procedure for intermediate A- 4, by using A-2 and 3-(R)-phenylpiperidine as starting materials. MS (M+1): 341.
Intermediate A-55
2-(4-(3-Methoxyphenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- carboxylic acid (A-55)
Figure imgf000177_0003
Intermediate A-55 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-(3-methoxyphenyl)piperidine as starting materials. MS (M+1): 371. Intermediate A-56 2-(4-(2-Fluorophenyl)piperidin-1-yl)-4-trifluoromethyloxazole-5- car boxy lie acid (A-56)
Figure imgf000178_0001
Intermediate A-56 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-(2-fluorophenyl)piperidine as starting materials. MS
(M+1): 359.
Intermediate A-57
2-(1-benzylpyrrolidin-3-ylamino)-4-(trifluoromethyl)oxazole-5-carboxylic acid
(A-57)
Figure imgf000178_0002
A-57
Intermediate A-57 was prepared by the general procedure for intermediate A-
4, by using A-2 and 4-amino-1 -benzylpiperidine as starting materials. MS
(M+1): 356.
Intermediate A-58
2-(1 -Benzylpiperidin-4-ylamino)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-58)
Figure imgf000178_0003
Intermediate A-58 was prepared by the general procedure for intermediate A- 4, by using A-2 and 4-amino-1-benzylpiperidine as starting materials. MS (M+1): 370.
Intermediate A-62
2-(Piperidin-1 -ylmethyl)-4-(trifluoromethyl)thiazole-5-carboxylic acid (A-62)
Figure imgf000179_0001
Step 1 : Ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate (A-59) To a solution of thioacetamide (7.5 g, 0.10 mol) in acetonitrile was added ethyl 4,4,4-trifluoro-2-chloroacetoacetate (21.9 g, 0.10 mol). The resulting reaction mixture was stirred at room temperature for 12 h then cooled to 0 0C. Triethylamine (10.1 g, 14 ml_, 0.10 mol) and 2-picoline (22.3 g, 23.7 ml_, 0.24 mol) were added. After stirring for 15 mins, trifluoroacetic anhydride (22.1 g, 0.10 mol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h then concentrated. EtOAc (200 ml_) was added, and the organic solution was washed with 1 N HCI then brine. The combined organic extract was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (eluant: 0-15% EtOAc - hexane) to give ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate (A-59) as a yellow solid (13.5 g, 58% yield). MS (M+1 ): 240.
Step 2: Ethyl 2-(bromomethy)-4-trϊlϊuoromethylthiazole-5-carboxylate (A-60) A mixture of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate (A-59) (4.78 g, 20.2 mmol), N-bromosuccinimide (5.34 g, 30.0 mmol), and dibenzoyl peroxide (0.96 g, 4.0 mmol) in carbon tetrachloride was heated at 80 0C for 4 h. The reaction mixture was cooled and concentrated. Water was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (eluant: 0-10% EtOAc - hexane) to give ethyl 2-(bromomethy)-4-trifluoromethylthiazole-5-carboxylate (A-60) as a yellow oil (1.5 g, 23% yield). MS (M+1 ): 320.
Step 3: ethyl 2-(piperidin-1 -ylmethyl)-4-(trifluoromethyl)thiazole-5-carboxylate (A-61) To a solution of ethyl 2-(bromomethy)-4-trifluoromethylthiazole-5-carboxylate
(A-60) (0.32 g, 1.0 mmol) in dry THF was added piperidine (0.26 g, 3.0 mmol).
The reaction mixture was stirred at room temperature for 30 mins. EtOAc was added, and the solution was washed with saturated NaHCO3. The organic extract was dried (MgSO4), filtered, and concentrated to give ethyl 2-
(piperidin-1 -ylmethyl)-4-(trifluoromethyl)thiazole-5-carboxylate (A-61) as a yellow oil (0.32 g, 100% yield). MS (M+1): 323.
Step 4: 2-(piperidin-1 -ylmethyl)-4-(trif luoromethyl)thiazole-5-carboxylic acid
(A-62)
Intermediate A-62 was prepared using the general procedure for saponification. MS (M+1 ): 295.
Intermediate A-64
2-(2-fluorophenylamino)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-
64)
Figure imgf000180_0001
Step 1 : ethyl 2-(2-fluorophenylamino)-4-(trifluoromethyl)oxazole-5- carboxylate (A-63)
To a solution of 1-(2-fluorophenyl)urea (1.1 g, 7.1 mmol) in DMF (2 ml_) was added ethyl 4,4,4-trifluoro-2-chloroacetoacetate (1.0 ml_, 5.9 mmol). The reaction mixture was heated at 120 0C under atmosphere. After 17 h of heating, the reaction mixture was cooled to RT and diluted with H2O (200 ml_). The yellow precipitate was filtered, washed with H2O, and dried in vacuo to give the product, ethyl 2-(2-fluorophenylamino)-4-(trifluoromethyl)oxazole-5- carboxylate (A-63), which was used for the next step without further purification.
Step 2: 2-(2-fluorophenylamino)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-64) To a solution of compound A-63 obtained from Step 1 dissolved in THF (50 ml_) was added 1 N NaOH (30 ml_) at RT. The reaction mixture was stirred at RT 22 h then concentrated to ~ 25 mL in volume by rotary evaporator, and the precipitate was removed by filtration and washed with H2O (-50 mL). The filtrate was washed with Et2O (5 x 100 mL). The aqueous layer was acidified to ~ pH 1 by addition of 1 N HC;, and extracted with EtOAc (4 x 100 mL). The EtOAc extracts were combined, dried over Na2SO4, filtered, concentrated, and dried in vacuo to yield 2-(2-fluorophenylamino)-4-(trifluoromethyl)oxazole-5- carboxylic acid (A-64) as a yellow solid (0.85 g, 50% yield over two steps). 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1 H), 7.89 (dt, 1 H, J = 8.4, 1.8 HZ), 7.17 - 7.33 (m, 3H). LCMS (ESI) Rt = 3.72 min, calcd for [M+1]+ 291.0 found 291.2.
Intermediate A-66 2-benzamido-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-66)
Figure imgf000181_0001
Step 1 : ethyl 2-benzamido-4-(trifluoromethyl)oxazole-5-carboxylate (A- 65)
To a solution of compound A-1 (0.95 g, 4.2 mmol) in THF (20 mL) was added a catalytic amount of DMAP, triethylamine (0.59 mL) and benzoyl chloride (0.54 mL). The reaction mixture was stirred at RT under N2 for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with sat NaHCO3 (3 x 100 mL), H2O (3 x 100 mL), brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was suspended in CH2CI2, and the insoluble materials were removed by filtration. The filtrate was concentrated, and the resulting material was purified by silica gel column chromatography (eluant: EtOAc and hexane gradient) to yield ethyl 2- benzamido-4-(trifluoromethyl)oxazole-5-carboxylate (A-65) as a light yellow solid (0.45 g, 32% yield). Step 2: 2-benzamido-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-66) To a solution of compound A-65 (0.39 g, 1.2 mmol) in THF (10 mL) was added 1 N NaOH (6 mL) at RT. The reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with H2O (50 ml_) and washed with Et2O (2 x 50 ml_). Then, the aqueous layer was acidified to ~ pH 1 by addition of 1 N HCI, and extracted with EtOAc (3 x 50 ml_). The EtOAc extracts were combined, dried over Na2SO4, filtered, concentrated, and dried in vacuo Xo yield 2-benzamido-4-(trϊlϊuoromethyl)oxazole-5-carboxylic acid (A-66) as a white solid (0.35 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1 H), 8.00 (m, 2H), 7.67 (m, 1 H), 7.55 (m, 2H). LCMS (ESI) Rt = 3.07 min, calcd for [M+1]+ 301.0 found 301.2. Intermediate A-67 2-(3-fluorophenylamino)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A- 67)
Figure imgf000182_0001
Intermediate A-67 was prepared by the general procedures for intermediate A-64, by using ethyl 2-bromooxazole-5-carboxylate as starting material. MS (M+1): 239.
Intermediate B-1 Ethyl 1-(5-aminopyridin-2-yl)piperidine-4-carboxylate
(B-1)
Figure imgf000182_0002
Intermediate B-1 was prepared by following the known procedure for the compound. (Meerpoel et al, WO 2005/058824) Intermediate B-5 4-(5-Am i nopy rid i n-2-y l)-N-(2-l I uoropheny I )pi perazi ne-1 -carboxam ide (B-
5)
Figure imgf000183_0001
Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (B-2) To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 ml_) was added N1N- diisopropylethylamine (24.5 g, 31.3 ml_, 0.189 mol). The reaction mixture was heated at 100 0C for 16 h then cooled to RT and concentrated. Water (300 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc-CH2CI2) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-1 -carboxylate (B-2) as a yellow solid (19.45 g, 100% yield). MS (M+1): 309. Step 2: /V-(5-nitropyridin-2-yl)piperazine (B-3)
To compound B-2 (19.45 g, 0.0631 mol) dissolved in CH2CI2 (250 ml_) and cooled to 0 0C was added trifluoroacetic acid (50 ml_). The resulting reaction mixture was stirred at RT for 16 h then concentrated. The crude product was dissolved in CH2CI2 (250 ml_) and made basic with the addition of 1 N aqueous NaOH (200 ml_) and 3 N aqueous NaOH (100 ml_). The layers were separated, and the aqueous solution extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product N-(2-fluorophenyl)-4-(5-nitropyridin-2-yl)piperazine-1-carboxamide (B- 3) as a yellow solid (13.13 g, 100% yield). MS (M+1): 209. Step 3: 4-(5-Nitropyridin-2-yl)-N-(2-fluorophenyl)piperazine-1- carboxamide (B-4) To compound B-3 (6.6 g, 32 mmol) dissolved in dry THF (200 ml_) was added triethylamine (8.8 ml_, 63 mmol) and 2-fluorophenyl isocyanate (4.3 ml_, 38 mmol). The resulting reaction mixture was heated at 80 0C for 16 h then cooled to RT and concentrated. Water (150 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give a yellow solid. The solid was triturated with water, filtered, and dried to give the product 4-(5-nitropyridin-2- yl)-N-(2-fluorophenyl)piperazine-1 -carboxamide (B-4) as a yellow solid (11.4 g, 100% yield). MS (M+1): 346.
Step 4: 4-(5-Aminopyridin-2-yl)-N-(2-f luorophenyl)piperazine-1 - carboxamide (B-5)
To compound B-4 (11.0 g, 31.8 mmol) suspended in ethyl acetate (100 mL) and isopropanol (100 mL) under a nitrogen atmosphere was added platinum dioxide catalyst (0.72 g, 3.18 mmol). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The catalyst was removed by filtration through celite and washed with isopropanol. The filtrate was concentrated to give the product 4-(5-aminopyridin-2-yl)-N-(2- fluorophenyl)piperazine-1 -carboxamide (B-5) as a white solid (9.2 g, 92% yield). MS (M+1): 316. Intermediate B-6 t-Butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (B-6)
Figure imgf000184_0001
Intermediate B-6 was prepared by the general procedure for intermediate B-5, by using B-2 as a starting material. LCMS [M+1]+ 279.2. Intermediate B-7 Ethyl 2-(5-aminopyridin-2-ylamino)propanoate (B-7)
Figure imgf000184_0002
Intermediate B-7 was prepared by the general procedures for step 1 and step 4 of intermediate B-5, by using 5-nitro-2-chloropyridine and DL-alanine ethyl ester as starting materials. LCMS [M+1]+ 210.1. Intermediate B-8 tert-Butyl 1-(5-aminopyridin-2-yl)piperidin-4-ylcarbamate (B-8)
Figure imgf000185_0001
Intermediate B-8 was prepared by the general procedures for step 1 and step 4 of intermediate B-5, by using 5-nitro-2-chloropyridine and 4-BOCamino- piperidine as starting materials. LCMS [M+1]+ 293.2. Intermediate B-12
(R)-3-(5-Aminopyridin-2-ylamino)-N-(2-fluorophenyl)pyrrolidine-1- carboxamide (B-12)
Figure imgf000185_0002
Step 1 : (R)-tert-butyl 3-(5-nitropyridin-2-ylamino)pyrrolidine-1 -carboxylate (B- 9)
2-Chloro-5-nitropyridine (1.50 g, 9.46 mmol) and 1 -BOC-4(R)- aminopyrrolidine (2.11 g, 11.35 mmol) were combined in dry DMF (30 ml_) and heated at 100 0C for 20 h. The reaction mixture was cooled and concentrated. Water (50 ml_) was added, and the aqueous solution was extracted with CH2CI2 (3 x 50 ml_). The combined organic extract was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (eluant: 20% EtOAc - CH2CI2 to 30% EtOAc - CH2CI2) to give (R)-tert-butyl 3-(5-nitropyridin-2-ylamino)pyrrolidine-1 - carboxylate (B-9) as a yellow foam (2.58 g, 88% yield). MS (M+1 ): 309. Step 2: (R)-5-Nitro-N-(pyrrolidin-3-yl)pyridin-2-amine (B-10)
To a solution of (R)-tert-butyl 3-(5-nitropyridin-2-ylamino)pyrrolidine-1 - carboxylate (B-9) (2.57 g, 8.34 mmol) in CH2CI2 (50 ml_) was added 4 N HCI in dioxane (16.7 ml_, 66.7 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated. The solid was dried under high vacuum to give (R)-5-nitro-N-(pyrrolidin-3-yl)pyridin-2-amine hydrochloride salt (B-10) as a beige solid (2.04 g, 100% yield). MS (M+1): 209. Step 3: (R)-3-(5-Nitropyridin-2-ylamino)-N-(2-fluorophenyl)pyrrolidine-1- carboxamide (B-11) To a suspension of (R)-5-nitro-N-(pyrrolidin-3-yl)pyridin-2-amine hydrochloride salt (B-10) (1.00 g, 4.09 mmol) in dry THF (30 ml_) was added triethylamine (1.24 g, 1.7 ml_, 12.3 mmol) and 2-fluorophenylisocyanate (0.67 g, 0.55 ml_, 4.94 mmol). The reaction mixture was heated at reflux for 18 h then cooled and concentrated. Water (30 ml_) was added, and the aqueous solution was extracted with CH2CI2 (3 x 50 ml_). The combined organic extract was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (eluant: CH2CI2 to 40% EtOAc - CH2CI2) to give (R)-3-(5-nitropyridin-2-ylamino)-N-(2-fluorophenyl)pyrrolidine-1 - carboxamide (B-11) as a yellow solid (0.90 g, 64% yield). MS (M+1): 346. Step 4: (R)-3-(5-Aminopyridin-2-ylamino)-N-(2-f luorophenyl)pyrrolidine-1 - carboxamide (B-12)
To a suspension of (R)-3-(5-nitropyridin-2-ylamino)-N-(2- fluorophenyl)pyrrolidine-1 -carboxamide (B-11) (0.89 g, 2.58 mmol) in isopropanol (20 ml_) and EtOAc (20 ml_) was added platinum oxide (0.045 g). The reaction mixture was stirred under a balloon of hydrogen for 18 h. The catalyst was removed by filtration through celite, and the celite pad was washed with CH2CI2. The filtrate was concentrated to give (R)-3-(5- aminopyridin-2-ylamino)-N-(2-fluorophenyl)pyrrolidine-1 -carboxamide (B-12) as a pink foam (0.81 g, 100% yield). MS (M+1): 316. Intermediate B-13
(S)-3-(5-Aminopyridin-2-ylamino)-N-(2-fluorophenyl)pyrrolidine-1- carboxamide (B-13)
Figure imgf000186_0001
Intermediate B-13 was prepared by the general procedure for intermediate B- 12, by using 2-chloro-5-nitropyridine and 1-BOC-4(S)-aminopyrrolidine as starting materials. MS (M+1): 316. Intermediate B-14
4-(5-Aminopyridin-2-ylamino)-N-(2-fluorophenyl)piperidine-1- carboxamide (B-14)
Figure imgf000187_0001
Intermediate B-14 was prepared by the general procedure for intermediate B-
12, by using 2-chloro-5-nitropyridine and 1-BOC-4-aminopiperidine as starting materials. MS (M+1): 330.
Intermediate B-15
1 -(1 -(5-Aminopyridin-2-yl)pyrrolidin-3-yl)-3-(2-f luorophenyl)urea (B-15)
Figure imgf000187_0002
Intermediate B-15 was prepared by the general procedure for intermediate B-
12, by using 2-chloro-5-nitropyridine and 4-(BOC-amino)-pyrrolidine. MS (M+1): 316. Intermediate B-16 ethyl 2-(1-(5-aminopyridin-2-yl)piperidin-4-yl)acetate (B-16)
Figure imgf000187_0003
Intermediate B-16 was prepared by following the known procedure for the compound. (Meerpoel, Lieven; Viellevoye, Marcel, WO/ 2005058824) Intermediate B-17 ethyl 2-(1-(5-aminopyridin-2-yl)piperazin-4-yl)acetate (B-17)
Figure imgf000187_0004
Intermediate B-17 was prepared by following the general procedure for intermediate B-2 using 2-chloro-5-nitropyridine and ethyl piperazinoacetate as starting materials. MS (M+1): 265. Intermediate B-18
6-[[2-[[(2-fluorophenyl)amino]carbonyl]methylamino]ethyl]amino]- pyridin-3-amine (B-18)
Figure imgf000188_0001
B-18 Intermediate B-18 was prepared by the general procedure for intermediate B- 12, by using 2-chloro-5-nitropyridine, t-butyl N-2-aminoethyl-N-methyl-N- carboxylate, and 2-fluorophenylisocyanate as starting materials. MS (M+1): 304.
Intermediate B-19 4-(4-aminophenyl)-N-(2-fluorophenyl)piperazine-1-carboxamide (B-19)
Figure imgf000188_0002
Intermediate B-19 was prepared by using 1-(4-nitrophenyl)-piperazine and 2- fluorophenylisocyanate as starting materials. MS (M+1): 315. Example 1 /V-(6-(4-(hydroxymethyl)piperidin-1 -yl)pyridin-3-yl)-2-(piperidin-1 -yl)-4- (trifluoromethyl)oxazole-5-carboxamide (1 )
Figure imgf000188_0003
Step 1 : Ethyl 1-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (C-1 ) To a solution of intermediate A-4 (0.080 g) and B-1 (0.091 g) in DMF (3 ml_) were added O-(7-azabenzotriazol-1 -y\)-N,N,N',N -tetramethyluronium hexafluorophosphate (0.14 g, HATU), 4-dimethylaminopyridine (0.005 mg, DMAP), and Λ/,Λ/-diisopropylethylamine (0.080 ml_). The reaction mixture was stirred at RT for 17 h then diluted with EtOAc (25 ml_), washed with H2O (4 x 10 ml_), saturated NH4CI (1 x 10 ml_), sat. NaHCO3 (I x 10 ml_), brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by prep-TLC (eluant: 30% CH3CN in CH2CI2) to give ethyl 1 -(5-(2- (piperidin-1 -yl)-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin-2- yl)piperidine-4-carboxylate (C-1) as a white solid (0.125 g, 83% yield).
1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1 H), 8.31 (d, 1 H, J = 2.6 Hz), 7.78 (dd, 1 H, J = 9.2, 2.9 Hz), 6.87 (d, 1 H, J = 9.2 Hz), 4.16 (m, 2H), 4.07 (q, 2H, J = 7.0 Hz), 3.61 (br s, 4H), 2.91 (m, 2H), 2.58 (m, 1 H), 1.87 (m, 2H), 1.64 (br s, 6H), 1.53 (m, 2H), 1.18 (t, 3H, J = 7.0 Hz). LCMS (ESI) Rt = 3.22 min, [M+1]+ 496.3.
Step 2: /V-(6-(4-(hydroxymethyl)piperidin-1 -yl)pyrϊdin-3-yl)-2-(piperidin-1 - yl)-4-(trifluoromethyl)oxazole-5-carboxamide (1 ) To a solution of compound C-1 (0.058 g) in THF (5 mL) was added a solution of LiBH4 (0.36 mL, 2.0 M in THF) at RT. The reaction mixture was stirred at RT under N2 for 2 h then treated with anhydrous MeOH (0.032 mL). After 18 h of additional stirring at RT under N2, the reaction mixture was quenched by the addition of saturated NaHCO3 (I mL). The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (3 x 100 mL), brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by prep-TLC (eluant: 50% CH3CN in CH2CI2) to yield Λ/-(6-(4- (hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (2) as a white solid (0.042 g, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.29 (d, 1 H, J = 2.6 Hz), 7.75 (dd, 1 H, J = 9.2, 2.6 Hz), 6.83 (d, 1 H, J = 8.8 Hz), 4.48 (t, 1 H, J = 5.5 Hz), 4.25 (d, 2H, J = 13.2 Hz), 3.61 (br s, 4H), 3.26 (t, 2H, J = 5.5 Hz), 2.74 (dt, 2H1 J = 12.8, 2.6 Hz), 1.70 (m, 2H), 1.61 (br s, 6H), 1.57 (m, 1 H), 1.10 (dq, 2H, J = 12.1 , 4.0 Hz). LCMS (ESI) Rt = 2.83 min, [M+1]+ 454.2. Example 2 /V-(6-morpholinopyridin-3-yl)-2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (2)
Figure imgf000190_0001
Compound 2 was prepared by the general procedure for compound C-1 , by using intermediates A-4 and 6-(4-morpholinyl)pyridine-3-amine as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1 H), 8.36 (d, 1 H, J = 2.9 Hz), 7.83 (dd, 1 H, J = 9.2, 2.6 Hz), 6.87 (d, 1 H, J= 9.2 Hz), 3.70 (t, 4H, J = 5.1 Hz), 3.61 (br s, 4H), 3.40 (t, 4H, J= 4.8 Hz), 1.61 (br s, 6H). LCMS (ESI) Rt = 2.81 min, [M+1]+ 426.2. Example 3
/V-(6-(Piperazin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (3)
Figure imgf000190_0002
Step 1 :_ferf-Butyl 4-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (C-2)
Compound C-2 was prepared by the general procedure for compound C-1 , by using intermediates A-4 and B-6 as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1 H), 8.35 (d, 1 H, J = 2.6 Hz), 7.84 (dd, 1 H, J = 9.2, 2.9 Hz), 6.88 (d, 1 H, J = 9.2 Hz), 3.61 (br s, 4H), 3.44 (m, 8H), 1.61 (br s, 6H), 1.42 (s, 9H). LCMS (ESI) Rt = 3.52 min, [M+1 ]+ 525.3.
Step 2: ΛK6-(piperazin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (3) To a solution of compound C-2 (1.37 g) in CH2CI2 (20 ml_) and CH3CN (20 ml_) was added a solution of HCI (4 ml_, 4.0 N in dioxane). The reaction mixture was stirred at RT under N2 for 20 h. The reaction mixture was diluted with H2O (100 ml_) and 1 N HCI(aq) (25 rriL), and the aqueous solution was washed with Et2O (2 x 100 ml_). The ether layers were discarded, and the aqueous layer was basified to pH = 14 by the addition of 1 N NaOH(aq) and extracted with CH2CI2 (4 x 100 ml_). The combined organic extract was dried over Na2SO4, filtered, concentrated, and dried in vacuo to give Λ/-(6- (piperazin-1-yl)pyridin-3-yl)-2-(piperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamide (3) as a white solid (0.83 g, 75 % yield). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1 H), 8.32 (d, 1 H, J = 2.6 Hz), 7.78 (dd, 1 H, J = 9.2, 2.9 Hz), 6.81 (d, 1 H, J= 9.2 Hz), 3.61 (s, 4H), 3.35 (m, 4H), 2.76 (m, 4H), 1.60 (br s, 6H). LCMS (ESI) Rt = 2.58 min, [M+1]+ 425.2. Example 4 2-(3-Methylpiperidin-1 -yl)-N-(6-(piperazin-1 -yl)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (4)
Figure imgf000191_0001
Compound 4 was prepared by the general procedure for compound 3, by using compound A-7 and B-6 as starting materials. Examples 5 - 35
N-(6-(4-(2-liuorophenylcarbamoyl)pipera2in-1-yl)pyridin-3-yl)-2- (piperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (5)
Figure imgf000191_0002
Compound 5 was prepared by the general procedure for compound B-4, by using compound 3 and 2-fluorophenyl isocyanate as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1 H), 8.42 (s, 1 H), 8.37 (d, 1 H, J = 2.9 Hz), 7.84 (dd, 1 H, J = 9.2, 2.6 Hz), 7.44 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 2H), 6.93 (d, 1 H, J = 9.2 Hz), 3.61 - 3.52 (m, 12H), 1.61 (br s, 6H). LCMS (ESI) Rt = 3.08 min, [M+1]+ 562.3.
Alternatively, compounds 5 - 35 were prepared by the method for urea combinatorial library synthesis described below.
Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 1 ml_ of the solution of compound 3 (for compounds 5 - 24) or 4 (for compounds 25 - 35) in DCE (10 mg of 3 or 4 for each cartridge), and 45.6 μl_ of each isocyanate (1 M solution in DCE). The cartridges were stoppered and shaken overnight. Then, to the each cartridge was added 31.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 48.4 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μl_ of DCE. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed vials, and the resins were washed with acetonitrile (6 x 500 μl_). Upon concentration of the filtrates, the ureas listed below were obtained as products.
Figure imgf000192_0001
Rt = 3.35 min, [M+1]+ 524.3
Figure imgf000193_0001
-
Rt = 3.43 min, [M+1]+ 536.3
Figure imgf000193_0002
Rt = 3.45 min, [M+1]+ 558.3
Figure imgf000193_0003
Rt = 3.49 min, [M+1]+ 558.3
Figure imgf000193_0004
Rt = 3.55 min, [M+1]+ 572.3
Figure imgf000193_0005
Rt = 3.45 min, [M+1]+ 574.3
Figure imgf000194_0001
Rt = 3.69 min, [M+1]+ 586.3
Figure imgf000194_0002
Rt = 3.66 min, [M+1 ]+ 612.3
Figure imgf000194_0003
Rt = 3.88 min, [M+1 ]+ 626.3
Figure imgf000194_0004
Rt = 3.42 min, [M+1 ]+ 569.3
Figure imgf000194_0005
Rt = 3.33 min, [M+1]+ 574.3
Figure imgf000195_0001
Rt = 3.38 min, [M+1]+ 578.3
Figure imgf000195_0002
Rt = 3.17 min, [M+1]+ 580.3
Figure imgf000195_0003
Rt = 3.49 min, [M+1]+ 589.3
Figure imgf000195_0004
Rt = 3.31 min, [M+1]+ 612.3
Figure imgf000195_0005
Rt = 3.60 min, [M+1]+ 620.3
Figure imgf000196_0001
Rt = 3.37 min, [M+1]+ 630.3
Figure imgf000196_0002
Rt = 3.42 min, [M+1]+ 583.3
Figure imgf000196_0003
Rt = 3.57 min, [M+1]+ 588.3
Figure imgf000196_0004
Rt = 3.57 min, [M+1]+ 592.3
Figure imgf000196_0005
Figure imgf000197_0001
Figure imgf000198_0002
Example 36
4-[5-[[2-(3,5-Dimethyl-1-piperidinyl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (36)
Figure imgf000198_0001
Compound 36 was prepared by the general procedure for compound C-1 , by using intermediates A-5 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.25 (s, 1 H), 8.10 (t, 1 H, J=8 Hz), 8.05 (s, 1 H), 7.65 (s, 1 H), 7.10 (m, 2H), 7.00 (m, 1 H), 6.70 (d, 1 H, J=9 Hz), 6.65 (s, 1 H)1 4.15 (d, 2H, J=9.5 Hz), 3.70 (m, 8H), 3.30 (m, 1/3H), 2.55 (t, 2H, J=12.5 Hz), 2.10 (m, 1/3H), 1.90 (d, 1 H, J= 13.5 Hz), 1.75 (m, 2H), 1.50 (m, 1/3H), 1.00 (d, 6H, J=6.5Hz). MS (M+1): 590. Example 37
4-[5-[[2-(3,3-Dimethyl-1-piperidinyl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (37)
Figure imgf000199_0001
Compound 37 was prepared by the general procedure for compound C-1 , by using intermediates A-6 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) 68.25 (d, 1 H, J=3 Hz),8.10 (t, 1 H, J=8.5 Hz), 8.05 (s, 1 H), 7.60 (s, 1 H), 7.10 (m, 2H), 7.00 (m, 1H), 6.70 (d, 1H, J=9 Hz), 6.65 (s, 1 H), 3.70 (m, 8H), 3.60 (t, 2H, J=6 Hz), 3.30 (s, 2H), 1.75 (m, 2H), 1.50 (t, 2H, J=6 Hz), 1.00 (s, 6H). MS (M+1): 590. Example 38
4-[5-[[2-(3-Methyl-1-piperidinyl)-4-methy)-5-oxazolyl]carbonylamino]-2- pyridinyl]-N-(2-fluorophenyl)-1-piperazinecarboxamide (38)
Figure imgf000199_0002
Compound 38 was prepared by the general procedure for compound C-1 , by using intermediates A-7 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1 H, J=2.5 Hz), 8.10 (t, 1 H, J=8.5 Hz), 8.00 (d, 1 H, J=9 Hz), 7.40 (s, 1H), 7.10 (m, 2H), 7.00 (m, 1H), 6.70 (d, 1H, J=9 Hz), 6.65 (s, 1H), 4.10 (t, 2H, J=13 Hz), 3.70 (dd, 6H, J=6.5, 12.5 Hz), 3.00 (t, 1H, J=12.5 Hz), 2.70 (t, 1 H, J=12.5 Hz)1 1.90 (d, 1 H, Λ=13 Hz), 1.60-1.85 (m, 5H), 1.15 (q, 1 H, J=12 Hz), 1.00 (d, 3H, J=6.5 Hz). MS (M+1): 522. Example 39
4-[5-[[2-(Cyclohexylthio)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-2- pyridinyl]-N-(2-fluorophenyl)-1-piperazinecarboxamide (39)
Figure imgf000200_0001
Compound 39 was prepared by the general procedure for compound C-1 , by using intermediates A-9 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.25 (d, 1 H, J=3 Hz), 8.10 (t, 1 H, J=8 Hz)1 8.05 (dd, 1 H, J=2.5, 9 Hz), 7.85 (S, 1 H), 7.15 (t, 1 H, J=7.5 Hz), 7.10 (d, 1 H, J=11 Hz), 7.00 (m, 1 H), 6.70 (d, 1 H, J=9 Hz), 6.65 (d, 1 H1 J=3.5 Hz), 3.90 (m, 1 H), 3.70 (br s, 8H), 2.20 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.50 (m, 2H), 1.40 (m, 1 H), 1.30 (m, 1 H). MS (M+1): 593. Example 40 4-[5-[[2-(Cyclopentylthio)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]- 2-pyridinyl]-N-(2-f luorophenyl)-1 -piperazinecarboxamide (40)
Figure imgf000200_0002
Compound 40 was prepared by the general procedure for compound C-1 , by using intermediates A-10 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) 5 8.25 (d, 1 H, J=2.5 Hz), 8.10 (t, 1 H, J=8.5 Hz), 8.05 (m, 1 H), 7.15 (t, 1 H, J=8 Hz), 7.10 (d, 1 H, J=11.5 Hz), 7.00 (m, 1 H), 6.70 (d, 1 H, J=9.5 Hz), 6.65 (m, 1 H), 4.10 (m, 1 H), 3.70 (br s, 8H), 2.30 (m, 2H), 1.85 (m, 2H), 1.75 (m, 4H). MS (M+1): 579. Example 41 4-[5-[[2-2(E)-(Phenylethenyl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (41)
Figure imgf000201_0001
Compound 41 was prepared by the general procedure for compound C-1 , by using intermediates A-13 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) 5 8.30 (d, 1 H, J=3 Hz), 8.20 (s, 1 H), 8.10 (m, 2H), 7.80 (d, 1 H, ^ 6.5 Hz), 7.60 (m, 2H), 7.45 (m, 3H), 7.10 (m, 2H), 7.00 (m, 1 H), 7.00 (d, 1 H, J=λ 6.5 Hz), 6.70 (d, 1 H, J=9.5 Hz), 6.65 (s, 1 H), 3.70 (br s, 8H). MS (M+1 ): 581.
Example 42
4-[5-[[2-(Cyclopentyl(methyl)amino)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (42)
Figure imgf000201_0002
Compound 42 was prepared by the general procedure for compound C-1 , by using intermediates A-14 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H, J=9.5 Hz), 7.45 (br s, 1 H), 7.20 (m, 1 H), 7.15 (br s, 2H), 6.95 (d, 1 H, J=8.5 Hz), 4.65 (t, 1 H, J=9 Hz), 3.55 (m, 8H), 3.05 (s, 3H), 1.85 (m, 2H), 1.65 (m, 6H). MS (M+1): 576. Example 43 4-[5-[[2-(Cyclohexyl(methyl)amino)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (43)
Figure imgf000202_0001
Compound 43 was prepared by the general procedure for compound C-1 , by using intermediates A-15 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 2H), 6.95 (d, 1 H, J=9 Hz), 4.00 (m, 1 H), 3.55 (m, 8H), 3.05 (s, 3H), 1.80 (d, 2H, J=12.5 Hz), 1.70 (d, 2H, J=1 1.5 Hz), 1.55 (q, 2H, ^2.5 Hz), 1.40 (q, 2H1 J=12.5 Hz). MS (M+1): 590. Example 44
4-[5-[[2-(4-Phenylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (44)
Figure imgf000202_0002
Compound 44 was prepared by the general procedure for compound C-1 , by using intermediates A-16 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.45 (s, 1 H), 8.40 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (br s, 1 H), 7.30 (m, 4H), 7.20 (m, 2H), 7.15 (m, 2H), 6.95 (d, 1 H, J=9 Hz), 4.35 (d, 2H, J=13 Hz), 3.55 (m, 8H), 3.20 (t, 2H, J=13 Hz), 2.80 (t, 1 H, J=12.5 Hz), 1.90 (m, 2H), 1.75 (q, 2H, J=9.5). MS (M+1): 638. Example 45 4-[5-[[2-(3-Phenylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (45)
Figure imgf000203_0001
Compound 45 was prepared by the general procedure for compound C-1, by using intermediates A-17 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (S, 1H), 8.40 (S, 1H), 8.35 (s, 1H), 7.80 (d, 1H, J=9 Hz), 7.45 (m, 1H), 7.35 (m, 4H), 7.25 (m, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 6.95 (d, 1H, Λ=10.5 Hz), 4.25 (t, 2H, J=12 Hz), 3.55 (m, 8H), 3.25 (t, 1H, J=13.5 Hz), 3.15 (t, 1H, J=13.5Hz), 2.85 (m, 1H), 1.95 (m, 1H), 1.85 (d, 1H, J=10.5 Hz), 1.70 (m, 2H). MS(M+1):638. Example 46
4-[5-[[2-(3-Trifluoromethylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (46)
Figure imgf000203_0002
Compound 46 was prepared by the general procedure for compound C-1 , by using intermediates A-18 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.40 (S, 1H), 8.35 (s, 1H), 7.85 (d, 1H, J=9.5 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (br s, 2H), 6.95 (d, 1 H, J=9,5 Hz), 4.30 (d, 1 H, J=15 Hz), 4.15 (d, 1 H, J=14 Hz), 3.55 (m, 8H), 3.25 (t, 1 H, J=11.5 Hz), 3.15 (t, 1H, J=13Hz), 2.00 (d, 1H, J=7.5 Hz), 1.85 (d, 1H, J=13.5 Hz), 1.60 (m, 2H). MS(M+1):630. Example 47 4-[5-[[2-(3-Fluoropiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (47)
Figure imgf000204_0001
Compound 47 was prepared by the general procedure for compound C-1 , by using intermediates A-19 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.85 (d, 1 H, J=8.5 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 2H), 6.95 (d, 1 H1 J=9 Hz), 4.95 (s, 1/2H), 4.85 (s, 1/2H), 4.10 (m, 1 H), 3.95 (d, 1 H, J^l 3.5 Hz), 3.65 (d, 1/2H, J-=13.5 Hz), 3.60 (d, 1/2H, J=13.5 Hz), 3.55 (m, 8H), 1.95 (m, 2H), 1.85 (m, 2H), 1.65 (m, 1 H). MS (M+1 ): 580. Example 48
4-[5-[[2-(3-Hydroxypiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (48)
Figure imgf000204_0002
Compound 48 was prepared by the general procedure for compound C-1 , by using intermediates A-20 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.45 (s, 1 H), 8.40 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 2H), 6.95 (d, 1 H, J=9 Hz), 5.05 (d, 1 H, J=A Hz), 3.90 (d, 1 H, ^12.5 Hz), 3.80 (d, 1 H, J=13.5 Hz), 3.65 (m, 1 H), 3.55 (m, 8H), 3.15 (m, 2H), 1.85 (m, 2H), 1.50 (m, 2H). MS (M+1): 578. Example 49 4-[5-[[2-(3-Methoxypiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridiny|]-N-(2-fluorophenyl)-1- piperazinecarboxamide (49)
Figure imgf000205_0001
Compound 49 was prepared by the general procedure for compound C-1 , by using intermediates A-21 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.45 (d, 2H, J=6.5 Hz), 8.15 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.35 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 2H), 3.75 (d, 1 H, J=11 Hz), 3.65 (m, 12H), 3.30 (s, 3H), 1.85 (m, 1 H), 1.80 (m, 1 H), 1.65 (m, 1 H), 1.55 (m, 1 H). MS (M+1): 592. Example 50
4-[5-[[2-(3-Methoxypyrrolidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (50)
Figure imgf000205_0002
Compound 50 was prepared by the general procedure for compound C-1 , by using intermediates A-22 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.45 (s, 2H), 8.10 (br s, 1 H), 7.45 (m, 1 H), 7.20 (m, 2H), 7.15 (m, 2H), 4.10 (s, 1 H), 3.65 (m, 11 H), 3.55 (q, 1 H, J=8 Hz), 3.30 (S, 3H), 2.10 (m, 2H). MS (M+1): 578. Example 51
4-[5-[[2-(3-Methylpyrrolidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (51)
Figure imgf000206_0001
Compound 51 was prepared by the general procedure for compound C-1 , by using intermediates A-23 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.50 (s, 2H), 8.15 (m, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 3.75 (t, 1H, J=9 Hz), 3.65 (m, 9H), 3.55 (q, 1H, J=9.5 Hz), 3.10 (t, 1H, J=9 Hz), 2.40 (m, 1H), 2.10 (m, 1H), 1.65 (m, 1H), 1.10 (d,3H,J=7 Hz). MS(M+1):562. Example 52
4-[5-[[2-(Pyr rol id i n-1 -y l)-4-(tr if I uoromethy l)-5-oxazoly l]carbony lam i no]-2- pyridinyl]-N-(2-fluorophenyl)-1-piperazinecarboxamide (52)
Figure imgf000206_0002
Compound 52 was prepared by the general procedure for compound C-1 , by using intermediates A-24 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.50 (s, 2H), 8.15 (br s, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 3.70 (m, 4H), 3.65 (m, 4H), 3.60 (m, 4H), 1.95 (br s, 4H). MS (M+1): 548. Example 53 2-(Cyclohexyloxy)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide
(53)
Figure imgf000206_0003
Sodium hydride (60 wt % in oil, 26 mg, 0.64 mmol) was added to a solution of cyclohexanol (160 mg, 1.62 mmol) in THF (5 ml_) at 0 0C followed by stirring for 15 min. The reaction mixture was then cooled down to - 78 °C, and intermediate A-27 (180 mg, 0.32 mmol) dissolved in THF (2 ml_) was added. The reaction mixture was stirred for 5 h while the temperature was slowly warmed to RT. The solvent was concentrated, and purification by chromatography on a silica-gel column (eluant: 0 - 30% EtOAc in CH2CI2 gradient) gave 2-(cyclohexyloxy)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin- 1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (53) as a white solid ( 590 mg, 32% yield). 1H NMR (500 MHz, CDCI3) δ 8.23 (d, 1 H, J = 2.4 Hz), 8.14 - 8.17 (m, 2H), 7.736 (s, 1 H), 7.15 - 7.08 (m, 2H), 7.13 (m, 1 H), 6.70 (d, 1 H, J = 9.1 Hz), 6.65 (d, 1 H, J = 3.4 Hz), 5.06 (m, 1 H), 3.74 - 6.66 (m, 8H), 2.14 - 2.06 (m, 2H), 1.86 - 1.80 (m, 2H), 1.76 - 1.66 (m, 2H), 1.64 - 1.56 (m, 2H), 1.54 - 1.44 (m, 2H); LCMS (ESI) Rt = 3.57 min, calcd for [M+1 ]+ 577.2, found 577.3.
Example 54 2-(2-Oxopyrrolidin-1 -y l)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl(-4-
(trifluoromethyl)oxazole-5-carboxamide (54)
Figure imgf000207_0001
Compound 54 was prepared by the general procedure for compound C-1 , by using intermediates A-29 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.55 (br s, 1 H), 8.42 (m, 2H), 7.87 (m, 1 H), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.12 (m, 2H), 6.96 (d, 1 H, J = 9.4 Hz), 4.03 (t, 2H, J = 7.1 Hz), 3.56 (m, 8H), 2.59 (t, 2H, J = 8.0 Hz), 2.15 (m, 2H); LCMS (ESI) Rt = 2.92 min, calcd for [M+1 ]+ 562.2, found 562.3.
Example 55 2-(2-Oxopiperidin-1 -yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl(-4-
(trifluoromethyl)oxazole-5-carboxamide (55)
Figure imgf000208_0001
Compound 55 was prepared by the general procedure for compound C-1 , by using intermediate A-30 and B-5 as starting materials. 1H NMR (500 MHz, CD3OD-d4) δ 8.46 (d, 1 H, J= 3.0 Hz), 7.96 (dd, 1 H, J= 9.1 , 2.8 Hz), 7.49 (m, 1 H), 7.20 - 7.12 (m, 4H), 6.94 (d, 1 H, J= 9.2 Hz), 4.05 (t, 2H, J= 6.0 Hz), 3.72 - 3.68 (m, 5H), 3.66 - 3.60 (m, 4H), 2.70 (t, 2H, J = 6.6 Hz), 2.06 - 1 ,94 (m, 4H); LCMS (ESI) Rt = 3.09 min, calcd for [M+1]+ 594.2, found 594.3. Example 56 4-[5-[[2-(1 -Piperidinyl)-4-(trif luoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]- N-(2-fluorophenyl)-1- piperazinecarboxamide (56)
Figure imgf000208_0002
To a solution of intermediate A-32 (0.100 g, 0.357 mmol) and B-5 (0.146 g, 0.464 mmol) in CH2CI2 (10 ml_) were added O-(7-azabenzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate (0.204 g, 0.535 mmol HATU), 1 -hydroxy-7-azabenzotriazole (0.073 g, 0.535 mmol HOAT), and N,N- diisopropylethylamine (0.187 ml_, 1.07 mmol). The reaction mixture was stirred at RT for 17 h. Then, the reaction mixture was concentrated in vacuo. The product was purified by silica gel column chromatography to give 4-[5-[[2- (1-piperidinyl)-4-(trifluoromethyl)-5-thiazolyl]carbonylamino]-2-pyridinyl]- Λ/-(2- fluorophenyl)-1 -piperazinecarboxamide (56) as a light yellow solid (0.106 g, 74% yield). 1H NMR (500 MHz, CDCI3) δ 8.24 (d, 1 H, J= 2.5 Hz), 8.14-8.11 (m, 1 H), 7.93-7.91 (m, 1 H), 7.64 (m, 1 H), 7.15-6.98 (m, 3H), 6.71-6.65 (m, 2H), 3.71-3.67 (m, 8H), 3.55 (m, 4H), 1.72 (m, 6H); LCMS (ESI) [M+1]+ 578.3. Example 57 ΛA-[6-(4-Morpholinyl)-3-pyridinyl]-2-(1-piperidinyl)-4- (trifluoromethyl)-5-thiazolecarboxamide (57)
Figure imgf000209_0001
Compound 57 was prepared by the general procedure for compound 56 by using intermediates A-32 and 5-amino-2-(N-morpholino)-pyridine as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.22 (d, 1 H, J= 2.5 Hz), 7.92-7.90
(m, 1 H), 7.63 (m, 1 H), 6.67 (d, 1 H, J= 9.0 Hz), 3.86-3.84 (m, 4H), 3.55-3.49
(m, 8H), 1.71 (m, 6H); LCMS (ESI) [M+1]+ 442.3.
Example 58 Λ/-(6-Methoxy-3-pyridinyl)-2-(1-piperidinyl)-4-
(tri1luoromethyl)-5-thiazolecarboxamide (58)
Figure imgf000209_0002
58
Compound 58 was prepared by the general procedure for compound 56, by using intermediates A-32 and 5-amino-2-methoxy-pyridine as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.23 (d, 1H, J= 2.5 Hz), 7.94-7.91 (m, 1 H), 7.65 (m, 1 H), 6.78 (d, 1 H, J= 9.0 Hz), 3.95 (s, 3H), 3.56-3.55 (m, 4H), 1.72 (m, 6H); LCMS (ESI) [M+1]+ 387.3. Example 59
4-[5-[[2-(4-Phenylpiperidi-1-nyl)-4-(trifluoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (59)
Figure imgf000209_0003
Compound 59 was prepared by the general procedure for compound C-1, by using intermediates A-33 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.85 (d, 1 H, J=10 Hz), 7.45 (m, 1H), 7.30 (m, 4H), 7.20 (m, 2H), 7.15 (m, 2H), 6.90 (d, 1H, J=9 Hz), 4.00 (d, 2H, J= 11 Hz), 3.55 (m, 4H), 3.50 (m, 4H), 3.25 (t, 2H, J=11.5 Hz), 2.85 (t, 1 H, J= I 2 Hz), 1.90 (d, 2H, J=11.5 Hz), 1.75 (q, 2H, J=8.5 Hz). MS (M+1): 654. Example 60
4-[5-[[2-(3-Methylpyrrolidin-1-yl)-4-(trifluoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (60)
Figure imgf000210_0001
Compound 60 was prepared by the general procedure for compound C-1 , by using intermediates A-34 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H, J=7.5 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 2H), 6.90 (d, 1H, J=9 Hz), 3.55 (m, 4H), 3.50 (m, 4H), 3.40 (m, 1 H), 3.00 (t, 1 H, J=8.5 Hz), 2.45 (m, 1 H), 2.15 (m, 1 H), 1.70 (m, 1 H), 1.10 (d, 3H, J=7 Hz). MS (M+1): 578. Example 61
4-[5-[[2-(Phenylthio)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-2- pyridinyl]-N-(2-fluorophenyl)-1-piperazinecarboxamide (61)
Figure imgf000210_0002
Compound 61 was prepared by the general procedure for compound C-1 , by using intermediates A-35 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.15 (d, 1 H, J=2.5 Hz), 8.10 (t, 1 H, J=8.5 Hz), 7.85 (s, 1 H), 7.70 (d, 2H, J=8 Hz), 7.50 (m, 3H), 7.15 (t, 1 H, J=7.5 Hz), 7.10 (t, 1 H, J=11.5 Hz), 7.00 (m, 1H), 6.65 (br s, 2H), 3.70 (br s, 8H). MS (M+1): 587. Example 62
4-[5-[[2-(Benzylthio)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-2- pyridinyl]-N-(2-f luorophenyl)-1 -piperazinecarboxam ide (62)
Figure imgf000211_0001
Compound 62 was prepared by the general procedure for compound C-1 , by using intermediates A-36 and B-5 as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.25 (s, 1 H), 8.10 (t, 1 H, J=8 Hz)1 7.90 (s, 1 H), 7.45 (d, 2H, J=8.5 Hz), 7.35 (m, 3H), 7.15 (t, 1 H, J=Q Hz), 7.10 (m, 1 H), 7.00 (m, 1 H), 6.70 (d, 1 H, J=9.5 Hz), 6.65 (m, 1 H), 4.55 (s, 2H), 3.70 (br s, 8H). MS (M+1): 601. Example 63
4-[5-[[2-(Diethylamino)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-2- pyridinyl]-N-(2-fluorophenyl)-1-piperazinecarboxamide (63)
Figure imgf000211_0002
Compound 63 was prepared by the general procedure for compound C-1 , by using intermediates A-37 and B-5 as starting materials. 1H NMR (500 MHz,
DMSO-d6) δ 10.0.3 (s, 1 H), 8.44 (s, 1 H), 8.36 (s, 1 H), 7.82 (d, 1 H, J=9 Hz),
7.45 (m, 1 H), 7.20 (m, 1 H), 7.12 (m, 2H), 6.95 (d, 1 H, J=9 Hz), 3.55 (m, 12 H),
1.20 (t, 6H, J=7 Hz). MS (M+1): 550.
Example 64 4-[5-[[2-(4-Phenylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (64)
Figure imgf000212_0001
Compound 64 was prepared by the general procedure for compound C-1 , by using intermediates A-38 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (S1 1 H), 8.45 (s, 1 H), 8.40 (s, 1H), 7.85 (d, 1 H, J=11.5 Hz), 7.45 (m, 1 H), 7.35 (t, 2H, J=8.5 Hz), 7.15 (m, 5H), 6.95 (d, 1 H, J=9 Hz), 4.35 (d, 2H, J=U Hz), 3.55 (m, 4H), 3.50 (m, 4H), 3.20 (t, 2H, JM 2.5 Hz), 2.85 (t, 1 H, J=12 Hz), 1.85 (d, 2H, J=U Hz), 1.75 (m, 2H). MS (M+1): 656. Example 65
4-[5-[[2-(4-(4-Methoxyphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (65)
Figure imgf000212_0002
Compound 65 was prepared by the general procedure for compound C-1 , by using intermediates A-39 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H)1 8.45 (s, 1 H), 8.40 (s, 1 H), 7.90 (d, 1 H, J=9.5 Hz), 7.45 (m, 1 H), 7.25(m, 3H), 7.15 (broad s, 2H), 7.00 (d, 1H, J=9.5 Hz), 6.90 (d, 2H, J=8.5 Hz), 4.35 (d, 2H, J=U Hz), 3.55 (m, 8H), 3.20 (t, 2H, J=12.5 Hz), 2.75 (t, 1 H, J=12.5 Hz), 1.85 (d, 2H, J=11.5 Hz), 1.70 (m, 2H). MS (M+1 ): 668. Example 66
4-[5-[[2-(3-(4-Fluorophenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazoly l]carbony lam i no]-2-py rid i ny l]-N-(2-f I uoropheny l)-1 - piperazinecarboxamide (66)
Figure imgf000213_0001
Compound 66 was prepared by the general procedure for compound C-1 , by using intermediates A-40 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.40 (s, 1 H), 8.35 (s, 1 H), 7.85 (d, 1 H, J=8.5 Hz), 7.45 (m, 3H), 7.20 (m, 3H), 7.15 (broad s, 2H), 6.95 (d, 1 H, J=9.5 Hz), 4.25 (d, 2H, J=12.5 Hz), 3.55 (m, 8H), 3.20 (t, 1 H, J=12.5 Hz), 3.15 (t, 1 H, J=12.5 Hz), 2.85 (m, 1 H), 1.90 (d, 1 H, J=11.5 Hz), 1.85 (d, 1 H, J=12 Hz), 1.70 (m, 2H). MS (M+1): 656. Example 67
4-[5-[[2-(4-Propylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (67)
Figure imgf000213_0002
Compound 67 was prepared by the general procedure for compound C-1 , by using intermediates A-41 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (broad s, 1 H), 7.20 (m, 1 H), 7.10 (broad s, 2H), 6.95 (d, 1 H, J=9 Hz), 4.20 (d, 2H, ^2.5 Hz), 3.55 (m, 8H), 3.08 (t, 2H, J=12 Hz), 1.75 (d, 2H, J=13 Hz), 1.50 (m, 1 H), 1.35 (m, 2H), 1.10-1.25 (m, 4H), 0.90 (t, 3H, J=7 Hz). MS (M+1): 604. Example 68
4-[5-[[2-(4-Trifluoromethylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (68)
Figure imgf000214_0001
Compound 68 was prepared by the general procedure for compound C-1 , by using intermediates A-42 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.15 (broad s, 2H), 6.95 (d, 1 H, J=9 Hz), 4.30 (d, 2H, J=U Hz), 3.55 (m, 8H), 3.15 (t, 2H, J-=12 Hz), 2.65 (m, 1 H), 1.95 (d, 2H, J^l 2.5 Hz), 1.55 (m, 2H). MS (M+1): 630. Example 69
4-[5-[[2-(4-Benzylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-f luorophenyl)-1 - piperazinecarboxamide (69)
Figure imgf000214_0002
Compound 69 was prepared by the general procedure for compound C-1 , by using intermediates A-43 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.30 (m, 2H), 7.20 (m, 4H), 7.13 (broad s, 2H), 6.94 (d, 1 H, J=9 Hz), 4.20 (d, 2H, J=12.5 Hz), 3.55 (m, 8H), 3.05 (t, 2H, J=\ 1 Hz), 2.55 (d, 2H, J=7 Hz), 1.80 (m, 1 H), 1.70 (d, 2H, J=11.5 Hz), 1.25 (m, 2H). MS (M+1 ): 652. Example 70 4-[5-[[2-(4-Methylpiperidin-1 -yl)-4-(trif luoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (70)
Figure imgf000215_0001
Compound 70 was prepared by the general procedure for compound C-1 , by using intermediates A-44 and B-5 as starting materials. 1H NMR (500 MHz, DMSCKJ6) δ 10.08 (s, 1H), 8.42 (s, 1 H), 8.38 (s, 1H), 7.85 (d, 1 H, J=9.5 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.13 (broad s, 2H), 6.95 (d, 1 H, J=8.5 Hz), 4.20 (d, 2H, J=12.5 Hz), 3.55 (m, 8H), 3.10 (t, 2H, JM 2.5 Hz), 1.75 (d, 2H, Jb1 1.5 Hz), 1.65 (m, 1 H), 1.20 (m, 2H), 0.95 (t, 3H, J=6.5 Hz). MS (M+1 ): 576. Example 71
4-[5-[[2-(3-(2-Fluorophenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (71)
Figure imgf000215_0002
Compound 71 was prepared by the general procedure for compound C-1 , by using intermediates A-45 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1 H), 8.42 (s, 1 H), 8.35 (S, 1 H), 7.80 (d, 1 H, J=9 Hz), 7.45 (m, 2H), 7.35 (m, 1 H), 7.25 (m, 4H), 7.15 (broad s, 2H), 6.90 (d, 1 H, J=9 Hz), 4.25 (d, 2H, Jb11.5 Hz), 3.55 (m, 8H), 3.30 (t, 1 H, J=12.5 Hz), 3.15 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H). MS (M+1 ): 656. Example 72
4-[5-[[2-(3-(3-Fluorophenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (72)
Figure imgf000216_0001
Compound 72 was prepared by the general procedure for compound C-1 , by using intermediates A-46 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1 H), 8.42 (s, 1 H), 8.35 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 2H), 7.25 (m, 3H), 7.15 (m, 3H), 6.95 (d, 1 H, J=9.5 Hz), 4.25 (t, 2H, J=12.5 Hz), 3.55 (m, 8H), 3.25 (t, 1 H, J=12.5 Hz), 3.15 (t, 1 H, J=12.5 Hz), 2.90 (m, 1 H), 1.95 (d, 1 H, J=10.5 Hz), 1.85 (d, 1 H, J=12 Hz), 1.70 (m, 2H). MS (M+1): 656. Example 73
4-[5-[[2-(3-(2-Methoxyphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (73)
Figure imgf000216_0002
Compound 73 was prepared by the general procedure for compound C-1 , by using intermediates A-47 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.35 (s, 1 H), 7.85 (d, 1 H, J=9.5 Hz), 7.45 (m, 1 H), 7.25 (m, 2H), 7.20 (m, 1 H), 7.15 (broad s, 2H), 7.00 (d, 1 H, J=8.5 Hz), 6.95 (m, 2H), 4.25 (m, 2H), 3.80 (s, 3H), 3.55 (m, 8H), 3.15 (m, 3H), 1.85 (d, 2H, J=9.5 Hz), 1.70 (m, 2H). MS (M+1 ): 668. Example 74
4-[5-[[2-(3-(4-Methoxyphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridiny|]-N-(2-fluorophenyl)-1- piperazinecarboxamide (74)
Figure imgf000217_0001
Compound 74 was prepared by the general procedure for compound C-1 , by using intermediates A-48 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H, J=8.5 Hz), 7.45 (m, 1 H), 7.25 (d, 2H, J=8.5 Hz), 7.20 (m, 1 H), 7.15 (broad s, 2H), 6.95 (m, 3H), 4.25 (d, 2H, J=12 Hz), 3.75 (s, 3H), 3.55 (m, 8H), 3.15 (m, 2H), 2.80 (m, 1 H), 1.90 (m, 2H), 1.70 (m, 2H). MS (M+1 ): 668. Example 75
4-[5-[[2-(3-(3-Methylphenyl)piperidin-1-yl)-4-(trffluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (75)
Figure imgf000217_0002
Compound 75 was prepared by the general procedure for compound C-1 , by using intermediates A-49 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H, J=9 Hz) 7.45 (m, 1 H), 7.15 (m, 7H), 6.90 (d, 1 H, J=9 Hz), 4.25 (m, 2H), 3.55 (m, 8H), 3.20 (t, 1 H, J=12.5 Hz), 3.15 (t, 1 H, J=12 Hz), 2.80 (m, 1 H), 2.30 (s, 3H), 1.95 (d, 1H, J=12.5 Hz), 1.85 (d, 1 H, J=13.5 Hz), 1.70 (m, 2H). MS (M+1): 652. Example 76
4-[5-[[2-(3-(S)-Phenylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (76)
Figure imgf000218_0001
Compound 76 was prepared by the general procedure for compound C-1 , by using intermediates A-50 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.80 (d, 1 H, J=6.5 Hz), 7.45 (m, 1 H), 7.37 (broad s, 4H), 7.27 (m, 1 H), 7.20 (m, 1 H), 7.12 (d, 2H, J=5 Hz), 6.92 (d, 1 H, J=9.5 Hz), 4.25 (t, 2H, J=λ 1.5 Hz), 3.56 (m, 4H), 3.53 (m, 4H). 3.25 (t, 1 H, J=12 Hz), 3.15 (t, 1 H, J=11.5 Hz), 2.85 (m, 1 H), 1.95 (d, 1 H, J=11.5 Hz), 1.85 (d, 1 H, J=12.5 Hz), 1.70 (m, 2H). MS (M+1): 638. Example 77
4-[5-[[2-(3-Phenylpyrrolidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (77)
Figure imgf000218_0002
Compound 77 was prepared by the general procedure for compound C-1 , by using intermediates A-51 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 1H), 7.38 (broad s, 4H), 7.28 (m, 1 H), 7.20 (m, 1 H), 7.13 (broad s, 2H), 6.93 (d, 1 H, J=9.5 Hz), 4.10 (t, 1 H, J=7.5 Hz), 3.85 (t, 1 H, J=9.5 Hz), 3.65 (m, 1 H), 3.55 (m, 8H). 3.35 (m, 2H), 2.40 (m, 1 H), 2.15 (m, 1 H). MS (M+1): 624. Example 78
4-[5-[[2-(3-(4-Methylphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (78)
Figure imgf000219_0001
Compound 78 was prepared by the general procedure for compound C-1 , by using intermediates A-52 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1 H), 8.40 (s, 1 H), 8.34 (s, 1 H), 7.80 (d, 1 H, J=10.5 Hz), 7.45 (m, 1 H), 7.15 (m, 7H), 6.90 (d, 1 H, J=9.5 Hz), 4.25 (d, 2H, J=12 Hz), 3.55 (m, 8H), 3.20 (t, 1 H, J=12 Hz), 3.15 (t, 1 H, JM2.5 Hz), 2.80 (m, 1 H), 2.30 (s, 3H), 1.90 (d, 1 H, J=9.5 Hz), 1.85 (d, 1 H, J=9.5 Hz), 1.70 (m, 2H). MS (M+1): 652. Example 79
4-[5-[[2-(4-(2-Methoxyphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (79)
Figure imgf000219_0002
Compound 79 was prepared by the general procedure for compound C-1, by using intermediates A-53 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.42 (s, 1 H), 8.39 (s, 1 H), 7.88 (d, 1 H, J=8.5 Hz), 7.45 (m, 1 H), 7.22 (m, 3H), 7.13 (broad s, 2H), 7.00 (d, 2H, J=8 Hz), 6.92 (t, 1H, J=7.5 Hz), 4.35 (d, 2H, J=λ 1 Hz), 3.82 (s, 3H), 3.55 (m, 8H), 3.20 (m, 3H), 1.82 (d, 2H, J= 11 Hz), 1.70 (m, 2H). MS (M+1 ): 668. Example 80
4-[5-[[2-(3-(R)-Phenylpiperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (80)
Figure imgf000220_0001
Compound 80 was prepared by the general procedure for compound C-1 , by using intermediates A-54 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.35 (s, 1 H), 7.80 (d, 1 H1 J=7.5 Hz), 7.45 (m, 1 H), 7.35 (broad s, 4H), 7.25 (m, 1 H), 7.20 (m, 2H), 7.12 (broad s, 2H), 6.93 (d, 1 H, J=9.5 Hz), 4.25 (t, 2H, J=13 Hz), 3.55 (m, 8H), 3.25 (t, 1 H, J=12.5 Hz), 3.15 (t, 1 H, J=12 Hz), 2.85 (m, 1 H), 1.95 (d, 1 H, J=10.5 Hz), 1.85 (d, 1 H, Jb-lθ.5 Hz), 1.70 (m, 2H). MS (M+1): 638. Example 81
4-[5-[[2-(4-(3-Methoxyphenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (81)
Figure imgf000220_0002
Compound 81 was prepared by the general procedure for compound C-1 , by using intermediates A-55 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.45 (m, 1 H), 7.20 (m, 2H), 7.13 (broad s, 2H), 6.93 (d, 1 H, J=9 Hz), 6.86 (broad s, 2H), 6.78 (d, 1 H, J=7.5 Hz), 4.35 (d, 2H, J=12.5 Hz), 3.75 (s, 3H), 3.55 (m, 8H), 3.20 (t, 2H, J=12.5 Hz), 2.80 (t, 1 H, J=1 1.5 Hz), 1.90 (d, 2H, J=12 Hz), 1.75 (m, 2H). MS (M+1 ): 668. Example 82
4-[5-[[2-(4-(2-Fluorophenyl)piperidin-1-yl)-4-(trifluoromethyl)-5- oxazolyl]carbonylamino]-2-pyridinyl]-N-(2-fluorophenyl)-1- piperazinecarboxamide (82)
Figure imgf000221_0001
Compound 82 was prepared by the general procedure for compound C-1, by using intermediates A-56 and B-5 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.42 (s, 1 H), 8.39 (s, 1 H), 7.85 (d, 1 H, J=9 Hz), 7.43 (m, 2H), 7.30 (m, 1 H), 7.15 (m, 4H), 6.95 (d, 1 H, J=9 Hz), 4.35 (d, 2H, Λ=13.5 Hz), 3.55 (m, 8H), 3.25 (t, 2H, J="\2 Hz), 3.13 (t, 1 H, J=11 Hz), 1.85 (m, 4H). MS (M+1): 656. Example 83
4-[5-[[2-(1-Piperidinyl)-5-thiazolyl]carbonylamino]-2-pyridinyl]- N-(2- fluorophenyl)-1-piperazinecarboxamide (83)
Figure imgf000221_0002
Compound 83 was prepared by the general procedure for compound C-1, by using intermediates A-32 and B-5 as starting materials. 1H NMR (500 MHz, (CD3)2CO) δ 9.91 (s, 1 H), 8.42-8.37 (m, 2H), 8.00 (s, 1 H), 7.86-7.83 (m, 1 H), 7.48-7.43 (m, 1 H), 7.22-7.11 (m, 3H), 6.92 (d, 1 H, J= 9.0 Hz), 3.58-3.51 (m, 12H), 1.61 (m, 6H); LCMS (ESI) [M+1]+ 510.3. Example 84
Ethyl 2-(5-(2-(piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxam ido)py rid i n-2-y lam i no)propanoate (84)
Figure imgf000221_0003
Compound 84 was prepared by the general procedure for compound C-1 , by using intermediates A-4 and B-7 as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1 H), 8.10 (d, 1 H, J = 2.9 Hz), 7.61 (dd, 1 H, J= 9.2, 2.6 Hz), 6.97 (d, 1 H, J= 7.0 Hz), 6.57 (d, 1 H, J= 9.2 Hz), 4.34 (t, 1H, J= 7.0 Hz), 4.06 (q, 2H, J= 7.3 Hz), 3.60 (s, 4H), 1.60 (s, 6H), 1.35 (d, 3H, J= 7.0 Hz), 1.15 (t, 3H, J= 7.0 Hz); LCMS (ESI) Rt = 3.20 min, [M+1]+ 456.3. Example 85
N-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (85)
Figure imgf000222_0001
Compound 85 was prepared by the general procedure for compound 3, by using intermediates A-4 and B-8 as starting materials. 1H NMR (400 MHz,
DMSO-d6) δ 9.99 (s, 1 H), 8.29 (d, 1 H1 J= 2.6 Hz), 7.75 (dd, 1 H, J = 9.2, 2.6
Hz), 6.84 (d, 1 H1 J= 9.2 Hz), 4.13 (m, 2H), 3.61 (s, 4H), 2.85 (m, 2H), 2.77
(m, 1 H), 1.74 (m, 2H), 1.61 (s, 6H), 1.18 (m, 2H); LCMS (ESI) Rt = 2.34 min,
[M+1]+ 439.2. Example 86
/V-(6-(4-(2,6-dichlorobenzamido)piperidin-1-yl)pyridin-3-yl)-2-(piperidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (86)
Figure imgf000222_0002
Compound 86 was prepared by the general procedure for compound A-27, by using compound 85 and 2,6-dichlorobenzoyl chloride as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1 H), 8.67 (d, 1 H, J= 8.1 Hz), 8.32 (d, 1 H, J = 2,6 Hz), 7.79 (dd, 1 H1 J = 8.8, 2.6 Hz), 7.40 - 7.50 (m, 3H), 6.89 (d, 1 H, J = 9.2 Hz), 4.15 (m, 2H), 4.02 (m, 1 H), 3.61 (s, 4H), 3.03 (m, 2H), 1.90 (m, 2H), 1.61 (br s, 6H), 1.47 (m, 2H). LCMS (ESI) Rt = 3.28 min, [M+1]+ 611.3. Example 87
/V-(6-(4-(2-chlorobenzamido)piperidin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)- 4-(trifluoromethyl)oxazole-5-carboxamide (87)
Figure imgf000223_0001
Compound 87 was prepared by the general procedure for compound C-1 , by using compound 85 and 2-chlorobenzoic acid as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1 H), 8.42 (d, 1 H, J = 7.7 Hz), 8.32 (d, 1 H, J = 2.6 Hz), 7.79 (dd, 1 H1 J = 9.2, 2.9 Hz), 7.35 - 7.50 (m, 4H), 6.88 (d, 1 H, J = 9.2 Hz), 4.20 (m, 2H), 4.00 (m, 1 H), 3.61 (s, 4H), 2.99 (m, 2H), 1.98 (m, 2H), 1.61 (br s, 6H)1 1.48 (m, 2H). LCMS (ESI) Rt = 3.17 min, [M+1]+ 577.3. Example 88 yV-(6-(4-(2,6-difluorobenzamido)piperidin-1-yl)pyridin-3-yl)-2-(piperidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (88)
Figure imgf000223_0002
Compound 88 was prepared by the general procedure for compound C-1 , by using compound 85 and 2,6-difluorobenzoic acid as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1 H), 8.72 (d, 1 H, J = 7.7 Hz), 8.32 (d, 1 H, J= 2.9 Hz), 7.79 (dd, 1 H, J = 8.0, 2.6 Hz), 7.50 (m, 1 H), 7.16 (m, 2H), 6.89 (d, 1 H, J= 9.2 Hz), 4.17 (m, 2H), 4.02 (m, 1 H), 3.61 (s, 4H), 3.01 (m, 2H), 1.88 (m, 2H), 1.61 (br s, 6H), 1.45 (m, 2H). LCMS (ESI) Rt = 3.14 min, [M+1]+ 579.3. Examples 89 - 98
/V-(6-(4-(2-fluorobenzamido)piperidin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)- 4-(trifluoromethyl)oxazole-5-carboxamide (89)
Figure imgf000224_0001
Compound 89 was prepared by the general procedure for compound C-1 , by using compound 85 and 2-fluorobenzoic acid as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1 H), 8.32 (d, 1 H, J = 2.9 Hz), 8.29 (d, 1 H, J = 7.7 Hz), 7.79 (dd, 1 H, J = 9.2, 2.6 Hz), 7.47 - 7.57 (m, 2H), 7.22 - 7.29 (m, 2H), 6.89 (d, 1 H, J= 9.2 Hz), 4.22 (m, 2H), 4.20 (m, 1 H), 3.61 (s, 4H), 2.97 (m, 2H), 1.98 (m, 2H), 1.61 (br s, 6H), 1.50 (m, 2H). LCMS (ESI) Rt = 3.14 min, [M+1]+ 561.3. Alternatively, compounds 89 - 98 were prepared by the method for amide combinatorial library synthesis described below.
Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 49.2 mg of EDC resin (3 equiv. @ 1.39 mmol/g), 1 ml_ solution of compound 85 and HOBt in 3:1 CH3CNiTHF (10.0 mg of 85 and 4.6 mg of HOBt for each cartridge), and 45.6 μl_ of each carboxylic acid (1 M solution in DMF). The cartridges were stoppered and shaken overnight. Then, to each cartridge was added 30.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 46.9 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μl_ of 3:1 CH3CNTHF. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed bar- coded vials, and the resins were washed with CH3CN (6 x 500 μl_). Upon concentration of the filtrates, the amides listed below were obtained as products.
Figure imgf000224_0002
Figure imgf000225_0001
Rt = 3.28 min, [M+1]+ 549.3
Figure imgf000226_0001
Rt = 3.10 min, [M+1]+ 571.3
Figure imgf000226_0002
Rt = 3.17 min, [M+1]+ 61 1.3
Figure imgf000226_0003
Example 99 /V-(6-(4-(2-f luorophenylcarbamoyl)piperidin-1 -yl)pyridin-3- yl)-2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (99)
Figure imgf000226_0004
Step 1 : 1-(5-(2-(Piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (C-3)
Compound C-3 was prepared by the general procedure for compound A-4, by using compound C-1 as a starting material. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1 H), 8.35 (d, 1 H, J = 2.6 Hz), 7.90 (m, 1 H), 7.05 (m, 1 H), 4.13 (m, 2H), 3.61 (s, 4H), 3.02 (m, 2H), 2.45 (m, 1 H), 1.89 (m, 2H), 1.61 (br s, 6H), 1.55 (m, 2H). LCMS (ESI) Rt = 2.60 min, [M+1]+ 468.3. Step 2: Λ/-(6-(4-(2-f luorophenylcarbamoyl)piperidin-1 -yl)pyridin-3-yl)-2- (piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxamide (99) Compound 99 was prepared by the general procedure for compound C-1 , by using compound C-3 and 2-fluoroaniline as starting materials. 1H NMR (400 MHz, CDCI3) δ 8.28 (m, 1 H), 8.17 (bs, 1 H), 8.04 (d, 1 H, J= 7.7 Hz), 7.64 (m, 1 H), 7.47 (m, 1 H), 7.13-7.00 (m, 3H), 6.72 (d, 1 H, J = 9.5 Hz), 4.32 (d, 2H, J = 12.8 Hz), 3.61 (br s, 4H), 2.91 (m, 2H), 3.00 (t, 2H, J = 9.92 Hz), 2.56 (m, 1 H), 2.03 (m, 2H), 1.89 (d, 2H, J = 11.4 Hz), 1.67 (m, 6H); LCMS (ESI) Rt = 3.38 min, [M+1]+ 561.3. Examples 100 - 110
Compounds 100 - 110 were prepared by the method for amide combinatorial library synthesis described below. Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 49.2 mg of EDC resin (3 eq. @ 1.39 mmol/g), 1 rriL solution of compound C-3 and HOBt in 3:1 CH3CNTHF (10.0 mg of C-3 and 4.6 mg of HOBt for each cartridge), and 45.6 μL of each amines (1 M solution in DMF). The cartridges were stoppered and shaken overnight. Then, to each cartridge was added 30.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 46.9 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μL of 3:1 CH3CN :TH F. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed bar-coded vials, and the resins were washed with CH3CN (6 x 500 μL). Upon concentration of the filtrates, the amides listed below were obtained as products.
Figure imgf000227_0001
Rt = 4.45 min, [M+1]+ 481.3
Figure imgf000228_0001
Rt = 4.64 min, [M+1]+ 495.3
Figure imgf000228_0002
Rt = 4.71 min, [M+1]+ 507.3
Figure imgf000228_0003
Rt = 4.91 min, [M+1]+ 509.3
Figure imgf000228_0004
Rt = 4.86 min, [M+1]+ 509.3
Figure imgf000228_0005
Rt = 4.92 min, [M+1]+ 521.3
Figure imgf000229_0001
Rt = 5.05 min, [M+1]+ 521.3
Figure imgf000229_0002
Rt = 5.13 min, [M+1]+ 523.3
Figure imgf000229_0003
Rt = 4.57 min, [M+1]+ 525.3
Figure imgf000229_0004
Rt = 3.40 min, [M+1]+ 535.3
Figure imgf000229_0005
Figure imgf000230_0001
Example 111
2-(1-Benzylpyrrolidin-3-ylamino)-N-(6-((R)-1-(2- fluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (111)
Figure imgf000230_0002
To a solution of intermediate A-57 (125 mg, 0.347 mmol) dissolved in dry DMF (5 ml_) was added intermediate B-12 (160 mg, 0.507 mmol), Hunig's base (0.12 ml_, 0.694 mmol), and HATU (264 mg, 0.694 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated. Water (15 ml_) was added, and the aqueous solution was extracted with CH2CI2 (3 x 15 ml_). The combined organic extract was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (eluant: 3 - 5% MeOH with NH3 - CH2CI2) to give a red foam which was triturated with ether and filtered to give 2-(1- benzylpyrrolidin-3-ylamino)-N-(6-((R)-1-(2-fluorophenylcarbamoyl)pyrrolidin-3- ylamino)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (111) as a pink solid (1 15 mg, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.00 (broad s, 1 H), 8.52 (broad s, 1 H), 8.20 (s, 1 H), 7.88 (s, 1 H), 7.65 (d, 1 H, J = 9.5 Hz), 7.40 (m, 5H), 7.18 (m, 1 H), 7.10 (m, 2H), 6.85 (broad s, 1 H), 6.55 (d, 1 H, J = 8.5 Hz), 4.38 (m, 3H), 3.73 (broad s, 1H), 3.55 (m, 4H), 3.27 (m, 1 H), 3.15 (m, 1 H), 2.60 (m, 2H), 2.18 (m, 2H), 1.90 (m, 2H). MS (M+1): 653.4 Example 112 2-(1 -Benzylpyrrolidin-3-ylamino)-N-(6-((S)-1 -(2- fluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-4- (trif luoromethyl)oxazole-5-carboxamide (112)
Figure imgf000231_0001
Compound 112 was prepared by the general procedure for compound 111 , by using intermediates A-57 and B-13 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.00 (broad s, 1 H), 8.52 (broad s, 1 H), 8.20 (s, 1 H), 7.88 (s, 1 H), 7.65 (d, 1 H, J = 8 Hz), 7.35 (m, 5H), 7.18 (m, 1 H), 7.10 (m, 2H), 6.85 (d, 1 H, J = 6 Hz), 6.55 (d, 1 H, J = 9 Hz), 4.38 (broad s, 2H), 4.30 (broad s, 1 H), 3.73 (broad s, 1H), 3.55 (m, 4H), 3.27 (m, 1H), 2.85 (m, 1 H), 2.55 (m, 2H), 2.20 (m, 2H), 1.88 (m, 2H). MS (M+1): 653.4. Example 113
2-(1-Benzylpiperidin-4-ylamino)-N-(6-(1-(2- fluorophenylcarbamoyl)piperidin-4-ylamino)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (113)
Figure imgf000231_0002
Compound 113 was prepared by the general procedure for compound 111 , by using intermediates A-58 and B-14 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1 H), 9.40 (broad s, 1/2H), 8.50 (broad s, 1/2H), 8.30 (s, 1 H), 8.15 (s, 2H), 7.62 (d, 1 H, J = 9 Hz), 7.40 (m, 5H), 7.18 (m, 1 H), 7.10 (m, 2H), 6.53 (d, 1 H, J = 7.5 Hz), 6.48 (d, 1 H, J = 9 Hz), 4.30 (broad s, 1 H), 4.00 (d, 1 H, J = 13.5 Hz), 3.90 (broad s, 1 H), 3.62 (m, 2H), 3.45 (m, 2H), 3.15 (m, 2H), 3.00 (t, 2H, J = 13 Hz), 2.07 (m, 2H), 1.90 (m, 2H), 1.62 (m, 2H), 1.35 (q, 2H, J = 9 Hz). MS (M+1): 681.4 Example 114
2-(1 -benzylpiperidin-4-ylamino)-N-(6-(3-(3-(2-fluorophenyl)ureido)pyrrolidin-1- yl)pyridin-3-yl)-4-(trif luoromethyl)oxazole-5-carboxamide (1 14)
Figure imgf000232_0001
Compound 114 was prepared by the general procedure for compound 111, by using intermediates A-58 and B-15 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (broad s, 1 H), 9.40 (broad s, 1 H), 8.52 (d, 1 H, J = 7.5 Hz), 8.30 (s, 1 H), 8.20 (s, 1 H), 8.15 (t, 1 H, J = 8 Hz), 7.80 (broad s, 1 H), 7.50 (s, 4H), 7.17 (m, 1 H), 7.10 (t, 1 H, J= 8 Hz), 7.00 (d, 1 H, J= 7 Hz), 6.93 (m, 1 H), 6.55 (broad s, 1 H), 4.32 (m, 2H), 3.80 (broad s, 1 H), 3.63 (m, 1H), 3.38 (m, 5H), 3.10 (m, 2H), 2.20 (m, 2H), 2.05 (m, 1 H), 1.92 (m, 1 H), 1.72 (q, 1 H, J = 11 Hz). MS (M+1): 667.4. Example 115 ethyl 1-(5-(2-(2-f luorophenylamino)-4-
(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)piperidine-4- carboxylate (115)
Figure imgf000232_0002
Compound 115 was prepared by the general procedure for compound 111 , by using intermediates A-64 and B-1 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1 H), 10.33 (s, 1 H), 8.35 (d, 1 H, J = 2.9 Hz), 7.91 (dt, 1 H, J = 8.4, 1.8 Hz), 7.82 (dd, 1 H, J = 9.2, 2.6 Hz), 7.17 - 7.34 (m, 3H), 6.88 (d, 1 H, J= 9.2 Hz), 4.15 (m, 2H), 4.07 (q, 2H, J= 7.3 Hz), 2.92 (m, 2H), 2.59 (m, 1 H), 1.86 (m, 2H), 1.53 (m, 2H), 1.18 (t, 3H, J= 7.3 Hz). LCMS (ESI) Rt = 3.37 min, calcd for [M+1 ]+ 522.2, found 522.3.
Example 116 ethyl 2-(1-(5-(2-(2-liuorophenylamino)-4-
(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)piperidin-4- yl)acetate (116)
Figure imgf000233_0001
Compound 116 was prepared by the general procedure for compound 111 , by using intermediates A-64 and B-16 as starting materials. 1H NMR (500 MHz, DMSO-d6) 5 10.67 (s, 1 H), 10.31 (s, 1 H), 8.33(d, 1 H, J = 2.6 Hz), 7.91 (dt, 1 H1 J = 8.0, 1.5 Hz), 7.81 (dd, 1 H1 J = 9.2, 2.6 Hz), 7.18 - 7.34 (m, 3H), 6.85 (d, 1 H, J = 9.2 Hz), 4.23 (m, 2H), 4.06 (q, 2H, J = 7.3 Hz), 2.78 (m, 2H), 2.25 (d, 2H, J = 7.3 Hz), 1.92 (m, 1 H), 1.69 (m, 2H), 1.19 (m, 2H), 1.18 (t, 3H, J = 7.3 Hz). LCMS (ESI) Rt = 3.44 min, calcd for [M+1]+ 536.2, found 536.3. Example 117 1 -(5-(2-(2-f luorophenylamino)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (117)
Figure imgf000233_0002
To a solution of compound 115 (0.0430 g, 0.0825 mmol) in THF (5 ml_) was added 1 Λ/ NaOH (2 ml_) at RT. The reaction mixture was stirred at RT for 16 h, then treated with additional 1 Λ/ NaOH (2 ml_) After 5 h of additional stirring, the reaction mixture was diluted with H2O (50 ml_) and 1 N NaOH (5 ml_). The resulting solution was washed with Et2O (2 x 50 ml_). The ether washes were discarded, and the aqueous layer was acidified to pH = 5 by addition of 1 N HCI. The aqueous layer was extracted with EtOAc (3 x 50 ml_). The combined organic extract was dried over Na2SO4, filtered, concentrated, and dried in vacuo to yield 1-(5-(2-(2-fluorophenylamino)-4- (trifluoromethyOoxazole-δ-carboxamidoJpyridin^-yOpiperidine^-carboxylic acid (117) as a yellow solid (0.0333 g, 82% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.22 (br s, 1 H), 10.68 (br s, 1 H), 10.33 (s, 1 H), 8.35(d, 1 H, J = 2.6 Hz), 7.91 (dt, 1 H, J = 8.0, 1.8 Hz), 7.82 (dd, 1 H, J = 9.2, 2.5 Hz), 7.16 - 7.34 (m, 3H), 6.87 (d, 1 H1 J = 9.2 Hz), 4.15 (m, 2H), 2.91 (m, 2H), 2.47 (m, 1 H), 1.85 (m, 2H), 1.53 (m, 2H). LCMS (ESI) Rt = 3.15 min, calcd for [M+1]+ 494.2, found 494.3.
Example 118 2-(1-(5-(2-(2-fluorophenvlamino)-4-(trifluoromethyl)oxazole- 5-carboxamido)pyridin-2-yl)piperidin-4-yl)acetic acid (118)
Figure imgf000234_0001
Compound 118 was prepared by the general procedure for compound 117, by using compound 116 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 10.68 (s, 1 H), 10.32 (s, 1H), 8.33(d, 1 H, J= 2.6 Hz), 7.91 (dt, 1 H, J= 8.0, 1.5 Hz), 7.80 (dd, 1 H, J= 9.2, 2.5 Hz), 7.16 - 7.34 (m, 3H), 6.85 (d, 1H, J= 9.2 Hz), 4.23 (m, 2H), 2.77 (m, 2H), 2.16 (d, 2H, J = 7.0 Hz), 1.88 (m, 1H), 1.71 (m, 2H), 1.17 (m, 2H). LCMS (ESI) Rt = 3.21 min, calcd for [M+1]+ 508.2, found 508.3.
Example 119 ethyl 1-(5-(2-benzamido-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (119)
Figure imgf000234_0002
Compound 119 was prepared by the general procedure for compound 111, by using intermediates A-66 and B-1 as starting materials. 1H NMR (500 MHz, DMSO-d6) 5 12.36 (s, 1 H), 10.60 (s, 1H), 8.38 (d, 1 H, J= 2.6 Hz), 8.02 (m, 2H), 7.85 (dd, 1 H, J= 9.2, 2.6 Hz), 7.68 (m, 1 H), 7.57 (m, 2H), 6.88 (d, 1 H, J = 9.2 Hz), 4.16 (m, 2H), 4.07 (q, 2H, J= 7.0 Hz), 2.93 (m, 2H), 2.59 (m, 1H), 1.86 (m, 2H), 1.53 (m, 2H), 1.18 (t, 3H, J= 7.3 Hz). LCMS (ESI) Rt = 3.07 min, calcd for [M+1]+ 532.2, found 532.3.
Example 120 ethyl 2-(1-(5-(2-benzamido-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidin-4-yl)acetate (120)
Figure imgf000235_0001
Compound 120 was prepared by the general procedure for compound 111 , by using intermediates A-66 and B-16 as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.58 (s, 1H), 8.36 (d, 1H, J= 2.6 Hz), 8.02 (m, 2H), 7.83 (dd, 1H, J= 9.2, 2.6 Hz), 7.68 (m, 1 H), 7.57 (m, 2H), 6.86 (d, 1 H, J = 9.2 Hz), 4.23 (m, 2H), 4.06 (q, 2H, J= 7.0 Hz), 2.78 (m, 2H), 2.25 (d, 2H, J = 7.0 Hz), 1.92 (m, 1 H), 1.69 (m, 2H), 1.20 (m, 2H), 1.18 (t, 3H, J= 7.3 Hz). LCMS (ESI) Rt = 3.11 min, calcd for [M+1]+ 546.2, found 546.3. Example 121 1-(5-(2-benzamido-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (121)
Figure imgf000235_0002
Compound 121 was prepared by the general procedure for compound 117, by using compound 119 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1 H), 12.17 (s, 1 H), 10.61 (s, 1 H), 8.38 (d, 1 H, J= 2.9 Hz), 8.02 (m, 2H), 7.85 (dd, 1 H, J = 9.2, 2.6 Hz), 7.68 (m, 1 H), 7.58 (m, 2H), 6.88 (d, 1 H, J = 9.5 Hz), 4.16 (m, 2H), 2.92 (m, 2H), 2.47 (m, 1 H), 1.86 (m, 2H), 1.52 (m, 2H). LCMS (ESI) Rt = 2.57 min, calcd for [M+1]+ 504.2, found 504.3. Example 122 2-(1 -(5-(2-benzamido-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidin-4-yl)acetic acid (122)
Figure imgf000235_0003
Compound 122 was prepared by the general procedure for compound 117, by using compound 120 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1 H), 12.10 (S, 1 H), 10.59 (s, 1 H), 8.36 (d, 1 H1 J = 2.6 Hz), 8.02 (m, 2H), 7.83 (dd, 1 H, J = 9.2, 2.6 Hz), 7.68 (m, 1 H), 7.58 (m, 2H), 6.86 (d, 1 H, J = 9.2 Hz), 4.23 (m, 2H), 2.78 (m, 2H), 2.27 (d, 2H, J= 7.0 Hz), 1.89 (m, 1 H), 1.72 (m, 2H), 1.16 (m, 2H). LCMS (ESI) Rt = 2.62 min, calcd for [M+1]+ 518.2, found 518.3. Example 123 ethyl 4-[5-[[[2-[(3-fluorophenyl)amino]-5-thiazolyl]carbonyl]amino]-2- pyridinyl]-1 -piperazineacetate (123)
Figure imgf000236_0001
Compound 123 was prepared by the general procedure for compound 111 , by using intermediate B-17 as starting material. 1H NMR (500 MHz, (CD3)2CO) δ 10.87 (bs, 1 H), 10.1 (S, 1 H), 8.36 (m, 1 H), 8.1 (s, 1 H), 7.82-7.71 (m, 2H), 7.40-7.30 (m, 2H), 6.87-6.81 (m, 2H), 4.10 (q, 2H, J = 7.0 Hz), 3.46-3.44 (m, 4H), 3.28 (S, 2H), 2.61-2.59 (m, 4H), 1.20 (t, 3H, J= 7.0 Hz); LCMS (ESI) [M+1]+ 485.3. Example 124
Ethyl 1-(5-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (124)
Figure imgf000236_0002
Compound 124 was prepared by the general procedure for compound 111 , by using intermediates A-24 and B-1 as starting materials. 1H NMR (400 MHz, CDCI3) δ 8.13 (d, 1 H, J= 2.6 Hz), 8.01 (dd, 1 H, J= 9.2, 2.6 Hz), 7.51 (br s, 1 H), 6.70 (d, 1 H1 J= 9.2 Hz), 4.19 (dt, 2H, J= 13.2, 3.7 Hz), 4.15 (q, 2H, J = 7.0 Hz), 3.64 (t, 4H, J = 6.6 Hz), 2.99 - 2.91 (m, 4H), 2.52 (m, 1 H), 2.08 - 2.05 (m, 4H), 2.00 (dd, 1 H, J = 13.6, 3.7 Hz), 1.77 (dq, 2H, J = 11.7, 4.4 Hz), 1.27 (t, 3H, J = 7.0 Hz). LCMS (ESI) Rt = 3.03 min, [M+1]+ 482.3. Example 125 Ethyl 1 -(5-(2-(piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (125)
Compound 125 was prepared by the general procedure for compound 111 , by using intermediates A-4 and B-1 as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.31 (d, 1 H, J= 2.6 Hz), 7.78 (dd, 1H, J = 9.2, 2.9 Hz), 6.87 (d, 1 H, J= 9.2 Hz), 4.16 (m, 2H), 4.07 (q, 2H, J= 7.0 Hz), 3.61 (br s, 4H), 2.91 (m, 2H), 2.58 (m, 1 H), 1.87 (m, 2H), 1.64 (br s, 6H), 1.53 (m, 2H), 1.18 (t, 3H, J= 7.0 Hz). LCMS (ESI) Rt = 3.22 min, [M+1] 496.3. Example 126
Ethyl 2-(1 -(5-(2-(piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidin-4-yl)acetate (126)
Figure imgf000237_0002
Compound 126 was prepared by the general procedure for compound 111 , by using intermediates A-4 and B-16 as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.30 (d, 1H, J= 2.6 Hz), 7.76 (dd, 1H, J= 9.2, 2.9 Hz), 6.84 (d, 1 H, J= 9.2 Hz), 4.23 (m, 2H), 4.06 (q, 2H, J= 7.3 Hz), 3.61 (br s, 4H), 2.76 (m, 2H), 2.25 (d, 2H1 J= 7.3 Hz), 1.92 (m, 1 H), 1.70 (m, 2H), 1.60 (br s, 6H), 1.18 (t, 3H, J= 7.0 Hz), 1.17 (m, 2H). LCMS (ESI) Rt = 3.25 min, [M+1 r 510.3. Example 127
1-(5-(2-(Piperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin- 2-yl)piperidine-4-carboxylic acid (127)
Figure imgf000238_0001
To a solution of compound 125 (0.081 g) in THF (5 ml_) was added 1 N NaOH (2 ml_) at RT. The reaction mixture was stirred at RT for 4 h then treated with additional 1 N NaOH (2 ml_). After 15 h of additional stirring at RT, the reaction mixture was diluted with H2O (50 ml_) and 1 N NaOH (5 ml_). The resulting solution was washed with Et2O (2 x 50 ml_). The ether washes were discarded, and the aqueous layer was acidified to pH = 5 by addition of 1 N HCI. The aqueous layer was extracted with EtOAc (3 x 50 ml_). The combined organic extract was dried over Na2SO4, filtered, concentrated, and dried in vacuo to yield 1 -(5-(2-(piperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamidotøyridin^-yOpiperidine^-carboxylic acid (127) as a yellow solid (0.075 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.13 (S, 1 H), 8.35 (d, 1 H, J = 2.6 Hz), 7.90 (d, 1 H, J = 8.4 Hz), 7.05 (m, 1 H), 4.13 (m, 2H), 3.61 (br s, 4H), 3.01 (m, 2H), 2.52 (m, 1 H), 1 ,89 (m, 2H), 1.60 (br s, 6H), 1.55 (m, 2H). LCMS (ESI) Rt = 2.6 min, [M+1 ]+ 468.3. Example 128
2-(1 -(5-(2-(Piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidin-4-yl)acetic acid (128)
Figure imgf000238_0002
Compound 128 was prepared by the general procedure for compound 127, by using compound 126 as starting material. 1H NMR (400 MHz, DMSO-d6) δ 12.1 1 (br s, 1 H), 10.03 (s, 1 H), 8.31 (d, 1 H, J = 2.6 Hz), 7.79 (d, 1 H1 J = 7.3 Hz), 6.89 (d, 1 H, J = 9.2 Hz), 4.22 (d, 2H, J= 13.2 Hz), 3.60 (br s, 4H), 2.80 (d, 2H, J = 11.7 Hz), 2.17 (d, 2H, J= 7.0 Hz), 1.90 (m, 1 H), 1.73 (d, 2H1 J = 1 1.7 Hz), 1.61 (br s, 6H), 1.17 (m, 2H). LCMS (ESI) Rt = 2.66 min, [M+1]+ 482.3. Example 129
Ethyl 1 -(5-(2-(4,4-dif luoropiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (129)
Figure imgf000239_0001
Compound 129 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, CDCI3) δ 8.15 (d, 1 H, J = 2.9 Hz), 7.95 (dd, 1 H1 J = 9.2, 2.9 Hz), 7.48 (br s, 1 H), 6.68 (d, 1 H, J= 9.2 Hz), 4.19 (dt, 2H, J= 13.2, 3.7 Hz), 4.16 (q, 2H1 J = 7.0 Hz), 3.82 (t, 4H, J= 5.5 Hz), 3.00 - 2.94 (m, 4H), 2.53 (m, 1 H), 2.18 - 2.09 (m, 4H), 2.00 (dd, 1 H, J= 13.6, 3.3 Hz), 1.76 (dq, 2H, J = 11.4, 4.0 Hz), 1.27 (t, 3H, J= 7.3 Hz). LCMS (ESI) Rt = 3.47 min, [M+1]+ 532.3.
Example 130
Ethyl 1-(5-(2-(2-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (130)
Figure imgf000239_0002
Compound 130 was prepared by the general procedure for compound 111.
1H NMR (400 MHz, CDCI3) 6 8.14 (d, 1 H, J= 2.6 Hz), 8.01 (d, 1 H1 J = 8.0 Hz),
7.48 (br s, 1 H), 6.69 (d, 1 H, J = 9.2 Hz), 4.52 (m, 1 H), 4.19 (dt, 2H, J = 12.8,
3.3 Hz), 4.16 (q, 2H, J= 7.0 Hz), 4.03 (d, 1 H, J= 13.2 Hz), 3.21 (dt, 1 H, J = 12.8, 2.9), 3.00 - 2.94 (m, 2H), 2.53 (m, 1 H), 2.02 - 1.97 (m, 2H), 1.83 - 1.66
(m, 8H), 1.30 (d, 3H, J = 6.6 Hz), 1.27 (t, 3H, J= 7.0 Hz). LCMS (ESI) Rt =
3.27 min, [M+1]+ 510.3.
Example 131
Ethyl 1 -(5-(2-morpholino-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylate (131)
Figure imgf000240_0001
Compound 131 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, CDCI3) δ 8.13 (d, 1H, J= 2.6 Hz), 7.97 (dd, 1 H, J= 9.2, 2.9 Hz), 7.49 (br s, 1 H), 6.68 (d, 1 H1 J= 9.2 Hz), 4.19 (dt, 2H, J= 13.6, 3.3 Hz), 4.16 (q, 2H, J= 7.0 Hz), 3.83 (t, 4H, J= 4.4 Hz), 3.67 (t, 4H, J= 4.4 Hz), 3.00 - 2.94 (m, 2H), 2.53 (m, 1 H), 2.02 - 1.98 (m, 2H), 1.82 - 1.74 (m, 2H), 1.27 (t, 3H, J= 7.0 Hz). LCMS (ESI) Rt = 2.71 rnin, [M+1]+ 498.3. Example 132
Ethyl 4-(5-(2-(azetidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (132)
Figure imgf000240_0002
Compound 132 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 2.89 min, [M+1]+ 469.3. Example 133 Ethyl 4-(5-(2-(pyrrolidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (133)
Figure imgf000240_0003
Compound 133 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, CDCI3) δ 8.17 (d, 1 H, J= 2.6 Hz), 8.04 (dd, 1 H, J= 9.2, 2.9 Hz), 7.58 (br s, 1 H), 6.67 (d, 1 H, J = 9.2 Hz), 4.18 (q, 2H, J = 7.0 Hz), 3.66 - 3.58 (m, 4H), 3.53 - 3.50 (m, 2H), 2.08 - 2.05 (m, 2H), 1.29 (t, 3H, J = 7.0 Hz). LCMS (ESI) Rt = 2.75 min, [M+1]+ 483.3. Example 134
Ethyl 4-(5-(2-(piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (134)
Figure imgf000241_0001
Compound 134 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1 H), 8.35 (d, 1 H, J= 2.6 Hz), 7.83 (dd, 1 H, J = 9.2, 2.9 Hz), 6.88 (d, 1 H, J = 9.2 Hz), 4.06 (q, 2H, J = 7.3 Hz), 3.61 (br s, 4H), 1.61 (br s, 6H), 1.20 (t, 3H, J = 7.3 Hz). LCMS (ESI) Rt = 3.23 min, [M+1]+ 497.3. Example 135
Ethyl 4-(5-(2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (135)
Figure imgf000241_0002
Compound 135 was prepared by the general procedure for compound 111.
1H NMR (400 MHz, CDCI3) δ 8.17 (d, 1 H, J= 2.6 Hz), 7.99 (dd, 1H, J= 9.2, 2.9 Hz), 7.52 (br s, 1 H), 6.67 (d, 1 H, J= 9.2 Hz), 4.18 (q, 2H, J= 7.0 Hz), 3.83 (t, 4H), 3.61 - 3.59 (m, 4H), 3.54 - 3.51 (m, 4H), 2.14 (m, 4H), 1.29 (t, 3H, J = 7.0 Hz). LCMS (ESI) Rt = 3.08 min, [M+1]+ 533.3. Example 136
Ethyl 4-(5-(2-(2-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (136)
Figure imgf000242_0001
Compound 136 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, CDCI3) δ 8.18 (d, 1 H, J= 2.6 Hz), 8.04 (d, 1 H, J= 8.8 Hz), 7.55 (br s, 1H), 6.67 (d, 1 H, J= 9.2 Hz), 4.52 (t, 1 H, J= 7.0 Hz), 4.18 (q, 2H, J = 7.0 Hz), 4.03 (dd, 1 H, J = 13.2, 3.3 Hz), 3.61 - 3.59 (m, 4H), 3.53 - 3.51 (m, 4H), 3.21 (dt, 1 H, J = 12.8, 2.9 Hz), 1.82 - 1.78 (m, 2H), 1.72 - 1.53 (m, 4H), 1.29 (t, 6H, J= 7.0 Hz). LCMS (ESI) Rt = 3.17 min, [M+1]+ 511.3. Example 137
Ethyl 4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (137)
Figure imgf000242_0002
Compound 137 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 3.71 min, [M+1 ]+ 511.3. Example 138 Ethyl 4-(5-(2-(4-methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (138)
Figure imgf000242_0003
Compound 138 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 3.73 min, [M+1]+ 511.3. Example 139 Ethyl 4-(5-(2-morpholino-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (139)
Figure imgf000243_0001
Compound 139 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, CDCI3) 6 8.16 (d, 1 H1 J= 2.6 Hz), 8.00 (dd, 1 H, J= 9.2, 2.6 Hz), 7.45 (br S, 1 H), 6.67 (d, 1 H, J= 9.2 Hz), 4.18 (q, 2H, J= 7.0 Hz), 3.83 (t, 4H, J = 4.4 Hz), 3.66 (t, 4H, J= 4.8 Hz), 3.61 - 3.59 (m, 4H), 3.53 - 3.51 (m, 4H), 1.29 (t, 3H, J = 7.0 Hz). LCMS (ESI) Rt = 2.63 min, [M+1 ]+ 499.3. Example 140 tert-Butyl 4-(5-(6-(4-(ethoxycarbonyl)piperazin-1-yl)pyridin-3- ylcarbamoyl)-4-(trifluoromethyl)oxazol-2-yl)piperazine-1-carboxylate (140)
Figure imgf000243_0002
Compound 140 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 3.39 min, [M+1]+ 598.3. Example 141
Ethyl 4-(5-(2-(4-hydroxy-4-phenylpiperidin-1 -yl)-4- (trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)piperazine-1- carboxylate (141 )
Figure imgf000243_0003
Compound 141 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 3.21 min, [M+1]+ 589.3. Example 142
Ethyl 4-(5-(2-(azepan-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (142)
Figure imgf000244_0001
Compound 142 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 3.28 min, [M+1]+ 511.3. Example 143 Ethyl 4-(5-(2-(1 ,4-oxazepan-4-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (143)
Figure imgf000244_0002
Compound 143 was prepared by the general procedure for compound 111. LCMS (ESI) Rt = 2.72 min, [M+1]+ 513.3. Example 144 terf-butyl 4-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (144)
Figure imgf000244_0003
Compound 144 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1 H), 8.35 (d, 1H, J = 2.6 Hz), 7.84 (dd, 1H1 J = 9.2, 2.9 Hz), 6.88 (d, 1 H1 J = 9.2 Hz), 3.61 (br s, 4H), 3.44 (m, 8H), 1.61 (br s, 6H), 1.42 (s, 9H). LCMS (ESI) Rt = 3.52 min, [M+1 ]+ 525.3. Example 145 Methyl 4'-[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5- oxazoly|]carbonylamino]-(1 ,1 '-biphenyl)-4-carboxylate (145)
Figure imgf000245_0001
Compound 145 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.15 (bd, 2H1 J=8.5Hz), 7.78 (bd, 2H, J=8.5Hz), 7.77 (S, 1H), 7.71 (bd, 2H, J=8.5Hz), 7.68 (d, 2H, J=8.5Hz), 4.16 (bt, 2H, J=MHz), 4.00 (s, 3H), 3.10 (bt, 2H, J=12.5Hz), 2.78 (bt, 1 H, J=12.5Hz), 2.00- 1.59 (m, 6H), 1.30-1.19 (m, 1 H), 1.05 (d, 3H, J=7Hz). LCMS (ESI) Rt = 5.40 min, 488.3 [M+1]+. Example 146 4l-[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5- oxazolylJcarbonylaminoHI.I'-biphenylH-carboxylic acid (146)
Figure imgf000245_0002
Compound 145 (100 mg, 0.2 mmol) was stirred in a mixture of THF (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (84 mg, 2 mmol) was added. The reaction mixture was stirred 17 h and then concentrated to dryness. Water was added, followed by 1 N HCI (2.5 mL). The precipitate was collected by filtration, washed with water and ether. The solid was then dissolved in DMF and purified by chromatography on a C-18 reverse phase column (eluant: acetonitrile / water gradient) to give 4'-[[2-(3- methyl-1 -piperidinyl)-4-(trif luoromethyl)-5-oxazolyl]carbonylamino]-(1 , 1 '- biphenyl)-4-carboxylic acid (146) (58 mg, 59% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.02 (bd, 2H, J=8.5Hz), 7.87-7.81 (m, 4H), 7.79 (bd, 2H, J=8.5Hz), 6.69 (bs, 2H), 4.12 (q, 2H, J=13Hz), 3.08 (td, 2H, J=12.5Hz, J=ZHz), 2.77 (bt, 1 H, J=12.5Hz), 1.79 (bt, 2H, J=MHz), 1.69 (m, 1 H), 1.55 (bq, 2H, J=12Hz), 1.17 (bq, 1 H), 0.95 (d, 3H, J=IHz). LCMS (ESI) Rt = 4.77 min, 474.3 [M+1]+. Example 147 N-[4'-[(phenylamino)carbonyl]-(1 ,1 '-biphenyl)-4-yl]-2-(3- methyl-1 -piperidinyl)-4-(trif luoromethyl)-5-oxazolecarboxamide (147)
Figure imgf000246_0001
To a solution of compound 146 (101 mg, 0.21 mmol) and aniline (30 μl_, 0.32 mmol) in DMF (1 ml_) were added O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'- tetramethyluronium hexafluorophosphate (122 mg, 0.32 mmol, HATU), and Λ/,Λ/-diisopropylethylamine (235 μl_, 1.4 mmol). The reaction mixture was stirred at RT for 17 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with 1 N HCI, 1 N NaOH, and brine. The solution was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMF and purified by chromatography on a C-18 reverse phase column, (eluant: acetonitrile / water gradient) to give N-[4'- [(phenylamino)carbonyl]-(1 ,1'-biphenyl)-4-yl]-2-(3-methyl-1-piperidinyl)-4- (trifluoromethyl)-5-oxazolecarboxamide (147) (112 mg, 96% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1 H), 10.25 (s, 1 H), 8.07 (bt, 2H), 7.90-7.77 (m, 8H), 7.37 (q, 2H, J=7.5Hz), 7.12 (q, 1 H, J=7.5Hz), 4.12 (q, 2H, J=λZ.5Hz), 3.08 (bt, 2H), 2.76 (bq, 1 H), 1.79 (bt, 2H), 1.69 (m, 1 H), 1.56 (m, 1 H), 1.17 (m, 1 H), 0.95 (m, 3H). LCMS (ESI) Rt = 5.63 min, 549.3 [M+1]+. Example 148 N-[4'-[[(2-methylphenyl)amino]carbonyl]-(1 ,1 '-biphenyl)-4- yl]-2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolecarboxamide (148)
Figure imgf000246_0002
Compound 148 was prepared by the general procedure for compound 147, by using compound 146 and o-toluidine as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.02 (bin, 3H), 7.79 (bm, 6H), 7.69 (bm, 2H), 7.19 (bm, 1 H), 4.16 (bt, 2H), 3.76 (bt, 1 H), 3.15 (bt, 1 H), 2.42 (s, 3H), 2.05 (s, 2H), 1.98-1.76 (m, 3H), 1.74-1.58 (m, 3H), 1.36-1.16 (m, 2H), 1.05 (bd, 3H, J=6Hz). LCMS (ESI) Rt = 5.49 min, 563.3 [M+1]+. Example 149
N-[4'-[[(2-methoxyphenyl)amino]carbonyl]-(1 ,1'-biphenyl)-4-yl]-2-(3- methyl-1 -pi per id i ny l)-4-(tr if luoromethyl)-5-oxazolecarboxamide (149)
Figure imgf000247_0001
Compound 149 was prepared by the general procedure for compound 147, by using compound 146 and o-anisidine as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.66 (s, 1 H), 8.61 (d, 1 H1 J=QHz), 8.02 (d, 2H, J=QHz), 7.79-7.76 (dds, 5H, J=QHz, J=QHz), 7.69 (d, 2H, J=QHz), 7.15 (t, 1 H, J=LbHz), 7.09 (t, 1 H, J=LbHz), 6.99 (d, 1 H, J=IHz), 4.17 (bt, 2H, J=MHz), 4.00 (s, 3H), 3.11 (td, 1 H, J= 12.5Hz, J=2.5Hz), 2.78 (t, 1 H, J=12.5Hz), 2.05 (s, 2H), 1.95 (bd, 1 H, J=14Hz), 1.88 (d, 1H, J=UHl), 1.83(bm, 1 H), 1.71-1.60 (m), 1.36-1.18 (bm), 1.05 (d, 3H1 J=6.5Hz). LCMS (ESI) Rt = 5.72 min, 579.3 [M+1]+. Example 150 N-[4'-[[(2-fluorophenyl)amino]carbonyl]-(1 ,1 '-biphenyl)-4- yl]-2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolecarboxamide (150)
Figure imgf000247_0002
Compound 150 was prepared by the general procedure for compound 147, by using compound 146 and o-fluoroaniline as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.55 (td, 1 H, J=8Hz, J=1.5Hz), 8.16 (bs, 1 H), 8.02 (d, 2H, J=8.5Hz), 7.82-7.75 (m, 5H), 7.69 (d, 2H, J=8.5Hz), 7.28-7.12 (m, 3H), 4.17 (bt, 2H, J= 16Hz), 3.11 (td, 1 H, J=12.5Hz, J=3Hz), 2.78 (t, 1 H, J=12.5Hz), 2.06 (S, 2H), 1.95 (bd, 1 H), 1.90 (dt, 1 H, J=13.5Hz, J=3Hz), 1.82(bm, 1 H), 1.76- 1.60 (m, 3H), 1.44-1.17 (bm, 2H), 1.05 (d, 3H, J=6.5Hz). LCMS (ESI) Rt = 5.36 min, 567.3 [M+1 J+. Example 151
N-[4'-[[(2-chlorophenyl)amino]carbonyl]-(1,1'-biphenyl)-4-yl]-2-(3-methyl- 1 -piperidinyl)-4-(trif luoromethyl)-5-oxazolecarboxamide (151 )
Figure imgf000248_0001
Compound 151 was prepared by the general procedure for compound 147, by using compound 146 and o-chloroaniline as starting materials. 1H NMR (500 MHz, CDCI3 ) δ 8.64 (d, 1H, J=QHz) 8.55 (s, 1H), 8.05 (d, 2H, J=8Hz), 7.84-7.76 (m, 5H1), 7.70 (d, 2H, J=8.5Hz), 7.49 (d, 1H, J=QHz), 7.41 (t, 1 H, J=I.5Hz), 7.15 (t, 1H, J=I.5Hz), 4.17 (bt, 2H, J= 16Hz), 3.11 (td, 1 H, J= 12.5Hz, J=2.5Hz), 2.78 (t, 1 H, J=12.5Hz), 2.06 (s, 2H)1 1.95 (bd, 1 H, J= 71 Hz), 1.88 (dt, 1H, J=13Hz, J=3Hz), 1.81(bm, 1H), 1.76-1.56 (m, 3H), 1.32-1.17 (bm, 2H), 1.05 (d, 3H, J=6.5Hz). LCMS (ESI) Rt = 5.64 min, 583.3 [M+1]+. Example 152 ethyl 4-[5-[[2-(1-piperidinyl)-4-(trifluoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]-1-piperazinecarboxylate (152)
Figure imgf000248_0002
Compound 152 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.22 (d, 1H, J= 2.5 Hz), 7.91-7.89 (m, 1 H), 7.62 (m, 1H), 6.69 (d, 1H, J = 9.0 Hz), 4.20 (q, 2H, J= 7.0 Hz), 3.62-3.53 (m, 12H), 1.71 (m, 6H), 1.31 (t, 3H, J = 7.0 Hz); LCMS (ESI) [M+1 ]+ 513.3. Example 153 1,1-dimethylethyl 4-[5-[[2-(1-piperidinyl)-4-(trifluoromethyl)- 5-thiazolyl]carbonylamino]-2-pyridinyl]-1 -piperazinecarboxylate (153)
Figure imgf000248_0003
Compound 153 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.21 (d, 1H, J= 2.5 Hz), 7.91-7.88 (m, 1H), 7.60 (m, 1H), 6.68 (d, 1 H, J= 9.0 Hz), 3.56-3.51 (m, 12H), 1.71 (m, 6H), 1.51 (s, 9H); LCMS (ESI) [M+1]+ 541.3. Example 154 ethyl 1-[5-[[2-(1 -piperidinyl)-4-(trif luoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]-4-piperidinecarboxylate (154)
Figure imgf000249_0001
Compound 154 was prepared by the general procedure for compound 111. 1H
NMR (500 MHz, CDCI3) δ 8.19 (d, 1 H, J = 2.5 Hz), 7.88-7.85 (m, 1 H), 7.58 (m, 1H), 6.70 (d, 1 H, J = 9.0 Hz), 4.23-4.15 (m, 4H), 3.55-3.54 (m, 4H), 3.01-
2.95 (m, 2H), 2.58-2.51 (m, 1H), 2.03-2.00 (m, 2H), 1.83-1.75 (m, 2H), 1.71
(m, 6H), 1.29 (t, 3H, J= 7.0 Hz); LCMS (ESI) [M+1]+ 512.3.
Example 155
N-[6-[[1-[[(2-fluorophenyl)amino]carbonyl]-3(R)-pyrrolidinyl]amino]-3- pyridinyl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamide (155)
Figure imgf000249_0002
Compound 155 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.15 (t, 1 H, J= 8 Hz), 8.13 (s, 1 H), 7.90 (d, 1 H1 J = 9 Hz), 7.70 (broad s, 1 H), 7.08 (m, 2H), 6.97 (m, 1 H), 6.46 (d, 1H, J= 9 Hz), 6.43 (m, 1H), 4.85 (broad s, 1H), 4.50 (broad s, 1 H), 4.10 (t, 2H, J= 13 Hz), 3.90 (m, 1H), 3.65 (m, 2H), 3.45 (m, 1H), 3.05 (t, 1H, J= 10 Hz), 2.70 (t, 1H, J = 12.5 Hz), 2.35 (m, 1 H), 2.05 (m, 1 H), 1.60-1.90 (m, 3H), 1.20 (q, 1 H, J = 12 Hz), 1.00 (d, 3H, J = 6.5 Hz). MS (M+1 ): 576. Example 156 N-[6-[[1-[[(2-fluorophenyl)amino]carbonyl]-3(S)-pyrrolidinyl]amino]-3- pyridinyl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-
carboxamide(156)
Figure imgf000250_0001
Compound 156 was prepared by the general procedure for compound 111.1H NMR (500 MHz, CDCI3) δ 8.14 (s, 1H), 8.14 (t, 1H, J= 8.5 Hz), 7.90 (d, 1H, J = 9 Hz), 7.75 (S11H), 7.10 (m, 2H), 6.95 (m, 1H), 6.48 (d, 1H, J = 9.5 Hz), 6.45 (m, 1H), 5.00 (broad s, 1H), 4.45 (broad s, 1H), 4.10 (t, 2H, J= 13.5 Hz), 3.90 (m, 1H), 3.65 (m, 2H), 3.45 (m, 1H), 3.05 (t, 1 H, J= 12.5 Hz), 2.70 (t, 1H, J= 11.5 Hz), 2.35 (m, 1H)12.10 (m, 1H), 1.70-1.85 (m, 3H), 1.60(m, 1H), 1.20 (q, 1 H, J = 11 Hz), 1.00 (d, 3H, J = 6.5 Hz). MS (M+1 ): 576. Example 157
N-[6-[3-[[[(2-fluorophenyl)amino]carbonyl]amino]-1-pyrrolidinyl]-3- pyr id iny l]-2-(3-methy I pi per id i n-1 -y l)-4-(tr if I uoromethy l)oxazole-5-
carboxamide (157)
Figure imgf000250_0002
Compound 157 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (t, 1H, J= 8 Hz), 7.75 (d, 1H1 J= 9 Hz), 7.15 (m, 1H), 7.10 (t, 1H, J= 8 Hz), 7.00 (d, 1H1 J= 6.5 Hz), 6.95 (m, 1H), 6.55 (broad s, 1H), 4.35 (broad s, 1H), 4.10 (m, 2H), 3.65 (m, 1H), 3.50 (t, 2H, J= 7 Hz), 3.05 (t, 1 H, J= 12.5 Hz), 2.90 (d, 1 H, J = 12.5 Hz), 2.75 (t, 1 H, J = 11.5 Hz), 2.20 (m, 1 H), 1.95 (m,
1H), 1.60-1.80 (m, 3H), 1.50 (m, 1H), 1.15 (q, 1 H, J= 11.5 Hz), 0.95 (d, 3H, J = 6.5 Hz). MS (M+1): 576. Example 158 N-[6-[[2-[[[(2-fluorophenyl)amino]carbonyl]methylamino]ethyl]amino]-3- pyridinyl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-
carboxamide (158)
Figure imgf000251_0001
Compound 158 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 6 8.35 (S, 1 H), 8.30 (s, 1 H), 7.95 (d, 1 H, J = 9.5 Hz), 7.80 (t, 1 H, J = 7.5 Hz), 7.10 (m, 2H), 7.05 (m, 2H), 6.75 (d, 1 H, J= 9.5 Hz), 4.20 (d, 1 H, J= 14 Hz), 4.15 (d, 1 H, J = 13 Hz), 3.55 (broad S, 4H), 3.15 (S, 3H), 3.15 (m, 1 H), 3.00 (t, 1 H, J= 12 Hz), 2.70 (t, 1 H, J= 13 Hz), 1.85 (m, 2H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15 (q, 1 H, J= 11.5 Hz), 1.00 (d, 3H, J= 6.5 Hz). MS (M+1): 564. Example 159
N-(2-fluorophenyl)-4-[4-[[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5- oxazolyl]carbonyl]amino]phenyl]-1-piperazinecarboxamide (159)
Figure imgf000251_0002
Compound 159 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCj3 6 8.10 (t, 1 H, J= 8.5 Hz), 7.65 (s, 1 H), 7.55 (d, 2H, J= 9 Hz), 7.15 (t, 1 H, J= 8 Hz), 7.10 (t, 1 H, J = 11.5 Hz), 7.00 (t, 1 H1 J= 6 Hz), 6.95 (d, 2H, J = 9.5 Hz), 6.65 (d, 1 H, J= 3.5 Hz), 4.10 (t, 2H, J= 14.5 Hz), 3.70 (m, 4H), 3.25 (m, 4H), 3.05 (t, 1 H, J= 10 Hz), 2.70 (t, 1 H, J = 1 1 Hz), 1.60-1.95 (m, 4H), 1.20 (q, 1 H, J = 12 Hz), 1.00 (d, 3H, J = 7 Hz). MS (M+1): 575. Example 160
Ethyl 4-[5-[[[2-(1 -pi per id i ny l)-4-(tr if luoromethyl)-5- thiazolyl]carbonyl]amino]-2-pyridinyl]-1-piperazineacetate (160)
Figure imgf000252_0001
Compound 160 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1 H, J = 2.5 Hz), 7.89-7.87 (m, 1 H), 7.59 (m, 1 H), 6.68 (d, 1 H, J= 9.0 Hz), 4.23 (q, 2H, J= 7.0 Hz), 3.62-3.54 (m, 8H), 3.29 (s, 2H), 2.73-2.71 (m, 4H), 1.71 (m, 6H), 1.31 (t, 3H, J= 7.0 Hz); LCMS (ESI) [M+1]+ 527.3. Example 161
4-[5-[[[2-(1-Piperidinyl)-4-(trifluoromethyl)-5-thiazolyl]carbonyl]amino]-2- pyridinyl]-1-piperazineacteic acid (161)
Figure imgf000252_0002
Compound 161 was prepared by the general procedure for compound 127, by using compound 160 as starting material. 1H NMR (500 MHz, (CD3)2CO) δ 10.37 (s, 1H), 8.31 (s, 1 H), 7.79-7.77 (m, 1H), 6.85 (d, 1H, J= 9.0 Hz), 3.49- 3.46 (m, 8H), 3.16 (s, 2H), 2.65-2.63 (m, 4H), 1.63 (m, 6H); LCMS (ESI) [M+1]+ 499.3. Example 162
Methyl 4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yloxy)benzoate (162)
Figure imgf000252_0003
Compound 162 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.35 (dd, 1 H, J= 2.5, 9 Hz), 8.27 (d, 1 H1 J= 2.5 Hz), 8.13 (d, 2H, J= 8.5 Hz), 7.73 (s, 1 H), 7.40 (t, 2H, J= 7.5 Hz), 7.28 (d, 2H, J = 7 Hz), 7.20 (d, 2H, J = 8.5 Hz), 7.05 (d, 1 H, J = 9 Hz), 4.42 (d, 2H, J = 13.5 Hz), 3.95 (s, 3H), 3.28 (t, 2H, J = 12.5 Hz), 2.85 (t, 1 H, J = 12.5 Hz), 2.07 (d, 2H, J= 13 Hz), 1.90 (q, 2H, J= 13 Hz). MS (M+1): 567. Example 163
4-(5-(2-(4-Phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yloxy)benzoic acid (163)
Figure imgf000253_0001
Compound 163 was prepared by the general procedure for compound 127, by using compound 162 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1 H), 8.48 (s, 1 H), 8.20 (d, 1 H1 J= 9 Hz), 8.00 (d, 2H, J = 8.5 Hz), 7.30 (m, 4H), 7.20 (m, 4H), 4.35 (d, 2H, J= 12.5 Hz), 3.25 (t, 2H, J = 13 Hz), 2.83 (t, 1 H, J = 12 Hz), 1.90 (d, 2H, J = 12 Hz), 1.75 (q, 2H, J = 13 Hz). MS (M+1): 553. Example 164
Methyl 4'-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenyl-4-carboxylate (164)
Figure imgf000253_0002
Compound 164 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.15 (d, 2H, J = 8 Hz), 7.80 (s, 1 H), 7.80 (d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J= 8 Hz), 7.70 (d, 2H1 J= 8.5 Hz), 7.40 (t, 2H, J= 7.5 Hz), 7.30 (m, 3H), 4.45 (d, 2H, J= 12.5 Hz), 4.00 (s, 3H), 3.28 (td, 2H, J = 13, 2.5 Hz), 2.85 (tt, 1 H, J= 3, 13 Hz), 2.08 (d, 2H, J= 12.5 Hz), 1.89 (qd, 2H, J = 12.5, 4 Hz). MS (M+1): 550. Example 165
4'-(2-(4-Phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenyl-4-carboxylic acid (165)
Figure imgf000254_0001
Compound 165 was prepared by the general procedure for compound 127, by using compound 164 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.02 (d, 2H, J= 8.5 Hz), 7.82 (m, 6H), 7.30 (m, 4H), 7.23 (m, 1H), 4.38 (d, 2H, J = 13 Hz), 3.25 (t, 2H, J= 13.5 Hz), 2.83 (t, 1 H, J= 12.5 Hz), 1.90 (d, 2H, J = 11.5 Hz), 1.77 (q, 2H, J = 12.5 Hz). MS (M+1 ): 536. Example 166
2-(4-Phenylpiperidin-1-yl)-N-(6-(4-(o-tolylcarbamoyl)phenoxy)pyridin-3- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (166)
Figure imgf000254_0002
Compound 166 was prepared by the general procedure for compound 147, by using compound 163 and 2-methylaniline as starting materials. 1H NMR (500 MHz, CDCI3) δ 8.33 (dd, 1 H, J = 2.5, 8.5 Hz), 8.28 (d, 1 H, J = 2.5 Hz), 7.97 (d, 2H, J = 8.5 Hz), 7.95 (broad s, 1 H), 7.85 (s, 1 H), 7.70 (s, 1 H), 7.40 (t, 2H, J = 7.5 Hz), 7.30 (m, 7H), 7.18 (t, 1H, J= 7.5 Hz), 7.07 (d, 1 H, J= 9 Hz), 4.43 (d, 2H, J= 13 Hz), 3.25 (td, 2H, J= 13, 2 Hz), 2.83 (tt, 1 H, J= 3, 12.5 Hz), 2.38 (s, 3H), 2.05 (m, 2H), 1.87 (qd, 2H, J= 13, 4.5 Hz). MS (M+1): 642. Example 167
2-(4-Phenylpiperidin-1-yl)-N-(4'-(o-tolylcarbamoyl)biphenyl-4-yl)-4- (trif luoromethyl)oxazole-5-carboxamide (167)
Figure imgf000254_0003
Compound 167 was prepared by the general procedure for compound 147, by using compound 165 and 2-methylaniline as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1 H), 9.94 (s, 1 H), 8.10 (d, 2H, J = 8 Hz), 7.85 (d, 4H, J = 8 Hz), 7.80 (d, 2H, J= 9 Hz), 7.35 (t, 1H, J= 8 Hz), 7.30 (m, 5H), 7.25 (m, 2H), 7.20 (t, 1H, J= 6 Hz), 4.40 (d, 2H, J= 13 Hz), 3.25 (t, 2H, J= 11 Hz), 2.85 (t, 1 H1 J= 11.5 Hz), 2.27 (s, 3H), 1.90 (d, 2H, J= 11.5 Hz), 1.75 (q, 2H, J = 12.5 Hz). MS (M+1): 625. Example 168
N-(4'-(2-ethylphenylcarbamoyl)biphenyl-4-yl)-2-(3-methylpiperidin-1-yl)- 4-(trifluoromethyl)oxazole-5-carboxamide (168)
Figure imgf000255_0001
Compound 168 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 8.00 (broad s, 1 H), 8.00 (d, 2H, J= 8 Hz), 7.80 (m, 6H), 7.70 (d, 2H, J= 8.5 Hz), 7.35 (t, 1 H, J= 8 Hz), 7.25 (t, 1 H, J= 7.5 Hz), 4.15 (t, 2H, J= 13.5 Hz), 3.10 (t, 1H, J= 12.5 Hz), 2.75 (m, 3H), 1.95 (d, 1 H, J = 9.5 Hz), 1.60-1.90 (m, 3H), 1.35 (t, 3H, J = 7.5 Hz), 1.25 (q, 1 H, J = 9.5 Hz), 1.05 (d, 3H1 J= 6.5 Hz). MS (M+1 ): 577. Example 169
N-(4'-(2,6-dimethylphenylcarbamoyl)biphenyl-4-yl)-2-(3-methylpiperidin- 1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (169)
Figure imgf000255_0002
Compound 169 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 8.05 (d, 2H, J= 8 Hz), 7.80 (m, 5H), 7.70 (d, 2H, J = 8 Hz), 7.50 (s, 1H), 7.20 (broad s, 3H), 4.15 (t, 2H, J= 13 Hz), 3.10 (t, 1H, J = 10 Hz), 2.80 (t, 1 H, J = 1 1.5 Hz), 2.35 (s, 6H), 1.65-1.95 (m, 4H), 1.25 (q, 1 H1 J= 10.5 Hz), 1.05 (d, 3H, J= 6.5 Hz). MS (M+1 ): 577. Example 170
2-(3-Methylpiperidin-1-yl)-N-(4'-(2-propylphenylcarbamoyl)biphenyl-4-yl)- 4-(trifluoromethyl)oxazole-5-carboxamide (170)
Figure imgf000256_0001
Compound 170 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 8.05 (broad s, 1 H), 8.00 (d, 2H, J = 8 Hz), 7.80 (m, 6H), 7.70 (d, 2H, J = 8.5 Hz), 7.35 (t, 1 H, J = 8.5 Hz)1 7.30 (m, 1H), 7.20 (t, 1 H1 J= 8 Hz), 4.17 (m, 2H), 3.10 (t, 1 H, J= 12.5 Hz), 2.78 (t, 1 H, J= 11 Hz), 2.70 (t, 2H, J = 7.5 Hz), 1.65-1.95 (m, 6H), 1.25 (q, 1 H, J= 12.5 Hz), 1.05 (m, 6H). MS (M+1): 591. Example 171
N-(4'-(2-butylphenylcarbamoyl)biphenyl-4-yl)-2-(3-methylpiperidin-1-yl)- 4-(trif luoromethyl)oxazole-5-carboxamide (171 )
Figure imgf000256_0002
Compound 171 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) 6 8.05 (d, 1 H, J= 6.5 Hz), 8.00 (d, 2H, J= 8.5 Hz), 7.80 (m, 6H), 7.70 (d, 2H, J= 8.5 Hz), 7.35 (t, 1 H, J= 8.5 Hz), 7.30 (m, 1 H), 7.20 (t, 1 H, J = 7 Hz), 4.15 (m, 2H), 3.10 (t, 1 H, J= 12.5 Hz), 2.78 (t, 1 H, J = 1 1 Hz), 2.73 (t, 2H, J = 8 Hz), 1.65-1.95 (m, 6H), 1.48 (m, 2H), 1.25 (q, 1 H, J = 12.5 Hz), 1.05 (d, 3H, J = 6.5 Hz), 1.00 (t, 3H, J = 7.5 Hz). MS (M+1 ): 605. Example 172
Ethyl 3-(4'-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenyl-4-ylcarboxamido)propanoate (172)
Figure imgf000257_0001
Compound 172 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 7.90 (d, 2H, J= 8.5 Hz), 7.78 (m, 3H), 7.70 (d, 2H, J= 8.5 Hz), 7.65 (d, 2H, J= 8.5 Hz), 6.95 (t, 1H1 J= 6 Hz), 4.25 (m, 2H), 4.15 (t, 2H, J= 13.5 Hz), 3.80 (m, 2H)1 3.10 (t, 1 H, J= 9 Hz), 2.78 (t, 1 H, J= 11 Hz), 2.72 (m, 2H), 1.65-1.95 (m, 4H), 1.35 (t, 3H, J= 7.5 Hz), 1.25 (q, 1 H, J = 11.5 Hz), 1.05 (d, 3H, J = 6.5 Hz). MS (M+1 ): 573. Example 173
(2S)-Methyl 1-(4'-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenylcarbonyl)pyrrolidine-2-carboxylate (173)
Figure imgf000257_0002
Compound 173 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) 57.75 (m, 3H)1 7.65 (m, 6H), 4.75 (broad s, 1 H), 4.15 (m, 3H), 3.85 (s, 3H), 3.77 (m, 1 H), 3.65 (broad s, 1 H), 3.10 (t, 1 H, J= 13 Hz), 2.75 (t, 1H, J= 11 Hz), 2.40 (m, 1H), 1.65-2.10 (m, 6H), 1.25 (q, 1 H, J= 13.5 Hz), 1.05 (d, 3H, J= 6.5 Hz). MS (M+1): 585. Example 174
(2S)-1-(4'-(2-(3-Methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenylcarbonyl)pyrrolidine-2-carboxylic acid (174)
Figure imgf000257_0003
Compound 174 was prepared by the general procedure for compound 146, by using compound 173 as starting material. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1 H), 7.83 (m, 2H), 7.77 (m, 4H), 7.63 (d, 2H, J= 8 Hz), 4.45 (m, 1H), 4.15 (d, 1 H, J= 13.5 Hz), 4.10 (d, 1 H, J= 13 Hz), 3.55 (m, 2H), 3.07 (t, 1 H, J = 10.5 Hz), 2.77 (t, 1 H, J= 12.5 Hz), 2.30 (m, 1 H), 1.50-1.95 (m, 7H), 1.18 (m, 1 H), 0.95 (d, 3H, J = 7 Hz). MS (M+1): 571. Example 175 - 183
Compounds 175 - 183 were prepared by the method for amide combinatorial library synthesis described below. Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 49.2 mg of EDC resin (3 eq. @ 1.39 mmol/g), 1 ml_ solution of compound 3 and HOBt in 3:1 CH3CNfTHF (10.0 mg of compound 3 and 4.6 mg of HOBt for each cartridge), and 45.6 μl_ of each carboxylic acid (1 M solution in DMF). The cartridges were stoppered and shaken overnight. Then, to each cartridge was added 30.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 46.9 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μl_ of 3:1 CH3CN:THF. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed bar- coded vials, and the resins were washed with CH3CN (6 x 500 μl_). Upon concentration of the filtrates, the amides listed below were obtained as products.
Figure imgf000258_0001
Rt = 3.12 min, [M+I]+ 481.3
Figure imgf000259_0001
Rt = 3.32 min, [M+1]+ 495.3
Figure imgf000259_0002
Rt = 3.32 min, [M+1]+ 507.3
Figure imgf000259_0003
Rt = 3.54 min, [M+1]+ 521.3
Figure imgf000259_0004
Rt = 3.50 min, [M+1]+ 529.3
Figure imgf000259_0005
Rt = 3.66 min, [M+1]+ 535.3
Figure imgf000260_0001
Rt = 3.59 min, [M+1]+ 547.3
Figure imgf000260_0002
Rt = 3.84 min, [M+1]+ 597.3
Figure imgf000260_0003
Example 184 - 194
Compounds 184 - 194 were prepared by the method for amide combinatorial library synthesis described below.
Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 49.2 mg of EDC resin (3 eq. @ 1.39 mmol/g), 1 ml_ solution of compound 128 and HOBt in 3:1 CH3CNiTHF (10.0 mg of 128 and 4.6 mg of HOBt for each cartridge), and 45.6 μl_ of each amine (1 M solution in DMF). The cartridges were stoppered and shaken overnight. Then, to each cartridge was added 30.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 46.9 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μl_ of 3:1 CH3CN:THF. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed bar-coded vials, and the resins were washed with CH3CN (6 x 500 μl_). Upon concentration of the filtrates, the amides listed below were obtained as products. Rt = 3.30 min, [M+1]+ 535.3
Figure imgf000262_0001
Rt = 5.20 min, [M+1]+ 535.3
Figure imgf000262_0002
Rt = 3.39 min, [M+1]+ 537.3
Figure imgf000262_0003
Rt = 4.69 min, [M+1]+ 539.3
Figure imgf000262_0004
Rt = 3.45 min, [M+1]+ 549.3
Figure imgf000262_0005
Rt = 5.14 min, [M+1]+ 535.3
Figure imgf000263_0001
Example 195
/V-(6-(4-(2-(2-f luorophenylam i no)-2-oxoethyl)pi perid i n-1 -y l)pyr id in-3-y l)-2-
(piperidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxamide (195)
Figure imgf000263_0002
Compound 195 was prepared by the general procedure for compound 147.
1H NMR (400 MHz, CDCI3) 58.32 (t, 1 H, J= 7.9 Hz), 8.14 (s, 1 H), 7.97 (d, 1 H,
J = 12.0 Hz), 7.97 (s, 1 H), 7.40 (s, 1 H), 7.17-7.02 (m, 3H), 6.67 (d, 1 H1 J= 9.2
Hz), 4.26 (d, 2H, J= 13.3 Hz), 4.06 (q, 2H, J= 7.3 Hz), 3.61 (br s, 4H), 3.61- 2.83 (m, 2H), 2.35 (d, 1 H, J= 6.9 Hz), 2.18 (m, 1H), 1.88 (d, 2H, J= 12.4 Hz),
1.68 (m, 6H) ), 1.35 (q, 2H, J= 12.5 Hz); LCMS (ESI) Rt = 3.32 min, [M+1]+
575.3.
Example 196 tert-Butyl 1-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidin-4-ylcarbamate (196)
Figure imgf000263_0003
Compound 196 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.30 (d, 1 H, J= 2.6 Hz), 7.76 (dd, 1 H, J= 9.2, 2.9 Hz), 6.86 (s, 1 H), 6.85 (d, 1 H, J= 9.2 Hz), 4.17 (m, 2H), 3.61 (br s, 4H), 3.47 (m, 1 H), 2.86 (m, 2H), 1.76 (m, 2H), 1.61 (br s, 6H), 1.38 (s, 9H), 1.33 (m, 2H); LCMS (ESI) Rt = 3.27 min, [M+1]+ 539.3. Example 197 - 208
Figure imgf000264_0001
Step 1 : N-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-2-(piperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (C-4)
Compound C-4 was prepared by the general procedure for compound 3, by using compound 196 as a starting material. LCMS (ESI) Rt = 2.34 min, [M+1]+ 439.2.
Compounds 197 - 208 were prepared by the method for urea combinatorial library synthesis described below.
Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 1 mL of the solution of compound C-4 in DCE (10 mg of C-4 for each cartridge), and 45.6 μL of each isocyanate (1 M solution in DCE). The cartridges were stoppered and shaken overnight. Then, to the each cartridge was added 31.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 48.4 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μL of DCE. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed vials, and the resins were washed with acetonitrile (6 x 500 μL). Upon concentration of the filtrates, the ureas listed below were obtained as products.
Figure imgf000264_0002
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Example 209
1-(5-(2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (209)
Figure imgf000267_0002
Compound 209 was prepared by the general procedure for compound 146. LCMS (ESI) Rt = 3.05 min, [M+1]+ 504.3. Example 210
1-(5-(2-(2-Methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (210)
Figure imgf000267_0003
Compound 210 was prepared by the general procedure for compound 146. LCMS (ESI) Rt = 2.98 min, [M+1]+ 482.3. Example 211 1 -(5-(2-Morpholino-4-(trif luoromethyl)oxazole-5-carboxamido)pyridin-2- yl)piperidine-4-carboxylic acid (211)
Figure imgf000268_0001
Compound 211 was prepared by the general procedure for compound 146.
LCMS (ESI) Rt = 2.38 min, [M+1]+ 470.3.
Example 212
1 -(5-(2-(Pyrrolidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (212)
Figure imgf000268_0002
Compound 212 was prepared by the general procedure for compound 146. LCMS (ESI) Rt = 2.47 min, [M+1]+ 454.2. Example 213 Ethyl 4-[5-[[[2-(1-piperidinyl)-4-(trifluoromethyl)-5- thiazolyl]carbonyl]amino]-2-pyridinyl]-1 -piperazineacetate (213)
Figure imgf000268_0003
Compound 213 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1 H, J= 2.5 Hz), 7.89-7.87 (m, 1 H), 7.59 (m, 1 H), 6.68 (d, 1 H, J= 9.0 Hz), 4.23 (q, 2H, J= 7.0 Hz), 3.62-3.54 (m, 8H), 3.29 (S1 2H), 2.73-2.71 (m, 4H), 1.71 (m, 6H), 1.31 (t, 3H, J= 7.0 Hz); LCMS (ESI) [M+1]+ 527.3.
Example 214 4-[5-[[[2-(1 -Piperidinyl)-4-(trif luoromethyl)-5- thiazolyl]carbonyl]amino]-2-pyridinyl]-1 -piperazineacteic acid (214)
Figure imgf000269_0001
Compound 214 was prepared by the general procedure for compound 146. 1H
NMR (500 MHz, (CDg)2CO) δ 10.37 (s, 1 H), 8.31 (S1 1 H), 7.79-7.77 (m, I H),
6.85 (d, 1H, J= 9.0 Hz), 3.49-3.46 (m, 8H), 3.16 (s, 2H), 2.65-2.63 (m, 4H),
1.63 (m, 6H); LCMS (ESI) [M+1]+ 499.3.
Example 215 methyl 2-((1 r,4r)-4-(4-(2-(4-phenylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)phenyl)cyclohexyl)acetate (215)
Figure imgf000269_0002
Compound 215 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 7.70 (s, 1 H), 7.54 (d, 2H, J= 8.5 Hz), 7.34 (t, 2H, J = 7.0 Hz), 7.24-7.30 (m, 3H), 7.20 (d, 2H, J = 8.5 Hz), 4.37 (d, 2H, J = 11.0 Hz), 4.16 (m, 1 H), 3.70 (s, 3H), 3.22 (t, 2H, J = 13.0 Hz), 2.80 (m, 2H), 2.48 (m, 2H), 2.27 (d, 2H, J = 6.5 Hz), 1.79-2.03 (m, 6H), 1.49(q, 2H, J = 12.5 Hz), 1.16 (q, 2H, J= 12.5 Hz); MS (M+1): 556.3 Example 216
2-((1r,4r)-4-(4-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)phenyl)cyclohexyl)acetic acid (216)
Figure imgf000269_0003
Compound 216 was prepared by the general procedure for compound 146. 1H MMR (500 MHz, DMSO-J6) δ 10.09 (s, 1H), 7.58 (d, 2H, J = 8.0 Hz), 7.29-7.34 (m, 5H), 7.20 (d, 2H, J = 8.5 Hz), 4.35 (d, 2H, J = 12.5 Hz), 3.21 (t, 2H, J =
12.5 Hz), 2.81 (t, 1 H, J = 12.0 Hz), 2.49 (t, 1 H, J = 12.0 Hz), 2.14 (d, 2H, J =
7.0 Hz), 1.71-1.90 (m, 9H), 1.45(q, 2H, J= 12.0 Hz)1 1.12 (q, 2H, J= 12.0 Hz);
MS (M+1): 590.2
Example 217 methyl 2-((1 r,4r)-4-(4-(2-(3-methylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)phenyl)cyclohexyl)acetate (217)
Figure imgf000270_0001
Compound 217 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-cfe) δ 10.03 (s, 1 H), 7.57 (d, 2H, J = 7.0 Hz), 7.22 (d,
2H, J = 7.5 Hz), 4.08 (dd, 2H, J = 25.0, 12.5 Hz), 3.60 (s, 3H), 3.38(m, 2H),
3.05 (d, 2H, J = 12.0 Hz), 2.75 (t, 2H, J = 12.0 Hz), 2.48 (m, 2H), 2.25 (d, 2H,
J = 6.5 Hz), 1.65-1.80 (m, 4H), 1.42-1.54(m, 3H), 1.14 (m, 2H), 0.93(d, 3H, J
= 6.5 Hz); MS (M+1): 508.3 Example 218
2-((1 r,4r)-4-(4-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)phenyl)cyclohexyl)acetic acid (218)
Figure imgf000270_0002
Compound 218 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 1 H), 10.05 (s, 1 H), 7.55 (d, 2H, J= 9.0 Hz), 7.22 (d, 2H, J= 8.5 Hz), 4.08 (dd, 2H, J= 25.0, 12.5 Hz), 3.38(m, 2H), 3.05 (d, 2H, J= 11.0 Hz), 2.74 (t, 2H, J= 11.0 Hz), 2.47 (m, 2H), 2.14 (d, 2H, J= 7.0 Hz), 1.64-1.80 (m, 4H), 1.41-1.57(m, 3H), 1.08-1.17 (m, 2H), 0.93(d, 3H, J= 6.5 Hz); MS (M+1): 494.3 Example 219
ΛA-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (219)
Figure imgf000271_0001
Compound 219 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1 H), 8.83 (d, 1 H, J = 2.5 Hz), 8.40 (br d, 2H, J = 1 1.8 Hz), 7.89 (dd, 1 H, J= 2.2, 9.3 Hz), 7.48-7.42 (m, 1 H), 7.34- 7.26 (m, 4H), 7.24-7.17 (m, 2H), 7.15-7.10 (m, 2H), 6.94 (d, 1 H, J = 8.8 Hz), 4.90-4.82 (m, 2H), 3.57 (br s, 4H), 3.51 (br s, 4H), 3.13 (t, 2H, J = 12.1 Hz), 2.90 (br t, 1 H, J= 12.0 Hz), 1.92 (d, 2H1 J= 12.5 Hz), 1.61 (dq, 2H, J = 3.0, 12.0 Hz). MS (M+1): 649.4. Example 220
2-(cyclopentyl(methyl)amino)-Λ/-(6-(4-(2-fluorophenylcarbamoyl)piperazin-i - yl)pyridin-3-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (220)
Figure imgf000271_0002
Compound 220 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1 H), 8.80 (s, 1 H), 8.41 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.87 (dd, 1 H, J = 2.9, 9.0 Hz), 6.93 (d, 1 H, J = 8.7 Hz), 3.57 (br s, 4H), 3.60-3.55 (m, 4H), 3.54-3.49 (m, 4H), 3.18 (d, 1 H, J= 5.2 Hz), 3.06 (s, 3H), 1.89-1.80 (m, 2H, 1.78-1.71 (m, 2H, 1.70-1.57 (m, 4H). MS (M+1 ): 587.4. Example 221
2-(cyclopentylthio)-Λ/-(6-(4-(2-flijorophenylcarbamoyl)piperazin-1 -yl)pyridin-3- yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (221 )
Figure imgf000272_0001
Compound 221 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1 H), 9.17 (s, 1 H), 8.42 (s, 1 H), 8.37 (d, 1 H, J = 2.7 Hz), 7.88 (dd, 1 H, J= 2.5, 8.8 Hz), 7.47-7.43 (m, 1 H), 7.23-7.17 (m, 1 H), 7.15-7.11 (m, 2H), 6.96 (d, 1 H1 J = 9.3 Hz), 4.06-4.00 (m, 1 H), 3.59- 3.55 (m, 4H), 3.55-3.51 (m, 4H), 2.28-2.19 (m, 2H), 1.79-1.70 (m, 2H), 1.70- 1.57 (m, 4H). MS (M+1): 590.3. Example 222 methyl 4-(6-(2-(3-methylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-3-yl)benzoate (222)
Figure imgf000272_0002
Compound 222 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.61 (m, 2H), 8.49 (d, 1 H, J = 8.8 Hz), 8.16 (m, 2H), 8.03 (dd, 1 H, J = 2.5, 8.8 Hz), 7.68 (m, 2H), 4.17 (m, 2H), 3.98 (s, 3H), 3.08 (m, 1 H), 2.75 (m, 1 H), 1.85 (m, 2H), 1.65 (m, 2H), 1.20 (m, 1 H), 1.02 (d, 3H, J= 6.6 Hz). MS (M+1 ): 489.3 Example 223 methyl 6'-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)-3,3'-bipyridine-6-carboxylate (223)
Figure imgf000273_0001
Compound 223 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.99 (s, 1 H), 8.61 (s, 1 H), 8.53 (m, 2H), 8.27 (d, 1 H, J = 8.2 Hz), 8.04 (m, 2H), 4.14 (m, 2H), 4.07 (s, 3H), 3.05 (m, 1 H), 2.72 (m, 1 H), 1.76 (m, 4H), 1.24 (m, 1 H), 1.02 (d, 3H, J= 6.6 Hz). MS (M+1): 490.3
Example 224
4-(6-(2-(3-methylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-3-yl)benzoic acid (224)
Figure imgf000273_0002
Compound 224 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 13.01 (S1 1 H), 11.05 (s, 1 H), 8.82 (s, 1 H), 8.25 (m, 2H), 8.05 (d. 2H, J = 8.5 Hz), 7.91 (d, 2H, J = 8.5 Hz), 4.18 (m, 2H), 3.05 (m, 1 H), 2.75 (m, 1 H), 1.73 (m, 3H), 1.53 (m, 1 H), 1.16 (m, 1 H), 0.95 (d, 3H, J= 6.6 Hz). MS (M+1 ): 475.3 Example 225
N-(5-(4-(2-fluorophenylcarbamoyl)phenyl)pyridin-2-yl)-2-(3-methylpiperidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (225)
Figure imgf000273_0003
Compound 225 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 10.25(s, 1 H), 8.72 (d, 1 H, J = 9.1 Hz), 8.56 (s, 1H), 8.51 (m, 1 H), 8.20 (m, 1H), 8.13 (s, 1 H), 8.05 (d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 8.5 Hz), 7.19 (m, 3H), 4.26 (m, 2H), 3.09 (m, 1 H), 2.77 (m, 1 H), 1.77 (m, 4H), 1.22 (m, 1 H), 1.01 (d, 3H, J = 6.6 Hz). MS (M+1): 568.3 Example 226 methyl 5-(4-(2-(3-methylpiperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamido)phenyl)picolinate (226)
Figure imgf000274_0001
Compound 226 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 5 9.10 (s, 1 H), 8.29 (d, 1 H, J = 8.2 Hz), 8.20 (m, 1 H), 7.84 (s, 1 H), 7.81 (d, 2H, J = 8.5 Hz), 7.68 (d, 2H, J = 8.5 Hz), 4.14 (m, 2H), 3.09 (m, 1 H), 2.75 (m, 1 H), 1.80 (m, 4H), 1.22 (m, 1 H), 1.02 (d, 3H, J = 6.6 Hz). MS (M+1): 489.3
Example 227 2-(3-methylpiperidin-1 -yl)-N-(5-(4-(o- tolylcarbamoyl)phenyl)pyridin-2-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (227)
Figure imgf000274_0002
Compound 227 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 10.90 (s, 1 H), 8.81 (d, 1 H, J = 8.8 Hz), 8.54 (s, 1 H), 8.26 (d, 1 H, J = 9.1 Hz), 8.05 (d, 2H, J = 7.9 Hz), 7.98 (d, 1 H, J = 7.6 Hz), 7.74 (m, 3H), 7.30 (m, 2H), 7.18 (t, 1 H, J = 7.6 Hz), 4.32 (m, 2H), 3.09 (m, 1 H), 2.78 (m, 1 H), 2.40 (s, 3H), 1.84 (m, 3H), 1.65 (m, 1 H), 1.22 (m, 1 H), 1.01 (d, 3H, J = 6.6 Hz). MS (M+1): 564.3
Example 228 6'-(2-(3-methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)-3,3'-bipyridine-6-carboxylic acid (228)
Figure imgf000275_0001
Compound 228 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) 611.11 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H), 8.36 (m, 2H), 8.26 (d.1H, J = 8.5 Hz), 8.14 (d, 1H, J = 8.2 Hz), 4.18 (m, 2H), 3.04 (m, 1H), 2.74 (m, 1H), 1.73 (m, 3H), 1.53 (m, 1H), 1.16 (m, 1H), 0.95 (d, 3H, J = 6.6 Hz). MS (M+1): 476.3
Example 2295-(4-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)phenyl)picolinic acid (229)
Figure imgf000275_0002
Compound 229 was prepared by the general procedure for compound 146.
1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.06 (s, 1H), 8.29 (d, 1H, J =
8.2 Hz), 8.11 (d, 1 H, J = 8.2 Hz), 7.88 (m, 4H), 4.12 (m, 2H), 3.04 (m, 1 H),
2.74 (m, 1H), 1.65 (m, 4H), 1.16 (m, 1H), 0.95 (d, 3H, J= 6.6 Hz). MS (M+1):
475.3
Example 230 N-(6'-(2-fluorophenylcarbamoyl)-3,3'-bipyridin-6-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (230)
Figure imgf000275_0003
Compound 230 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 10.34 (s, 1H), 8.90 (s, 1H), 8.63 (m, 2H), 8.54 (d, 1H, J = 8.8 Hz), 8.50 (s, 1H), 8.41 (d, 1H, J = 7.9 Hz), 8.13 (m, 1H), 8.05 (m, 1 H), 7.18 (m, 2H), 4.16 (m, 2H), 3.09 (m, 1 H), 2.77 (m, 1 H), 1.77 (m, 4H)1 1.22 (m, 1 H), 1.01 (d, 3H, J= 6.6 Hz). MS (M+1 ): 569.3 Example 231 N-(4-(6-(2-fluorophenylcarbamoyl)pyridin-3-yl)phenyl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (231)
Figure imgf000276_0001
Compound 231 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) 5 8.89 (s, 1 H), 8.63 (m, 1 H), 8.36 (d, 1 H, J = 8.2 Hz), 8.1 1 (m, 1 H), 7.82 (d, 1 H, J = 8.8 Hz), 7.77 (s, 1 H), 7.68 (d, 2H, J = 8.5 Hz), 7.18 (m, 3H), 4.16 (m, 2H), 3.09 (m, 1 H), 2.77 (m, 1 H), 1.77 (m, 4H), 1.22 (m, 1 H), 1.01 (d, 3H, J = 6.6 Hz). MS (M+1): 568.3 Example 232 2-(3-methylpiperidin-1-yl)-N-(4-(6-(o-tolylcarbamoyl)pyridin-3- yl)phenyl)-4-(trifluoromethyl)oxazole-5-carboxamide (232)
Figure imgf000276_0002
Compound 232 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) 5 10.1 1 (s, 1 H), 8.87 (s, 1 H), 8.38 (d, 1 H1 J = 8.2 Hz), 8.33 (d, 1 H1 J = 7.9 Hz), 8.1 1 (m, 1 H), 7.82 (d, 2H, J = 8.8 Hz), 7.80 (s, 1 H), 7.67 (d, 2H, J = 8.5 Hz), 7.30 (m, 2H), 7.12 (t, 1 H, J = 7.2 Hz), 4.14 (m, 2H), 3.09 (m, 1 H), 2.75 (m, 1 H), 2.47 (s, 3H), 1.84 (m, 3H), 1.65 (m, 1 H), 1.22 (m, 1 H), 1.02 (d, 3H, J = 6.6 Hz). MS (M+1 ): 564.3
Example 233 2-(3-methylpiperidin-1 -yl)-N-(6'-(o-tolylcarbamoyl)-3,31- bipyridin-6-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (233)
Figure imgf000277_0001
Compound 233 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 10.09 (s, 1 H), 8.88 (s, 1 H), 8.63 (s, 1 H), 8.55 (d, 1 H, J = 8.8 Hz), 8.53 (s, 1 H), 8.43 (d, 1 H1 J = 8.8 Hz), 8.33 (d, 1 H, J = 8.2 Hz), 8.14 (m, 1 H), 8.05 (m, I H), 7.31 (m, 2H), 7.12 (m, 1 H), 4.17 (m, 2H), 3.09 (m, 1 H), 2.75 (m, 1 H), 2.47 (s, 3H), 1.84 (m, 3H), 1.65 (m, 1 H), 1.22 (m, 1 H), 1.03 (d, 3H, J = 6.6 Hz). MS (M+1): 565.3 Example 234 methyl 4-(6-(2-(4-phenylpiperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamido)pyridin-3-yl)benzoate (234)
Figure imgf000277_0002
Compound 234 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.59 (s, 1 H), 8.54 (s, 1 H), 8.48 (d, 1 H, J = 8.8 Hz), 8.16 (s, 2H, J = 7.9 Hz), 8.03 (m, 1 H), 7.68 (d, 2H, J = 8.5 Hz), 7.37 (t, 2H, J = 7.6 Hz), 7.27 (m, 3H), 4.44 (m, 2H), 3.98 (s, 3H), 3.26 (m, 2H), 2.82 (m, 1 H), 2.05 (m, 2H), 1.85 (m, 2H). MS (M+1): 551.3 Example 235 2-(4-phenylpiperidin-1 -yl)-N-(5-(4-(o- tolylcarbamoyl)phenyl)pyridin-2-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (235)
Figure imgf000277_0003
Compound 235 was prepared by the general procedure for compound 147. 1H NMR (500 MHz, CDCI3) δ 8.61 (d, 1 H, J = 2.2 Hz), 8.57 (s, 1H), 8.49 (d, 1 H, J = 8.5 Hz), 8.03 (m, 4H), 7.74 (m, 3H), 7.37 (t, 2H, J = 7.6 Hz), 7.29 (m, 4H), 7.17 (m, 1 H), 4.44 (m, 2H), 3.26 (m, 2H), 2.82 (m, 1 H), 2.39 (s, 3H), 2.05 (m, 2H), 1.85 (m, 2H). MS (M+1): 626.3
Example 236 N-(5-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)pyridin-2-yl)-2- (3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (236)
Figure imgf000278_0001
Compound 236 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.42 (s, 1 H), 8.30 (d, 1 H, J = 9.1 Hz), 8.11 (m, 1 H), 8.00 (d, 1 H, J = 2.8 Hz), 7.36 (m, 1 H), 7.15 (t, 1 H, J = 7.6 Hz), 7.10 (m, 1 H), 7.02 (m, 1 H), 7.67 (d, 1 H, J = 3.8 Hz), 4.14 (m, 2H), 3.74 (m, 4H), 3.28 (m, 4H), 3.05 (m, 1 H), 2.72 (m, 1 H), 1.76 (m, 4H), 1.18 (m, 1 H), 1.01 (d, 3H, J = 6.6 Hz). MS (M+1): 576.3
Example 237 N-(5-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)pyridin-2-yl)-2- (4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (237)
Figure imgf000278_0002
Compound 237 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.75 (s, 1 H), 8.33 (d, 1 H1 J = 8.2 Hz), 8.1 1 (t, 1 H, J = 8.2 Hz), 7.97 (s, 1 H), 7.37 (m, 3H), 7.26 (m, 3H), 7.12 (m, 2H), 7.03 (m, 1 H), 6.67 (d, 1 H, J = 3.5 Hz), 4.44 (m, 2H), 3.74 (m, 4H), 3.28 (m, 4H), 3.23 (m, 2H), 2.80 (m, 1 H), 2.02 (m, 2H), 1.84 (m, 2H). MS (M+1): 638.4 Example 238 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- (piperidin-1 -ylmethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (238)
Figure imgf000279_0001
Compound 238 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.50 (s, 1 H), 7.97 (m, 1 H), 7.49 (m, 1 H), 7.16 (m, 4H), 4.81 (s, 2H), 3.75 (m, 8H), 3.64 (br s, 2H), 3.20 (br s, 2H), 1.90 (m, 6H). MS (M+1): 592.3
Example 239 methyl 4-(6-(2-(piperidin-1 -ylmethyl)-4-(trifluoromethyl)thiazole- 5-carboxamido)pyridin-3-yl)benzoate (239)
Figure imgf000279_0002
Compound 239 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.58 (s, 1 H), 8.35 (d, 1 H, J = 8.8 Hz), 8.16 (d, 2H, J = 8.2 Hz), 8.05 (m, 1 H), 7.67 (d, 2H, J = 8.2 Hz), 4.38 (s, 2H), 3.97 (s, 3H), 3.17 (br s, 4H), 1.92 (m, 6H). MS (M+1): 505.3
Example 240 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- (morpholinomethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (240)
Figure imgf000279_0003
Compound 240 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.27 (d, 1 H, J = 2.5 Hz), 8.11 (m, 1 H), 7.93 (m, 1 H), 7.67 (s, 1 H), 7.14 (t, 1 H, J = 7.9 Hz), 7.09 (m, 1 H), 7.02 (m, 1 H), 6.72 (d, 1 H, J = 9.1 Hz), 6.65 (d, 1 H, J = 3.5 Hz), 3.87 (s, 2H), 3.79 (m, 4H), 3.71 (m, 8H), 2.70 (m, 4H). MS (M+1 ): 594.3 Example 241 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- ((phenylamino)methyl)-4-(triliuoromethyl)thiazole-5-carboxamide (241)
Figure imgf000280_0001
Compound 241 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.23 (s, 1 H), 8.11 (t, 1 H, J = 8.2 Hz), 7.89 (m, 1 H), 7.67 (s, 1 H), 7.24 (t, 1 H1 J = 7.6 Hz), 7.1 1 (m, 2H), 7.02 (m, 1 H), 6.85 (t, 1 H, J = 8.5 Hz), 6.67 (m, 4H), 4.70 (s, 2H), 3.69 (m, 8H). MS (M+1): 600.3 Example 242 2-(3-methylpiperidin-1-yl)-N-(4-(5-(o-tolylcarbamoyl)pyridin-2- yl)phenyl)-4-(trifluoromethyl)oxazole-5-carboxamide (242)
Figure imgf000280_0002
Compound 242 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 5 9.29 (s, 1 H), 8.51 (s, 1 H), 8.10 (s, 1 H), 8.05 (d, 2H, J = 8.5 Hz), 7.98 (d, 1 H, J = 8.2 Hz), 7.94 (s, 1 H), 7.85 (m, 3H), 7.29 (m, 2H), 7.21 (m, 1 H), 4.14 (m, 2H), 3.08 (m, 1 H), 2.75 (m, 1 H), 2.36 (s, 3H), 1.82 (m, 4H), 1.22 (m, 1 H), 1.01 (d, 3H, J = 6.6 Hz). MS (M+1): 564.3 Example 243 tert-butyl (5-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 - yl)pyridin-3-ylcarbamoyl)-4-(trifluoromethyl)thiazol-2- yl)methyl(propyl)carbamate (243)
Figure imgf000280_0003
Compound 243 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.89 (s, 1 H), 8.51 (m, 2H), 7.89 (t, 1 H, J = 7.3 Hz), 7.04 (m, 5H), 4.67 (s, 2H), 3.80 (br s, 8H), 3.27 (t, 2H, J = 7.3 Hz), 1.59 (m, 2H), 1.48 (s, 9H), 0.89 (t, 3H, J = 7.3 Hz). MS (M+1): 666.4 Example 244 2-(piperidin-1 -ylmethyl)-N-(5-(4-(o- tolylcarbamoyl)phenyl)pyridin-2-yl)-4-(trifluoromethyl)thiazole-5-carboxamide (244)
Figure imgf000281_0001
Compound 244 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.67 (d, 1 H, J = 8.8 Hz), 8.57 (s, 1 H), 8.31 (m, 1 H), 8.07 (d, 2H, J = 7.9 Hz), 7.96 (s, 1 H), 7.75 (m, 3H), 7.30 (m, 3H), 7.19 (t, 1 H, J = 7.6 Hz), 4.66 (s, 2H), 3.30 (br s, 4H), 2.40 (s, 3H), 2.00 (m, 6H). MS (M+1): 580.3
Example 245 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- ((propylamino)methyl)-4-(trifluoromethyl)thiazole-5-carboxamide (245)
Figure imgf000281_0002
Compound 245 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.41 (d, 1 H1 J = 2.5 Hz), 7.92 (m, 1 H), 7.49 (m, 1 H), 7.16 (m, 3H), 6.96 (t, 1 H, J = 9.1 Hz), 4.74 (s, 2H), 3.68 (m, 8H), 3.15 (m, 2H), 1.81 (m, 2H), 1.08 (t, 3H, J = 7.6 Hz). MS (M+1): 566.3 Example 246 N-(6-(4-(2-lϊuorophenylcarbamoyl)piperazin-1 -yl)pyridin-3-yl)-2- ((N-propylacetamido)methyl)-4-(trifluoromethyl)thiazole-5-carboxamide (246)
Figure imgf000282_0001
Compound 246 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 10.38 (s, 1 H), 8.51 (m, 2H), 7.78 (m, 1 H), 7.24 (S1 1 H), 7.08 (m, 4H), 4.75 (s, 2H), 3.82 (br S, 8H), 3.37 (t, 2H, J = 7.9 Hz), 2.14 (s, 3H), 1.66 (m, 2H), 0.93 (t, 3H, J = 7.3 Hz). MS (M+1): 608.3 Example 247 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- ((methyl(phenyl)amino)methyl)-4-(trifluoromethyl)thiazole-5-carboxamide (247)
Figure imgf000282_0002
Compound 247 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.29 (s, 1 H), 8.05 (t, 1 H, J = 8.2 Hz), 8.00 (m, 1 H), 7.92 (s, 1 H), 7.30 (m, 2H), 7.12 (m, 2H), 7.02 (m, 1 H), 6.87 (t, 1 H, J = 7.3 Hz), 6.81 (m, 2H), 6.73 (d, 1 H, J = 9.5 Hz), 6.65 (d, 1 H, J = 3.5 Hz), 4.77 (s, 2H), 3.71 (br s, 8H), 3.15 (s, 3H). MS (M+1): 614.3 Example 248 N-(6-(4-(2-f luorophenylcarbamoyl)piperazin-1 -yl)pyridin-3-yl)-2- ((N-methylbenzamido)methyl)-4-(trifluoromethyl)thiazole-5-carboxamide (248)
Figure imgf000282_0003
Compound 248 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.68 (s, 1 H), 8.31 (s, 1 H), 8.17 (d, 1 H, J = 9.1 Hz), 8.03 (t, 1 H, J = 7.9 Hz), 7.47 (m, 5H), 7.11 (m, 2H), 7.02 (m, 1 H), 6.81 (m, 2H), 4.98 (s, 2H), 3.73 (br s, 8H), 3.15 (s, 3H). MS (M+1): 642.4 Example 249 (1 s,4s)-4-(4-(6-(2-(3-methylpiperidin-1 -yl)-4- (trifluoromethyl)oxazole-5-carboxamido)pyridin-3-yl)piperazine-1- carbonyl)cyclohexanecarboxylic acid (249)
Figure imgf000283_0001
Compound 249 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, CD3OD-d4) δ 7.96 (m, 2H), 7.84 (d, 1 H, J = 9.1 Hz), 4.23 (m, 2H), 3.79 (m, 4H), 3.32 (m, 4H), 3.15 (m, 1 H), 2.81 (m, 2H), 2.65 (m, 1 H), 2.21 (m, 2H), 1.78 (m, 10H), 1.26 (m, 1 H), 1.02 (d, 3H, J= 6.6 Hz). MS (M+1): 593.3
Example 250 2-((methyl(phenyl)amino)methyl)-N-(5-(4-(o- tolylcarbamoyOphenylJpyridin^-yO^-^rifluoromethyOthiazole-δ-carboxamide (250)
Figure imgf000283_0002
Compound 250 was prepared by the general procedure for compound 111. 1H MMR (500 MHz, CDCI3) δ 8.64 (d, 1 H, J = 8.2 Hz), 8.55 (s, 1 H), 8.26 (m, 1 H), 8.05 (d, 1 H, J = 7.9 Hz), 7.97 (s, 1 H), 7.73 (m, 3H), 7.31 (m, 5H), 7.18 (t, 1 H, J = 7.9 Hz), 6.89 (t, 1 H, J = 7.3 Hz), 6.85 (d, 2H, J = 8.8 Hz), 4.82 (s, 2H), 3.17 (s, 3H), 2.39 (s, 3H). MS (M+1): 602.3
Example 251 1 -(6-(4-(2-(3-methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5- carboxamido)phenyl)nicotinoyl)piperidine-4-carboxylic acid (251 )
Figure imgf000284_0001
Compound 251 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, CD3OD-d4) δ 8.73 (s, 1 H), 8.08 (m, 4H), 7.89 (d, 2H, J = 9.1 Hz), 4.51 (m, 1 H), 4.22 (m, 2H), 3.79 (m, 1 H), 3.14 (m, 3H), 2.79 (m, 1 H), 2.70 (m, 1 H), 1.86 (m, 8H), 1.26 (m, 1 H), 1.02 (d, 3H, J= 6.6 Hz). MS (M+1): 586.3
Example 252 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)pyridin-3-yl)-2- (phenoxymethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (252)
Figure imgf000284_0002
Compound 252 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.62 (d, 1 H, J = 2.2 Hz), 8.03 (m, 1 H), 7.50 (m, I H), 7.36 (m, 3H), 7.16 (m, 3H), 7.09 (m, 3H), 5.50 (s, 2H), 3.81 (s, 8H). MS (M+1 ): 601.3
Example 253 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- (phenylthiomethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (253)
Figure imgf000284_0003
Compound 253 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.56 (d, 1 H, J = 2.5 Hz), 7.98 (m, 1 H), 7.47 (m, 3H), 7.36 (m, 2H), 7.28 (m, 2H), 7.16 (m, 3H), 4.59 (s, 2H), 3.78 (s, 8H). MS (M+1): 617.3 Example 254 2-(phenylthiomethyl)-N-(5-(4-(o-tolylcarbamoyl)phenyl)pyridin- 2-yl)-4-(trilluoromethyl)thiazole-5-carboxamide (254)
Figure imgf000285_0001
Compound 220 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.72 (s, I H), 8.23 (m, 1 H), 8.12 (d, 2H, J = 8.2 Hz), 7.86 (d, 2H, J = 8.2 Hz), 7.46 (m, 2H), 7.3 (m, 8H), 4.59 (s, 2H), 2.35 (S, 3H). MS (M+1 ): 605.3 Example 255
2-(4,4-dimethylpiperidin-1-yl)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 - yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (255)
Figure imgf000285_0002
Compound 255 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J = 9 Hz), 7.45 (m, 1 H), 7.20 (m, 1 H), 7.12 (m, 2H), 6.93 (d, 1 H, J = 9.5 Hz), 3.63 (m, 4H), 3.56 (m, 4H), 3.54 (m, 4H), 1.43 (m, 4H), 1.00 (s, 6H). MS (M+1): 590.2 Example 256
(R)-N-(6-(1-(2-fluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (256)
Figure imgf000285_0003
Compound 256 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (broad s, 1 H), 8.28 (s, 1 H), 7.95 (s, 1 H), 7.83 (broad s, 1 H), 7.52 (m, 1 H), 7.30 (m, 4H), 7.22 (m, 2H), 7.10 (m, 2H), 6.78 (broad s, 1 H), 4.35 (d, 2H, J = 12 Hz), 3.75 (m, 1 H), 3.55 (m, 2H), 3.35 (m, 2H), 3.23 (t, 2H, J= 12.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 2.23 (m, 1 H), 1.95 (broad s, 1 H), 1.90 (d, 2H, J= 12 Hz), 1.75 (q, 2H, J = 12 Hz). MS (M+1): 638.4
Example 257
(S)-N-(6-(1 -(2-lluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (257)
Figure imgf000286_0001
Compound 257 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (broad s, 1 H), 8.28 (s, 1 H), 7.95 (s, 1 H), 7.83 (broad s, 1 H), 7.53 (m, 1 H), 7.30 (m, 4H), 7.22 (m, 2H), 7.12 (m, 2H), 6.80 (broad s, 1 H), 4.35 (d, 2H, J= 13.5 Hz), 3.75 (m, 1 H), 3.55 (m, 2H), 3.35 (m, 2H), 3.23 (t, 2H, J= 13 Hz), 2.82 (t, 1 H, J= 12 Hz), 2.25 (m, 1 H), 1.95 (m, 1 H), 1.90 (d, 2H, J = 1 1.5 Hz), 1.75 (q, 2H, J = 9 Hz). MS (M+1 ): 638.4
Example 258
(R)-N-(6-(1-(2-fluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trilluoromethyl)thiazole-5-carboxamide (258)
Figure imgf000286_0002
Compound 258 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1 H), 8.22 (s, 1 H), 7.88 (s, 1 H), 7.65 (d, 1H, J= 9.5 Hz), 7.53 (m, 1H), 7.30 (m, 4H), 7.22 (t, 1H, J= 7.5 Hz), 7.18 (m, 1 H), 7.10 (m, 2H), 6.88 (broad s, 1 H), 6.55 (d, 1 H, J = 8 Hz), 4.37 (broad s, 1 H), 4.03 (d, 2H, J= 12 Hz), 3.73 (broad s, 1 H), 3.55 (t, 1 H, J= 9 Hz), 3.48 (m, 1 H), 3.27 (m, 3H), 2.83 (t, 1 H, J= 11.5 Hz), 2.17 (m, 1 H), 1.90 (m, 3H), 1.73 (q, 2H, J= 12.5 Hz). MS (M+1): 654.4 Example 259
(S)-N-(6-(1-(2-fluorophenylcarbamoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxamide (259)
Figure imgf000287_0001
Compound 259 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1 H), 8.23 (s, 1 H), 7.90 (s, 1 H), 7.67 (d, 1 H, J= 7 Hz), 7.53 (m, 1 H), 7.30 (m, 4H), 7.22 (t, 1H, J= 7 Hz), 7.18 (m, 1 H), 7.10 (m, 2H), 6.95 (broad s, 1 H), 6.60 (broad s, 1H), 4.37 (broad s, 1 H), 4.03 (d, 2H, J= 12 Hz), 3.72 (broad s, 1 H), 3.55 (t, 1 H, J= 9 Hz), 3.50 (m, 1 H), 3.30 (m, 3H), 2.83 (t, 1 H, J= 12 Hz), 2.18 (m, 1 H), 1.90 (m, 3H), 1.73 (q, 2H, J= 12.5 Hz). MS (M+1): 654.3 Example 260
N-(6-((S)-1-(2-fluorobenzoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (260)
Figure imgf000287_0002
Compound 260 was prepared by the general procedure for compound 111. 1 :1 rotamers 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1/2H), 9.92 (s, 1/2H), 8.22 (s, 1/2H), 8.10 (s, 1/2H), 7.67 (d, 1/2H, J = 8.5 Hz), 7.62 (d, 1/2H, J = 8.5 Hz), 7.45 (m, 2H), 7.28 (m, 2H), 6.90 (broad s, 1 H), 6.58 (d, 1/2H, J= 9 Hz), 6.53 (d, 1/2H, J= 9 Hz), 4.40 (m, 1/2H), 4.32 (m, 1/2H), 4.07 (m, 2H), 3.83 (m, 1/2H), 3.70 (m, 1/2H), 3.60 (m, 2H), 3.37 (m, 2H), 3.13 (m, 1 H), 3.03 (m, 1 H), 2.23 (m, 1/2H), 2.17 (m, 1/2H), 1.93 (m, 1/2H), 1.88 (m, 1/2H), 1.75 (m, 2H), 1.65 (broad s, 1 H), 1.52 (broad s, 1 H), 1.27 (d, 1 1/2H, J = 7 Hz), 1.25 (d, 1 1/2H, J= 7 Hz). MS (M+1): 561.3 Example 261
N-(6-((R)-1-(2-fluorobenzoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (261)
Figure imgf000288_0001
Compound 261 was prepared by the general procedure for compound 111. 1 :1 rotamers 1H MMR (500 MHz, DMSO-d6) δ 9.98 (s, 1/2H), 9.92 (s, 1/2H),
8.22 (S, 1/2H), 8.10 (s, 1/2H), 7.67 (d, 1/2H, J = 8 Hz), 7.62 (d, 1/2H, J= 9 Hz), 7.45 (m, 2H), 7.27 (m, 2H), 6.90 (broad s, 1 H), 6.58 (d, 1/2H, J= 9 Hz), 6.52 (d, 1/2H, J= 8 Hz), 4.40 (m, 1/2H), 4.32 (m, 1/2H), 4.07 (m, 2H), 3.83 (m, 1/2H), 3.70 (m, 1/2H), 3.60 (m, 2H), 3.38 (m, 2H), 3.13 (m, 1 H), 3.03 (m, 1 H),
2.23 (m, 1/2H), 2.17 (m, 1/2H), 1.93 (m, 1/2H), 1.88 (m, 1/2H), 1.75 (m, 2H), 1.65 (broad s, 1 H), 1.52 (broad s, 1 H), 1.27 (d, 1 1/2H, J= 7 Hz), 1.25 (d, 1 1/2H, J= 6.5 Hz). MS (M+1 ): 561.2
Example 262
(R)-N-(6-(1-(2-fluorophenylcarbamoyl)pyrrolidin-3-yloxy)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (262)
Figure imgf000288_0002
Compound 262 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1 H), 8.44 (s, 1 H), 7.97 (s, 2H), 7.52 (m, 1 H), 7.30 (m, 4H), 7.20 (m, 2H), 7.10 (m, 2H), 6.90 (d, 1 H, J= 9 Hz), 5.55 (s, 1 H), 4.35 (d, 2H, J = 13 Hz), 3.75 (d, 1 H, J= 11 Hz), 3.60 (t, 2H, J= 12.5 Hz), 3.50 (q, 1 H, J = 8 Hz), 3.23 (t, 2H, J= 12 Hz), 2.82 (t, 1 H, J= 12 Hz), 2.25 (m, 1 H), 2.15 (m, 1 H), 1.90 (d, 2H, J= 12 Hz), 1.75 (q, 2H, J= 12.5 Hz). MS (M+1): 639.2 Example 263 N-(6-((R)-1-(2-fluorophenylcarbamoyl)pyrrolidin-3-yloxy)pyridin-3-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (263)
Figure imgf000289_0001
Compound 263 was prepared by the general procedure for compound 111. 1H MMR (500 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.43 (S, 1H), 7.97 (s, 1H), 7.95 (m, 1H), 7.52 (m, 1H), 7.18 (m, 1H), 7.10 (m, 2H), 6.89 (d, 1H, J= 8.5 Hz), 5.55 (s, 1 H), 4.12 (d, 1 H, J= 12 Hz), 4.07 (d, 1 H, J= 10.5 Hz), 3.75 (m, 1 H), 3.60 (t, 2H1 J= 11.5 Hz), 3.50 (m, 1H), 3.06 (t, 1 H, J= 10.5 Hz), 2.75 (t, 1 H1 J = 12.5 Hz), 2.25 (m, 1 H), 2.15 (m, 1 H), 1.77 (m, 2H), 1.67 (m, 1 H), 1.54 (m, 1H), 1.15 (m, 1H), 0.93 (d, 3H, J= 6.5 Hz). MS (M+1): 577.2 Example 264
(S)-N-(6-(1-(2-fluorophenylcarbamoyl)pyrrolidin-3-yloxy)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (264)
Figure imgf000289_0002
Compound 264 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.44 (s, 1H), 8.17 (broad s, 1 H), 7.97 (s, 2H), 7.52 (m, 1 H), 7.31 (m, 3H), 7.20 (m, 2H), 7.10 (m, 2H), 6.90 (d, 1 H, J= 9 Hz), 5.55 (s, 1 H), 4.35 (m, 2H), 3.75 (d, 1 H, J= 12 Hz), 3.52 (q, 1 H, J= 7.5 Hz), 3.23 (t, 2H, J= 13 Hz), 3.15 (m, 2H), 2.82 (t, 1 H, J= 12.5 Hz), 2.25 (m, 1H), 2.14 (m, 1 H), 1.90 (d, 2H, J = 12.5 Hz), 1.75 (q, 2H, J= 12 Hz). MS (M+1): 639.3 Example 265
N-(6-((S)-1-(2-fluorophenylcarbamoyl)pyrrolidin-3-yloxy)pyridin-3-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (265)
Figure imgf000290_0001
Compound 265 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.95 (m, 1H), 7.52 (m, 1 H), 7.18 (m, 1H), 7.11 (m, 2H), 6.89 (d, 1 H, J= 8.5 Hz), 5.55 (s, 1H), 4.12 (d, 1 H, J= 13 Hz), 4.07 (d, 1H, J= 11 Hz), 3.75 (d, 1H, J = 11 Hz), 3.60 (m, 2H), 3.50 (q, 1H, J= 7.5 Hz), 3.06 (t, 1H, J= 13 Hz), 2.75 (t, 1H, J= 11 Hz), 2.25 (m, 1 H), 2.15 (m, 1H), 1.78 (t, 2H, J= 16.5 Hz), 1.68 (m, 1H), 1.53 (q, 1H, J= 12 Hz), 1.15 (q, 1H, J= 13.5 Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 577.2 Example 266
(R)-N-(6-(4-(2-fluorophenylcarbamoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-2- (4-phenylcyclohexyl)-4-(trifluoromethyl)oxazole-5-carboxamide (266)
Figure imgf000290_0002
1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.36 (s, 1H), 8.33 (s, 1H), 7.83 (d, 1H, J= 9.5 Hz), 7.43 (m, 1H), 7.31 (m, 4H), 7.22 (m, 2H), 7.12 (m, 2H), 6.93 (d, 1 H, J = 9 Hz), 4.42 (broad s, 1 H), 4.35 (d, 2H, J = 11.5 Hz), 4.20 (d, 1H, J= 11.5 Hz), 4.12 (d, 1H, J= 13 Hz), 3.95 (d, 1H, J= 12.5 Hz), 3.62 (m, 1/2H), 3.35 (m, 1/2H), 3.22 (t, 2H, J= 12 Hz), 3.11 (d, 1H, J= 9.5 Hz), 2.90 (t, 1H, J= 12 Hz), 2.82 (t, 1H, J= 12 Hz), 1.90 (d, 2H1 J= 12 Hz), 1.75 (q, 2H, J = 12 Hz), 1.18 (d, 3H, J= 6 Hz). MS (M+1): 652.5 Example 267
N-(6-((R)-4-(2-fluorophenylcarbamoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-2- (3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (267)
Figure imgf000291_0001
Compound 267 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1 H), 8.34 (d, 2H, J = 7.5 Hz), 7.82 (d, 1H, J = 9 Hz), 7.43 (m, 1 H), 7.20 (m, 1 H), 7.12 (m, 2H), 6.92 (d, 1 H, J= 9 Hz), 4.42 (broad s, 1 H), 4.20 (d, 1 H, J= 12.5 Hz), 4.12 (d, 2H, J= 12.5 Hz), 4.07 (d, 1 H, J= 11.5 Hz), 3.95 (d, 1 H, J= 13.5 Hz), 3.62 (m, 1/2H), 3.23 (t, 1 H, J= 9.5 Hz), 3.12 (m, 1 1/2H), 3.05 (t, 1 H, J= 12.5 Hz), 2.88 (t, 1 H, J= 12 Hz), 2.75 (t, 1 H1 J= 11.5 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (q, 1 H, J = 12Hz), 1.17 (d, 3H, J= 6.5 Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 590.4 Example 268
(S)-N-(6-(4-(2-fluorophenylcarbamoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-2- (4-phenylcyclohexyl)-4-(trifluoromethyl)oxazole-5-carboxamide (268)
Figure imgf000291_0002
Compound 268 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1 H), 8.35 (S, 1 H), 8.32 (s, 1H), 7.83 (d, 1 H, J= 9 Hz), 7.43 (m, 1 H), 7.31 (m, 4H), 7.22 (m, 2H), 7.13 (m, 2H), 6.92 (d, 1H, J= 9 Hz), 4.42 (broad s, 1 H), 4.36 (d, 2H, J= 12 Hz), 4.20 (d, 1H, J = 12 Hz), 4.12 (d, 1 H, J= 12.5 Hz), 3.95 (d, 1 H1 J= 13.5 Hz), 3.22 (t, 3H, J = 12.5 Hz), 3.11 (d, 1H, J= 13 Hz), 2.88 (t, 1 H, J= 12 Hz), 2.82 (t, 1 H, J= 12 Hz), 1.90 (d, 2H, J= 13 Hz), 1.75 (q, 2H, J= 12.5 Hz), 1.18 (d, 3H, J= 6.5 Hz). MS (M+1): 652.4 Example 269
N-(6-((S)-4-(2-fluorophenylcarbamoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-2- (3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (269)
Figure imgf000292_0001
Compound 269 was prepared by the general procedure for compound 111, 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.34 (d, 2H, J= 9.5 Hz), 7.82 (d, 1 H, J = 8.5 Hz), 7.44 (m, 1 H), 7.20 (m, 1 H), 7.13 (m, 2H), 6.93 (d, 1 H, J = 9 Hz), 4.42 (m, 1H), 4.20 (d, 1H, J = 13.5 Hz), 4.12 (d, 2H, J= 12.5 Hz), 4.07 (d, 1H, J= 13 Hz), 3.95 (d, 1H, J= 13 Hz), 3.63 (m, 1H), 3.23 (t, 1H, J= 12 Hz), 3.14 (m, 1H), 3.05 (t, 1H, J= 13 Hz), 2.90 (td, 1H, J= 12.5, 3.5 Hz), 2.75 (t, 1H1J= 12.5 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.54 (m, 1H), 1.17 (d, 3H, J = 7 Hz), 0.94 (d, 3H, J= 7 Hz). MS (M+1): 590.2 Example 270
(R)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(3- phenylpyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide(270)
Figure imgf000292_0002
Compound 270 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.45 (s, 1H), 8.43 (d, 1H, J = 2.5 Hz), 8.10 (d, 1H, J= 9.5 Hz), 7.45 (m, 1H), 7.37 (m, 5H), 7.28 (m, 1H), 7.21 (m, 1H), 7.13 (m, 2H), 4.10 (t, 1H, J= 7 Hz), 3.85 (t, 1H, J= 8.5 Hz), 3.66 (broad s, 8H), 3.56 (m, 3H), 2.40 (m, 1H), 2.15 (m, 1H). MS (M+1): 624.3
Example 271
(S)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(3- phenylpyrrolidin-1 -yl)-4-(trifluoromethyl)oxazole-5-carboxamide (271 )
Figure imgf000293_0001
Compound 271 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1 H), 8.45 (s, 1H), 8.42 (s, 1H), 8.07 (d, 1 H, J = 8 Hz), 7.45 (m, 1 H), 7.38 (m, 4H), 7.28 (m, 2H), 7.21 (m, 1H), 7.13 (m, 2H), 4.10 (t, 1 H, J = 7.5 Hz), 3.84 (t, 1H, J= 9.5 Hz), 3.65 (m, 9H), 3.56 (m, 2H), 2.40 (m, 1 H), 2.15 (t, 1 H, J= 11 Hz). MS (M+1): 624.3 Example 272
2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoylJpiperazin-i-ylJpyridin-S-ylJ^-^rifluoromethylJoxazole- 5-carboxamide (272)
Figure imgf000293_0002
Compound 272 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1 H), 8.43 (s, 1H), 8.41 (s, 1H), 7.97 (broad s, 1 H), 7.43 (m, 4H), 7.20 (t, 3H, J= 8.5 Hz), 7.13 (m, 2H), 4.08 (t, 1 H, J= 8 Hz), 3.83 (t, 1 H, J = 10.5 Hz), 3.60 (m, 10H), 3.51 (t, 1 H, J = 10 Hz), 2.39 (m, 1 H), 2.13 (t, 1 H, J= IO Hz). MS (M+1): 642.3 Example 273
2-(4-(4-chlorophenyl)piperidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoylJpiperazin-i-yOpyridin-S-ylJ^-^rifluoromethylJoxazole- 5-carboxamide (273)
Figure imgf000294_0001
Compound 273 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1 H), 8.44 (s, 1 H), 8.43 (s, 1 H), 8.08 (d, 1 H, J =10.5 Hz), 7.45 (m, 1 H), 7.38 (d, 2H, J= 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.30 (m, 1 H), 7.21 (m, 1 H), 7.13 (m, 2H), 4.34 (d, 2H, J = 12.5 Hz), 3.65 (S, 8H), 3.23 (t, 2H, J = 11.5 Hz), 2.86 (t, 1 H, J = 11.5 Hz), 1.89 (d, 2H1 J = 12.5 Hz), 1.73 (q, 2H, J = 12.5 Hz). MS (M+1): 672.3 Example 274
2-(4-(3-chlorophenyl)piperidin-1 -yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (274)
Figure imgf000294_0002
Compound 274 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1 H), 8.43 (s, 1 H), 8.42 (d, 1 H, J = 2.5 Hz), 8.03 (broad s, 1 H), 7.45 (m, 1 H), 7.39 (s, 1 H), 7.35 (d, 1 H1 J = 7.5 Hz), 7.28 (d, 2H, J = 7.5 Hz), 7.21 (m, 2H), 7.13 (m, 2H), 4.35 (d, 2H, J = 11 Hz), 3.63 (S, 8H), 3.22 (t, 2H, J = 12 Hz), 2.86 (t, 1 H, J= 10.5 Hz), 1.90 (d, 2H, J= 11.5 Hz), 1.75 (q, 2H, J = 12 Hz). MS (M+1): 672.1 Example 275
2-(3-(2-fluorophenyl)pyrrolidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (275)
Figure imgf000295_0001
Compound 275 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1 H), 8.43 (d, 2H, J = 8 Hz), 8.07 (d, IH, J= 9 Hz), 7.46 (m, 2H), 7.35 (m, 1 H), 7.30 (d, 1H, J= 8 Hz), 7.23 (m, 3H), 7.14 (m, 2H), 4.08 (t, 1 H, J = 9 Hz)1 3.82 (m, 2H), 3.65 (m, 9H), 3.59 (t, 1 H, J = 9.5 Hz), 2.40 (m, 1 H), 2.20 (m, 1 H). MS (M+1 ): 642.4 Example 275A
2-(4-(2,4-difluorophenyl)piperidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (275A)
Figure imgf000295_0002
Compound 275A was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1 H), 8.77 (d, 1/2H, J= 4 Hz), 8.54 (d, 1/2H1 J= 8.5 Hz), 8.43 (d, 1 1/2H, J= 8 Hz), 8.06 (d, 1 H, J= 7 Hz), 7.53 (dd, 1/2H, J= 4.5, 8.5 Hz), 7.45 (m, 2H), 7.27 (m, 1/2H), 7.21 (m, 2H), 7.13 (m, 1 1/2H), 7.07 (t, 1 H, J = 8.5 Hz), 4.35 (d, 2H, J= 12 Hz), 3.65 (s, 8H), 3.27 (t, 2H1 J= 12 Hz), 3.11 (t, 1H, J= 11.5 Hz), 1.85 (m, 2H), 1.79 (m, 2H). MS (M+1): 674.3. Example 276
2-(3-(4-chlorophenyl)pyrrolidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoyOpiperazin-i-ylJpyridin-S-ylJ^-^rifluoromethylJoxazole- 5-carboxamide (276)
Figure imgf000296_0001
Compound 276 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.42 (d, 2H, J = 10 Hz), 8.03 (d, 1 H, J = 8 Hz), 7.42 (m, 5H), 7.21 (m, 2H), 7.14 (m, 2H), 4.08 (t, 1 H, J= 8.5 Hz), 3.83 (t, 1 H, J = 8 Hz), 3.64 (m, 10H), 3.53 (t, 1 H, J= 9.5 Hz), 2.39 (m, 1 H), 2.12 (m, 1 H). MS (M+1 ): 658.3 Example 277
2-(4-(3-fluorophenyl)piperidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (277)
Figure imgf000296_0002
Compound 277 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1 H), 8.44 (s, 1 H), 8.42 (d, 1 H, J = 2.5 Hz), 8.06 (d, 1 H, J = 8.5 Hz), 7.45 (m, 1 H), 7.37 (q, 1 H, J = 8 Hz), 7.27 (broad s, 1 H), 7.15 (m, 5H), 7.05 (td, 1 H, J = 8.5, 2.5 Hz), 4.34 (d, 2H, J= 13 Hz), 3.65 (s, 8H), 3.23 (t, 2H, J= 12 Hz), 2.88 (t, 1 H, J= 12 Hz), 1.91 (d, 2H, J = 11 Hz), 1.76 (qd, 2H, J = 13, 4 Hz). MS (M+1 ): 656.4 Example 278
2-(4-(3,5-difluorophenyl)piperidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (278)
Figure imgf000297_0001
Compound 278 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1 H), 8.43 (d, 2H, J= 9.5 Hz), 8.06 (d, IH, J= 8.5 Hz), 7.45 (m, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.13 (m, 2H), 7.08 (m, 3H), 4.34 (d, 2H, J= 13.5 Hz), 3.65 (s, 8H), 3.21 (t, 2H, J= 12 Hz), 2.90 (t, 1 H, J= 12 Hz), 1.91 (d, 2H, J= 12.5 Hz), 1.75 (q, 2H, J= 12.5 Hz). MS (M+1): 674.3
Example 279 2-(3-(3-fluorophenyl)pyrrolidin-1 -yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide (279)
Figure imgf000297_0002
Compound 279 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-dβ) δ 10.02 (s, 1 H), 8.42 (s, 1H), 8.38 (d, 1 H, J= 3 Hz), 7.85 (dd, 1H, J= 9, 2.5 Hz), 7.45 (m, 1 H), 7.40 (m, 1 H), 7.26 (d, 1 H, J = 10.5 Hz), 7.23 (d, 1 H, J= 8 Hz), 7.19 (m, 1 H), 7.13 (m, 3H), 6.93 (d, 1 H, J= 9 Hz), 4.10 (t, 1 H, J= 9.5 Hz), 3.84 (t, 1 H, J= 8 Hz), 3.63 (m, 2H), 3.55 (m, 9H)1 2.40 (m, 1 H), 2.15 (m, 1 H). MS (M+1): 642.3 Example 280
2-(4-(4-methylphenyl)piperidin-1-yl)-N-(6-(4-(2- fluorophenylcarbamoylJpiperazin-i-yOpyridin-S-yO^-^rifluoromethyOoxazole- 5-carboxamide (280)
Figure imgf000298_0001
Compound 280 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.42 (s, 1H), 8.38 (d, 1H, J = 2.5 Hz), 7.85 (dd, 1H, J= 9, 2.5 Hz), 7.45 (m, 1H), 7.20 (m, 1H), 7.18 (d, 2H, J = 8 Hz), 7.13 (m, 4H), 6.93 (d, 1H, J = 9 Hz), 4.34 (d, 2H, J= 12.5 Hz), 3.56 (m, 4H), 3.54 (m, 4H), 3.21 (t, 2H, J = 11 Hz), 2.77 (t, 1 H, J = 12.5 Hz), 1.86 (d, 2H1J= 11 Hz), 1.72(q, 2H1J= 12.5 Hz). MS (M+1): 652.3 Example 281 2-(3-(3-chlorophenyl)pyrrolidin-1 -yl)-N-(6-(4-(2- fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole- 5-carboxamide(281)
Figure imgf000298_0002
Compound 281 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.42 (s, 1H), 8.38 (d, 1H, J = 2.5 Hz), 7.85 (dd, 1H, J= 9.5, 2.5 Hz), 7.48 (s, 1H), 7.45 (m, 1H)17.39 (d, 1H, J= 7.5 Hz), 7.35 (m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 6.93 (d, 1H, J= 9 Hz), 4.09 (t, 1H1 J= 9.5 Hz), 3.84 (t, 1H, J= 8.5 Hz), 3.63 (m, 2H), 3.56 (m, 4H), 3.54 (m, 4H), 2.40 (m, 1H), 2.15 (m, 1H). MS (M+1): 658.3 Example 282
2-(4-phenylpiperidin-1-yl)-N-(6-(4-(p-tolylcarbamoyl)piperazin-1-yl)pyridin-3- yl)-4-(trifluoromethyl)oxazole-5-carboxamide(282)
Figure imgf000299_0001
Compound 282 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (S, 1 H), 8.52 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.86 (dd, 1 H, J = 9, 2.5 Hz), 7.36 (d, 2H, J = 8 Hz), 7.31 (m, 4H), 7.22 (m, 1 H), 7.05 (d, 2H, J = 8.5 Hz), 6.94 (d, 1 H, J = 9 Hz), 4.35 (d, 2H, J= 12.5 Hz), 3.55 (m, 4H), 3.53 (m, 4H), 3.22 (t, 2H, J= 12 Hz), 2.82 (t, 1 H, J = 12.5 Hz), 2.24 (s, 3H), 1.90 (d, 2H, J= 11 Hz), 1.75 (qd, 2H, J = 12.5, 4 Hz). MS (M+1): 634.3 Example 283
2-(4-phenylpiperidin-1-yl)-N-(6-(4-(m-tolylcarbamoyl)piperazin-1-yl)pyridin-3- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (283)
Figure imgf000299_0002
Compound 283 was prepared by the general procedure for compound 111. 1H MMR (500 MHz, DMSO-d6) δ 10.09 (S, 1 H), 8.55 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.85 (dd, 1 H, J = 9, 2.5 Hz), 7.31 (m, 6H), 7.22 (m, 1 H), 7.12 (t, 1 H, J = 7.5 Hz), 6.93 (d, 1 H, J= 9.5 Hz), 6.77 (d, 1 H, J = 7.5 Hz), 4.36 (d, 2H, J = 12 Hz), 3.56 (m, 4H), 3.53 (m, 4H), 3.22 (t, 2H, J= 12.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 2.26 (S, 3H), 1.89 (d, 2H, J= 12 Hz), 1.75 (qd, 2H, J = 12.5, 4 Hz). MS (M+1 ): 634.3 Example 284
N-(6-(4-(2-fluorobenzoyl)piperazin-1 -yl)pyridin-3-yl)-2-(4-phenylpiperidin-1-yl)- 4-(trifluoromethyl)oxazole-5-carboxamide (284)
Figure imgf000300_0001
Compound 284 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.86 (dd, 1 H, J = 9.5, 2.5 Hz), 7.53 (q, 1 H, J = 7.5 Hz), 7.46 (t, 1 H, J = 6 Hz), 7.32 (m, 6H), 7.22 (t, 1H, J = 6.5 Hz), 6.90 (d, 1H, J = 9 Hz), 4.35 (d, 2H, J= 13 Hz), 3.77 (m, 2H), 3.59 (m, 2H), 3.47 (m, 2H), 3.35 (m, 2H), 3.22 (t, 2H, J = 12.5Hz), 2.81 (t, 1H, J= 12 Hz), 1.89 (d, 2H1J= 11 Hz), 1.75 (q, 2H, J= 13 Hz). MS (M+1): 623.3 Example 285
N-(6-(4-(3-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (285)
Figure imgf000300_0002
Compound 285 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.83 (s, 1H), 8.38 (d, 1H, J= 3 Hz), 7.85 (dd, 1H, J= 9, 2.5 Hz), 7.46 (d, 1H, J= 12 Hz), 7.31 (m, 6H), 7.22 (m, 1H), 6.94 (d, 1H, J= 9 Hz), 6.75 (m, 1H), 4.36 (d, 2H, J= 12.5 Hz), 3.57 (m, 4H), 3.54 (m, 4H), 3.22 (t, 2H, J= 12.5 Hz), 2.82 (t, 1H, J= 12 Hz), 1.89 (d, 2H, J= 12.5 Hz), 1.75 (qd, 2H, J= 13, 4.5 Hz). MS (M+1): 638.3 Example 286
N-(6-(4-(4-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (286)
Figure imgf000301_0001
Compound 286 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.66 (s, 1 H), 8.38 (d, 1H, J = 2.5 Hz), 7.85 (dd, 1 H, J = 9, 2.5 Hz), 7.49 (d, 1 H, J= 5 Hz), 7.47 (d, 1 H1 J = 5.5 Hz), 7.31 (m, 4H), 7.22 (t, 1 H, J = 6.5 Hz), 7.09 (t, 2H, J= 9 Hz), 6.94 (d, 1 H, J= 9.5 Hz), 4.35 (d, 2H, J = 14 Hz), 3.56 (m, 4H), 3.53 (m, 4H), 3.22 (t, 2H, J = 12.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 1.89 (d, 2H, J= 1 1 Hz), 1.75 (qd, 2H, J= 13, 4 Hz). MS (M+1): 638.3 Example 287
N-(6-(4-(phenylcarbamoyl)piperazin-1 -yl)pyridin-3-yl)-2-(4-phenylpiperidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (287)
Figure imgf000301_0002
Compound 287 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.62 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.85 (dd, 1 H, J= 9.5, 2.5 Hz), 7.48 (d, 2H, J = 8 Hz), 7.31 (m, 4H), 7.24 (m, 3H), 6.95 (t, 2H, J = 8.5 Hz), 4.35 (d, 2H, J= 13.5 Hz), 3.57 (m, 4H), 3.53 (m, 4H), 3.22 (t, 2H, J= 10.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 1.90 (d, 2H, J = 11 Hz), 1.75 (qd, 2H, J= 12.5, 3.5 Hz). MS (M+1): 620.3 Example 288
N-(6-(4-(2-hydroxybenzoyl)piperazin-1-yl)pyridin-3-yl)-2-(4-phenylpiperidin-1 - yl)-4-(trifluoromethyl)oxazole-5-carboxamide (288)
Figure imgf000302_0001
Compound 288 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (broad s, 1 H), 9.88 (broad s, 1 H), 8.37 (d, 1 H, J= 2 Hz), 7.84 (dd, 1 H, J= 9, 2 Hz), 7.31 (m, 4H), 7.23 (m, 2H), 7.16 (dd, 1 H, J = 7.5, 1.5 Hz), 6.89 (d, 2H, J = 7.5 Hz), 6.86 (t, 1 H, J = 7 Hz), 4.35 (d, 2H, J= 13 Hz), 3.72 (broad s, 2H), 3.52 (broad s, 4H), 3.34 (broad s, 2H), 3.22 (t, 2H, J = 13 Hz), 2.81 (t, 1 H, J= 12 Hz), 1.89 (d, 2H, J= 1 1 Hz), 1.75 (qd, 2H, J= 12.5, 4 Hz). MS (M+1): 621.3 Example 289
N-(6-(4-(2-(2-fluorophenyl)-2-oxoethyl)piperazin-1-yl)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (289)
Figure imgf000302_0002
Compound 289 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1 H), 8.35 (s, 1 H), 7.85 (t, 1 H, J= 7 Hz), 7.81 (dd, 1 H, J = 9, 2.5 Hz), 7.67 (q, 1 H, J= 6.5 Hz), 7.33 (m, 6H), 7.22 (t, 1 H, J = 7 Hz), 6.86 (d, 1 H, J = 9 Hz), 4.36 (m, 2H), 3.83 (s, 2H), 3.45 (m, 4H), 3.21 (t, 2H, J= 12 Hz), 2.81 (t, 1 H, J = 1 1.5 Hz), 2.62 (m, 4H), 1.89 (d, 2H, J = 1 1.5 Hz), 1.74 (qd, 2H, J = 13, 4 Hz). MS (M+1 ): 637.4 Example 290 methyl 4-(4-(5-(2-(4-phenylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoate (290)
Figure imgf000303_0001
Compound 290 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 9.02 (s, 1 H), 8.39 (d, 1 H, J = 2.5 Hz), 7.85 (m, 3H), 7.65 (d, 2H, J = 9 Hz), 7.31 (m, 4H), 7.22 (t, 1 H, J= 6.5 Hz), 6.93 (d, 1 H, J = 9.5 Hz), 4.35 (d, 2H, J= 13 Hz), 3.81 (s, 3H), 3.61 (m, 4H), 3.54 (m, 4H), 3.22 (t, 2H, J= 12 Hz), 2.82 (t, 1 H, J= 12 Hz), 1.90 (d, 2H, J= 11.5 Hz), 1.75 (qd, 2H, J= 12.5, 3.5 Hz). MS (M+1 ): 678.5 Example 291 methyl 2-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoate (291 )
Figure imgf000303_0002
Compound 291 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1 H), 10.09 (s, 1 H), 8.39 (d, 1 H, J = 2.5 Hz), 8.35 (d, 1 H, J = 8.5 Hz), 7.94 (dd, 1 H, J = 8, 1.5 Hz), 7.86 (dd, 1 H, J = 9, 2.5 Hz), 7.58 (td, 1 H, J = 7, 1.5 Hz), 7.31 (m, 4H), 7.22 (m, 1 H), 7.07 (t, 1 H, J= 8 Hz), 6.93 (d, 1 H, J = 9.5 Hz), 4.36 (d, 2H, J = 12.5 Hz), 3.89 (s, 3H), 3.61 (m, 8H), 3.22 (t, 2H, J= 13 Hz), 2.82 (t, 1 H, J = 11.5 Hz), 1.89 (d, 2H, J = 11.5 Hz), 1.75 (qd, 2H, J= 12.5, 4 Hz). MS (M+1 ): 678.5 Example 292
2-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoic acid (292)
Figure imgf000304_0001
Compound 292 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 13.60 (broad s, 1H), 10.96 (s, 1H), 10.24 (s, 1 H), 8.44 (broad s, 2H), 8.01 (broad s, 1 H), 7.97 (d, 1 H, J = 7.5 Hz), 7.56 (t, 1 H, J = 8.5 Hz), 7.31 (m, 4H), 7.22 (m, 1 H), 7.11 (broad s, 1 H), 7.04 (t, 1 H, J = 7.5 Hz), 4.36 (d, 2H, J = 11.5 Hz), 3.67 (s, 8H), 3.23 (t, 2H, J = 11.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 1.90 (d, 2H, J = 13 Hz), 1.75 (qd, 2H, J = 12, 3.5 Hz). MS (M+1): 664.5 Example 293
4-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoic acid (293)
Figure imgf000304_0002
Compound 293 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.05 (broad s, 1 H), 7.84 (d, 2H, J = 9 Hz), 7.63 (d, 2H, J= 8.5 Hz), 7.31 (m, 4H), 7.22 (t, 1 H, J= 6.5 Hz), 7.17 (broad S, 1 H), 4.36 (d, 2H, J= 13 Hz), 3.65 (s, 8H), 3.23 (t, 2H, J= 12 Hz), 2.82 (t, 1 H, J= 12 Hz), 1.90 (d, 2H, J= 13 Hz), 1.75 (qd, 2H, J= 12.5, 3.5 Hz). MS (M+1): 664.4 Example 294 ethyl 3-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoate (294)
Figure imgf000305_0001
Compound 294 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.87 (s, 1H), 8.39 (d, 1H, J = 2.5 Hz), 8.13 (s, 1H), 7.85 (dd, 1H, J= 9, 2.5 Hz), 7.81 (d, 1H, J= 9 Hz), 7.55 (d, 1H1 J= 8 Hz)17.39 (t, 1H, J= 7.5 Hz), 7.31 (m, 4H), 7.22 (m, 1H), 6.94 (d, 1H, J= 9 Hz), 4.35 (d, 2H, J= 13 Hz), 4.31 (q, 2H, J= 7.5 Hz), 3.60 (m, 4H), 3.54 (m, 4H), 3.22 (t, 2H, J= 11 Hz), 2.82 (t, 1H1J= 12 Hz), 1.90(d, 2H, J = 11.5Hz), 1.75 (qd, 2H1 J= 13, 4.5 Hz), 1.33 (t, 3H, J= 7 Hz). MS(M+1): 692.4
Example 295
3-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoic acid (295)
Figure imgf000305_0002
Compound 295 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 10.31 (S, 1H), 8.88 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 8.09 (broad s, 1H), 7.78 (d, 1H, J= 7.5 Hz), 7.53 (d, 1H, J= 7.5 Hz), 7.37 (t, 1H, J= 7.5 Hz), 7.31 (m, 4H), 7.22 (m, 2H), 4.37 (d, 2H, J= 12.5 Hz), 3.66 (s, 8H), 3.24 (t, 2H, J= 12 Hz), 2.82 (t, 1 H, J= 12.5 Hz), 1.90 (d, 2H, J = 11.5 Hz), 1.75 (qd, 2H, J= 13, 3 Hz). MS (M+1): 664.5 Example 296 trans-4-(4-(5-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carbonyl)cyclohexanecarboxylicacid (296)
Figure imgf000306_0001
Compound 296 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (broad s, 1H), 10.08 (s, 1 H), 8.38 (d, 1 H, J = 2.5 Hz), 7.85 (dd, 1 H, J = 9, 2.5 Hz), 7.31 (m, 4H), 7.22 (t, 1 H, J = 6.5 Hz), 6.90 (d, 1 H, J = 9 Hz), 4.35 (d, 2H, J = 13 Hz)1 3.60 (broad s, 2H), 3.55 (broad s, 2H), 3.50 (broad s, 2H), 3.44 (broad s, 2H), 3.38 (broad s, 1H), 3.22 (t, 2H, J= 13.5 Hz), 2.82 (t, 1 H, J = 12 Hz), 2.70 (broad s, 1 H), 2.53 (broad s, 1H), 2.01 (m, 2H), 1.90 (d, 2H, J = 13 Hz), 1.75 (qd, 2H, J= 13, 4 Hz), 1.54 (m, 5H). MS (M+1): 655.4 Example 297 methyl 4-(4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoate (297)
Figure imgf000306_0002
Compound 297 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1 H), 9.03 (s, 1 H), 8.37 (d, 1 H, J = 2.5 Hz), 7.86 (d, 2H, J= 8.5 Hz), 7.84 (dd, 1 H, J= 9, 3 Hz), 7.65 (d, 2H, J = 8.5 Hz), 6.93 (d, 1 H, J= 9 Hz), 4.12 (d, 1 H, J= 13.5 Hz), 4.07 (d, 1 H, J= 11.5 Hz), 3.81 (s, 3H), 3.60 (m, 4H), 3.54 (m, 4H), 3.06 (t, 1 H, J= 12.5 Hz), 2.75 (t, 1 H, J= 11 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (q, 1 H, J= 12.5 Hz), 1.15 (q, 1 H, J = 11 Hz), 0.94 (d, 3H, J = 7 Hz). MS (M+1 ): 616.3 Example 298 ethyl 3-(4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoate (298)
Figure imgf000307_0001
Compound 298 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.88 (s, 1H), 8.38 (d, 1H, J= 2 Hz), 8.13 (s, 1H), 7.84 (d, 1H, J= 9, 2 Hz), 7.81 (d, 1H, J= 9 Hz), 7.55 (d, 1H, J = 7.5 Hz), 7.39 (t, 1 H, J = 7.5 Hz), 6.93 (d, 1 H, J = 9 Hz), 4.32 (q, 2H, J = 7 Hz), 4.12 (d, 1H, J= 12 Hz), 4.07 (d, 1H, J= 12 Hz), 3.60 (m, 4H), 3.54 (m, 4H), 3.05 (t, 1 H, J= 11.5 Hz), 2.75 (t, 1 H, J = 12 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (q, 1H, J= 11.5 Hz), 1.33 (t,3H, J= 6.5 Hz), 1.15 (q, 1H, J= 12 Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 630.4 Example 299 methyl 2-(4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoate (299)
Figure imgf000307_0002
Compound 299 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 10.05 (s, 1H), 8.38 (d, 1H, J = 2.5 Hz), 8.35 (d, 1H, J= 8.5 Hz), 7.95 (dd, 1 H, J= 8, 1.5 Hz), 7.84 (dd, 1H, J = 8.5, 3 Hz), 7.58 (td, 1 H, J= 7, 1.5 Hz), 7.07 (t, 1H, J= 8 Hz), 6.93 (d, 1H, J = 9.5 Hz), 4.12 (d, 1 H, J= 11.5 Hz), 4.07 (d, 1 H, J= 13.5 Hz), 3.89 (s, 3H), 3.61 (broad s, 8H), 3.05 (td, 1 H, J= 12, 3 Hz), 2.75 (t, 1H, J= 11 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (q, 1H, J= 13 Hz), 1.15 (q, 1H, J= 10Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 616.4 Example 300
2-(4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxamido)benzoicacid (300)
Figure imgf000308_0001
Compound 300 was prepared by the general procedure for compound 146.
1H NMR (500 MHz, DMSO-d6) δ 10.96 (S, 1 H), 10.14 (s, 1 H), 8.43 (d, 1 H, J =
8.5 Hz), 8.41 (d, 1H1 J= 2.5 Hz), 7.97 (dd, 1 H, J = 8, 1.5 Hz), 7.94 (d, 1 H, J = 7.5 Hz), 7.55 (t, 1 H, J= 9 Hz), 7.04 (t, 2H, J= 7.5 Hz), 4.13 (d, 1 H, J= 13 Hz),
4.07 (d, 1 H, J = 12.5 Hz), 3.64 (s, 8H), 3.06 (t, 1 H, J = 10 Hz), 2.75 (t, 1 H, J =
11 Hz), 1.77 (m, 2H), 1.66 (m, 1 H), 1.53 (q, 1 H, J= 12 Hz), 1.15 (q, 1H1 J =
9.5 Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 602.3
Example 301 3-(4-(5-(2-(3-methylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoic acid (301 )
Figure imgf000308_0002
Compound 301 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.12 (S, 1 H), 8.01 (broad S, 1H), 7.78 (d, 1 H, J= 7.5 Hz), 7.53 (d, 1 H, J= 7.5 Hz), 7.37 (t, 1 H, J= 8 Hz), 7.15 (broad S, 1 H), 4.12 (d, 1 H, J= 12 Hz), 4.09 (d, 1 H, J= 13.5 Hz), 3.64 (s, 8H), 3.06 (t, 1H, J= 11 Hz), 2.76 (t, 1 H, J= 12 Hz), 1.78 (m, 2H), 1.68 (m, 1 H), 1.54 (q, 1 H, J= 12.5 Hz), 1.15 (q, 1 H, J= 11.5 Hz), 0.94 (d, 3H, J= 6.5 Hz). MS (M+1): 602.3 Example 302
4-(4-(5-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxamido)benzoic acid (302)
Figure imgf000309_0001
Compound 302 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1 H), 9.01 (s, 1 H), 8.42 (s, 1H), 7.98 (broad s, 1 H), 7.84 (d, 2H, J = 8.5 Hz), 7.63 (d, 2H, J = 8.5 Hz), 7.11 (broad s, 1H), 4.13 (d, 1H, J = 12.5 Hz), 4.08 (d, 1H, J = 12.5 Hz), 3.63 (m, 8H), 3.06 (t, 1 H, J = 10.5 Hz), 2.76 (t, 1H, J= 12 Hz), 1.77 (m, 2H), 1.67 (m, 1 H), 1.53 (q, 1 H, J= 12 Hz), 1.15 (q, 1 H, J= 12 Hz), 0.94 (d, 3H, J = 7 Hz). MS (M+1): 602.3
Example 303 N-(6-(1 -(2-fluorophenylcarbamoyl)piperidin-4-ylamino)pyridin-3-yl)-2-(3- methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (303)
Figure imgf000309_0002
Compound 303 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 68.13 (d, 1 H, J = 2.5 Hz), 8.05 (t, 1 H, J= 8.5 Hz), 7.93 (d, 1 H, J= 8.5 Hz), 7.68 (s, 1 H), 7.12 (t, 1 H, J= 8 Hz), 7.08 (t, 1 H, J = 11 Hz). 7.00 (t, 1 H1 J = 7.5 Hz), 6.68 (d, 1 H, J = 3.5 Hz), 6.47 (d, 1 H, J = 9.5 Hz), 4.78 (broad s, 1 H), 4.10 (m, 4H), 3.90 (broad s, 1 H), 3.17 (t, 2H, J = 8 Hz), 3.05 (t, 1 H, J= 9.5 Hz), 2.72 (t, 1 H1 J = 11.5 Hz), 2.17 (d, 2H, J= 11 Hz), 1.50-1.87 (m, 6H), 1.18 (q, 1 H, J = 13 Hz), 1.00 (d, 3H, J = 6.5 Hz). MS (M+1): 590.3 Example 304
(S)-N-(6-(1-(2-fluorobenzoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (304)
Figure imgf000310_0001
Compound 304 was prepared by the general procedure for compound 111. 1 :1 rotamers 1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1/2H, J = 3 Hz), 8.12 (d, 1/2H, J = 2.5 Hz), 7.88 (broad s, 1/2H), 7.85 (dd, 1/2H, J = 2.5, 9 Hz), 7.82 (dd, 1/2H, J = 2.5, 9 Hz), 7.72 (s, 1/2H), 7.42 (m, 2H), 7.35 (t, 2H, J = 7.5 Hz), 7.23 (m, 5H), 7.13 (t, 1/2H, J= 7.5 Hz), 7.10 (t, 1/2H, J= 9 Hz), 6.50 (d, 1/2H, J = 9 Hz), 6.43 (d, 1/2H, J = 8.5 Hz), 4.88 (d, 1/2H, J = 5 Hz), 4.70 (d, 1/2H, J = 7.5 Hz), 4.43 (m, 2H), 4.03 (dd, 1/2H, J= 6.5, 12.5 Hz), 3.85 (m, 1/2H), 3.75 (m, 1 H), 3.70 (t, 1 H, J = 6.5 Hz), 3.67 (t, 1 H, J= 6.5 Hz), 3.62 (dd, 1/2H, J = 4.5, 13 Hz), 3.55 (m, 1/2H), 3.45 (m, 1/2H), 3.27 (dd, 1/2H, J= 4.5, 1 1 Hz), 3.20 (t, 1 H1 J = 1 1 Hz), 2.78 (tm, 1 H, J= 1 1.5 Hz), 2.35 (m, 1/2H), 2.28 (m, 1/2H), 2.00 (d, 2H, J = 11.5 Hz), 1.82 (m, 2H). MS (M+1 ): 623.3 Example 305
(R)-N-(6-(1-(2-fluorobenzoyl)pyrrolidin-3-ylamino)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (305)
Figure imgf000310_0002
Compound 305 was prepared by the general procedure for compound 111. 1 :1 rotamers 1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1/2H, J= 2.5 Hz), 8.12 (d, 1/2H, J = 2.5 Hz), 7.90 (broad s, 1/2H), 7.85 (dd, 1/2H, J = 2.5, 9 Hz), 7.82 (dd, 1/2H, J= 3, 8.5 Hz), 7.73 (s, 1/2H), 7.43 (m, 2H), 7.35 (t, 2H, J= 8 Hz), 7.25 (m, 5H), 7.13 (t, 1/2H, J = 9.5 Hz), 7.10 (t, 1/2H, J = 9.5 Hz), 6.52 (d, 1/2H, J = 8.5 Hz), 6.45 (d, 1/2H1 J= 9 Hz), 4.95 (d, 1/2H, J = 5 Hz), 4.75 (d, 1/2H, J= 7.5 Hz), 4.43 (m, 2H), 4.02 (dd, 1/2H, J= 6.5, 12.5 Hz), 3.85 (m, 1/2H), 3.77 (m, 1 H), 3.70 (t, 1 H, J = 6.5 Hz), 3.68 (t, 1 H, J= 6.5 Hz), 3.62 (dd, 1/2H, J= 4.5, 12.5 Hz), 3.55 (m, 1/2H), 3.45 (m, 1/2H), 3.27 (dd, 1/2H, J = 5, 1 1.5 Hz), 3.20 (t, 1 H, J = 13 Hz), 2.78 (tm, 1 H, J= 12 Hz), 2.37 (m, 1/2H), 2.28 (m, 1/2H), 2.00 (d, 2H, J= 12.5 Hz), 1.83 (m, 2H). MS (M+1): 623.3 Example 306
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(tetrahydro- 2H-pyran-4-ylamino)-4-(trifluoromethyl)oxazole-5-carboxamide (306)
Figure imgf000311_0001
Compound 306 was prepared by the general procedure for compound 111.
1H NMR (500 MHz, CDCI3) δ 8.20 (d, 1 H, J = 3 Hz), 8.07 (t, 1 H, J= 8.5 Hz),
8.03 (d, 1 H1 J= 9 Hz), 7.72 (s, 1 H), 7.13 (t, 1 H, J= 7.5 Hz), 7.08 (t, 1 H, J = 9.5 Hz), 7.00 (m, 1 H), 6.68 (d, 1 H, J = 9 Hz), 6.67 (m, 1 H), 4.03 (d, 2H, J =
11.5 Hz), 3.95 (m, 1 H), 3.68 (m, 4H), 3.66 (m, 4H), 3.55 (t, 2H, J = 11.5 Hz),
2.10 (d, 2H, J = 1 1 Hz), 1.60 (m, 2H). MS (M+1): 578.3
Example 307
2-(1-benzylpyrrolidin-3-ylamino)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin- 1 -yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (307)
Figure imgf000311_0002
Compound 307 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.53 (broad s, 1 H), 8.42 (s, 1 H), 8.37 (s, 1 H), 7.85 (d, 1 H, J = 9.5 Hz), 7.45 (m, 1 H), 7.33 (m, 4H), 7.20 (m, 1 H), 7.13 (m, 2H), 6.92 (d, 1 H, J = 9 Hz), 4.28 (broad s, 1 H), 3.60 (m, 2H), 3.55 (m, 4H), 3.53 (m, 4H), 2.83 (broad s, 1 H), 2.60 (broad s, 1 H), 2.45 (m, 2H), 2.25 (broad s, 1 H), 1.72 (broad s, 1 H). MS (M+1): 653.4 Example 308 2-(1 -benzylpiperidin-4-ylamino)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1- yl)pyridin-3-yl)-4-(trifluoronnethyl)oxazole-5-carboxamide (308)
Figure imgf000312_0001
Compound 308 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1 H), 9.50 (broad s, 1 H), 8.55 (broad s, 1 H), 8.42 (s, 1 H), 8.37 (s, 1 H), 7.85 (d, 1 H, J = 9 Hz), 7.45 (m, 5H), 7.20 (m, 1 H), 7.13 (m, 2H), 6.92 (d, 1 H, J = 9 Hz), 4.30 (broad s, 1 H), 3.80 (broad s, 1 H), 3.52 (m, 4H), 3.56 (m, 4H), 3.45 (m, 3H), 3.10 (broad s, 2H), 2.08 (m, 3H), 1.72 (broad s, 1 H). MS (M+1 ): 667.4 Example 309
(S)-N-(6-(4-(2-fluorophenylcarbamoyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-2- (4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (309)
Figure imgf000312_0002
Compound 309 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.22 (d, 1 H, J = 2.5 Hz), 8.13 (t, 1 H, J= 8.5 Hz), 8.03 (m, 1 H), 7.63 (s, 1 H), 7.37 (t, 2H, J= 7.5 Hz), 7.25 (m, 3H), 7.13 (t, 1 H, J = 7.5 Hz), 7.10 (m, 1 H), 7.00 (m, 1 H), 6.63 (m, 2H), 4.50 (m, 1 H), 4.40 (d, 2H, J= 13 Hz), 4.08 (d, 2H, J = 9 Hz), 3.88 (d, 1 H, J= 13 Hz), 3.53 (dd, 1 H, J= 4, 13 Hz), 3.33 (m, 2H), 3.23 (t, 2H, J= 10.5 Hz), 2.03 (d, 2H, J= 13.5 Hz), 1.85 (q, 2H, J= 13 Hz), 1.25 (d, 3H, J= 6.5 Hz). MS (M+1 ): 652.4 Example 310
(R)-N-(6-(4-(2-fluorophenylcarbamoyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-2- (4-phenylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5-carboxamide (310)
Figure imgf000313_0001
Compound 310 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.22 (d, 1 H, J= 2.5 Hz), 8.12 (t, 1 H, J= 8 Hz), 8.02 (m, 1 H), 7.64 (s, 1 H), 7.37 (t, 2H, J= 7.5 Hz), 7.25 (m, 3H), 7.13 (t, 1 H, J = 7.5 Hz), 7.09 (m, 1 H), 7.00 (m, 1H), 6.63 (m, 2H), 4.50 (m, 1 H), 4.40 (d, 2H, J= 13 Hz), 4.08 (d, 2H, J= 9 Hz), 3.88 (d, 1 H, J= 12.5 Hz), 3.55 (dd, 1 H, J = 3.5, 13.5 Hz), 3.34 (m, 2H), 3.23 (t, 2H, J = 13 Hz), 2.03 (d, 2H, J= 12 Hz), 1.85 (q, 2H, J = 12.5 Hz), 1.25 (d, 3H, J = 6.5 Hz). MS (M+1 ): 652.4 Example 311
2-(4-phenylpiperidin-1-yl)-N-(4-(2-(o-tolylcarbamoyl)thiazol-4-yl)phenyl)-4- (trifluoromethyl)oxazole-5-carboxamide (311 )
Figure imgf000313_0002
Compound 311 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.28 (s, 1H), 8.47 (s, 1 H), 8.17 (d, 2H, J= 8.5 Hz), 7.85 (d, 2H, J= 9 Hz), 7.50 (d, 1 H, J= 8 Hz), 7.32 (m, 5H), 7.27 (t, 1H, J= 7.5 Hz), 7.22 (m, 2H), 4.38 (d, 2H, J= 11.5 Hz), 3.24 (t, 2H, J= 12 Hz), 2.83 (t, 1 H, J= 12.5 Hz), 2.31 (s, 3H), 1.90 (d, 2H, J= 12 Hz), 1.75 (q, 2H, J= 13 Hz). MS (M+1): 632.3 Example 312
2-(4-phenylpiperidin-1-yl)-N-(3'-(o-tolylcarbamoyl)biphenyl-4-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (312)
Figure imgf000314_0001
Compound 312 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1 H), 10.04 (s, 1 H), 8.30 (s, 1 H), 7.95 (d, 1 H, J = 8 Hz), 7.92 (d, 1 H, J = 8 Hz), 7.86 (d, 2H, J= 7 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.62 (t, 1H, J = 7.5 Hz), 7.32 (m, 6H), 7.22 (m, 3H), 4.38 (d, 2H, J= 11.5 Hz), 3.23 (t, 2H, J= 12.5 Hz), 2.83 (t, 1 H, J= 12 Hz), 2.27 (s, 3H), 1.90 (d, 2H, J = 11 Hz), 1.75 (q, 2H, J = 12.5 Hz). MS (M+1 ): 625.3 Example 313
2-(4-phenylpiperidin-1-yl)-N-(4-(4-(o-tolylcarbamoyl)phenyl)thiazol-2-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (313)
Figure imgf000314_0002
Compound 313 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1 H), 9.95 (s, 1 H), 8.12 (d, 2H, J = 7.5 Hz), 8.07 (d, 2H, J= 8.5 Hz), 7.94 (s, 1 H), 7.32 (m, 6H), 7.23 (m, 2H), 7.18 (t, 1 H, J= 7 Hz), 4.50 (d, 2H, J= 12.5 Hz), 3.23 (t, 2H, J= 13 Hz), 2.84 (t, 1 H, J= 12 Hz), 2.25 (s, 3H), 1.90 (d, 2H, J= 11.5 Hz), 1.75 (q, 2H, J= 12 Hz). MS (M+1): 632.3 Example 314
N-(6-((R)-4-(2-fluorophenylcarbamoyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-2- (3-methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxamide (314)
Figure imgf000314_0003
Compound 314 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.03(s, 1 H), 8.37 (m, 2H), 7.82 (d, 1 H, J= 9 Hz), 7.43 (m, 1 H), 7.20 (m, 1 H), 7.13 (m, 2H), 6.85 (d, 1 H, J = 9.5 Hz), 4.50 (broad s, 1H), 4.13 (t, 2H, J= 12 Hz), 4.07 (d, 1H, J= 12.5 Hz), 4.01 (t, 2H, J = 12 Hz), 3.22 (d, 1 H, J= 10 Hz), 3.07 (m, 3H), 2.73 (m, 1H), 1.77 (m, 2H), 1.67 (m, 1 H), 1.52 (q, 1 H, J= 11.5 Hz), 1.15 (q, 1 H, J= 11 Hz), 1.08 (d, 3H, J = 6.5 Hz), 0.93 (d, 3H, J= 6.5 Hz). MS (M+1): 590.3 Example 315
N-(6-((S)-4-(2-fluorophenylcarbamoyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-2- (3-methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxamide (315)
Figure imgf000315_0001
Compound 315 was prepared by the general procedure for compound 111.
1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.36 (d, 2H, J= 8 Hz), 7.81 (d,
1 H, J = 9 Hz), 7.43 (m, 1 H), 7.20 (m, 1 H), 7.13 (m, 2H), 6.85 (d, 1 H, J = 8.5
Hz), 4.50 (broad s, 1H), 4.14 (t, 2H, J= 12 Hz), 4.07 (d, 1 H, J= 14 Hz), 4.01 (t, 2H, J= 12 Hz), 3.22 (d, 1 H, J= 10.5 Hz), 3.05 (m, 3H), 2.73 (t, 1 H, J= 5.5
Hz), 1.77 (m, 2H), 1.67 (m, 1 H), 1.53 (m, 1 H), 1.17 (m, 1 H), 1.08 (d, 3H, J =
6.5 Hz), 0.93 (d, 3H, J= 6.5 Hz). MS (M+1): 590.3
Example 316
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2- (methyl(phenethyl)amino)-4-(trif luoromethyl)oxazole-5-carboxamide (316)
Figure imgf000315_0002
Compound 316 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.19 (d, 1 H, J= 2.5 Hz), 8.11 (t, 1 H, J= 8 Hz), 8.05 (d, 1 H, J = 2.5 Hz), 8.04 (s, 1 H), 7.33 (d, 1 H, J = 7.5 Hz), 7.30 (d, 1 H, J = 9.5 Hz), 7.23 (m, 3H), 7.14 (t, 1 H, J= 8 Hz), 7.09 (m, 1H), 7.00 (m, 1H), 6.70
(d, 1H, J = 9 Hz), 6.66 (d, 1H, J = 3.5 Hz), 3.78 (t, 2H, J= 6.5 Hz), 3.68 (m,
8H), 3.16 (s, 3H), 2.99 (t, 2H, J= 6.5 Hz). MS (M+1): 612.3
Example 317
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(methyl((1- phenylcyclopropyl)methyl)amino)-4-(trifluoromethyl)oxazole-5-carboxamide
(317)
Figure imgf000316_0001
Compound 317 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1 H), 8.42 (s, 1H), 8.37 (s, 1H), 7.82 (d, 1H, J= 9.5 Hz), 7.45 (m, 1 H), 7.39 (d, 2H, J= 7.5 Hz), 7.19 (t, 3H, J= 7.5 Hz), 7.13 (m, 3H), 6.94 (d, 1 H, J= 9 Hz), 3.83 (s, 2H), 3.57 (m, 4H), 3.55 (m, 4H), 3.06 (s, 3H), 0.97 (s, 2H), 0.88 (S, 2H). MS (M+1): 638.4 Example 318
2-(4-phenylpiperidin-1-yl)-N-(6-(4-(o-tolylcarbamoyl)piperazin-1-yl)pyridin-3- yl)-4-(trif luoromethyl)oxazole-5-carboxamide (318)
Figure imgf000316_0002
Compound 318 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 8.38 (s, 1 H), 8.15 (s, 1H), 7.85 (d, 1H, J= 7.5 Hz), 7.31 (m, 4H), 7.21 (m, 1H), 7.19 (t, 2H, J= 9 Hz), 7.13 (t, 1 H, J= 7.5 Hz), 7.05 (t, 1 H, J= 7.5 Hz), 6.93 (d, 1 H, J= 9.5 Hz), 4.35 (d, 2H, J= 12.5 Hz), 3.56 (m, 4H), 3.54 (m, 4H), 3.22 (t, 2H, J= 12.5 Hz), 2.82 (t, 1H, J= 11.5 Hz), 2.18 (s, 3H), 1.90 (d, 2H, J= 11.5 Hz), 1.75 (q, 2H, J= 12.5 Hz). MS (M+1): 634.3 Example 319
N-(6-(4-(2,4-difluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxannide (319)
Figure imgf000317_0001
Compound 319 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 8.42 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, 1 H, J = 8 Hz), 7.41 (q, 1 H, J = 6 Hz), 7.31 (m, 4H), 7.24 (m, 2H), 7.02 (t, 1 H1 J= 7.5 Hz), 6.93 (d, 1 H, J = 9 Hz), 4.35 (d, 2H, J = 13.5 Hz)1 3.55 (m, 4H), 3.53 (m, 4H), 3.22 (t, 2H, J = 12.5 Hz), 2.82 (t, 1 H, J= 12 Hz), 1.89 (d, 2H, J = 12 Hz), 1.75 (q, 2H, J = 12.5 Hz). MS (M+1 ): 656.4 Example 320
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)-4-methylpyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (320)
Figure imgf000317_0002
Compound 320 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1 H), 8.41 (s, 1 H), 7.97 (s, 1 H), 7.45 (m, 1 H) 7.31 (m, 4H), 7.21 (m, 2H), 7.12 (m, 2H), 6.85 (s, 1 H), 4.35 (d, 2H, J = 12 Hz), 3.56 (m, 8H), 3.21 (t, 2H, J = 12 Hz), 2.81 (t, 1 H, J = 11.5 Hz), 2.17 (s, 3H), 1.88 (d, 2H, J = 11 Hz), 1.75 (q, 2H, J= 12.5 Hz). MS (M+1 ): 652.4 Example 321
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)-4-methylpyridin-3-yl)-2-(3- methylpiperidin-1 -yl)-4-(trif luoromethyl)oxazole-5-carboxamide (321 )
Figure imgf000318_0001
Compound 321 was prepared by the general procedure for compound 111. 1H NMR (500 MHz1 CDCI3) 6 8.31 (s, 1 H), 8.12 (t, 1 H, J = 8.5 Hz), 7.38 (s, 1 H), 7.13 (t, I H, J = 8 Hz), 7.09 (m, 1 H), 7.00 (t, 1 H, J = 7 Hz), 6.65 (d, 1 H, J = 3.5 Hz), 6.55 (S, 1 H), 4.12 (t, 2H, J= 13.5 Hz), 3.69 (s, 8H), 3.05 (td, 1 H, J = 13, 3.5 Hz), 2.72 (t, 1 H, J= 11 Hz), 1.90 (d, 1 H, J= 13 Hz), 1.82 (d, 1 H1 J = 13.5 Hz), 1.75 (m, 1 H), 1.63 (m, 1 H), 1.18 (q, 1 H, J = 11 Hz), 0.99 (d, 3H, J = 6.5 Hz). MS (M+1): 590.3 Example 322
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)-5-methylpyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (322)
Figure imgf000318_0002
Compound 322 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.15 (d, 1 H, J = 3 Hz), 8.11 (m, 2H), 7.76 (s, 1 H), 7.36 (t, 2H, J= 8 Hz), 7.28 (m, 1 H) 7.24 (d, 2H, J= 8.5 Hz), 7.13 (t, 1 H, J = 8 Hz), 7.09 (tm, 1 H1 J= 11 Hz), 7.00 (m, 1 H)1 6.68 (d, 1 H, J= 3.5 Hz), 4.40 (d, 2H, J= 13 Hz), 3.68 (m, 4H), 3.23 (t, 2H, J= 13 Hz), 3.21 (m, 4H), 2.80 (m, 1 H), 2.34 (s, 3H), 2.03 (d, 2H, J = 13 Hz), 1.85 (qd, 2H, J = 13, 4 Hz). MS (M+1): 652.4 Example 323
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 -yl)-2-methylpyridin-3-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (323)
Figure imgf000319_0001
Compound 323 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.12 (t, 1H, J = 8 Hz), 7.95 (d, 1H, J= 9 Hz), 7.46 (s, 1 H), 7.36 (d, 2H, J = 7.5 Hz), 7.28 (d, 1 H, J = 7 Hz) 7.25 (d, 2H, J = 8.5Hz), 7.13 (t, 1H1 J= 8 Hz), 7.09 (tm, 1 H, J= 11.5 Hz), 7.00 (m, 1H), 6.66 (s, 1H), 6.54 (d, 1H, J= 9 Hz), 4.37 (d, 2H, J= 13 Hz), 3.68 (s, 8H), 3.23 (t, 2H, J = 13 Hz), 2.80 (m, 1 H), 2.44 (s, 3H), 2.02 (d, 2H, J = 13 Hz), 1.85 (qd, 2H1J= 12.5,3.5 Hz). MS (M+1): 652.4 Example 324
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide(324)
Figure imgf000319_0002
Compound 324 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 7.85 (d, 1H, J= 9 Hz), 7.54 (d, 2H, J= 8 Hz), 7.45 (m, 1H), 7.35 (t, 2H, J= 7.5 Hz), 7.24 (t, 1H, J= 7 Hz), 7.20 (m, 1H), 7.12 (m, 2H), 6.93 (d, 1H, J= 9.5 Hz), 4.17 (d, 2H, J= 10 Hz), 3.54 (m, 9H), 3.10 (m, 1H), 2.07 (td, 2H, J= 13, 4.5 Hz), 1.72 (d, 2H, J= 12.5 Hz). MS (M+1): 654.4 Example 325
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4-fluoro-4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide(325)
Figure imgf000320_0001
Compound 325 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 7.85 (d, 1H, J = 9 Hz), 7.50 (d, 2H, J= 8 Hz), 7.45 (m, 1H), 7.42 (t, 2H, J = 7.5 Hz), 7.35 (t, 1H, J= 7 Hz), 7.20 (m, 1H)17.13 (m, 2H), 6.94 (d, 1H, J = 9 Hz), 4.30 (d, 2H, J= 14.5 Hz), 3.56 (m, 4H), 3.54 (m, 4H), 3.45 (t, 2H, J= 12.5 Hz), 2.32 (m, 1H), 2.24 (m, 1H), 2.04 (t, 2H, J= 10 Hz). MS (M+1): 656.4 Example 326
N-(6-(4-(benzylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-(4-phenylpiperidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxamide (326)
Figure imgf000320_0002
Compound 326 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.37 (d, 1H, J= 2.5 Hz)17.84 (dd, 1H, J= 9.5, 2.5 Hz), 7.31 (m, 8H) 7.21 (m, 3H), 6.91 (d, 1H, J= 9 Hz), 4.35 (d, 2H, J= 13 Hz), 4.27 (d, 2H, J= 6 Hz), 3.46 (s, 8H), 3.22 (t, 2H, J = 12.5Hz), 2.81 (t, 1H1J= 12 Hz), 1.89 (d, 2H, J= 11 Hz), 1.75 (qd, 2H, J = 12.5, 4Hz). MS (M+1): 634.3 Example 327
N-(2-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyrimidin-5-yl)-2-(4- phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (327)
Figure imgf000321_0001
Compound 327 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1 H), 8.62 (s, 2H), 8.43 (s, 1 H), 7.45 (m, 1H), 7.31 (m, 4H) 7.22 (m, 2H), 7.13 (m, 2H), 4.35 (d, 2H, J = 13 Hz), 3.78 (m, 4H), 3.55 (m, 4H), 3.23 (t, 2H, J= 11.5 Hz), 2.82 (t, 1 H, J= 12 Hz), 1.90 (d, 2H, J= 12.5 Hz), 1.75 (qd, 2H, J= 12.5, 4 Hz). MS (M+1): 639.2 Example 328
3-(4'-(2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamidojbiphenyl^-ylcarboxamidojpropanoic acid (328)
Figure imgf000321_0002
Compound 328 was prepared by the general procedure for compound 146.
1H NMR (500 MHz, CD3OD) 67.87 (m, 2H), 7.73 (m, 4H), 4.19 (m, 2H), 3.64
(m, 2H), 3.08 (m, 1 H), 2.75 (m, 1H), 2.65 (m, 2H), 1.79 (m, 4H), 1.00 (m, 3H).
MS (M+1): 545
Example 329
Ethyl 2-(4'-(2-(4-phenylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenyl-4-yl)acetate (329)
Figure imgf000321_0003
Compound 329 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 7.69 (m, 3H), 7.55 (m, 3H), 7.34 (m, 4H), 7.23 (m, 4H), 4.38 (m, 2H), 4.16 (m, 2H), 3.65 (s, 2H), 3.22 (m, 2H), 2.78 (m, 1 H), 2.01 (m, 2H), 1.85 (m, 2H), 1.56 (s, 2H), 1.27 (m, 3H). MS (M+1): 578 Example 330
N-(4'-(2-oxo-2-(o-tolylamino)ethyl)biphenyl-4-yl)-2-(4-phenylpiperidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (330)
Figure imgf000322_0001
Compound 330 was prepared by the general procedure for compound 111.
1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1 H), 9.53 (s, 1 H), 7.79 (m, 2H), 7.67 (m, 4H), 7.46 (m, 2H), 7.38 (m, 1 H), 7.31 (m, 3H), 7.22 (m, 2H), 7.15 (m,
1 H), 7.08 (m, 1 H), 4.36 (m, 2H), 3.72 (s, 2H), 3.23 (m, 2H), 2.82 (m, 1 H), 2.19
(s, 3H), 1.89 (m, 2H), 1.77 (m, 2H). MS (M+1): 639
Example 331
2-(4'-(2-(4-phenylpiperidin-1 -yl)-4-(trifluoromethyl)oxazole-5- carboxamido)biphenyl-4-yl)acetic acid (331)
Figure imgf000322_0002
Compound 331 was prepared by the general procedure for compound 146. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1 H), 10.23 (s, 1 H), 7.79 (m, 2H),
7.70 (m, 4H), 7.62 (m, 5H), 7.31 (m, 1 H), 4.36 (m, 2H), 3.61 (s, 2H), 3.23 (m,
2H), 2.82 (m, 1 H),1.89 (m, 2H), 1.76 (m, 2H) MS (M+1 ): 550
Example 332
2-(4-phenylpiperidin-1 -yl)-N-(6-(4-(o-tolylcarbamoyl)phenyl)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (332)
Figure imgf000323_0001
Compound 332 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 5 8.71 (m, 1 H), 8.47 (m, 1 H), 8.13 (m, 2H), 7.98 (m, 4H), 7.81 (m, 1 H), 7.76 (m, 1H), 7.35 (m, 1 H), 7.28 (m, 7H), 7.15 (m, 1H), 4.40 (m, 2H), 4.30 (m, 1 H), 3.25 (m, 2H), 3.15 (m, 1 H), 2.81 (m, 2H), 2.38 (s, 3H), 2.02 (m, 3H), 1.85 (m, 3H), 1.63 (m, 3H). MS (M+1): 636 Example 333
2-(3-methylpiperidin-1-yl)-N-(6-(4-(o-tolylcarbamoyl)phenyl)pyridin-3-yl)-4- (trifluoromethyl)oxazole-5-carboxamide (333)
Figure imgf000323_0002
Compound 333 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) 5 10.44 (s,1 H), 9.99 (s, 1 H)1, 8.99 (S, 1 H), 8.24 (m, 3H), 8.10 (m, 3H), 7.29 (m, 4H), 4.14 (m, 2H), 3.09 (m, 1 H), 2.78 (m, 1 H), 2.26 (S, 3H), 1.81 (m, 3H), 1.56 (m, 1 H). MS (M+1): 564 Example 334 2-(azepan-1 -yl)-N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1 - yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (334)
Figure imgf000323_0003
Compound 334 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-Cf6) δ 10.01 (S, 1 H), 8.42 - 8.36 (m, 2 H), 7.83 (dd, J=2.0, 9.0 Hz, 1 H), 7.47 - 7.43 (m, 1 H), 7.22 - 7.12 (m, 3 H), 6.93 (d, J=9.0 Hz, 1 H), 3.67 (t, J=6.0 Hz, 4 H), 3.57 - 3.53 (m, 8 H), 1.78 - 1.72 (m, 4 H), 1.58 - 1.54 (m, 4 H) ; MS (ESI) [M+1 J+ 576. Example 335
2-(3,4-dihydroisoquinolin-2(1H)-yl)-N-(6-(4-(2-fluorophenylcarbamoyl)- piperazin-1-yl)pyridin-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (335)
Figure imgf000324_0001
Compound 335 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.24 (d, J=2.5 Hz, 1 H), 8.09 (dt, Jt=I .0, 8.0 Hz, 1 H), 8.03 (dd, J=1.0, 9.0 Hz, 1 H), 7.79 (s, 1 H), 7.29 - 7.19 (m, 4 H), 7.13 - 6.98 (m, 3 H), 6.69 - 6.65 (m, 2 H), 4.82 (s, 2 H), 3.93 (t, J=6.0 Hz, 2 H), 3.69 - 3.65 (m, 8 H), 3.02 (t, J=6.0 Hz, 2 H); MS (ESI) [M+1]+ 610. Example 336 2-(4-(2-fluorophenyl)piperazin-1 -yl)-N-(6-(4-(2- fluorophenylcarbamoyO-piperazin-i-ylJpyridin-S-yO^-^rifluoromethyOoxazole- 5-carboxamide (336)
Figure imgf000324_0002
Compound 336 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) δ 8.23 (d, J=2.5 Hz, 1 H), 8.11 (dt, J=1.5, 8.0 Hz, 1 H), 8.04 (dd, J=3.0, 9.0 Hz, 1 H), 7.67 (s, 1 H), 7.14 - 6.98 (m, 7 H), 6.69 (d, J=9.0 Hz, 1 H), 6.65 (d, J=4.0 Hz, 1 H), 3.88 - 3.86 (m, 4 H), 3.71 - 3.66 (m, 8 H), 3.23 - 3.21 (m, 4 H); MS (ESI) [M+1]+ 657.
Example 337 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)- 2-(3-azaspiro[5.5]undecan-3-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (337)
Figure imgf000325_0001
Compound 337 was prepared by the general procedure for compound 111.
1H NMR (500 MHz, DMSO-Cf6) δ 10.06 (s, 1 H), 8.42 (s, 1 H), 8.38 (d, J=2.0
Hz, 1 H), 7.85 (dd, J=2.0, 9.0 Hz, 1 H), 7.47 - 7.43 (m, 1 H), 7.22 - 7.12 (m, 3
H), 6.93 (d, J=9.0 Hz, 1 H), 3.63 - 3.53 (m, 12 H), 1.51 - 1.40 (m, 14 H); MS
(ESI) [M+1]+ 630.
Example 338 N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-
2-(4-phenylazepan-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (338)
Figure imgf000325_0002
Compound 338 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-cfe) δ 10.02 (s, 1 H), 8.41 (s, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 7.83 (dd, J=2.0, 9.0 Hz, 1 H), 7.47 - 7.43 (m, 1 H), 7.30 - 7.12 (m, 8 H), 6.93 (d, J=9.0 Hz, 1 H), 4.00 - 3.97 (m, 1 H), 3.85 - 3.82 (m, 1 H), 3.74 - 3.61 (m, 2 H), 3.57 - 3.53 (m, 8 H), 2.76 - 2.71 (m, 1 H), 2.05 - 1.68 (m, 6 H); MS (ESI) [M+1]+ 652. Example 339
N-(6-(4-(2-fluorophenylcarbamoyl)piperazin-1-yl)pyridin-3-yl)-2-morpholino-4- (trifluoromethyl)oxazole-5-carboxamide (339)
Figure imgf000325_0003
Compound 339 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-Ob) δ 10.1 1 (s, 1 H), 8.42 (s, 1 H)1 8.37 (d, J=2.0 Hz, 1 H), 7.85 (dd, J=3.0, 9.0 Hz, 1 H), 7.47 - 7.43 (m, 1 H), 7.22 - 7.12 (m, 3 H), 6.94 (d, J=9.0 Hz, 1 H), 3.74 - 3.73 (m, 4 H), 3.64 - 3.62 (m, 4 H), 3.57 - 3.53 (m, 8 H); MS (ESI) [M+1]+ 564. Example 340 cis-4-[[4-[5-[[[2-(3-methyl-1 -piperidinyl)-4-(trifluoromethyl)-5- oxazolyl]carbony|]amino]-2-pyridinyl]-1- piperazinyl]carbonyl]cyclohexanecarboxylic acid (340)
Figure imgf000326_0001
Compound 4 HCI salt (50 mg, 0.1 mmol) was mixed with cis- hexanedicarboxylic acid (35 mg), diisopropylethylamine (0.1 mL), and HATU (60 mg) in 1 mL of dry DMF. The mixture was stirred at room temperature for 4 h, diluted with 2 mL of DMF, and then subjected to Gilson HPLC purification to give 18 mg of product 340. 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 8.38 (s, 1 H), 7.88 (d, 1 H, J = 8.2 Hz), 6.98 (d, 1 H, J = 8.5 Hz), 4.10 (m, 2H), 3.54 (m, 6H), 3.06 (m, 1 H), 2.76 (m, 2H), 2.54 (m, 1 H), 2.00 (m, 2H), 1.72 (m, 3H), 1.53 (m, 6H), 1.20 (m, 3H), 0.93 (d, 3H, J = 6.6 Hz), 0.85 (m, 1H). MS (M+1): 593.3 Example 341 trans-4-[[4-[5-[[[2-(3-methyl-1 -piperidinyl)-4-(trifluoromethyl)-5- oxazolyl]carbonyl]amino]-2-pyridinyl]-1- piperaziny|]carbonyl]cyclohexanecarboxylic acid (341)
Figure imgf000326_0002
Compound 341 was prepared by the general procedure for compound 340. 1H MMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 8.38 (s, 1 H), 7.89 (d, 1 H, J = 9.1 Hz), 6.99 (d, 1 H, J = 8.5 Hz), 4.10 (m, 2H), 3.55 (m, 6H), 3.06 (m, 1 H), 2.71 (m, 2H), 1.96 (m, 3H), 1.75 (m, 4H), 1.53 (m, 5H), 1.42 (m, 2H), 1.20 (m, 2H), 0.93 (d, 3H, J = 6.6 Hz). MS (M+1): 593.3 Example 342
Cyclopentyl 4-[5-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl]piperazine-1 -carboxylate (342)
Figure imgf000327_0001
Compound 342 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1 H), 8.40 (s, 1 H), 8.05 (d, 1 H,
J=7.5 Hz), 7.20 (br s, 1 H), 5.00 (br s, 1 H), 3.55 (m, 8H), 3.50 (m, 4H), 2.00 (br s, 4H), 1.80 (m, 2H), 1.60 (m, 6H). MS (M+1): 523.
Example 343 lsopropyl 4-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1 -carboxylate (343)
Figure imgf000327_0002
Compound 343 was prepared by the general procedure for compound 111. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1 H), 8.35 (d, 1 H, J = 2.6 Hz), 7.83 (dd, 1 H, J = 9.2, 2.6 Hz), 6.88(d, 1 H, J = 9.2 Hz), 4.80 (m, 1 H), 3.61 (br s, 4H), 3.46 (s, 8H), 1.61 (br s, 6H), 1.20 (d, 6H, J = 6.2 Hz). LCMS (ESI) Rt = 3.21 min, [M+1]+ 51 1.3. Example 344 - 346
Cyclopentyl 4-(5-(2-(piperidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl)piperazine-1-carboxylate (344)
Figure imgf000328_0001
Compound 344 was pre red by the general proc tedurre fo>r compound 111. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1 H), 8.35 (d, 1 H, J = 2.9 Hz), 7.83 (dd, 1 H, J = 9.2, 2.6 Hz), 6.88 (d, 1 H, J = 9.2 Hz), 5.00 (m, 1 H), 3.61 (br s, 4H), 3.45 (br s, 8H), 1 ,79 (m, 2H), 1.66 - 1.54 (m, 12 H). LCMS (ESl) Rt = 3.53 min, [M+1]+ 537.3.
Alternatively, compound 344 was prepared by the method for the carbamates combinatorial library synthesis described below. Using a shaker with a capacity of 24 cartridges, the following reactions were run. To each cartridge were added 1 ml_ of the solution of intermediate piperazine in DCE (10.0 mg for each cartridge), 33.1 mg of diisopropylethylamine resin (5 eq. @ 3.56 mmol/g) and 47.1 μl_ of chloroformates (1 M solutions in DCE for the chloroformates; 2 equivalents). The cartridges were stoppered and shaken overnight. Then, to the each cartridge was added 31.7 mg of Trisamine resin (6 eq. @ 4.46 mmol/g), 48.4 mg of ICN resin (3 eq. @ 1.46 mmol/g), and an additional 500 μl_ of DCE. The cartridges were re-stoppered and shaken overnight. The cartridges were filtered into pre-weighed vials, and the resins were washed with acetonitrile (6 x 500 μl_). Upon concentration of the filtrates, the carbamates listed below were obtained as products.
Figure imgf000328_0002
Figure imgf000329_0001
Example 347
Cyclopentyl 4-[5-(2-(3,4-dihydro-1 (2H)-quinolinyl)-4-
(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl]piperazine-1- carboxylate (347)
Figure imgf000329_0002
Compound 347 was prepare by the general proce rdureo for compound 111.
1H NMR (500 MHz, DMSO-d6) δ 8.40 (S, 1 H), 8.05 (d, 1 H, J=8.5 Hz), 7.85 (d,
1 H, J=8.5 Hz), 7.20 (m, 2H), 7.05 (t, 1 H, J=7.5 Hz), 6.90 (d, 1 H, J=9.5 Hz), 5.00 (m, 1 H), 4.10 (m, 2H), 3.45 (br s, 8H), 2.85 (m, 2H), 2.00 (t, 2H, J=6 Hz),
1.85 (m, 2H), 1.65 (m, 4H), 1.55 (m, 2H). MS (M+1): 585.
Example 348
Cyclopentyl 4-[5-(2-(2,3-dihydro-1 H-indol-1-yl)-4-
(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl]piperazine-1- carboxylate (348)
Figure imgf000330_0001
Compound 348 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1 H), 7.85 (t, 2H, J=12 Hz), 7.30 (m, 2H), 7.05 (t, 1 H, J=7 Hz), 6.90 (t, 1 H, J=9 Hz), 5.00 (br s, 1 H), 4.30 (t, 2H, J=8.5 Hz), 3.45 (m, 8H), 3.30 (t, 2H, J=8.5 Hz), 1.80 (m, 2H), 1.65 (m, 4H), 1.55 (m, 2H). MS (M+1): 571. Example 349
Cyclopentyl 4-[5-(2-(3,4-dihydro-2(1 H)-isoquinolinyl)-4- (trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl]piperazine-1- carboxylate (349)
Figure imgf000330_0002
Compound 349 was prepared by the general procedure for compound 111.
1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1 H), 7.85 (dd, 1 H, J=2.5, 9 Hz), 7.25
(m, 4H), 6.90 (d, 1 H, J=9 Hz), 5.00 (m, 1 H), 4.80 (s, 2H), 3.90 (t, 2H, J=6 Hz), 3.45 (br s, 8H), 3.00 (t, 2H, J=6 Hz), 1.80 (m, 2H), 1.65 (m, 4H), 1.55 (m, 2H).
MS (M+1 ): 585.
Example 350
Cyclopentyl 4-[5-(2-(3-trif luoromethylpiperidin-1 -yl)-4-
(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl]piperazine-1- carboxylate (350)
Figure imgf000330_0003
Compound 350 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.45 (s, 1H), 8.10 (d, 1H, J=W Hz), 7.25 (d, 1H, J=8 Hz), 5.00 (s, 1H), 4.30 (d, 1H, Λ=13 Hz), 4.20 (d, 1H, Λ=13 Hz), 3.65 (m, 4H), 3.50 (m, 4H), 3.25 (t, 1H, Λ=13 Hz), 3.15 (t, 1H, J=λ 2.5 Hz), 2.75 (m, 1 H), 2.00 (d, 1H, J=11 Hz), 1.80 (m, 3H), 1.60 (m, 8H). MS(M+1):605. Example 351
Cyclopentyl 4-[5-(2-(3-fluoropiperidin-1-yl)-Φ(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl]piperazine-1-carboxylate (351 )
Figure imgf000331_0001
Compound 351 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.35 ( s, 1H), 8.45 (s, 1H), 8.10 (m, 1H), 7.20(m, 1H), 5.00 (brs, 1H), 4.95 (s, 1/2H), 4.85 (s, 1/2H), 4.10 (m, 1H), 3.95 (d, 1H, Jt12.5 Hz), 3.70 (d, 1H, J=13.5 Hz), 3.60 (m, 4H), 3.50 (m, 4H), 3.40 (m, 1H), 1.95 (m, 2H), 1.80 (m, 3H), 1.60 (m, 7H). MS (M+1): 555. Example 352
Cyclopentyl 4-[5-(2-(3-hydroxypiperidin-1-yl)-4-(trifluoromethyl)oxazole- 5-carboxamido)pyridin-2-yl]piperazine-1-carboxylate(352)
Figure imgf000331_0002
Compound 352 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.40 (s, 1H), 8.05 (d, 1H, J=W Hz), 7.20 (d, 1 H, J=8.5 Hz), 5.00 (br s, 1 H), 3.90 (d, 1 H, J=9.5 Hz), 3.75 (d, 1H, Λ=13.5 Hz), 3.65 (m, 1H), 3.60 (m, 4H), 3.50 (m, 4H), 3.35 (m, 1H), 3.20 (m, 1H), 1.80 (m, 4H), 1.65 (m, 4H), 1.50 (m, 4H). MS (M+1): 553. Example 353 Cyclopentyl 4-[5-(2-(3-methoxypiperidin-1-yl)-4-(trifluoromethyl)oxazole- 5-carboxamido)pyridin-2-yl]piperazine-1 -carboxylate (353)
Figure imgf000332_0001
Compound 35 was prepared by the general procedure foor compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.45 (s, 1 H), 8.10 (d, 1 H1
J=8.5 Hz), 7.25 (br s, 1 H), 5.00 (br s, 1 H), 3.75 (d, 1 H, J=13 Hz), 3.60 (m,
7H), 3.50 (m, 4H), 3.40 (m, 1 H), 3.30 (s, 3H), 1.80 (m, 4H), 1.60 (m, 8H). MS
(M+1): 567.
Example 354 Cyclopentyl 4-[5-(2-(3-methylpyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl]piperazine-1 -carboxylate (354)
Figure imgf000332_0002
Compound 354 was prepare by the general procedure fOor compound 111.
1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.45 (s, 1 H), 8.15 (d, 1 H, J=7.5 Hz), 7.25 (br s, 1 H), 5.00 (br s, 1 H), 3.80 (t, 1 H, J=7.5 Hz), 3.70 (m,
1 H), 3.65 (m, 5H), 3.50 (m, 5H), 3.10 (t, 1 H, J=8.5 Hz), 2.40 (m, 1 H), 2.10 (m,
1 H), 1.80 (m, 2H), 1.60 (m, 7H), 1.10 (d, 3H, J=6.5 Hz). MS (M+1): 537.
Example 355
Cyclopentyl 4-[5-(2-(3-methoxypyrrolidin-1-yl)-4-(trifluoromethyl)oxazole- 5-carboxamido)pyridin-2-yl]piperazine-1 -carboxylate (355)
Figure imgf000332_0003
Compound 355 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1 H), 8.45 (s, 1 H), 8.10 (d, 1 H, J=8 Hz), 7.25 (d, 1 H, J=8.5 Hz), 5.00 (br s, 1 H), 4.10 (s, 1H), 3.65 (t, 2H, J=10.5 Hz), 3.60 (m, 5H), 3.50 (m, 5H), 3.25 (s, 3H), 2.10 (m, 2H), 1.80 (m, 2H), 1.65 (m, 4H), 1.55 (m, 2H). MS (M+1 ): 553. Example 356
Cyclopentyl 4-[5-(2-(diethylamino)-4-(trifluoromethyl)oxazole-5- carboxamido)pyridin-2-yl]piperazine-1 -carboxylate (356)
Figure imgf000333_0001
Compound 356 was prepared by the general proc tedurXe fo>r compound 111. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1 H), 8.40 (s, 1H), 8.00 (d, 1H, J=9.5 Hz), 7.15 (d, 1 H, J=7.5 Hz), 5.00 (br s, 1 H), 3.55 (m, 8H), 3.50 (m, 4H), 1.80 (m, 2H), 1.65 (m, 4H), 1.55 (m, 2H), 1.20 (t, 6H, J=7 Hz). MS (M+1 ): 525. Example 357 cyclopentyl 4-(5-(2-(2-oxopyrrolidin-1-yl)-4- (trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)piperazine-1- carboxylate (357)
Figure imgf000333_0002
Compound 357 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CD3OD-d4) δ 8.44 (d, 1 H, J= 2.8 Hz), 7.94 (dd, 1 H, J= 9.1 , 2.9 Hz), 6.92 (d, 1 H, J= 9.1 Hz), 5.12 (m, 1 H), 4.13 (t, 2H, J= 7.1 Hz), 3.62 - 3.50 (m, 10H), 2.74 (t, 2H, J= 8.2 Hz), 2.29 (m, 2H), 1.94 - 1.84 (m, 2H), 1.80 - 1.72 (m, 4H), 1.70 - 1.60 (m, 2H); LCMS (ESI) Rt = 3.2 min, [M+1 ]+ 537.3. Example 358 cyclopentyl 4-[5-[[2-(1-piperidinyl)-4-(trifluoromethyl)-5- thiazolyl]carbonylamino]-2-pyridinyl]-1 -piperazinecarboxylate (358)
Figure imgf000334_0001
Compound 358 was prepared by the general procedure for compound 111. 1H NMR (500 MHz, CDCI3) 5 8.21 (d, 1 H, J = 2.5 Hz), 7.91-7.89 (m, 1 H), 7.61 (m, 1 H), 6.68 (d, 1 H, J = 9.0 Hz), 5.18-5.15 (m, 1 H), 3.59-3.52 (m, 12H), 1.78-1.72 (m, 10H), 1.92-1.85 (m, 2H), 1.66-1.60 (m, 2H); LCMS (ESI) [M+1]+ 553.3.
ASSAY
A useful assay to determine the DGAT inhibitory activity of the inventive compounds is described below:
The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes. The reaction is initiated by the addition of the combined substrates 1 ,2-dioleoyl-sn-glycerol and [14C]-palmitoyl-CoA and incubated with test compounds and microsomal membranes for 2 hours at room temperature. The assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3-cholamidopropyldimethyl-ammonio-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.
Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus nonspecific binding). IC5O values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation: Y = A + (B-A)/(1 +10Λ((LoglC50-X))), where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration. The IC50 values for several illustrative compounds of the invention are shown in the Table below, where A represents IC50 = 1 to 10 nM, B represents IC50 = 11 to 100 nM, and C represents IC50 = 101 to 500 nM. TABLE
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound, or pharmaceutically acceptable salt of said compound, the compound being represented by the formula I:
Figure imgf000341_0001
I wherein: each A is independently selected from C(R3) and N; or alternately the moiety:
Figure imgf000341_0002
X is independently selected from C(R3), N, N(R4), O and S, provided that no more than one X is S or O, and at least one X or one Y is N, O, or S;
Y is independently selected from C and N;
Z is a bond, N(R4) or O;
L is either one of the three options (i), (ii) or (iii):
R1 W !
(i) *, wherein W is selected from alkyl, alkenyl, alkynyl,
Figure imgf000341_0003
_ wnerein Q is selected from the group consisting of -NH-, -N(R11)-. -O-, -S-, -C(O)-NH-, and - NH-C(O)-; t is 0, 1 , 2 or 3; R11 is H or alkyl; and R1 is selected from alkyl, aryl or cycloalkyl, wherein each of said alkyl, aryl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, haloalkoxy, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)R0, -C(O)OR0, -C(O)N(R°)(Rd), -SF5, -OSF5, -Si(R°)3, -SRC, -S(O)N(R°)(Rd),
-CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb),
-CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected; or do Rlϊ— w— I wherein W is selected from alkyl, alkenyl, alkynyl, < (CH2)t--Q I or
i— Q-(CH2)t--| ^ wnerejn Q jS selected from the group consisting of - NH-, -N(R11)-, -O-, -S-, -C(O)-NH-, and -NH-C(O)-; t is O, 1 , 2 or 3; R11 is H or alkyl; and R12 is a heterocycloalkyl containing 1 -4 heteroatoms which can be the same or different and are independently selected from the group consisting of O, S and N, wherein said heterocycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd,
-N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected;
or alternatively, said heterocycloalkyl for R12 in (ii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN, -ORC, -C(O)R0, -C(O)OR0, -C(O)N(R°)(Rd), -SF5, -OSF5, -Si(Rc)3, -SR0, -S(O)N(R°)(Rd), -CH(R°)(Rd), -S(O)2N(R°)(Rd), -C(=NOR°)Rd, -P(O)(OR°)(ORd), -N(R°)(Rd), -alkyl-N(R°)(Rd), -N(R°)C(O)Rd, -CH2-N(R°)C(O)Rd, -CH2-N(R°)C(O)N(Rd)(Rb), -CH2-R0; -CH2N(R°)(Rd),
-N(R°)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(R°)S(O)2Rd, -N(R°)S(O)2N(Rd)(Rb), -N(R°)S(O)N(Rd)(Rb), -N(R°)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)R0, -N3, -NO2 and -S(O)2R0, wherein each Rb, R° and Rd is independently selected;
or still alternatively, said heterocycloalkyl for R12 in (ii) can be fused with aryl, wherein each of said heterocycloalkyl and aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =0, -C(O)RC, -C(O)OR0, -C(O)N(R°)(Rd), -SF5, -OSF5, -Si(R0J3, -SR0, S(O)N(R°)(Rd),
-CH(R°)(Rd), -S(O)2N(R°)(Rd), -C(=NOR°)Rd, P(O)(OR°)(ORd), -N(R°)(Rd), -alkyl-N(R°)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-R0; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected; or (iii) L is a heterocycloalkyl containing 1-4 heteroatoms which can be the same or different and are independently selected from the group consisting of O, S and N, wherein said heterocycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =O, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd,
-CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and -S(O)2RC, wherein each Rb, Rc and Rd is independently selected;
or alternatively, said heterocycloalkyl for L in (iii) can be fused with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -CN, -ORC, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC,
-S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, -N3, -NO2 and -S(O)2R0, wherein each Rb, Rc and Rd is independently selected;
or still alternatively, said heterocycloalkyl for L in (iii) can be fused with aryl, wherein each of said heterocycloalkyl and aryl can be unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -ORC, =O, -C(O)RC, -C(O)ORC, -C(O)N(Rc)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, P(O)(ORc)(ORd),
-N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-R0; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd,-N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, -NO2 and
-S(O)2R0, wherein each Rb, Rc and Rd is independently selected;
R3 is selected from the group of H, lower alkyl, hydroxy, halo, O-alkyl, O-haloalkyl, O-cycloalkyl, S-alkyl, S-haloalkyl, CN, CF3, -SF5, -OSF5, -Si(Rc)3, -SRC , cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, N-alkyl, N-haloalkyl, and N-cycloalkyl;
R4 is selected from the group of H, lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl;
R5 is selected from the group of lower alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryl, and heteroaryl; and R10 is (i) a 5-6-membered heterocyclyl ring having from 1 to 3 ring N atoms, (ii) an aryl ring, or (iii) a heteroaryl ring, wherein each of said heterocyclyl ring, aryl ring and heteroaryl ring is unsubstituted or optionally independently substituted, off of a ring N atom or a ring C atom, with one or more G moieties, wherein G is the same or different and is selected independently from:
*/wv>-(CH2),-C(O)-N(Rb)-Ra;
Figure imgf000346_0001
V/WVΛ-(CH2),-C(0)-0H; vAΛAΛ-C(O)-(cycloalkyl)- -C(O)-N(Rb)-Ra; v/vw-C(O)-(cycloalkyl)- -C(O)-OR5; vAΛΛΛ-C(O)-(cycloalkyl)— C(O)-OH; and
Figure imgf000346_0002
bioisostere; wherein Ra is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one or more moieties which are the same or different, each moiety being selected independently from the group consisting of O-haloalkyl, S-haloalkyl, CN, NO2, CF3, cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, N-alkyl, N-haloalkyl, and N-cycloalkyl; alkyl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -ORC, -C(O)RC, -C(O)OR0, -C(O)N(R°)(Rd), -SF5, -OSF5, -Si(Rc)3, -SRC, -S(O)N(Rc)(Rd), -CH(Rc)(Rd), -S(O)2N(Rc)(Rd), -C(=NORc)Rd, -P(O)(ORc)(ORd), -N(Rc)(Rd), -alkyl-N(Rc)(Rd), -N(Rc)C(O)Rd, -CH2-N(Rc)C(O)Rd, -CH2-N(Rc)C(O)N(Rd)(Rb), -CH2-RC; -CH2N(Rc)(Rd), -N(Rc)S(O)Rd, -N(Rc)S(O)2Rd, -CH2-N(Rc)S(O)2Rd, -N(Rc)S(O)2N(Rd)(Rb), -N(Rc)S(O)N(Rd)(Rb), -N(Rc)C(O)N(Rd)(Rb), -CH2-N(Rc)C(O)N(Rd)(Rb), -N(Rc)C(O)ORd, -CH2-N(Rc)C(O)ORd, -S(O)RC, =NORC, -N3, and -S(O)2R0; wherein each Rb, Rc and Rd is independently selected; Rb is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; Rc is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; Rd is H, lower alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein each of said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl in Rb, Rc, and Rd can be unsubstituted or optionally independently substituted with 1-2 substituents independently selected from halo, OH, NH2, CF3, CN, Oalkyl, MHalkyl, N(alkyl)2 and Si(alkyl)3; and t is 0, 1 , 2 or 3.
2. A compound, or a pharmaceutically acceptable salt of said compound, wherein the compound is selected from the group consisting of the following:
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000351_0003
Figure imgf000351_0002
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
3. A pharmaceutical composition comprising an effective amount of at least one compound of Claim 1 and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising an effective amount of at least one compound of Claim 2 and a pharmaceutically acceptable carrier.
5. A method of treating a cardiovascular disease, a metabolic disorder, obesity, an obesity-related disorder, dyslipidemia, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose in a patient, comprising administering to the patient an effective amount of at least one compound of Claim 1.
6. A method of treating a cardiovascular disease, a metabolic disorder, obesity, an obesity-related disorder, dyslipidemia, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose in a patient, comprising administering to the patient an effective amount of at least one compound of Claim 2.
7. The method of claim 5, wherein the disease treated is diabetes.
8. The method of claim 6, wherein the diabetes is Type Il diabetes.
9. The method of claim 5, wherein the disease treated is obesity.
10. The method of claim 5, wherein the disease treated is a metabolic disorder.
11. The method of claim 5, further comprising administering to the patient an effective amount of at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is selected from an antidiabetic agent or an antiobesity agent.
12. The method of claim 11 , wherein the disease treated is diabetes.
13. The method of claim 12, wherein the diabetes is Type Il diabetes.
14. The method of claim 6, wherein the disease treated is a metabolic disorder.
15. The method of claim 6, further comprising administering to the patient an effective amount of at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is selected from an antidiabetic agent or an antiobesity agent.
PCT/US2009/064747 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase WO2010059606A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP09752999A EP2346853A2 (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase
US13/129,830 US20110224136A1 (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase
AU2009316790A AU2009316790A1 (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase
MX2011005233A MX2011005233A (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase.
CA2743723A CA2743723A1 (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase
JP2011536592A JP2012509275A (en) 2008-11-19 2009-11-17 Diacylglycerol acyltransferase inhibitors
CN2009801549615A CN102282138A (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11598208P 2008-11-19 2008-11-19
US11598508P 2008-11-19 2008-11-19
US61/115,985 2008-11-19
US61/115,982 2008-11-19

Publications (2)

Publication Number Publication Date
WO2010059606A2 true WO2010059606A2 (en) 2010-05-27
WO2010059606A3 WO2010059606A3 (en) 2010-09-16

Family

ID=42110050

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/064747 WO2010059606A2 (en) 2008-11-19 2009-11-17 Inhibitors of diacylglycerol acyltransferase

Country Status (10)

Country Link
US (1) US20110224136A1 (en)
EP (1) EP2346853A2 (en)
JP (1) JP2012509275A (en)
CN (1) CN102282138A (en)
AR (1) AR074129A1 (en)
AU (1) AU2009316790A1 (en)
CA (1) CA2743723A1 (en)
MX (1) MX2011005233A (en)
TW (1) TW201031658A (en)
WO (1) WO2010059606A2 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011046954A1 (en) * 2009-10-13 2011-04-21 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
WO2012024179A1 (en) * 2010-08-18 2012-02-23 Merck Sharp & Dohme Corp. Substituted amide derivatives as dgat-1 inhibitors
WO2012029032A3 (en) * 2010-09-03 2012-05-18 Piramal Life Sciences Limited Heterocyclic compounds as dgat1 inhibitors
US9126992B2 (en) 2009-05-12 2015-09-08 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
US9820975B2 (en) 2009-06-26 2017-11-21 Romark Laboratories L.C. Compounds and methods for treating influenza

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2009004785A (en) * 2006-10-31 2009-06-05 Schering Corp 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors.
WO2010059602A2 (en) * 2008-11-19 2010-05-27 Schering Corporation Inhibitors of diacylglycerol acyltransferase
JP4494516B1 (en) * 2008-11-21 2010-06-30 花王株式会社 Liquid detergent composition
WO2017068090A1 (en) 2015-10-23 2017-04-27 Vifor (International) Ag Novel ferroportin inhibitors
JOP20180036A1 (en) 2017-04-18 2019-01-30 Vifor Int Ag Novel ferroportin-inhibitor salts

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026197A1 (en) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Novel inhibitors of impdh enzyme
WO2005030206A1 (en) * 2003-09-24 2005-04-07 Imclone Systems Incorporated Aryl-1,3-azole derivatives and methods for inhibiting heparnase activity
WO2006064189A1 (en) * 2004-12-14 2006-06-22 Astrazeneca Ab Oxadiazole derivatives as dgat inhibitors
WO2007022258A1 (en) * 2005-08-17 2007-02-22 Schering Corporation Novel high affinity thiophene-based and furan-based kinase ligands
CA2649043A1 (en) * 2006-04-19 2007-11-01 Astellas Pharma Inc. Azolecarboxamide derivative

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8153644B2 (en) * 2007-05-22 2012-04-10 Madrigal Pharmaceuticals, Inc. Diacylglycerol acyltransferase inhibitors
US8058299B2 (en) * 2007-05-22 2011-11-15 Via Pharmaceuticals, Inc. Diacylglycerol acyltransferase inhibitors
US20090076275A1 (en) * 2007-09-19 2009-03-19 David Robert Bolin Diacylglycerol acyltransferase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026197A1 (en) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Novel inhibitors of impdh enzyme
WO2005030206A1 (en) * 2003-09-24 2005-04-07 Imclone Systems Incorporated Aryl-1,3-azole derivatives and methods for inhibiting heparnase activity
WO2006064189A1 (en) * 2004-12-14 2006-06-22 Astrazeneca Ab Oxadiazole derivatives as dgat inhibitors
WO2007022258A1 (en) * 2005-08-17 2007-02-22 Schering Corporation Novel high affinity thiophene-based and furan-based kinase ligands
CA2649043A1 (en) * 2006-04-19 2007-11-01 Astellas Pharma Inc. Azolecarboxamide derivative

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE47786E1 (en) 2009-05-12 2019-12-31 Romark Laboratories L.C. Haloalkyl heteroaryl benzamide compounds
US9126992B2 (en) 2009-05-12 2015-09-08 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
USRE46724E1 (en) 2009-05-12 2018-02-20 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
AU2010247816B2 (en) * 2009-05-12 2015-12-17 Romark Laboratories L.C. Haloalkyl heteroaryl benzamide compounds
US9820975B2 (en) 2009-06-26 2017-11-21 Romark Laboratories L.C. Compounds and methods for treating influenza
US11850237B2 (en) 2009-06-26 2023-12-26 Romark Laboratories L.C. Compounds and methods for treating influenza
US10912768B2 (en) 2009-06-26 2021-02-09 Romark Laboratories L.C. Compounds and methods for treating influenza
US10363243B2 (en) 2009-06-26 2019-07-30 Romark Laboratories L.C. Compounds and methods for treating influenza
US9144557B2 (en) 2009-10-13 2015-09-29 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
US9622991B2 (en) 2009-10-13 2017-04-18 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
WO2011046954A1 (en) * 2009-10-13 2011-04-21 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
WO2012024179A1 (en) * 2010-08-18 2012-02-23 Merck Sharp & Dohme Corp. Substituted amide derivatives as dgat-1 inhibitors
JP2013538808A (en) * 2010-09-03 2013-10-17 ピラマル エンタープライジーズ リミテッド Heterocyclic compounds as DGAT1 inhibitors
CN103228633A (en) * 2010-09-03 2013-07-31 皮拉马尔企业有限公司 Heterocyclic compounds as DGAT1 inhibitors
WO2012029032A3 (en) * 2010-09-03 2012-05-18 Piramal Life Sciences Limited Heterocyclic compounds as dgat1 inhibitors

Also Published As

Publication number Publication date
JP2012509275A (en) 2012-04-19
MX2011005233A (en) 2011-06-01
EP2346853A2 (en) 2011-07-27
AR074129A1 (en) 2010-12-22
US20110224136A1 (en) 2011-09-15
TW201031658A (en) 2010-09-01
CA2743723A1 (en) 2010-05-27
CN102282138A (en) 2011-12-14
WO2010059606A3 (en) 2010-09-16
AU2009316790A1 (en) 2010-05-27

Similar Documents

Publication Publication Date Title
US8716312B2 (en) Inhibitors of diacylglycerol acyltransferase
EP2346853A2 (en) Inhibitors of diacylglycerol acyltransferase
US20120172369A1 (en) Inhibitors of diacylglycerol acyltransferase
US8637507B2 (en) Bicyclic compounds as inhibitors of diacylglycerol acyltransferase
US8586751B2 (en) Nicotinamide compounds useful as kinase modulators
US20070167435A1 (en) Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
CA2634847A1 (en) Substituted aniline derivatives useful as histamine h3 antagonists
AU2014248763A1 (en) Substituted piperidine compounds and their use as orexin receptor modulators
EP3373935B1 (en) Cyanopyridine derivatives as liver x receptor beta agonists, compositions, and their use
US20110224193A1 (en) Inhibitors of diacylglycerol acyltransferase
US9486448B2 (en) Pyrrolidine derived beta 3 adrenergic receptor agonists
US20240279215A1 (en) Nampt modulators

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980154961.5

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09752999

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2009316790

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 3510/DELNP/2011

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2743723

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2011536592

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 13129830

Country of ref document: US

Ref document number: MX/A/2011/005233

Country of ref document: MX

Ref document number: 2009752999

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2009316790

Country of ref document: AU

Date of ref document: 20091117

Kind code of ref document: A