WO2015123355A1 - Substituted prolines / piperidines as orexin receptor antagonists - Google Patents

Substituted prolines / piperidines as orexin receptor antagonists Download PDF

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WO2015123355A1
WO2015123355A1 PCT/US2015/015500 US2015015500W WO2015123355A1 WO 2015123355 A1 WO2015123355 A1 WO 2015123355A1 US 2015015500 W US2015015500 W US 2015015500W WO 2015123355 A1 WO2015123355 A1 WO 2015123355A1
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methyl
compound
disorder
group
substituted
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PCT/US2015/015500
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French (fr)
Inventor
Theodore M. Kamenecka
Yuanjun He
Rong Jiang
William Nguyen
Xinyi Song
Robert Jason Herr
Keith Barnes
Steven D. Young
Qin Jiang
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Eolas Therapeutics, Inc.
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Priority claimed from US14/179,432 external-priority patent/US9499517B2/en
Priority claimed from US14/460,289 external-priority patent/US9440982B2/en
Application filed by Eolas Therapeutics, Inc. filed Critical Eolas Therapeutics, Inc.
Publication of WO2015123355A1 publication Critical patent/WO2015123355A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • 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
    • 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
    • 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

Definitions

  • each R' is independently at each occurrence hydrogen, (C 1 -C 12 )-alkyl, (C 2 - C 12 )-alkenyl, (C 2 -C 12 )-alkynyl, (C 3 -C 10 )-cycloalkyl, (C 3 -C 10 )-cycloalkenyl, [(C 3 - C 10 )cycloalkyl or (C 3 -C 10 )-cycloalkenyl]-[(C 1 -C 12 )-alkyl or (C 2 -C 12 )-alkenyl or (C 2 -C 12 )- alkynyl], (C 6 -Ci 0 )-aryl, (C 6 -Ci 0 )-aryl-[(Ci-Ci 2 )-alkyl or (C 2 -Ci 2 )-alkenyl or (C 2 -Ci 2 )- alkynyl], mono- or bicycl
  • each ring in any bicyclic or tricyclic ring system, each ring is linearly fused, bridged, or spirocyclic, wherein each ring is either aromatic or nonaromatic, wherein each ring can be fused to a (C6-C 1 o)aryl, mono- or bicyclic 5-10 membered heteroaryl, (C 3 -C 1 o)cycloalkyl or mono- or bicyclic 3-10 membered heterocyclyl;
  • C 1-3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • C 3 _ 6 cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6 carbon ring atoms.
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy- carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl
  • tetrahydropyranyl substituted ethyl ethers such as ethoxyethyl, tert-butyl, or allyl; acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form carbonates with the protected hydroxyl) such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
  • adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
  • the oxygen substituent is termed an "oxo” group.
  • a divalent substituent such as NR' is double-bonded to a carbon atom
  • (Cycloalkyl) alkyl groups also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • a "cycloheteroalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cyclohetero alkyl ring can also be termed a “heterocyclyl,” described below.
  • the term “heteroalkenyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • the term "amine” also includes ammonium ions as used herein.
  • benzenesulfonic pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric, salicylic, galactaric and galacturonic acid.
  • pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
  • a "hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • Z can be an oxygen atom, in which case R 2 is absent.
  • D comprises a carbonyl group (e.g., pyridoyl, quinoloyl, benzofuranoyl, and the like)
  • Z as an oxygen atom forms an ester bond with the D group.
  • D does not comprise a carbonyl group in the bonding position (pyridyl, quinolyl, benzofuranyl, and the like)
  • Z as an oxygen atom forms an ether bond with the D group.
  • the invention provides a compound of formula (I) wherein B comprises phenyl, pyridyl, pyrazidinyl, pyrimidinyl, pyrazinyl, pyrolyl, pyrazolyl, oxazolyl, imidazolyl, oxadiazolyl, ⁇ l,2,3)-triazolyl, (l,2,4)-triazolyl, wherein B can each independently be unsubstituted or can each independently be mono- or multi- substituted with J or with R' , or both; or any salt or hydrate thereof.
  • R 10 is H or methyl
  • heteroatoms selected from the group consisting of N, O, and S;
  • each R x is independently selected from the group consisting of -F, -CI, -Br, methyl, methoxy, -CN, - CF 3 , cyclopropyl, and cyano-cyclopropyl. In some embodiments, R x is -CF or -CI.
  • t is 1. In still other embodiments, t is 2. In some embodiments, the group
  • compounds as described herein are of Formula (la):
  • the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically- acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
  • Drug or substance abuse or addiction includes relapse.
  • Drug abuse and addiction can include abuse of or addiction to cocaine, opiates, amphetamines, or nicotine.
  • Drug abuse and/or addiction can also include abuse of and/or addiction to alcohol, cannabis, heroin, and/or any other drug of abuse.
  • the compounds described herein are useful in a method of treating disorders including, but not limited to, sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the ratio of the time that a subject sleeps relative to the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency, or duration of REM sleep bouts;
  • cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline;
  • schizophrenia including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder
  • mood disorders including depression, mania, bipolar disorders
  • Y for eventual displacement in a nucleophilic substitution reaction by amine D-NHR , particularly when the D group is not bonded to the nitrogen atom via a carbonyl group, e.g., when D is pyridyl instead of pyridoyl, quinolyl instead of quinoloyl, etc.
  • D is pyridyl instead of pyridoyl
  • quinolyl instead of quinoloyl
  • Y may also be a carboxaldehyde group and coupled with DNHR by reductive amination.
  • the atom labeled Y becomes the Z group of formula (I).
  • pyrrolidine, piperidine, and aziridine precursors can be prepared according to literature procedures and upon disclosed synthetic approaches described below in the Examples, using the knowledge of ordinary practitioners of organic synthetic chemistry.
  • Example 16 rac-ci5 , -(2-(((5-Ethylpyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
  • Example 26 rac-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(2-methyl-6-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
  • Part I rac-(2-(Aminomethyl)-6-methylpiperidin-l-yl)(2-methyl-4-phenylthiazol-5- yl)methanone.
  • N-((5,5-Dimethoxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedures I, using (2-(Hydroxymethyl)-5,5-dimethoxypiperidin-l-yl)(2-methyl-4-phenylthiazol-5 yl)methanone.
  • Example 45 N-((l-(2-Methyl-4-phenylthiazole-5-carbonyl)-5- (methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide.
  • N-((5-(Ethylamino)-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide and ethyl amine. (ESI) 514 (M+H).
  • Example 48 N-((5-(Isopropylamino)-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
  • Example 58 rac-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methyl)benzofuran-4-carboxamide.
  • Example 62 rac-ci5 , -N-((3-Methyl-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)
  • Part III Ethyl 2-(2-benzyloctahydro-lH-isoindol-l-yl)acetate.
  • Part III (l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl- 5-phenylthiazol-4-yl)methanone.
  • Example 71 N-(((l t S , ,3a t S'Ja t S')-2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahvdro-lH- isoindol-l-yl)methyl)benzofuran-4-carboxamide.
  • Example 73 rac-ci5 , -(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-5-phenylthiazol-4-yl)methanone.
  • Example 76 rac-ci5 , -(3-Ethyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) -(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.

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Abstract

The present invention is directed to compounds that modulate the bioactivity of an orexin receptor such as OX1 or OX2, or both; to pharmaceutical compositions and combinations comprising a compound of the invention; to methods of treatment of malconditions in patients wherein modulation of an orexin receptor is medically indicated; and to methods of preparation of compounds of the invention. For example, orexin receptor- modulatory compounds of the present invention can be used in treatment of an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction including addiction to cocaine, opiates, amphetamines, or nicotine, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, post-traumatic stress disorder, seasonal affective disorder, an eating disorder, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, headache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, or renal disease.

Description

SUBSTITUTED PROLINES / PIPERIDINES AS OREXIN RECEPTOR
ANTAGONISTS
STATEMENT OF GOVERNMENT SUPPORT
[0001] This invention was made with government support under Grant Numbers 5 ROl DA023915, 1 P01 DA033622, and 1U01NS083614 awarded by the National Institutes of Health. The government has certain rights in the invention.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims priority to U.S. Provisional Application Serial No.
62/037,471, filed August 14, 2014, U.S. Application Serial No. 14/460,289, filed August 14, 2014, and U.S. Application Serial No. 14/179,432, filed February 12, 2014. The content of the above-referenced applications are incorporated herein by reference in their entireties.
BACKGROUND
[0003] Orexins are a family of homologous peptides including species orexin A, or OR-A, and orexin B, or OR-B. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell (1998), 92, 573-585). Orexins are produced in neurons of the lateral hypothalamus and bind to at least two distinct G-protein-coupled receptors, termed OXi and OX2 receptors. The receptor OXi is selective for OR-A, while the receptor OX2 can bind both OR-A and OR-B. Orexins are found to stimulate food consumption, regulate states of sleep and wakefulness, and may be involved in neural mechanisms of drug abuse and addiction.
[0004] There remains a need for small molecule modulators of orexin receptors, including OXi and OX2, with desirable pharmaceutical properties. Certain piperidine amide compounds have been found in the context of this invention to have this advantageous activity profile.
SUMMARY
[0005] The present invention is directed to compounds that can modulate the bioactivity of an orexin receptor such as OXi or OX2, or both; to pharmaceutical compositions and combinations comprising a compound of the invention; to methods of treatment of malconditions in patients wherein modulation of an orexin receptor is medically indicated; and to methods of preparation of compounds of the invention. [0006] In various embodiments, the invention provides receptor-modulatory non-peptidic small molecules that can activate or inhibit one or more classes of orexin receptors in the human nervous system. In one embodiment, the invention provides a compound of formula (I),
Figure imgf000004_0001
wherein
A comprises aryl or heteroaryl;
B is absent, or comprises aryl, aryloxy, heteroaryl, or heteroaryloxy;
wherein A or B or both can each independently be unsubstituted or can each independently be mono- or multi- substituted with J or with R', or both;
D comprises aryl, aroyl, heteroaryl, or heteroaroyl, wherein D can be unsubstituted or can be mono- or independently multi- substituted with J or with R', or with both;
Z is N or O, provided that when Z is O, R is absent
R1 comprises independently at each occurrence halo, oxo, hydroxy, cyano, (C1-4)alkyl, (C1-4)alkoxy, (C1-4)acyloxy, (C1-4)acylamido, haloalkyl, haloalkoxy, NRaRb, C(=0)NRaRb, C(=0)ORa, S02Ra, S02NRaRb, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl;
or one or more R1 groups together with the ring to which they are bonded form a bicyclo[2.2.2], bicyclo[3.3.0], or bicyclo[4.3.0] ring system, wherein any bicyclo ring system can be ds-fused or inms-fused, wherein any alkyl, alkoxy, bicyclo ring system, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl can be mono- or independently multi-substituted with J or with R', or with both;
Ra and Rb are independently at each occurrence H, (C1_4)alkyl, aralkyl, (C1_s)acyl, or Ra and Rb together with the nitrogen atom to which they are bonded form a 4-7 membered ring optionally further comprising 1 or 2 NRC, O, S, SO, or S02, wherein Rc is H or (C .
4)alkyl, wherein any Ra, Rb, or Rc can be mono- or independently multi- substituted with J or with R', or both; R 2 comprises H, (C1_4)alkyl, or (C1_s)acyl, or R 2 together with D and the nitrogen atom to which they are bonded form a phthalimido group, wherein any alkyl, acyl, or phthalimido group is optionally mono- or independently multi- substituted with J or with R', or with both;
J is halogen, (Cl-C6)alkyl, OR', CN, CF3, OCF3, =0, =S, C(O), S(O),
methylenedioxy, ethylenedioxy, (CH2)o-pN(R')2, (CH2)0-PSR', (CH2)0-pS(O)R', (CH2)0_ pS(0)2R', (CH2)o-pS(0)2N(R')2, (CH2)0-pSO3R', (CH2)0-pC(O)R', (CH2)0_pC(O)C(O)R', (CH2)0_ pC(0)CH2C(0)R', (CH2)o-PC(S)R', (CH2)0-PC(O)OR', (CH2)0-POC(O)R', (CH2)0-PC(O)N(R')2, (CH2)o-POC(0)N(R')2, (CH2)o-PC(S)N(R')2, (CH2)0-PNH-C(O)R', (CH2)0-PN(R')N(R')C(O)R', (CH2)o-pN(R')N(R')C(0)OR', (CH2)0-PN(R')N(R')CON(R')2, (CH2)0-pN(R')SO2R', (CH2)0_ pN(R')S02N(R')2, (CH2)o-pN(R')C(0)OR', (CH2)0-pN(R')C(O)R', (CH2)0-PN(R')C(S)R', (CH2)0_ pN(R')C(0)N(R')2, (CH2)o-PN(R')C(S)N(R')2, (CH2)0-PN(COR')COR', (CH2)0-PN(OR')R', (CH2)o-PC(=NH)N(R')2, (CH2)o-PC(0)N(OR')R', or (CH2)0-PC(=NOR')R';
wherein, each R' is independently at each occurrence hydrogen, (C1-C12)-alkyl, (C2- C12)-alkenyl, (C2-C12)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, [(C3- C10)cycloalkyl or (C3-C10)-cycloalkenyl]-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)- alkynyl], (C6-Ci0)-aryl, (C6-Ci0)-aryl-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)- alkynyl], mono- or bicyclic 3-10 membered heterocyclyl, mono- or bicyclic 3-10 membered heterocyclyl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 5-10 membered heteroaryl, or mono- or bicyclic 5-10 membered heteroaryl-[(C1-C12)-alkyl or (C2- C12)-alkenyl or (C2-C12)-alkynyl], wherein R' is substituted with 0-3 substituents selected independently from J ;
or, when two R' are bound to a nitrogen atom or to two adjacent nitrogen atoms, the two R' groups together with the nitrogen atom or atoms to which they are bound can form a 3- to 8-membered monocyclic heterocyclic ring, or an 8- to 20-membered, bicyclic or tricyclic, heterocyclic ring system, wherein any ring or ring system can further contain 1-3 additional heteroatoms selected from the group consisting of N, NR', O, S, S(O) and S(0)2, wherein each ring is substituted with 0-3 substituents selected independently from J ;
wherein, in any bicyclic or tricyclic ring system, each ring is linearly fused, bridged, or spirocyclic, wherein each ring is either aromatic or nonaromatic, wherein each ring can be fused to a (C6-C1o)aryl, mono- or bicyclic 5-10 membered heteroaryl, (C3-C1o)cycloalkyl or mono- or bicyclic 3-10 membered heterocyclyl;
JR is halogen, OR, CN, CF3, OCF3, =0, =S, C(O), S(O), methylenedioxy,
ethylenedioxy, (CH2)0_PN(R)2, (CH2)0_PSR, (CH2)0_pS(O)R, (CH2)0_pS(O)2R, (CH2)0_ pS(0)2N(R)2, (CH2)o-pS03R, (CH2)0_pC(O)R, (CH2)0_pC(O)C(O)R, (CH2)0_pC(O)CH2C(O)R, (CH2)o-pC(S)R, (CH2)o-pC(0)OR, (CH2)0_pOC(O)R, (CH2)0_pC(O)N(R)2, (CH2)0_ pOC(0)N(R)2, (CH2)o-pC(S)N(R)2, (CH2)0_pNH-C(O)R, (CH2)0_pN(R)N(R)C(O)R, (CH2)0_ pN(R)N(R)C(0)OR, (CH2)o-PN(R)N(R)CON(R)2, (CH2)0_PN(R)SO2R, (CH2)0_
pN(R)S02N(R)2, (CH2)o-PN(R)C(0)OR, (CH2)0_PN(R)C(O)R, (CH2)0_PN(R)C(S)R, (CH2)0_ pN(R)C(0)N(R)2, (CH2)o-pN(R)C(S)N(R)2, (CH2)0_PN(COR)COR, (CH2)0_PN(OR)R, (CH2)0_ PC(=NH)N(R)2, (CH2)o-pC(0)N(OR)R, or (CH2)0-PC(=NOR)R; and,
R is independently at each occurrence hydrogen, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-Ci2)-alkynyl, (C3-Ci0)-cycloalkyl, (C3-Ci0)-cycloalkenyl, [(C3-Ci0)cycloalkyl or (C3-C10)- cycloalkenyl]-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)-alkynyl], (C6-Ci0)-aryl, (C6- C1o)-aryl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 3-10 membered heterocyclyl, mono- or bicyclic 3-10 membered heterocyclyl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 5-10 membered heteroaryl, or mono- or bicyclic 5-10 membered heteroaryl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)- alkynyl] ;
m is 0, 1, 2, 3, 4, 5, or 6; n is 1, 2, or 3; p = 0, 1, or 2; r = 0, 1, 2, or 3;
or any salt or hydrate thereof.
[0007] In another embodiment, the invention relates to a chemical entity of the following Formula (la):
Figure imgf000006_0001
wherein
X is NH, N(C1_4alkyl), or O;
R1 is pyridinyl, pyrimidinyl, benzoxazolyl, benzothiazolyl, or quinazolinyl, each
unsubstituted or substituted with one or more substituents selected from the group consisting of Ci^haloalkyl or halo; or
X and R1 taken together form pyrrolyl or dihydropyrrolyl, unsubstituted or substituted with C^haloalkyl or halo;
R 2" and R 3J are defined as in (a) or (b):
(a) R 2 is thiazolyl substituted with C1-4alkyl; and R 3 is phenyl substituted with halo; or
(b) R is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C^alkyl, -OC^alkyl, or halo; and R is triazolyl or pyrimidinyl; or a pharmaceutically acceptable salt thereof.
[0008] In various embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.
[0009] In various embodiments, the invention provides a method of modulating an orexin receptor, such as OXi or OX2, or both, comprising contacting the receptor with an effective amount or concentration of a compound of the invention.
[0010] In various embodiments, the invention provides a method of treating a malcondition in a patient wherein modulation of an orexin receptor is medically indicated, comprising administering to the patient a compound of the invention in a dose, at a frequency, and for a duration to provide a beneficial effect to the patient. The orexin receptor can be OX1; or can be OX2. In various embodiments, the malcondition can comprise an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine- related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, and renal disease. Drug abuse and addiction can include abuse of or addiction to cocaine, opiates, amphetamines, ethanol,
cannabis/marijuana, or nicotine.
[0011] In certain embodiments, the compound is a compound selected from those species described or exemplified in the detailed description below.
[0012] In a further aspect, described herein is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof.
Pharmaceutical compositions as described herein may further comprise a pharmaceutically acceptable excipient. Also described herein is a compound of Formula (I) of Formula (la) or a pharmaceutically acceptable salt thereof for use as a medicament.
[0013] In another aspect, described herein are methods of treating a disease, disorder, or medical condition mediated by orexin receptor activity, such as those described herein, comprising administering to a subject in need of such treatment an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.
[0014] In another aspect, described herein is the use of a compound described herein in the preparation of a medicament for the treatment of such diseases and medical conditions, and the use of such compounds and salts for treatment of such diseases and medical conditions. [0015] In yet another aspect, described herein is a method of modulating the activity of an orexin receptor, such as one or both of OXi or OX2, comprising contacting a cell comprising an orexin receptor with an effective amount of at least one compound described herein or a salt thereof, and/or with at least one compound or pharmaceutical composition as described herein, wherein the contacting is in vitro, ex vivo, or in vivo.
[0016] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.
[0017] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1 shows the results of testing Example 11 (racemic, see PCT Publ. No.
WO2011/119639) in a food and nicotine self-administration assay. Figure 1A shows the food acquisition results for knock-out (KO) and wild-type (WT) mice. Figure IB shows the food acquisition results for Example 11. Figure 1C shows the results for mice that were given a virus to site- specifically restore Hcrt-IR expression or an empty vector (control) in the dorsal thalamus three weeks prior to the initiation of the experiment. Figure ID shows that lentiviral restoration of Hcrt-IR expression in the dorsal thalamus of KO mice restored nicotine self-administration.
[0019] FIG. 2 shows the results of the nicotine self-administration assay for an orexin-2 selective antagonist, JNJ 10397049 at 5 mg/kg and 10 mg/kg. Figure 2A shows the effect of the test compound on food self-administration. Figure 2B shows the results for JNJ 10397049 in the nicotine self-administration arm.
[0020] FIG. 3 shows the effects of Example Al in the nicotine self-administration assay (rats). Figure 3 A shows that Example Al produced a dose-dependent reduction in nicotine self-administration, while Figure 3B shows that Example Al does not have a significant effect on food intake.
[0021] FIG. 4 shows the percent baseline responding for food or nicotine using Example Al at several doses in the nicotine self-administration assay (rats).
[0022] FIG. 5 shows the results of the nicotine self-administration assay for Example Bl. In Figure 5 A, Example B 1 is shown to produce a dose-dependent reduction in nicotine self- administration. Figure 5B shows that food intake is not affected by Example Bl at a range of doses. [0023] FIG. 6 shows the effect of Example Bl in a model of relapse measuring the extinction (Figure 6A) and reinstatement (Figure 6B) of nicotine-seeking behavior in rats.
[0024] FIG. 7 shows the effect of the dual OXi/OXi antagonist, suvorexant, in the nicotine self-administration assay. Figure 7A shows the effect on nicotine self-administration and Figure 7B shows the effect on food intake.
[0025] FIG. 8 shows the effect of varenicline in the nicotine self-administration assay. Figure 8A shows the effect on nicotine self-administration. Figure 8B shows the effect on food intake.
[0026] FIG. 9 shows the results of the nicotine self-administration assay for Example A259. FIG. 9A shows the effect of Example A259 on nicotine self-administration with oral dosing. FIG. 9B shows no effect on responding for food at the same doses.
[0027] FIG. 10 shows the effect of Example A259 on nicotine self-administration with chronic oral dosing on days 4-8.
DETAILED DESCRIPTION OF THE INVENTION
[0028] It is to be understood that the present description is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.
[0030] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. [0031] The term "about" as used herein, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.
[0032] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about." It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[0034] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley- Interscience, 2001.
[0035] The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. This nomenclature has generally been derived using the commercially- available ChemBioDraw Ultra software (Cambridgesoft/Perkin Elmer), Version 12.0.
[0036] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub -combination of chemical groups was individually and explicitly disclosed herein.
[0037] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.
[0038] As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats. Non-mammals include, for example, fish and birds.
[0039] The term "disease" or "disorder" or "malcondition" are used interchangeably, and are used to refer to diseases or conditions wherein an orexin receptor plays a role in the biochemical mechanisms involved in the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on the receptor. "Acting on" an orexin receptor can include binding to the orexin receptor and/or inhibiting the bioactivity of the orexin receptor.
[0040] The expression "effective amount", when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on an orexin receptor in the individual's tissues wherein the orexin receptor involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
[0041] "Substantially" as the term is used herein means completely or almost completely; for example, a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is
"substantially pure" is there are only negligible traces of impurities present.
[0042] By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only
"chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
[0043] When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.
[0044] All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. In various embodiments, the invention can provide enantiomerically pure forms of the claimed compounds, or racemic mixtures, or enantionmerically enriched mixtures, or (when more than a single chiral center is present), diastereomerically pure compounds, or diastereomeric mixtures in any relative proportions.
[0045] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium (1H), deuterium
( 2 H), or tritium ( 3 H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as UC, 12C, 13C, or 14C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13N, 14N, or 15N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14N and 15N, 32S and 34S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, 14C and 3H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14C and 3H are
incorporated into precursor molecules, followed by further elaboration as needed.
[0046] Additional isotopically labeled forms include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, UC, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, 36C1, and 125I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies
(with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies. PET and SPECT studies may be performed as described, for example, by Brooks, D.J., "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development," NeuroRx 2005, 2(2), 226-236, and references cited therein. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0047] The nomenclature "(ATOM);. ' with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3). Similarly, for example, C3_6cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6 carbon ring atoms.
[0048] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ^ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
[0049] The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in "Protective Groups in Organic Synthesis," Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy- carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl,
a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl- 9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl,
cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
[0050] The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in "Protective Groups in Organic Synthesis," Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include substituted methyl ethers such as methoxymethyl or
tetrahydropyranyl; substituted ethyl ethers such as ethoxyethyl, tert-butyl, or allyl; acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form carbonates with the protected hydroxyl) such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)- 1- methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl,
isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand. [0051] A "carboxyl-activating" group or procedure, as the term is used herein, refers to a group replacing the hydroxyl group of a carboxyl to form a species that more readily undergoes reactions with nucleophilic reagents such as alcohols and amines. An example is an acyl halide, such as an acid chloride, that is activated for reactions leading to the formation of esters and amides. Another example is an N-hydroxy ester of a carboxylic acid, such as an N-hydroxysuccinimide ester, or an N-hydroxybenzotriazole ester. Another example is a carbodiimide that reacts with the hydroxyl group of a carboxyl group to form an O- acylisourea, that is thus activated for subsequent reaction with a nucleophile.
[0052] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, or I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R')2, CN, NO, N02, ON02, azido, CF3, OCF3, R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', S02R', S02N(R')2, S03R', C(0)R', C(0)C(0)R', C(0)CH2C(0)R', C(S)R', C(0)OR',
OC(0)R', C(0)N(R')2, OC(0)N(R')2, C(S)N(R')2, (CH2)0-2N(R')C(O)R', (CH2)0_2N(R')N(R')2, N(R')N(R')C(0)R', N(R')N(R')C(0)OR', N(R')N(R')CON(R')2, N(R')S02R', N(R')S02N(R')2, N(R')C(0)OR', N(R')C(0)R', N(R')C(S)R', N(R')C(0)N(R')2, N(R')C(S)N(R')2,
N(COR')COR', N(OR')R', C(=NH)N(R')2, C(0)N(OR')R', or C(=NOR')R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.
[0053] When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as
0, which is divalent, it can be bonded to the atom it is substituting by more than one bond,
1. e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=0, which can also be written as "CO," "C(O)," or "C(=0)," wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. When a divalent substituent such as NR' is double-bonded to a carbon atom, the resulting C(=NR') group is termed an "imino" group. When a divalent substituent such as S is double-bonded to a carbon atom, the results C(=S) group is termed a "thiocarbonyl" group.
[0054] Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(0)2 can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non- adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR'2)n wherein n is 1, 2, 3, or more, and each R' is
independently selected.
[0055] C(O) and S(0)2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom. For example, when a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide" or "carboxamide." When a C(O) group is bound to two nitrogen atoms, the functional group is termed a urea. When a
S(0)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide." When a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamate."
[0056] Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
[0057] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein. [0058] By a "ring system" as the term is used herein is meant a moiety comprising one, two, three, or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyclic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
[0059] As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
[0060] Selected substituents within the compounds described herein are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
[0061] Recursive substituents are an intended aspect of the disclosed subject matter. One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in a claim of the disclosed subject matter, the total number should be determined as set forth above.
[0062] Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and t- pentyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. [0063] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some
embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term
"cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.
[0064] The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N - 1 (N minus 1) substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
[0065] (Cycloalkyl) alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
[0066] Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. [0067] Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
[0068] (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
[0069] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH3), - C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.
[0070] The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH2-CH2-CH3, -CH2-CH2CH2-OH,
-CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2CH2-S(=0)-CH3, and -CH2CH2-0-CH2CH2-0- CH . Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH , or -CH2-CH2-S-S-CH3.
[0071] A "cycloheteroalkyl" ring is a cycloalkyl ring containing at least one heteroatom. A cyclohetero alkyl ring can also be termed a "heterocyclyl," described below. [0072] The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-0-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3,
-CH2-CH=CH-CH2-SH, and and -CH=CH-0-CH2CH2-0-CH3.
[0073] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be
unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
[0074] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
Representative aralkyl groups include benzyl and phenylethyl groups and fused
(cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
[0075] An "aroyl" group, as the term is used herein, refers to an aryl group bonded via an exocyclic carbonyl group, such as a benzoyl group.
[0076] Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
[0077] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. In some embodiments, heteroaryl groups have 5, 6, 8, 9, or 10 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2- heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6- membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4- heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be un substituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
[0078] A "heteroaroyl" group, as the term is used herein, refers to a heteroaryl group bonded via an exocyclic carbonyl group, analogous to a benzoyl group but wherein the phenyl ring of the benzoyl group is replaced by a heteroaryl group.
[0079] Various synonyms can be used throughout in the naming of heteroaryl groups, among others. As used herein, the term "pyridyl" is synonymous with "pyridinyl," the term "quinolyl" is synonymous with the term "quinolinyl," and so forth. The term
"phthalimidoyl" or "phthalimido" refers to a phthalimide group bonded by its nitrogen atom. The term "pyridoyl" refers to a pyridylcarbonyl group; the term "quinoloyl" refers to a quinolylcarbonyl group, and so forth. The carbonyl group can be disposed at any position; for example, for "pyridoyl", any of the following structures are indicated:
Figure imgf000023_0001
wavy line indicates a point of attachment. Similarly, the term "quinoloyl" refers to a quinoline ring bearing a carbonyl group at any chemically feasible position of substitution, the term "isoquinoloyl" refers to an isoquinoline ring bearing a carbonyl group at any chemically feasible position of substitution, and so forth.
[0080] Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),
6- (2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo [b] thiophenyl) , 3- (2,3-dihydro-benzo [b] thiophenyl) , 4-(2,3 -dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,
3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,
4- indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8 -benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7- benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl,
5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,1 l-dihydro-5H-dibenz[b,f]azepine (10,1 l-dihydro-5H-dibenz[b,f]azepine-l-yl,
10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
[0081] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.
[0082] Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
[0083] The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert- butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
[0084] The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.
[0085] A "haloalkyl" group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, l,3-dibromo-3,3-difluoropropyl, perfluorobutyl, fluoromethyl, difluoromethyl, bromomethyl, l-fluoroethyl, 2,2,2- trifluoroethyl and the like.
[0086] A "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, l,3-dibromo-3,3- difluoropropoxy, perfluorobutoxy, and the like.
[0087] The term "(Cx-Cy)perfluoroalkyl," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(C1-C6)perfluoroalkyl, more preferred is -(C1-C3)perfluoroalkyl, most preferred is -CF3.
[0088] The term "(Cx-Cy)perfluoroalkylene," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(C1-C6)perfluoroalkylene, more preferred is -(C1-C3)perfluoroalkylene, most preferred is -CF2-.
[0089] The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety.
Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
[0090] An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a
"haloacyl" group. An example is a trifluoroacetyl group.
[0091] The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.
[0092] An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NR +, wherein each R is independently selected, and protonated forms of each, except for -NR3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group.
[0093] An "ammonium" ion includes the unsubstituted ammonium ion NH4 +, but unless otherwise specified, it also includes any protonated or quaternized forms of amines, and salts thereof. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
[0094] The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR2, and -NRC(0)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH2) and formamide groups (-NHC(O)H). A
"carboxamido" group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryl, etc. [0095] The term "azido" refers to an N3 group. An "azide" can be an organic azide or can be a salt of the azide (N3 ~) anion. The term "nitro" refers to an N02 group bonded to an organic moiety. The term "nitroso" refers to an NO group bonded to an organic moiety. The term nitrate refers to an ON02 group bonded to an organic moiety or to a salt of the nitrate (N03 ~) anion.
[0096] The term "urethane" ("carbamoyl" or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR2 groups, respectively.
[0097] The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e., -S02NR2 and -NRS02R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-S02NH2). An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
[0098] The term "amidine" or "amidino" includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH2.
[0099] The term "guanidine" or "guanidino" includes groups of the formula
-NRC(NR)NR2. Typically, a guanidino group is -NHC(NH)NH2.
[0100] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a solvate, such as a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. Any formula given herein is intended to refer to amorphous and/or crystalline physical forms of the compound. The compounds described herein may be analytically pure, or a mixture in which the compound comprises at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% by weight of the mixture.
[0101] The invention also includes pharmaceutically acceptable salts of the compounds described herein, preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. The invention can provide a salt form of a compound of the invention, i.e., a structure as shown, but in the form of a salt, such as a salt of an amine and an acid.
Compounds of the invention can be amines, and as such can form salts with organic or inorganic acids. Salts can be used either as dosing forms for patients, in which case the salts are "pharmaceutically acceptable salts," or can be salts formed with any acid that is useful, e.g., in chemical processing. A "salt," as is well known in the art, includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
[0102] A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceutically-acceptable salts." The term "pharmaceutically- acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1- sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.
[0103] Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
[0104] Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et ah, Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein. [0105] For a compound described herein that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
[0106] The invention also relates to pharmaceutically acceptable prodrugs of the compounds described herein, and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to a compound described herein). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
[0107] The present invention also relates to pharmaceutically active metabolites of compounds described herein, and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound described herein or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J.
Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). [0108] A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
[0109] A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate,"" which can again be stoichiometic or non- stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
[0110] A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0111] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.
[0112] The present invention further embraces isolated compounds according to the described formulae. The expression "isolated compound" refers to a preparation of a compound of the described formulae, or a mixture of compounds according to the described formulae, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an "isolated compound" refers to a preparation of a compound of the described formulae or a mixture of compounds according to the described formulae, which contains the named compound or mixture of compounds according to the described formulae in an amount of at least 10 percent by weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50% by weight of the total weight; more preferably at least 80% by weight of the total weight; and most preferably at least 90%, at least 95% or at least 98% by weight of the total weight of the preparation.
[0113] The compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
Isomerism and Tautomerism in Compounds of the Invention
Tautomerism
[0114] Within the present invention it is to be understood that a compound described herein or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
Figure imgf000032_0001
[0115] Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like. Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. For example, the equilibrium:
Figure imgf000033_0001
S an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer.
Optical Isomerism
[0116] It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures. The present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention.
[0117] The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
Figure imgf000033_0002
(R) configuration (S) configuration [0118] The present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof.
Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
[0119] "Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight. Compounds of the present invention are provided in any of these degrees of enantiomeric purity, e.g., a racemic mixture of enantiomers (50% enantiomerically pure), or 80% enantiomerically pure, or 90% enantiomerically pure, or 98% enantiomerically pure, or 99+% enantiomerically pure.
[0120] Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions.
[0121] Isolated optical isomers (enantiomerically pure compounds) can also be prepared by the use of chiral intermediates or catalysts in synthesis. When a chiral synthetic intermediate is used, the optical center (chiral center) can be preserved without racemization throughout the remainder of the preparative procedure, as is well known in the art. Chiral catalyst can be used to impart at least some degree of enantiomeric purity to products of reactions catalyzed by the chiral catalyst. And, in some cases, compounds having at least some degree of enantiomeric enrichment can be obtained by physical processes such as selective
crystallization of salts or complexes formed with chiral adjuvants.
Rotational Isomerism
[0122] It is understood that due to chemical properties (i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated as, and exist indefinitely, as a single stable rotamer. The present invention therefore includes any possible stable rotamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states.
Figure imgf000035_0001
Regioisomerism
[0123] The preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for 1,4-substitution, "meta" for
1,3-substitution and "ortho" for 1,2-substitution as shown below.
Figure imgf000035_0002
"para-" "meta-" "ortho-"
[0124] In various embodiments, a compound as shown in any of the Examples, or among the exemplary compounds, is provided.
[0125] Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
[0126] In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments. Description
[0127] In various embodiments, the invention provides a compound of formula (I),
Figure imgf000036_0001
wherein
A comprises aryl or heteroaryl;
B is absent, or comprises aryl, aryloxy, heteroaryl, or heteroaryloxy;
wherein A or B or both can each independently be unsubstituted or can each independently be mono- or multi- substituted with J or with R', or with both;
D comprises aryl, aroyl, heteroaryl, or heteroaroyl, wherein D can be unsubstituted or can be mono- or independently multi- substituted with J or with R', or with both;
Z is N or O, provided that when Z is O, R is absent
R1 comprises independently at each occurrence halo, oxo, hydroxy, cyano, (C1_4)alkyl, (Ci_4)alkoxy, (C1_4)acyloxy, (C1_4)acylamido, haloalkyl, haloalkoxy, NRaRb, C(=0)NRaRb, C(=0)ORa, S02Ra, S02NRaRb, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl;
or one or more R1 groups together with the ring to which they are bonded form a bicyclo[2.2.2], bicyclo[3.3.0], or bicyclo[4.3.0] ring system, wherein any bicyclo ring system can be as-fused or trans-fused, wherein any alkyl, alkoxy, bicyclo ring system, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl can be mono- or independently multi-substituted with J or with R', or with both;
Ra and Rb are independently at each occurrence H, (C1-4)alkyl, aralkyl, (C1_s)acyl, or Ra and Rb together with the nitrogen atom to which they are bonded form a 4-7 membered ring optionally further comprising 1 or 2 NRC, O, S, SO, or S02, wherein Rc is H or (Ci- 4)alkyl, wherein any Ra, Rb, or Rc can be mono- or independently multi- substituted with J or with R', or with both;
2 2
R comprises H, (C1-4)alkyl, or (C1_s)acyl, or R together with D and the nitrogen atom to which they are bonded form a phthalimido group, wherein any alkyl, acyl, or phthalimido group is optionally mono- or independently multi- substituted with J or with R', or with both; J is halogen, (Cl-C6)alkyl, OR', CN, CF3, OCF3, =0, =S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH2)o-pN(R')2, (CH2)0-PSR', (CH2)0-pS(O)R', (CH2)0_ pS(0)2R', (CH2)o-PS(0)2N(R')2, (CH2)0-PSO3R', (CH2)0-PC(O)R', (CH2)0-PC(O)C(O)R', (CH2)0_ pC(0)CH2C(0)R', (CH2)o_pC(S)R', (CH2)0-PC(O)OR', (CH2)0-POC(O)R', (CH2)0-PC(O)N(R')2, (CH2)o-pOC(0)N(R')2, (CH2)o-pC(S)N(R')2, (CH2)0_pNH-C(O)R', (CH2)0-pN(R')N(R')C(O)R', (CH2)o-pN(R')N(R')C(0)OR', (CH2)0-PN(R')N(R')CON(R')2, (CH2)0-pN(R')SO2R', (CH2)0_ pN(R')S02N(R')2, (CH2)o-PN(R')C(0)OR', (CH2)0-PN(R')C(O)R', (CH2)0-PN(R')C(S)R', (CH2)0_ pN(R')C(0)N(R')2, (CH2)o-PN(R')C(S)N(R')2, (CH2)0-PN(COR')COR', (CH2)0-PN(OR')R', (CH2)o-pC(=NH)N(R')2, (CH2)o-pC(0)N(OR')R', or (CH2)0-PC(=NOR')R';
wherein, each R' is independently at each occurrence hydrogen, (C1-C12)-alkyl, (C2- Ci2)-alkenyl, (C2-Ci2)-alkynyl, (C3-Ci0)-cycloalkyl, (C3-Ci0)-cycloalkenyl, [(C3- C10)cycloalkyl or (C3-C10)-cycloalkenyl]-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)- alkynyl], (C6-C10)-aryl, (C6-C10)-aryl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)- alkynyl], mono- or bicyclic 3-10 membered heterocyclyl, mono- or bicyclic 3-10 membered heterocyclyl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 5-10 membered heteroaryl, or mono- or bicyclic 5-10 membered heteroaryl-[(C1-C12)-alkyl or (C2- C12)-alkenyl or (C2-C12)-alkynyl], wherein R' is substituted with 0-3 substituents selected independently from J ;
or, when two R' are bound to a nitrogen atom or to two adjacent nitrogen atoms, the two R' groups together with the nitrogen atom or atoms to which they are bound can form a 3- to 8-membered monocyclic heterocyclic ring, or an 8- to 20-membered, bicyclic or tricyclic, heterocyclic ring system, wherein any ring or ring system can further contain 1-3 additional heteroatoms selected from the group consisting of N, NR', O, S, S(O) and S(0)2, wherein each ring is substituted with 0-3 substituents selected independently from J ;
wherein, in any bicyclic or tricyclic ring system, each ring is linearly fused, bridged, or spirocyclic, wherein each ring is either aromatic or nonaromatic, wherein each ring can be fused to a (C6-Cio)aryl, mono- or bicyclic 5-10 membered heteroaryl, (C3-C1o)cycloalkyl or mono- or bicyclic 3-10 membered heterocyclyl;
JR is halogen, OR, CN, CF3, OCF3, =0, =S, C(O), S(O), methylenedioxy,
ethylenedioxy, (CH2)0_PN(R)2, (CH2)0_PSR, (CH2)0_pS(O)R, (CH2)0_pS(O)2R, (CH2)0_ pS(0)2N(R)2, (CH2)o-PS03R, (CH2)0_PC(O)R, (CH2)0_PC(O)C(O)R, (CH2)0_PC(O)CH2C(O)R, (CH2)o-PC(S)R, (CH2)o-PC(0)OR, (CH2)0_POC(O)R, (CH2)0_PC(O)N(R)2, (CH2)0_
pOC(0)N(R)2, (CH2)o-pC(S)N(R)2, (CH2)0_pNH-C(O)R, (CH2)0_pN(R)N(R)C(O)R, (CH2)0_ pN(R)N(R)C(0)OR, (CH2)o-pN(R)N(R)CON(R)2, (CH2)0_pN(R)SO2R, (CH2)0_ pN(R)S02N(R)2, (CH2)o-pN(R)C(0)OR, (CH2)0_pN(R)C(O)R, (CH2)0_PN(R)C(S)R, (CH2)0_ pN(R)C(0)N(R)2, (CH2)o-pN(R)C(S)N(R)2, (CH2)0_PN(COR)COR, (CH2)0_PN(OR)R, (CH2)0_ PC(=NH)N(R)2, (CH2)o_pC(0)N(OR)R, or (CH2)0-PC(=NOR)R; and,
R is independently at each occurrence hydrogen, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, [(C3-C10)cycloalkyl or (C3-C10)- cycloalkenyl]-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)-alkynyl], (C6-Ci0)-aryl, (C6- C1o)-aryl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 3-10 membered heterocyclyl, mono- or bicyclic 3-10 membered heterocyclyl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)-alkynyl], mono- or bicyclic 5-10 membered heteroaryl, or mono- or bicyclic 5- 10 membered heteroaryl-[(C1-C12)-alkyl or (C2-C12)-alkenyl or (C2-C12)- alkynyl] ;
m is 0, 1, 2, 3, 4, 5, or 6; n is 1, 2, or 3; p = 0, 1, or 2; r = 0, 1, 2, or 3;
or any salt or hydrate thereof.
[0128] In various embodiments, Z can be a nitrogen atom, substituted with R2 as defined herein. When D comprises a carbonyl group (e.g., pyridoyl, quinoloyl, benzofuranoyl, and the like), then Z as a nitrogen atom forms an amide bond with the D group. When D does not comprise a carbonyl group in the bonding position (pyridyl, quinolyl, benzofuranyl, and the like), then Z as a nitrogen atom forms an amine bond with the D group.
[0129] In other embodiments, Z can be an oxygen atom, in which case R2 is absent. When D comprises a carbonyl group (e.g., pyridoyl, quinoloyl, benzofuranoyl, and the like), Z as an oxygen atom forms an ester bond with the D group. When D does not comprise a carbonyl group in the bonding position (pyridyl, quinolyl, benzofuranyl, and the like), then Z as an oxygen atom forms an ether bond with the D group.
[0130] In various embodiments, the invention provides a compound of formula (I) wherein A comprises phenyl, thiazolyl, pyrazolyl, pyridyl, or quinolyl, wherein A can each
independently be unsubstituted or can each independently be mono- or multi- substituted with J or with R' , or both; or any salt or hydrate thereof.
[0131] In various embodiments, the invention provides a compound of formula (I) wherein B comprises phenyl, pyridyl, pyrazidinyl, pyrimidinyl, pyrazinyl, pyrolyl, pyrazolyl, oxazolyl, imidazolyl, oxadiazolyl, { l,2,3)-triazolyl, (l,2,4)-triazolyl, wherein B can each independently be unsubstituted or can each independently be mono- or multi- substituted with J or with R' , or both; or any salt or hydrate thereof. [0132] In various embodiments, the invention provides a compound of formula (I) wherein D comprises pyridyl, pyridoyl, pyridazinyl, pyridazinoyl, pyrimidinyl, pyrimidinoyl, pyrazinyl, pyrazinoyl, quinolyl, quinoloyl, benzofuranyl, benzofuranoyl, benzoxazolyl, benzoxazoloyl, benzthiazolyl, or benzthiazoloyl; or wherein D combined with R and the nitrogen atom to which they are bonded comprises phthalimidoyl, wherein D can be unsubstituted or can be mono- or independently multi- substituted with J or with R', or both; or any salt or hydrate thereof.
[0133] In various embodiments, the invention provides a compound of formula (I) comprising a bicyclic compound of any of formulas (IIA) or (IIB)
Figure imgf000039_0001
or any salt or hydrate thereof. Formula (IIA) is a bicyclo[3.3.0] system, and formula (IIB) is a bicyclo[4.3.0] system, and in both formulas (IIA) and (IIB), Z of formula (I) is nitrogen. The bicyclo ring junction can be as-fused or trans-fused, and the sidechain can be of any relative orientation stereochemically in any of formulas (IIA) through (IID). The invention can provide mixed or pure diastereomeric forms, any one of which can be racemic or enantiomerically enriched. Alternatively, these bicyclo ring systems can be included in analogous structures wherein Z of formula (I) is oxygen. In various embodiments, the invention can provide a compound of formula (IIC), a bicyclo[3.3.0] system, or of formula (IID), a bicyclo[4.3.0] system:
Figure imgf000039_0002
(IIC) In various embodiments, the invention provides a compound of formula (I) comprising any of formulas (IIIA), (IIIB), (IIIC), (HID), (HIE), or (IIIF):
Figure imgf000040_0001
wherein Z, D, R 1 , m, and R 2 are as defined for Formula (I), n is 1 or 2, q = 1, 2, or 3, r = 1 or 2; Het1 is an unsubstituted or J-substituted pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, trizolyl, pyrimidinyl, or pyridyl; Ar1 is an unsubstituted or J-substituted phenyl; wherein J- substituted indicates the presence of 1-3 J substituents; or any salt or hydrate thereof. In various embodiments, each J is independently selected from the set consisting of F, CI, and methoxy. More specifically, the invention provides a compound of any of formulas (IIIA), (IIIB), (IIIC), (HID), (HIE), or (IIIF), wherein n = 1 or 2 (i.e., a pyrrolidine or a piperidine), and wherein m = 1 or 2. In various embodiments, R1 is F, oxo, methyl, trifluoromethyl, hydroxy, acetoxy, methoxy, NH2, N-methylamino, N-ethylamino, Ν,Ν-dimethylamino, N- isopropylamino, N-benzylamino, hydoxyethylamino, or acetamido; or any salt or hydrate thereof. More specifically, the invention provides in various embodiments a compound of any of formulas (IIIA), (IIIB), (IIIC), (HID), (HIE), or (IIIF) wherein D comprises pyridyl, pyridoyl, quinolyl, quinoloyl, or benzofuranyl, or wherein D combined with R and the nitrogen atom to which they are bonded comprises phthalimidoyl; or any salt or hydrate thereof.
[0134] In various embodiments, the invention provides a compound of formula (I) comprising a compound of formula (IV A) 1 )
Figure imgf000041_0001
or a compound of formula (IVC)
(R1 )
Figure imgf000041_0002
or a compound of formula (IVD)
Figure imgf000042_0001
wherein A, B, and R1, are as defined herein, wherein m = 1 or 2, n = 1 or 2; and r = 1 or 2; and Het is an unsubstituted or J-substituted quinolyl, pyridyl, pyrimidyl, benzoxazolyl, benzimidazolyl, or benzthiazolyl; wherein J-substituted indicates the presence of 1-3 J substituents;
or any salt or hydrate thereof.
[0135] In various embodiments, the invention can provide a compound of formula (VA) or of formula (VB):
Figure imgf000042_0002
wherein A, B, D, R , are as defined herein, and r = 1 or 2; or any salt or hydrate thereof.
[0136] In some embodiments, compounds as described herein are of Formula (VI):
Figure imgf000042_0003
wherein
R10 is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S; wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Ru)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, -CN, and -CF ;
or a pharmaceutically acceptable salt thereof.
[0137] In some embodiments of Formula (VI), compounds are racemic at the stereocenters shown. In other embodiments, compounds of Formula (VI) are have one stereoisomer at the stereocenters shown. In other embodiments, compounds are the (2S),(3R) stereoisomer at the stereocenters shown.
[0138] In some embodiments of Formula (VI), the compound is not: Example 11, 12, 15- 24, 72-73, 75-78, 82-88, 91, 97-98, 103-108, 112-117, 119-121, 123, 142-144, 146-161, 163, or 170-177, or a pharmaceutically acceptable salt thereof, or any combination thereof. In other embodiments of Formula (VI), the compound is not a compound from Table 1. In other embodiments of Formula (VI), the compound is not a compound from Table 1, wherein the compounds in Table 1 are racemic compounds. [0139] In some embodiments, compounds are of the Formula (VIA):
Figure imgf000044_0001
wherein
B is phenyl, pyridyl, or pyrimidinyl, each unsubstituted or substituted with one or two
substituents selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
X2 is CH or N;
R10 is H or methyl;
R200 is H, -CF3, or chloro; and
(a) one of R 20 and R 22 is methyl, chloro, or fluoro, the other of R 20 and R 22 is H, and R 102 is H; or
(b) R21 is H, chloro, or fluoro, and R20 and R22 are both H;
or a pharmaceutically acceptable salt thereof.
[0140] In some embodiments of Formula (VIA), compounds are racemic at the
stereocenters shown. In other embodiments, compounds of Formula (VIA) are single isomers at the stereocenters shown. In other embodiments, compounds are the (2S),(3R) stereoisomer at the stereocenters shown.
[0141] In other embodiments, compounds as described herein are of Formula (VII):
Figure imgf000044_0002
(VII)
wherein
R1U is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S; wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Ru)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, -CN, and -CF ;
or a pharmaceutically acceptable salt thereof.
[0142] In some embodiments of Formula (VII), the compound is not: Example 99, 100, or 164-169, or a pharmaceutically acceptable salt thereof, or any combination thereof. In other embodiments of Formula (VII), the compound is not a compound from Table 1. In other embodiments of Formula (VII), the compound is not a compound from Table 1, wherein the compounds in Table 1 are racemic compounds.
[0143] Some embodiments of Formula (VII) are compounds of Formula (VIIA):
Figure imgf000045_0001
where each variable is as defined above. In some embodiments, compounds of Formula (VIIA) are racemic at the stereocenters shown. In other embodiments, are non-racemic or single stereoisomeric forms at the stereocenters shown. [0144] In some embodiments compounds as described herein are of Formula (VIII):
Figure imgf000046_0001
wherein
R1U is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Rn)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C^alkyl, C^alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof.
[0145] In some embodiments of Formula (VIII), compounds are racemic at the stereocenter shown. In other embodiments, compounds have the "R" configuration at the stereocenter shown.
[0146] In some embodiments, compounds as described herein are of Formula (IX):
Figure imgf000047_0001
wherein
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1-4alkyl, Ci^alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Rn)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof.
[0147] In some embodiments of Formula (IX), the compound is not: Example 79-81, or 89-90, or a pharmaceutically acceptable salt thereof, or any combination thereof. In other embodiments of Formula (IX), the compound is not a compound from Table 1. In other embodiments of Formula (IX), the compound is not a compound from Table 1, wherein the compounds in Table 1 are racemic compounds. [0148] In some embodiments of Formula (IX), compounds are racemic at the stereocenters shown. In other embodiments, compounds of Formula (IX) are single isomers at the stereocenters shown. In other embodiments, compounds are the (2S),(3R) stereoisomer at the stereocenters shown.
[0149] In some embodiments of Formulae (VI), (VII), and (VIII), is H. In other embodiments, R10 is methyl.
[0150] In some embodiments of Formulae (VI), (VII), (VIII), and (IX), Het2 is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally fused to phenyl or a monocyclic heteroaryl, and each optionally substituted with one or two substituents Rx. In some embodiments, Het2 is thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzoxazolyl, quinazolinyl, or triazolo-pyrimidinyl, each optionally substituted with one or two substituents Rx. In some embodiments, Het2 is attached to -N(R10) at the 2- position of the monocyclic heteroaryl. In other embodiments, Het is attached to -N(R10) at a position alpha to an N in the monocyclic heteroaryl ring. In other embodiments, Het is benzoxazolyl. In other embodiments, Het2 is pyridyl. In some embodiments, each Rx is independently selected from the group consisting of -F, -CI, -Br, methyl, methoxy, -CN, - CF3, cyclopropyl, and cyano-cyclopropyl. In some embodiments, Rx is -CF or -CI.
[0151] In some embodiments, X is N, Y is CH, and Z is S. In other embodiments, X is N, Y is CHCH, and Z is CH. In still other embodiments, X is CH, Y is CHCH, and Z is CH. In each case, the CH groups are optionally substituted with B and (Ru)t as shown.
[0152] In some embodiments, each R11 is independently methyl, chloro, fluoro, or -CN. In some embodiment, R11 is chloro or fluoro. In some embodiments, t is 0. In other
embodiments, t is 1. In still other embodiments, t is 2. In some embodiments, the group
(XX):
Figure imgf000048_0001
is a group of Formula (Xa), or is a group of Formula (Xb), or is a group of Formula (Xc):
Figure imgf000048_0002
(Xa) (Xb) (Xc) wherein X1 is CH or N and B is unsubstituted or is substituted as described for Formula (VI), (VII), (VIII), or (IX). In some embodiments, X1 is CH or CR11. In other embodiments, X1 is N. In other embodiments, the group (XX) is a group of Formula (Xd):
Rioi
Figure imgf000049_0001
where (a) one of R101 and R103 is methyl, chloro, or fluoro, the other of R101 and R103 is H, and R102 is H; or (b) R102 is H, chloro, or fluoro, and R101 and R103 are both H.
[0153] In some embodiments, ring B is phenyl, or is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally substituted with one or two substituents Ry. In some embodiments, ring B is phenyl, pyrrolyl, triazolyl, pyrimidinyl, pyridyl, pyrrolyl, isoxazolyl, pyrazinyl, imidazolyl, tetrazolyl, thiazolyl, pyridazinyl, each optionally substituted with one or two substituents Ry. In some embodiments, ring B is pyrazolyl or triazolyl. In some embodiments, each Ry is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, isopropoxy, -F, -CI, -Br, -CN, or -CF3. In other embodiments, there is one Ry. In other embodiments, Ry is methyl, ethyl, isopropyl, methoxy, -F, or -CF3.
[0154] In some embodiments, compounds as described herein are of Formula (la):
Figure imgf000049_0002
wherein
X is NH, N(Ci-4alkyl), or O;
R1 is pyridinyl, pyrimidinyl, benzoxazolyl, benzothiazolyl, or quinazolinyl, each
unsubstituted or substituted with one or more substituents selected from the group consisting of Ci^haloalkyl or halo;
where Ra and Rb are each independently H or C1-4alkyl; or
X and R1 taken together form pyrrolyl or dihydropyrrolyl, unsubstituted or substituted with C1_4haloalkyl or halo;
R 2" and R 3J are defined as in (a) or (b):
(a) R 2 is thiazolyl substituted with C1-4alkyl; and R 3 is phenyl substituted with halo; or (b) R is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1_4alkyl, -OC1-4alkyl, or halo; and R is triazolyl or pyrimidinyl; or a pharmaceutically acceptable salt thereof.
[0155] In some embodiments of Formula (la), X is NH. In other embodiments, X is N(Ci_ 4alkyl). In other embodiments, X is O.
[0156] In some embodiments of Formula (la), R1 is an optionally substituted pyrimidinyl or pyridinyl. In other embodiments, R1 is optionally substituted 2-pyrimidinyl or 2-pyridinyl. In other embodiments, R1 is optionally substituted benzoxazolyl or benzothiazolyl. In other embodiments, R1 is optionally substituted 2-benzoxazolyl or 2-benzothiazolyl. In other embodiments, R1 is optionally substituted 2-quinazolyinyl. In other embodiments, R1 is substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, -CF3, -CHF2, -CH2F, -F, -Br, or -CI. In other embodiments, R1 is substituted with one or more substituents selected from the group consisting of -CF3, -F, -CI, or -Br. In other embodiments, R1 is pyrimidinyl, substituted with -CF3 or -CI. In other embodiments, R1 is pyridinyl, substituted with -CF3. In other embodiments, R1 is benzoxazolyl or benzothiazolyl, unsubstituted or substituted with -CF3, -CI. or -F.In some embodiments, R1 is 2-pyrimidinyl, 2-pyridinyl, 2-benzoxazolyl, 2-benzothiazolyl, or 2- quinazolinyl, each substituted at the 5-position.
[0157] In some embodiments, X and R1 taken together form pyrrolyl or dihydropyrrolyl, unsubstituted or substituted with C^haloalkyl or halo. In other embodiments, the pyrrolyl or dihydropyrrolyl is substituted with -CF3.
[0158] In some embodiments of Formula (la), R2 is thiazolyl substituted with methyl. In other embodiments, R is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1-4alkyl, -OC^alkyl, or halo. In other embodiments,
R 2 is phenyl substituted with one or two substituents. In other embodiments, R 2 is phenyl substituted with methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CI, or -F. In other embodiments, R is phenyl substituted with one or two substituents independently selected from methyl, methoxy, -F, and -CI. In other embodiments, R is phenyl substituted with one methyl, methoxy, -F, or -CI. In other embodiments, R is phenyl substituted with -
F and optionally further substituted. In other embodiments, R is phenyl substituted with -F and methyl. In other embodiments, R is difluoro-substituted phenyl. In other embodiments,
R 2 is dimethyl-substituted phenyl. In other embodiments, R 2 is phenyl substituted at the 3- position with -F, and optionally further substituted with methyl. In other embodiments, R is phenyl substituted at the 4-position with -F, and optionally further substituted with methyl. In other embodiments, R is phenyl substituted at the 5-position with -F, and optionally further substituted with methyl. In other embodiments, R is phenyl substituted at the 6- position with -F, and optionally further substituted with methyl.
[0159] In some embodiments of Formula (la), R3 is phenyl substituted with halo. In other embodiments, R 3 is phenyl substituted with -F. In other embodiments, R 3 is 4-fluorophenyl.
In other embodiments, R 3 is triazolyl or pyrimidinyl. In other embodiments, R 3 is triazolyl.
In other embodiments, R 3 is 1,2,3-triazolyl. In other embodiments, R 3 is pyrimidinyl. In other embodiments, R is 2-pyrimidinyl.
[0160] In various embodiments, the invention provides any of the compounds as listed below in "Table 1: Exemplary Compounds of the Invention," or any salt or hydrate thereof, or in Table 1A, or any salt or hydrate thereof. Compounds of the invention can possess bioactivity as orexin receptor modulators, e.g., as orexin receptor antagonists, as described in greater detail below.
[0161] In some embodiments, compounds as described herein are of Formula (lb):
Figure imgf000051_0001
wherein
A is aryl, wherein A can be unsubstituted or can be mono- or multi- substituted with halo or CF3;
B is heteroaryl, wherein B can be unsubstituted or can be mono- or multi-substituted;
D comprises aryl or heteroaryl, wherein D can be unsubstituted or can be mono- or independently multi- substituted with halo, C1-4 alkyl, C1-4 alkoxy, -CN, -CF3, or C3_6 cycloalkyl;
Z is N or O, provided that when Z is O, R is absent; and
R is H or methyl;
or any salt or hydrate thereof. [0162] In some embodiments, compounds as described herein are of Formula (Vic):
Figure imgf000052_0001
wherein
R1U is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
each R11 is independently selected from the group consisting of cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2; and
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C^alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof.
[0163] In some embodiments, optionally, the compound of Formula (la) is not a compound in Table A:
Table A
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula (la) or a pharmaceutically acceptable salt thereof is not a compound in Table A, or a pharmaceutically acceptable salt thereof, wherein the compounds and salts are in racemic form.
[0164] In some embodiments, optionally, the compound of Formula (la) is not a compound in Table B:
Table B
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Pharmaceutical Methods and Uses
[0165] "Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms. "Preventative" treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. "Preventative" treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to about 2 g daily, or about 1 mg to about 1 g daily, or about 1 mg to about 50 mg daily, or about 10 mg to about 50 mg daily, or about 50 to about 250 mg daily, or about 250 mg to about 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
[0166] Once improvement of the patient's disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
[0167] The term "subject" refers to a mammal in need of such treatment, such as a domestic animal (e.g., mouse, rat, guinea pig, dog, cat, household pet, or farm animal), a non- domestic animal (e.g., wildlife), or a human. In some embodiments, the subject is a human.
[0168] As set forth herein, compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, pharmaceutically acceptable salts and mixtures thereof. Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein. The compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications. [0169] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein, including those active against another target associated with the disease. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The compounds described herein may be administered simultaneously or sequentially with (i.e., prior to or after) one or more other active pharmaceutical ingredients. Additional active ingredients may be administered separately or in a combination formulation with one or more compounds described herein. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. Exemplary additional active ingredients include those that target the same disease or disorder as the disclosed compounds, or a symptom of that disease or disorder. For example, additional active ingredients include those that are known to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, anti-diabetic agents, cardiovascular therapies, anti-obesity agents, other orexin receptor antagonists, pain medications, anti-depressants, anti-anxiety agents, cognition-enhancing agents, anti- Alzheimer's Disease therapies, and other active ingredients. Exemplary active pharmaceutical ingredients and other therapies that are suitable for combination with the presently described compounds include those listed in PCT Publ. No. WO2008/147518 at pages 23-29, which are hereby incorporated by reference. The pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
[0170] Typical compositions include a compound of the invention and one or more pharmaceutically acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti- oxidants, binders, coloring agents, bulking agents, emulsifiers, taste-modifying agents, or carriers. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
[0171] The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired, including compositions that are in accord with national and local regulations governing such compositions.
[0172] The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, inhalation (e.g., pulmonary), buccal, topical, subdermal, intradermal, transdermal or parenteral, (e.g., rectal), depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ocular (e.g., ophthalmic solution) or an ointment, the oral or intravenous routes being preferred.
[0173] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. [0174] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to about 2 g daily, or about 1 mg to about 1 g daily, or about 1 mg to about 50 mg daily, or about 10 mg to about 50 mg daily, or about 50 to about 250 mg daily, or about 250 mg to about 1 g daily.
[0175] If a solid carrier is used for oral administration, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
[0176] If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically- acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
[0177] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in injectable dosage forms. Injectable dosage forms generally include sterile aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Such dosage forms are buffered to an appropriate pH and isotonicity. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer' s solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
[0178] For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.
[0179] The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.
[0180] Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
[0181] For nasal, inhaled, or oral administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
[0182] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in
polyhydroxylated castor oil.
[0183] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
[0184] Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
[0185] A typical tablet that can be prepared by conventional tabletting techniques can contain:
Core:
Active compound (as free compound or salt thereof) 250 mg
Colloidal silicon dioxide (Aerosil)® 1.5 mg
Cellulose, microcryst. (Avicel)® 70 mg
Modified cellulose gum (Ac-Di-Sol)® 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg
*Mywacett 9-40 T approx. 0.9 mg
Acylated monoglyceride used as plasticizer for film coating. [0186] A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
[0187] In various embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, as described above.
[0188] In various embodiments, compounds of the invention can be used to modulate, such as to activate (agonist), or to block activation of (antagonist), an orexin receptor.
Accordingly, in various embodiments, the invention provides a method of modulating an orexin receptor comprising contacting the receptor with an effective amount or concentration of a compound of the invention. The orexin receptor can be OXi or OX2. In various embodiments, the compound of the invention is an antagonist of an orexin receptor such as OXi or OX2, or both, and can be a selective inhibitor of one or the other. In various embodiments, contacting can take place in vivo within tissues of a patient, such as a human patient. In various embodiments, modulation of an orexin receptor, for example, antagonism of orexin- 1, by a compound of the invention can be used to treat a disease, disorder, or medical condition in a patient, as described herein. In the modulatory methods of the invention, an "effective amount" means an amount sufficient to modulate the biological activity of the target receptor. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
[0189] In various embodiments, the invention provides a method of treating a disease, disorder, medical condition or malcondition in a patient wherein modulation of an orexin receptor is medically indicating, comprising administering to the patient a compound of the invention in a dose, at a frequency, and for a duration to provide a beneficial effect to the patient. Modulation, such as agonism or antagonism, of an orexin receptor can be medically indicated in treatment of a disease, disorder, medical condition or malcondition wherein the orexin receptor plays a metabolic or regulatory role. Certain malconditions can be treated by selective modulation of a single class of orexin receptor, such as modulation of OXi while OX2 is not influenced by administration of the compound of the invention at the dose provided. In various embodiments, compounds of the invention can be orexin- 1 antagonists, and some of those are selective orexin-1 antagonists with respect to orexin-2. By "selective" is meant that one receptor is modulated at concentrations of the compound at least 10 times lower than the concentrations at which the comparative receptor is modulated by that compound. Accordingly, in various embodiments, the compound of the invention can be a selective modulator, e.g., an antagonist, of orexin receptor OXi. Or, the compound of the invention can be a selective modulator (e.g., antagonist) of an orexin receptor OX2. Or the compound of the invention can further modulate other types or classes of receptors having affinity for one of more forms of the orexin class of natural peptidic ligands.
[0190] In various embodiments, modulation of an orexin receptor, for example, antagonism of orexin-1, by a compound of the invention can be used to treat a disease, disorder, medical condition or malcondition in a patient wherein the malcondition comprises an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, and renal disease. Drug or substance abuse or addiction includes relapse. Drug abuse and addiction can include abuse of or addiction to cocaine, opiates, amphetamines, or nicotine. Drug abuse and/or addiction can also include abuse of and/or addiction to alcohol, cannabis, heroin, and/or any other drug of abuse.
[0191] In various embodiments, the invention provides a use of a compound of the invention for treatment of a disease, disorder, medical condition or malcondition in a patient. For example, a compound of the invention can be used in the preparation of a medicament for administration to a patient suffering from a disease, disorder, medical condition or malcondition. More specifically, the malcondition can comprise an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, and renal disease. Drug or substance abuse or addiction includes relapse. Drug abuse and addiction can include abuse of or addiction to cocaine, opiates, amphetamines, or nicotine. Drug abuse and/or addiction can also include abuse of and/or addictionto alcohol, cannabis, heroin and/or any other drug of abuse.
[0192] In other embodiments, the malcondition is narcolepsy, insomnia, learning disorders, memory disorders, depression, anxiety, addiction, obsessive compulsive disorder, affective neurosis, depressive neurosis, anxiety neurosis, dysthymic disorder, behavior disorder, mood disorder, sexual dysfunction, psychosexual dysfunction, sex disorder, schizophrenia, manic depression, delirium, dementia, severe mental retardation or dyskinesias (such as
Huntington's Disease or Tourette Syndrome), eating disorders (such as anorexia, bulimia, cachexia, or obesity), addictive feeding behaviors, binge/purge feeding behaviours, cardiovascular diseases, diabetes, appetite/taste disorders, emesis, vomiting, nausea, asthma, cancer, Parkinson's Disease, Cushing's Syndrome/Disease, basophile adenoma,
prolactinoma, hyperprolactinemia, hypophysis tumor/adenoma, hypothalamic diseases, inflammatory bowel disease, gastric dyskinesia, gastric ulcers, Froehlich's Syndrome, adrenohypophysis disease, hypophysis diseases, adrenohypophysis hypofunction, adrenohypophysis hyperfunction, hypothalamic hypogonadism, Kallman's syndrome (anosmia, hyposmia), functional or psychogenic amenorrhea, hypopituitarism, hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, idiopathic hyperprolactinemia, hypothalamic disorders of growth hormone deficiency, idiopathic growth deficiency, dwarfism, gigantism, acromegaly, disturbed biological and circadian rhythms, sleep disturbances associated with disease such as neurological disorders, neuropathic pain, diabetic neuropathy, and restless leg syndroms, heart and lung diseases, acute and congestive heart failure, hypotension, hypertension, urinary retention, osteoporosis, angina pectoris, myocardial infarction, ischemic or hemorrhagic stroke, subsrachnoic hemorrhage, ulcers, allergies, benign prostatic hypertrophy, chronic renal failure, renal disease, impaired glucose tolerance, migraine, episodic migraine, headache disorders (such as tension-type headache, cluster headache, other trigeminal autonomic cephalalgias, other primary headaches such as hemicranias continua, secondary headaches, cranial neuralgia, or central or primary facial pain), hyperalgesia, pain, enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, or allodynia, acute pain, burn pain, atypical facial pain, neuropathic pain, back pain, complex regional pain syndrome I or II, arthritic pain, sports injury pain, pain related to infection (e.g., HIV), post-chemotherapy pain, post-stroke pain, post-operative pain, neuralgia, emesis, nausea, vomiting, conditions associated with visceral pain (such as irritable bowel syndrome or angina), urinary bladder incontinence (e.g., urge incontinence), tolerance to narcotics or withdrawal from narcotics, sleep disorders, sleep apnea, parasomnia, jet lag syndrome, neurodegenerative disorders, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, epilepsy, seizure disorders, or other diseases related to general orexin system dysfunction.
[0193] In still other embodiments, the compounds described herein are useful in a method of treating disorders including, but not limited to, sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the ratio of the time that a subject sleeps relative to the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency, or duration of REM sleep bouts;
altering the timing, frequency, or duration of slow wave (such as stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep;
enhancing EEG-delta activity during sleep; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease, or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders that accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift- work schedules, conditions due to drugs that cause reductions in REM sleep as a side effect; fibromyalgia; syndromes that are manifested by non-restorative sleep and muscle pain; sleep apnea that is associated with respiratory disturbances during sleep; conditions that result from a diminished quality of sleep; increasing learning; augmenting memory; increasing retention of memory; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related disorders including overeating and bulimia nervosa, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute
lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia,
hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy; diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis, or schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder, and cyclothymic disorder, mood disorders due to a general medical condition, and substance- induced mood disorders; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced mood disorders; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy;
cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions;
cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline;
schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, addictive feeding, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, or anxiolytics); movement disorders, including akinesias and akinetic-rigid syndromes
(including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism- ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalized dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis;
schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders);
trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage;
retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, posttraumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache.
[0194] In other embodiments, the disease, disorder, or medical condition is an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine -related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, and renal disease.
[0195] In still other embodiments, the disease, disorder, or medical condition is substance addiction (including relapse), panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.
[0196] Thus, in specific embodiments the present invention provides methods for:
enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep;
increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia;
enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of the present invention.
[0197] It is believed that antagonism of orexin-1, in particular, is medically indicated for the treatment of the above-listed conditions. By antagonism is meant blocking a receptor, in this case an orexin receptor, without causing it to transduce a signal. That is, antagonism results in blocking an endogenous or exogenous ligand from activating, or causing agonism, of the receptor.
[0198] The compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a disease, disorder, medical condition or malcondition. Such mammals include also animals, both domestic animals, e.g. household pets, farm animals, and non-domestic animals such as wildlife.
[0199] The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used. A typical dosage is about 10 mg to about 1000 mg per day, or 25 to 200 mg per day, or 50 to 100 mg per day, or less than 100 mg per day. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
[0200] Generally, the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage. In other embodiments, a unit dosage form includes from about 10 to about 200 mg of active ingredient.
[0201] Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal
administration include from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent. [0202] Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. In some embodiments, dosage form are administered once or twice daily.
[0203] It is within ordinary skill to evaluate any compound disclosed and claimed herein for effectiveness in modulation of an orexin receptor and in the various cellular assays using the procedures described above or found in the scientific literature. Accordingly, the person of ordinary skill can prepare and evaluate any of the claimed compounds without undue experimentation .
[0204] Any compound found to be an effective modulator, agonist or antagonist, can likewise be tested in animal models and in human clinical studies using the skill and experience of the investigator to guide the selection of dosages and treatment regimens. Preparation of Compounds of the Invention
[0205] Compounds of the invention can be synthesized according to established literature procedures for analogous compounds and general techniques and reactions well known to persons of ordinary skill in the art.
[0206] As shown in General Synthetic Scheme I, below, a 2-(aminomethyl)pyrrolidine, 2- (aminomethyl)piperidine, or aminomethylaziridine precursor {i.e., wherein n = 0, 1, or 2), appropriately substituted with R1 groups, can be coupled sequentially with the B-A-C(=0) fragment and the D fragment to provide a compound of the invention. The coupling steps can be carried out in either order, if necessary using appropriate protecting groups for functional R1 or J groups with which the reactants can be substituted. General synthetic scheme I details a synthesis for compounds wherein group Z is nitrogen.
General Synthetic Scheme I
Figure imgf000088_0001
[0207] For a compound of formula (I) wherein R2 is hydrogen and Z is N (formula (la)), the compound can be prepared from an appropriately protected aminomethylpyrrolidine, aminomethylpiperidine, or aminomethylaziridine, as shown. The group PG designates an N- protecting group, as are well-known in the art, to allow selective acylation of the ring nitrogen to occur for reaction with an activated B-A-C(=0)OH carboxylic acid, wherein X represents a carboxyl-activating group, e.g., an N-hydroxy ester, or a O-acylisourea, or a halogen. The carboxylic acid can be activated by any method known in the art, for example using l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 oxide hexafluorophosphate (HATU) as is described below in General Synthetic Procedure A in the Examples, below. Then, the acylated intermediate can undergo deprotection of the aminomethyl protecting group (PG) using techniques suitable for the particular protecting group, and the amino group then reacted with an activated form of group D. For example, if D comprises a carboxylic acid group which is coupled with the aminomethyl group to form an amide, the carboxylic acid group can be activated using the techniques described above to form activated species D-X, which then forms the final product. For cases where D is an aryl, heteroaryl, or heterocyclic ring, the aminomethyl group can react with the corresponding aryl, heteroaryl or heterocyclic halide through a displacement reaction in the presence of a base or through standard metal mediated procedures (Buchwald, Ulmann) known to those skilled in the art. For further elaboration of R , the nitrogen atom can be reacted with an appropriate reagent; e.g. by alkylation, to provide compounds of formula (la) wherein R is other than hydrogen.
[0208] It is understood that the synthesis can proceed in an alternative sequence by starting with an aminomethylpyrrolidine, aminomethylpiperidine, or aminomethylaziridine precursor wherein the protecting group is on the ring nitrogen atom and the exocyclic aminomethyl group is unprotected. Condensation with the D fragment, followed by deprotection of the ring nitrogen atom and coupling with the activated carboxylic acid B-A-C(=0)-X can provide the compound of formula (I).
[0209] When the group Z of formula (I) is an oxygen atom, by coupling group D bearing an appropriate leaving group with a compound analogous to the penultimate intermediate shown in Scheme I, above, but bearing a hydroxyl group instead of an amino group on the sidechain.
[0210] Alternatively, synthesis of a compound of formula (I) can be achieved according General Synthetic Scheme II, below, wherein a D-NH2 fragment is coupled with an activated 2-methyl pyrrolidine or piperidine, which can be derivatized with the B-A-C(=0)OH fragment either prior to or following the coupling.
[0211] For the embodimends of structure wherein group Z of formula (I) is an oxygen atom, a D-OH fragment can be coupled with an appropriately activated B-A-C fragment, either bearing a carboxyl group (to form an ester) or a leaving group (for form an ether).
General Synthetic Scheme II
Figure imgf000090_0001
[0212] An appropriately substituted pyrrolidine or piperidine or aziridine can bear a group
Y for eventual displacement in a nucleophilic substitution reaction by amine D-NHR , particularly when the D group is not bonded to the nitrogen atom via a carbonyl group, e.g., when D is pyridyl instead of pyridoyl, quinolyl instead of quinoloyl, etc. For example, when
D is pyridyl and R 2 is hydrogen, the D-NHR 2 reagent can be an aminopyridine, such as 2-, 3-, or 4-aminopyridine. For example Y can be a halo, or Y can be a hydroxyl. It is understood that Y can be in a protected form for the first step, if necessary, then deprotected and activated for the coupling with DNHR . For example, Y can be a protected hydroxyl group in the coupling of the first reagent with the activated B-A-C(=0)-X carboxylic acid, which is then converted to Y being a free hydroxyl group, followed by activation for nucleophilic displacement, e.g., as a sulfonate ester, to provide the third reagent above that is then condensed with the D-NHR reagent to provide the compound of formula (I). Y may also be a carboxaldehyde group and coupled with DNHR by reductive amination. In the final product (2a) or (2b) in Synthetic Scheme II, above, the atom labeled Y becomes the Z group of formula (I).
[0213] In Synthetic Scheme II, it is also understood that the sequence can proceed in an alternative order of steps, i.e., coupling of the D-NHR reagent with the activated Y-bearing ring system (with the ring nitrogen atom optionally protected as needed), followed by ring nitrogen deprotection and coupling with the activated B-A-C(=0)-X carboxylic acid.
[0214] Alternatively, when Y=OH, the alcohol may be coupled to DX (X=halogen or some other leaving group) to afford the ether product II. This can be done using any inorganic (for instance, CS2CO3, K2C03, etc.) or organic (for instance, Et3N, iPr2Net, DBU, etc) base in the appropriate solvent and at the appropriate temperature.
[0215] Appropriately substituted pyrrolidine, piperidine, and aziridine precursors can be prepared according to literature procedures and upon disclosed synthetic approaches described below in the Examples, using the knowledge of ordinary practitioners of organic synthetic chemistry.
General Synthetic Scheme III
Figure imgf000091_0001
(3b)
[0216] An appropriately substituted piperidine may be synthesized according to the protocol generally described in Synthetic Scheme III. A substituted 2-cyanopyridine can be reduced to the 2-aminomethyl pyridine and protected with a suitable protecting group.
Further reduction of the ring provides the differentially protected 2-aminomethyl piperidine 3a. Alternatively, a 2-carboxypyridine (protected as the ester or as the acid) can be reduced to the substituted pipecolic acid and then reduced (using borane, or LAH, for instance) to the amino alcohol. Further functionalization to final products can follow protocols outlined in Schemes I and II above.
General Synthetic Scheme IV
Figure imgf000091_0002
[0217] Enantiomerically pure 3-substituted 2-aminomethyl piperidines or 2-hydroxymethyl piperidines can be made as described in Synthetic Scheme IV. The 3-substituted pipecolic acids can be made as described in the literature in Royer et ah, J. Org. Chem. 1994, 59, 3769, and Royer et ah, Tetrahedron Lett. 1999, 40, 3699. R can be alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, or the like. Reduction of the carboxylic acid with lithium aluminum hydride or borane or other suitable reducing agent provides the primary alcohol after protecting the piperidine nitrogen atom with a suitable protecting group. Conversion of the primary alcohol to the primary amine can be done by several standard approaches as described in the literature and known to those skilled in the art. One such way would be through Mitsunobu reaction with phthalamide and tripheylphosphine and
diisopropylazodicarboxylate, followed by cleavage of the phthalimide group with hydrazine to give intermediate 4a. Further functionalization to final products can follow protocols outlined in Schemes I and II above.
[0218] One of ordinary skill in the art will recognize that compounds of Formulae (VI), (VII), and (VIII) are prepared using the approaches outlined in the above schemes.
General Synthetic Scheme V
Figure imgf000092_0001
[0219] Enantiomerically pure 3-substituted 2-aminomethyl piperidines can be made as described in Synthetic Scheme V. Hydrogenation of an appropriately substituted pyridine carboxylic acid followed by amino group protection affords pipecolic acid derivatives (5a). Resolution of the acid into its enantiomers can be accomplished with a variety of
commercially available or synthetically prepared enantiomerically pure amines via their diasteriomeric salts. Alternatively, the enantiomers of (5a) can be separated on a chiral column. Further functionalization to final products can follow protocols outlined in Schemes I-IV above.
Examples [0220] The following examples of the compounds of the invention further demonstrate features and aspects of specific embodiments of the invention. The parameters and characteristics of the compounds of the invention are set forth by the foregoing text. In some embodiments are contemplated compounds as in Table 1.
Table 1 : Exemplary Compounds of the Invention
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
102
Figure imgf000105_0001
Figure imgf000106_0001
below)
Figure imgf000107_0001
Figure imgf000108_0001
F below)
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
and pharmaceutically acceptable salts thereof.
[0221] P = prophetic example (compounds with a "P" designation and a reference to an Example in Table 1A have been prepared as single enantiomers as shown in Table 1A).
[0222] Further exemplary compounds are shown in Table 1A. In some embodiments are contemplated compounds as in Table 1A. In still other embodiments are contemplated compounds as in Table 1A, except for compounds Al l, A12, A14, A29, A69, A70, A104, and A108. In some embodiments, compounds as in Table 1A have the absolute stereochemistry as shown.
Table 1A
Figure imgf000111_0002
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
and pharmaceutically acceptable salts thereof.
[0223] In other embodiments, the compound of Formula (la) is selected from the group shown in Table IB.
Table IB
Figure imgf000144_0002
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
and pharmaceutically acceptable salts thereof.
[0224] Compounds described herein include compound that are racemic mixtures, are enhanced stereochemical mixtures, or are substantially pure single enantiomers.
[0225] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
Synthetic Examples
[0226] Example 1: N-((5-Fluoro-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamid
Figure imgf000173_0002
[0227] ie/t-Butyl (5-fluoropyridin-2-yl)methylcarbamate.
Figure imgf000173_0003
A solution of (Boc)20 (1.11 g, 5.16 mmol) in CH2C12 (3 mL) was added to a mixture of (5- fluoropyridin-2-yl)methanamine (0.64 g, 3.44 mmol) in CH2C12 dropwise at rt. The resulting mixture was stirred at rt overnight and quenched with saturated NaHC03. The organic portion was separated, dried with MgS04 and concentrated in vacuo to give desired iert-butyl (5- fluoropyridin-2-yl)methylcarbamate in 83% yield. 1H NMR (MeOH-J4, 400 MHz) δ 8.39 (d, 1H), 7.63-7.58 (m, 1H), 7.44-7.40 (m, 1H), 4.35 (s, 2H), 1.53 (s, 2H), 1.48 (s, 7H). MS (ESI) 227 (M+H).
[0228] l-Benzyl-2-((ieri-butoxycarbonylamino)methyl)-5-fluoropyridinium bromide. NHBoc
Figure imgf000174_0001
A mixture of benzyl bromide (4.21 mmol, 0.5 mL), tert-butyl (5-fluoropyridin-2- yl)methylcarbamate (3.49 mmol, 0.79 g) and acetone (4 mL) in a sealed tube was heated to 80 °C overnight. According to analytical HPLC, around 50% of the starting material remained. Additional benzyl bromide (33.68 mmol, 4.0 mL) was added and the reaction was continued for extra 8 h. The reaction mixture was concentrated in vacuo and loaded on a pad of silica which was rinsed with ether until benzyl bromide was gone. Then, the silica pad was rinsed with MeOH. Removal of MeOH in vacuo afforded desired product l-benzyl-2-((tert- butoxycarbonylamino)methyl)-5-fluoropyridinium bromide as light orange solid in 43% yield. MS (ESI) 317 (M+H).
[0229] rac-ie/t-Butyl (l-benzyl-5- ydropyridin-2-yl)methylcarbamate.
Figure imgf000174_0002
NaBH4 (5.56 mmol, 0.21 g) was added to a solution of l-benzyl-2-((tert- butoxycarbonylamino)methyl)-5-fluoropyridinium bromide (1.40 mmol, 0.60 g) in MeOH at 0 °C. The resulting mixture was stirred at 0 °C for 40 min. An aliquot was checked by analytical HPLC and some of the starting material remained. Additional NaBH4 (5.56 mmol, 0.21 g) was added at 0 °C and the resulting mixture was stirred for extra 40 min. The reaction mixture was diluted with EtOAc and washed with brine. EtOAc layer was separated, dried with MgS04 and concentrated in vacuo to give desired tert-butyl (l-benzyl-5-fluoro-l,2,3,4- tetrahydropyridin-2-yl)methylcarbamate in 62% yield which was used for next step without further purification. MS (ESI) 321 (M+H).
[0230] ie/t-Butyl (5-fluoropiperidi -2-yl)methylcarbamate.
Figure imgf000174_0003
The above described tert-butyl (l-benzyl-5-fluoro-l,2,3,4-tetrahydropyridin-2- yl)methylcarbamate and 10% Pd/C in MeOH was stirred at rt under a hydrogen balloon overnight. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo to provide the desired product tert-butyl (5-fluoropiperidin-2-yl)methylcarbamate in quantitative yield which was used for next step without further purification. 1H NMR (CDCI3,
400 MHz) δ 4.56-4.47 (m, 1H), 3.34-3.17 (m, 2H), 3.02-2.95 (m, 1H), 2.67-2.60 (m, 2H),
2.19-2.14 (m, 1H), 1.81-1.76 (m, 1H), 1.59-1.45 (m, 2H), 1.45 (s, 9H).
[0231] (2-(Aminomethyl)-5-fluoropiperidin-l-yl)(2-methyl-5-phenylthiazol-4- yl)methanone.
Figure imgf000175_0001
General procedure A: Amide Coupling using HATU as coupling agent.
[0232] A mixture of tert-butyl (5-fluoropiperidin-2-yl)methylcarbamate (0.43 mmol, 0.1 g), 2-methyl-5-phenyl-l,3-thiazole-4-carboxylic acid (made as described in the literature: see for instance, WO2008/020405, 0.47 mmol, 0.1 g), diisopropyl ethyl amine (0.47 mmol, 0.08 mL) and HATU (0.47 mmol, 0.18 g) in dimethyl acetamide (2 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with IN NaOH and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo to provide desired tert-butyl (5-fluoro-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methylcarbamate which was used for next step without further purification.
[0233] The above described tert-butyl (5-fluoro-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methylcarbamate was stirred in CH2CI2 (5 mL) and TFA (5 mL) overnight and concentrated in vacuo. The resulting residue was taken in EtOAc and washed with saturated NaHC03. EtOAc layer was separated, dried with MgS04 and concentrated in vacuo to afford desired (2-(aminomethyl)-5-fluoropiperidin-l-yl)(2-methyl-5-phenylthiazol- 4-yl)methanone in 42% yield over two steps.
[0234] The final product N-((5-fluoro- l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin- 2-yl)methyl)quinoline-8-carboxamide was prepared by following general procedure A using (2-(aminomethyl)-5-fluoropiperidin-l-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. The NMR of desired product indicated the presence of two rotamers in 1/2 ratio. 1H NMR (DMSO-J6, 400 MHz) δ 11.02-10.99 (m, 0.33 H), 10.73- 10.70 (m, 0.67 H), 9.05-9.03 (m, 0.33 H), 8.98-8.97 (m, 0.67 H), 8.62-8.59 (m, 1.33 H), 8.52-8.50 (M, 0.67 h), 8.24-8.19 (m, 1H), 7.81-7.74 (m, 1.33 H), 7.72-7.68 (m, 0.67 H), 7.47-7.43 (m, 0.67 H), 7.34-7.32 (m, 2.33 H), 7.19-7.10 (m, 2H), 5.08-4.67 (m, 2H) 3.98- 3.34 (m, 4H), 2.65 (s, 1H), 2.23 (s, 2H), 2.12-1.69 (m, 2.67 H), 1.41-1.39 (m, 1.33 H). MS (ESI) 489 (M+H).
[0235] Example 2: N-((5-Fluoro-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methyl)benzofuran-4-carboxamide.
Figure imgf000176_0001
N-((5-Fluoro-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)benzofuran-4- carboxamide was prepared by following general procedure A using (2-(aminomethyl)-5- fluoropiperidin- l-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and benzofuran-4-carboxylic acid. MS (ESI) 478 (M+H).
[0236] Example 3: (5-Fluoro-2-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)piperidin- l-yl)(2-methyl-5-phenylthiazol-4-yl)methanone.
Figure imgf000176_0002
General procedure B: Amination of 2-chloro-5-(trifluoromethyl)pyridine. A mixture of (2- (aminomethyl)-5-fluoropiperidin-l-yl)(2-methyl-5-phenylthiazol-4-yl)methanone (0.18 mmol, 0.06 g), 2-chloro-5-(trifluoromethyl)pyridine (0.38 mmol, 0.07 g) and CS2CO3 in DMF (1.5 mL) was stirred at 120 °C overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The desired (5-fluoro-2-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)piperidin-l- yl)(2-methyl-5-phenylthiazol-4-yl)methanone was isolated by preparative HPLC. MS (ESI) 479 (M+H). [0237] Example 4: N-(((2lS',4R)-l-(Biphenylcarbonyl)-4-hydroxypyrrolidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000177_0001
[0238] Biphenyl-2-yl((2lS',4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-l-yl)methanone.
Figure imgf000177_0002
Formation of the amide bond was carried out using an adaptation of General Method A, above. A mixture of commercially available (2S,4R)-tert-butyl 4-hydroxy-2- (hydroxymethyl)pyrrolidine-l-carboxylate (3.26 g, 15 mmol) in 50 mL of DCM/TFA (3:2, v/v) was stirred at rt for 4 h, concentrated in vacuo to give a brown oil as a crude TFA salt of (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol, which was dissolved in DMF (28 mL), added with biphenyl-2-carboxylic acid (3.05 g, 15.4 mmol) and HATU (5.86 g, 15.4 mmol). The resulting solution was cooled to 0 °C, added with Et3N (8.8 mL, 63 mmol) dropwise and was allowed to warm to rt gradually and stirred overnight. 2M NaOH (aq.) was added and the mixture was extracted with EtOAc (3x). The combined EtOAc solution was washed with brine, dried over MgS04 and concentrated in vacuo to a brown oil, which was purified by column chromatography on silica gel (10% MeOH in EtOAc) to provide biphenyl-2- yl((2lS',4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-l-yl)methanone as an off-white solid (2.0 g, 45% yield over two steps). 1H NMR (CDC13, 400 MHz) δ 7.59-7.57 (m, 2H), 7.54-7.40 (m, 7H), 4.44 (brs, 1H), 4.10 (s, 1H), 3.77-3.72 (m, 1H), 3.62 (brs, 1H), 3.32 (brs, 1H), 3.04- 2.96 (m, 1H), 2.60 (brs, 1H), 2.00-1.95 (m,lH), 1.61 (brs, 2H). MS (ESI) 298.04 (M+H).
[0239] 2-(((2lS',4R)-l-(Biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)isoindo line- 1,3- dione.
Figure imgf000178_0001
General Procedure C: Converting hydroxyl group to amino group by Mitsunobu protocol and hydrazine cleavage
A solution of biphenyl-2-yl((2lS',4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin- l-yl)methanone (1.67 g, 5.6 mmol), phthalimide (1.24 g, 8.4 mmol) and triphenylphosphine (2.20 g, 8.4 mmol) in THF (56 mL) was cooled to 0 °C and added with diisopropyl azodicarboxylate (DIAD; 1.63 mL, 8.4 mmol) dropwise. The resulting suspension was allowed to warm to rt gradually and stirred overnight, concentrated in vacuo to a brown oil which was eluted on silica gel column (70% EtOAc in Hexanes) to provide 2-(((2lS',4R)-l-(biphenylcarbonyl)-4- hydroxypyrrolidin-2-yl)methyl)isoindoline-l,3-dione as a white solid contaminated with triphenylphosphine oxide and used as-is.
[0240] ((2lS',4R)-2-(Aminomethyl)-4-hydroxypyrrolidin-l-yl)(biphenyl-2-yl)methanone.
Figure imgf000178_0002
A mixture of the above mentioned 2-(((2S,4R)-l-(biphenylcarbonyl)-4-hydroxypyrrolidin-2- yl)methyl)isoindoline-l,3-dione (-5.6 mmol) and hydrazine monohydrate (0.65 mL, 10 mmol) in MeOH was stirred at 70 °C for 4 h. The resulting white suspension was cooled to rt, filtered and the filtrate was concentrated in vacuo to a white solid, which was purified by column chromatography on silica gel (100% MeOH) to provide ((2S,4R)-2-(aminomethyl)-4- hydroxypyrrolidin-l-yl)(biphenyl-2-yl)methanone as a white solid (1.1 g, 66% yield over two steps. MS (ESI) 297.05 (M+H).
[0241] N-(((2lS',4R)-l-(Biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8- carboxamide.
N-(((2lS',4R)-l-(Biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8- carboxamide was obtained as a 3: 1 ro tamer mixture by following the general procedure A using ((2S,4R)-2-(aminomethyl)-4-hydroxypyrrolidin- l-yl)(biphenyl-2-yl)methanone and quinoline-8-carboxylic acid. 1H NMR (CDC13, 400 MHz) δ 11.28-11.01 (m, 1H), 8.84-8.70 (m, 1H), 8.60-8.40 (m, 1H), 8.13-8.08 (m, 1H), 7.80-7.77 (m, 1H), 7.50-7.03 (m, 11H), 4.41-4.30 (m 1H), 3.99-3.91 (m, lH), 3.54-3.28 (m, 2H), 2.86-2.56 (m, 3H), 1.99-1.70 (m, 2H). MS (ESI) 452.16 (M+H).
[0242] Example 5: N-(((2lS,,4lS,)- l-(Biphenylcarbonyl)-4-fluoropyrrolidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000179_0001
General Procedure D: Fluorination of hydroxyl group:
A mixture of N-(((2lS',4R)- l-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline- 8-carboxamide (0.045 g, 0.10 mmol) in DCM was cooled to -78 °C, added with bis(2- methoxyethyl) amino sulfur trifluoride (Aldrich) (41 μί, 0.22 mmol) dropwise. The resulting solution was stirred at -78°C for 0.5 h, allowed to warm to rt gradually over 1.5 h and stirred at rt for 0.5 h, which was quenched by slow addition of MeOH and purified by preparative HPLC using acetonitrile and water (0.1% TFA) as eluent to provide N-(((2S,4S)- 1- (biphenylcarbonyl)-4-fluoropyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid. MS (ESI) 454.14 (M+H).
[0243] Example 6: (lS')-N-((l-(Biphenylcarbonyl)-4-oxopyrrolidin-2-yl)methyl)quinoline- 8-carboxamide.
Figure imgf000179_0002
General Procedure E: Swern oxidation of alcohols to ketones:
To a solution of oxalyl chloride (39 μί, 0.45 mmol) in DCM (7 mL) at -78 °C, was added a solution of DMSO (64 μΐ,, 0.90 mmol) in DCM (4 mL). After stirring at -78 °C for 15 min, a solution of N-(((2S,4R)- 1 -(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8- carboxamide (0.135 g, 0.30 mmol) in DCM (4 mL) was added. The resulting mixture was stirred at -78 °C for 1 h, treated with Et3N (0.25 mL, 1.8 mmol) dropwise and then allowed to warm to rt gradually over 1.5 h. The mixture was then concentrated in vacuo to a beige solid and purified by column chromatography on silica gel (70% MeOH in EtOAc) to provide (51)- N-((l-(biphenylcarbonyl)-4-oxopyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid (0.071 g, 53% yield). MS (ESI) 450.12 (M+H).
[0244] Example 7: (lS')-N-((l-(Biphenylcarbonyl)-4,4-difluoropyrrolidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000180_0001
General Procedure F: Fluorination of carbonyl group:
Bis(2-methoxyethyl)aminosulfur trifluoride (32 μί, 0.18 mmol) was added dropwise to a solution of (lS')-N-((l-(biphenylcarbonyl)-4-oxopyrrolidin-2-yl)methyl)quinoline-8- carboxamide (0.036 g, 0.080 mmol) in DCM (80 μΙ_), followed by addition of EtOH (1 μΐ.) and stirred at rt overnight. The mixture was quenched with MeOH and purified by preparative HPLC using acetonitrile and water (0.1% TFA) as eluent to provide (5)-Λ^-((1- (biphenylcarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid. MS (ESI) 472.14 (M+H).
[0245] Example 8: rac-cw-N-((3-Methyl- l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000180_0002
[0246] 3-Methylpicolinamide.
Figure imgf000181_0001
A mixture of 3-methylpicolinonitrile (2.36 g, 20 mmol) and cone, sulfuric acid (12.5 mL) was stirred at 80°C for 25 min. The solution was cooled to rt, poured into water (80 mL), followed by addition of sat. Na2C03 (aq.) until pH ~7. The resulting mixture was extracted with DCM (3x) and the combined organic layer was dried over MgS04 and concentrated in vacuo to provide 3-methylpicolinamide as a white solid (2.65 g, 97%). 1H NMR (CDC13, 400 MHz) δ 8.43 (dd, 1H), 7.93 (brs, 1H), 7.62 (dd, 1H), 7.35 (dd, 1H), 5.44 (brs, 1H), 2.76 (s, 3H).
[0247] rac-ci5'-3-Methylpiperidine-2-carboxamide.
Figure imgf000181_0002
A mixture of 3-methylpicolinamide (2.23 g, 16.4 mmol) and Pt02 (0.18 g, 0.8 mmol) in acetic acid (55 mL) was placed in a Parr shaker type hydrogenation apparatus, pressurized to 4.70 bar with H2 and maintained at rt for 7 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to a solid. A mixture of this crude solid and DCM and solid Na2C03, were stirred at rt overnight. The resulting suspension was filtered and the filtrate was concentrated in vacuo to provide rac-ci5,-3-methylpiperidine-2- carboxamide as a white solid (2.0 g, 86% yield). 1H NMR (CDC13, 400 MHz) δ 6.51 (brs, 1H), 5.32 (brs, 1H), 3.37 (d, 1H), 3.14-3.10 (m, 1H), 2.70-2.63 (m, 1H), 2.33-2.28 (m, 1H), 1.73-1.58 (m,4H), 1.42-1.39 (m, 1H), 1.00 (d, 3H).
[0248] rac-cis- l-(4-Methoxybenzyl)-3-methylpiperidine-2-carboxamide.
Figure imgf000181_0003
l-(Chloromethyl)-4-methoxybenzene (1.0 mL, 7.5 mmol) was added to a mixture of rac-cis- (2S,3R)-3-methylpiperidine-2-carboxamide (0.71 g, 5.0 mmol) in sat. Na2C03 (aq.)/DCM (15 mL, 1:2 v/v) and stirred vigorously at rt overnight. The resulting suspension was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo to a white residue, which was purified by column chromatography on silica gel (100% EtOAc) to provide rac-cis-l-(4-methoxybenzyl)- 3-methylpiperidine-2-carboxamide as a white solid (0.61 g, 41% yield. MS (ESI) 262.98 (M+H).
[0249] rac-cis -(I- (4-Methoxybenzyl) - 3 -methylpiperidin-2-yl)methanamine .
Figure imgf000182_0001
rac-ci5'-l-(4-Methoxybenzyl)-3-methylpiperidine-2-carboxamide (0.61 g, 2.33 mmol) was added portionwise to a suspension of LiAlH4 (0.30 g, 7.50 mmol) and THF (12 mL) and heated to reflux for 14 h. The reaction mixture was then cooled to 0 °C and quenched with water and NaOH (aq.). The resulting mixture was stirred at rt for 1 h, filtered and the filtrated was concentrated in vacuo to provide rac-ci5,-(l-(4-methoxybenzyl)-3-methylpiperidin-2- yl)methanamine as a colorless oil, used as-is without further purification.
[0250] rac-ci5'-N-((l-(4-Methoxybenzyl)-3-methylpiperidin-2-yl)methyl)quinoline-8- carboxamide.
Figure imgf000182_0002
rac-cis -N-((l-(4-Methoxybenzyl)-3-methylpiperidin-2-yl)methyl)quinoline-8-carboxamide was obtained by following the general procedure A using the fore-mentioned crude rac-cis- (l-(4-methoxybenzyl)-3-methylpiperidin-2-yl)methanamine and quinoline-8-carboxylic acid. MS (ESI) 404.24 (M+H).
[0251] rac-cis -N-((3-Methylpipe oline-8-carboxamide.
Figure imgf000182_0003
Cerium ammonium nitrate (1.25 g, 2.28 mmol) was added portionwise to a mixture of rac- ci5,-N-((l-(4-methoxybenzyl)-3-methylpiperidin-2-yl)methyl)quinoline-8-carboxamide (0.23 g, 0.57 mmol) in acetone/water (10 mL, 9: 1 v/v) at 0 °C and allowed to stir at rt for 5 h. Sat. NaHCC"3 (aq.) was added and the resulting suspension was stirred at r.t for 10 min, concentrated in vacuo to remove the acetone, then filtered through diatomaceous earth and rinsed with EtOAc. The bi-layer filtrate was extracted with EtOAc and the combined organic layer was washed with brine, dried over MgS04 and concentrated in vacuo to provide a brown oil as a 1: 1 mixture of rac-cw-N-iiS-methylpiperidin-l-y^methy^quinoline-S- carboxamide / 4-methoxybenzaldehyde, which was used as-is without further purification. MS (ESI) 284.13 (M+H).
[0252] mc-c? ,-N-((3-Methyl-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide. rac-cis-N-((3-Met y\- l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was obtained as a 1: 1 rotamer mixture by following the general procedure A using the fore-mentioned crude rac-cis-N-((3- methylpiperidin-2-yl)methyl)quinoline-8-carboxamide and 2-methyl-5-phenylthiazole-4- carboxylic acid. MS (ESI) 485.12 (M+H).
[0253] Example 9: rac-cw-N-((3-Methyl-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000183_0001
rac-ci5'-N-((3-Methyl-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was obtained by following the general procedure A using the fore-mentioned crude rac-ci5,-N-(((2lS,,3R)-3-methylpiperidin-2-yl)methyl)quinoline-8- carboxamide and 2-methyl-4-phenylthiazole-5-carboxylic acid. MS (ESI) 485.15 (M+H).
[0254] Example 10: rac-ci5,-N-((l-(3-Fluoro-2-methoxybenzoyl)-3-methylpiperidin-2- yl)methyl)quinoline-8-carboxami
Figure imgf000183_0002
rac-cw-N-iil-iS-Fluoro-l-methoxybenzoy^-S-methylpiperidin-l-y^methy^quinoline-S- carboxamide was obtained by following the general procedure A using the fore-mentioned crude rac-ci5'-N-(((25,3R)-3-methylpiperidin-2-yl)methyl)quinoline-8-carboxamide and 3- fluoro-2-methoxybenzoic acid. MS (ESI) 436.14 (M+H).
[0255] Example 11 : rac-ci5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000184_0001
[0256] rac-ds-tert-Butyl ((3-methylpiperidin-2-yl)methyl)carbamate.
Figure imgf000184_0002
To a solution of 3-methyl-2-cyanopyridine (5g) in acetic acid was added 10% Pd/C. The Pan- shaker bottle was evacuated/H2 purged 3x, and then shaken at 50 psi until starting material was consumed (typically < lh). The reaction was filtered through diatomaceous earth and concentrated to yield (3-methylpyridin-2-yl)methanamine acetic acid salt which was used without further purification. To the crude salt in THF was added aq 1 M NaOH, followed by BOC20 (2 eq). The reaction was allowed to stir at rt overnight. After -16 h, the reaction mixture was transferred to a separatory funnel, diluted with EtOAc, and water, and the layers were separated. The organic layer was washed with brine, dried (MgS04), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel
(EtO Ac/hex) to afford tert-butyl ((3-methylpyridin-2-yl)methyl)carbamate. To a solution of the BOC -protected pyridylamine in MeOH was added Nishimura' s catalyst. The parr shaker bottle was evacuated/purged with H2 (3x) and then shaken at 50 psi for 24h. The reaction was filtered through diatomaceous earth, and concentrated in vacuo to give the title compound as a near colorless oil, and was used without further purification. 1H NMR (de- DMSO, 400 MHz) δ 6.7 (br s, NH), 4.0 (br s, 1H), 2.9-2.7 (m, 3H), 2.6-2.5 (m, 1H), 2.5-2.4 (m, 1H), 1.7-1.6 (br s, 1H), 1.6-1.45 (m, 3H), 1.4 (s, 9H), 1.3-1.2 (m, 1H), 0.8 (d,3H).
[0257] rac-ci5'-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000185_0001
To a solution of iert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (1.5 g) from the previous step in CH2CI2 was added DIPEA (2 eq) followed by 2-methyl-5-(4- fluorophenylthiazole)-4-carboxylic acid (2 g) and HATU (3.3 g). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the CH2CI2. The crude residue was taken up in EtOAc and washed with 1M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give tert-butyl ((l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)carbamate as a light yellow oil which crystallized (2 g). To a solution of this carbamate in CH2CI2 was added TFA (1: 1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried
(MgS04), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 348.06 (M+H).
[0258] rac-cw-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)( 3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. A mixture of (2- (aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-(trifluoromethyl)pyridine, and K2C03 in DMAC was stirred at 120 °C overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtO Ac/hex) to give the title compound as a pale yellow oil which solidified. MS (ESI) 493.01 (M+H). [0259] Example 12: rac-ci5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(2-methyl-5-phenylthiazol-4-yl)methanone.
Figure imgf000186_0001
[0260] rac-ci5'-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-methyl-5-phenylthiazol-4- yl)methanone.
Figure imgf000186_0002
The title compound was synthesized following the same general protocol as described in Example 11 using rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate and 2- methyl-5-phenylthiazole-4-carboxylic acid. MS (ESI) 330.08 (M+H).
[0261] rac-c? ,-(2-((benzordloxazol-2-ylamino)methyl)-3-methylpiperidin-l-yl)(2-methyl- 5-phenylthiazol-4-yl)methanone. A mixture of (2-(aminomethyl)-3-methylpiperidin-l-yl)(2- methyl-5-phenylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2CI2 was stirred at 60 °C overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et20/hexanes to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 447.03 (M+H).
[0262] Example 13: rac-ci5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3- (trifluoromethyl)piperidin-l-yl) 2-methyl-5-phenylthiazol-4-yl)methanone.
Figure imgf000186_0003
[0263] rac-cis-tert-buty\ ((3-(Trifluoromethyl)piperidin-2-yl)methyl)carbamate.
Figure imgf000187_0001
The title compound was synthesized following the same general protocol as described for
Figure imgf000187_0002
(((2S,3R)-3-methylpiperidin-2-yl)methyl)carbamate starting with 3- (trifluoromethyl)picolinonitrile. 1H NMR (d6-DMSO, 400 MHz) δ 5.1 (br s, NH), 3.25 (br s, 2H), 3.1 (br s, IH), 2.8 (br, 2H), 2.7 (br, 2H), 2.4 (br , IH), 1.8-1.6 (m, 3H), 1.4 (s, 9H); MS (ESI) 283.2 (M+H).
[0264] rac-c? ,-(2-((Benzordloxazol-2-ylamino)methyl)-3-(trifluoromethyl)piperidin-l- yl)(2-methyl-5-phenylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Examples 11 and 12. MS (ESI) 501.05 (M+H).
[0265] Example 14: rac-cw-(2-Methyl-5-phenylthiazol-4-yl)(3-(trifluoromethyl)-2-(((5- (trifluoromethyl)pyridin-2-yl)amino methyl)piperidin-l-yl)methanone.
Figure imgf000187_0003
The title compound was prepared following the same general protocol as described for Examples 11 and 12 starting with 3-(trifluoromethyl)picolinonitrile. MS (ESI) 528.98 (M+H).
[0266] Example 15: rac-ci5,-(2-(((5-Bromopyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000187_0004
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 5-bromo-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 120 °C for lh in a microwave reactor. The reaction was complete as judged by reverse-phase analytical HPLC. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 505.88 (M+H).
[0267] Example 16: rac-ci5,-(2-(((5-Ethylpyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000188_0001
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 5-ethyl-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110 °C for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 454.02 (M+H).
[0268] Example 17: rac-ci5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(2-(((4- methoxypyrimidin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000188_0002
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 4-methoxy-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110 °C for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.02 (M+H). [0269] Example 18: rac-ci5,-(2-(((5-Chloropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000189_0001
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 2-fluoro-5-chloropyridine, and K2CO3 in DMAC was stirred at 120 °C for 16 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 458.95 (M+H).
[0270] Example 19: rac-ci5,-(2-(((2-Chloropyrimidin-4-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000189_0002
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 2,4-dichloropyrimidine, and K2CO3 in DMAC was stirred at 120 °C for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound as the major isomer. MS (ESI) 459.94 (M+H).
[0271] Example 20: rac-ci5,-(2-(((4-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000190_0001
The title compound was isolated as the minor isomer in the reaction described for Example
19. MS (ESI) 459.94 (M+H).
[0272] Example 21: rac-ci5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000190_0002
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 2-bromo-4-(trifluoromethyl)pyridine, Pd2dba3, BINAP, and NaOtBu in toluene was purged with argon, and then stirred at 70 °C for 12 h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 492.97 (M+H).
[0273] Example 22: rac-ci5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((3- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000190_0003
The title compound was prepared following the same general protocol as described for Example 21 using 2-bromo-3-(trifluoromethyl)pyridine. MS (ESI) 493.01 (M+H). [0274] Example 23: rac-ci5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((6- methylpyridin-2-yl)amino)methyl)piperidin- 1 -yl)methanone.
Figure imgf000191_0001
The title compound was prepared following the same general protocol as described for Example 21 using 2-bromo-6-(methyl)pyridine. MS (ESI) 439.04 (M+H).
[0275] Example 24: rac-ci5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000191_0002
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2CI2 was stirred at 60 °C overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et20/hex to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 465.03 (M+H).
[0276] Example 25: rac-(2-((Benzo[d]oxazol-2-ylamino)methyl)-6-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. [0277] ie/t-Butyl ((6-methyl
Figure imgf000192_0001
To a solution of 6-methyl-2-cyanopyridine (5 g) and BOC20 in EtOAc was added 10% Pd/C. The reaction mixture was stirred under a balloon of H2 for 24 h, and then filtered through diatomaceous earth and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (EtOAc/hex) to give the title compound as a colorless oil. 1H NMR (d6-DMSO, 400 MHz) δ 7.6 (t, IH), 7.4 (br s, NH), 7.2 (d, IH), 7.1 (d, IH), 4.2 (d, 2H), 2.4 (s, 3H), 1.4 (s, 9H).
[0278] rac-ie/t-Butyl ((6-methylpiperidin-2-yl)methyl)carbamate.
Figure imgf000192_0002
To a solution of the product from the previous step in MeOH was added Nishimura' s catalyst. The parr shaker bottle was evacuated/purged with H2 (3x) and then shaken at 50 psi for 24 h. The reaction was filtered through diatomaceous earth, and concentrated in vacuo to give the title compound as a near colorless oil, and was used without further purification. 1H NMR (d6-DMSO, 400 MHz) δ 6.75 (br s, NH), 3.3 (br s, IH), 2.9-2.8 (m, IH), 2.8-2.7 (m, IH), 2.5- 2.4 (m, IH), 2.0-1.8 (br s, IH), 1.75-1.65 (m, IH), 1.55-1.45 (m, 2H), 1.4 (s, 9H), 1.3-1.2 (m, IH), 0.95 (d,3H), 0.9-0.8 (m, 2H).
[0279] rac-(2-(Aminomethyl)-6-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol- 4-yl)methanone.
Figure imgf000193_0001
The title compound was made following the same general protocol as described for Example 11. MS (ESI) 348.11 (M+H).
[0280] rac-(2-((Benzordloxazol-2-ylamino)methyl)-6-methylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was made following the same general protocol as described for Example 12. MS (ESI) 465.08 (M+H).
[0281] Example 26: rac-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(2-methyl-6-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000193_0002
The title compound was made following the same general protocol as described for Example 11. MS (ESI) 493.04 (M+H).
[0282] Example 27: rac-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(2-methyl-6-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000193_0003
The title compound was made following the same general protocol as described for Example 11. MS (ESI) 494.04 (M+H). [0283] Example 28: rac-(2-(((5-Chloropyrimidin-2-yl)amino)methyl)-6-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000194_0001
The title compound was made following the same general protocol as described for Example 11. MS (ESI) 460.04 (M+H).
[0284] Example 29: rac-N-((6-Methyl-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin- 2-yl)methyl)quinoline-8-carboxamide.
Figure imgf000194_0002
[0285] Part I: rac-(2-(Aminomethyl)-6-methylpiperidin-l-yl)(2-methyl-4-phenylthiazol-5- yl)methanone.
Figure imgf000194_0003
General Procedure G: Curtius Rearrangement of carboxylic acid. Ethyl chloroformate (0.28 mmol, 0.027 mL) and triethylamine (0.28 mmol, 0.04 mL) were added to a solution of 2-(6-methyl-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)acetic acid (0.14 mmol, 0.05 g) sequentially at 0 °C. The resulting mixture was stirred at rt for 1 h. Then, an aqueous solution of NaN3 (1.40 mmol, 0.045 g) in water (1 mL) was added at 0 °C with vigorously stirring. The reaction was tracked by analytical HPLC. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The resulting residue was mixed with toluene/ iBuOH (5 mL/5 mL) and refluxed at 110 °C overnight. The solvent was removed in vacuo to give ie/t-butyl (6- methyl- l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methylcarbamate which was deprotected of Boc in TFA/CH2CI2 (volume: 1/1) to give desired rac-(2-(aminomethyl)-6- methylpiperidin-l-yl)(2-methyl-4-phenylthiazol-5-yl)methanone.
[0286] mc-N-((6-Methyl-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide. The title compound was prepared by following the general procedure A using rac-(2-(aminomethyl)-6-methylpiperidin-l-yl)(2-methyl-4- phenylthiazol-5-yl)methanone and quinoline-8-carboxylic acid. MS (ESI) 485 (M+H).
[0287] Example 30: rac-(2-Methyl-4-phenylthiazol-5-yl)(2-methyl-6-(2- phenoxyethyl)piperidin- 1 -yl)meth
Figure imgf000195_0001
[0288] Part I: 2-Methyl-6-(2-phenoxyethyl)pyridine.
Figure imgf000195_0002
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0 °C dropwise. The resulting mixture was stirred at 0 °C for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2- yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90 °C for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2- phenoxyethyl)pyridine as a colorless oil in 26% yield. [0289] Part II: rac-2-Methyl-6-(2-phenoxyethyl)piperidine.
Figure imgf000196_0001
General Procedure H: Hydrogenation of pyridine to piperdine using Adam Catalyst. 2-
Methyl-6-(2-phenoxyethyl)pyridine (0.19 mmol, 0.04 g) and Adam Catalyst (0.09 mmol, 0.02g) in MeOH was stirred at rt under a hydrogen balloon overnight. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo to provide the desired product 2-methyl-6-(2-phenoxyethyl)piperidine in 30% conversion. This crude residue was used in the next step without further purification.
[0290] Part III. The title compound was prepared according to general procedure A using rac-2-methyl-6-(2-phenoxyethyl)piperidine and 2-methyl-5-phenyl- 1 ,3-thiazole-4-carboxylic acid. 1H NMR (CDC13, 400 MHz) δ 7.64-7.60 (m, 2H), 7.37-7.29 (m, 3H), 7.24-7.14 (m, 2H), 6.93-6.85 (m, 2H), 6.64-6.62 (m, 1H), 4.87-4.78 (m, 1H), 4.07-4.01 (m, 1H), 3.93- 3.78 (m, 1H), 3.62-3.50 (m, 1H), 3.13-3.07 (m, 1H), 2.69 (s, 1H), 2.55 (s, 2H), 2.01-2.00 (m, 1H), 1.48-1.21 (m, 9H). MS (ESI) 421 (M+H).
[0291] Example 31: rac-Biphenyl-2-yl(2-methyl-6-(2-phenoxyethyl)piperidin-l- yl)methanone.
Figure imgf000196_0002
The title compound was prepared according to general procedure A using 2-methyl-6-(2- phenoxyethyl)piperidine and biphenyl-2-carboxylic acid. MS (ESI) 400 (M+H).
[0292] Example 32: N-((l-(Biphenylcarbonyl)-5-hydroxypiperidin-2-yl)methyl)quinoline- 8-carboxamide.
Figure imgf000196_0003
[0293] Part I: Methyl 5,5-dimethox iperidine-2-carboxylate.
Figure imgf000197_0001
5-Oxopiperidine-2-carboxylic acid hydrochloride salt (41.1 mmol, 7.36 g) in MeOH was added thionyl chloride (206.7 mmol, 15 mL) drop wise by an additional funnel at -10 °C. The resulting mixture was refluxed at 60 °C overnight. The reaction mixture was concentrated in vacuo to give desired product methyl 5,5-dimethoxypiperidine-2-carboxylate as the HCl salt. 1H NMR (CDCI3, 400 MHz) δ 4.28-4.20 (m, 1H), 3.78 (s, 3H), 3.35-3.32 (m, 1H), 3.16 (s, 3H), 3.14 (s, 3H), 3.31-1.98 (m, 2H), 1.82-1.69 (m, 2H).
[0294] Part II: Methyl 5-oxopiperi .
Figure imgf000197_0002
The above described ketal was stirred in TFA at rt for 4 h. An aliquot was taken for NMR which confirmed 100% conversion of starting material. The reaction mixture was diluted with water and extracted with DCM. The DCM layer was discarded and the water layer was concentrated in vacuo to give desired methyl 5-oxopiperidine-2-carboxylate as the TFA salt in quantitative yield.
[0295] Part III: Methyl l-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate.
Figure imgf000197_0003
Methyl l-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate was prepared according to general procedure A using methyl 5-oxopiperidine-2-carboxylate and biphenyl-2-carboxylic acid. MS (ESI) 338 (M+H).
[0296] Part IV: Biphenyl-2-yl(2-(hydroxymethyl)-5,5-dimethoxypiperidin-l- yl)methanone.
Figure imgf000197_0004
Methyl l-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate was converted to methyl 1- (biphenylcarbonyl)-5,5-dimethoxypiperidine-2-carboxylate (4.3 mmol, 1.65g) following the general protocol described in Part I above. To a solution of this ketal in anhydrous THF was added LiBH4 (2M in THF) (9.4 mmol, 4.7 mL) at 0 °C under argon. The resulting mixture was stirred at rt and the reaction was tracked by analytical HPLC. The reaction was carefully quenched with saturated NH4C1 and extracted with EtOAc. The organic layer was separated, dried with MgS04, and concentrated in vacuo to give desired biphenyl-2-yl(2- (hydroxymethyl)-5,5-dimethoxypiperidin-l-yl)methanone in quantitative yield which was used for next step without further purification.
[0297] Part V: 2-((l-(Biphenylcarbonyl)-5,5-dimethoxypiperidin-2-yl)methyl)isoindoline- 1,3-dione.
Figure imgf000198_0001
General Procedure I: Mitsunobu reaction of alcohol with phthalimide. DIAD (15.15 mmol, 2.93 mL) was added to a mixture of (biphenyl-2-yl(2-(hydroxymethyl)-5-methoxy-
3.4- dihydropyridin-l(2H)-yl)methanone (4.5 mmol, 1.63 g), phthalimide (15.15 mmol, 2.23 g) and PPh3 (15.15 mmol, 3.97 g) in anhydrous THF dropwise at 0 °C under argon. The resulting mixture was stirred at rt for overnight and concentrated in vacuo to give a crude residue which was purified by chromatography to give the desired 2-((l-(biphenylcarbonyl)-
5.5- dimethoxypiperidin-2-yl)methyl)isoindoline-l,3-dione with slight contamination of triphenylphosphine oxide. This contaminated product was used for next step without further purification.
[0298] Part VI: (2-(Aminomethyl)-5,5-dimethoxypiperidin-l-yl)(biphenyl-2- yl)methanone.
Figure imgf000198_0002
General Procedure J. Conversion of phthalimide to primary amine using hydrazine. A mixture of the above described 2-((l-(biphenylcarbonyl)-5,5-dimethoxypiperidin-2- yl)methyl)isoindoline-l,3-dione (1.13 g, 2.3 mmol) and hydrazine monohydrate (10.0 mmol, 0.4 g) in MeOH (10 mL) was stirred at 60 °C. The reaction was tracked by analytical HPLC. MeOH was removed in vacuo and the reaction mixture was diluted with water followed by extraction with EtOAc. The organic layer was separated, dried with MgS04, and concentrated in vacuo to give desired (2-(aminomethyl)-5,5-dimethoxypiperidin-l-yl)(biphenyl-2- yl)methanone.
[0299] Part VII: N-((l-(Biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide.
Figure imgf000199_0001
N-((l-(Biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure A using quinoline-8-carboxylic acid and N-((l- (biphenylcarbonyl)-5-methoxy-l,2,3,4-tetrahydropyridin-2-yl)methyl)quinoline-8- carboxamide which was synthesized from the product from Part VI above, following ketal cleavage using TFA and CH2C12. MS (ESI) 464 (M+H).
[0300] General procedure K. Reduction of ketone to alcohol. NaBH4 (3.49 mmol, 0.13 g) was added to a solution of N-((l-(biphenylcarbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide TFA salt (0.46 mmol, 0.26 g) in MeOH (10 mL) at 0 °C in three portions. The resulting mixture was stirred at rt and the reaction was tracked by analytical HPLC. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried with MgS04, and concentrated in vacuo to give crude residue which was purified by preparative HPLC to give desired N-((l-(biphenylcarbonyl)-5- hydroxypiperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y:75%). MS (ESI) 466 (M+H).
[0301] Example 33: N-((5-Hydroxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000200_0001
[0302] Part i: Methyl 5,5-dimethoxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidine- 2-carboxylate.
Figure imgf000200_0002
Methyl 5,5-dimethoxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidine-2-carboxylate was prepared according to general procedure A using methyl 5,5-dimethoxypiperidine-2- carboxylate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
[0303] Part II: (2-(Hydroxymethyl)-5,5-dimethoxypiperidin-l-yl)(2-methyl-4- phenylthiazol-5 - yl)methanone .
Figure imgf000200_0003
The title compound was prepared from the product of Part I following the same general protocol as described for Example 32 Part IV.
[0304] Part III: N-((5,5-Dimethoxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000201_0001
N-((5,5-Dimethoxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedures I, using (2-(Hydroxymethyl)-5,5-dimethoxypiperidin-l-yl)(2-methyl-4-phenylthiazol-5 yl)methanone.
[0305] Part IV: N-((l-(2-Methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamid
Figure imgf000201_0002
The title compound was prepared from the product of Part III above using TFA/CH2CI2. MS (ESI) 485 (M+H). N-((5-hydroxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure K using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide. MS (ESI) 487 (M+H).
[0306] Example 34: N-((5,5-Difluoro-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin- 2-yl)methyl)quinoline-8-carboxamide.
Figure imgf000202_0001
General Procedure L: Difluorination of ketone with Bis(2-methoxyethyl)aminosulfur trifluoride. Bis(2-methoxyethyl)aminosulfur trifluoride (0.17 mmol, 0.032 mL) in DCM (0.2 mL) was added to a solution of N-((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5- oxopiperidin-2-yl)methyl)quinoline-8-carboxamide (0.10 mmol, 0.05 g) in DCM (0.2 mL) in a sealed tube at rt. Then EtOH (0.02 mmol, 0.0008 g) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and quenched with saturated NaHC03. The organic layer was separated, dried with MgS04, and concentrated in vacuo to give crude residue which was purified by prep. HPLC to give desired N-((5,5- difluoro-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8- carboxamide (Y:56 ). MS (ESI) 507 (M+H).
[0307] Example 35: N-((5-Fluoro-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamid
Figure imgf000202_0002
General Procedure M: Fluorination of alcohol with bis(2-methoxyethyl)aminosulfur trifluoride. A solution of N-((5-hydroxy-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin- 2-yl)methyl)quinoline-8-carboxamide (0.07 mmol, 0.036 g) in DCM (0.3 mL) was added to a mixture of bis(2-methoxyethyl)aminosulfur trifluoride (0.14 mmol, 0.027 mL) in DCM (0.2 mL) at -78 °C under argon. The resulting mixture was stirred at -78 °C for 1 h and at rt for another 1.5 h. The desired product was purified by preparative TLC to give N-((5-fluoro-l- (2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y: 16 ). MS (ESI) 489 (M+H). [0308] Example 36: N-((l-(Biphenylcarbonyl)-5,5-difluoropiperidin-2- yl)methyl)quinoline-8-carboxamid
Figure imgf000203_0001
N-((l-(Biphenylcarbonyl)-5,5-difluoropiperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure L using N-((l-(biphenylcarbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide. MS (ESI) 486 (M+H).
[0309] Example 37: N-((l-(Biphenylcarbonyl)-5-fluoropiperidin-2-yl)methyl)quinoline-8- carboxamide (Diastereomer 1).
Figure imgf000203_0002
[0310] Example 38: N-((l-(Biphenylcarbonyl)-5-fluoropiperidin-2-yl)methyl)quinoline-8- carboxamide (Diastereomer 2).
Figure imgf000203_0003
Example 37 and Example 38 were two different fractions isolated from the fluorination of N- ((l-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide by following general procedure M. However, the stereochemistry of isomers has not been verified. MS (ESI) 468 (M+H).
[0311] Example 39: N-((5-Amino-l-(biphenylcarbonyl)piperidin-2-yl)methyl)quinoline-8- carboxamide.
Figure imgf000204_0001
General Procedure N: Reductive amination of ketone. NaB¾CN (0.18 mmol, 0.011 g) was added to a solution of N-((l-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide (0.06 mmol, 0.027 g) and NH4Oac (0.6 mmol, 0.011 g) in MeOH. The resulting mixture was stirred at rt for overnight and quenched with saturated NH4C1. The aqueous solution was extracted with EtOAc and the organic layer was separated, dried with MgS04, and concentrated in vacuo to give crude residue which was purified by preparative HPLC to give desired N-((5-amino-l-(biphenylcarbonyl)piperidin-2-yl)methyl)quinoline-8- carboxamide. (ESI) 465 (M+H).
[0312] Example 40: N-((5-(Benzylamino)-l-(biphenylcarbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000204_0002
N-((5-(Benzylamino)-l-(biphenylcarbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure N using N-((l-(biphenylcarbonyl)-5-oxopiperidin- 2-yl)methyl)quinoline-8-carboxamide and benzyl amine. (ESI) 555 (M+H). [0313] Example 41: N-((l-(Biphenylcarbonyl)-5-(dimethylamino)piperidin-2- yl)methyl)quinoline-8-carboxami
Figure imgf000205_0001
N-((l-(Biphenylcarbonyl)-5-(dimethylamino)piperidin-2-yl)methyl)quinoline-8-carboxam ^ was prepared according general procedure N using N-((l-(biphenylcarbonyl)-5-oxopiperidin- 2-yl)methyl)quinoline-8-carboxamide and dimethyl amine. (ESI) 493 (M+H).
[0314] Example 42: N-((l-(Biphenylcarbonyl)-5-(2-hydroxyethylamino)piperidin-2- yl)methyl)quinolone-8-carboxamide.
Figure imgf000205_0002
N-((l-(Biphenylcarbonyl)-5-(2-hydroxyethylamino)piperidin-2-yl)methyl)quinoline-8- carboxamide was prepared according general procedure N using N-((l-(biphenylcarbonyl)-5- oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and 2-aminoethanol. (ESI) 509 (M+H).
[0315] Example 43: N-((5-Acetamido-l-(biphenylcarbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000205_0003
Example 43 was isolated as a byproduct from the preparation of Example 39. (ESI) 507 (M+H).
[0316] Example 44: N-((5-Amino-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxami
Figure imgf000206_0001
N- ( (5 - Amino- 1 - (2-methyl-4-phenylthiazole- 5 -carb onyl)piperidin-2- yl)methyl)quinoline- 8 - carboxamide was prepared according to general procedure N using N-((l-(2-methyl-4- phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide. (ESI) 486 (M+H).
[0317] Example 45: N-((l-(2-Methyl-4-phenylthiazole-5-carbonyl)-5- (methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide.
Figure imgf000206_0002
N- ( ( 1 - (2-Methyl-4-phenylthiazole- 5 -carbonyl)- 5 - (methylamino)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide and methyl amine. (ESI) 500 (M+H).
[0318] Example 46: N-((5-(Ethylamino)-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000207_0001
N-((5-(Ethylamino)-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide and ethyl amine. (ESI) 514 (M+H).
[0319] Example 47: N-((5-(2-Hydroxyethylamino)-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000207_0002
N-((5-(2-Hydroxyethylamino)-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide and 2-aminoethanol. (ESI) 530 (M+H).
[0320] Example 48: N-((5-(Isopropylamino)-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000207_0003
N-((5-(Isopropylamino)-l-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8- carboxamide and isopropyl amine. (ESI) 528 (M+H).
[0321] Example 49: N-((l-(Biphenylcarbonyl)-5-(methylamino)piperidin-2- yl)methyl)quinoline-8-carboxami
Figure imgf000208_0001
N-((l-(Biphenylcarbonyl)-5-(methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((l-(biphenylcarbonyl)-5- oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and methyl amine. (ESI) 479 (M+H).
[0322] Example 50: N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5- methoxypiperidin-2-yl)methyl)
Figure imgf000208_0002
[0323] Part I: Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5,5- dimethoxypiperidine-2-carboxylate.
Figure imgf000209_0001
Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5,5-dimethoxypiperidine-2- carboxylate was prepared according to general procedure A using product methyl 5,5- dimethoxypiperidine-2-carboxylate and 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
[0324] Part II: Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidine- 2-carboxylate.
Figure imgf000209_0002
The title compound was prepared from the product of Part I above using TFA/CH2CI2.
[0325] Part III: Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5- hydroxypiperidine-2-carboxylate.
Figure imgf000209_0003
Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-hydroxypiperidine-2- carboxylate was prepared according to general procedure K using methyl l-(5-(3- fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidine-2-carboxylate.
[0326] Part IV: Methyl l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5- methoxypiperidine-2-carboxylate.
Figure imgf000210_0001
Mel (6.8 mmol, 0.43 mL) was added to a mixture of methyl l-(5-(3-fluorophenyl)-2- methylthiazole-4-carbonyl)-5-hydroxypiperidine-2-carboxylate (0.68 mmol, 0.26 g) and Ag20 (3.4 mmol, 0.8 g) in CH3CN (3 mL) at rt. The resulting mixture was stirred at rt for two days. The reaction mixture was diluted with DCM and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to give desired product methyl l-(5-(3- fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidine-2-carboxylate which was used for next step without further purification (Y: 96%).
[0327] Part V: (5-(3-Fluorophenyl)-2-methylthiazol-4-yl)(2-(hydroxymethyl)-5- methoxypiperidin- 1 -yl)methanone.
Figure imgf000210_0002
The title compound was prepared from the product of Part IV following the same general protocol as described for Example 32 Part IV.
[0328] Part VI: 2-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5- methoxypiperidin-2-yl)methyl)iso
Figure imgf000210_0003
2-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidin-2- yl)methyl)isoindoline-l,3-dione was prepared according to general procedure I using (5-(3- fluorophenyl)-2-methylthiazol-4-yl)(2-(hydroxymethyl)-5-methoxypiperidin-l-yl)methanone and phthalimide.
[0329] Part VII: (2-(Aminomethyl)-5-methoxypiperidin-l-yl)(5-(3-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000211_0001
(2-(Aminomethyl)-5-methoxypiperidin-l-yl)(5-(3-fluorophenyl)-2-methylthiazol-4- yl)methanone was prepared according to general procedure J using 2-((l-(5-(3- fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidin-2-yl)methyl)isoindoline- 1,3-dione. (ESI) 364 (M+H).
[0330] N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidin-2- yl)methyl)quinoline-8-carboxamide. The title compound was prepared according to general procedure A using (2-(aminomethyl)-5-methoxypiperidin-l-yl)(5-(3-fluorophenyl)-2- methylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. (ESI) 519 (M+H).
[0331] Example 51: N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5- hydroxypiperidin-2-yl)methyl)
Figure imgf000211_0002
[0332] Part I: N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000212_0001
N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide was prepared in a similar fashion as N-((l-(2-methyl-4- phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide.
[0333] N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-hvdroxypiperidin-2- yl)methyl)quinoline-8-carboxamide. The title compound was prepared according to general procedure K using N-((l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide. (ESI) 505 (M+H).
[0334] Example 52: rac-N-((5,5-Difluoro-l-(5-(3-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2- yl)methyl)qu
Figure imgf000212_0002
N-((5,5-Difluoro-l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure L using N- ((l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline- 8-carboxamide. (ESI) 525 (M+H).
[0335] Example 53: N-((5-Amino-l-(5-(3-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000213_0001
N-((5-Amino-l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N- ((l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline- 8-carboxamide. (ESI) 504 (M+H).
[0336] Example 54: N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-(2- hydroxyethylamino)piperidin- -yl)methyl)quinoline-8-carboxamide.
Figure imgf000213_0002
N-((l-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-(2-hydroxyethylamino)piperidin- 2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((l-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide. (ESI) 548 (M+H).
[0337] Example 55: N-((5-Amino-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000214_0001
N-((5-Amino-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)quinoline-8- carboxamide was prepared according to general procedure N using N-((l-(2-methyl-5- phenylthiazole-4-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide which was obtained in a similar fashion as N-((l-(2-methyl-4-phenylthiazole-5-carbonyl)-5- oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and NH4OAC. (ESI) 486 (M+H).
[0338] Example 56: rac-N-((5,5-Difluoro-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2- yl)methyl)qu
Figure imgf000214_0002
N-((5,5-Difluoro-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)quinoline- 8-carboxamide was prepared according to general procedure L using N-((l-(2-methyl-5- phenylthiazole-4-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide. . (ESI) 507 (M+H).
[0339] Example 57: rac-N-((5,5-Difluoro-l-(5-(4-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2-yl)methyl)-2-methylbenzofuran-4-carboxamide.
Figure imgf000214_0003
[0340] Part I: rac-Ethyl 5,5-diethoxypiperidine-2-carboxylate.
Figure imgf000215_0001
The title compound was prepared according following the same general protocol as described in Example 32 Part I using 5-oxopiperidine-2-carboxylic acid and EtOH. 1H NMR (CDC13, 400 MHz) δ 4.22-4.17 (m, 2H), 3.74-3.42 (m, 4H), 3.82-3.35 (m, 1H), 3.23-3.13 (m, 1H), 2.62 (d, 1H), 2.10-2.05 (m, 1H), 1.98-1.93 (m, 1H), 1.92 (brs, 1H), 1.69-1.56 (m, 2H), 1.30- 1.27 (m, 3H), 1.23-1.16 (m, 6H).
[0341] Part II: rac-(5,5-Diethoxypip ol.
Figure imgf000215_0002
General Procedure O: LAH reduction of amino ester to amino alcohol. A suspension of LAH (0.47 g, 12.25 mmol) in anhydrous THF (5 mL) was added a solution of ethyl 5,5- diethoxypiperidine-2-carboxylate (0.6 g, 2.45 mmol) in anhydrous THF (5 mL) dropwise at rt. The resulting mixture was refluxed at 70 °C for overnight. The reaction mixture was cooled down to 0 °C and quenched sequentially with water (0.47 g), 15% NaOH (0.47 g) and water (1.41 g). The resulting suspension was stirred at rt for 1 h and filtered. The filtrate was concentrated in vacuo to give desired rac-(5,5-diethoxypiperidin-2-yl)methanol in 95% yield as colorless oil. 1H NMR (CDC13, 400 MHz) δ 3.54-3.32 (m, 6H), 3.11-3.04 (m, 1H), 2.56- 2.46 (m, 2H), 2.05-2.00 (m, 1H), 1.52-1.23 (m, 3H), 1.15-1.07 (m, 6H).
[0342] Part III: rac-(5,5-Diethoxy-2-(hydroxymethyl)piperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000215_0003
The title compound was prepared according to general procedure A using 5-(4-fluorophenyl)- 2-methylthiazole-4-carboxylic acid and rac-(5,5-diethoxypiperidin-2-yl)methanol. [0343] Part IV: rac-2-((5,5-Diethoxy-l-(5-(4-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2-yl)methyl)i
Figure imgf000216_0001
The title compound was prepared according to general procedure I using rac-(5,5-diethoxy-2-
(hydroxymethyl)piperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. H
NMR (CDCI3, 400 MHz) δ 7.73-7.71 (m, 2H), 7.63-7.62 (m, 2H), 7.38-7.35 (m, 2H), 7.21- 6.91 (m, 2H), 4.86-4.81 (m, IH), 4.10-4.03 (m, 2H), 3.10 (d, IH), 2.27 (s, 3H), 1.89-1.83 (m, IH), 1.70-1.61 (m, IH), 1.32-1.28 (m, 2H), 1.19-1.03 (m, 6H). MS (ESI) 506 (M+H): desired product lost EtOH in LC/MS.
[0344] Part V: rac-2-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin- 2-yl)methyl)isoindoline- 1 ,3-dion
Figure imgf000216_0002
The title compound was prepared from the product of Part IV above using TFA/CH2CI2. NMR reported as a mixture of two possible rotamers. 1H NMR (CDC13, 400 MHz) δ 7.83- 7.80 (m, 2H), 7.79-7.74 (m, 2H), 7.43-7.40 (m, IH), 7.37-7.28 (m, IH), 7.01-6.97 (m, IH), 6.88-6.84 (m, IH), 5.25-5.07 (m, IH), 4.31-3.53 (m, 4H), 2.64 (s, 1.3 H), 2.47 (s, 1.7 H), 2.45-2.31 (m, 2H), 2.19-1.63 (m, 2H). MS (ESI) 478 (M+H).
[0345] Part VI: rac-2-((5,5-Difluoro-l-(5-(4-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2-yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000217_0001
The title compound was prepared according to general procedure L using rac-2-((l-(5-(4- fluorophenyl)-2-methylthiazole-4-carbonyl)-5-oxopiperidin-2-yl)methyl)isoindoline-l,3- dione. MS (ESI) 500 (M+H).
[0346] Part VII: rac-(2-(Aminomethyl)-5,5-difluoropiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000217_0002
The title compound was prepared using methods described herein. MS (ESI) 370 (M+H).
[0347] Part VIII. rac-N-((5,5-Difluoro- l-(5-(4-fluorophenyl)-2-methylthiazole-4- carbonyl)piperidin-2-yl)methyl)-2-methylbenzofuran-4-carboxamide was prepared according to general procedure A using N-((5,5-difluoro-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)-2-methylbenzofuran-4-carboxamide and 2- methylbenzofuran-4-carboxylic acid. The NMR was reported as a mixture of possible rotamers. 1H NMR (MeOH-d4, 400 MHz) δ 7.61-7.54 (m, 2H), 7.49-7.29 (m, 2H), 7.29- 7.25 (m, IH), 7.05-7.01 (m, 2H), 6.88-6.83 (m, IH), 4.19-4.17 (m, IH), 3.86-3.70 (m, 2H), 3.50-3.35 (m, 2H), 2.50-2.48 (m, 3H), 2.25 (s, 3H), 2.10-1.99 (m, 2H), 1.69-1.65 (m, IH), 1.33-1.25 (m, IH). MS (ESI) 528 (M+H).
[0348] Example 58: rac-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methyl)benzofuran-4-carboxamide.
Figure imgf000218_0001
[0349] Part I: rac-iert-Butyl (6-methylpiperidin-2-yl)methylcarbamate.
Figure imgf000218_0002
Nishimura catalyst (0.53 g) was added to a solution of tert-butyl (6-methylpyridin-2- yl)methylcarbamate (4.4 g, 0.02 mmol) in MeOH (60 mL) in a Parr Shaker high pressure vessel which was installed on Parr Shaker. The vessel was shaken under constant 5 bar hydrogen pressure for 30 min. The reaction mixture was filtered through a pad of
diatomaceous earth and the filtrate was concentrated in vacuo to give desired product rac- ieri-butyl (6-methylpiperidin-2-yl)methylcarbamate which was used for next step without further purification. 1H NMR (CDC13, 400 MHz) δ 3.20-3.17 (m, 1H), 3.01-2.96 (m, 1H), 2.72-2.64 (m, 2H), 1.82-1.77 (m, 1H), 1.63-1.54 (m, 2H), 1.49 (s, 9H), 1.39-1.35 (m, 2H), 1.12-0.99 (m, 5H).
[0350] Part II: rac-tert-Butyl (l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methylcarbamat
Figure imgf000218_0003
rac-tert- Butyl (l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6-methylpiperidin-2- yl)methylcarbamate was prepared according to general procedure A using rac -tert-butyl (6- methylpiperidin-2-yl)methylcarbamate and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
[0351] Part III: rac-(2-(Aminomethyl)-6-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000219_0001
To a solution of rac-iert-butyl (l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methylcarbamate in DCM was added TFA. The solution was aged at rt until starting material was consumed as judged by reverse phase analytical HPLC analysis. The solution was then concentrated in vacuo to give the TFA salt of the title compound as an oil which was used without further purification. MS (ESI) 348 (M+H).
[0352] rac-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-6-methylpiperidin-2- yl)methyl)benzofuran-4-carboxamide. The title compound was prepared by following the general procedure A using rac-2-(aminomethyl)-6-methylpiperidin-l-yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone and benzofuran-4-carboxylic acid. MS (ESI) 492 (M+H).
[0353] Example 59: rac-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methyl)quinoli -8-carboxamide.
Figure imgf000219_0002
The title compound was prepared according to general procedure A using rac-2- (aminomethyl)-6-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. MS (ESI) 503 (M+H).
[0354] Example 60: rac-3-Fluoro-N-((l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)- 6-methylpiperidin-2-yl)methyl)-2-methoxybenzamide
Figure imgf000220_0001
The title compound was prepared according to general procedure A using rac-2- (aminomethyl)-6-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 3-fluoro-2-methoxybenzoic acid. MS (ESI) 500 (M+H).
[0355] Example 61: rac-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methyl)-2-methylbenzofuran-4-carboxamide.
Figure imgf000220_0002
The title compound was prepared according to general procedure A using 2- methylbenzofuran-4-carboxylic acid and rac-(2-(aminomethyl)-6-methylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone which was obtained by removal of the BOC protecting group from
Figure imgf000220_0003
(l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6- methylpiperidin-2-yl)methylcarbamate following general procedure as described for Example 58. MS (ESI) 506 (M+H).
[0356] Example 62: rac-ci5,-N-((3-Methyl-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)
Figure imgf000220_0004
The title compound was obtained following the general protocol as described for the synthesis of Example 8 using benzofuran-4-carboxylic acid. MS (ESI) 474.1 (M+H). [0357] Example 63: rac-ci5,-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)ben
Figure imgf000221_0001
The title compound was obtained following the general protocol as described for the synthesis of Example 8 using benzofuran-4-carboxylic acid and 5-(4-fluorophenyl)-2- methylthiazole-4-carboxylic acid. MS (ESI) 492.1 (M+H).
[0358] Example 64 and Example 65
Example 64: N-(((ltS',3aR,7atS' -2-(2-Methyl-4-phenylthiazole-5-carbonyl octahvdro-lH- isoindol-l-yl)methyl)quinoline- -carboxamide.
Figure imgf000221_0002
Example 65: N-(((ltS,,3atS'JatS')-2-(2-Methyl-4-phenylthiazole-5-carbonyl)octahydro-lH- isoindol-l-yl)methyl)quinoline- -carboxamide.
Figure imgf000221_0003
[0359] Part I: (E)-Ethyl 3-(2-(hydroxymethyl)cyclohexyl)acrylate.
Figure imgf000221_0004
DIBAL-H (1M in toluene) (35.2 mmol, 35.2 mL) was added dropwise to a solution of hexahydroisobenzofuran-l(3H)-one (33.5mol, 4.7 g) in anhydrous ether (100 mL) at -10 °C under argon. The resulting mixture was stirred at -10 °C for 30 min under argon and quenched with MeOH (30 mL). The mixture was stirred at rt for overnight and the resulting suspension was added saturated Rochelle's salt aqueous solution and stirred for additional 30 min at rt. The organic layer was separated and washed with saturated Rochelle's salt aqueous solution. The combined aqueous layer was extracted with ether (3X). The organic layer were combined, dried with dried with MgS04 and concentrated in vacuo to give lactol
octahydroisobenzofuran-l-ol which was used for next step without further purification. (Carbethoxymethylene)triphenylphosphorane (17.7 g, 50.7 mmol) was added to a solution of the above described octahydroisobenzofuran-l-ol in acetonitrile (100 mL) and the resulting mixture was refluxed at 85 °C overnight. Acetonitrile was removed in vacuo and the resulting residue was diluted with ether which was stirred at rt for 2 h. The white precipitate was filtered off and washed with cold ether. All ether portion was combined and concentrated in vacuo to give crude product which was purified by chromatograph to afford desired (E)-ethyl 3-(2-(hydroxymethyl)cyclohexyl)acrylate as colorless oil (Y: 78.9 % over two steps). 1H
NMR (CDC13, 400 MHz) δ 7.12-7.05 (m, 1H), 5.80 (d, 1H), 4.15-4.09 (m, 2H), 3.40-3.37 (m, 2H), 2.63-2.59 (m, 1H), 1.80-1.29 (m, 9H), 1.25-1.19 (m, 3H).
[0360] Part II: (E)-Ethyl 3-(2-formylcyclohexyl)acrylate.
Figure imgf000222_0001
General Procedure P: Oxidation of alcohol to aldehyde using PCC. A solution of (E)- ethyl 3-(2-(hydroxymethyl)cyclohexyl)acrylate (3.84 g, 18.1 mmol) in DCM (20 mL) was added to a suspension of PCC (5.86 g, 27.2 mmol) and diatomaceous earth (4.2 g) in DCM (40 mL). The resulting mixture was stirred under argon for 2 h and filtered through a pad of silica which was rinsed with ether. The organic solvent was removed in vacuo to give desired product which was used for next step without further purification (Y: 85%). 1H NMR
(CDCI3, 400 MHz) δ 9.67 (s, 1H), 7.16-7.09 (m, 1H), 5.88 (d, 1H), 4.22-4.17 (m, 2H), 2.83- 2.81 (m, 1H), 2.60-2.57 (m, 1H), 1.96-1.90 (m, 1H), 1.80-1.55 (m, 8H), 1.33-1.26 (m, 3H).
[0361] Part III: Ethyl 2-(2-benzyloctahydro-lH-isoindol-l-yl)acetate.
Figure imgf000222_0002
A mixture of (E)-ethyl 3-(2-formylcyclohexyl)acrylate, benzyl amine and NaBH(Oac)3 in DCM was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHC03. The organic layer was separated and the aqueous layer was extracted with DCM (2X). All organic layers were combined, dried with dried with MgS04 and concentrated in vacuo to give the crude product which was purified by chromatography to afford desired ethyl 2- (2- benzyloctahydro-lH-isoindol-l-yl)acetate. MS (ESI) 302 (M+H).
[0362] Part IV: Ethyl 2-(octahydro-l -isoindol-l-yl)acetate.
Figure imgf000223_0001
Ethyl 2-(octahydro-lH-isoindol-l-yl)acetate was prepared following the same general protocol as described in Example 1 for debenzylation from ethyl 2-(2-benzyloctahydro-lH- isoindol- l-yl)acetate.
[0363] Part V: Ethyl 2-(2-(2-methyl-4-phenylthiazole-5-carbonyl)octahydro-lH-isoindol-l- yl) acetate.
Figure imgf000223_0002
Ethyl 2-(2-(2-methyl-4-phenylthiazole-5-carbonyl)octahydro-lH-isoindol-l-yl)acetate was prepared according general procedure A from ethyl 2-(octahydro-lH-isoindol-l-yl)acetate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
[0364] Part VI: 2-(2-(2-Methyl-4-phenylthiazole-5-carbonyl)octahydro-lH-isoindol-l- yl)acetic acid.
Figure imgf000223_0003
2-(2-(2-Methyl-4-phenylthiazole-5-carbonyl)octahydro-lH-isoindol-l-yl)acetic acid was prepared according general procedure B from ethyl 2-(2-(2-methyl-4-phenylthiazole-5- carbonyl) octahydro- 1 H-i soindol- 1 -yl) acetate .
[0365] Part VII: (l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2- methyl-4-phenylthiazol- 5 -yl)meth
Figure imgf000224_0001
(l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-4-phenylthiazol- 5-yl)methanone was prepared according to general procedure G using 2-(2-(2-methyl-4- phenylthiazole-5-carbonyl)octahydro- lH-isoindol- l-yl)acetic acid.
The pair of stereo isomers Examples 64 and 65 were isolated by preparative HPLC from the coupling reaction according general procedure A using (l-(aminomethyl)-lH-isoindol- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-4-phenylthiazol-5-yl)methanone and quinoline- 8-carboxylic acid. The assignment of stereochemistry was not verified. MS (ESI) 511 (M+H).
[0366] Example 66 and Example 67
Example 66: N-(((ltS,,3aR JatS,)-2-(Biphenylcarbonyl)octahydro- lH-isoindol- 1- yl)methyl)quinoline-8-carboxami
Figure imgf000224_0002
Example 67: N-(((ltS,,3atS'JatS')-2-(Biphenylcarbonyl)octahydro-lH-isoindol-l- yl)methyl)quinoline-8-carboxami
Figure imgf000224_0003
[0367] Part I: Ethyl 2-(2-(biphenylcarbonyl)octahydro-lH-isoindol-l-yl)acetate.
Figure imgf000225_0001
Ethyl 2-(2-(biphenylcarbonyl)octahydro-lH-isoindol-l-yl)acetate was prepared according to general procedure A using ethyl 2-(octahydro-lH-isoindol-l-yl)acetate and biphenyl-2- carboxylic acid.
[0368] Part II: 2-(2-(Biphenylcarbonyl)octahydro-lH-isoindol-l-yl)acetic acid.
Figure imgf000225_0002
2-(2-(Biphenylcarbonyl)octahydro-lH-isoindol-l-yl)acetic acid was prepared by hydrolysis of ethyl 2-(2-(biphenylcarbonyl)octahydro-lH-isoindol-l-yl)acetate according to general procedure B.
[0369] Part III: (l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(biphenyl- 2-yl)methanone.
Figure imgf000225_0003
(l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(biphenyl-2-yl)methanone was prepared by following general procedure G using 2-(2-(biphenylcarbonyl)octahydro-lH- isoindol-l-yl)acetic acid.
The pair of stereo isomers Examples 66 and 67 were isolated by preparative HPLC from the coupling reaction according general procedure A using (l-(aminomethyl)-lH-isoindol- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(biphenyl-2-yl)methanone and quinoline-8-carboxylic acid. The assignment of stereochemistry was not verified. MS (ESI) 335 (M+H). [0370] Example 68 and Example 69
Example 68: N-(((1 JaR JaS)-2-(2-Metfayl-5-phenyltfaiazole-4-carbonyl)octahydro-lH- isoindol-l-yl)methyl)quinoline- -carboxamide.
Figure imgf000226_0001
Example 69: N-(((ltS' atS'JatS')-2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahydro-lH- isoindol-l-yl)methyl)quinoline- -carboxamide.
Figure imgf000226_0002
[0371] Part I: Ethyl 2-(2-(2-methyl-5-phenylthiazole-4-carbonyl)octahydro-lH-isoindol-l- yl) acetate.
Figure imgf000226_0003
Ethyl 2-(2-(2-methyl-5-phenylthiazole-4-carbonyl)octahydro-lH-isoindol-l-yl)acetate was prepared according to general procedure A using ethyl 2-(octahydro-lH-isoindol-l-yl)acetate and 2-methyl-5-phenylthiazole-4-carboxylic acid.
[0372] Part II: 2-(2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahydro-lH-isoindol-l- yl)acetic acid.
Figure imgf000226_0004
2-(2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahydro-lH-isoindol-l-yl)acetic acid was prepared according to general procedure B using ethyl 2-(2-(2-methyl-5-phenylthiazole-4- carbonyl)octahydro-lH-isoindol-l-yl)acetate
[0373] Part III: (l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl- 5-phenylthiazol-4-yl)methanone.
Figure imgf000227_0001
(l-(Aminomethyl)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-5-phenylthiazol- 4-yl)methanone was prepared according to general procedure G using 2-(2-(2-methyl-5- phenylthiazole-4-carbonyl)octahydro- lH-isoindol- l-yl)acetic acid.
The pair of stereo isomers Examples 68 and 69 were isolated by preparative HPLC from the coupling reaction according general procedure A (l-(aminomethyl)-lH-isoindol- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and quinoline- 8-carboxylic acid. The assignment of stereochemistry was not verified. MS (ESI) 511 (M+H).
[0374] Example 70 and Example 71
Example 70: N-(((ltS',3aR,7atS')-2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahvdro-lH- isoindol-l-yl)methyl)benzofura -4-carboxamide.
Figure imgf000227_0002
Example 71: N-(((ltS,,3atS'JatS')-2-(2-Methyl-5-phenylthiazole-4-carbonyl)octahvdro-lH- isoindol-l-yl)methyl)benzofuran-4-carboxamide.
Figure imgf000228_0001
The pair of stereo isomers Examples 70 and 71 were isolated by preparative HPLC from the coupling reaction according general procedure A (l-(aminomethyl)-lH-isoindol- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and benzofuran- 4-carboxylic acid. The assignment of stereochemistry is not verified. MS (ESI) 500 (M+H).
[0375] Example 72: rac-ci5,-(2-((Benzo[d]thiazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000228_0002
The title compound was prepared following the same general protocol as described for Example 12 using 2-chlorobenzothiazole. MS (ESI) 481.3 (M+H)
[0376] Example 73: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-5-phenylthiazol-4-yl)methanone.
Figure imgf000228_0003
The title compound was prepared following the same general protocol as described for Example 11 using 2-methyl-5-phenylthiazole-4-carboxylic acid and rac-cis-tert-butyl ((3- methylpiperidin-2-yl)methyl)carbamate. MS (ESI) 475.2 (M+H) [0377] Example 74: rac-ci5,-(3-Methyl-2-((quinolin-8-ylamino)methyl)piperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000229_0001
The title compound was prepared following the same general protocol as described for Example 21 using 8-bromoquinoline. MS (ESI) 475.2 (M+H)
[0378] Example 75: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl) -(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000229_0002
The title compound was prepared following the same general protocol as described for Example 18 using 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 494.2 (M+H)
[0379] Example 76: rac-ci5,-(3-Ethyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) -(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000229_0003
[0380] rac-ci5'-(2-(Aminomethyl)-3-ethylpiperidin- 1 -yl)(5-(4-fluorophenyl)-2-methylthiazol- 4-yl)methanone.
Figure imgf000230_0001
The title compound was synthesized following the same general protocol as described in Example 11 using 3-ethylpicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4- carboxylic acid. MS (ESI) 361.1 (M+H)
[0381] rac-ci5,-(3-Ethyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- (4-fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Example 11 using rac-cis-(2- (aminomethyl)-3-ethylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 507.2 (M+H)
[0382] Example 77: rac-ci5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3-ethylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000230_0002
The title compound was prepared following the same general protocol as described for Example 12 using rac-ci5,-(2-(aminomethyl)-3-ethylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone. MS (ESI) 479.3 (M+H).
[0383] Example 78: rac-ci5,-(3-Ethyl-2-(((5-ethylpyrimidin-2-yl)amino)methyl)piperidin-l- yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000231_0001
The title compound was prepared following the same general protocol as described for Example 16 using rac-ci5,-(2-(aminomethyl)-3-ethylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone. MS (ESI) 468.4 (M+H).
[0384] Example 79: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin-l-yl) (5- -fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000231_0002
[0385] rac-ci5'-(3-Methylpiperidin-2-yl)methanol.
Figure imgf000231_0003
To a solution of methyl 3-methylpicolinate (5g) and 36% HCl (2 eq) in methanol was added 10% Pd/C. The Parr shaker bottle was evacuated/H2 purged 3x, and then shaken at 50 psi until starting material was consumed (typically < lh). The reaction was filtered through diatomaceous earth and concentrated to yield methyl 3-methylpiperidine-2-carboxylate hydrochloride salt without further purification._To a suspension of LiAlH4 (4eq) in THF (40 ml) was added in portions the above crude salt at 0 °C. The reaction was allowed to stir to rt overnight and then refluxed for 2 h. The reaction mixture was then quenched with saturated Na2S04 at 0 °C and stirred for lh. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a white solid. 1H NMR (CDC13, 400 MHz) δ 3.4 (m, 2H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 1.7 (m, 1H), 1.6 - 1.4 (m, 4H), 0.8 (d,3H).
[0386] rac-ci5'-(2-(Hydroxymethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000232_0001
To a solution of the product from the previous step (1.4 g) in DMAC was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (2.3 g) and HATU (1.1 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMAC. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtO Ac/hex) to give the title compound as a brown oil which crystallized (2.6 g). MS (ESI) 349.4 (M+H).
[0387] rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-l-yl) (5- (4-fluorophenyl)-2-methylthiazol-4-yl)methanone. To a stirred solution of rac-ci5,-(2- (hydroxymethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone in THF was added NaH (4 eq) at 0 °C and stirred for 30 min at RT. 2-Chloro- 5-(trifluoromethyl)pyridine (2 eq) was then added and solution refluxed for 2 h. The reaction was cooled and quenched with saturated NH4C1 and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 493.7 (M+H).
[0388] Example 80: rac-ci5,-(2-((Benzo[d]oxazol-2-yloxy)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000232_0002
The title compound was prepared following the same general protocol as described for Example 79 using 2-chlorobenzoxazole. MS (ESI) 466.1 (M+H). [0389] Example 81: rac-ci5,-(2-(((5-Ethylpyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000233_0001
The title compound was prepared following the same general protocol as described for Example 79 using 2-chloro-5-ethylpyrimidine. MS (ESI) 454.8 (M+H).
[0390] Example 82: rac-ci5,-(2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-me
Figure imgf000233_0002
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine. MS (ESI) 460.0 (M+H).
[0391] Example 83: rac-ci5,-(3-Methyl-2-(((5-methylpyrimidin-2- yl)amino)methyl)piperidin-l-yl)(5- -fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000233_0003
The title compound was prepared following the same general protocol as described for Example 16 using 2-chloro-5-methylpyrimidine. MS (ESI) 440.0 (M+H). [0392] Example 84: rac-ci5,-((2lS',3lS,)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3- isopropylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000234_0001
[0393] 3-(Prop- l-en-2-yl)picolinonitrile.
Figure imgf000234_0002
A mixture of 3-bromopicolnonitrile, isopropenylboronic acid pinacol ester, Pd(PPh3)4, and K2C03 in dioxane/water (4: 1) was stirred at 100 °C for lh in a microwave reactor. The reaction mixture was transferred to a seperatory funnel, diluted with EtOAc, and water, and the layers were separated. The organic layer was washed with brine, dried (MgS04), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. 1H NMR (CDC13, 400 MHz) δ 8.6 (m, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 5.5 (s, 1H), 5.4 (s, 1H), 2.2 (s, 3H).
[0394] ie/t-Butyl ((3-isopropylpyrid -2-yl)methyl)carbamate.
Figure imgf000234_0003
To a solution of 3-(prop-l-en-2-yl)picolinonitrile in acetic acid was added 10% Pd/C. The Parr shaker bottle was evacuated/H2 purged 3x, and then shaken at 50 psi until starting material was consumed (typically < lh). The reaction was filtered through diatomaceous earth and concentrated to yield (3-isopropylpyridin-2-yl)methanamine_acetic acid salt which was used without further purification. To the crude salt in THF was added aq 1M NaOH, followed by BOC20 (2 eq). The reaction was allowed to stir at rt overnight. After -16 h, the reaction mixture was transferred to a seperatory funnel, diluted with EtOAc, and water, and the layers were separated. The organic layer was washed with brine, dried (MgS04), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound as a clear oil. 1H NMR (CDC13, 400 MHz) δ 8.4 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 4.5 (s, 2H), 3.1 (s, 1H), 1.4 (s, 9H), 1.2 (d, J = 3.5 Hz, 6H)
[0395] rac-cis-tert-Butyl (((2lS',3lS,)-3-isopropylpiperidin-2-yl)methyl)carbamate.
Figure imgf000235_0001
To a solution of the BOC -protected pyridylamine prepared above in MeOH was added Nishimura' s catalyst. The parr shaker bottle was evacuated/purged with H2 (3x) and then shaken at 50 psi for 24 h. The reaction was filtered through diatomaceous earth, and concentrated in vacuo to give the title compound as a near colorless oil, and was used without further purification. MS (ESI) 251.3 (M+H)
[0396] rac-ci5'-((2lS,,3lS,)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-isopropylpiperidin-l-yl)(5- (4-fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Examples 11 and 12 using Γαί-ίί^- ((2lS',3lS,)-2-((benzo[d]oxazol-2-ylamino)methyl)-3-isopropylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 493.3 (M+H).
[0397] Example 85: rac-ci5,-(2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-methyl
Figure imgf000235_0002
[0398] rac-ci5'-l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidine-2- carbaldehyde.
Figure imgf000235_0003
To a stirred solution of rac-ci5,-(2-(hydroxymethyl)-3-methylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone in DCM was added Dess-Martin periodinane (1.5 eq) and stirred at rt for 4 h. The reaction mixture was transferred to a seperatory funnel, diluted with more DCM, water and the layers were separated. The organic layer was washed with brine, dried (MgS04), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtO Ac/hex) to afford the title compound. MS (ESI) 347.1 (M+H).
[0399] mc-c? ,-(2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone. To a stirred solution of rac-cis-l-(5-(4- fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidine-2-carbaldehyde and 5- fluoropyridin-2-amine in methanol/acetic acid (50: 1) was added sodium cyanoborohydride at 0 °C. The reaction was then stirred at rt overnight. After ~ 16 h, the reaction mixture was transferred to a seperatory funnel, diluted with EtO Ac, saturated NaHC03 and the layers separated. The organic layer was washed with water, brine, dried (MgS04), and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 443.2 (M+H).
[0400] Example 86: rac-ci5,-(3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin-l- yl)(5-(4-fluorophenyl)-2-methylth
Figure imgf000236_0001
The title compound was prepared following the same general protocol as described for Example 85 using 5-methylpyridin-2-amine. MS (ESI) 439.2 (M+H).
[0401] Example 87: rac-ci5,-(3-Methyl-2-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000237_0001
The title compound was prepared following the same general protocol as described for Example 85 using 6-(trifluoromethyl)pyridin-2-amine. MS (ESI) 493.2 (M+H).
[0402] Example 88: rac-ci5,-(2-(((5-Methoxypyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl) (5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000237_0002
A mixture of rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone, 2-chloro-5-methoxypyrimidine, Pd2dba3, BINAP, and NaOtBu in toluene was purged with argon, and then stirred at 70 °C for 72h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.2 (M+H).
[0403] Example 89: rac-ci5,-(2-(((5-Methoxypyrimidin-2-yl)oxy)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000237_0003
The title compound was prepared following the same general protocol as described for Example 81 using 2-chloro-5-methoxypyrimidine. MS (ESI) 457.2 (M+H). [0404] Example 90: rac-ci5,-(2-(((5-Chloropyrimidin-2-yl)oxy)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000238_0001
The title compound was prepared following the same general protocol as described for Example 81 using 2,5-dichloropyrimidine. MS (ESI) 461.1 (M+H).
[0405] Example 91: rac-ci5,-6-(((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)
Figure imgf000238_0002
The title compound was prepared following the same general protocol as described for Example 18 using 6-chloronicotinonitrile. MS (ESI) 450.2 (M+H).
[0406] Example 92: rac-ci5,-(3-Methoxy-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) 5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000238_0003
[0407] rac-ci5'-(2-(Aminomethyl)-3-methoxypiperidin- 1 -yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000239_0001
The title compound was synthesized following the same general protocol as described in Example 11 using 3-methoxypicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4- carboxylic acid. MS (ESI) 464.4 (M+H)
[0408] rac-ci5,-(3-Methoxy-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l- yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Example 11 using rac-ci5,-(2- (aminomethyl)-3-methoxypiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone. MS (ESI) 509.4 (M+H).
[0409] Example 93: rac-ci5,-(2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methoxypiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000239_0002
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-ci5,-(2-(aminomethyl)-3-methoxypiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 476.0 (M+H).
[0410] Example 94: rac-ci5,-(2-((Benzo[d]thiazol-2-ylamino)methyl)-3-methoxypiperidin-l- yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000240_0001
The title compound was prepared following the same general protocol as described for Example 12 using 2-chlorobenzothiazole and rac-ci5,-(2-(aminomethyl)-3-methoxypiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 497.0 (M+H).
[0411] Example 95: rac-iraw5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-methyl
Figure imgf000240_0002
[0412] l-Benzyl-2-(((ieri-Butoxycarbonyl)amino)methyl)-3-methylpyridin-l-ium bromide.
Figure imgf000240_0003
ie/t-Butyl ((3-methylpyridin-2-yl)methyl)carbamate (4.5 g) and benzyl bromide (2 eq) in 80 ml of acetonitrile was heated in a sealed tube at reflux overnight and then concentrated in vacuo to give the title compound and was used without further purification. MS (ESI) 313 (M+H)
[0413] rac-tert- Butyl ((l-benzyl- -methyl-l,2,5,6-tetrahydropyridin-2-yl)methyl)carbamate.
Figure imgf000240_0004
To a solution of l-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-l-ium bromide (1.5 g) in MeOH (100 ml) was added NaBH4 (3 eq) in three portions at 0 °C. The solution was then stirred for 3 h at rt and then concentrated in vacuo. The crude residue was taken up in EtOAc and washed with sat aq. NaHC03, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtO Ac/hex) to give the title compound as a pale yellow oil in 63% yield. MS (ESI) 317 (M+H).
[0414] rac-iraws-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate.
Figure imgf000241_0001
A mixture of rac-tert-bv y\ ((l-benzyl-3-methyl-l,2,5,6-tetrahydropyridin-2- yl)methyl)carbamate and Pd(OH)2/C (20% wt, O.leq) was pressurized to 4 bar with H2 and maintained at rt for 5 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil. MS (ESI) 229.2 (M+H).
[0415] rac-iraw5,-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000241_0002
To a solution of rac-trans-tert-bv y\ ((3-methylpiperidin-2-yl)methyl)carbamate (leq) from the previous step in DMF was added DIPEA (2eq) followed by 5-(4-fluorophenyl)-2- methylthiazole-4-carboxylic acid (1.5eq) and HATU (2eq). The reaction was allowed to stir at rt for 15h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtO Ac/hex) to give tert-butyl (((2R,3R)-l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in CH2C12 was added TFA (1: 1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried (MgS04), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 348.2 (M+H). [0416] rac-iraw5,-(2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l-yl)(5-(4- fluorophenyl)-2-methylthiazol-4-yl)methanone.
A mixture of iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(2-methyl-5-phenylthiazol-4- yl)methanone, 2-chlorobenzoxazole, and DIPEA in ACN was stirred at 60 °C overnight. The reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 465.1 (M+H).
[0417] Example 96: rac-iraw5,-(2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000242_0001
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-iraw5,-(2-(aminomethyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 460.4 (M+H).
[0418] Example 97: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000242_0002
[0419] rac-ci5'-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000242_0003
To a solution of rac-cis-tert-bv y\ ((3-methylpiperidin-2-yl)methyl)carbamate (1 eq) from Example 11 in DMF was added DIPEA (2 eq) followed by 5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtO Ac/hex) to give rac-cis- tert-butyl ((3-methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)piperidin-2- yl)methyl)carbamateas a light yellow oil. To a solution of this carbamate in CH2CI2 was added TFA (1: 1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried (MgS04), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 314.1 (M+H).
[0420] rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example 18 using rac-cis-(2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460.0 (M+H).
[0421] Example 98: rac-ci5,-(2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2H-l,2,3-tri
Figure imgf000243_0001
The title compound was prepared following the same general protocol as described for Example 16 starting with rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 426.4 (M+H).
[0422] Example 99: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(l- (hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methanone.
Figure imgf000244_0001
[0423] rac-Diethyl 2-acetylhexahydrocyclopenta[c]pyrrole- 1 , 1 (2H)-dicarboxylate.
Figure imgf000244_0002
The title compound was prepared from cyclopenten-1 -aldehyde (1 eq) and diethyl acetamidomalonate (leq) using the procedure by Chung et al. (J. Org. Chem. 1990, 55,270). MS (ESI) 298 (M+H)
[0424] Octahydrocyclopenta[c]pyrrole- -carboxylic acid hydrobromide.
Figure imgf000244_0003
A solution of the rac-diethyl 2-acetylhexahydrocyclopenta[c]pyrrole-l,l(2H)-dicarboxylate prepared above in 48% aqueous HBr and AcOH (4: 1) was heated at 120 °C for 16 h. The reaction mixture was cooled, concentrated in vacuo and lyophilized to yield the title compound. MS (ESI) 156 (M+H).
[0425] 2-(ieri-Butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid.
Figure imgf000244_0004
The amino acid prepared above and NaHC03 (2 eq.) were dissolved in water/dioxane (1: 1, v/v) and Boc20 (1.5 eq.) was added. After stirring overnight at rt, water was added and the resulting solution was washed with EtOAc (4 times). The aqueous solution was then acidified with IN HC1 to pH 1-2 and extracted with EtOAc (4 times), dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc : CH2C12 = 1 : 3) to give the title compound as a creamy white solid. MS (ESI) 256 (M+H).
[0426] ie/t-Butyl ((3-tert-butyl l-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate.
Figure imgf000245_0001
To a stirred solution of 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (1 eq) in THF was added BH3Sme2 (10 M, 2 eq) dropwise over 5 min at 0 °C. The reaction was then allowed to stir overnight at rt and then quenched with cooled water at 0 °C. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was concentrated in vacuo to give the title compound as a clear oil. MS (ESI) 242.2 (M+H).
[0427] (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(l- (hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methanone.
Figure imgf000245_0002
To a solution of the carbamate above in CH2C12 was added TFA (1: 1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried (MgS04), and concentrated to afford (octahydrocyclopenta[c]pyrrol-l-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-l-yl)methanol (1 eq) in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 361.1 (M+H)
[0428] 2-((2-(5-(4-Fluorophenyl)-2-methylthiazole-4- carbonyl)octahydrocyclopenta[c]p line-l,3-dione.
Figure imgf000246_0001
A solution of (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(l-
(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methanone (1 eq), phthalimide (2 eq) and triphenylphosphine (3 eq) in THF (56 mL) was cooled to 0 °C and added with DIAD (5 eq) dropwise. The resulting suspension was allowed to warm to rt gradually and stirred overnight, concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 490.4 (M+H).
[0429] ( l-(Aminomethyl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000246_0002
2-((-2-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)octahydrocyclopenta[c]pyrrol-l- yl)methyl)isoindoline-l,3-dione (1 eq) and hydrazine monohydrate (4 eq) in MeOH was stirred at 70 °C for 3 h and then concentrated in vacuo to a yellow oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (20% MeOH in EtOAc) to firstly remove the impurities and then (2:8: 1 MeOH/EtOAc/TEA) to elute the title compound which was concentrated to yield a yellow oil. MS (ESI) 360.3 (M+H).
[0430] (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(l-
(hydroxymethyl)hexahydrocyclopentarclpyrrol-2(lH)-yl)methanone. The title compound was prepared following the same general protocol as described for Example 18 using (1- (aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-(4-fluorophenyl)-2-methylthiazol- 4-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 506.4 (M+H).
[0431] Example 100: (l-((Benzo[d]oxazol-2- ylamino)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000247_0001
A mixture of (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in ACN was stirred at 60 °C overnight. The reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 477.4 (M+H).
[0432] Example 101: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(l-(((5-
(trifluoromethyl)pyridin-2-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)methanone.
Figure imgf000247_0002
The title compound was prepared following the same general protocol as described for Example 79 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(l- (hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methanone. MS (ESI) 506.2 (M+H).
[0433] Example 102: (l-((Benzo[d]oxazol-2-yloxy)methyl)hexahydrocyclopenta[c]pyrrol- 2(lH)-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000248_0001
The title compound was prepared following the same general protocol as described for Example 80 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(l- (hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)methanone and 2- chlorobenzoxazole. MS (ESI) 478.2 (M+H).
[0434] Example 103: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000248_0002
[0435] rac-ci5'-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-bromo-5- methylphenyl)methanone .
Figure imgf000248_0003
The title compound was synthesized following the same general protocol as described in Example 11 using rac-ds-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate and 2- bromo-5-methylbenzoic acid. ESI-MS (m/z): 325, 327, [M]+, [M+2]+.
[0436] rac-ci5'-(2-Bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -
Figure imgf000249_0001
The title compound was prepared following the same general protocol as described for Example 11 starting with rac-ci5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(2-bromo-5- methylphenyl)methanone and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470, 472, [M]+, [M+2]+.
[0437] rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l- yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone. The mixture of rac-ci5,-(2- bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)methanone (0.045 g, 0.097 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.024 g, 0.116 mmol), P(PPh3)4 (0.017 g, 0.015 mmol), K2C03 (0.4 g, 0.291 mmol) and dioxane/H20 (4: 1, 3 mL) was degassed for 5 min and heated overnight at 100 °C oil bath. The completion of reaction was monitored by analytical HPLC. The mixture was cooled and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03 and dried over Na2S04. The solvent was removed in vacuo to obtain a crude residue, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 472, [M+l]+.
[0438] Example 104: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridin-3-yl)phenyl)methanone.
Figure imgf000249_0002
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with pyridin-3-ylboronic acid. ESI-MS (m/z): 469, [M+l]+.
[0439] Example 105: rac-cw-iS-Methyl-l-iiiS-itrifluoromethy^pyridin-l- yl)amino)methyl)piperidin-l-y -methyl-2-(6-methylpyridin-3-yl)phenyl)methanone.
Figure imgf000250_0001
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with (6-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 483, [M+l]+.
[0440] Example 106: rac-cw-iS-Methyl-l-iiiS-itrifluoromethy^pyridin-l- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridin-4-yl)phenyl)methanone.
Figure imgf000250_0002
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with pyridin-4-ylboronic acid. ESI-MS (m/z): 469, [M+l]+.
[0441] Example 107: rac-cw-iS-Methyl- -iiiS-itrifluoromethy^pyridin- - yl)amino)methyl)piperidin-l-y -methyl-2-(pyrimidin-5-yl)phenyl)methanone.
Figure imgf000250_0003
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with pyrimidin-5-ylboronic acid. ESI-MS (m/z): 470, [M+l]+.
[0442] Example 108: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)methanone.
Figure imgf000251_0001
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole. ESI-MS (m/z): 472, [M+l]+.
[0443] Example 109: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(2-(4-methylpiperazin-l-yl)pyrimidin-5- yl)phenyl)methanone.
Figure imgf000251_0002
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with 2-(4-methylpiperazin-l-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidine. ESI-MS (m/z): 568, [M+l]+.
[0444] Example 110: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)phenyl)methanone.
Figure imgf000252_0001
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine. ESI-MS (m/z): 567, [M+l]+.
[0445] Example 111: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-(2-morpholinoethyl)-lH-pyrazol-4- yl)phenyl)methanone.
Figure imgf000252_0002
The title compound as TFA salt was prepared following the same general protocol as described for Example 103 starting with 4-(2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl)ethyl)morpholine. ESI-MS (m/z): 571, [M+l]+.
[0446] Example 112: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000252_0003
The mixture of rac-ci5,-(2-bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)piperidin-l-yl)methanone (0.03 g, 0.0638 mmol), 2- (tributylstannyl)pyrimidine (0.028 g, 0.0766 mmol), P(PPh3)4 (0.011 g, 0.01 mmol), Cs2C03 (0.42 g, 0.13 mmol) and dioxane (1 mL) was degassed for 5 min and heated overnight at 140 °C oil bath. The completion of reaction was monitored by analytical HPLC. The mixture was cooled and extracted with EtOAc. The combine organic layers were washed with saturated NaHCC"3 and dried over Na2S04. The solvent was removed in vacuo to obtain the crude, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 470, [M+l]+.
[0447] Example 113: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(oxazol-2-yl)phenyl)methanone
Figure imgf000253_0001
The title compound as TFA salt was prepared following the same general protocol as described for Example 112 starting with 2-(tributylstannyl)oxazole. ESI-MS (m/z): 459, [M+l]+.
[0448] Example 114: rac-cw-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000253_0002
[0449] rac-ds-Allyl 2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpiperidine- 1- carboxylate.
Figure imgf000253_0003
To the mixture of rac-cis-tert-bv y\ ((3-methylpiperidin-2-yl)methyl)carbamate (9.48 g, 41.53 mmol) in THF (25 mL) was added NaOH (2 M, 25 mL), followed by allyl
chloroformate (6.65 mL, 62.3 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with H20 and Brine. The solvent was removed in vacuo and the resulting crude residue was purified by chromatography on silica gel (0-100%
DCM/EtOAc) to obtain the title compound as a colorless oil.
[0450] rac-cis-Allyl 2-(aminomethyl)- -methylpiperidine- 1-carboxylate.
Figure imgf000254_0001
To a solution of this carbamate in CH2C12 was added TFA (1: 1 v/v). The reaction was aged at rt and monitored for disappearance of starting material thin layer chromatography (TLC). When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried
(MgS04), and concentrated to afford the title compound.
[0451] rac-ds-Allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine- 1-carboxylate.
Figure imgf000254_0002
A mixture of rac-ds-Allyl 2-(aminomethyl)-3-methylpiperidine- 1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2C03 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80 °C for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound. ESI-MS (m/z): 358, [M+l]+.
[0452] rac-ci5,-N-((3-Methylpiperi oromethyl)pyridin-2-amine.
Figure imgf000254_0003
To a mixture of rac-ds-allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidine- 1-carboxylate (1.18 g, 3.32 mmol), Pd(PPh3)4 (0.384 g, 0.003 mmol) and THF (20 mL) was added morpholine (3.0 mL, 33.2 mmol). The mixture was degassed for 5 min and stirred at rt. The reaction was monitored for disappearance of starting material by analytical reverse-phase HPLC. After ~1 h, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHC03, brine, dried (MgS04), and concentrated and the resulting crude residue was purified by silica gel chromatography (0-100% DCM/EtOAc) to afford the title compound ESI-MS (m/z): 472, [M+l]+.
[0453] 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid and 5-methyl-2-(lH-l,2,3-triazol-l- yl)benzoic acid.
Figure imgf000255_0001
The mixture of 2-bromo-5-methylbenzoic acid (1 g, 4.65 mmol), 1,2,3-triazole (0.58 g, 8.37 mmol), (lS,2S)-N1,N2-dimethylcyclohexane-l,2-diamine (0.265 g, 1.86 mmol), Cs2C03 (3.0 g, 9.3 mmol) and Cul (0.089 g, 0.465 mmol) in DMF (15 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The reaction was cooled to RT, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to obtain the faster eluting acid 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid as the major product and the second eluting 5-methyl-2-(lH-l,2,3-triazol-l-yl)benzoic acid as the minor product. ESI-MS (m/z): 204, [M+l]+.
[0454] rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. The title compound was synthesized following the same general protocol as described in Example 11 using 5-methyl- 2-(2H-l,2,3-triazol-2-yl)benzoic acid and rac-ci5,-N-((3-methylpiperidin-2-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 459, [M+l]+.
[0455] Example 115: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(lH-l,2,3-triazol-l-yl)phenyl)methanone.
Figure imgf000255_0002
The title compound was synthesized following the same general protocol as described in Example 11 using 5-methyl-2-(lH- l,2,3-triazol-l-yl)benzoic acid and rac-cis-N-((3- methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESTMS (m/z): 459, [M+l]+.
[0456] Example 116: rac-ci5,-(2-(lH-Imidazol-l-yl)-5-methylphenyl)(3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000256_0001
[0457] 2-(lH-Imidazol- l-yl)-5-methylbenzoic acid.
Figure imgf000256_0002
The title compound was synthesized following the same general protocol as described in Example 114 using imidazole instead of 1,2,3-triazole. ESTMS (m/z): 203, [M+l]+.
[0458] rac-cw-(2-(lH-Imidazol-l-yl)-5-methylphenyl)(3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. The title compound was synthesized following the same general protocol as described in Example 11 using 2- (lH-imidazol- l-yl)-5-methylbenzoic acid and rac-ci5,-N-((3-methylpiperidin-2-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 458, [M+l]+.
[0459] Example 117: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(lH- l,2,4-triazol- l-yl)phenyl)methanone.
Figure imgf000256_0003
[0460] 5-Methyl-2-(lH-l,2,4-triazol- l-yl)benzoic acid.
Figure imgf000257_0001
The title compound was synthesized following the same general protocol as described in Example 114 using lH- l,2,4-triazole instead of 1,2,3-triazole. ESI-MS (m/z): 204, [M+l]+.
[0461] rac-cw-(2-(lH-Imidazol-l-yl)-5-methylphenyl)(3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. The title compound was synthesized following the same general protocol as described in Example 11 using 5- methyl-2-(lH- l,2,4-triazol-l-yl)benzoic acid and rac-ci5,-N-((3-methylpiperidin-2- yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 459, [M+l]+.
[0462] Example 118: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl) -phenoxyphenyl)methanone.
Figure imgf000257_0002
The title compound was synthesized following the same general protocol as described in Example 11 using 2-phenoxybenzoic acid and rac-ci5,-N-((3-methylpiperidin-2-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470, [M+l]+.
[0463] Example 119: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) -phenyl-lH-pyrazol-5-yl)methanone.
Figure imgf000257_0003
The title compound was synthesized following the same general protocol as described in Example 11 using l-phenyl-lH-pyrazole-5-carboxylic acid and rac-cis-N-((3- methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 444, [M+l]+.
[0464] Example 120: rac-ci5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000258_0001
A mixture of rac-ci5,-(2-bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)methanone (0.0326 g, 0.0693 mmol), pyrazole (0.0094 g, 0.139 mmol), (lS,2S)-N1,N2-dimethylcyclohexane-l,2-diamine (0.004 g, 0.0277 mmol), Cs2C03 (0.045 g, 0.139 mmol) and Cul (0.003 g, 0.0139 mmol) and dioxane (1.0 mL) was degassed and heated overnight at 140 °C. The reaction was cooled to RT, and acidified with TFA to pH4~5. The solvent was removed in vacuo to obtain the crude which as purified by preparative-HPLC to obtain the title compound as a TFA salt. ESI-MS (m/z): 458, [M+l]+.
[0465] Example 121: rac-ci5,-(2-(((3-Chloropyrazin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-me
Figure imgf000258_0002
The title compound was prepared following the same general protocol as described for Example 18 using 2,3-dichloropyrazine. MS (ESI) 460.2 (M+H). [0466] Example 122: rac-ci5,-(2-(((5-Chloropyrimidin-2-yl)amino
methylpiperidin- 1 - yl) (2- (trifluoromethoxy)phenyl)methanone .
Figure imgf000259_0001
[0467] rac-ds-Allyl 2-(((5-chloropyrimidin-2-yl)amino)methyl)-3-methylpiperidine- 1- carboxylate.
Figure imgf000259_0002
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-cis-aXXyX 2-(aminomethyl)-3- methylpiperidine- l-carboxylate. MS (ESI) 325.2 (M+H).
[0468] rac-ci5'-5-Chloro-N-((3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine.
Figure imgf000259_0003
The title compound was prepared following the same general protocol as described for Example 114 using rac-cis-aXXyX 2-(((5-chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidine- l-carboxylate_from the previous step. (ESI) 241.4 (M+H).
[0469] mc-c? ,-(2-(((5-chloropyrimidin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(2- (trifluoromethoxy)phenyl)methanone. To a solution of the forementioned rac-cis-S-chloro- N-((3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine and diisopropylamine (3e q) in DCM was added 2-(trifluoromethoxy)benzoyl chloride (1.2 eq) dropwise. The reaction was stirred at reflux for 3 h and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. (ESI) 429.1 (M+H).
[0470] Example 123: rac-ci5,-(2-(((6-Chloropyrazin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000260_0001
The title compound was prepared following the same general protocol as described for Example 18 using 2,6-dichloropyrazine. MS (ESI) 460.2 (M+H).
[0471] Example 124: rac-cw-2-Methyl-N-((3-methyl-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)benzofuran-4-carboxamide.
Figure imgf000260_0002
The title compound was obtained following the general protocol as described for the synthesis of Example 8 using 2-methylbenzofuran-4-carboxylic acid. MS (ESI) 488.1 (M+H).
[0472] Example 125: rac-ci5,-N-((l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)
Figure imgf000260_0003
The title compound was obtained following the general protocol as described for the synthesis of Example 8 using 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 503.1 (M+H).
[0473] Example 126: N-(((25,45J-l-([l,l'-Biphenyl]-2-carbonyl)-4-hydroxypyrrolidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000261_0001
The title compound was synthesized following the same standard protocol as described in Examples 4 starting with (2S,4S)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-l- carboxylate. MS (ESI) 452.2 (M+H).
[0474] Example 127: N-(((25,45 -l-([1 '-Biphenyl]-2-carbonyl)-4-methoxypyiiOUdin-2- yl)methyl)quinoline-8-carboxamide
Figure imgf000261_0002
To a vigorously stirred suspension of the product from the previous example in CH2CI2 and 45% HBF4(aq) at 0 °C was added in three portions 0.1 mL 2M TMS-CH2N2 hexane solution dropwise over 10 min. The reaction was allowed to stir at rt overnight. The crude mixture was loaded directly onto a reverse-phase prep-HPLC and two peaks were collected, the first being the desired product, the second being recovered starting material. MS (ESI) 466.2
(M+H).
[0475] Example 128: N-(((2lS',4R)-l-(Biphenylcarbonyl)-4-fluoropyrrolidin-2- yl)methyl)quinoline-8-carboxami
Figure imgf000261_0003
The title compound was synthesized following the same standard protocol as described in Examples 5 starting with N-ff^^^J-l-iflJ'-bipheny^-l-carbony^-^hydroxypyrrolidin-l- yl)methyl)quinoline-8-carboxamide. MS (ESI) 454.1 (M+H).
[0476] Example 129 : N-(((25,4R -l-([1 '-biphenyl]-2-carbonyl)-4-methoxypyiiOUdin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000262_0001
The title compound was made following the same general protocol as described for Example 127 using the product from Example 4. MS (ESI) 466.2 (M+H).
[0477] Example 130: N-(((2R,35)-3-Hydroxy-l-(2-methyl-4-phenylthiazole-5- carbonyl)pyrrolidin-2-yl)methyl)quinoline-8-carboxamide.
Figure imgf000262_0002
[0478] (2R,3S)-tert-Buty\ 2-(aminomethyl)-3-hydroxypyrrolidine- 1-carboxylate.
Figure imgf000262_0003
To a solution of (2S,3S)- l-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid in THF at 0 °C was added BH3-DMS. The reaction was allowed to warm to rt overnight, and then quenched by the careful addition of MeOH. The reaction was concentrated in vacuo to give (2R,35,)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-l-carboxylate as a near colorless oil which was used without further purification.
Figure imgf000262_0004
3-hydroxy-2- (hydroxymethyl)pyrrolidine- 1-carboxylate was converted to the title compound following the same general protocol for Mitsunobu reaction with phthalimide followed by hydrazine cleavage as described for Example 32 Part V and Part VI.
[0479]
Figure imgf000263_0001
3-hydroxy-2-((quinoline-8-carboxamido)methyl)pyrrolidine- 1- carboxylate.
Figure imgf000263_0002
The title compound was prepared according general procedure A using quinoline-8- carboxylic acid and the product from the previous step. MS (ESI) 371.93 (M+H).
[0480] N-CCC R.S^-S-Hvdroxy-l-C -methyl^-phenylthiazole-S-carbonvDpyrrolidin- - yl)methyl)quinoline-8-carboxamide. To a solution of the product from the previous step in CH2CI2 was added TFA. The reaction was aged at rt for 1 h, and then concentrated in vacuo to give the crude amine as a TFA salt. This crude amine was coupled with 2-methyl-4- phenylthiazole-5-carboxylic acid according to general procedure A to give the title compound as a pale yellow solid. MS (ESI) 473.1 (M+H).
[0481] Example 131: (35,55)-l-([l,l'-Biphenyl]-2-carbonyl)-5-((quinoline-8- carboxamido)methyl)pyrrolidin-3-yl acetate.
Figure imgf000263_0003
To a 0 °C solution of the product from Example 4 in THF was added Ph3P, acetic acid, followed by DIAD. The reaction was allowed to warm to rt overnight. After 18 h, the reaction mixture was directly loaded onto a reverse-phase preparative HPLC, and the desired product was isolated as a colorless solid. MS (ESI) 494.1 (M+H).
[0482] Example 132: (R)-N-((l-(2-Methyl-4-phenylthiazole-5-carbonyl)-3-oxopyrrolidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000264_0001
To a -78 °C solution of (COCl)2 in CH2C12 was added a solution of DMSO in CH2C12. After 20 min, a solution of the product from Example 130 in CH2C12 was added dropwise. The reaction was aged at -78 °C for 3h, and then allowed to warm to rt over 1 h. The reaction mixture was concentrated in vacuo to give a beige solid which was purified by
chromatography on silica gel to give the title compound as a colorless solid. MS (ESI) 471.1 (M+H).
[0483] Example 133: (R)-N-((3,3-Difluoro-l-(2-methyl-4-phenylthiazole-5- carbonyl)pyrrolidin-2-yl)methyl uinoline-8-carboxamide.
Figure imgf000264_0002
The title compound was prepared following the same general protocol as described for Example 7. MS (ESI) 493.1 (M+H).
[0484] Example 134: N-(((2S,4R)-4-Hydroxy-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000264_0003
The title compound was prepared following the same standard protocols as described for Example 130 starting with (2lS',4R)-l-(iert-butoxycarbonyl)-4-hydroxypiperidine-2- carboxylic acid. MS (ESI) 487.1 (M+H).
[0485] Example 135: (lS,)-N-((l-(2-Methyl-4-phenylthiazole-5-carbonyl)-4-oxopiperidin-2- yl)methyl)quinoline-8-carboxamide.
Figure imgf000265_0001
The title compound was prepared following the same standard protocol as described for Example 132 starting with the product from Example 134. MS (ESI) 485.1 (M+H).
[0486] Example 136: (5)-N-((4,4-Difluoro-l-(2-methyl-4-phenylthiazole-5- carbonyl)piperidin-2- yl)methyl) uinoline- 8 -carb oxamide .
Figure imgf000265_0002
The title compound was prepared following the same standard protocol as described for Example 133 starting with the product from Example 135. MS (ESI) 507.1 (M+H).
[0487] Example 137: rac-irara-N-(((25,,3lS,)-3-Methyl-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2- yl)methyl)quinoline- 8 -carb oxamide .
Figure imgf000265_0003
[0488] rac-trans-tert-Buty\ (((25,35)-3-Methyl-l-(2-methyl-5-phenylthiazole-4- carbonyl)piperidin-2-yl)methyl)carbamate.
Figure imgf000266_0001
The title compound was made following General Procedure A using tert-butyl rac-trans-((3- methylpiperidin-2-yl)methyl)carbamate from Example 95 and 2-methyl-5-phenylthiazole-4- carboxylic acid. MS (ESI) 429.83 (M+H).
[0489] rac-?m?¾ ,-N-((3-Methyl-l-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2- yl)methyl)qinoline-8-carboxamide. The title compound was made following BOC- deprotection of the compound from the previous step using TFA/CH2CI2, followed by coupling to quinoline-8-carboxylic acid using the standard protocol as describe in General Procedure A. The product was isolated as a beige solid. MS (ESI) 485.1 (M+H).
[0490] Example 138: rac-ds-N-((l-(2-Methyl-5-phenylthiazole-4-carbonyl)-3- (trifluoromethyl)piperidin-2-yl)meth l)quinoline-8-carboxamide.
Figure imgf000266_0002
[0491] rac-cis-tert-Butyl ((l-(2-Methyl-5-phenylthiazole-4-carbonyl)-3- (trifluoromethyl)piperidin-2-yl)methyl)carbamate.
Figure imgf000266_0003
The title compound was made following General Procedure A using rac-cis-tert-bv y\ ((3- (trifluoromethyl)piperidin-2-yl)methyl)carbamate from Example 13 and 2-methyl-5- phenylthiazole-4-carboxylic acid. MS (ESI) 483.8 (M+H). [0492] mc-c? ,-N-((l-(2-Methyl-5-phenylthiazole-4-carbonyl)-3-(trifluoromethyl)piperidm yl)methyl)quinoline-8-carboxamide. The title compound was made following BOC- deprotection of the compound from the previous step using TFA/CH2CI2, followed by coupling to quinoline-8-carboxylic acid using the standard protocol as describe in General Procedure A. The product was isolated as a near colorless solid. MS (ESI) 539.14 (M+H).
[0493] Example 139: rac-cw-N-((l-(2-Methyl-5-phenylthiazole-4-carbonyl)-3- (trifluoromethyl)piperidin-2-yl)meth l)benzofuran-4-carboxamide.
Figure imgf000267_0001
The title compound was made following the same general protocol as described for Example 138 using benzofuran-4-carboxylic acid. MS (ESI) 528.1 (M+H).
[0494] Example 140: N-(((ls,4s)-2-([l,l'-Biphenyl]-2-carbonyl)-2-azabicyclo[2.2.2]octan- 3-yl)methyl)quinoline-8-carboxamide.
Figure imgf000267_0002
[0495] (ls,4s)-2-Azabicyclo[2.2.2]octan- -ylmethanol.
Figure imgf000267_0003
The title compound was prepared following General Procedure O starting with commercially available (ls,4s)-ethyl 2-azabicyclo[2.2.2]octane-3-carboxylate. 1H NMR (CDC13, 400 MHz) δ 3.7-3.6 (m, 1H), 3.6-3.48 (m, 2H), 3.2 (t, 1H), 2.6-2.35 (m, 2H), 1.8-1.4 (m, 5H), 1.3-1.1 (m, 2H), 1.1-0.9 (m, 1H). [0496] [l,l'-Biphenyl]-2-yl((l5, )-3-(hydroxymethyl)-2-azabicyclo[2.2.2]octan-2- yl)methanone.
Figure imgf000268_0001
The title compound was prepared following General Procedure A starting with the product from the previous step and [l,l'-biphenyl]-2-carboxylic acid.
[0497] [lJ'-Biphenyl]-2-yl((ls,4s)-3-(aminomethyl)-2-azabicyclo[2.2.2]octan-2- yl)methanone.
Figure imgf000268_0002
The title compound was prepared following General Procedure C starting with the product from the previous step. MS (ESI) 321.1 (M+H).
[0498] N-((('l^, -2-('ri,l,-Biphenyll-2-carbonyl -2-azabicvclor2.2.21octan-3- yl)methyl)quinoline-8-carboxamide. The title compound was prepared following General Procedure A starting with the product from the previous step and quinoline-8-carboxylic acid. MS (ESI) 476.2 (M+H).
[0499] Example 141: N-(((l^)-2-(2-Methyl-5-phenylthiazole-4-carbonyl)-2- azabicyclo[2.2.2]octan-3-yl)methyl)quinoline-8-carboxamide.
Figure imgf000268_0003
The title compound was prepared following same general protocol as described for Example 140, but using 2-methyl-5-phenylthiazole-4-carboxylic acid. MS (ESI) 497.2 (M+H). [0500] Additional synthetic examples are described in the following procedures for Examples Al to A389.
[0501] Example Al: ((25,3R)-3-Methyl-2-(((5-(trifluoromethyl)quinoline-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000269_0001
[0502] Step 1. rac-3-Methylpiperidine- -carboxylic acid hydrochloride.
Figure imgf000269_0002
3-Methylpicolinic acid (50 g, 365 mmol) was dissolved in 400 mL of EtOH:H20 (1: 1) with 60 mL of aq. HCI (32%). Pt02 (5g) was then added and the reaction stirred at rt under a hydrogen balloon until NMR indicated completion. The reaction was filtered through diatomaceous earth and concentrated to yield the title compound as a white solid which was used without further purification (60.5g, 92%). 1H NMR (MeOD, 400 MHz) δ 4.13-4.11 (m, IH), 3.40-3.33 (m, IH), 3.05-2.99 (m, IH), 2.61-2.58 (m, IH), 1.92-1.72 (m, 4H), 1.09 (d, J = 7.0 Hz, 3H). MS (ESI) 452.16 (M+H).
[0503] Step 2. rac-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid.
Figure imgf000269_0003
3-Methylpiperidine-2-carboxylic acid hydrochloride (28.5 g, 31.6 mmol) was dissolved in (1: 1) 2 M NaOH/THF (600 mL) and cooled to 0 °C. Benzyl chloroformate (31.57 ml, 222 mmol) was then added dropwise and the reaction was stirred overnight. Toluene was then added and organic layer discarded to remove unreacted chloroformate. The aqueous layer was made acidic (pH = 2) with cone. HCI and the product was extracted with EtOAc, dried (MgS04), and concentrated in vacuo to give a crude residue which was used without further purification (41.6 g, 94.5%). 1H NMR (CDC13, 400 MHz) δ 7.40-7.37 (m, 5H), 5.19 (m, 2H), 4.95-4.72 (m, IH), 4.14-4.03 (m, IH), 3.36-3.25 (m, IH), 1.93-1.53 (m, 5H), 1.20-1.05 (m, 3H).
[0504] Step 3. D-Tyrosine Hydrazide.
Figure imgf000270_0001
D-Tyrosine methyl ester (30 g, 129 mmol, 99% ee) was dissolved in 150 mL of methanol and stirred until dissolved. Hydrazine hydrate (23 ml, 453 mmol) was then added and solution stirred overnight. Methanol was removed at reduced pressure and saturated NaHC03 was added (150 ml). The product was precipitated, filtered and dried to yield the title compound as a white powder (23.5 g, 93%). 1H NMR (CD3OD, 400 MHz) δ 7.03 (ad, J = 8.8 Hz, 2H), 6.72 (ad, J = 8.8 Hz, 2H), 3.44 (t, J = 6.8 Hz, IH), 2.91-2.86 (m, IH), 2.76-2.71 (m, IH). ESI-MS (m/z): 196.1 [M+l]+.
[0505] Step 4A. (2lS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylate D- tyrosine hydrazide salt.
Figure imgf000270_0002
rac-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (41.6 g, 150 mmol) was dissolved in 100 ml of methanol and 300 ml of isopropanol. D-Tyrosine hydrazide (11.71 g, 60 mmol) was added to give a heterogenous mixture which was heated to reflux. Methanol was added in 100 mL portions until a homogenous solution was formed. The reaction was stirred for 1 h and then allowed to cool to rt overnight to yield thick slurry. The reaction mixture was filtered and washed with isopropanol to yield the title compound as a white solid with 92.0% ee (23g, 81%). The white solid was again dissolved in isopropanol (1.2 L) and heated at reflux until homogenous. The reaction was stirred overnight to yield a slurry which was filtered and washed with isopropanol to yield the title compound as a white solid with 98.9% ee (21g, 73%).
[0506] Step 4B. (2R,3lS')-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylate D- tyrosine hydrazide salt.
Figure imgf000271_0001
The 2R,3S enantiomer was prepared in the same fashion as described above in >98% ee using L- tyro sine hydrazide.
[0507] Step 5. (25,,3R)-Benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate.
Figure imgf000271_0002
(2lS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylate D-tyrosine hydrazide salt (17 g, 37.3 mmol) was dissolved in ethyl acetate and washed with 1 M HC1 (150 ml x 3) and brine (100 mL), dried (MgS04), and concentrated to yield a clear oil (10.2 g, 98%). The clear oil was then dissolved in 150 mL of THF and cooled to 0 °C. 1 M Borane THF complex solution (40.4 mL, 40.4 mmol) was then added dropwise over 15 min. The reaction was then allowed to warm to rt overnight and then quenched with water at 0 °C. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was concentrated in vacuo to give the title compound as a clear oil which was used without further purification (8.7 g, 89%). ESI-MS (m/z): 263.93 [M+l]+.
[0508] Step 6. (25,,3R)-Benzyl 2-((l,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-l- carboxylate.
Figure imgf000271_0003
A solution of PPh3 (21.5 g, 82 mmol) in 30 ml of THF was cooled to 0 °C. DIAD (16.1 mL, 82 mmol) was then added dropwise and reaction stirred for 20 min. A solution of (2S,3R)- benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate (8.7 g, 32.9 mmol) in 15 mL THF was then added dropwise and stirred at 0 °C for 30 min. Phthalimide (6.3 g, 42.7 mmol) was then added and the reaction was warmed to rt overnight. The resulting suspension was concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel
(EtOAc/hexanes) to give the title compound (14.2 g, 110%, DIAD contamination), which was used without further purification. 1H NMR (CDC13, 400 MHz) δ 7.72-7.71 (m, 1H), 7.62-7.60 (m, 3H), 7.17-7.13 (m, 3H), 7.05-7.04 (m, 1H), 6.98-6.96 (m, 1H), 4.76-4.69 (m, 1H), 4.54-4.39 (m, 1H), 4.03-3.98 (m, 2H), 3.63-3.54 (m, 1H), 3.25-3.07 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.54 (m, 2H), 1.47-1.25 (m, 2H), 1.07-1.04 (m, 3H). ESI-MS (m/z): 263.93 [M+l]+.
[0509] Step 7. 2-(((2lS,,3R)-3-Methylpiperidin-2-yl)methyl)isoindoline-l,3-dione.
Figure imgf000272_0001
To a solution of (2S,3R)-benzyl 2-((l,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-l- carboxylate (14.2 g, 36.1 mmol) in acetic acid (40 ml) was added 10% Pd/C (1.5 g). The reaction was then stirred under H2 until HPLC indicated complete removal of the Cbz group. The reaction was the filtered through diatomaceous earth and concentrated. The crude residue was then dissolved in EtOAc and washed with saturated NaHC03, brine, dried (MgS04), and concentrated to yield the title compound as a yellow solid (8.2 g, 88%). 1H NMR (CDC13, 400 MHz) δ 7.82-7.81 (m, 2H), 7.71-7.70 (m, 2H), 4.19-4.15 (m, 1H), 3.81- 3.78 (m, 2H), 3.44 (m, 2H), 2.96 (m, 1H), 2.31 (m, 1H), 1.79-1.67 (m, 2H), 1.27 (d, J = 4.0 Hz, 3H). ESI-MS (m/z): 259.2 [M+l]+.
[0510] Alternative Synthesis of 2-(((2lS',3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3- dione:
[0511] Step 7a. (+)-2,3-ds'-3-Methylpip oxylic acid hydrochloride.
Figure imgf000272_0002
A suspension of 3-methylpyridine-2-carboxylic acid (25.0 g, 182 mmol) and Pt02 (3.00 g) in HOAc (200 mL) was stirred under H2 (1 atm, balloon) at rt for 3 days. After that time, the reaction mixture was flushed with N2, filtered through a short pad of diatomaceous earth, and washed with EtOH/H20 (1: 1, 150 mL). The combined filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in H20 (100 mL). To the resulting solution was added concentrated HCl (20 mL), followed by concentration to dryness. The residue was dried under high vacuum to give the title compound as a white solid (32.7 g, quant.). 1H NMR (300 MHz, DMSO-J6) δ 13.91 (br s, 1H), 9.61 (br s, 1H), 8.76 (br s, 1H), 4.04 (br s, 1H), 3.37-2.75 (m, 2H), 2.42-2.38 (m, 1H), 1.90-1.55 (m, 4H), 0.97 (d, J = 7.3 Hz, 3H).
[0512] Step 7b. (±)-2,3-ci5'- l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid.
Figure imgf000273_0001
To a suspension of (±)-2,3-ci5'-3-methylpiperidine-2-carboxylic acid hydrochloride (32.7 g, 182 mmol) in 2 M NaOH aqueous solution (500 mL) and THF (500 mL) at 0 °C was added Cbz-Cl (46.6 g, 273 mmol) dropwise over 15 min. The reaction mixture was slowly warmed to rt over 1 h and stirred at rt for 18 h. The reaction mixture was then diluted with toluene (400 mL) and H20 (200 mL). The layers were separated and the aqueous layer was washed with toluene (400 mL), acidified with concentrated HCl to pH < 2. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the title compound as a colorless oil (43.8 g, 87%). 1H NMR (300 MHz, DMSO- ) δ 12.74 (br s, 1H), 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H). ESI MS (M-H) 276.
[0513] Step 7c. (-)-(2lS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid and (+)-(2R,3lS')-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid.
Figure imgf000273_0002
(±)-2,3-ci5'- l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (43.8 g, 158 mmol) was separated by preparative HPLC (Chiralcel OD column, 5 cm x 50 cm, 20 μ) elution with hexanes/i-PrOH/TFA (90: 10:0.1, 80 mL/min) and monitored by UV at 254 nm. The capacity of each injection was 1.4 g/injection [1 g in 20 mL of hexanes/i-PrOH (60:40)] . Collection and concentration of the first peak (retention time: -14 min) gave enantiomer A (21.5 g, 49%, > 99% ee) and enantiomer B (RT = 31 min, 21.6 g, 49%, > 99% ee) as colorless oils. Enantiomer A: [a]25 D = -28.2° (c = 0.46, MeOH); 1H NMR (300 MHz, DMSO- ) δ 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H). Enantiomer B: [ γ D = +25.9° (c = 0.52, MeOH); 1H NMR (300 MHz, DMSO-J6) δ 12.74 (br s, 1H), 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H).
[0514] Step 7d. (25,,3R)-Benzyl 2-(Hydroxymethyl)-3-methylpiperidine-l-carboxylate.
Figure imgf000274_0001
To a stirred solution of (-)-(2lS',3R)-l-((benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (6.05 g, 21.8 mmol) in anhydrous THF (80 mL) was added BH3 «THF (1 M in THF, 43.6 mL, 43.6 mmol) dropwise over 10 min at rt under nitrogen. The reaction mixture was then stirred at rt for 46 h. After this time, the reaction was quenched by the slow addition of ice cold water (10 mL) followed by 2 N HCl (20 mL). The resulting mixture was stirred at rt for 30 min and then extracted with EtOAc (3 x 100 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 20% to 50%
EtOAc/CH2Cl2 to afford the title compound as a colorless oil (5.30 g, 92%). ESI MS (M+H) 264.
[0515] Example 7e. (25,,3R)-Benzyl 2-((l,3-Dioxoisoindolin-2-yl)methyl)-3- methylpiperidine- 1 -carboxylate.
Figure imgf000274_0002
To a stirred solution of (25,,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate (4.61 g, 17.5 mmol) and w-Bu3P (10.6 g, 52.4 mmol) in anhydrous THF (150 mL) was added l,l'-(azodicarbonyl)dipiperidine (ADDP; 8.83 g, 35.0 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 30 min. To the reaction mixture was then added isoindoline-l,3-dione (3.09 g, 21.0 mmol), followed by heating at reflux for 20 h. After this time, the reaction mixture was cooled to rt, diluted with Et20 (100 mL), and further cooled with an ice/water bath. The resulting mixture was filtered and the filter cake was washed with Et20 (40 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8). The material obtained from the chromatography was triturated with hexanes/CH2Cl2 (5: 1) and solids removed by filtration. Concentration of the filtrate afforded the title compound as a colorless oil (6.12 g, 89%). ESI MS (M+H) 393.
[0516] Step 8. Methyl 2-bromo-5-methylbenzoate.
Figure imgf000275_0001
2-Bromo-5-methylbenzoic acid (9.3 g, 43.4 mmol) was dissolved in MeOH (100 mL) and then cat. cone. H2S04 was added. The mixture was refluxed at 100 °C overnight. The mixture was cooled to rt and the solvent was removed at reduced pressure. The crude residue was dissolved with EtOAc, and washed with water twice, followed by saturated NaHC03 and brine, dried over anhydrous Na2S04. The solvent was removed in vacuo to obtain the title compound with no further purification.
[0517] Step 9. Methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate.
Figure imgf000275_0002
A mixture of methyl 2-bromo-5-methylbenzoate (1.01 g, 4.41 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.1 g, 5.28 mmol), Pd(PPh3)4 (0.764 g, 0.66 mmol), K2C03 (1.83 g, 13.23 mmol) and dioxane/H20 (4: 1, 15 mL) was degassed for 10 min and then heated overnight at 100 °C. The mixture was cooled, diluted with brine, and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03 and dried over Na2S04. The solvent was removed in vacuo to obtain the crude material, which was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 231 [M+l]+.
[0518] Alternate Synthesis of methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate: A stirred solution of 2-iodo-5-methylbenzoic acid (17.3 g, 66.0 mmol) and concentrated H2S04 (3 mL) in MeOH (200 mL) was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt, concentrated to one third volume, diluted with EtOAc (300 mL), washed with saturated NaHC03 (2 x 200 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was dried under high vacuum to afford methyl 2-iodo-5-methylbenzoate as a colorless oil (18.2 g, quant.). 1H NMR (300 MHz, CDCI3) δ 7.84 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.99-6.96 (m, 1H), 3.92 (s, 3H), 2.33 (s, 3H). A stirred suspension of methyl 2-iodo-5-methylbenzoate (18.2 g, 66.0 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (15.2 g, 73.3 mmol), K2CO3 (27.5 g, 200 mmol), and Pd(PPh3)4 (11.5 g, 9.99 mmol) in 1,4-dioxane (150 mL) and H20 (50 mL) was heated at 100 °C for 18 h under nitrogen. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (400 mL), washed with saturated NaHC03 (2 x 300 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 80% EtOAc/hexanes to afford methyl 5-methyl-2-(l-methyl-lH- pyrazol-4-yl)benzoate as a colorless oil (13.3 g, 87%). 1H NMR (300 MHz, CDC13) δ 7.55- 7.25 (m, 5H), 3.94 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H).
[0519] Step 10. 5-Methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoic acid.
Figure imgf000276_0001
Methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate (~1 g, -4.41 mmol) was dissolved in MeOH/H20 (4: 1, 50 mL) and then LiOH (0.36 g, 15 mmol) was added. The mixture was heated at reflux for 2 h at 100 °C. The analytical HPLC indicated the starting material was consumed, the mixture was cooled to 0 °C and 2 M HC1 solution was added bring the pH ~4. MeOH was removed in vacuo and the acid was precipitated. The acid was collected by filtration and dried in vacuo and used without further purification. ESI-MS (m/z): 217
[M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 12.87 (br s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.39- 7.27 (m, 3H), 3.85 (s, 3H), 2.32 (s, 3H).
[0520] Step 11. 2-(((25,3R)-3-Methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)benzoyl)piperidin-2-yl)meth
Figure imgf000276_0002
A mixture of 2-(((2lS',3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.66 g, 2.55 mmol), 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoic acid (0.5 g, 2.318 mmol),
diisopropylethylamine (0.7 mL, 6.954 mmol) and HATU (0.881 g, 2.318 mmol) in DCM was stirred at rt for 1 h. The reaction mixture was diluted with DCM and washed with satd.
NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel
(EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 457 [M+l]+.
[0521] Step 12. ((2lS,,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl- lH-pyrazol-4-yl)phenyl)methanone
Figure imgf000277_0001
A mixture of 2-(((2S,3R)-3-methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)benzoyl)piperidin-2-yl)methyl)isoindoline-l,3-dione (0.67 g, 1.5 mmol) and hydrazine hydrate (0.46 g, 9.27 mmol) in MeOH (10 mL) was heated at 60 °C for 2 h. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2x), brine, and then dried (Na2S04). The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESI-MS (m/z): 327 [M+l]+.
[0522] Step 13. ((25,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone. A mixture of ((2lS',3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-4-yl)phenyl)methanone (0.282 g, 0.864 mmol) and 2-fluoro-5- (trifluoromethyl)pyridine (0.29 g, 1.728 mmol) and anhydrous K2C03 (0.24 g, 1.73 mmol) in DMF (10 mL) was heated at 100 °C overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHC03, brine, and dried (MgS04). The solvent was removed and the crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. 1H NMR
(CDC13, 400 MHz) δ 8.31-8.32 (m, IH), 7.63-7.53 (m, 4H), 7.26-7.14 (m, 2H), 6.53-6.50 (m, IH), 4.20-4.11 (m, IH), 3.92 (s, 3H), 3.60-3.25 (m, 2H), 3.01-2.94 (m, IH), 2.38 (s, IH), 2.22 (s, 2H), 1.45-1.22 (m, 4H), 1.04 (d, J = 7.0 Hz, 3H), 0.73-0.44 (m, IH); ESI-MS (m/z): 472 [M+l]+. [CC]25D= -8.9 =0.1, MeOH). [0523] Example A2: (rac-ci5,-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(l-methyl-lH-p .
Figure imgf000278_0001
A mixture of (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-4-yl)phenyl)methanone (40 mg, 122 μιηοΐ), 2-chlorobenzoxazole (38 mg, 245 μιηοΐ) and diisopropylethyl amine (DIPEA; 43 μί, 245 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHC03, brine, and dried (MgS04). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 442 (M+H).
[0524] Example A3: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000278_0002
[0525] Step 1. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-bromo-5- methylphenyl)methanone .
Figure imgf000278_0003
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, starting with 2-((rac-ds,-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione and 2-bromo-5-methylbenzoic acid. ESTMS (m/z): 325, 327 [M]+, [M+2]+. [0526] Step 2. (2-Bromo-5-methylphenyl)(rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000279_0001
The title compound was prepared following the same general protocol as described for Example Al, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-bromo-5- methylphenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 470, 472 [M]+, [M+2]+.
[0527] Step 3. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(lH-pyrazol-4-yl)phenyl)methanone. A mixture of (2-bromo-5-methylphenyl)(rac-ci5'-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)methanone (0.045 g, 0.097mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (0.034 g, 0.116 mmol), Pd(PPh3)4 (0.017 g, 0.015 mmol), K2C03 (0.4 g, 0.291 mmol) and dioxane /H20 (4: 1, 3 mL) was degassed for 5 min and heated overnight at 100 °C. The completion of the reaction was monitored by anal. HPLC. The mixture was cooled and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03 and dried over Na2S04. The solvent was removed in vacuo to obtain the crude, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 458 [M+l]+.
[0528] Example A4: (2-(2-Methoxypyrimidin-5-yl)-5-methylphenyl)(rac-ci5,-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000279_0002
The title compound was prepared following the same general protocol as described for Example A3, using (2-methoxypyrimidin-5-yl)boronic acid. ESTMS (m/z): 500 [M+l]+. [0529] Example A5: (rac-cw-S-Methyl-l-iiiS-itrifluoromethy^pyridin-l- yl)amino)methyl)piperidin-l-y -methyl-2-(5-methylpyridin-3-yl)phenyl)methanone.
Figure imgf000280_0001
The title compound was prepared following the same general protocol as described for Example A3, using (3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine. ESI- MS (m/z): 483 [M+l]+.
[0530] Example A6: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrrol-3-yl)phenyl)methanone.
Figure imgf000280_0002
The title compound was prepared following the same general protocol as described for Example A3, using l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole. ESI-MS (m/z): 471 [M+l]+.
[0531] Example A7: (2-(3,5-Dimethylisoxazol-4-yl)-5-methylphenyl)(rac-ci5'-:
(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000280_0003
[0532] Step 1. rac-ds-Allyl 2-(aminomethyl)-3-methylpiperidine-l-carboxylate.
Figure imgf000281_0001
To a solution of l-iirac-cw-S-methylpiperidin-l-y^methy^isoindoline-^S-dione (5g, 19.4 mmol) in CH2C12 at 0 °C was added DIPEA (3.8 niL), followed by allyl chloroformate (2.6 mL). The reaction was allowed to warm to rt overnight. After 16 h, the reaction was concentrated to remove the CH2C12, and then re-suspended in EtOAc and washed with 1 M HCl (2x), brine (2x), dried (MgS04) and concentrated to give the crude carbamate which was used without further purification. A mixture of the crude carbamate and hydrazine hydrate (2 g, 39 mmol) in MeOH (100 mL) was heated at 60 °C for 2 h. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2x), brine, and then dried (Na2S04). The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESTMS (m/z): 213 [M+l]+.
[0533] Step 2. rac-ds-Allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidine- 1 -carboxylate.
Figure imgf000281_0002
A mixture of rac-ds-allyl 2-(aminomethyl)-3-methylpiperidine-l -carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2C03 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80 °C for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound. ESI-MS (m/z): 358 [M+l]+.
[0534] Step 3. N-((rac-ci5,-3-Methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2- amine.
Figure imgf000281_0003
A mixture of rac-ds-allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidine-l -carboxylate (0.528 g, 1.48 mmol), Pd(PPh3)4 (0.086 g, 0.0074 mmol) and l,3-dimethylpyrimidine-2,4,6(lH,3H,5H)-trione (0.14 g, 0.89 mmol) in DCM (20 mL) was stirred at rt. When the starting material was consumed as judged by reverse-phase HPLC analysis, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHC03, brine, dried (MgS04), and concentrated to obtain the crude which was purified by silica gel (0-100% DCM/EtOAc) to afford the title compound. ESI-MS (m/z): 274 [M+l]+.
[0535] Step 4. 2-(3,5-Dimethylisoxaz -4-yl)-5-methylbenzoic acid.
Figure imgf000282_0001
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole. ESI-MS (m/z): 232 [M+l]+.
[0536] Step 5. (2-(3,5-Dimethylisoxazol-4-yl)-5-methylphenyl)(rac-ci5,-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. The title compound was prepared following the same general protocol as described for Example Al, using 2-(3,5- dimethylisoxazol-4-yl)-5-methylbenzoic acid and N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 487 [M+l]+.
[0537] Example A8: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methylpyridin-3-yl)phenyl)methanone.
Figure imgf000282_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using (4-methylpyridin-3- yl)boronic acid. ESI-MS (m/z): 228 [M+l]+. [0539] Step 2. (rac-ds-3-Methyl-2-(((5-(trifluoro
yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methylpyridin-3-yl)phenyl)meth The title compound was prepared following the same general protocol as described for Example Al, using 5-methyl-2-(4-methylpyridin-3-yl)benzoic acid and N-^rac-ds-S-methylpiperidin- 2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 483 [M+l]+.
[0540] Example A9: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridin-2-yl)phenyl)methanone.
[0541] Step 1. Methyl 5-meth
Figure imgf000283_0001
A mixture of methyl 2-bromo-5-methylbenzoate (0.629 g, 2.747 mmol), 2- (tributylstannyl)pyridine (1.32 g, 3.585 mmol), CsF (0.834 g, 5.494 mmol), Pd(PPh3)4 (0.4 g, 0.27 mmol), and Cul (0.105 g, 0.549 mmol) in DMF (20 mL) was degassed for 10 min and then heated in the microwave reactor for 30 min at 130 °C. The mixture was cooled and the solvent was removed in vacuo. The crude was dissolved with EtOAc and then washed with saturated NaHC03 and dried over Na2S04. The solvent was removed in vacuo to obtain the crude, which was purified by silica gel to obtain the title compound. ESTMS (m/z): 228 [M+l]+.
[0542] Step 2. 5-Methyl-2-(pyridin-2- l)benzoic acid.
Figure imgf000283_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using methyl 5-methyl-2- (pyridin-2-yl)benzoate. ESI-MS (m/z): 214 [M+l]+. [0543] Step 3. ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, starting from 5-methyl-2-(pyridin-2-yl)benzoic acid and 2-(((2S,3R)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione. ESI-MS (m/z): 469 [M+l]+.
[0544] Example A10: (rac-ci5,-2-(((6-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methy -2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000284_0001
The title compound was prepared following the same general protocol as described for Example Al using 2,6-dichlorobenzoxazole. MS (ESI) 478 (M+H).
[0545] Example Al l: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000284_0002
[0546] Step 1. 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000284_0003
A mixture of 2-bromo-5-methylbenzoic acid (2.0 g, 9.30 mmol), 1,2,3-triazole (1.08 mL, 18.6 mmol), (lS,2S)-Nl,N2-dimethylcyclohexane-l,2-diamine (2.23 mL, 13.95 mmol), Cs2C03 (4.55g, 13.95 mmol) and Cul (124 mg, 0.65 mmol) in DMF (12 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a yellow oil (1.5g, 61%). MS (ESI) 204 (M+H).
[0547] Step 2. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000285_0001
The title compound was prepared following the same general protocol as described for (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).
[0548] Step 3. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example A2 using 2,5- dichlorobenzoxazole. MS (ESI) 465 (M+H).
[0549] Example A12: (rac-ci5,-2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000285_0002
The title compound was prepared following the same general protocol as described for Example A2 using 2,5-dichlorobenzoxazole. MS (ESI) 478 (M+H).
[0550] Example A13: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000286_0001
[0551] Step 1. 2-((rac-ci5,-l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)isoi
Figure imgf000286_0002
To a solution of 2-((rac-ci5,-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (100 mg, 387 μηιοΐ) in DMF was added DIPEA (202 μΐ,, 1.16 mmol) followed by 5-(4-fluorophenyl)- 2-methylthiazole-4-carboxylic acid (137 mg, 580 μιηοΐ) and HATU (176 mg, 465 μιηοΐ). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 2-((rac-ds,-l-(5-(4-fluorophenyl)-2- methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione as a light yellow oil (130 mg, 71%). MS (ESI) 478 (M+H).
[0552] Step 2. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000286_0003
A mixture of 2-((rac-ci5,-l-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (130 mg, 272 μιηοΐ) and hydrazine hydrate (67 μί, 1.36 mmol) in MeOH (3 mL) was heated at reflux for 2 h. The mixture was cooled and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2x) and brine. The organic solution was dried over anhydrous Na2S04. The solvent was removed to obtain the title compound which was used without further purification. MS (ESI) 348 (M+H).
[0553] Step 3. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Example A2 using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 499 (M+H).
[0554] Example A14: (rac-ci5,-2-(((6-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methy -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000287_0001
The title compound was prepared following the same general protocol as described for Example Al l using 2,6-dichlorobenzoxazole. MS (ESI) 465 (M+H).
[0555] Example A15: (rac-ci5,-2-(((5-Fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000287_0002
A mixture of (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone (40 mg, 115 μιηοΐ), 2-chloro-5-fluorobenzoxazole (24 mg, 138 μιηοΐ) and DIPEA (60 μΐ, 345 μιηοΐ) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHC03 and brine. The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 483 (M+H).
[0556] Example A16: (rac-cw-S-Methyl-l-iiiS-itrifluoromethy^pyridin-l- yl)amino)methyl)piperidin- 1 -yl)(5-methyl-2-(5-methyl- 1H- 1 ,2,4-triazol- 1 - yl)phenyl)methanone.
Figure imgf000288_0001
[0557] Step 1. 5-Methyl-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzoic acid and 5-methyl-2-(5- methyl- 1H- 1 ,2,4-triazol- 1 -yl)benzoic acid.
Figure imgf000288_0002
The title compound was synthesized following the same general protocol as described in Example Al 1 using 3-methyl-lH-l,2,4-triazole. The faster eluting 5-methyl-2-(3-methyl- lH-l,2,4-triazol-l-yl)benzoic acid was the major product and the slower eluting 5-methyl-2- (5-methyl-lH-l,2,4-triazol-l-yl)benzoic acid was the minor product. ESTMS (m/z): 218
[M+l]+.
[0558] Step 2. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)(5-methyl-2-(5-methyl- 1H- 1 ,2,4-triazol- 1 - yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al, using 5-methyl-2-(5-methyl-lH-l,2,4-triazol-l-yl)benzoic acid and N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESTMS (m/z): 473 [M+l]+.
[0559] Example A17: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)(5-methyl-2-(3-methyl- 1H- 1 ,2,4-triazol- 1 - yl)phenyl)methanone.
Figure imgf000289_0001
The title compound was prepared following the same general protocol as described for Example A16, using 5-methyl-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzoic acid. ESTMS (m/z): 473 [M+l]+.
[0560] Example A18: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-3-yl)phenyl)methanone.
Figure imgf000289_0002
[0561] Step 1. Methyl 5-methyl-2-(lH-pyrazol-5-yl)benzoate.
Figure imgf000289_0003
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using (lH-pyrazol- 5-yl)boronic acid. ESI-MS (m/z): 217 [M+l]+.
[0562] Step 2. Methyl 5-methyl-2-(l-methyl-lH-pyrazol-3-yl)benzoate.
Figure imgf000289_0004
To a solution of methyl 5-methyl-2-(lH-pyrazol-3-yl)benzoate (0.16 g, 0.744 mmol) in DMF (3 mL) at rt was added NaH (60%, 0.081 g, 2.02 mmol) under argon protection. The mixture was stirred atrt for 1 h, and then Mel (0.07 mL, 1.116 mmol) was added. The resulting mixture was stirred for another 1 h. The solvent was removed in vacuo. The crude was dissolved with EtOAc and washed with satd. NaHC03, brine, and dried (MgS04). The solvent was removed and the crude was purified by silica gel chromatography to obtain the faster eluting methyl 5-methyl-2-(l-methyl-lH-pyrazol-5-yl)benzoate as the minor product and the slower eluting methyl 5-methyl-2-(l-methyl- lH-pyrazol-3-yl)benzoate as the title compound and major product. ESI-MS (m/z): 231 [M+l]+.
[0563] Step 3. 5-Methyl-2-(l-methyl-lH-pyrazol-3-yl)benzoic acid.
Figure imgf000290_0001
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using methyl 5-methyl-2- (l-methyl-lH-pyrazol-3-yl)benzoate. ESI-MS (m/z): 217 [M+l]+.
[0564] Step 4. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-3-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al, using 5-methyl-2-(l-methyl-lH-pyrazol-3-yl)benzoic acid and N-((rac-cis-3- methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472
[M+l]+.
[0565] Example A19: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyrazin-2-yl)phenyl)methanone.
Figure imgf000290_0002
[0566] Step 1. Methyl 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate.
Figure imgf000290_0003
A mixture of methyl 2-bromo-5-methylbenzoate (1.153 g, 5.03 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.9 g, 5.533 mmol), PdCl2(PPh3)2 (0.35 g, 0.5 mmol) and AcOK (0.98 g, 10.06 mmol) in dioxane (10 mL) was degassed and heated for 16 h at 100 °C. The mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc. The organic phase was washed with satd. aq. NaHC03,brine, and dried (MgS04). The solvent was removed in vacuo and the resulting crude residue was purified by silica gel chromatography (EtOAc/hexanes) to give the title compound.
[0567] Step 2. Methyl 5-methyl-2-(pyrazin-2-yl)benzoate.
Figure imgf000291_0001
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using methyl 5- methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate and using 2-iodopyrazine ESI-MS (m/z): 229 [M+l]+.
[0568] Step 3. 5-Methyl-2-(pyrazin-2-yl)benzoic acid.
Figure imgf000291_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using methyl 5-methyl-2- (pyrazin-2-yl)benzoate. ESI-MS (m/z): 215 [M+l]+.
[0569] Step 4. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(pyrazin-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al, using 5-methyl-2-(pyrazin-2-yl)benzoic acid and N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)- 5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470 [M+l]+.
[0570] Example A20: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-imidazol-2-yl)phenyl)methanone.
Figure imgf000292_0001
[0571] Step 1. 5-Methyl-2-(l-methyl-lH-imidazol-2-yl)benzoic acid.
Figure imgf000292_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-bromo-l -methyl- 1H- imidazole. ESI-MS (m/z): 217 [M+l]+.
[0572] Step 2. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-imidazol-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(l-methyl-lH-imidazol-2-yl)benzoic acid and N-((rac-cis-3- methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESTMS (m/z): 472
[M+l]+.
[0573] Example A21 : (2-(4-Methoxypyrimidin-2-yl)-5-methylphenyl)(rac-ci5'-:
(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin- l-yl)methanone.
Figure imgf000292_0003
[0574] Step 1. 2-(4-Methoxypyrimidin-2-yl)-5-methylbenzoic
Figure imgf000292_0004
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4- methoxypyrimidine. ESI-MS (m/z): 245 [M+l]+.
[0575] Step 2. (2-(4-Methoxypyrimidin-2-yl)-5-methylphenyl)(rac-cw-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 2- (4- methoxypyrimidin-2-yl)-5-methylbenzoic acid and N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 500 [M+l]+.
[0576] Example A22: 4-Methyl-2-(rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidine- 1 -carbonyl)benzonitrile.
Figure imgf000293_0001
A mixture of (2-bromo-5-methylphenyl)(rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)methanone (synthesized from Example A3, 0.35 g, 0.744 mmol), Zn(CN)2 (0.105 g, 0.818 mmol), Pd2(dba)3 (0.068 g, 0.074 mmol) and 2- dicyclohexylphophino-2',6'-dimethoxybiphenyl (S-Phos; 0.076 g, 0.186 mmol) in wet DMF (DMF:H20 10: 1, 20 mL) was degassed and sealed and heated in a microwave reactor for lh at 150 °C. The reaction was cooled to rt and the solvent was removed in vacuo. The crude was dissolved with EtOAc, washed with satd. aq. NaHC03 and brine and dried over Na2S04. The solvent was removed and the crude was purified in silica gel with 0-100% EtO Ac/Hex to obtain the title compound. ESI-MS (m/z): 417 [M+l]+.
[0577] Example A23: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-tetrazol-5-yl)phenyl)methanone.
Figure imgf000293_0002
A mixture of 4-methyl-2-(rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidine-l-carbonyl)benzonitrile (obtained from Example A22, 0.098 g, 0.235 mmol), TMSN3 (0.06 mL, 0.47 mmol) and SnO(n-Bu)2 (0.006 g, 0.024 mmol) in toluene (2 mL) was heated at 110 °C overnight. The mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with methanol. The solvent was removed in vacuo and the resulting crude residue was purified by reverse-phase preparative HPLC to obtain the title compound. ESI-MS (m/z): 460 [M+l]+.
[0578] Example A24: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(thiazol-2-yl)phenyl)methanone.
Figure imgf000294_0001
[0579] Step 1. 5-Methyl-2-(thiazol-2-yl)benzoic acid.
Figure imgf000294_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-bromothiazole. ESI- MS (m/z): 220 [M+l]+.
[0580] Step 2. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(thiazol-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(thiazol-2-yl)benzoic acid and N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)- 5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+l]+.
[0581] Example A25: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(thiazol-5-yl)phenyl)methanone.
Figure imgf000295_0001
[0582] Step 1. 5-Methyl-2-(thiazol-5-yl)benzoic acid.
Figure imgf000295_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 5-bromothiazole. ESI- MS (m/z): 220 [M+l]+.
[0583] Step 2. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(thiazol-5-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(thiazol-5-yl)benzoic acid and N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)- 5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+l]+.
[0584] Example A26: (rac-ci5,-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-imidazol-5-yl)phenyl)methanone.
Figure imgf000295_0003
[0585] Step 1. 5-Methyl-2-(l-methyl-lH-imidazol -5- l)benzoic acid.
Figure imgf000295_0004
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 5-bromo-l -methyl- 1H- imidazole. ESI-MS (m/z): 217 [M+l]+. [0586] Step 2. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-imidazol-5-yl)phenyl)meth The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(l-methyl-lH-imidazol-5-yl)benzoic acid and N-((rac-cis-3- methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472
[M+l]+.
[0587] Example A27: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(2-methylpyrimidin-4-yl)phenyl)methanone.
Figure imgf000296_0001
[0588] Step 1. Methyl 2-(2-chloropyrimidin-4-yl)-5-methylbenzoate.
Figure imgf000296_0002
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using methyl 5- methyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate and 2,4-dichloropyrimidine. ESI-MS (m/z): 263 [M+l]+.
[0589] Step 2. Methyl 5-methyl-2-(2-methylpyrimidin-4-yl)benzoate.
Figure imgf000296_0003
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using methyl 2-(2- chloropyrimidin-4-yl)-5-methylbenzoate and 2,4,6-trimethyl- 1 ,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 243 [M+l]+.
[0590] Step 3. 5-Methyl-2-(2-methylpyrimidin-4-yl)benzoic acid.
Figure imgf000297_0001
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using methyl 5-methyl-2- (2-methylpyrimidin-4-yl)benzoate. ESI-MS (m/z): 229 [M+l]+.
[0591] Step 4. rac-ds-Allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidine- 1 -carboxylate.
Figure imgf000297_0002
A mixture of rac-ds-allyl 2-(aminomethyl)-3-methylpiperidine-l -carboxylate (0.804 g, 3.787 mmol), 2,5-dichlorobenzo[d]oxazole (0.712 g, 3.787 mmol) and DIPEA (1 mL, 5.68 mmol) in acetonitrile (15 mL) was heated at 40 °C overnight. The solvent was removed in vacuo and the crude was purified via silica gel with 0-100% EtOAc/hexanes to obtain the title compound. ESI-MS (m/z): 364 [M+l]+.
[0592] Step 5. 5-Chloro-N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2- amine.
Figure imgf000297_0003
To a solution of rac-ds-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidine- 1 -carboxylate (1.18 g, 3.248 mmol) and morpholine (2.8 mL, 32.48 mmol) in THF (30 mL) was added Pd(PPh3)4 (0.375 g, 0.32 mmol). The mixture was stirred at rt for 2 h. The solvent was removed in vacuo. The crude was purified via silica gel with 0-100% EtOAc/DCM to obtain the title compound. ESI-MS (m/z): 280 [M+l]+.
[0593] Step 6. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2-methylpyrimidin-4-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (2-methylpyrimidin-4-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+l]+. [0594] Example A28: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- l-yl)(5-meth -2-( 1H- 1 ,2,4-triazol- l-yl)phenyl)methanone.
Figure imgf000298_0001
[0595] Step l. 5-Methyl-2-(lH-l,2,4-triazol-l-yl)benzoic acid.
Figure imgf000298_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using lH-l,2,4-triazole. ESI- MS (m/z): 204 [M+l]+.
[0596] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(lH-l,2,4-triazol-l-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (lH-l,2,4-triazol-l-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 465 [M+l]+.
[0597] Example A29: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanone.
Figure imgf000298_0003
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(3-methyl-lH-l,2,4-triazol-l-yl)benzoic acid and 5-chloro-N- ((rac-ci5'-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESTMS (m/z): 479
[M+l]+. [0598] Example A30: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(thiazol-2-yl)phenyl)methanone.
Figure imgf000299_0001
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(thiazol-2-yl)benzoic acid and 5-c \oro-N-((rac-cis-3- methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+l]+.
[0599] Example A31: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino
methylpiperidin- 1 - yl) (5 -meth -2- (pyridin- 3 -yl)phenyl)methanone .
Figure imgf000299_0002
[0600] Step 1. 5-Methyl-2-(pyridin-3-yl)benzoic acid.
Figure imgf000299_0003
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using pyridin-3-ylboronic acid. ESI-MS (m/z): 214 [M+l]+.
[0601] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(pyridin-3-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(pyridin- 3-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2- amine. ESI-MS (m/z): 475 [M+l]+.
[0602] Example A32: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino
methylpiperidin- l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000300_0001
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(pyridin-2-yl)benzoic acid and S-c loro-N-drac-cisS- methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESTMS (m/z): 475 [M+l]+.
[0603] Example A33: (2-(lH-Imidazol-l-yl)-5-methylphenyl)(rac-cw-2-(((5- chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000300_0002
[0604] Step 1. 2-(lH-Imidazol-l-yl)-5-methylbenzoic acid.
Figure imgf000300_0003
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l, using imidazole. ESI-MS (m/z): 203 [M+l]+.
[0605] Step 2. (2-(lH-Imidazol-l-yl)-5-methylphenyl)(rac-ci5,-2-(((5-chlorobenzo[d]oxazol- 2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 2-(lH-imidazol-l- yl)-5-methylbenzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 464 [M+l]+.
[0606] Example A34: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 - yl) (5 - methyl-2- (thiazol- 5 -yl)phenyl)methanone .
Figure imgf000301_0001
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(thiazol-5-yl)benzoic acid and 5-c \oro-N-((rac-cis-3- methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+l]+.
[0607] Example A35: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(4-methylpyrimidin-2-yl)phenyl)methanone.
Figure imgf000301_0002
[0608] Step 1. 5-Methyl-2-(4-methylpyrimidin-2-yl)benzoic
Figure imgf000301_0003
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4- methylpyrimidine. ESI-MS (m/z): 229 [M+l]+.
[0609] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(4-methylpyrimidin-2-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (4-methylpyrimidin-2-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+l]+.
[0610] Example A36: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 - yl) (5 -methyl-2- ( 1 -methyl- 1 H-pyrazol- 5 -yl)phenyl)methanone .
Figure imgf000302_0001
[0611] Step 1. 5-Methyl-2-(l-methyl-lH-pyrazol-5-yl)benzoic acid.
Figure imgf000302_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. ESI-MS (m/z): 217 [M+l]+.
[0612] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (l-methyl-lH-pyrazol-5-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478 [M+l]+.
[0613] Example A37: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(2-methylpyridin-4-yl)phenyl)methanone.
Figure imgf000302_0003
[0614] Step 1. 5-Methyl-2-(2-methylpyridin-4-yl)benzoic acid.
Figure imgf000302_0004
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine. ESI-MS (m/z): 228 [M+l]+.
[0615] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2-methylpyridin-4-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (2-methylpyridin-4-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+l]+.
[0616] Example A38: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(6-methylpyridin-3-yl)phenyl)methanone.
Figure imgf000303_0001
[0617] Step 1. 5-Methyl-2-(6-methylpyridin-3-yl)benzoic
Figure imgf000303_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using (6-methylpyridin-3- yl)boronic acid. ESI-MS (m/z): 228 [M+l]+.
[0618] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(6-methylpyridin-3-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2- (6-methylpyridin-3-yl)benzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+l]+.
[0619] Example A39: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(2-(2-methoxypyrimidin-5-yl)-5-methylphenyl)methanone.
Figure imgf000304_0001
[0620] Step 1. 2-(2-Methoxypyrimidin-5-yl)-5-methylbenzoic
Figure imgf000304_0002
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(l -methyl- lH-pyrazol-4-yl)benzoic acid in Example Al, using (2- methoxypyrimidin-5-yl)boronic acid. ESI-MS (m/z): 245 [M+l]+.
[0621] Step 2. (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(2-(2-methoxypyrimidin-5-yl)-5-methylphenyl)methanone. The title compound was prepared following the same general protocol as described in Example Al, using 2- (2- methoxypyrimidin-5-yl)-5-methylbenzoic acid and 5-chloro-N-((rac-ci5,-3-methylpiperidin-2- yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 506 [M+l]+.
[0622] Example A40: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000304_0003
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoic acid and 5-chloro-N- ((rac-ci5'-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478
[M+l]+. [0623] Example A41: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000305_0001
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone (50 mg, 145 μιηοΐ), 2,5-dichloropyrimidine (43 mg, 287 μιηοΐ), and DIPEA (75 mg, 431 μιηοΐ) in isopropanol was stirred at 120 °C for 1 h in a microwave reactor. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H). 1H NMR (500 MHz, CDC13) δ 8.25-6.85 (m, 7H), 5.55-2.65 (m, 8H), 1.95-0.85 (m, 8H).
[0624] Example A42: ((2R,3S)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-(4-fluorophenyl)-2-meth
Figure imgf000305_0002
[0625] Step 1. 2-(((2R,3S)-3-Methylpiperidin-2-yl)methyl)isoindoline-l,3-dione.
Figure imgf000305_0003
The title compound was prepared following the same general protocol as described for 2- (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione in Example Al instead using (2R,3S)-l-((benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid. MS (ESI) 259 (M+H).
[0626] Step 2. ((2R,3S)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000306_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone in Example A13 using 2-(((2R,3S)-3-methylpiperidin-2-yl)methyl)isoindoline- 1,3-dione. MS (ESI) 348 (M+H).
[0627] Step 3. ((2R,3S)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l-yl)(5- (4-fluorophenyl)-2-methylthiazol-4-yl)methanone. The title compound was prepared following the same general protocol as described for Example A2 using ((2R,3S)-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 459 (M+H).
[0628] Example A43: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)((2R,3S)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000306_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2R,3S)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone. MS (ESI) 465 (M+H).
[0629] Example A44: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000307_0001
A mixture of (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-il-methyl-lH- pyrazol-4-yl)phenyl)methanone (80 mg, 245μιηο1), 2-bromo-5-fluoropyridine (47 mg, 270 μιηοΐ), Pd2dba3 (5.0 mg, 4.9μιηο1), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 4.2 mg, 7μιηο1), and NaOtBu (35 mg, 368 μιηοΐ) in dioxane (2 mL) was purged with argon, and then stirred at 100 °C overnight. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 422 (M+H).
[0630] Example A45: 6-((( rac-ds-3-Methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000307_0002
A mixture of (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-4-yl)phenyl)methanone (80 mg, 245 μιηοΐ), 6-chloronicotinonitrile (50 mg, 368 μιηοΐ) and anhydrous K2C03 (102 mg, 735 μπιοΐ) in DMF (2 mL) was heated at 100 °C overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHC03, brine and then dried (MgS04). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 429 (M+H).
[0631] Example A46: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 416 (M+H).
[0632] Example A47: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000308_0002
The title compound was prepared following the same general protocol as described for Example A44 using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone. MS (ESI) 409.2 (M+H).
[0633] Example A48: ((2S,3R)-3-Methyl-2-(((5-methylpyridin-2- yl)amino)methyl)piperidin-l-yl) -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000308_0003
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. MS (ESI) 409.2 (M+H).
[0634] Example A49: (rac-ci5,-3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000309_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-methylpyridine. MS (ESI) 409.2 (M+H).
[0635] Example A50: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 - yl) (5 -meth -2- ( 1 -methyl- 1 H-pyrazol- 5 -yl)phenyl)methanone .
Figure imgf000309_0002
The title compound was prepared following the same general protocol as described in Example Al, using 5-methyl-2-(l-methyl-lH-pyrazol-5-yl)benzoic acid and 5-chloro-N- ((rac-ci5'-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESTMS (m/z): 478 [M+l]+.
[0636] Example A51: 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4- triazol-l-yl)benzoyl)piperidin- -yl)methyl)amino)nicotinonitrile.
Figure imgf000309_0003
[0637] Step 1. 5-Methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)benzoic acid.
Figure imgf000309_0004
The title compound was synthesized following the same general protocol as described in Example Al l using 3-(trifluoromethyl)-lH-l,2,4-triazole. ESI-MS (m/z): 272 [M+l]+.
[0638] Step 2. tert-Butyl ((rac-cw-3-methyl-l-(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4- triazol- 1 -yl)benzoyl)piperidin-2-yl)methyl)carbamate.
Figure imgf000310_0001
To a mixture of 5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)benzoic acid (0.24 g, 0.869 mmol), tert-butyl ((rac-ci5,-3-methylpiperidin-2-yl)methyl)carbamate (0.22 g, 0.96 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was added HATU (0.33 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. NaHC03 and brine and dried over Na2S04. The solvent was removed in vacuo to obtain the title compound with no further purification for next step. ESI-MS (m/z): 482 [M+l]+.
[0639] Step 3. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- (trifluoromethyl)- 1H- 1 ,2,4-triazol- 1 -yl)phenyl)methanone.
Figure imgf000310_0002
tert-Butyl((rac-ci5'-3-methyl-l-(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l- yl)benzoyl)piperidin-2-yl)methyl)carbamate obtained from the previous step was dissolved in DCM (20 mL) and then TFA (8 mL) was added. The mixture was stirred at rt for 2 h. The solvent was removed in vacuo to give the crude product as a TFA salt which was used without further purification. ESI-MS (m/z): 482 [M+l]+.
[0640] Step 4. 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile. The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-ci5,-2-(aminomethyl)-3- methylpiperidin-l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l- yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 484 [M+l]+.
[0641] Example A52: 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(3-methyl-lH-l,2,4-triazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000311_0001
[0642] Step 1. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl-lH- l,2,4-triazol-l-yl)phenyl)methanon
Figure imgf000311_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5'-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(3-methyl-lH- l,2,4-triazol-l-yl)benzoic acid. ESI-MS (m/z): 328 [M+l]+.
[0643] Step 2. 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(3-methyl-lH-l,2,4-triazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile. The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-ci5,-2-(aminomethyl)-3- methylpiperidin-l-yl)(5-methyl-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanone and 6- chloronicotinonitrile. ESI-MS (m/z): 430 [M+l]+.
[0644] Example A53: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2-methylpyridin-4-yl)phenyl)methanone.
Figure imgf000312_0001
[0645] Step 1. (rac-cw-l-iAminomethy^-S-methylpiperidin-l-y^iS-methyl-l-il- methylpyridin-4-yl)phenyl)methano
Figure imgf000312_0002
The title compound was synthesized following the same general protocol as described for (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-iS-itrifluoromethy^-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(2-methylpyridin- 4-yl)benzoic acid. ESI-MS (m/z): 338 [M+l]+.
[0646] Step 2. (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5- methyl-2-(2-methylpyridin-4-yl)phenyl)methanone. The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2-methylpyridin-4- yl)phenyl)methanone. ESI-MS (m/z): 433 [M+l]+.
[0647] Example A54: (rac-ci5,-3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(3-methyl- 1H- -triazol- l-yl)phenyl)methanone.
Figure imgf000312_0003
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- methyl- lH-l,2,4-triazol-l-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 419 [M+l]+.
[0648] Example A55: (rac-ci5,-2-(((5-fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(3-methyl- 1H- -triazol- l-yl)phenyl)methanone.
Figure imgf000313_0001
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- methyl-lH- 1,2,4-triazol- l-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESTMS (m/z): 423 [M+l]+.
[0649] Example A56: (rac-ci5,-3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone.
Figure imgf000313_0002
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- (trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 473 [M+l]+.
[0650] Example A57: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone.
Figure imgf000313_0003
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-iS- (trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 477 [M+l]+.
[0651] Example A58: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000314_0001
[0652] Step 1. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin-2- yl)phenyl)methanone.
Figure imgf000314_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5'-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(pyridin-2- yl)benzoic acid. ESI-MS (m/z): 324 [M+l]+.
[0653] Step 2. (mc-c? ,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5- methyl-2-(pyridin-2-yl)phenyl)methanone. The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3- methylpiperidin-l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5- fluoropyridine. ESI-MS (m/z): 419 [M+l]+.
[0654] Example A59: (rac-ci5,-3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000315_0001
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-ipyridin- 2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 415 [M+l]+.
[0655] Example A60: 6-(((rac-ci5,-3-Methyl-l-(5-methyl-2-(pyridin-2-yl)benzoyl)piperidin- 2-yl)methyl)amino)nicotinonitrile.
Figure imgf000315_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 6- chloronicotinonitrile. ESI-MS (m/z): 426 [M+l]+.
[0656] Example A61: (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)methanone.
Figure imgf000315_0003
[0657] Step 1. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH- pyrazol-5-yl)phenyl)methanone. NH2
Figure imgf000316_0001
The title compound was synthesized following the same general protocol as described for (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-iS-itrifluoromethy^-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(l-methyl-lH- pyrazol-5-yl)benzoic acid. ESI-MS (m/z): 327 [M+l]+.
[0658] Step 2. (rac-ci5,-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5- methyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)methanone. The title compound was synthesized following the same general protocol as described in Example A44, using (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESTMS (m/z): 422 [M+l]+.
[0659] Example A62: (rac-ci5,-3-Methyl-2-(((5-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)methanone.
Figure imgf000316_0002
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-5-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 418 [M+l]+.
[0660] Example A63: 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-5- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000317_0001
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-ci5,-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+l]+.
[0661] Example A64: (rac-ci5,-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l- yl)phenyl)methanone.
Figure imgf000317_0002
The title compound was synthesized following the same general protocol as described for rac-ds-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone. ESI-MS (m/z): 533 [M+l]+.
[0662] Example A65: rac-iraw5,-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000317_0003
[0663] Step 1. l-Benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-l-ium bromide.
Figure imgf000318_0001
A solution of tert-butyl ((3-methylpyridin-2-yl)methyl)carbamate (9.2 g,41 mmol) and benzyl bromide (9.9 mL, 83 mmol) in 150 ml of acetonitrile was heated in a sealed vessel at reflux overnight and then concentrated in vacuo to give the title compound which was used without further purification. MS (ESI) 313 (M+H).
[0664] Step 2. rac-tert-Butyl ((l-benzyl-3-methyl-l,2,5,6-tetrahydropyridin-2- yl)methyl)carbamate.
Figure imgf000318_0002
To a solution of l-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-l-ium bromide (10.9 g, 35 mmol) in MeOH (500 ml) was added NaBH4 (3.95 g, 104 mmol) in three portions at 0 °C. The solution was then stirred for 3 h at rt and then concentrated in vacuo. The crude residue was taken up in EtOAc and washed with sat aq. NaHC03, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel
(EtOAc/hexanes) to give the title compound as a pale yellow oil (6.67, 61%). MS (ESI) 317 (M+H).
[0665] Step 2. rac-inms-tert-Butyl -3-methylpiperidin-2-yl)methyl)carbamate.
Figure imgf000318_0003
A mixture of rac-inms-tert-butyl ((l-benzyl-3-methyl-l,2,5,6-tetrahydropyridin-2- yl)methyl)carbamate (2.5 g) and Pd(OH)2/C (20% wt, 0.5 eq) was pressurized to 4 bar with
H2 and maintained at rt for 5 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The mixture was then precipitated using hexane to yield the title compound as a white solid (404 mg, 29%). MS (ESI) 229.2 (M+H).
[0666] Step 3. rac-iraw5,-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000319_0001
To a solution of rac-trans-tert-bv y\ ((3-methylpiperidin-2-yl)methyl)carbamate (37 mg, 162 μmol) from the previous step in DMF was added DIPEA (85 μΐ, 486 μιηοΐ) followed by 5-(4- fluorophenyl)-2-methylthiazole-4-carboxylic acid (57 mg, 243 μιηοΐ) and HATU (123 mg, 324 μιηοΐ). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give
Figure imgf000319_0002
((l-(5-(4- fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in DCM was added TFA (1: 1 v/v). The reaction was aged at rt. When analytical reverse-phase HPLC indicated disappearance of starting material, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHC03, brine, dried (MgS04), and concentrated to afford the title compound as a pale yellow oil (34 mg, 60%). MS (ESI) 348.2 (M+H).
[0667] Step 4. The title compound was prepared following the same general protocol as described for Example Al using rac-iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 416 (M+H).
[0668] Example A66: rac-iraw5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000319_0003
[0669] Step 1. rac-iraw5,-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl- lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000320_0001
The title compound was prepared following the same general protocol as described for rac- iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone in Example A65 using 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoic acid. MS (ESI) 327 (M+H).
[0670] Step 2. The title compound was prepared following the same general protocol as described for Example Al using rac-iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 472 (M+H).
[0671] Example A67: rac-iraw5,-(3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000320_0002
[0672] Step 1. rac-iraw5,-(2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000320_0003
The title compound was prepared following the same general protocol as described for rac- iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone in Example A65 using 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).
[0673] Step 2. The title compound was prepared following the same general protocol as described for Example Al using rac-iraw5,-(2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 459 (M+H). [0674] Example A68: (l-(((5-Chlorobenzo[d]oxazol-2- yl)amino)methyl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000321_0001
[0675] Step 1. Diethyl 2-acetylhexahydrocyclopenta[c]pyrrole- 1,1 (2H)-dicarboxylate.
Figure imgf000321_0002
The title compound was prepared from cyclopenten-1 -aldehyde (1 equiv.) and diethyl 2- acetamidomalonate using the procedure by Chung et al (J. Org. Chem. 1990, 55, 270). MS (ESI) 298 (M+H).
[0676] Step 2. Octahydrocyclopenta[c]pyrrole-l-carboxylic acid hydrobromide.
Figure imgf000321_0003
A solution of diethyl 2-acetylhexahydrocyclopenta[c]pyrrole-l,l(2H)-dicarboxylate prepared above in 48% aq. HBr and AcOH (4: 1) was heated at 120 °C for 16 h. The reaction mixture was cooled, concentrated in vacuo and lyophilized to yield the title compound. MS (ESI) 156 (M+H).
[0677] Step 3. 2-(tert-Butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid.
Figure imgf000321_0004
A mixture of the amino acid prepared above, NaHC03 (2 equiv.) and Boc20 (1.5 equiv.) were dissolved in water/dioxane (1: 1, 10 mL) and stirred at rt overnight. Water was added and the resulting solution was washed with EtOAc (4x). The aqueous solution was then acidified with 1 N HC1 to pH 1-2 and extracted with EtOAc (4x), dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (1:3
EtOAc/CH2Cl2) to give the title compound as a creamy white solid. MS (ESI) 256 (M+H).
[0678] Step 4. tert-Butyl ((3-tert-butyl l-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole- 2(lH)-carboxylate.
Figure imgf000322_0001
To a stirred solution of 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (1 equiv.) in THF was added BH3*SMe2 (10 M, 2 equiv.) dropwise over 5 min at 0 °C. The reaction was then allowed to stir overnight at rt and then quenched with cooled water at 0 °C. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was concentrated in vacuo to give the title compound as a clear oil. MS (ESI) 242.2 (M+H).
[0679] Step 5. (l-(Hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2- (2H- 1 ,2,3-triazol-2-yl)phenyl)meth
Figure imgf000322_0002
To a solution of the carbamate above in DCM was added TFA (1: 1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHC03, brine, dried (MgS04), and concentrated to afford (octahydrocyclopenta[c]pyrrol-l-yl)methanol as a pale yellow oil. To a solution of
(octahydrocyclopenta[c]pyrrol-l-yl)methanol (1 equiv.) from the previous step in DMF was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid (1.5 equiv.) and HATU (2 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a clear oil. MS (ESI) 326 (M+H).
[0680] Step 6. 2-((2-(5-Methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)octahydrocyclopenta[c]pyrrol-l-yl)methyl)isoindoline-l,3-dione.
Figure imgf000323_0001
To a 0 °C solution of (l-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl- 2-(2H-l,2,3-triazol-2-yl)phenyl)methanone (1 equiv.), phthalimide (2 equiv.) and PPh3 (3 equiv.) in THF (0.5M in amine) was added with DIAD (5 equiv.) dropwise. The resulting suspension was allowed to warm to rt gradually, stirred overnight, and then concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 456 (M+H).
[0681] Step 7. (l-(Aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone
Figure imgf000323_0002
A solution of 2-((2-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)octahydrocyclopenta[c]pyrrol-l-yl)methyl)isoindoline-l,3-dione (1 equiv.) and hydrazine monohydrate (4 equiv.) in MeOH (0.5M) was stirred at 70 °C for 3 h and then concentrated in vacuo to a yellow oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (20% MeOH in EtOAc) to firstly remove the impurities and then (2:8: 1 MeOH/EtOAc/TEA) to elute the title compound which was concentrated to yield a yellow oil. MS (ESI) 326 (M+H). [0682] Step 8. The title compound was prepared following the same general protocol as described for Example A2 using (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 477 (M+H).
[0683] Example A69: (5-Methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)(l-(((5-
(trifluoromethyl)pyridin-2-yl)amino)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)methanone.
Figure imgf000324_0001
The title compound was prepared following the same general protocol as described for Example Al using (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 471 (M+H).
[0684] Example A70: (l-(((5-Chlorobenzo[d]oxazol-2- yl)amino)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(l-methyl-lH-pyrazol- 4-yl)phenyl)methanone.
Figure imgf000324_0002
[0685] Step 1. (l-(Aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000324_0003
The title compound was prepared following the same general protocol as described for (1- (aminomethyl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone in Example A68 using 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoic acid. MS (ESI) 339 (M+H).
[0686] Step 2. The title compound was prepared following the same general protocol as described for Example A2 using (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone. MS (ESI) 490 (M+H).
[0687] Example A71: (5-Methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)(l-(((5-
(trifluoromethyl)pyridin-2-yl)amino)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)methanone.
Figure imgf000325_0001
The title compound was prepared following the same general protocol as described for Example Al using (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone. MS (ESI) 484 (M+H).
[0688] Example A72: (l-(((5-Chlorobenzo[d]oxazol-2- yl)amino)methyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol- 1 -yl)phenyl)methanone.
Figure imgf000325_0002
[0689] Step 1. (l-(Aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)(5-methyl-2-(3- (trifluoromethyl)- 1H- 1 ,2,4-triazol- 1 -yl)phenyl)methanone.
Figure imgf000326_0001
The title compound was prepared following the same general protocol as described for (1- (aminomethyl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone in Example A68 using 5-methyl-2-(3-(trifluoromethyl)-lH- 1,2,4- triazol-l-yl)benzoic acid. MS (ESI) 394 (M+H).
[0690] Step 2. The title compound was prepared following the same general protocol as described for Example A2 using (l-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)(5-methyl-2-(3-(trifluoromethyl)-lH-l,2,4-triazol-l-yl)phenyl)methanone. MS (ESI) 539 (M+H)
[0691] Example A73: (3-(4-Fluorophenyl)-6-methylpyridin-2-yl)(rac-ci5,-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000326_0002
[0692] Step 1. 5-Bromo-2-methylpyridine 1-oxide.
Figure imgf000326_0003
A solution of 5-bromo-2-methylpyridine (10 g, 58.13 mmol) and meta-chloroperbenzoic acid (mCPBA, 30 g, 174.39 mmol) in CHC13 (160 mL) was heated at 60 °C for 16 h. The mixture was cooled to rt and neutralized with satd. NaHC03. The resulting mixture was extracted with DCM. The organic layers were combined and washed with brine and dried (MgS04). The solvent was removed in vacuo. The crude was purified by silica gel chromatography (EtOAc/hexanes) to obtain the title compound. [0693] Step 2. 3-Bromo-6-methylpicolinonitrile.
Figure imgf000327_0001
To the solution of 5-bromo-2-methylpyridine 1-oxide (8.935 g, 47.52 mmol) in acetonitrile (240 mL) was added trimethylsilyl cyanide (TMSCN) (25 mL, 190 mmol) and triethylamine (20 mL, 142.56 mmol). The reaction was heated at 100 °C for 16 h. The mixture was cooled to rt and concentrated in vacuo. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to obtain the title compound.
[0694] Step 3. 3-(4-Fluorophenyl)-6-methylpicolinonitrile.
Figure imgf000327_0002
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using 2- (4- fluorophenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane and 3-bromo-6-methylpicolinonitrile. ESI-MS (m/z): 213 [M+l]+.
[0695] Step 4. 3-(4-Fluorophenyl)-6-methylpicolinic acid.
Figure imgf000327_0003
To the solution of 3-(4-fluorophenyl)-6-methylpicolinonitrile (0.555 g, 2.615 mmol) in MeOH (3 mL) was added NaOH (1.1 g, 27.5 mmol) and H20 (1.8 mL). The mixture was heated at 100 °C for 8 h. The reaction was cooled to rt and acidifed to pH~5. The solvent was removed in vacuo. The crude was extracted with MeOH. The solvent was removed in vacuo and the obtained acid was dried in vacuum for next step with no further purification. ESI-MS (m/z): 233 [M+l]+.
[0696] Step 5. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(3-(4-fluorophenyl)-6- methylpyridin-2- yl)methanone .
Figure imgf000328_0001
The title compound was synthesized following the same general protocol as described for (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-iS-itrifluoromethy^-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A51, starting from 3-(4-fluorophenyl)-6- methylpicolinic acid. ESI-MS (m/z): 342 [M+l]+.
[0697] Step 6. The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-(4-fluorophenyl)-6-methylpyridin-2- yl)methanone. ESI-MS (m/z): 487 [M+l]+.
[0698] Example A74: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(6-methyl-3-(l-methyl-lH-pyrazol-4-yl)pyridin-2- yl)methanone.
Figure imgf000328_0002
The title compound was synthesized following the same general protocol as in Example A73, starting with l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. ESI-MS (m/z): 473 [M+l]+.
[0699] Example A75: (3-Fluoro-2-methoxyphenyl)(rac-ci5,-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000328_0003
[0700] Step 1. (rac-cw-l-iAminomethy^-S-methylpiperidin-l-y^iS-fluoro-l- methoxyphenyl)methanone.
Figure imgf000329_0001
The title compound was prepared following the same general protocol as described for (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 3-fluoro-2-methoxybenzoic acid. MS (ESI) 281 (M+H).
[0701] Step 2. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro- 2-methoxyphenyl)methanone. MS (ESI) 426 (M+H).
[0702] Example A76: (6-(6-Chlorobenzo[d]oxazol-2-yl)octahydro-lH-pyrrolo[3,4- b]pyridin-l-yl)(5-(4-fluorophen l)-2-methylthiazol-4-yl)methanone.
Figure imgf000329_0002
[0703] Step 1. (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(octahydro-lH-pyrrolo[3,4- b] pyridin- 1 - yl)methanone .
Figure imgf000329_0003
The title compound was prepared following the same general protocol as described for rac- ((2S,3S)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4- yl)methanone in Example A65 using tert-butyl hexahydro-lH-pyrrolo[3,4-b]pyridine-6(2H)- carboxylate. MS (ESI) 346 (M+H). [0704] Step 2. The title compound was prepared following the same general protocol as described for Example A2 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(octahydro-lH- pyrrolo[3,4-b]pyridin-l-yl)methanone and 2,6-dichlorobenzoxazole. MS (ESI) 497 (M+H).
[0705] Example A77: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(6-(5- (trifluoromethyl)pyridin-2-yl)octah dro-lH-pyrrolo[3,4-b]pyridin-l-yl)methanone.
Figure imgf000330_0001
The title compound was prepared following the same general protocol as described for Example Al using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(octahydro-lH-pyrrolo[3,4- b]pyridin-l-yl)methanone. MS (ESI) 491 (M+H).
[0706] Example A78: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000330_0002
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-chloropyridine. MS (ESI) 425 (M+H).
[0707] Example A79: (rac-ci5,-3-Methyl-2-(((6-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000330_0003
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-6-methylpyridine. ESI-MS (m/z): 405 [M+l]+.
[0708] Example A80: (rac-ci5,-2-(((6-Methoxypyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methy -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000331_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-6-methoxypyridine. ESTMS (m/z): 421 [M+l]+.
[0709] Example A81: 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)picolinonitrile.
Figure imgf000331_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 6-chloropicolinonitrile. ESI-MS (m/z): 416 [M+l]+.
[0710] Example A82: (rac-ci5,-2-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000331_0003
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+l]+.
[0711] Example A83: (rac-ci5,-2-(((3-Fluoro-5-(trifluoromethyl)pyridin— 2- yl)amino)methyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone.
Figure imgf000332_0001
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using 2-bromo-3- fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 490 [M+l]+.
[0712] Example A84: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.
Figure imgf000332_0002
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 499 (M+H).
[0713] Example A85: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000333_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone. MS (ESI) 493 (M+H). 1H NMR (500 MHz, DMSO-J6) δ 8.25-6.35 (m, 8H), 4.95-2.35 (m, 8H), 1.75-0.65 (m, 8H).
[0714] Example A86: 6-(((rac-cw-3-Methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)benzoyl)piperidin-2-yl)methyl)amino)picolinonitrile.
Figure imgf000333_0002
The title compound was prepared following the same general protocol as described for Example Al using 6-chloropicolinonitrile. ESI-MS (m/z): 429 [M+l]+.
[0715] Example A87: (rac-ci5,-3-Methyl-2-(((6-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000333_0003
The title compound was synthesized following the same general protocol as described in Example A44, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-bromo-6-methylpyridine. ESI-MS (m/z): 418 [M+l]+. [0716] Example A88: (rac-cw-3-Methyl-2-(((3-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000334_0001
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-3-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+l]+.
[0717] Example A89: (rac-cw-3-Methyl-2-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000334_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+l]+.
[0718] Example A90: 2-(((rac-cw-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)
Figure imgf000334_0003
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-cis-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloronicotinonitrile. ESI-MS (m/z): 416 [M+l]+.
[0719] Example A91: (rac-ci5,-2-(((3,5-Difluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000335_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-3,5-difluoropyridine. ESI-MS (m/z): 427 [M+l]+.
[0720] Example A92: ((2S,3R)-2-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-chloro-3-fluoropyridine. ESI-MS (m/z): 443 [M+l]+.
[0721] Example A93: (rac-cw-3-Methyl-2-(((3-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000335_0003
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using 2-chloro-3- (trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+l]+.
[0722] Example A94: (rac-cw-3-Methyl-2-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000336_0001
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using 2-chloro-6- (trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+l]+.
[0723] Example A95: 2-(((rac-cw-3-Methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)benzoyl)piperidin-2-yl)methyl)
Figure imgf000336_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5- methyl-2-(l -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using 2- chloronicotinonitrile. ESI-MS (m/z): 429 [M+l]+.
[0724] Example A96: (rac-ci5,-2-(((3,5-Difluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000337_0001
The title compound was prepared following the same general protocol as described for Example A44 using (rac-cw-l-iaminomethy^-S-methylpiperidin-l-y^iS-methyl-l-il- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-bromo-3,5-difluoropyridine. ESTMS (m/z): 440 [M+l]+.
[0725] Example A97: (rac-ci5,-2-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000337_0002
The title compound was prepared following the same general protocol as described for Example A44 using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. ESTMS (m/z): 456 [M+l]+.
[0726] Example A98: (rac-ci5,-2-(((3-Methoxypyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2- -l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000337_0003
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-3-methoxypyridine. ESI-MS (m/z): 421 [M+l]+.
[0727] Example A99: (rac-ci5,-3-Methyl-2-(((3-methylpyridin-2-yl)amino)methyl)piperidin- l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000338_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-3-methylpyridine. ESI-MS (m/z): 405 [M+l]+.
[0728] Example A100: (rac-ds-3-Methyl-2-(((3-methylpyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000338_0002
The title compound was prepared following the same general protocol as described for Example A44 using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methylpyridine. ESI-MS (m/z): 418 [M+l]+.
[0729] Example A101: (rac-ci5,-2-(((3-Methoxypyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2- -methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000338_0003
The title compound was prepared following the same general protocol as described for Example A44 using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methoxypyridine. ESI-MS (m/z): 434 [M+l]+.
[0730] Example A102: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000339_0001
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone (0.032 g, 0.1 mmol), 2-chloro-5-(trifluoromethyl)- 1,3,4- thiadiazole (0.019 g, 0.1 mmol) and K2C03 (0.018 g, 0.13 mmol) in DMF was heated at 80 °C overnight. The mixture was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 466 [M+l]+.
[0731] Example A103: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000339_0002
The title compound was prepared following the same general protocol as described for Example A102 using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone. ESI-MS (m/z): 479 [M+l]+.
[0732] Example A104: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(6-methylpyridin-2-yl)phenyl)methanone.
Figure imgf000339_0003
[0733] Step 1. 2-(4-Methoxypyrimidin-2-yl)-5-methylbenzoic
Figure imgf000340_0001
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, using 2-bromo-6-methylpyridine. EST MS (m/z): 228 [M+l]+.
[0734] Step 2. tert-Butyl ((rac-cw-3-methyl-l-(5-methyl-2-(6-methylpyridin-2- yl)benzoyl)piperidin-2-yl)methyl)carbamate.
Figure imgf000340_0002
To the mixture of 5-methyl-2-(6-methylpyridin-2-yl)benzoic acid (0.229 g, 0.868mmol), tert- butyl ((rac-ci5'-3-methylpiperidin-2-yl)methyl)carbamate (0.24 g, 1.04 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was slowly added 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU; 0.278 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. aq. NaHC03 and brine and dried over Na2S04. The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESTMS (m/z): 438 [M+l]+.
[0735] Step 3. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(6- methylpyridin-2-yl)phenyl)methano
Figure imgf000340_0003
The title compound was synthesized following the same general protocol as described for (rac-ci5'-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-(trifluoromethyl)-lH- 1,2,4- triazol-l-yl)phenyl)methanone in Example A52, using 2-bromo-6-methylpyridine. ESTMS (m/z): 338 [M+l]+. [0736] Step 4. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(6-methylpyridin-2-yl)phenyl)methanon^ The title compound was synthesized following the same general protocol as described for (rac- ci5,-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)(5-methyl-2- (1 -methyl- lH-pyrazol-4-yl)phenyl)methanone in Example Al, using (rac-ci5,-2- (aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(6-methylpyridin-2- yl)phenyl)methanone. ESI-MS (m/z): 483 [M+l]+.
[0737] Example A 105: (rac-ci5,-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000341_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-chloropyridine. MS (ESI) 438 (M+H).
[0738] Example A106: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin-l-yl)( -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
[0739] Step 1. ((2S,3R)-3-Met
Figure imgf000341_0002
To a solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate (5 g) in methanol was added 10% Pd/C (0.5g). The flask was evacuated/H2 purged (3x), and then stirred under a balloon of H2 until starting material was consumed as judged by TLC analysis. The reaction was filtered through diatomaceous earth and concentrated to yield (2S,3R)- methyl 3-methylpiperidine-2-carboxylate as a white solid which was used without further purification. 1H NMR (CDC13, 400 MHz) δ 3.4 (m, 2H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 1.7 (m, 1H), 1.6-1.4 (m, 4H), 0.8 (d, 3H).
[0740] Step 2. ((2S,3R)-2-(Hydroxymethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000342_0001
((2S,3R)-3-Methylpiperidin-2-yl)methanol from the previous step in DMA (0.2M) was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid (1.2 eq) and HATU (1.1 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMAC. The crude residue was taken up in EtOAc and washed with 1M HC1, sat aq. NaHC03, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a brown oil which crystallized (2.6 g). MS (ESI) 315 (M+H).
[0741] Step 3. ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin-l-yl) (5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. To a stirred solution of ((2S,3R)-2-(hydroxymethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone in THF was added NaH (4 equiv.) at 0 °C. The reaction was allowed to warm to rt and stirred an additional 30 min. 2-Chloro-5-(trifluoromethyl)pyridine (2 equiv.) was then added and the solution was warmed to reflux for 2 h. The reaction was cooled and quenched with satd. aq. NH4C1 and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H).
[0742] Example A107: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(4-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000342_0002
[0743] Step 1. 5-Methyl-2-(4-methyl-lH-pyrazol-l-yl)benzoic acid.
Figure imgf000343_0001
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 4-methyl-lH-pyrazole. MS (ESI) 217 (M+H).
[0744] Step 2. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4-methyl-lH- pyrazol-l-yl)phenyl)methanone.
Figure imgf000343_0002
The title compound was prepared following the same general protocol as described for (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-methyl-2-(4-methyl-lH-pyrazol-l-yl)benzoic acid. MS (ESI) 327 (M+H).
[0745] Step 3. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methyl-lH-pyrazol-l-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4-methyl- lH-pyrazol-l-yl)phenyl)methanone. MS (ESI) 472 (M+H).
[0746] Example A108: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000343_0003
[0747] Step 1. 5-Methyl-2-(3-methyl-lH-pyrazol-l-yl)benzoic acid.
Figure imgf000344_0001
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 3-methyl-lH-pyrazole. MS (ESI) 217 (M+H).
[0748] Step 2. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl-lH- pyrazol-l-yl)phenyl)methanone.
Figure imgf000344_0002
The title compound was prepared following the same general protocol as described for (rac- ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-methyl-2-(3-methyl-lH-pyrazol-l-yl)benzoic acid. MS (ESI) 327 (M+H).
[0749] Step 3. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl- lH-pyrazol-l-yl)phenyl)methanone. MS (ESI) 472 (M+H).
[0750] Example A109: (5-(3-Fluorophenyl)-2-methylthiazol-4-yl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000344_0003
[0751] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-(3-fluorophenyl)-2- methylthiazol-4-yl)methanone.
Figure imgf000345_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 348 (M+H).
[0752] Step 2. (5-(3-Fluorophenyl)-2-methylthiazol-4-yl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(3-fluorophenyl)-2-methylthiazol-4- yl)methanone. MS (ESI) 493 (M+H).
[0753] Example A110: (2-(l-Ethyl-lH-pyrazol-4-yl)-5-methylphenyl)(rac-cw-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000345_0002
The title compound was prepared following the same general protocol as described for Example Al starting with l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole. ESI-MS (m/z): 486 [M+l]+.
[0754] Example Al l l: (2-(l-Isopropyl-lH-pyrazol-4-yl)-5-methylphenyl)(rac-ci5,-3-methyl- 2-(((5-(trifluoromethyl)pyridin- -yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000345_0003
The title compound was prepared following the same general protocol as described for Example Al starting with l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole. ESI-MS (m/z): 500 [M+l]+.
[0755] Example A112: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methyl-2H-l,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000346_0001
[0756] Step 1. 5-Methyl-2-(4-methyl-2H-l,2,3-triazol-2-yl)benzoic acid and 5-methyl-2-(4- methyl- 1H- 1 ,2,3-triazol- l-yl)benzoic acid.
Figure imgf000346_0002
The title compound was synthesized following the same general protocol as described in Example Al 1 using 4-methyl-2H-l,2,3-triazole. The faster eluting 5-methyl-2-(4-methyl- 2H-l,2,3-triazol-2-yl)benzoic acid was the major product and the slower eluting 5-methyl-2- (4-methyl-lH-l,2,3-triazol-l-yl)benzoic acid was the minor product. ESTMS (m/z): 218 [M+l]+.
[0757] Step 2. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4-methyl-2H- l,2,3-triazol-2-yl)phenyl)methanon
Figure imgf000346_0003
The title compound was synthesized following the same general protocol as described for (rac-ci5'-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, starting with 5-methyl-2-(4-methyl-2H-l,2,3-triazol-2- yl)benzoic acid. ESI-MS (m/z): 328 [M+l]+. [0758] Step 3. (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methyl-2H-l,2,3-triazol-2- yl)phenyl)methanone. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone. ESI-MS (m/z): 473 [M+l]+.
[0759] Example A113: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)(5-methyl-2-(4-methyl- 1H- 1 ,2,3-triazol- 1 - yl)phenyl)methanone.
Figure imgf000347_0001
[0760] Step 1. (rac-ci5,-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4-methyl-lH- l,2,3-triazol-l-yl)phenyl)methanon
Figure imgf000347_0002
The title compound was synthesized following the same general protocol as described for (rac-ci5'-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, starting 5-methyl-2-(4-methyl-lH-l,2,3-triazol-l- yl)benzoic acid. ESI-MS (m/z): 328 [M+l]+.
[0761] Step 2. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl- 2-(4-methyl-lH-l,2,3-triazol-l-yl)phenyl)methanone. ESI-MS (m/z): 473 [M+l]+.
[0762] Example A114: (rac-cw-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000348_0001
[0763] Step 1. (rac-cw-l-iHydroxymethy^-S-methylpiperidin-l-y^iS-methyl-l-il-methyl- lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000348_0002
The title compound was prepared following the same general protocol as described for (rac- ci5,-2-(hydroxymethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone in Example A106 using 5-methyl-2-(3-methyl-lH-pyrazol-l-yl)benzoic acid. MS (ESI) 328 (M+H).
[0764] Step 2. The title compound was prepared following the same general protocol as described for Example Al using (rac-ci5,-2-(hydroxymethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone. MS (ESI) 473 (M+H).
[0765] Example A115: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(3-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000348_0003
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone. ESI-MS (m/z): 478 [M+l]+.
[0766] Example A116: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000349_0001
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone. ESI-MS (m/z): 479 [M+l]+.
[0767] Example A117: ((2S,3R)-2-(((5-chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(pyridin-2-yl)phenyl)methanone.
Figure imgf000349_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin- 2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 435 [M+l]+.
[0768] Example A118: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(5-methylpyridin-2-yl)phenyl)methanone.
Figure imgf000349_0003
[0769] Step 1. 5-Methyl-2-(5-methylpyridin-2-yl)benzoic acid.
Figure imgf000349_0004
The title compound was synthesized following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, using 2-bromo-5-methylpyridine. EST MS (m/z): 228 [M+l]+.
[0770] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(5- methylpyridin-2-yl)phenyl)methano
Figure imgf000350_0001
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, starting with 5-methyl-2-(5-methylpyridin-2- yl)benzoic acid. ESI-MS (m/z): 338 [M+l]+.
[0771] Step 3. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(5-methylpyridin-2-yl)phenyl)methanone. ESI-MS (m/z): 483 [M+l]+.
[0772] Example A119: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000350_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 460 [M+l]+.
[0773] Example A120: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000351_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- methyl-lH-pyrazol-l-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 438 [M+l]+.
[0774] Example A121: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000351_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4- methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 439 [M+l]+.
[0775] Example A122: ((2S,3R)-2-(((6-Bromoquinazolin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000351_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 6-bromo-2-chloroquinazoline. ESTMS (m/z): 520, 522 [M]+ [M+2]+. [0776] Example A123: ((2S,3R)-3-Methyl-2-(((4-(trifluoromethyl)thiazol-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000352_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-(trifluoromethyl)thiazole. ESTMS (m/z): 465 [M+l]+.
[0777] Example A124: ((2S,3R)-3-Methyl-2-(((4-methylthiazol-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000352_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-methylthiazole. ESTMS (m/z): 411 [M+l]+.
[0778] Example A125: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methyl-2H-l,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000352_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4- methyl-2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 474 [M+l]+.
[0779] Example A126: ((2S,3R)-2-(((5-Methoxypyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methy -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000353_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-methoxypyridine. ESI-MS (m/z): 421 [M+l]+.
[0780] Example A127: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000353_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 416 [M+l]+.
[0781] Example A128: (rac-ci5,-2-(((5-Fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(pyridin-2-yl)phenyl)methanone.
Figure imgf000353_0003
The title compound was synthesized following the same general protocol as described for rac-ds-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. ESI-MS (m z): 459 [M+l]+.
[0782] Example A129: ((2S,3R)-2-(((5-Fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000354_0001
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. ESI-MS (m/z): 449 [M+l]+.
[0783] Example A130: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000354_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl- lH-pyrazol-l-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 473 [M+l]+.
[0784] Example A131: 2-((((2S,3R)-3-Methyl-l-(5-methyl-2-(3-methyl-lH-pyrazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)pyrimidine-5-carbonitrile.
Figure imgf000355_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl- lH-pyrazol-l-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 430 [M+l]+.
[0785] Example A132: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl -methyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000355_0002
The title compound was prepared following the same general protocol as described for Example A102, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3- methyl-lH-pyrazol-l-yl)phenyl)methanone. ESI-MS (m/z): 479 [M+l]+.
[0786] Example A133: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(3-methyl-lH-pyrazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000355_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(3-methyl- lH-pyrazol-l-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+l]+.
[0787] Example A134: 2-((((2S,3R)-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)pyrimidine-5-carbonitrile.
Figure imgf000356_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESTMS (m/z): 417 [M+l]+.
[0788] Example A135: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(4-methyl-2H-l,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000356_0002
The title compound was prepared following the same general protocol as described for Example A102, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4- methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone. ESI-MS (m/z): 480 [M+l]+.
[0789] Example A136: ((2S,3R)-2-(((5-Cyclopropylpyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000356_0003
[0790] Step 1. ((2S,3R)-2-(((5-Bromopyridin-2-yl)amino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000357_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2,5-dibromopyridine. MS (ESI) 469, 471 [M]+, [M+2]+.
[0791] Step 2. A mixture of ((2S,3R)-2-(((5-bromopyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone (0.052 g, 0.089 mmol), cyclopropylboronic acid (0.011 g, 1 mmol), Pd(Oac)2 (0.004 g, 0.018 mmol), tricyclohexylphosphine (0.01 g, 0.036 mmol) and K3PO4 (0.057 g, 0.267 mmol) in toluene (5 mL) and H20 (0.5 mL) was degassed, sealed and heated overnight at 100 °C in a microwave reactor. The reaction was filtered through a pad of diatomaceous earth, washing with EtOAc. The solvent was removed in vacuo and the crude was purified by reverse-phase preparative- HPLC to obtain the title compound. ESI-MS (m/z): 431 [M+l]+.
[0792] Example A137: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000357_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 471 [M+l]+.
[0793] Example A138: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000358_0001
[0794] Step 1. 2-(((2S,3R)-l-(2-Iodo-5-methylbenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000358_0002
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.70 g, 2.71 mmol), 2-iodo-5-methylbenzoic acid (0.64 g, 2.71 mmol), DIPEA (1.41 mL, 8.13 mmol) and HATU (1.24 g, 3.25 mmol) in DMF (4 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 503 (M+H).
[0795] Step 2. 2-(((2S,3R)-3-Methyl-l-(5-methyl-2-(pyrimidin-2-yl)benzoyl)piperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000358_0003
A mixture of 2-(((2S,3R)-l-(2-iodo-5-methylbenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.20 g, 0.40 mmol), 2-(tributylstannyl)pyrimidine (0.15 mL, 0.48 mmol), CsF (121 mg, 0.80 mmol), Cul (15 mg, 0.08 mmol) and Pd(PPh3)4 (46 mg, 0.04 mmol) in DMF (10 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a brown oil (0.11 g, 61%). MS (ESI) 455 (M+H). [0796] Step 3. ((2S,3R)-2 Aminomethyl)-3-methylpiperidin -yl)(5-methyl-2-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000359_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al. MS (ESI) 325 (M+H).
[0797] Step 4. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
[0798] Example A139: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(pyrimidin-2- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000359_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESTMS (m/z): 427 [M+l]+.
[0799] Example A140: l-(6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)pyridin-3-yl)cyclopropanecarbonitrile.
Figure imgf000359_0003
The title compound was prepared following the same general protocol as described for Example A44 using l-(6-bromopyridin-3-yl)cyclopropanecarbonitrile. ESTMS (m/z): 456 [M+l]+.
[0800] Example A141: ((2S,3R)-2-(((5-Fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000360_0001
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(4-methyl-2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5- fluorobenzo[d]oxazole. ESI-MS (m/z): 463 [M+l]+.
[0801] Example A142: ((2S,3R)-2-(((5-Fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(4-methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000360_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(4- methyl-2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-fluoroyridine. ESI-MS (m/z): 423 [M+l]+.
[0802] Example A143: ((2S,3R)-3-Methyl-2-(((5-methylpyridin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000361_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESTMS (m/z): 416 [M+l]+.
[0803] Example A144: (rac-ci5,-2-(((6-Fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(pyridin-2-yl)phenyl)methanone.
Figure imgf000361_0002
The title compound was synthesized following the same general protocol as described for rac-ds-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using (rac-ci5,-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-6-fluorobenzo[d]oxazole. ESI-MS (m/z): 459 [M+l]+.
[0804] Example A145: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)pyridazine-3-carbonitrile.
Figure imgf000361_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 6-chloropyridazine-3-carbonitrile. ESI-MS (m/z): 417 [M+l]+. [0805] Example A146: ((2S,3R)-3-Methyl-2-(((6-methylpyridazin-3- yl)amino)methyl)piperidin-l-yl) -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000362_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-methylpyridazine. ESI-MS (m/z): 406 [M+l]+.
[0806] Example A147: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000362_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 426
[M+l]+.
[0807] Example A148: 5-Fluoro-6-((((2S,3R)-3-methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000362_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 6-chloro-5-fluoronicotinonitrile. ESI-MS (m/z): 434 [M+l]+.
[0808] Example A149: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000363_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+l]+.
[0809] Example A150: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000363_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin- 2-yl)phenyl)methanone and 3-chloro-6-trifluoromethylpyridazine. ESI-MS (m/z): 470
[M+l]+.
[0810] Example A151: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl) -methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000363_0003
The title compound was prepared following the same general protocol as described for Example A102 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyridin-2-yl)phenyl)methanone. ESI-MS (m/z): 476 [M+l]+.
[0811] Example A152: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridin-2-yl)phenyl)methanone.
Figure imgf000364_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin- 2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 470 [M+l]+.
[0812] Example A153: 2-((((2S,3R)-3-Methyl-l-(5-methyl-2-(pyridin-2- yl)benzoyl)piperidin-2-yl)methyl)amino)pyrimidine-5-carbonitrile.
Figure imgf000364_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin- 2-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESTMS (m/z): 427 [M+l]+.
[0813] Example A154: ((2S,3R)-3-Methyl-2-(((6-methylpyridazin-3- yl)amino)methyl)piperidin-l-yl) -methyl-2-(lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000364_0003
[0814] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(lH-pyrazol- 1 -yl)phenyl)methanone.
Figure imgf000365_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al l using 5-methyl-2-(lH-pyrazol-l-yl)benzoic acid. MS (ESI) 313 (M+H).
[0815] Step 2. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(lH-pyrazol-l-yl)phenyl)methanone and 3-bromo-6-methylpyridazine. MS (ESI) 405 (M+H).
[0816] Example A155: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(lH-pyrazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000365_0002
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(lH- pyrazol-l-yl)phenyl)methanone and 2-bromo-5-cyanopyridine. MS (ESI) 415 (M+H).
[0817] Example A156: 6-((((2S,3R)-3-Methyl-l-(5-methyl-2-(lH-pyrazol-l- yl)benzoyl)piperidin-2-yl)methyl)amino)pyridazine-3-carbonitrile.
Figure imgf000365_0003
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(lH- pyrazol-l-yl)phenyl)methanone and 6-chloropyridazine-3-carbonitrile. MS (ESI) 416 (M+H).
[0818] Example A157: ((2S,3R)-3-mMethyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-2-(lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000366_0001
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(lH- pyrazol-l-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 459 (M+H).
[0819] Example A158: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin- 1 - yl) (5 -methyl- - (5 - (trifluoromethyl)pyridin-2- yl)phenyl)methanone .
Figure imgf000366_0002
[0820] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(5- (trifluoromethyl)pyridin-2-yl)phen
Figure imgf000366_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-methyl-2-(5-(trifluoromethyl)pyridin-2- yl)benzoic acid. MS (ESI) 392 (M+H).
[0821] Step 2. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 503 (M+H).
[0822] Example A159: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(2-(5-fluoropyridin-2-yl)-5-methylphenyl)methanone.
Figure imgf000367_0001
[0823] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-(5-fluoropyridin-2-yl)- 5 -methylphenyl)methanone .
Figure imgf000367_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(5-fluoropyridin-2-yl)-5-methylbenzoic acid. MS (ESI) 342 (M+H).
[0824] Step 2. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-(5- fluoropyridin-2-yl)-5-methylphenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 453 (M+H).
[0825] Example A160: (5-Chloro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000368_0001
[0826] Step l. 5-Chloro-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000368_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 2-bromo-5- chlorobenzoic acid. MS (ESI) 224 (M+H).
[0827] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000368_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-chloro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 334 (M+H).
[0828] Step 3. The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- chloro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5- (trifluoromethyl)pyrimidine. MS (ESI) 480 (M+H).
[0829] Example A161: (5-Chloro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)- chloropyridin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000369_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 445 (M+H).
[0830] Example A162: (5-Chloro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000369_0002
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 480 (M+H).
[0831] Example A163: ((2S,3R)-3-Methyl-2-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000369_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+l]+. [0832] Example A164: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-3-(lH-pyrazol-l-yl)pyridin-2-yl)methanone.
Figure imgf000370_0001
[0833] Step 1. 6-Methyl-3-(lH-pyrazo -l-yl)picolinonitrile.
Figure imgf000370_0002
A mixture of 3-bromo-6-methylpicolinonitrile (1 g, 5.1 mmol), lH-pyrazole (0.52 ml, 7.61 mmol), (lS,2S)-Nl,N2-dimethylcyclohexane-l,2-diamine (0.97 ml, 6.09 mmol), Cs2C03 (2.48 g, 7.61 mmol) and Cul (97 mg, 0.51 mmol) in DMF (10 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a yellow oil (600 mg, 64%). MS (ESI) 185 (M+H).
[0834] Step 2. 6-Methyl-3-(lH-pyrazol-l-yl)picolinic acid.
Figure imgf000370_0003
6-Methyl-3-(lH-pyrazol-l-yl)picolinonitrile (0.60 g, 3.26 mmol) and NaOH (1.37 g, 34.2 mmol) were dissolved in methanol (3 mL) and stirred at reflux overnight. The reaction was cooled to rt, diluted with more methanol (5 mL), and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a clear oil (0.62 g, 94%). MS (ESI) 204 (M+H).
[0835] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(lH-pyrazol- l-yl)pyridin-2-yl)methanone. NH2
Figure imgf000371_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 6-methyl-3-(lH-pyrazol-l-yl)picolinic acid. MS (ESI) 314 (M+H).
[0836] Step 4. The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6- methyl-3-(lH-pyrazol-l-yl)pyridin-2-yl)methanone and 3-chloro-6- (trifluoromethyl)pyridazine. MS (ESI) 460 (M+H).
[0837] Example A165: ((2S,3R)-3-methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin- 1 -y ' -methyl- [2,3 ' -bipyridin] -2' -yl)methanone.
[0838] Step 1. 6'-Methyl-[2,3'
Figure imgf000371_0002
A mixture of 3-bromo-6-methylpicolinonitrile (1 g, 5.1 mmol), 2-(tributylstannyl)pyridine (2.43 ml, 6.60 mmol), cesium fluoride (150 mg, 10.2 mmol), Cul (193 mg, 1.02 mmol) and Pd(PPh3)4 (586 mg, 0.51 mmol) in DMF (10 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a brown oil (0.87g, 88%). MS (ESI) 196 (M+H).
[0839] Step 2. 6'-Methyl-[2,3'-bipyridine]-2'-carboxylic acid.
Figure imgf000372_0001
6'-Methyl-[2,3'-bipyridine]-2'-carbonitrile (0.87 g, 4.46 mmol) and NaOH (1.87 g, 46.8 mmol) were dissolved in methanol (3 mL) and stirred at reflux overnight. The reaction was cooled to rt, diluted with more methanol (5 ml), and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a clear oil (0.9 g, 94%).
[0840] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(6'-methyl-[2,3'- bipyridin] -2' -yl)methanone.
Figure imgf000372_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid. MS (ESI) 325 (M+H).
[0841] Step 4. The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6'- methyl-[2,3'-bipyridin]-2'-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 471 (M+H).
[0842] Example A166: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(lH-pyrazol-l-yl)pyridin-2-yl)methanone.
Figure imgf000372_0003
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(lH- pyrazol-l-yl)pyridin-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460 (M+H).
[0843] Example A167: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -y ' -methyl- [2,3 ' -bipyridin] -2' -yl)methanone.
Figure imgf000373_0001
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l- methyl-lH-pyrazol-4-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 471 (M+H).
[0844] Example A168: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- -(lH-pyrazol-l-yl)pyridin-2-yl)methanone.
Figure imgf000373_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(lH- pyrazol-l-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 425 (M+H).
[0845] Example A169: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)(6' -methyl- [2,3 ' -bipyridin] -2' -yl)methanone.
Figure imgf000374_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
[0846] Example A170: ((2S,3R)-2-(((5-Fluoropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(lH-pyrazol-l-yl)phenyl)methanone.
Figure imgf000374_0002
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(lH-pyrazol-l- yl)phenyl)methanone (30 mg, 96 μιηοΐ), 2-chloro-5-fluoropyrimidine (18 μΐ, 144 μιηοΐ) and anhydrous DIPEA (50 μg, 288 μπιοΐ) in CH3CN (2 inL) was heated at 100 °C for 3 days. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. aq. NaHC03,brine, and dried (MgS04). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 409 (M+H).
[0847] Example A171: ((2S,3R)-2-(((5-Fluoropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000374_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- -yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESI-MS (m/z): 410, 471
[0848] Example A172: ((2S,3R)-2-(((3,5-Difluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000375_0001
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-3,5-difluoropyridine. ESI-MS (m/z): 427 [M+l]+.
[0849] Example A173: ((2S,3R)-2-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000375_0002
The title compound was prepared following the same general protocol as described for Example A44 using 2-bromo-5-chloro-3-fluoropyridine. ESI-MS (m/z): 443 [M+l]+.
[0850] Example A174: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000375_0003
[0851] Step 1. 6-Methyl-3-(2H-l,2,3-triazol-2-yl)picolinic acid.
Figure imgf000375_0004
The title compound was prepared following the same general protocol as described for 6- methyl-3-(lH-pyrazol-l-yl)picolinic acid in Example A164, using 2H-l,2,3-triazole. ESI- MS (m/z): 205 [M+l]+.
[0852] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H-l,2,3- triazol-2-yl)pyridin-2-yl)methanone
Figure imgf000376_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, using 6-methyl-3-(2H-l,2,3-triazol-2-yl)picolinic acid. ESI-MS (m/z): 315 [M+l]+.
[0853] Step 3. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-fluoro-5- trifluoromethylpyridine. ESI-MS (m/z): 460 [M+l]+.
[0854] Example A175: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000376_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloro-5-trifluoromethylpyrimidine. ESI- MS (m/z): 461 [M+l]+.
[0855] Example A176: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-yl)(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000377_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI- MS (m/z): 461 [M+l]+.
[0856] Example A177: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- -(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000377_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 427 [M+l]+.
[0857] Example A178: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- -(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000377_0003
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 426 [M+l]+. [0858] Example A179: ((2S,3R)-2-(((5-Fluoropyrimidin-2-yl)amino
methylpiperidin-l-yl)(5-methyl- -(pyridin-2-yl)phenyl)methanone.
Figure imgf000378_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridin- 2-yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESTMS (m/z): 420 [M+l]+.
[0859] Example A180: ((2S,3R)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000378_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-((benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. MS (ESI) 431 (M+H).
[0860] Example A181: ((2S,3R)-2-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000378_0003
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. MS (ESI) 454 (M+H). [0861] Example A182: ((2S,3R)-2-(((3,5-Difluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-methyl- -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000379_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-3,5-difluoropyridine. MS (ESI) 438 (M+H).
[0862] Example A183: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000379_0002
[0863] Step 1. 2-(((2S,3R)-l-(3-Bromo-6-methylpicolinoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000379_0003
The title compound was prepared following the same general protocol as described for 2- (((2S,3R)-3-methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoyl)piperidin-2- yl)methyl)isoindoline-l,3-dione in Example Al, using 3-bromo-6-methylpicolinic acid. EST MS (m/z): 456, 458 [M]+ [M+2]+.
[0864] Step 2. 2 ((2S,3R)-3-Methyl-l-(6-methyl-3-(pyrimidin-2-yl)picolinoyl)piperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000380_0001
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-l-(3-bromo-6- methylpicolinoyl)-3-methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2- (tributylstannyl)pyrimidine. ESI-MS (m/z): 456,[M+1]+.
[0865] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(pyrimidin-2- yl)pyridin-2-yl)methanone.
Figure imgf000380_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, using 2-(((2S,3R)-3-methyl-l-(6-methyl-3-(pyrimidin- 2-yl)picolinoyl)piperidin-2-yl)methyl)isoindoline-l,3-dione. ESI-MS (m/z): 326 [M+l]+.
[0866] Step 4. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 471 [M+l]+.
[0867] Example A184: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000380_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone and 2-chloro-5-trifluoromethylpyrimidine. ESI-MS (m/z): 472 [M+l]+.
[0868] Example A185: ((2S,3R)-3-Methyl-2-(((6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)piperidin-l-y -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000381_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI- MS (m/z): 472 [M+l]+.
[0869] Example A186: ((2S,3R)-2-(((5-chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- -(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000381_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 437
[M+l]+.
[0870] Example A187: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000382_0001
The title compound was prepared following the same general protocol as described for Example A102 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone. ESI-MS (m/z): 478 [M+l]+.
[0871] Example A188: ((2S,3R)-2-(((3-Fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2- yl)methanone.
Figure imgf000382_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 478 [M+l]+.
[0872] Example A189: 6-((((2S,3R)-3-Methyl-l-(6-methyl-3-(2H-l,2,3-triazol-2- yl)picolinoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000382_0003
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 417 [M+l]+. [0873] Example A190: 2-((((2S,3R)-3-Methyl-l-(6-methyl-3-(2H-l,2,3-triazol-2- yl)picolinoyl)piperidin-2-yl)methyl)amino)pyrimidine-5-carbonitrile.
Figure imgf000383_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 418 [M+l]+.
[0874] Example A191: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)amino)methyl)piperidin-l-yl -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000383_0002
The title compound was prepared following the same general protocol as described for Example A102 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone. ESI-MS (m/z): 467 [M+l]+.
[0875] Example A192: ((2S,3R)-2-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- -(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000383_0003
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-chloropyridine. ESI-MS (m/z): 444 [M+l]+. [0876] Example A193: 5-Fluoro-6-((((2S,3R)-3-methyl-l-(6-methyl-3-(2H-l,2,3-triazol-2- yl)picolinoyl)piperidin-2-yl)methyl)amino)nicotinonitrile.
Figure imgf000384_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloro-5-fluoronicotinonitrile. ESI-MS (m/z): 435 [M+l]+.
[0877] Example A194: ((2S,3R)-3-Methyl-2-((methyl(5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000384_0002
To a solution of ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone (0.0215 g, 0.047 mmol) in DMF (0.5 mL) at rt was added NaH (60%, 0.006 g, 0.141 mmol). The mixture was stirred at rt for 1 h, then Mel (0.013 g, 0.094 mmol) was added. The reaction was stirred at rt for another 1 h. The crude was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 474 [M+l]+.
[0878] Example A195: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methy -3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000384_0003
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-l- carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone. ESI-MS (m/z): 466 [M+l]+.
[0879] Example A196: ((2S,3R)-3-Methyl-2-(((5-methylpyridin-2- yl)amino)methyl)piperidin-l-yl) -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000385_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-methylpyridine. ESTMS (m/z): 406 [M+l]+.
[0880] Example A197: ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyridazin-3-yl)phenyl)methanone.
Figure imgf000385_0002
[0881] Step 1. 5-Methyl-2-(pyridazin-3-yl)benzoic acid.
Figure imgf000385_0003
The title compound was prepared following the same general protocol as described for 5- methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting with 3-bromopyridazine. ESI- MS (m/z): 215 [M+l]+.
[0882] Step 2. 2-(((2S,3R)-3-Methyl-l-(5-methyl-2-(pyridazin-3-yl)benzoyl)piperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000386_0001
To a mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (1.09 g, 4.20 mmol), 5-methyl-2-(pyridazin-3-yl)benzoic acid (0.75 g, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20 mL) was added propylphosphonic anhydride (T3P) (50% in EtOAc, 4.2 mL, 7.0 mmol). The mixture was heated at 40 °C for 16 h. The mixture was cooled to rt and diluted with DCM. The mixture was washed with satd. aq. NaHC03, brine, and dried (MgS04). The solvent was removed in vacuo. The crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 455 [M+l]+.
[0883] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(pyridazin-3- yl)phenyl)methanone.
Figure imgf000386_0002
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, using 2-(((2S,3R)-3-methyl-l-(5-methyl-2-(pyridazin- 3-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-l,3-dione. ESI-MS (m/z): 325 [M+l]+.
[0884] Step 4. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- methyl-2-(pyridazin-3-yl)phenyl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI- MS (m/z): 470 [M+l]+.
[0885] Example A198: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(pyridazin-3-yl)phenyl)methanone.
Figure imgf000387_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyridazin-3-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 471 [M+l]+.
[0886] Example A199: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)(6' -methyl- ' -bipyridin] -2' -yl)methanone.
Figure imgf000387_0002
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 476 (M+H).
[0887] Example A200: (5-Chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000387_0003
[0888] Step 1. 2-(((2S,3R)-l-(5-Chloro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000388_0001
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.70 g, 2.71 mmol), 5-chloro-2-iodobenzoic acid (0.66 g, 2.32 mmol), DIPEA (1.21 mL, 6.97 mmol) and HATU (1.06g, 2.79 mmol) in DMF (5 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtO Ac/hex) to afford the title compound. MS (ESI) 523 (M+H).
[0889] Step 2. 2-(((2S,3R)-l-(5-Chloro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dion
Figure imgf000388_0002
A mixture of 2-(((2S,3R)-l-(5-chloro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.22g, 0.42 mmol), 2-(tributylstannyl)pyrimidine (0.16 ml, 0.51mmol), CsF (128 mg, 0.84 mmol), Cul (16 mg, 0.08 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in DMF (5 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a white solid (0.134g, 67%). MS (ESI) 475 (M+H).
[0890] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000388_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(((2S,3R)-l-(5-chloro-2-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 345 (M+H).
[0891] Step 4. The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- chloro-2-(pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 491 (M+H).
[0892] Example A201: (5-Chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000389_0001
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 491 (M+H).
[0893] Example A202: (5-Chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-(((5- chloropyrimidin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000389_0002
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2- (pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 457 (M+H). [0894] Example A203: (5-Chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-(((5-chloropyridin-2- yl)amino)methyl)-3-methylpip
Figure imgf000390_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-chloro-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 456 (M+H).
[0895] Example A204: ((2S,3R)-2-((Benzo[d]oxazol-2-ylamino)methyl)-3-methylpiperidin- l-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000390_0002
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-chlorobenzoxazole. MS (ESI) 442 (M+H).
[0896] Example A205: ((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-meth -2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000390_0003
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2,6-dichlorobenzoxazole. MS (ESI) 476 (M+H). [0897] Example A206: ((2S,3R)-2-(((5-Fluorobenzo[d]oxazol-2-yl)amino
methylpiperidin-l-yl)(5-meth -2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000391_0001
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. MS (ESI) 460 (M+H).
[0898] Example A207: (5-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000391_0002
[0899] Step l. 5-Fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000391_0003
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 2-bromo-5- fluorobenzoic acid. MS (ESI) 208 (M+H).
[0900] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000391_0004
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
[0901] Step 3. The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5- (trifluoromethyl)pyrimidine. MS (ESI) 464 (M+H).
[0902] Example A208: (5-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000392_0001
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 464 (M+H).
[0903] Example A209: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-fluoro- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000392_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 429 (M+H).
[0904] Example A210: (S)-(2-(((5-Chloropyridin-2-yl)amino)methyl)-4,4-difluoropiperidin- l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000393_0001
[0905] Step 1. Methyl 4-hydroxy-l-((S)-l-phenylethyl)piperidine-2-carboxylate.
Figure imgf000393_0002
The title compound was prepared from (R)-(+)-a-methylbenzylamine, 4-bromo-l-butene, and Et3N in CH3CN using a procedure by Skiles et al. (Bioorg. Med. Chem. Lett. 1996, 6(8), 963). MS (ESI) 264 (M+H).
[0906] Step 2. Methyl 4-oxo-l-((S)-l-phenylethyl)piperidine-2-carboxylate.
Figure imgf000393_0003
Methyl 4-hydroxy-l-((S)-l-phenylethyl)piperidine-2-carboxylate (3.4 g, 12.9 mmol), N- methylmorpholine N-oxide (3.0 g, 25.82 mmol) and 4 A molecular sieves were stirred together in 15 mL of DCM at rt under argon. Tetra-n-propylammonium perruthenate (454 mg, 1.29 mmol) was then added slowly and reaction stirred for 5 h. The reaction was then filtered through silica and washed with 10% methanol in DCM and concentrated to give the title compound as a clear oil (3.34g, 99%). MS (ESI) 262 (M+H).
[0907] Step 3. Methyl 4,4-difluoro-l-((S -l-phenylethyl)piperidine-2-carboxylate.
Figure imgf000393_0004
Methyl 4-oxo-l-((S)-l-phenylethyl)piperidine-2-carboxylate (3.0 g, 11.5mmol) was dissolved in 10 mL DCM and cooled to 0 °C. Bis(2-methoxyethyl)aminosulfur trifluoride (4.23 mL, 23.0 mmol) was then added slowly and reaction stirred at rt for 2 days. The reaction mixture was cooled to 0 °C and quenched with 20 mL of satd. aq. NaHC03. The resulting suspension was diluted with more DCM and washed with water, brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica g (EtOAc/hex) to give the title compound (1.15g, 35%). MS (ESI) 284 (M+H).
[0908] Step 4. (4,4-Difluoro-l-((S)-l-phen lethyl)piperidin-2-yl)methanol.
Figure imgf000394_0001
To a suspension of LiAlH4 (4 equiv.) in THF (40 ml) was added in portions the product from the previous step (1.15g) in THF at 0 °C. The reaction was allowed to stir at rt overnight and then at reflux for 2 h. The reaction mixture was then quenched with satd. aq. Na2S04 at 0 °C and stirred for 1 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a clear oil (750 mg, 76%). MS (ESI) 256 (M+H).
[0909] Step 5. 2-((4,4-Difluoro-l-((S)-l-phenylethyl)piperidin-2-yl)methyl)isoindoline-l,3- dione.
Figure imgf000394_0002
The title compound was prepared following the same general protocol as described for (2S,3R)-benzyl 2-((l,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-l-carboxylate in Example Al using (4,4-difluoro-l-((S)-l-phenylethyl)piperidin-2-yl)methanol (1.1 g, 97%). MS (ESI) 285 (M+H).
[0910] Step 6. 2-((4,4-Difluoropiperidin-2- l)methyl)isoindoline-l,3-dione.
Figure imgf000394_0003
To a solution of 2-((4,4-difluoro-l-((S)-l-phenylethyl)piperidin-2-yl)methyl)isoindoline-l,3- dione (1.1 g, 2.86 mmol) in acetic acid (10 mL) was added 10% Pd/C (200 mg). The reaction was then stirred under H2 until HPLC indicated complete removal of the phenethyl group. The reaction was the filtered through diatomaceous earth and concentrated. The crude residue was then dissolved in EtOAc and washed with saturated NaHC03, brine, dried (MgS04), and concentrated to yield the title compound as an orange oil (720 mg, 90%).
[0911] Step 7. (2-(Aminomethyl)-4,4-difluoropiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol- 2-yl)phenyl)methanone.
Figure imgf000395_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid and 2-((4,4-difluoropiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 336 (M+H).
[0912] Step 8. The title compound was prepared following the same general protocol as described for Example A44 using (2-(aminomethyl)-4,4-difluoropiperidin-l-yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 447 (M+H).
[0913] Example A211: (S)-(4,4-Difluoro-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000395_0002
The title compound was prepared following the same general protocol as described for Example A45 using (2-(aminomethyl)-4,4-difluoropiperidin-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 482 (M+H).
[0914] Example A212: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000396_0001
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 471 (M+H). 1H NMR (500 MHz, CD3OD) δ 8.90-6.60 (m, 8H), 5.15-3.00 (m, 5H), 2.45- 0.65 (m, 11H).
[0915] Example A213: ((2S,3R)-2-(((2,5-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone.
Figure imgf000396_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 7-chloro-2,5-dimethyl-[ 1 ,2,4]triazolo[ 1 ,5-a]pyrimidine. ESI-MS (m/z): 460 [M+l]+.
[0916] Example A214: ((2S,3R)-3-Methyl-2-(((5-methylquinazolin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000397_0001
[0917] Step 1. ((2S,3R)-2-(((5-Bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000397_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 5-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+, [M+2]+.
[0918] Step 2. The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5-methyl-2- (2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2,4,6-trimethyl- 1 ,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+l]+.
[0919] Example A215: ((2S,3R)-3-Methyl-2-(((7-methylquinazolin-2- yl)amino)methyl)piperidin-l- -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000397_0003
[0920] Step 1. ((2S,3R)-2-(((7-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000398_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 7-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+, [M+2]+.
[0921] Step 2. The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using ((2S,3R)-2-(((7-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5-methyl-2- (2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2,4,6-trimethyl- 1 ,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+l]+.
[0922] Example A216: ((2S,3R)-3-Methyl-2-((quinazolin-2-ylamino)methyl)piperidin-l- yl)(5-methyl-2-(2H-l,2,3-triaz -2-yl)phenyl)methanone.
Figure imgf000398_0002
A mixture of ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l- yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone ( 0.057 g, 0.111 mmol), HCOONH4 (0.14 g, 0.222 mmol) and Pd(PPh3)4 (0.026g, 0.022 mmol) in dioxane and water (4: 1, 2 mL) was heated for 2 h at 100 °C. The mixture was cooled to rt and filtered through diatomaceous earth. The solvent was removed and the crude residue was purified via silica gel
chromatography to obtain the title compound. ESI-MS (m/z): 442 [M+l]+.
[0923] Example A217: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)(6' -methyl- [2,3 ' -bipyridin] -2' -yl)methanone.
Figure imgf000399_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone. MS (ESI) 470 (M+H).
[0924] Example A218: (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperi
Figure imgf000399_0002
[0925] Step 1. 2-(2H-l,2,3-Triazol-2-yl)benzoic acid.
Figure imgf000399_0003
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 2-bromobenzoic acid. MS (ESI) 190 (M+H).
[0926] Step 2. (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3- methylpiperidin- 1 -yl)methanone.
Figure imgf000399_0004
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 300 (M+H).
[0927] Step 3. The title compound was prepared following the same general protocol as described for Example A2 using (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)- 3-methylpiperidin-l-yl)methanone. MS (ESI) 417 (M+H).
[0928] Example A219: (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2S,3R)-2-(((5- chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000400_0001
The title compound was prepared following the same general protocol as described for Example A2 using (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 451 (M+H).
[0929] Example A220: ((2S,3R)-3-Methyl-2-(((6-methylquinazolin-2- yl)amino)methyl)piperidin-l- -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000400_0002
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoate in Example Al, using ((2S,3R)-2- (((6-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l-yl)(5-methyl-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone (synthesized in Example A122) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+l]+.
[0930] Example A221: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000401_0001
The title compound was prepared following the same general protocol as described for Example A207 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyridine. MS (ESI) 430 (M+H).
[0931] Example A222: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- '-bipyridin]-2-yl)methanone.
Figure imgf000401_0002
[0932] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-[3,3'- bipyridin] -2-yl)methanone.
Figure imgf000401_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-(4-fluorophenyl)-6-methylpyridin-2- yl)methanone in Example A73 using pyridin-3-ylboronic acid. ESI-MS (m/z): 325 [M+l]+.
[0933] Step 2. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6- methyl-[3,3'-bipyridin]-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 437 [M+l]+.
[0934] Example A223: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(6-methyl-[3,3'-bipyridin]-2-yl)methanone.
Figure imgf000402_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-[3,3'- bipyridin]-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+l]+.
[0935] Example A224: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(6-methyl- '-bipyridin]-2-yl)methanone.
Figure imgf000402_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-methyl-[3,3'- bipyridin]-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 436 [M+l]+.
[0936] Example A225: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(isoquinoli -l-yl)methanone.
Figure imgf000402_0003
[0937] Step 1. 2-(((2S,3R)-l-(Isoquinoline-l-carbonyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000403_0001
The title compound was prepared following the same general protocol as described for 2- (((2S,3R)-3-methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoyl)piperidin-2- yl)methyl)isoindoline-l,3-dione in Example Al, using isoquinoline-l-carboxylic acid. EST MS (m/z): 414 [M+l]+.
[0938] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(isoquinolin-l- yl)methanone.
Figure imgf000403_0002
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, using 2-(((2S,3R)-l-(isoquinoline-l-carbonyl)-3- methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. ESI-MS (m/z): 284 [M+l]+.
[0939] Step 3. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l- yl)(isoquinolin-l-yl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 396 [M+l]+.
[0940] Example A226: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-fluoro- -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000403_0003
[0941] Step 1. 2-(((2S,3R)-l-(2-Bromo-5-fluorobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000404_0001
The title compound was prepared following the same general protocol as described for 2- (((2S,3R)-3-methyl-l-(5-methyl-2-(l-methyl-lH-pyrazol-4-yl)benzoyl)piperidin-2- yl)methyl)isoindoline-l,3-dione in Example Al, using 2-bromo-5-fluorobenzoic acid. ESI- MS (m/z): 459, 461 [M]+ [M+2]+.
[0942] Step 2. 2-(((2S,3R)-l-(5-Fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000404_0002
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-l-(2-bromo-5- fluorobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2- (tributylstannyl)pyrimidine. ESI-MS (m/z): 445 [M+l]+.
[0943] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000404_0003
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al, using 2-(((2S,3R)-l-(5-fluoro-2-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. ESTMS (m/z): 329
[M+l]+.
[0944] Step 4. The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5- fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+l]+.
[0945] Example A227: (5-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000405_0001
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 475 [M+l]+.
[0946] Example A228: (5-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000405_0002
The title compound was prepared following the same general protocol as described for Example Al, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 474 [M+l]+.
[0947] Alternative Synthesis:
[0948] Step 228a: 2-(((25,3R)-l-(5-Fluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000405_0003
To a stirred solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (440 mg, 1.70 mmol), 5-fluoro-2-iodobenzoic acid (543 mg, 2.04 mmol), and DIPEA (438 mg, 3.40 mmol) in anhydrous DMA (10 mL) was added HATU (971 mg, 2.55 mmol) at rt under nitrogen and the reaction stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (0% to 70% EtOAc/hexanes) to afford the title compound as a yellow oil (537 mg, 62%). ESI MS (M+H) 507.
[0949] Step 228b. 2-(((25,3R)-l-(5-fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000406_0001
A suspension of the product of Step 228a (537 mg, 1.05 mmol), CsF (322 mg, 2.13 mmol), and Cul (40 mg, 0.210 mmol) in anhydrous DMF (5 mL) was flushed with argon gas for 10 min, then 2-(tributylstannyl)pyrimidine (582 mg, 1.58 mmol) and Pd(PPh3)4 (122 mg, 0.105 mmol) were added at rt. The reaction mixture was then heated to 105 °C under nitrogen for 16 h. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and filtered through a short pad of diatomaceous earth. The filter cake was rinsed with EtOAc (50 mL) and water (50 mL). The layers of the combined filtrate were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with 10% aq. LiCl (3 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a yellow foam (274 mg, 56%): ESI MS (M+H) 459.
[0950] Step 228c. ((25,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2- (pyrimidin-2-yl)phenyl)methanone. NH2
Figure imgf000407_0001
A stirred solution of the product of Step 228b (274 mg, 0.590 mmol) and ΝΗ2ΝΗ2·Η20 (114 mg, 2.27 mmol) in MeOH (10 mL) was heated to reflux for 2.5 h. After this time, the reaction mixture was cooled to rt then concentrated under reduced pressure. The resulting residue was triturated with a mixture of CH2Cl2/hexanes (1: 1) and the solid was filtered off. The filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound as a white foam (182 mg, 93%). ESI MS (M+H) 329.
[0951] Step 228d. (5-Fluoro-2-(pyrimidin-2-yl)phenyl)((25,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000407_0002
A suspension of the product of Step 228c (181 mg, 0.550 mmol), 2-fluoro-5- (trifluoromethyl)pyridine (108 mg, 0.655 mmol), and K2C03 (152 mg, 1.10 mmol) in anhydrous DMF (4 mL) was heated at 100 °C under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3 x 50 mL), dried over Na2SC"4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) then lyophilized from acetonitrile/water (2: 1) to afford the title compound as a white solid (220 mg, 84%). 1H NMR (500 MHz, CDC13) δ 8.95-6.05 (m, 10H), 5.25-2.85 (m, 5H), 2.15-0.75 (m, 8H); ESI MS (M+H) 474.
[0952] Example A229: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000408_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 440 [M+l]+.
[0953] Example A230: (3-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000408_0002
[0954] Step 1. 2-(((2S,3R)-l-(3-Fluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000408_0003
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.4 g, 1.55 mmol), 3-fluoro-2-iodobenzoic acid (0.37 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtO Ac/hex) to afford the title compound. MS (ESI) 507 (M+H).
[0955] Step 2. 2-(((2S,3R)-l-(3-Fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000409_0001
A mixture of 2-(((2S,3R)-l-(3-fluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.493 g, 0.974 mmol), 2-(tributylstannyl)pyrimidine (0.4 g, 1.07 mmol), CsF (0.3 g, 1.948 mmol), Cul (0.0185 g, 0.098 mmol) and Pd(PPh3)4 (0.112 g, 0.098 mmol) in DMF (5 mL) was degassed and heated at 100 °C oil bath for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel
chromatography (0-100% EtOAc/hexanes) to yield the title compound as a white solid (0.331 g, 75%). MS (ESI) 459 (M+H).
[0956] Step 3. ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000409_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(((2S,3R)-l-(3-fluoro-2-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 329 (M+H).
[0957] Step 4. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro- 2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 9.05-6.65 (m, 9H), 4.80-2.75 (m, 5H), 1.70-0.65 (m, 8H).
[0958] Example A231: (3-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- chloropyrimidin-2-yl)amino)methyl)piperidin- 1 -yl)methanone.
Figure imgf000410_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 441 [M+l]+.
[0959] Example A232: ((2S,3R)-2-(((5-chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000410_0002
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 440
[M+l]+.
[0960] Example A233: (3-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000410_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 474
[M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 9.00-6.55 (m, 10H), 4.75-2.75 (m, 5H), 1.75- 0.65 (m, 8H). [0961] Example A234: (4-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000411_0001
[0962] Step 1. 2-(((2S,3R)-l-(4-Fluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000411_0002
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.4 g, 1.549 mmol), 4-fluoro-2-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtO Ac/hex) to afford the title compound. MS (ESI) 507 (M+H).
[0963] Step 2. 2-(((2S,3R)-l-(4-Fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000411_0003
A mixture of 2-(((2S,3R)-l-(4-fluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.51 g, 1.0 mmol), 2-(tributylstannyl)pyrimidine (0.406 g, 1.1 mmol), CsF (0.304 g, 2.0 mmol), Cul (0.019 g, 0.1 mmol) and Pd(PPh3)4 (0.116 g, 0.1 mmol) in DMF (5 mL) was degassed and heated at 100 °C for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a white solid (0.370 g, 81%). MS (ESI) 459 (M+H).
[0964] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000412_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(((2S,3R)-l-(4-fluoro-2-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 329 (M+H).
[0965] Step 4. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro- 2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 474 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 9.00-6.55 (m, 10H), 4.90-2.80 (m, 5H), 1.95-0.65 (m, 8H).
[0966] Example A235: (4-Fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000412_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 475
[M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 9.00-6.70 (m, 9H), 4.95-2.75 (m, 5H), 2.00-0.65
(m, 8H). [0967] Example A236: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4-fluoro- -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000413_0001
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 441 [M+l]+.
[0968] Example A237: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4-fluoro- -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000413_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 440 [M+l]+.
[0969] Example A239: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000413_0003
[0970] Step 1. 2-(((2S,3R)-l-(2-Fluoro-6-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000414_0001
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.4 g, 1.549 mmol), 2-fluoro-6-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtO Ac/hex) to afford the title compound. MS (ESI) 507 (M+H).
[0971] Step 2. 2-(((2S,3R)-l-(2-Fluoro-6-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000414_0002
A mixture of 2-(((2S,3R)-l-(2-fluoro-6-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.6 g, 1.185 mmol), 2-(tributylstannyl)pyrimidine (0.437 g, 1.185 mmol), CsF (0.36 g, 2.37 mmol), Cul (0.023g, 0.119 mmol) and Pd(PPh3)4 (0.14 g, 0.119 mmol) in DMF (5 mL) was degassed and heated at 100 °C for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a white solid. MS (ESI) 459 (M+H).
[0972] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(pyrimidin-2- yl)phenyl)methanone.
Figure imgf000414_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(((2S,3R)-l-(2-fluoro-6-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 329 (M+H).
[0973] Step 4. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-fluoro- 2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 441
[M+l]+.
[0974] Example A240: (2-Fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000415_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 475 [M+l]+.
[0975] Alternative Synthesis:
[0976] Step 240a. 2-(((2lS',3R)-l-(2-Fluoro-6-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000415_0002
A solution of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (366 mg, 1.67 mmol), 2-chloro-4,6- dimethoxy-l,3,5-triazine (292 mg, 1.67 mmol), and N-methylmorpholine (421 mg, 4.18 mmol) in anhydrous 1,4-dioxane (10 mL) was stirred at rt under nitrogen for 1.5 h. A solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (359 mg, 1.39 mmol) in anhydrous 1,4-dioxane (3 mL) was added at rt. After the addition was completed, the reaction was heated to 80 °C under nitrogen for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), subsequently washed with 0.1 N HC1 (100 mL), 0.1 N NaOH (100 mL), and brine (100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a white foam (99 mg, 15%). ESI MS (M+H) 459.
[0977] Step 240b. ((25,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6- (pyrimidin-2-yl)phenyl)methanone.
Figure imgf000416_0001
A stirred solution of the product of Step 240a (99 mg, 0.216 mmol) and ΝΗ2ΝΗ2·Η20 (43 mg, 0.864 mmol) in MeOH (10 mL) was heated to reflux for 2 h. The reaction mixture was cooled to rt then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with CH2Cl2/MeOH/conc. NH4OH (100:0:0 to 90:9: 1) to afford the title compound as a white foam (33 mg, 45%). ESI MS (M+H) 329.
[0978] Step 240c. A suspension of the product of Step 240b (32 mg, 0.0975 mmol), 2- chloro-5-(trifluoromethyl)pyrimidine (21 mg, 0.177 mmol), and K2C03 (27 mg, 0.195 mmol) in anhydrous DMF (3 mL) was heated at 100 °C under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes), then lyophilized from acetonitrile/water (2: 1) to afford the title compound as a yellow solid (19 mg, 41%). 1H NMR (300 MHz, DMSO-J6) δ 8.95-7.25 (m, 9H), 5.05-2.75 (m, 5H), 2.10-0.65 (m, 8H). ESI MS (M+H) 475.
[0979] Example A241: (2-Fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000417_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(6-fluoro-2-(pyrimidin- 2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 474
[M+l]+. 1H NMR (500 MHz, DMSO-J6) δ 8.90-6.50 (m, 10H), 4.95-2.70 (m, 5H), 2.00- 0.65 (m, 8H).
[0980] Example A242: (4,5-Difluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000417_0002
[0981] Step 1. 2-(((2S,3R)-l-(4,5-Difluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000417_0003
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (1.89 g, 3.38 mmol), 4,5-difluoro-2-iodobenzoic acid (0.8 g, 2.817 mmol), DIPEA (1.5 mL, 8.45 mmol) and HATU (1.07, 2.817 mmol) in DMF (15 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHC03 and brine successively. The organic layer was separated, dried with MgS04 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 525 (M+H).
[0982] Step 2. 2-(((2S,3R)-l-(4,5-Difluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione
Figure imgf000418_0001
A mixture of 2-(((2S,3R)-l-(4,5-difluoro-2-iodobenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (0.738 g, 1.409 mmol), 2-(tributylstannyl)pyrimidine (0.52, 1.409 mmol), CsF (0.43 g, 2.818 mmol), Cul (0.027 g, 0.14 mmol) and Pd(PPh3)4 (0.16 g, 0.14 mmol) in DMF (15 mL) was degassed and heated at 100 °C for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a white solid. MS (ESI) 477 (M+H).
[0983] Step 3. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2- (pyrimidin-2-yl)phenyl)methanone.
Figure imgf000418_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-(((2S,3R)-l-(4,5-difluoro-2-(pyrimidin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. MS (ESI) 347 (M+H).
[0984] Step 4. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5- difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. EST MS (m/z): 492 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 9.00-6.55 (m, 9H), 4.85-2.75 (m, 5H), 2.00-0.65 (m, 8H).
[0985] Example A243: (4,5-Difluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000419_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 493 [M+l]+. 1H NMR (500 MHz, DMSO-J6) δ 8.95-6.75 (m, 8H), 4.95-2.85 (m, 5H), 1.95-0.65 (m, 8H).
[0986] Example A244: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4,5-diflu anone.
Figure imgf000419_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2- (pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 459 [M+l]+.
[0987] Example A246: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4,5-diflu enyl)methanone.
Figure imgf000419_0003
[0988] Step l: 4,5-Difluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000419_0004
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 4,5-difluoro-2- iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+l]+.
[0989] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000420_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 4,5-difluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 336, (M+H).
[0990] Step 3. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5- difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 447 [M+l]+.
[0991] Example A247: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4,5-diflu enyl)methanone.
Figure imgf000420_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 448
[M+l]+.
[0992] Example A248: (4,5-Difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000421_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.30-6.85 (m, 7H), 4.90-2.70 (m, 5H), 1.90-0.65 (m, 8H).
[0993] Example A249: (4,5-Difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000421_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4,5-difluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESTMS (m/z): 481 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.30-6.50 (m, 8H), 4.80-2.70 (m, 5H), 1.90-0.65 (m, 8H).
[0994] Example A250: (4-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000421_0003
[0995] Step 1: 4-Fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000422_0001
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 4-fluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208.2 [M+l]+.
[0996] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000422_0002
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 4,5-difluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318.4 (M+H).
[0997] Step 3. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro- 2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI- MS (m/z): 463.4 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.40-6.55 (m, 9H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
[0998] Example A251: (4-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000422_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-fluoro-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464.4 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.80-6.65 (m, 8H), 4.95-2.70 (m, 5H), 1.95-0.65 (m, 8H).
[0999] Example A254: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000423_0001
[1000] Step 1: 3-Fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000423_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 3-fluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+l]+.
[1001] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000423_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 3-fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
[1002] Step 3. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3- fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESTMS (m/z): 429 [M+l]+. [1003] Example A255: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(3-fluoro-2- -l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000424_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 430 [M+l]+.
[1004] Example A256: (3-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000424_0002
The title compound was prepared following the same general protocol as described for
Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 464 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-6.75 (m, 8H), 4.80-2.70 (m, 5H), 1.65- 0.70 (m, 8H).
[1005] Example A257: (3-Fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000424_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-fluoro-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.40-6.55 (m, 9H), 4.75-2.70 (m, 5H), 1.70-0.75 (m, 8H).
[1006] Example A258: (2-Fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000425_0001
[1007] Step 1: 2-Fluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000425_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 2-fluoro-6-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+l]+.
[1008] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000425_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-fluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
[1009] Step 3. The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2- fluoro-6-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.40-6.50 (m, 9H), 4.95-2.70 (m, 5H), 2.05-0.65 (m, 8H).
[1010] Example A259: (2-Fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000426_0001
The title compound was prepared following the same general protocol as described for
Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 464 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.80-6.75 (m, 8H), 5.00-2.70 (m, 5H), 2.00- 0.65 (m, 8H).
[1011] Example A260: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(2-fluoro-6- -l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000426_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESTMS (m/z): 430 [M+l]+.
[1012] Example A261: ((2S,3R)-2-(((5-Chloropyridin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(2-fluoro-6- -l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000426_0003
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 429 [M+l]+.
[1013] Example A264: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-6-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000427_0001
[1014] Step 1: 2-Methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000427_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 6-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+l]+.
[1015] Step 2: ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(2-methyl-6-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000427_0003
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 2-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid. ESI-MS m/z: 314 [M+l]+.
[1016] Step 3. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2- methyl-6-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone_and 2-chloro-5-
(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-6.70 (m, 8H), 5.05-2.70 (m, 5H), 2.15-0.65 (m, 11H). [1017] Example A265: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-6-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000428_0001
The title compound was prepared following the same general protocol as described for Example A264 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-methyl-6-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+l]+. 1H NMR (500 MHz, CD3OD) δ 8.35-6.55 (m, 8H), 5.10-2.85 (m, 5H), 2.43-0.75 (m, 11H).
[1018] Example A266: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)(3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000428_0002
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 3-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+l]+.
[1020] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(3-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone
Figure imgf000429_0001
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314(M+H).
[1021] Step 3. The title compound was prepared following the same general protocol as described for Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3- methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.45-6.50 (m, 9H), 4.65-2.70 (m, 5H), 2.10-0.75 (m, 11H).
[1022] Example A267: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl) -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000429_0002
The title compound was prepared following the same general protocol as described for
Example Al using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 460 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.70-6.70 (m, 8H), 4.75-2.70 (m, 5H), 2.15- 0.70 (m, 11H).
[1023] Example A268: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000430_0001
The title compound was prepared following the same general protocol as described for Example Al using ((2S, 3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-fluoro-6-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.45-6.65 (m, 8H), 4.75-2.70 (m, 5H), 2.15-0.65 (m, 11H).
[1024] Example A271: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(4-methyl- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000430_0002
[1025] Step 1. 4-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000430_0003
The title compound was prepared following the same general protocol as described for 5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid in Example Al l using 4-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+l]+.
[1026] Step 2. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(4-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone.
Figure imgf000430_0004
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-methyl-2-(l-methyl-lH-pyrazol-4- yl)phenyl)methanone in Example Al using 4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).
[1027] Step 3. The title compound was prepared following the same general protocol as described for Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.45-6.45 (m, 8H), 4.90-2.70 (m, 5H), 2.35-0.65 (m, 11H).
[1028] Example A272: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000431_0001
The title compound was prepared following the same general protocol as described for Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460.2 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.45-6.65 (m, 8H), 4.90-2.70 (m, 5H), 2.45-0.60 (m, 11H).
[1029] Example A273: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000431_0002
The title compound was prepared following the same general protocol as described for
Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(4-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 459 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.40-6.45 (m, 9H), 4.85-2.70 (m, 5H), 2.45-0.50 (m, 11H). [1030] Example A298: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethy)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000432_0001
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-3-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+l]+.
[1031] Example A299: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000432_0002
The title compound was prepared following the same general protocol as described for Example A298 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(3-methyl-2- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 471 [M+l]+.
[1032] Example A304: ((25,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-y -methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000432_0003
The title compound was prepared using methods analogous to those described herein. H NMR (500 MHz, CD3OD) δ 9.00-6.70 (m, 8H), 5.15-2.85 (m, 5H), 2.45-0.65 (m, 11H); ESI MS (M+H) 471. [1033] Example A305: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl 4-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000433_0001
The title compound was prepared following the same general protocol as described for Example A242 using 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione, 2- iodo-4-methylbenzoic acid and 2-fluoro-5-(trifluoromethyl)pyridine. 1H NMR (500 MHz, CD3OD) δ 8.90-6.45 (m, 9H), 5.00-2.85 (m, 5H), 2.45-0.75 (m, 11H); ESI MS (M+H) 470.
[1034] Example A306: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-6-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000433_0002
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-6-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+l]+.
[1035] Example A307: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)( -methyl-6-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000433_0003
The title compound was prepared following the same general protocol as described for Example A306 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-methyl-6- (pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+l]+.
[1036] Example A310: ((2S,3R)-2-(((5-Chloropyrimidin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(3-methy -2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000434_0001
The title compound was prepared following the same general protocol as described for
Example Al using ((2S, 3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H- 1,2,3- triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463 [M+l]+. 1H NMR (500 MHz, DMSO-J6) δ 8.35-6.55 (m, 9H), 4.75-2.70 (m, 5H), 1.80-0.65 (m, 8H).
[1037] Example A311: (+/-)-cw-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000434_0002
The title compound was prepared following the same general protocol as described for Example Al using ((2S,3S)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 494 [M+l]+.
[1038] Example A312: (S)-(4,4-Difluoro-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000435_0001
The title compound was prepared following the same general protocol as described for Example A210 using 2-((4,4-difluoropiperidin-2-yl)methyl)isoindoline-l,3-dione and 5- methyl-2-(pyrimidin-2-yl)benzoic acid and Example A45 using 2-chloro-5- (trifluoromethyl)pyrimidine. ESI-MS (m/z): 493 (M+H).
[1039] Example A313: (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000435_0002
The title compound was prepared following the same general protocol as described for Example Al using (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 446 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-6.80 (m, 9H), 4.95-2.80 (m, 5H), 1.80- 0.50 (m, 8H); ESI MS (M+H) 446.
[1040] Example A314: (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2S,3R)-3-methyl-2-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000435_0003
The title compound was prepared following the same general protocol as described for Example Al using (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 445 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.35-6.60 (m, 10H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
[1041] Example A315: ((2R,3S)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl) -methyl-2-(l-methyl-lH-pyrazol-4-yl)phenyl)methanone.
Figure imgf000436_0001
The title compound is the (+)-enantiomer of Example Al and was prepared following the same general protocol as described for Example Al using (2R,3S)-l-((benzyloxy)carbonyl)- 3-methylpiperidine-2-carboxylate. ESI-MS (m/z): 472 [M+l]+. [a]25 D= +6.2 (c=0.3, MeOH).
[1042] Example A316: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin-l-yl)( -(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000436_0002
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodobenzoic acid to make ((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)(2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 456 [M+l]+. 1H NMR (500 MHz, DMSO-J6) δ 8.90-6.60 (m, 11H), 4.85-2.85 (m, 5H), 2.00-0.65 (m, 8H).
[1043] Example A317: ((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000437_0001
The title compound was prepared following the same general protocol as described for Example A316 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(2-(pyrimidin-2- yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESTMS (m/z): 457 [M+l]+. 1H NMR (500 MHz, CD3OD) δ 9.05-6.85 (m, 9H), 5.15-3.00 (m, 5H), 2.10-0.75 (m, 8H).
[1044] Example A318: (2-Fluoro-3-methyl-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000437_0002
[1045] Step 1. 2-Fluoro-3-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000437_0003
The title compound was synthesized following the same general protocol as described in Example Al l using 2-fluoro-6-iodo-3-methylbenzoic acid and 2H-l,2,3-triazole. ESTMS (m/z): 222 [M+1]+.
[1046] Step 2. The title compound was prepared following the same general protocol as described in Example Al, using 2-fluoro-3-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2- (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.45-6.45 (m, 8H), 4.90-2.70 (m, 5H), 2.35-0.65 (m, 11H)
[1047] Example A319: (2-Fluoro-3-methyl-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000438_0001
The title compound was prepared following the same general protocol as described in Example A318, using 2-fluoro-3-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)- 3-methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2-fluoro-5-
(trifluoromethyl)pyrimidine. ESI-MS (m/z): 478 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-7.00 (m, 7H), 4.94-2.70 (m, 5H), 2.35-0.65 (m, 11H).
[1048] Example A322: 3-((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidine-l- yl)benzonitrile.
Figure imgf000438_0002
[1049] Step 1: 5-Cyano-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000438_0003
The title compound was synthesized following the protocol as described in Boss, C. et al., WO2012/085852. ESI-MS (m/z): 215 [M+l]+.
[1050] Step 2. The title compound was prepared following the same general protocol as described in Example Al, using 5-cyano-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)- 3-methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2-fluoro-5- (trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+l]+.
[1051] Example A323: 3-((2S,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidine-l-carbonyl)-4-(pyrimidin-2-yl)benzonitrile.
Figure imgf000439_0001
The title compound was prepared following the same general protocol as described for Example A230 using 5-cyano-2-iodobenzoic acid to make 3-((2S,3R)-2-(aminomethyl)-3- methylpiperidine- l-carbonyl)-4-(pyrimidin-2-yl)benzonitrile and 2-chloro-5- (trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+l]+.
[1052] Example A324: (3,4-Difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin- -yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000439_0002
[1053] Step 1. 3,4-Difluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 2,3-difluoroaniline. MS (ESI) 226 (M+H).
[1054] Step 2. The title compound was prepared following the same general protocol as described in Example A318, using 3,4-difluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2- (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 481 [M+l]+.
[1055] Example A328: (3,5-Difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000439_0003
[1056] Step 1. 3,5-Difruoro-2-iodobenzoic acid. The title compound was prepared following the same general protocol as described for Example A342 using 3,5-difluorobenzoic acid. ESI-MS (m/z): 285 [M+l]+.
[1057] Step 2. 3,5-Difruoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared using the methods described herein, using 3,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+l]+.
[1058] Step 3. The title compound was prepared from 3,5-difluoro-2-(2H-l,2,3-triazol-2- yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione, and 2- fluoro-5-(trifluoromethyl)pyridine using the methods described herein. ESI-MS (m/z): 481 [M+l]+.
[1059] Example A332: (3,6-Difluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000440_0001
[1060] Step 1. 3,6-Difluoro-2-iodobenzoic acid. To freshly distilled diisopropylamine (14 mL, 0.1 mol) in THF (200 mL) at 0 °C was slowly added BuLi (40 mL, 2.5 M, 0.1 mol) under argon. After 30 min at rt, the mixture was cooled to -78 °C and treated with 1,4- difluoro-2-iodobenzene (24 g, 0.1 mol). After 1 h at -78 °C, the reaction was quenched with solid C02. The reaction was allowed to warm to rt and was concentrated. The resulting residue was partitioned between 4 N NaOH (aq) and diethyl ether. The aqueous phase was adjusted to pH 2 with 2 N HCl and extracted with EtOAc (3x). The combined extracts were washed with water and brine, dried (MgS04), filtered, and concentrated to provide the title compound.
[1061] Step 2. 3,6-Difluoro-2-(2H-l,2 -triazol-2-yl)benzoic acid. The title compound was prepared from 3,6-difluoro-2-iodobenzoic acid using the methods described herein. MS (ESI) 226 (M+H).
[1062] Step 3. The title compound was prepared from3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione, and 2- chloro-5-(trifluoromethyl)pyridine using the methods described herein. ESI-MS (m/z): 481 (M+H). [1063] Example A336: (2,3-Difluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)m*ethyl)piperidin-l-yl)methanone.
Figure imgf000441_0001
[1064] Step 1: 2,3-Difluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was synthesized following the same general protocol as described in Example Al l using 2,3- difluoro-6-iodobenzoic acidand 2H-l,2,3-triazole. ESI-MS (m/z): 226 [M+l]+.
[1065] Step 2. The title compound was prepared following the same general protocol as described in Example Al, using 2,3-difluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2- (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 481 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.40-6.45 (m, 8H), 4.95-2.70 (m, 5H), 1.90-0.65 (m, 8H).
[1066] Example A337: (2,3-Difluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyrimidin- -yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000441_0002
The title compound was prepared following the same general protocol as described in Example Al, using 2,3-difluoro-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3- methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2-chloro-5-
(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-7.05 (m, 7H), 5.05-2.70 (m, 5H), 1.95-0.65 (m, 8H).
[1067] Example A338: (2-Fluoro-3-methoxy-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000442_0001
[1068] Step 1: 2-Fluoro-3-methoxy-6-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000442_0002
The title compound was synthesized following the same general protocol as described in Example Al l using 2-fluoro-6-iodo-3-methoxybenzoic acid and 2H-l,2,3-triazole. ESI-MS (m/z): 238 [M+l]+.
[1069] Step 2. The title compound was prepared following the same general protocol as described in Example Al, using 2-fluoro-3-methoxy-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2 (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-fluoro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 493 [M+l]+. 1H NMR (500 MHz, DMSO-J6) δ 8.40-6.45 (m, 8H), 4.85-2.70 (m, 8H), 1.85-0.65 (m, 8H).
[1070] Example A339: (2-Fluoro-3-methoxy-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000442_0003
The title compound was prepared following the same general protocol as described in Example Al, using 2-fluoro-3-methoxy-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3- methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione and 2-chloro-5-
(trifluoromethyl)pyrimidine. ESI-MS (m/z): 494 [M+l]+. 1H NMR (300 MHz, DMSO-J6) δ 8.75-6.95 (m, 7H), 5.00-2.70 (m, 8H), 2.00-0.65 (m, 8H).
[1071] Example A340: ((25,3R)-3-Methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin-l-yl)(4-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000443_0001
[1072] Step 1. 4-Methyl-2-(pyrimidin-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for Example A389 using 2-bromo-4- methylbenzoic acid. ESI MS (M+H) 215.
[1073] Step 2. The title compound was prepared following the same general protocol as described for Example A389 using 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline- 1,3-dione, 4-Methyl-2-(pyrimidin-2-yl)benzoic acid and 2-chloro-5-
(trifluoromethyl)pyrimidine. 1H NMR (500 MHz, CD3OD) δ 9.00-6.70 (m, 8H), 5.15-2.85 (m, 5H), 2.45-0.65 (m, 11H); ESI MS (M+H) 471.
[1074] Example A342: (5-Fluoro-3-methyl-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-methyl-2- (((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000443_0002
[1075] Step 1. 5-Fluoro-3-methyl-2-nitrobenzoic acid. 3-Fluoro-5-methylbenzoic acid (4 g, 25.96 mmol) and KN03 (2.884 g, 28.556 mmol) were dissolved in cone. H2S04 (32 mL) at 0 °C. The mixture was stirred at rt for 1 h. Water (60 mL) was added, and the resulting precipitate was filtered and dried to provide the title compound, which was used without further purification.
[1076] Step 2. 2-Amino-5-fluoro-3-methylbenzoic acid. A mixture of 5-fluoro-3-methyl-2- nitrobenzoic acid (4.86 g, 24.42 mmol) and SnCl2 (16.5 g, 72.36 mmol) in EtOAc was heated at 70 °C overnight. After cooling at rt, the pH was adjusted to 7-8 with satd. aq. NaHC03. The mixture was extracted with EtOAc, and the organic layer was washed with brine, filtered through diatomaceous earth, and dried over Na2S04 to provide the title compound, which was used without further purification. ESI-MS (m/z): 170 [M+l]+. [1077] Step 3. 5-Fluoro-2-iodo-3-methylbenzoic acid. A 0 °C solution of 2-amino-5-fluoro- 3-methylbenzoic acid (1.5 g, 6.118 mmol) in cone. H2S04 (4 mL) and water (10 mL) was stirred for 10 min, and then a solution of NaN02 (0.55 g, 7.95 mmol) in water (1 mL) was added slowly. After 1 h, a solution of KI (5.1 g, 30.6 mmol) in water (6 mL) was added. After 16 h at rt, the reaction mixture was extracted with EtOAc, and the combined organic layers were washed with satd. aq. Na2S203 (aq) and brine, dried over MgS04, and
cocnentrated to provide the title compound. ESI-MS (m/z): 281 [M+l]+.
[1078] Step 4. 2-(((2S,3R)-l-(5-Fluoro-2-iodo-3-methylbenzoyl)-3-methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione. A mixture of 2-(((2S,3R)-3-methylpiperidin-2- yl)methyl)isoindoline-l,3-dione (1.2 eq.), 5-fluoro-2-iodo-3-methylbenzoic acid (1 eq.), DIPEA (3 eq.), and HATU (1 eq.) in DMF (0.2 M) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. NaHC03 and brine. The organic layer was separated, dried with MgS04, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound.
[1079] Step 5. 2-(((2S,3R)-l-(5-fluoro-3-methyl-2-(5-(trifluoromethyl)pyridin-2- yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione. The title compound was prepared from the product of Step 4 and 2-(tributylstannyl)pyrimidine.
[1080] Step 6. The product of Step 5 was converted into the title compound using the methods described herein. ESI-MS (m/z): 488 [M+l]+.
[1081] Example A344: (4-Fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000444_0001
[1082] Step 1. 4-Fluoro-2-iodo-3-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 3-fluoro-2-methylaniline. MS (ESI) 281 (M+H).
[1083] Step 2. 4-Fluoro-3-methyl-2-(2H-L2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-3-methylbenzoic acid. MS (ESI) 222 (M+H).
[1084] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 4-fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1085] Example A352: (6-Fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000445_0001
[1086] Step 1. (Z)-N-(5-Fluoro-2-methylphenyl)-2-(hydroxyimino)acetamide. 5-Fluoro-2- methylaniline (10 g, 80 mmol) and NaHC03 (67 g, 800 mmol) in DCM (200 mL) were cooled to -10 °C. A solution of freshly distilled 2,2-diacetoxyacetyl chloride (20 g,
103 mmol) was added dropwise. The mixture was removed from the cooling bath and allowed to warm to rt. When the complete consumption of the aniline was confirmed by TLC, the solid was removed by filtration, washed with DCM, and the filtrate was
concentrated to give the crude diacetate. Hydroxylamine hydrochloride (28 g, 400 mmol) was dissolved in a mixture of ethanol (200 mL) and water (100 mL), and the solution was then added to the crude diacetate. The mixture was heated under reflux for 2 h, cooled to rt, and concentrated until precipitation commenced. Water was then added to precipitate further product. The solid was collected by filtration and washed with water to yield the title compound (7.22g, 46%). 1H NMR (CDC13, 400 MHz) δ 8.25 (bs, 1H), 7.99 (bs, 1H), 7.85 (m, 1H), 7.55 (s, 1H), 7.05 (m, 1H), 6.7 (m, 1H), 2.20 (s, 3H).
[1087] Step 2. 4-Fluoro-7-methylindoline-2,3-dione. (Z)-N-(5-Fluoro-2-methylphenyl)-2- (hydroxyimino)acetamide (7.22, 37 mmol) was dissolved in neat H2S04 (50ml) and heated at 60 °C for 1 h. The resulting solid was collected by filtration and washed with water to yield the title compound. 1H NMR (CDC13, 400 MHz) δ 8.35 (bs, 1H), 7.45 (m, 1H), 6.73 (m, 1H), 2.25 (s, 3H). [1088] Step 3. 2-Amino-6-fluoro-3-methylbenzoic acid. 4-Fluoro-7-methylindoline-2,3- dione (6.20 g, 34.6 mmol) in 1M NaOH (114 mL) was treated dropwise with 30% aq. H202 (20 mL), heated to 50 °C for 30 min, cooled to rt and filtered. The filtrate was adjusted to pH 4 with cone. HC1, cooled to 4 °C and filtered. The filter cake was dried under vacuum to provide the desired product. 1H NMR (CDC13, 400 MHz) δ 7.15 (m, 1H), 6.40 (m, 1H), 2.15 (s, 3H).
[1089] Step 4. 6-Fluoro-2-iodo-3-methylbenzoic acid. 2-Amino-6-fluoro-3-methylbenzoic acid was dissolved in 7.5 mL of H2S04 and 15 mL of H20 and stirred for 30 min. The resultant suspension was cooled to 0 °C, and a solution of NaN02 (1.06 g, 11.8 mmol) in 2 mL of H20 was added dropwise to the reaction mixture at 0 °C. The temperature of the reaction mixture was maintained at 0 °C for 1.5 h. To this reaction mixture, a solution of KI (9.8 g, 59 mmol) in 10 mL of H20 was added slowly. The brown-colored mixture was vigorously stirred at rt overnight. Subsequently, the reaction mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with brine and Na2S203 solution followed by water and dried over anhydrous Na2S04. The solvent was removed in vacuo, and the residue was subjected to silica-gel chromatography (0 to 20%
EtOAc/hexanes). 1H NMR (CDC13, 400 MHz) δ 7.25 (m, 1H), 7.05 (m, 1H), 2.48 (s, 3H).
[1090] Step 5. 6-Fluoro-3-methyl-2-(2H- 2,3-triazol-2-yl)benzoic acid. A mixture of 6- fluoro-2-iodo-3-methylbenzoic acid (900 mg, 3.21 mmol), 1,2,3-triazole (208 μΐ, 4.82 mmol), (lS,2S)-Nl,N2-dimethylcyclohexane-l,2-diamine (103 μΐ, 642 μπιοΐ), Cs2C03 (1.57g, 4.82 mmol) and Cul (61 mg, 321 μιηοΐ) in DMF (5 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (40% EtOAc in hexanes) to yield the title compound. MS (ESI) 222 (M+H).
[1091] Step 5. The title compound was prepared following the same general protocol as described in Example A318, using 6-fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1092] Example A356: (3-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000447_0001
[1093] Step 1. 3-Fluoro-2-iodo-4-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 2-fluoro-3-methylaniline. MS (ESI) 281 (M+H).
[1094] Step 2. 3-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 222 (M+H).
[1095] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+l]+.
[1096] Example A360: (5-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000447_0002
[1097] Step 1. 5-Fluoro-2-iodo-4-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 4-fluoro-3-methylaniline. MS (ESI) 281 (M+H).
[1098] Step 2. 5-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 5-fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 222 (M+H). [1099] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 5-fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1100] Example A368: (4-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000448_0001
[1101] Step 1. 4-Fluoro-2-iodo-5-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 3-fluoro-4-methylaniline. MS (ESI) 281 (M+H).
[1102] Step 2. 4-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).
[1103] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 4-fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1104] Example A372: (3-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000448_0002
[1105] Step 1. 3-Fluoro-2-iodo-5-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 2-fluoro-4-methylaniline. MS (ESI) 281 (M+H). [1106] Step 2. 3-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).
[1107] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1108] Example A384: (3-Fluoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3- methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000449_0001
[1109] Step 1. 3-Fluoro-6-iodo-2-methylbenzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 4-fluoro-3-methylaniline. MS (ESI) 281 (M+H).
[1110] Step 2. 3-Fluoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H- l,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-6-iodo-2-methylbenzoic acid. MS (ESI) 222 (M+H).
[1111] Step 3. The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione and 2-chloro-5- (trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
[1112] Example A389: (2,3-Difluoro-6-(pyrimidin-2-yl)phenyl)((25,3R)-3
(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000450_0001
[1113] Step 1: Methyl 6-bromo-2 -difruorobenzoate. A stirred solution of 6-bromo-2,3- difluorobenzoic acid and cone. H2SO4 in MeOH was heated at reflux for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the residue was carefully added a satd. aq. NaHC03 solution. The resulting mixture was extracted with CH2CI2. The combined extracts were dried over anhydrous Na2S04, filtered, and
concentrated under reduced pressure. The residue obtained was dried under high vacuum to afford the title compound. ESI MS (M+H) 251.
[1114] Step 2: Methyl 2,3-difluoro-6-('4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl benzoate. A stirred suspension of methyl 6-bromo-2,3-difluorobenzoate, 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane), PdCi2(dppf), and KOAc) in anhydrous 1,4-dioxane was heated at 100 °C under nitrogen for 20 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was directly purified by flash column chromatography on silica gel (0% to 15% EtOAc/hexanes) to give the title compound. ESI MS (M+H) 299.
[1115] Step 3: Methyl 2,3-difluoro-6-(pyrimidin-2-yl)benzoate. A stirred suspension of methyl 2,3-difluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate, 2- chloropyrimidine , PdCl2(dppf) and K2C03 in 1,4-dioxane and water (3: 1, v/v) was heated at 90 °C under nitrogen for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was directly purified by flash column
chromatography on silica gel (0% to 50% EtOAc/hexanes) to give the title compound. ESI MS (M+H) 251.
[1116] Step 4: 2,3-Difluoro-6-(pyrimidin-2-yl)benzoic acid. A solution of methyl 2,3- difluoro-6-(pyrimidin-2-yl)benzoate in 2 N NaOH and water was heated at reflux for 4 h. After this time, the reaction mixture was cooled to rt and concentrated to half volume under reduced pressure. The resulting mixture was acidified to pH 4 with 1 N HC1 and extracted with EtOAc . The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the title compound. ESI MS (M+H) 237. [1117] Step 5. A solution of 2,3-difluoro-6-(pyrimidin-2-yl)benzoic acid (1 mmol), 2-chloro- 4,6-dimethoxy-l,3,5-triazine (1 mmol) and N-methylmorpholine (3 eq) in anhydrous 1,4- dioxane (10 mL) was stirred at rt under nitrogen for 1.5 h. After this time, a solution of 2- (((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (0.83 eq) in anhydrous 1,4- dioxane was added at rt. After the addition was completed, the reaction was heated to 80 °C under nitrogen for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc, subsequently washed with 0.1 N HC1, 0.1 N NaOH, and brine , dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound. ESI MS (M+H) 477.
[1118] Exemplary chemical entities useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to Formula (la). Isotopically labeled compounds as described herein are prepared according to the methods described below, using suitably labeled starting materials. Such materials are generally available from commercial suppliers of radiolabeled chemical reagents.
Scheme A
Figure imgf000452_0001
[1119] Compounds of Formula (la) may be prepared according to Scheme A. Chiral aminomethyl piperidine Al, with a suitable amino protecting group (PG) such as a Boc or phthalimide, is prepared using methods analogous to those described for Intermediates 1 and
3 2
2 below. The secondary amine is coupled with a suitable R -R - containing reagent, such as a carboxylic acid (under standard amide coupling conditions) or acyl chloride (in the presence of a suitable tertiary amine base), to provide amides A2. The amino protecting group is removed using standard conditions, to generate amines A3. The A3 amino group is then be reacted with RX-LG, where R1 is a heteroaryl group and LG is a suitably positioned leaving group such as chloro, in the presence of a suitable base such as K2CO3, to yield amino- alcohols A4. Where R1 is phenyl or a heteroaryl without an activated leaving group, the primary amine is coupled with R1 through metal-mediated procedures (e.g. , Buchwald or Ulmann couplings) known to those skilled in the art, to generate compounds of Formula (la) where X is NH. The NH may be alkylated using methods known to one of skill in the art to prepare compounds of Formula (la) where X is N(C1_4alkyl).
Scheme B
Figure imgf000452_0002
[1120] Compounds of Formula (la) may also be prepared according to Scheme B.
3 2
Compound B l is prepared as described in Intermediate 17. Coupling with a suitable R -R - containing reagent as described for Scheme A yields amides B2. The primary alcohol of B2 is reacted with a heteroaryl with an activated leaving group (RX-LG) as described above for Scheme A to yield compounds of Formula (la) where X is O. Alternatively, the primary alcohol is activated and displaced with R1-NH2 or R^-OH under, for example, Mitsunobu conditions, to give compounds of Formula (la) where X is NH or O.
Examples
[1121] The following examples are offered to illustrate but not to limit the invention. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (la). Additional suitable methods and synthetic intermediates are described in PCT Publication No. WO2013/119639.
Intermediate 1. 2-(((2lS',3R)-3-Methylpiperidin-2-yl)methyl)isoindoline- 1 ,3-dione.
Figure imgf000453_0001
[1122] Step 1. mc-3-Methylpiperidine-2-carboxylic acid hydrochloride. A solution of 3- methylpicolinic acid (50 g, 365 mmol) in 400 mL of EtOH/H20 (1: 1) and 60 mL of aq. HCl (32%) was treated with Pt02 (5g) and the mixture was stirred at rt under a H2 balloon until NMR indicated completion. The mixture was filtered through diatomaceous earth and concentrated to yield the title compound as a white solid which was used without further purification (60.5g, 92%). 1H NMR (MeOD, 400 MHz) δ 4.13-4.11 (m, 1H), 3.40-3.33 (m, 1H), 3.05-2.99 (m, 1H), 2.61-2.58 (m, 1H), 1.92-1.72 (m, 4H), 1.09 (d, J = 7.0 Hz, 3H). MS (ESI) 452.16 (M+H).
[1123] Step 2. rac- l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid. To a 0 °C solution of 3-methylpiperidine-2-carboxylic acid hydrochloride (28.5 g, 31.6 mmol) in (1: 1) 2 M NaOH/THF (600 mL) was added benzyl chloroformate (31.57 mL, 222 mmol). After 18 h at rt, toluene was added and organic layer discarded to remove unreacted chloroformate. The aqueous layer was acidified to pH 2 with cone. HCl and the product was extracted with EtOAc, dried (MgS04), and concentrated in vacuo to give a crude residue, which was used without further purification (41.6 g, 94.5%). 1H NMR (CDC13, 400 MHz) δ 7.40-7.37 (m, 5H), 5.19 (m, 2H), 4.95-4.72 (m, 1H), 4.14-4.03 (m, 1H), 3.36-3.25 (m, 1H), 1.93-1.53 (m, 5H), 1.20-1.05 (m, 3H).
[1124] Step 3. D-Tyrosine Hvdrazide. A solution of D-tyrosine methyl ester (30 g, 129 mmol, 99% ee) in 150 mL of methanol was treated with hydrazine hydrate (23 mL, 453 mmol) and stirred overnight. The mixture was concentrated and satd. aq. NaHC03 was added (150 mL). The product was precipitated, filtered, and dried to yield the title compound as a white powder (23.5 g, 93%). 1H NMR (CD3OD, 400 MHz) δ 7.03 (ad, J = 8.8 Hz, 2H), 6.72 (ad, J = 8.8 Hz, 2H), 3.44 (t, J = 6.8 Hz, 1H), 2.91-2.86 (m, 1H), 2.76-2.71 (m, 1H). ESI-MS (m/z): 196.1 [M+l]+.
[1125] Step 4. (2tS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylate D- tyrosine hydrazide salt. A mixture of rac-l-((benzyloxy)carbonyl)-3-methylpiperidine-2- carboxylic acid (41.6 g, 150 mmol) and D-tyrosine hydrazide (11.71 g, 60 mmol) in 100 mL of methanol was heated at reflux. Methanol was added in 100 mL portions until a
homogenous solution was formed. The reaction was stirred for 1 h and then allowed to cool to rt overnight to yield thick slurry. The resulting solid was filtered and washed with isopropanol to yield the title compound as a white solid with 92.0% ee (23g, 81%). The white solid was again dissolved in isopropanol (1.2 L) and heated at reflux until homogenous. After 18 h, the resulting slurry was filtered and washed with isopropanol to yield the title compound as a white solid with 98.9% ee (21g, 73%).
Figure imgf000454_0001
(2lS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylate D-tyrosine hydrazide salt (17 g, 37.3 mmol) was dissolved in ethyl acetate and washed with 1 M HC1 (3 x) and brine, dried (MgS04), and concentrated to yield a clear oil (10.2 g, 98%). A 0 °C solution of the clear oil in 150 mL of THF was treated with 1 M borane'THF complex (40.4 m:, 40.4 mmol) dropwise over 15 min. The resulting mixutre was allowed to warm to rt overnight and then quenched with water at 0 °C. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (MgS04), and concentrated to give the title compound as a clear oil, which was used without further purification (8.7 g, 89%). ESI-MS (m/z): 263.93 [M+l]+.
Figure imgf000454_0002
carboxylate. A 0 °C solution of triphenylphosphine (21.5 g, 82 mmol) in 30 mL of THF was treated dropwise with diisopropylazodicarboxylate (DIAD; 16.1 mL, 82 mmol). After stirring for 20 min, a solution of (25,,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-l- carboxylate (8.7 g, 32.9 mmol) in 15 ml THF was added dropwise. After 30 min at 0 °C, phthalimide (6.3 g, 42.7 mmol) was added and the reaction was warmed tort overnight. The resulting suspension was concentrated in vacuo, and the residue was diluted with EtOAc, washed with water and brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound (14.2 g, 110%, DIAD contamination), which was used without further purification. 1H NMR (CDC13, 400 MHz) δ 7.72-7.71 (m, 1H), 7.62-7.60 (m, 3H), 7.17-7.13 (m, 3H), 7.05-7.04 (m, 1H), 6.98-6.96 (m, 1H), 4.76-4.69 (m, 1H), 4.54-4.39 (m, 1H), 4.03-3.98 (m, 2H), 3.63-3.54 (m, 1H), 3.25-3.07 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.54 (m, 2H), 1.47-1.25 (m, 2H), 1.07-1.04 (m, 3H). ESI-MS (m/z): 263.93 [M+l]+.
[1128] Step 7. To a solution of (2S,3R)-benzyl 2-((l,3-dioxoisoindolin-2-yl)methyl)-3- methylpiperidine-l-carboxylate (14.2 g, 36.1 mmol) in acetic acid (40 ml) was added 10% Pd/C (1.5 g). The reaction was stirred under H2 until HPLC indicated complete removal of the Cbz group. The reaction was the filtered through diatomaceous earth and concentrated. The crude residue was then dissolved in EtOAc and washed with satd. aq. NaHC03 and brine, dried (MgS04), and concentrated to yield the title compound as a yellow solid (8.2 g, 88%). 1H NMR (CDC13, 400 MHz) δ 7.82-7.81 (m, 2H), 7.71-7.70 (m, 2H), 4.19-4.15 (m, 1H), 3.81-3.78 (m, 2H), 3.44 (m, 2H), 2.96 (m, 1H), 2.31 (m, 1H), 1.79-1.67 (m, 2H), 1.27 (d, J = 4.0 Hz, 3H). ESI-MS (m/z): 259.2 [M+l]+.
Intermediate 2. Alternative Synthesis of (2S3R)-henzy\ 2-((l,3-dioxoisoindolin-2- yl)methyl)-3-methylpiperidine- 1 -carboxylate.
[1129] Step 1. (+)-2,3-ds-3-Methylpiperidine-2-carboxylic acid hydrochloride. A suspension of 3-methylpyridine-2-carboxylic acid (25.0 g, 182 mmol) and Pt02 (3.00 g) in HOAc (200 mL) was stirred under H2 (1 atm, balloon) at rt for 3 days. After that time, the reaction mixture was flushed with N2, filtered through a short pad of diatomaceous earth, and washed with EtOH/H20 (1: 1, 150 mL). The combined filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in H20 (100 mL). The resulting solution was treated with cone. HC1 (20 mL) and concentrated to dryness. The residue was dried under high vacuum to give the title compound as a white solid (32.7 g, quant.). 1H NMR (300 MHz, DMSO-J6) δ 13.91 (br s, 1H), 9.61 (br s, 1H), 8.76 (br s, 1H), 4.04 (br s, 1H), 3.37-2.75 (m, 2H), 2.42-2.38 (m, 1H), 1.90-1.55 (m, 4H), 0.97 (d, J = 7.3 Hz, 3H).
[1130] Step 2. (+)-2 -c^-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid. To a suspension of (+)-2,3-ds'-3-methylpiperidine-2-carboxylic acid hydrochloride (32.7 g, 182 mmol) in 2 M NaOH aqueous solution (500 mL) and THF (500 mL) at 0 °C was added Cbz-Cl (46.6 g, 273 mmol) dropwise over 15 min. The reaction mixture was slowly warmed to rt over 1 h and stirred at rt for 18 h. The reaction mixture was then diluted with toluene (400 mL) and H20 (200 mL). The layers were separated and the aqueous layer was washed with toluene (400 mL) and acidified with cone. HC1 to pH < 2. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the title compound as a colorless oil (43.8 g, 87%). 1H NMR (300 MHz, DMSO- ) δ 12.74 (br s, 1H), 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H); ESI MS (M-H) 276.
[1131] Step 3. (-)-(2tS',3R)-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid and (+)-(2R,3tS')-l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid. (±)-2,3-cis- l-((Benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (43.8 g, 158 mmol) was separated by preparative HPLC (Chiralcel OD column, 5 cm x 50 cm, 20 μ) elution with hexanes/j-PrOH/trifluoroacetic acid (TFA; 90: 10:0.1, 80 mL/min) and monitored by UV at 254 nm. The capacity of each injection was 1.4 g/injection [1 g in 20 mL of hexanes/i-PrOH (60:40)]. Collection and concentration of the first peak (retention time: -14 min) gave enantiomer A (21.5 g, 49%, > 99% ee) and enantiomer B (RT = 31 min, 21.6 g, 49%, > 99% ee) as colorless oils. Enantiomer A: [a]25 D = -28.2° (c = 0.46, MeOH); 1H NMR (300 MHz, DMSO- ) δ 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H). Enantiomer B: [a]25 D = +25.9° (c = 0.52, MeOH); 1H NMR (300 MHz, DMSO-J6) δ 12.74 (br s, 1H), 7.45-7.25 (m, 5H), 5.14-5.02 (m, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.91-3.85 (m, 1H), 3.30-3.13 (m, 1H), 1.90-1.20 (m, 5H), 1.02-0.96 (m, 3H).
Figure imgf000456_0001
stirred solution of (-)-(2lS',3R)-l-((benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (6.05 g, 21.8 mmol) in anhydrous THF (80 mL) was added BH3 »THF (1 M in THF, 43.6 mL, 43.6 mmol) dropwise over 10 min at rt under nitrogen. The reaction mixture was then stirred at rt for 46 h. After this time, the reaction was quenched by the slow addition of ice cold water (10 mL) followed by 2 N HC1 (20 mL). The resulting mixture was stirred at rt for 30 min and then extracted with EtOAc (3 x 100 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 20% to 50%
EtOAc/CH2Cl2 to afford the title compound as a colorless oil (5.30 g, 92%). ESI MS (M+H) 264.
[1133] Step 5. To a stirred solution of (25,,3R)-benzyl 2-(hydroxymethyl)-3- methylpiperidine-l-carboxylate (4.61 g, 17.5 mmol) and w-Bu3P (10.6 g, 52.4 mmol) in anhydrous THF (150 mL) was added l,l'-(azodicarbonyl)dipiperidine (ADDP; 8.83 g, 35.0 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 30 min. To the reaction mixture was then added isoindoline-l,3-dione (3.09 g, 21.0 mmol), followed by heating at reflux for 20 h. After this time, the reaction mixture was cooled to rt, diluted with Et20 (100 mL), and further cooled with an ice/water bath. The resulting mixture was filtered and the filter cake was washed with Et20 (40 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8). The material obtained from the chromatography was triturated with hexanes/CH2Cl2 (5: 1) and solids removed by filtration. Concentration of the filtrate afforded the title compound as a colorless oil (6.12 g, 89%). ESI MS (M+H) 393.
Intermediate 3. 5-Fluoro-2-(2H-L2,3-triazol-2-yl)benzoic acid.
Figure imgf000457_0001
[1134] A mixture of 2-bromo-5-methylbenzoic acid (1 eq.), 1,2,3-triazole (2 eq.), (1S,2S)- Nl,N2-dimethylcyclohexane-l,2-diamine (1.5 eq.), Cs2C03 (1.5 eq.), and Cul (0.07 eq.) in DMF (0.775 M) was degassed and heated at 120 °C for 1 h in a microwave reactor. The reaction was cooled to RT, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a yellow oil. MS (ESI) 208 (M+H).
Intermediate 4. 3,4-Difluoro-2-(2H- -triazol-2-yl)benzoic acid.
Figure imgf000457_0002
[1135] The title compound was prepared from 2,3-difluoroaniline as described for
Intermediate 3. MS (ESI) 226 (M+H).
Intermediate 5. 5-Fluoro-2-iodo-3-methylbenzoic acid.
Figure imgf000457_0003
[1136] Step 1. 5-Fluoro-3-methyl-2-nitrobenzoic acid. 3-Fluoro-5-methylbenzoic acid (4 g, 25.96 mmol) and KN03 (2.884 g, 28.556 mmol) were dissolved in cone. H2S04 (32 mL) at 0 °C. The mixture was stirred at rt for 1 h. Water (60 mL) was added, and the resulting precipitate was filtered and dried to provide the title compound, which was used without further purification.
[1137] Step 2. 2-Amino-5-fluoro-3-methylbenzoic acid. A mixture of 5-fluoro-3-methyl-2- nitrobenzoic acid (4.86 g, 24.42 mmol) and SnCl2 (16.5 g, 72.36 mmol) in EtOAc was heated at 70 °C overnight. After cooling at rt, the pH was adjusted to 7-8 with satd. aq. NaHC03. The mixture was extracted with EtOAc, and the organic layer was washed with brine, filtered through diatomaceous earth, and dried over Na2S04 to provide the title compound, which was used without further purification. ESI-MS (m/z): 170 [M+l]+.
[1138] Step 3. A 0 °C solution of 2-amino-5-fluoro-3-mefhyibenzoic acid (1.5 g, 6.118 mmol) in cone. H2S04 (4 mL) and water (10 mL) was stirred for 10 min, and then a solution of NaN02 (0.55 g, 7.95 mmol) in water (1 mL) was added slowly. After 1 h, a solution of KI (5.1 g, 30.6 mmol) in water (6 mL) was added. After 16 h at rt, the reaction mixture was extracted with EtOAc, and the combined organic layers were washed with satd. aq. Na2S203 (aq) and brine, dried over MgS04, and cocnentrated to provide the title compound. ESI-MS (m/z): 281 [M+l]+.
Intermediate 6. 3,5-Difluoro-2-(2H- 2,3-triazol-2-yl)benzoic acid.
Figure imgf000458_0001
[1139] Step 1. 3,5-Difluoro-2-iodobenzoic acid. The title compound was prepared from 3,5- difluorobenzoic acid as described for Intermediate 5. ESI-MS (m/z): 285 [M+l]+.
[1140] Step 2. The title compound was prepared from 3,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole as described for Intermediate 3. ESI-MS (m/z): 226 [M+l]+.
Intermediate 7. 3,6-Difluoro-2-(2H- 2,3-triazol-2-yl)benzoic acid.
Figure imgf000458_0002
[1141] Step 1. 3,6-Difruoro-2-iodobenzoic acid. To freshly distilled diisopropylamine (14 niL, 0.1 mol) in THF (200 niL) at 0 °C was slowly added BuLi (40 niL, 2.5 M, 0.1 mol) under argon. After 30 min at rt, the mixture was cooled to -78 °C and treated with 1,4- difluoro-2-iodobenzene (24 g, 0.1 mol). After 1 h at -78 °C, the reaction was quenched with solid C02. The reaction was allowed to warm to rt and was concentrated. The resulting residue was partitioned between 4 N NaOH (aq) and diethyl ether. The aqueous phase was adjusted to pH 2 with 2 N HC1 and extracted with EtOAc (3x). The combined extracts were washed with water and brine, dried (MgS04), filtered, and concentrated to provide the title compound.
[1142] Step 2. The title compound was prepared from 3,6-difluoro-2-iodobenzoic acid using the methods described herein. MS (ESI) 226 (M+H).
Intermediate 8. 2 -Difluoro-6-(pyrimidin-2-yl)benzoic acid.
Figure imgf000459_0001
[1143] Step 1. Methyl 6-bromo-2,3-difluorobenzoate. A stirred solution of 6-bromo-2,3- difluorobenzoic acid and concentrated H2S04 in MeOH was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted carefully added satd. aq. NaHC03 and extracted with CH2C12. The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to afford the title compound. ESI MS (M+H) 251.
[1144] Step 2. Methyl 2,3-difluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate. A stirred suspension of methyl 6-bromo-2,3-difluorobenzoate, 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bis(l,3,2-dioxaborolane), PdCl2(dppf), and KOAc in anhydrous 1,4-dioxane was heated at 100 °C under nitrogen for 20 h. After this time, the reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was directly purified by flash column chromatography on silica gel eluting with 0% to 15% EtOAc/hexanes to give the title compound. ESI MS (M+H) 299.
[1145] Step 3. Methyl 2,3-difluoro-6-(pyrimidin-2-yl)benzoate. A stirred suspension of methyl 2,3-difluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate, 2- chloropyrimidine, PdCl2(dppf), and K2C03 in 1,4-dioxane and water (3: 1, v/v) was heated at 90 °C under nitrogen for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was directly purified by flash column
chromatography on silica gel eluting with 0% to 50% EtOAc/hexanes to give the title compound. ESI MS (M+H) 251.
[1146] Step 4. A solution of methyl 2,3-difluoro-6-(pyrimidin-2-yl)benzoate in 2 N NaOH and water was heated at reflux for 4 h. The reaction mixture was cooled to rt and
concentrated to half volume under reduced pressure. The resulting mixture was acidified to pH 4 with 1 N HC1 and extracted with EtOAc. The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the title compound. ESI MS (M+H) 237.
Intermediate 9. 4-Methyl-2-(pyrimidin-2-yl)benzoic acid.
Figure imgf000460_0001
[1147] The title compound was prepared following the same general protocol as described for Intermediate 8 using 2-bromo-4-methylbenzoic acid. ESI MS (M+H) 215.
Intermediate 10. 6-Fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000460_0002
[1148] Step 1. (Z)-N-(5-Fluoro-2-methylphenyl)-2-(hvdroxyimino)acetamide. A -10 °C mixture of 5-fluoro-2-methylaniline (10 g, 80 mmol) and NaHC03 (67 g, 800 mmol) in CH2C12 (200 mL) was treated dropwise with a solution of freshly distilled 2,2- diacetoxyacetyl chloride (20 g, 103 mmol). The mixture was allowed to warm to rt. When TLC indicated consumption of the aniline, the solid was removed by filtration, washed with CH2C12, and the filtrate was concentrated to give crude diacetate. Hydroxylamine hydrochloride (28 g, 400 mmol) was dissolved in a mixture of ethanol (200 mL) and water (100 mL), and the solution was then added to the crude diacetate. The mixture was heated at reflux for 2 h, cooled to rt, and concentrated until precipitation commenced. Water was then added to precipitate additional product. The solid was collected by filtration and washed with water to yield the title compound (7.22g, 46%). 1H NMR (CDC13, 400 MHz) δ 8.25 (bs, 1H), 7.99 (bs, 1H), 7.85 (m, 1H), 7.55 (s, 1H), 7.05 (m, 1H), 6.7 (m, 1H), 2.20 (s, 3H).
[1149] Step 2. 4-Fluoro-7-methylindoline-2,3-dione. A solution of (Z)-N-(5-Fluoro-2- methylphenyl)-2-(hydroxyimino)acetamide (7.22, 37 mmol) and cone. H2SO4 (50 mL) was heated at 60 °C for 1 h. Theresulting solid was collected by filtration and washed with water to yield the title compound. 1H NMR (CDC13, 400 MHz) δ 8.35 (bs, 1H), 7.45 (m, 1H), 6.73 (m, 1H), 2.25 (s, 3H).
[1150] Step 3. 2-Amino-6-fluoro-3-methylbenzoic acid. A solution of 4-fluoro-7- methylindoline-2,3-dione (6.20 g, 34.6 mmol) in 1 M NaOH (114 mL) was treated dropwise with 30% aq. H202 (20 mL) and the resulting mixture was heated at 50 °C for 30 min, cooled to rt, and filtered. The filtrate was adjusted to pH 4 with cone. HC1, cooled to 4 °C. and filtered. The filter cake was dried under vacuum to provide the desired product. 1H NMR (CDCI3, 400 MHz) δ 7.15 (m, 1H), 6.40 (m, 1H), 2.15 (s, 3H).
[1151] Step 4. 6-Fluoro-2-iodo-3-methylbenzoic acid. A solution of 2-amino-6-fluoro-3- methylbenzoic acid in 7.5 mL of H2S04 and 15 mL of H20 was stirred for 30 min. The resultant suspension was cooled to 0 °C, and treated dropwise with a solution of NaN02 (1.06 g, 11.8 mmol) in 2 mL of H20. After 1.5 h at 0 °C, the mixture was treated slowly with a solution of KI (9.8 g, 59 mmol) in 10 mL of H20. The resulting mixture was stirred vigorously at rt overnight, diluted with water and extracted with EtOAc. The combined extracts were washed with brine, aq. Na2S203, and water, dried over Na2S04, and
concentrated. The residue was subjected to silica-gel chromatography (0 to 20%
EtOAc/hexanes). 1H NMR (CDC13, 400 MHz) δ 7.25 (m, 1H), 7.05 (m, 1H), 2.48 (s, 3H).
[1152] Step 5. A mixture of 6-fluoro-2-iodo-3-methylbenzoic acid (900 mg, 3.21 mmol), 1,2,3-triazole (208 μί, 4.82 mmol), (lS,2S)-Nl,N2-dimethylcyclohexane-l,2-diamine (103 μΐ, 642 μιηοΐ), Cs2C03 (1.57g, 4.82 mmol), and Cul (61 mg, 321 μιηοΐ) in DMF (5 mL) was degassed and heated at 120 °C for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with MeOH, acidified with AcOH to pH4~5, and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to yield the title compound. MS (ESI) 222 (M+H).
[1153] Intermediates 11-16 were prepared as described for Intermediate 10. Intermediate 11. 4-Fluoro-3-methyl-2- -l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000462_0001
[1154] Step 1. 4-Fluoro-2-iodo-3-methylbenzoic acid. MS (ESI) 281 (M+H).
[1155] Step 2. MS (ESI) 222 (M+H).
Intermediate 12: 5-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid.
Figure imgf000462_0002
1156] Step 1. 5-Fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 281 (M+H). 1157] Step 2. MS (ESI) 222 (M+H). intermediate 13: 4-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid 1158] Step 1. 4-Fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 281 (M+H). 1159] Step 2. MS (ESI) 222 (M+H). intermediate 14: 3-Fluoro-5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid 1160] Step 1. 3-Fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 281 (M+H). 1161] Step 2. MS (ESI) 222 (M+H). intermediate 15: 3-Fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid 1162] Step 1. 3-Fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 281 (M+H). 1163] Step 2. MS (ESI) 222 (M+H). intermediate 16: 3-Fluoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)benzoic acid 1164] Step 1. 3-Fluoro-6-iodo-2-methylbenzoic acid. MS (ESI) 281 (M+H). 1165] Step 2. MS (ESI) 222 (M+H).
Intermediate 17: ((2S,3R)-3-Methylpiperidin-2-yl)methanol. [1166] To a solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate (5 g) in methanol was added 10% Pd/C (0.5g). The flask was evacuated/H2 purged (3x), and then stirred under a balloon of H2 until starting material was consumed as judged by t.l.c. analysis. The reaction was filtered through diatomaceous earth and concentrated to yield (2S,3R)-methyl 3-methylpiperidine-2-carboxylate as a white solid which was used without further purification. 1H NMR (CDC13, 400 MHz) δ 3.4 (m, 2H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 1.7 (m, 1H), 1.6-1.4 (m, 4H), 0.8 (d, 3H).
Example Bl. 5-(4-Fluorophenyl -2-methylthiazol-4-yl ('('2tS',3R -3-methyl-2-('('('5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000463_0001
[1167] Step 1. 2-(((2S,3R)- l-(5-(4-Fluorophenyl)-2-methylthiazole-4-carbonyl)-3- methylpiperidin-2- yl)methyl)isoindoline- 1 ,3-dione. To a stirred solution of 2-(((2S,3R)-3- methylpiperidin-2-yl)methyl)isoindoline-l,3-dione (3.80 g, 14.7 mmol), 5-(4-fluorophenyl)- 2-methylthiazole-4-carboxylic acid (prepared as described in WO2010/038200; 4.19 g, 17.7 mmol), and diisopropylethyl amine (DIPEA; 3.86 g, 29.9 mmol) in anhydrous
dimethylacetamide (DMA; 40 mL) was added l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4.5-b[pyridinium 3-oxide hexafluorophosphate (HATU; 6.73 g, 17.7 mmol) at rt. After 18 h at rt, the mixture was diluted with EtOAc (400 mL), washed with 10% aq. LiCl (3 x 100 mL) and brine (100 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 10% to 40% EtOAc/CH2Cl2 to afford the title compound as a light yellow solid (6.93 g, 99%). ESI MS (M+H) 478.
[1168] Step 2. ((2 R)-2-(Aminomethyl)-3-methylpiperidin- l-yl)(5-(4-fluorophenyl)-2- methylthiazol-4-yl)methanone. A stirred solution of the product of Step 1 (6.93 g, 14.5 mmol) and ΝΗ2ΝΗ2·Η20 (2.89 g, 57.7 mmol) in MeOH (180 mL) was heated at reflux for 5 h. After this time, the reaction mixture was cooled to rt and concentrated. The residue was triturated with a mixture of MeOH (40 mL), CH2C12 (100 mL), and hexanes (50 mL), and filtered. The filtrate was concentrated and the residue was triturated again with a mixture of MeOH (5 mL), CH2C12 (150 mL), and hexanes (150 mL), and filtered. The filtrate was concentrated and the residue obtained was dissolved in EtOAc (200 mL) and hexanes (50 mL), subsequently washed with half satd. aq. NaHC03 (50 mL), water (50 mL), and brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to afford the title compound as a light yellow solid (3.85 g, 76%). ESI MS (M+H) 348.
[1169] Step 3. A stirred suspension of the product of Step 2 (3.85 g, 11.1 mmol), 2-chloro-5- (trifluoromethyl)pyrimidine (2.93 g, 16.0 mmol), and K2C03 (4.07 g, 29.4 mmol) in anhydrous DMA (45 mL) was heated at 100 °C for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc (400 mL) and hexanes (50 mL), washed with 10% aq. LiCl (3 x 100 mL) and brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 10% to 100% EtOAc/CH2Cl2 followed by lyophilization from H20/CH3CN (1:2) to afford the title compound as an off-white solid (2.38 g, 44%). 1H NMR (300 MHz, CDC13) δ 8.50-8.45 (m, 2H), 7.63-7.41 (m, 3H), 7.12-7.01 (m, 2H), 5.92-2.67 (m, 8H), 1.90-0.88 (m, 8H). ESI MS (M+H) 494.
Example B2: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)((2tS',3R)-3-methyl-2-((5- (trifluoromethyl)- lH-indol- 1 -yPmethyPpiperidin- 1 -yPmethanone trifluoro acetate and Example B3: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)((2tS',3R)-3-methyl-2-((5- (trifluoromethyl)indolin- 1 -vPmethvPpiperidin- 1 -yPmethanone trifluoroacetate.
Figure imgf000464_0001
[1170] Step 1. ((2S R)-3-Methylpiperidin-2-vPmethanol. A suspension of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-l-carboxylate (254 mg, 0.965 mmol), 10% Pd/C (50% wet, 60 mg), and HC02NH4 (608 mg, 9.65 mmol) in MeOH (20 mL) was heated at reflux for 5 h. The reaction mixture was cooled to rt, filtered through a short pad of diatomaceous earth, and washed with MeOH (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was dried under high vacuum to afford the title compound as a colorless oil (115 mg, 92%). 1H NMR (300 MHz, CDC13) δ 3.55-2.60 (m, 7H), 1.90-1.35 (m, 5H), 0.89 (d, J = 7.1 Hz, 3H).
[1171] Step 2. ((2tS,,3R)-l-Benzyl-3-methylpiperidin-2-yl)methanol. A solution of the product of Step 1 (115 mg, 0.890 mmol), DIPEA (230 mg, 1.78 mmol), and benzyl bromide (230 mg, 1.35 mmol) in anhydrous THF (10 mL) was stirred at rt under nitrogen for 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with satd. aq. NaHC03 a (20 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 10% MeOH/CH2Cl2 to give the title compound as a colorless oil (131 mg, 67%). ESI MS (M+H) 220.
[1172] Step 3. (2tS',3R)-l-Benzyl-2-(chloromethyl)-3-methylpiperidine. To a stirred solution of the product of Step 2 (131 mg, 0.597 mmol) and Et3N (131 mg, 1.29 mmol) in anhydrous CH2CI2 (8 mL) was added methanesulfonyl chloride (138 mg, 1.20 mmol) at rt under nitrogen. After 22 h at rt, the reaction mixture was diluted with CH2CI2 (50 mL), washed with 10% aq. citric acid (20 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to afford the title compound as a light brown oil (132 mg, 93%). ESI MS (M+H) 238.
[1173] Step 4. l-(((2tS',3R)-l-Benzyl-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)-lH- indole. A suspension of the product of Step 3 (132 mg, 0.555 mmol), 5-(trifluoromethyl)-lH- indole (308 mg, 1.66 mmol), and Cs2C03 (723 mg, 2.22 mmol) in anhydrous DMA (5 mL) was heated at 80 °C under nitrogen for 19 h. The reaction mixture was cooled to rt, diluted with EtOAc (60 mL), washed with 10% aq. LiCl (3 x 20 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 5% to 20%
EtOAc/hexanes to afford the title compound as a light yellow oil (40 mg, 19%). ESI MS (M+H) 387.
[1174] Step 5. l-(((2tS',3R)-3-Methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)-lH-indole and l-(((2tS',3R)-3-Methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)indoline. A 200-mL pressure flask was charged with the product of Step 4 (40 mg, 0.104 mmol), 20% Pd(OH)2/C (50% wet, 10 mg), cone. HC1 (2 μί), and MeOH (10 mL). The flask was then evacuated and charged with hydrogen gas (35 psi). After shaking at rt for 20 h, the catalyst was removed by vacuum filtration through a short pad of diatomaceous earth. The filter cake was washed with MeOH (60 mL). The combined filtrate was concentrated. The residue was dried under high vacuum to afford a crude mixture of the title compounds as a light brown foam (47 mg), which was used directly without further purification. ESI MS (M+H) 297/299. [1175] Step 6. To a stirred solution of the material obtained from Step 5 (47 mg), 5- (4- fluorophenyl)-2-methylthiazole-4-carboxylic acid (30 mg, 0.126 mmol), and DIPEA (54 mg, 0.419 mmol) in anhydrous DMA (3 mL) was added HATU (79 mg, 0.208 mmol) at rt. After 20 h at rt, the reaction mixture was diluted with EtOAc (50 mL), washed with 10% aq. LiCl (3 x 20 mL) and brine (20 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 20% EtOAc/CH2Cl2 to afford a mixture of the title compounds, which were further separated by reverse -phase semi-preparative HPLC eluting with 0.05% TFA in
acetonitrile/water (gradient from 10% to 100%, Phenomenex Luna column) to provide Example 2 as an off-white solid (17 mg, 26% over two steps) and Example 3 as a white solid (27 mg, 41% over two steps). Example 2: 1H NMR (300 MHz, DMSO-J6) δ 8.05-6.55 (m,
9H), 5.25-3.15 (m, 5H), 2.75-0.85 (m, 11H); ESI MS (M+H) 516. Example 3: 1H NMR (300 MHz, DMSO- ) δ 7.50-6.05 (m, 7H), 5.00-2.80 (m, 9H), 2.75-2.35 (m, 3H), 1.85- 0.75 (m, 8H); ESI MS (M+H) 518.
Example B24. ((2tS,,3R)-2-(((5-Chlorobenzor loxazol-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-fluor -2-(2H-L2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000466_0001
[1176] Step 1. ((2S,3R)-2-(Aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone. The title compound was prepared using methods analogous to those described for Intermediate 1. MS (ESI) 318 (M+H).
[1177] Step 2. A solution of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-fluoro-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone (38 mg, 0.120 mmol), 2,5-dichlorobenzo[d]oxazole (27 mg, 0.140 mmol), and DIPEA (31 mg, 0.240 mmol) in anhydrous DMF (3 mL) was heated at 60 °C under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with 10% LiCl aqueous solution (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 0% to 100% EtOAc/hexanes then lyophilized from acetonitrile/water (2: 1) to afford the title compound as a white solid (54 mg, 98%): 1H NMR (300 MHz, DMSO-J6) δ 8.35-6.85 (m, 9H), 4.90-2.70 (m, 5H), 2.00-0.65 (m, 8H); ESI MS (M+H) 469.
Example B25: (5-Fluoro-2-(2H-l,2,3-triazol-2-yl phenyl ((2^,3R -2-(((5- fluorobenzor loxazol-2-yl)amino)methyl)-3-methylpiperidin-l-yl)methanone.
Figure imgf000467_0001
[1178] Step 1. 5-Fluorobenzordloxazole-2-thiol. A mixture of 2-amino-4-fluorophenol (1 g, 7.9 mmol) and ethylxanthic acid potassium salt (1.3 g, 7.9 mmol) in EtOH (10 mL) was heated at reflux for 7 h. The mixture was cooled to rt and concentrated in vacuo. The crude was dissolved in water and adjusted to pH 5 with acetic acid. The product was filtered to obtain the title compound, which was used without further purification.
[1179] Step 2. 2-Chloro-5-fluorobenzordloxazole. A mixture of 5-fluorobenzo[d]oxazole-2- thiol (300 mg, 1.7 mmol) in thionyl chloride (6 mL) and 2 drops of DMF was heated at 70 °C for 3 h. The mixture was cooled to rt and concentrated in vacuo. The crude was dissolved in EtOAc and filtered through silica gel. The filtrate was concentrated to obtain the title compound, which was used without further purification. 1H NMR (CDC13, 400 MHz) δ 7.44 (dd, J = 4.3, 8.6 Hz, 1H), 7.37 (dd, J = 2.8, 8.08 Hz, 1H), 7.09 (dt, J = 2.5, 9.09 Hz, 1H).
[1180] Step 3. The title compound was prepared from ((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)(5-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5- fluorobenzo[d]oxazole using methods analogous to those described herein. 1H NMR (300 MHz, DMSO- ) δ 8.30-6.75 (m, 9H), 4.85-2.70 (m, 5H), 2.00-0.65 (m, 8H). ESI MS (M+H) 453.
Example B46: rac-(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(3-methyl-2-(((5- (trifluoromethyl)benzordloxazol-2-yl)amino)methyl)piperidin-l-yl)methanone.
Figure imgf000468_0001
[1181] Step 1. 2-Chloro-5-(trifluoromethyl)benzordloxazole. The title compound was prepared following the same general protocol as described for Example 25, using 2-amino-4- trifluoromethylphenol. ESI-MS (m/z): 222 [M+l]+.
[1182] Step 2. The title compound was prepared from rac-((2S,3R)-2-(aminomethyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2-chloro-5- (trifluoromethyl)benzo[d]oxazole using methods analogous to those described herein. ESI- MS (m/z): 532 [M+l]+.
Example B53: ((2S,3R)-2-(((5-Bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-l-
Figure imgf000468_0002
[1183] A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-l-yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone (50 mg, 143 μmol), 5-bromo-2-chloroquinazoline (70 mg, 289 μπιοΐ), and K2C03 (60 mg, 431 μπιοΐ) in DMF (2 mL) was heated at 100 °C overnight. The mixture was cooled to rt andconcentrated in vacuo. The crude was dissolved in EtOAc and washed with satd. aq. NaHC03 and brine, dried (MgS04), and concentrated. The crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 555 (M+H).
Example B54: (5-(4-Fluorophenyl)-2-methylthiazol-4-yl)((2S,3R)-3-methyl-2-((quinazolin-
2-ylamino)methyl)piperidin- 1 -yPmethanone.
Figure imgf000469_0001
[1184] A mixture of ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3- methylpiperidin-l-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (15 mg, 27 μιηοΐ), paraformaldehyde (1 mg, 27 μιηοΐ), Cs2C03, (15 mg, 27 μιηοΐ) and Pd(PPh3)4 (3 mg, 2.7 μmol), in toluene (2.5 mL) and H20 (0.5 mL) was degassed, sealed, and heated overnight at 100 °C. The reaction was filtered through pad of diatomaceous earth, washing with EtOAc. The filtrate was concentrated and the crude was purified by reverse -phase preparative-HPLC to obtain the title compound. ESI-MS (m/z): 476 (M+H).
Example B98. (5-Fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl phenyl ((2S,3R -3-methyl-2-
(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-l-yl)methanone.
Figure imgf000469_0002
[1185] Step 1. 5-Fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid. The title compound was prepared from 2-iodo-5-fluoro-3-methylbenzoic acid using methods analogous to those described for Example 24. MS (ESI) 222 (M+H).
[1186] Step 2. The title compound was prepared from ((2S,3R)-3-methylpiperidin-2- yl)methanol, 5-fluoro-3-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid and 2-chloro-5- (trifluoromethyl)pyridine using methods analogous to those described herein. MS (ESI) 478 (M+H).
[1187] Additional Examples were prepared using the methods described in the preceding examples. Analytical data are shown in Tables 8A and 8B below. Table 8A: Analytical Data
Figure imgf000470_0001
methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-3-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A343 ESI-MS (m/z): 489 [M+l]+.
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(4-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A345 ESI-MS (m/z): 478 (M+H).
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(4-fluoro-3-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A346 ESI-MS (m/z): 488 (M+H).
(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(4-fluoro-3-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A347 ESI-MS (m/z) 489 [M+l]+.
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A348 MS (ESI) 477 (M+H).
(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A349 MS (ESI) 478 (M+H).
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(6-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A353 ESI-MS (m/z): 478 (M+H).
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(6-fluoro-3-methyl-2-(pyrimidin-2-
A354 yl)phenyl)((2S,3R)-3-methyl-2-(((5- ESI-MS (m/z): 488 (M+H).
(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(6-fluoro-3-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A355 ESI-MS (m/z): 489 (M+H).
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(3-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A357 ESI-MS (m/z): 478[M+1]+.
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(3-fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A358 ESI-MS (m/z): 488 (M+H).
(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(3-fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A359 ESI-MS (m/z) 489 [M+l]+.
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A361 ESI-MS (m/z): 478 (M+H) (trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A362 ESI-MS (m/z): 488 (M+H).
(trifluoromethyl)pyridin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(5-fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A363 ESI-MS (m/z) 489 [M+l]+.
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
(4-fluoro-5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
A369 ESI-MS (m/z): 478 (M+H).
(trifluoromethyl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methanone
Figure imgf000473_0001
Table 8B: Analytical Data
Figure imgf000473_0002
lH NMR (300 MHz, DMSO-J6) δ
(2-(2H- l,2,3-Triazol-2-yl)phenyl)((2S,3R)-2- 8.50-6.90 (m, 9H), 4.95-2.70 (m,
B4 (((5-chloropyrimidin-2-yl)amino)methyl)-3- 5H), 2.00-0.65 (m, 8H); ESI MS methylpiperidin- 1 -yl)methanone
(M+H) 412.
(5-Methoxy-2-(2H- l,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.75-6.45 (m, 8H), 4.90-2.70 (m,
B5
(trifluoromethyl)pyrimidin-2- 8H), 1.70-0.40 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 476.
(5-Methoxy-2-(2H- l,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.45-6.30 (m, 9H), 4.80-2.70 (m,
B6
(trifluoromethyl)pyridin-2- 8H), 1.80-0.40 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 475.
((2S,3R)-2-(((5-chloropyrimidin-2- lH NMR (300 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 - 8.45-6.45 (m, 8H), 4.90-2.70 (m,
B7
methoxy-2-(2H- l,2,3-triazol-2- 8H), 1.75-0.40 (m, 8H); ESI MS yl)phenyl)methanone (M+H) 442.
((2S,3R)-2-(((5-Chloropyrimidin-2- 1H NMR (300 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (2- 8.50-6.50 (m, 7H), 4.95-2.70 (m,
B8
fluoro-3-methyl-6-(2H- 1 ,2,3-triazol-2- 5H), 2.35-0.65 (m, 11H); ESI yl)phenyl)methanone MS (M+H) 444.
((2S,3R)-2-(((5-Chloropyrimidin-2- lH NMR (500 MHz, DMSO-J6) δ yl)amino)methyl)-3-methylpiperidin- 1 - 8.50-6.48 (m, 7H), 4.90-2.70 (m,
B9
yl)(4,5-dimethyl-2-(2H-l ,2,3-triazol-2- 5H), 2.45-0.65 (m, 14H); ESI yl)phenyl)methanone MS (M+H) 440.
(4,5-Dimethyl-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.85-6.50 (m, 7H), 4.95-2.70 (m,
B IO
(trifluoromethyl)pyrimidin-2- 5H), 2.35-0.55 (m, 14H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 474.
(4,5-Dimethyl-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.40-6.45 (m, 8H), 4.80-2.70 (m,
B l l
(trifluoromethyl)pyridin-2- 5H), 2.35-0.60 (m, 14H); .ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 473.
B 12 ((4-Methoxy-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.50-6.35 (m, 9Η), 4.85-2.70 (m, (trifluoromethyl)pyridin-2- 8Η), 1.95-0.65 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 475.
(4-Methoxy-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.75-6.40 (m, 8H), 4.95-2.70 (m,
B 13
(trifluoromethyl)pyrimidin-2- 8H), 2.00-0.50 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 476.
((2S,3R)-2-(((5-Chloropyrimidin-2- lH NMR (300 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (4- 8.50-6.45 (m, 8H), 4.95-2.70 (m,
B 14
methoxy-2-(2H- 1 ,2,3-triazol-2- 8H), 2.00-0.50 (m, 8H); ESI MS yl)phenyl)methanone (M+H) 442.
((2S,3R)-2-(((5-Chloropyrimidin-2- lH NMR (500 MHz, DMSO-J6) δ yl)amino)methyl)-3-methylpiperidin- 1 - 8.45-6.65 (m, 7H), 4.65-2.70 (m,
B 15
yl) (3 ,4-dimethyl-2- (2Η- 1 ,2,3-triazol-2- 5H), 2.35-0.75 (m, 14H); ESI yl)phenyl)methanone MS (M+H) 440.
(3,4-Dimethyl-2-(2H- l,2,3-triazol-2- lH NMR (500 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.75-6.65 (m, 7H), 4.75-2.70 (m,
B 16
(trifluoromethyl)pyrimidin-2- 5H), 2.35-0.75 (m, 14H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 474.
(3,4-Dimethyl-2-(2H- l,2,3-triazol-2- lH NMR (500 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.35-6.50 (m, 8H), 4.65-2.70 (m,
B 17
(trifluoromethyl)pyridin-2- 5H), 2.35-0.75 (m, 14H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 473.
((2S,3R)-2-(((5-Chloropyrimidin-2- lH NMR (500 MHz, DMSO-J6) δ yl)amino)methyl)-3-methylpiperidin- 1 - 8.45-6.45 (m, 7H), 4.85-2.70 (m,
B 18
yl)(4,5-dimethoxy-2-(2H- l,2,3-triazol-2- 11H), 2.05-0.65 (m, 8H); ESI yl)phenyl)methanone MS (M+H) 472.
(4,5-Dimethoxy-2-(2H- l,2,3-triazol-2- lH NMR (500 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.85-6.50 (m, 7H), 4.90-2.70 (m,
B 19
(trifluoromethyl)pyrimidin-2- 11H), 2.05-0.67 (m, 8H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 506.
(3,5-Dimethyl-2-(2H- l,2,3-triazol-2- 1H NMR (500 MHz, DMSO-J6) δ
B20
yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.35-6.25 (m, 8H), 4.65-2.70 (m, (trifluoromethyl)pyridin-2- 5Η), 2.35-0.75 (m, 14H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 473.
(3,5-Dimethyl-2-(2H- l,2,3-triazol-2- lH NMR (500 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.75-6.45 (m, 7H), 4.75-2.70 (m,
B21
(trifluoromethyl)pyrimidin-2- 5H), 2.35-0.75 (m, 14H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 474.
((2S,3R)-2-(((5-Chloropyrimidin-2- lH NMR (500 MHz, DMSO-J6) δ yl)amino)methyl)-3-methylpiperidin- 1 - 8.45-6.45 (m, 7H), 4.65-2.70 (m,
B22
yl)(3,5-dimethyl-2-(2H-l ,2,3-triazol-2- 5H), 2.35-0.75 (m, 14H); ESI yl)phenyl)methanone MS (M+H) 440.
(5-Chloro-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.35-6.50 (m, 9H), 4.85-2.70 (m,
B23
(trifluoromethyl)pyridin-2- 5H), 1.90-0.65 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 479.
((2S,3R)-2-(((6-Chlorobenzo[d]oxazol-2- lH NMR (300 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 - 8.30-6.85 (m, 9H), 4.85-2.70 (m,
B26
fluoro-2-(2H- 1 ,2,3-triazol-2- 5H), 1.90-0.65 (m, 8H); ESI MS yl)phenyl)methanone (M+H) 469.
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin- l-yl)(5-
B27 ESI MS (M+H) 435.
fluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-((benzo[d]thiazol-2- ylamino)methyl)-3-methylpiperidin- l-yl)(5-
B28 ESI MS (M+H) 451.
fluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(5-fluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B29 ESI MS (M+H) 469.
fluorobenzo[d]thiazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
(5-Fluoro-2-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ
B30 yl)phenyl)((25,3R)-2-(((6- 8.15-6.85 (m, 9H), 4.90-2.70 (m, fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- 5H), 2.05-0.65 (m, 8H); ESI MS methylpiperidin- 1 -yl)methanone (Μ+Η) 453.
((2S,3R)-2-(((5-Chlorobenzo[d]oxazol-2- lH NMR (500 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (2- 8.25-6.90 (m, 9H), 4.95-2.70 (m,
B31
fluoro-6-(2H- 1 ,2,3-triazol-2- 5H), 2.00-0.65 (m, 8H); ESI MS yl)phenyl)methanone (M+H) 469.
(2-Fluoro-6-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-2-(((5- 8.15-6.75 (m, 9H), 5.00-2.70 (m,
B32
fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- 5H), 1.90-0.65 (m, 8H); ESI MS methylpiperidin- 1 -yl)methanone (M+H) 453.
((2S,3R)-2-(((6-Chlorobenzo[d]oxazol-2- lH NMR (300 MHz, DMSO-J6) δ yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (2- 8.20-7.10 (m, 9H), 5.05-2.70 (m,
B33
fluoro-6-(2H- 1 ,2,3-triazol-2- 5H), 1.95-0.65 (m, 8H); ESI MS yl)phenyl)methanone (M+H) 469.
(2-Fluoro-6-(2H- 1 ,2,3-triazol-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-2-(((6- 8.20-6.90 (m, 9H), 4.95-2.70 (m,
B34
fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- 5H), 2.00-0.65 (m, 8H); ESI MS methylpiperidin- 1 -yl)methanone (M+H) 453.
lH NMR (300 MHz, DMSO-J6) δ
(5-Chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)- 8.95-6.60 (m, 10H), 4.85-2.75
B35 3 -methyl-2- ( ( (5 - (trifluoromethyl)pyridin-2- (m, 5H), 2.00-0.65 (m, 8H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone
MS (M+H) 490.
(2-Fluoro-3-methoxy-6-(pyrimidin-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.85-6.45 (m, 9H), 5.05-2.75 (m,
B36
(trifluoromethyl)pyridin-2- 8H), 2.05-0.65 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 504.
(2-Fluoro-3-methoxy-6-(pyrimidin-2- lH NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.95-7.05 (m, 8H), 5.00-2.75 (m,
B37
(trifluoromethyl)pyrimidin-2- 8H), 2.05-0.65 (m, 8H); ESI MS yl)amino)methyl)piperidin- 1 -yl)methanone (M+H) 505.
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2-
B38 yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 - ESI-MS (m/z): 480 [M+l]+. fluoro-2-(pyrimidin-2-yl)phenyl)methanone
B39 ((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- ESI-MS (m/z): 480 [M+l]+. yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 - fluoro-2-(pyrimidin-2-yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl)amino)methyl)-3-methylpiperidin- 1 -
B40 ESI-MS (m/z): 498 [M+l]+. yl)(4,5-difluoro-2-(pyrimidin-2- yl)phenyl)methanone.
(5-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)- 2-(((5-fluorobenzo[d]oxazol-2-
B41 ESI-MS (m/z): 464 [M+l]+. yl)amino)methyl)-3-methylpiperidin- 1 - yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2-
B42 yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 - ESI-MS (m/z): 481 [M+l]+. fluoro-2-(pyrimidin-2-yl)phenyl)methanone
(5-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)- 2-(((6-fluorobenzo[d]oxazol-2-
B43 ESI-MS (m/z): 464 [M+l]+. yl)amino)methyl)-3-methylpiperidin- 1 - yl)methanone
((2S,3R)-2-((benzo[d]oxazol-2-
B44 ylamino)methyl)-3-methylpiperidin-l-yl)(5- ESI-MS (m/z): 446 [M+l]+. fluoro-2-(pyrimidin-2-yl)phenyl)methanone
((2S,3R)-2-((benzo[d]thiazol-2-
B45 ylamino)methyl)-3-methylpiperidin-l-yl)(5- ESI-MS (m/z): 462 [M+l]+. fluoro-2-(pyrimidin-2-yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (6-
B47 ESI-MS (m/z): 483 (M+H). fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(6-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((5-
B48 ESI-MS (m/z): 467 (M+H). fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2-
B49 ESI-MS (m/z): 483 (M+H). yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (6- fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(6-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B50 ESI-MS (m/z): 467 (M+H). fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(6-
B51 ESI-MS (m/z): 449 (M+H). fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (6-
B52 ESI-MS (m/z): 488 (M+H). fluoro-3-methyl-2-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-(((6-fluorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 -
B55 ESI-MS (m/z): 483(M+H).
(4-fluorophenyl)-2-methylthiazol-4- yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 -
B56 ESI-MS (m/z): 499(M+H)
(4-fluorophenyl)-2-methylthiazol-4- yl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl)amino)methyl)-3-methylpiperidin- 1 -
B57 ESI-MS (m/z): 487 [M+l]+. yl)(3,4-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone
(3,4-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((5-
B58 ESI-MS (m/z): 471 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
(3,4-difluoro-2-(2H-l,2,3-triazol-2-
B59 yl)phenyl)((2S,3R)-2-(((6- ESI-MS (m/z): 471 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2- yl)amino)methyl)-3-methylpiperidin- 1 -
B60 ESI-MS (m/z): 487 [M+l]+. yl)(3,4-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(3,4-
B61 ESI-MS (m/z): 453 [M+l]+. difluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B62 ESI-MS (m/z): 483 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(3-
B63 ESI-MS (m/z): 449 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(3-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B64 ESI-MS (m/z): 483 [M+l]+. fluorobenzo[d]thiazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-((benzo[d]thiazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(3-
B65 ESI-MS (m/z): 465 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(3-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B66 ESI-MS (m/z): 467 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
(3-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((5-
B67 ESI-MS (m/z): 467 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone ((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B68 ESI-MS (m/z): 483 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]thiazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B69 ESI-MS (m/z): 499 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B70 ESI-MS (m/z): 494 [M+l]+. fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin- 1 -yl)(4-
B71 ESI-MS (m/z): 449 [M+l]+. fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (4-
B72 ESI-MS (m/z): 483 [M+l]+. fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(4-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((5-
B73 ESI-MS (m/z): 467 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (4-
B74 ESI-MS (m/z): 483 [M+l]+. fluoro-3-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(4-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B75 ESI-MS (m/z): 467 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
B76 ((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- ESI-MS (m/z): 483 [M+l]+. yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 - fluoro-2-methyl-6-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B77 ESI-MS (m/z): 494 [M+l]+ fluoro-2-methyl-6-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-((benzo[d]thiazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(3-
B78 ESI-MS (m/z): 476 [M+l]+. fluoro-2-methyl-6-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 -
B79 ESI-MS (m/z): 483 [M+l]+. fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (5 -
B80 ESI-MS (m/z): 494 [M+l]+. fluoro-4-methyl-2-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl) amino)methyl) - 3 -methylpiperidin- 1 - yl) (3 -
B81 ESI-MS (m/z): 494 [M+l]+. fluoro-5-methyl-2-(pyrimidin-2- yl)phenyl)methanone
((2S,3R)-2-(((5-chlorobenzo[d]oxazol-2- yl)amino)methyl)-3-methylpiperidin- 1 -
B82 ESI-MS (m/z): 487 [M+l]+. yl)(3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone
(3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((5-
B83 ESI-MS (m/z): 471 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-(((6-chlorobenzo[d]oxazol-2-
B84 ESI-MS (m/z): 487 [M+l]+. yl)amino)methyl)-3-methylpiperidin- 1 - yl)(3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone
(3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-2-(((6-
B85 ESI-MS (m/z): 471 [M+l]+. fluorobenzo[d]oxazol-2-yl)amino)methyl)-3- methylpiperidin- 1 -yl)methanone
((2S,3R)-2-((benzo[d]oxazol-2- ylamino)methyl)-3-methylpiperidin-l-yl)(3,6-
B86 ESI-MS (m/z): 453 [M+l]+. difluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone
(5-fluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B87 MS (ESI) 464(M+H).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone
(2-fluoro-6-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B88 MS (ESI) 464(M+H).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone
(3-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B89 MS (ESI) 478 (M+H)
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(4-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B90 MS (ESI) 478 (M+H).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(4-fluoro-5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B91 MS (ESI) 478 (M+H).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(5-fluoro-4-methyl-2-(2H- 1 ,2,3-triazol-2-
B92 yl)phenyl)((2S,3R)-3-methyl-2-(((5- MS (ESI) 478 (M+H).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(2-fluoro-3-methyl-6-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B93 MS (ESI) 478 (Μ+Η).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone
(3-fluoro-2-methyl-6-(2H- 1 ,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B94 MS (ESI) 478 (Μ+Η).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(3,4-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B95 MS (ESI) 482 (Μ+Η)
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
(3,6-difluoro-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B96 MS (ESI) 482 (Μ+Η).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone
(6-fluoro-3-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B97 MS (ESI) 478 (Μ+Η).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone
(3-fluoro-5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)((2S,3R)-3-methyl-2-(((5-
B99 MS (ESI) 478 (Μ+Η).
(trifluoromethyl)pyridin-2- yl)oxy)methyl)piperidin- 1 -yl)methanone.
((4,5-Dimethoxy-2-(2H- 1 ,2,3-triazol-2- 1H NMR (300 MHz, DMSO-J6) δ yl)phenyl)((25,3R)-3-methyl-2-(((5- 8.45-6.45 (m, 8H), 4.85-2.70 (m,
B100
(trifluoromethyl)pyridin-2- 11H), 1.80-0.65 (m, 8H); ESI yl)amino)methyl)piperidin- 1 -yl)methanone MS (M+H) 505.
[1188] Additional examples as shown in Table 1A and Table IB are prepared using methods analogous to those described in the preceding examples. Biological Example 1. Orexin Receptor Cell-based Functional Assay.
[1189] Measurement of [Ca2+]i using a FLIPR: CHO-OXi or CHO-OX2 cells are seeded into black-walled clear-base 384-well plates (Costar) at a density of 20,000 cells per well in F12- K medium supplemented with 10% FBS and selection antibiotic (500ug/ml G418 or 15ug/ml Blasticidin) and cultured overnight. The cells are incubated with equal volume of calcium4 loading buffer (Molecular Devices, Inc.) containing 2.5 mM probenecid at 37°C for 30 min, followed by putative OXi or OX2 receptor antagonists (dose-range 0.1 nM - 10 μΜ) for another 30 min. The plates are then placed into a FLIPR (Molecular Devices, Inc.) to monitor fluorescence (1 excitation 488 nm, 1 emission 540 nm) before and after the addition of EC90 of [OXA].
[1190] Alternatively, CHO-OXi or CHO-OX2 cells are seeded into black-walled clear-base 384-well plates (Corning, catalog #3712) at a density of 20,000 cells per well in F12-K medium supplemented with 10% FBS and then incubated in a 5% C02, 37 °C incubator overnight to reach 90% confluency. The cells are incubated with equal volume of calcium6 loading buffer (Molecular Devices, Inc.) containing 2.5 mM probenecid at 37 °C for 2 h, followed by test compounds (dose-range 0.1 nM - 10 μΜ) for another 30 min. The plates are then placed into a FLIPR (Molecular Devices, Inc.) to monitor fluorescence (λ excitation 488 nm, λ emission 540 nm) before and after the addition of EC90 of [OXA].
[1191] Data for compounds tested in this assay are presented in Tables 2, 2A and 2B. NT = not tested.
Table 2: IC 0 Bioactivity of Exemplary Compounds of the Invention with Respect to OX^ and
Figure imgf000485_0001
0.008 4.9 81 <0.010 >10
0.004 0.45 82 0.004 >10
0.009 0.22 83 0.030 >10
0.009 0.46 84 0.035 >10
0.001 >5.0 85 0.100 >10
0.008 >10.0 86 0.022 >10
0.052 1.8 87 0.22 0.070
0.016 1.5 88 0.042 >10
0.27 >10 89 NT NT
1.3 >10 90 NT NT
0.024 0.52 91 0.14 >10
0.082 >10 92 0.56 >4.0
0.06 1.4 93 0.100 >1.0
0.004 0.34 94 0.076 1.0
0.008 0.13 95 0.029 0.253
0.018 0.091 96 0.018 1.4
<0.10 NT 97 0.009 >10
<0.01 NT 98 0.006 >10
0.20 NT 99 0.082 5.0
0.22 NT 100 0.008 >10
0.010 NT 101 3.0 >10
0.002 0.014 102 >1.0 NT
0.020 NT 103 0.004 6.0
0.005 0.005 104 0.001 8.8
0.002 0.004 105 0.109 1.6
0.002 0.002 106 0.040 >1.0
0.001 0.003 107 0.078 >10
0.004 NT 108 0.013 >10
0.030 0.16 109 >1.0 NT
0.60 1.5 110 >1.0 NT
1.5 NT 111 >1.0 NT
0.027 0.14 112 0.017 >10 43 2.0 NT 113 0.025 0.190
44 NT 1.0 114 0.003 >10
45 <10 NT 115 0.010 >10
46 <10 NT 116 <0.10 NT
47 <10 NT 117 0.038 >10
48 <10 NT 118 0.262 >10
49 0.025 0.6 119 0.400 >10
50 0.007 0.025 120 0.003 0.50
51 0.010 0.075 121 >1.0 NT
52 0.001 0.010 122 3.5 5
53 0.065 0.75 123 3.6 3.2
54 0.18 1.2 124 0.015 0.237
55 0.12 2.0 125 0.010 0.095
56 <0.10 NT 126 0.006 0.008
57 <0.10 NT 127 0.008 0.025
58 0.001 0.008 128 0.035 0.030
59 0.040 1.2 129 0.12 0.32
60 0.001 0.37 130 0.006 NT
61 0.007 0.38 131 0.053 0.040
62 0.001 0.008 132 0.23 1.4
63 0.002 0.048 133 0.012 1.4
64 3.0 NT 134 0.005 >10
65 >2.0 NT 135 NT NT
66 0.35 NT 136 <1.0 NT
67 1.0 NT 137 0.003 0.10
68 0.12 NT 138 0.008 0.040
69 0.13 NT 139 0.003 0.017
70 0.17 NT 140 <0.1 NT
141 0.002 NT
Table 2A: Bioactivity with Respect to C¾ and OX?
Figure imgf000487_0001
Al 0.002 4.0 A168 0.010 >5.0
A2 0.061 >4.0 A169 0.008 >5.0
A3 0.006 >4.0 A170 NT NT
A4 0.025 >4.0 A171 0.37 >5.0
A5 0.006 3.5 A172 0.064 >5.0
A6 0.013 >4.0 A173 0.001 >5.0
A7 NT NT A174 0.001 >5.0
A8 0.058 >4.0 A175 0.001 >5.0
A9 0.009 3.7 A176 0.006 >5.0
A10 0.081 >4.0 A177 0.005 >5.0
Al l 0.003 0.045 A178 0.004 >5.0
A12 0.020 0.8 A179 0.49 >5.0
A13 0.003 >4.0 A180 0.004 0.16
A14 0.010 0.62 A181 0.004 >5.0
A15 NT NT A182 0.14 4.0
A16 0.26 >5.0 A183 0.003 4.0
A17 0.020 >4.0 A184 0.005 2.5
A18 0.007 >4.0 A185 0.046 >5.0
A19 0.004 0.23 A186 0.005 >5.0
A20 0.037 >4.0 A187 0.20 >5.0
A21 0.013 >4.0 A188 0.001 2.3
A22 NT NT A189 0.12 >5.0
A23 >1.0 NT A190 2.0 >5.0
A24 0.011 0.41 A191 0.043 >5.0
A25 0.005 >4.0 A192 0.010 >5.0
A26 NT NT A193 0.10 >5.0
A27 NT NT A194 0.006 >5.0
A28 NT NT A195 0.004 0.389
A29 0.087 >5.0 A196 0.017 >5.0
A30 NT NT A197 0.007 >5.0
A31 NT NT A198 0.005 >5.0
A32 0.009 0.42 A199 0.015 2.6 A33 NT NT A200 0.054 >5.0
A34 NT NT A201 0.004 2.8
A35 NT NT A202 0.018 >5.0
A36 NT NT A203 0.021 >5.0
A37 0.004 NT A204 0.003 0.26
A38 0.100 >5.0 A205 0.011 0.35
A39 NT NT A206 0.006 0.14
A40 0.020 0.900 A207 0.011 >5.0
A41 0.004 >4.0 A208 0.20 >5.0
A42 >1.0 NT A209 0.045 >5.0
A43 0.67 >4.0 A210 0.14 >5.0
A44 0.011 >5.0 A211 0.14 >5.0
A45 >1.0 NT A212 0.005 3.3
A46 0.005 >5.0 A213 NT NT
A47 0.15 >5.0 A214 NT NT
A48 0.025 >5.0 A215 0.010 1.3
A49 0.50 >5.0 A216 0.005 2.0
A50 0.23 >5.0 A217 0.15 >5.0
A51 >1.0 NT A218 0.13 >5.0
A52 NT NT A219 2.6 >5.0
A53 0.67 >5.0 A220 0.011 2.5
A54 NT NT A221 0.032 >5.0
A55 NT NT A222 0.082 >5.0
A56 >1.0 NT A223 0.037 >5.0
A57 >1.0 NT A224 0.013 >5.0
A58 0.23 2.4 A225 0.34 >5.0
A59 0.050 >2.0 A226 0.011 >5.0
A60 0.49 >5.0 A227 0.002 >5.0
A61 1.1 >5.0 A228 0.001 >5.0
A62 NT NT A229 0.004 >5.0
A63 NT NT A230 0.005 >5.0
A64 >1.0 NT A231 0.017 >5.0 A65 0.007 0.038 A232 0.008 >5.0
A66 0.15 2.5 A233 0.005 0.81
A67 0.006 0.13 A234 0.011 >5.0
A68 0.25 3.36 A235 0.012 2.4
A69 0.021 1.4 A236 NT NT
A70 2.5 7.8 A237 NT NT
A71 0.070 3.6 A239 0.083 >5.0
A72 2.4 3.9 A240 0.003 >5.0
A73 NT NT A241 0.009 >5.0
A74 NT NT A242 0.024 >5.0
A75 1.3 >5.0 A243 0.075 >5.0
A76 >1.0 NT A244 1.3 >5.0
A77 >1.0 NT A245
A78 0.007 2.9 A246 >0.10 >5.0
A79 0.31 >4.0 A247 >0.10 >5.0
A80 1.87 >4.0 A248 0.020 >5.0
A81 NT NT A249 0.018 >5.0
A82 0.008 0.84 A250 0.047 >5.0
A83 NT NT A251 0.058 >5.0
A84 0.003 >4.0 A252
A85 0.002 >5.0 A253
A86 NT NT A254 0.037 >5.0
A87 0.22 >4.0 A255 0.041 >5.0
A88 0.60 1.8 A256 0.005 >5.0
A89 NT NT A257 0.004 >5.0
A90 0.36 >5.0 A258 0.004 >5.0
A91 NT NT A259 0.009 >5.0
A92 0.001 >5.0 A260 0.085 >5.0
A93 0.46 >5.0 A261 0.005 >5.0
A94 NT NT A264 0.023 >5.0
A95 >1.0 NT A265 0.008 >5.0
A96 NT NT A266 0.004 1.1 A97 NT NT A267 0.006 2.6
A98 0.27 >5.0 A268 0.003 1.7
A99 0.34 >5.0 A271 0.086 9.4
A100 1.3 1.2 A272 0.014 8.5
A101 NT NT A273 0.006 4.4
A103 NT NT A298 0.005 0.483
A104 0.003 1.9 A299 0.003 2.35
A105 NT NT A304
A106 0.007 2.3 A305 0.009 >5.0
A107 0.004 0.14 A306 NT NT
A108 0.002 1.8 A307 0.25 >5.0
A109 <0.010 >4.0 A310 0.003 >5.0
A110 0.016 0.69 A311 0.027 3.1
Al l l 0.017 0.86 A312 0.144 >5.0
A112 0.002 0.25 A313 0.005 3.6
A113 NT NT A314 0.002 2.7
A114 >1.0 NT A315 2.5 >5.0
A115 0.016 >4.0 A316 0.004 >5.0
A116 0.004 1.1 A317 0.001 >1.0
A117 0.037 >5.0 A318 0.007 2.5
A118 0.015 2.2 A319 0.006 4.5
A119 0.019 >5.0 A320 0.002 1.4
A120 0.021 >5.0 A321 0.008 >5.0
A121 0.005 >5.0 A322 0.011 >5.0
A122 0.096 >5.0 A323 0.010 >5.0
A123 0.41 >5.0 A324 0.001 0.49
A124 NT NT A325 0.002 4.1
A125 0.025 >5.0 A328 0.003 >5.0
A126 0.043 >5.0 A329
A127 0.005 >5.0 A332 0.002 >5.0
A128 NT NT A333 0.015 >5.0
A129 0.003 0.10 A334 0.002 0.50 A130 0.021 >5.0 A335 0.004 >5.0
A131 0.020 >5.0 A336 0.010 >5.0
A132 0.16 >5.0 A337 0.009 >5.0
A133 0.093 >5.0 A338 <0.010 >5.0
A134 0.15 >5.0 A339 0.005 >5.0
A135 0.021 >5.0 A340 0.002 >5.0
A136 0.004 0.59 A342 0.001 0.38
A137 0.031 >5.0 A343 0.002 2.3
A138 0.012 3.4 A344 0.002 2.8
A139 0.14 >5.0 A345 0.001 >5.0
A140 0.013 0.79 A346 0.003 4.2
A141 0.003 0.086 A347 0.002 >5.0
A142 0.051 >5.0 A348 0.002 >4.0
A143 0.026 >5.0 A349 0.002 >1.0
A144 NT NT A352 0.004 1.5
A145 >1.0 NT A353 0.004 >5.0
A146 >1.0 NT A354 0.004 0.79
A147 0.008 >5.0 A355 0.003 0.87
A148 0.083 >5.0 A356 0.002 3.9
A149 0.003 >5.0 A357 0.005 >5.0
A150 0.130 4.0 A358 0.005 4.0
A151 0.083 >5.0 A359 0.006 >5.0
A152 0.004 2.0 A360 0.003 >5.0
A153 0.14 >5.0 A361 0.004 >5.0
A154 >1.0 NT A362 NT NT
A155 0.50 >5.0 A363 NT NT
A156 >1.0 NT A368 NT NT
A157 0.11 >5.0 A369 0.004 3.0
A158 0.22 >5.0 A372 0.001 0.49
A159 0.17 >5.0 A373 0.001 1.9
A160 0.001 1.3 A374 NT NT
A161 0.013 >5.0 A375 0.008 0.17 A162 0.015 >5.0 A384 0.019 5.0
A163 0.071 1.2 A385 0.024 >5.0
A164 0.075 >5.0 A386 0.005 >5.0
A165 0.027 >5.0 A387 0.030 >5.0
A166 0.008 >5.0 A388 0.004 >5.0
A167 0.005 >5.0 A389 0.005 2.0
Table 2B: Bioactivity with Respect to C¾ and OX?
Figure imgf000494_0001
B31 0.020 >5.0 B205 0.19 >5.0
B32 0.003 0.52 B206 0.028 >5.0
B33 0.003 1.0 B215 0.006 0.32
B34 0.002 0.43 B225 0.69 >5.0
B35 0.006 2.6 B253 0.012 0.93
B36 0.012 0.96 B254 0.020 >1.0
B37 0.008 0.52 B260 0.010 1.1
B38 0.009 >5.0 B261 0.002 0.96
B39 0.003 3.5 B262 0.02 >2.0
B40 0.032 7.2 B271 0.039 >5.0
B41 0.006 0.73 B272 0.09 0.33
B42 0.005 0.96 B273 0.014 1.5
B43 0.009 1.5 B274 0.024 0.72
B44 0.001 >5.0 B275 0.005 >1.0
B45 0.010 >5.0 B276 0.018 2.7
B46 4.5 >5.0 B277 0.008 0.032
B48 0.006 0.27 B278 0.012 0.12
B50 0.006 0.25 B279 0.007 0.049
B53 0.002 0.40 B280 0.005 >5.0
B54 0.002 2.4 B281 0.010 >5.0
B55 0.001 1.4 B282 0.006 2.5
B56 0.001 0.52 B283 0.003 2.9
B62 0.016 0.94 B284 0.003 >3.0
B63 0.006 >5.0 B285 0.13 7.2
B64 0.001 0.20 B286 0.008 0.49
B66 0.002 2.2 B287 0.022 >5.0
B67 0.005 1.3 B288 0.045 >5.0
B68 0.004 0.15 B289 0.31 5.0
B69 0.022 0.20 B292 0.026 2.6
B70 0.007 0.22 B293 0.008 0.30
B75 0.010 1.1 B294 0.017 1.7
B76 0.017 2.3 B295 0.008 0.96 B79 0.11 3.8 B319 0.11 >5.0
B82 0.019 >5.0 B331 0.017 2.3
B85 0.003 1.26 B334 0.19 >5.0
B93 0.007 >5.0 B343 0.09 >5.0
[1192] Compounds as shown in Table 1A (e.g., A201, A207, A207, and A259) show improved selectivity for OXi over OX2 as well as reduced inhibition of CYP3A4 relative to Examples 112 and 114, as shown in Table 4. The difference in CYP3A4 activity is particularly improved with regards to time-dependence inhibition.
Table 4.
Figure imgf000496_0001
[1193] The orientation of the 3-methylpiperidine substituent has a marked effect on OXi/OXi selectivity. As shown in Table 5, Comparative Example CE1, which lacks any 3 -methyl substituent on the central piperidine ring, shows approximately five-fold selectivity for OXI. Comparative Example CE2, which includes a dimethyl substituent at that position, has a selectivity ratio of approximately 20. Comparative Example CE3 (Ex. A311), a racemate with a "trans" methyl group, has a selectivity ratio of approximately 110, while Comparative Example CE4 (Example 75 from PCT Publ. No. WO2013/119639), a racemate with a "cis" methyl group, has a selectivity ratio of over 1000. Single enantiomer compound Example Bl herein has a selectivity ratio of 1300. Table 5.
Figure imgf000497_0001
CE1 CE4 (racemic) CE3 (racemic) CE2
OX, IC50: 13 nM OX, IC50: 3 nM OX, IC50: 27 nM OX, IC50: 137 nM 0X2 IC50: 70 nM 0X2 IC50: 3279 0X2 IC50: 3092 nM 0X2 IC50: 2637 nM
[1194] For the cis-methyl compounds, the (2S,3R)-enantiomer retains most to all of the potency against OXi as shown in Table 6. Individual enantiomers of both Example 11 and Example 103 were prepared. In both cases, the (2S,3R)-enantiomer is the more potent and selective of the two. As compared to Comparative Examples RC5 and RC6 (racemic compounds Examples 11 and 103, respectively, in WO2013/119639), the individual (2S,3R) enantiomers are more potent and selective.
Table 6.
Figure imgf000497_0003
[1195] Substituted benzoxazoles were synthesized with improved selectivity for OXi vs OX2. Analogs containing a 5-CH3 group showed < 100-fold selectivity for OXi vs OX2.
Substitution of a 5-F group for a 5-CH3 group resulted in a substantial increase in OXi vs OX2 selectivity, as shown in Table 7.
Series 1 Series 2
Figure imgf000497_0002
Table 7. Comparative Data for Exemplary Compounds.
Figure imgf000498_0001
[1196] Compounds of the invention are found to have bioactivity as modulators, e.g, as antagonists of both OXi and OX2. Certain compounds are seen to be selective inhibitors of the OXi receptor. In some embodiments, compounds of the generic formulae presented herein have greater than 50, greater than 100, greater than 200, greater than 300, greater than 500, greater than 1000, or greater than 2000-fold selectivity for OXi over OX2 in the cell- based functional assay described above.
Biological Example 2: Cytochrome P450 Inhibition Assay.
[1197] Compounds were tested for the potential to induce drug-drug interactions by inhibition of the cytochrome P450 3A4 isoform. The assay evaluated the metabolism of a specific marker substrate (CYP3A4, midazolam hydroxylation to Γ-hydroxymidazolam) in the presence or absence of 10 μΜ test compound. The concentration of the marker substrate was approximately its Km (Dixit et al., Biopharm. Drug Dispos. 2007, 28(5), 257-262). A specific inhibitor for the isoform was included in each run to validate the system. An appropriate positive control inhibitor was used. Mechanism-based inhibition was investigated where warranted using a classical method. To evaluate time-dependent inhibition, parallel samples may have been included where 10 μΜ probe compound was pre- incubated with human liver microsomes and NADPH for 30 min prior to the addition of the P450 substrate. The percent inhibition of the pre-incubated and non-pre-incubated samples were compared as a preliminary evaluation of time-dependent inhibition. Results are shown in Table 3 A and Table 3B.
Table 3A: Percent Inhibition of CYP3A4
Figure imgf000499_0001
A25 10 99 A186 10 53
A26 10 99 A187 10 40
A27 10 95 A188 10 59
A28 10 95 A189 10 37
A29 10 91 A190 10 24
A30 10 97 A191 10 44
A31 10 98 A192 10 51
A32 10 92 A193 10 45
A33 10 98 A194 10 79
A34 10 99 A195 10 57
A35 10 92 A196 10 50
A36 10 97 A197 10 83
A37 10 96 A198 10 51
A38 10 96 A199 10 62
A39 10 96 A200 10 73
A40 10 96 A201 10 38
A41 10 52 A202 10 44
A43 10 55 A203 10 70
A46 10 53 A204 10 60
A47 10 56 A205 10 72
A48 10 74 A206 10 58
A59 10 87 A207 10 44
A60 10 69 A208 10 59
A73 10 76 A209 10 69
A74 10 74 A210 10 76
A78 10 84 A211 10 60
A79 10 5 A212 10 49
A80 10 28 A213 10 19
A81 10 67 A214 10 69
A82 10 68 A215 10 67
A83 10 97 A216 10 67
A84 10 50 A217 10 NT A85 10 9 A218 10 75
A86 10 95 A219 10 84
A87 10 73 A220 10 68
A88 10 75 A221 10 53
A89 10 92 A223 10 93
A90 10 33 A226 10 60
A91 10 58 A227 10 59
A92 10 91 A228 10 72
A93 10 96 A229 10 72
A94 10 99 A230 10 50
A95 10 88 A231 10 54
A96 10 92 A232 10 65
A97 10 98 A233 10 72
A98 10 48 A239 10 50
A99 10 52 A240 10 42
A100 10 85 A241 10 62
A101 10 83 A242 10 87
A102 10 48 A243 10 68
A103 10 95 A244 10 70
A104 10 91 A246 10 69
A105 10 96 A247 10 65
A106 10 54 A248 10 67
A107 10 91 A249 10 83
A108 10 88 A254 10 63
A110 10 95 A255 10 41
Al l l 10 96 A256 10 52
A112 10 84 A257 10 69
A113 10 98 A258 10 69
A115 10 90 A259 10 37
A116 10 75 A260 10 53
A117 10 92 A261 10 77
A118 10 95 A266 10 76 A119 10 59 A267 10 65
A120 10 90 A268 10 60
A121 10 84 A298 10 75
A122 10 72 A299 10 51
A123 10 97 A307 10 46
A124 10 55 A310 10 75
A125 10 75 A311 10 57
A126 10 56 A312 10 40
A127 10 57 A313 10 60
A128 10 88 A314 10 76
A129 10 64 A316 10 63
A130 10 86 A317 10 46
A131 10 84 A318 10 79
A132 10 81 A319 10 53
A133 10 89 A322 10 40
A134 10 50 A323 10 39
A135 10 80 A324 10 87
A136 10 91 A325 10 80
A137 10 47 A332 10 62
A138 10 75 A333 10 38
A139 10 41 A334 10 54
A140 10 64 A335 10 44
A141 10 72 A342 10 83
A142 10 74 A343 10 56
A143 10 75 A344 10 75
A144 10 87 A345 10 60
A145 10 48 A346 10 62
A146 10 29 A347 10 35
A147 10 66 A348 10 77
A148 10 81 A349 10 59
A149 10 60 A354 10 49
A150 10 74 A355 10 25 A151 10 86 A356 10 86
A152 10 86 A357 10 83
A153 10 66 A358 10 83
A154 10 43 A359 10 52
A155 10 72 A368 10 83
A156 10 53 A369 10 60
A157 10 77 A372 10 83
A158 10 83 A373 10 60
A159 10 88 A374 10 76
A160 10 59 A375 10 48
Table 3B: Percent Inhibition of CYP3A4
Figure imgf000503_0001
B50 10 69 B155 3.4 50
B51 10 71 B156 10 81
B52 10 75 B157 10 84
B53 10 86 B158 10 71
B54 10 74 B159 10 44
B55 10 65 B160 10 70
B56 10 74 B161 1.6 50
B62 10 89 B162 10 62
B63 10 77 B164 10 53
B64 10 88 B165 10 79
B65 10 83 B168 10 70
B66 10 85 B196 10 75
B67 10 80 B205 10 84
B68 10 94 B225 10 89
B69 10 93 B261 4.1 50
B70 10 82 B262 1.1 50
B71 10 56 B271 3.6 50
B72 10 63 B272 4.1 50
B73 10 77 B273 4.8 50
B74 10 82 B274 11 50
B75 10 70 B281 36 50
B81 10 74 B282 22 50
B82 10 78 B283 8.6 50
B83 10 76 B284 15 50
B85 10 67 B285 10 72
B86 10 59 B287 10 80
B87 10 59 B319 10 77
B88 10 62 B331 10 69
B89 10 78 B343 10 49
B90 10 67
Cytochrome P450 inhibition results for selected compounds from PCT Publ. No. WO2013/119639 are shown in Table 3C. Table 3C: Percent Inhibition of CYP3A4
Figure imgf000505_0001
Biological Example 3A. Nicotine Self- Administration Assay (Mice)
[1198] Development of Animal Subjects. To generate Hcrt-Rl+/+ and Hcrt-Rl"71 mice, breeding pairs of male and female Hcrt-Rl+/" mice that were backcrossed > 10 generations on a C57BL/6 background were obtained from Jackson Laboratory (Bar Harbor, ME). For all experiments, mice weighing 25-35 g were housed in groups of 2-3 per cage, in a temperature- controlled vivarium under a reversed 12-h light/dark cycle (lights off at 8 am). Food and water were provided ad libitum until behavioral training commenced. During training, mice were food-restricted to maintain -85-90% of their free-feeding body weight. Behavioral testing occurred during the dark portion of the light/dark cycle between the hours of 9 am-1 pm, during the early portion of the dark phase of the cycle. All procedures were conducted in strict adherence with the National Institutes of Health Guide for the Care and Use of
Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute.
[1199] Assay Protocol. Mice were anesthetized by inhalation of 1-3% isoflurane in oxygen and silastic catheters were inserted into the jugular veins. Briefly, the catheters consisted of a 6 cm length of silastic tubing fitted to a guide cannula (Plastics One, Wallingford, CT), bent at a curved right angle and encased in dental acrylic. The catheter tubing was passed subcutaneously from each animal's back to the right jugular vein, and 1 cm length of the catheter tip was inserted into the vein. After surgery, catheters were flushed daily with 0.1 ml of a heparinized (30 USP units/ml) sterile saline solution. Following 7 d of surgical recovery, mice were mildly food restricted to 85-90% of their free-feeding body weight and trained to press a lever in an operant chamber (Med Associates, St. Albans, VT) for food pellets (20 mg; TestDiet, Richmond, IN) under a fixed-ratio 5, time out 20-s (FR5TO20 s) schedule of reinforcement prior to catheter implantation. Once stable responding was achieved (> 25 pellets per session), mice were permitted to acquire IV nicotine self-administration by autoshaping during 1-h daily sessions, 7 days per week. Nicotine was delivered through the tubing into the IV catheter by a Razel syringe pump (Med Associates). Each nicotine self- administration session was performed using two retractable levers (1 active; 1 inactive). Completion of the response criteria on the active lever resulted in the delivery of an IV nicotine infusion (0.03 mg/kg/infusion). After 1 week, the nicotine dose was increased to 0.1 mg/kg/inf for the remainder of the experiment, including subsequent training and test sessions. Delivery of all nicotine infusions coincided with the initiation of a 20-s time-out (TO) period, signaled by a light cue located above the lever. During the TO period, responding on the lever was recorded but without scheduled consequence. Catheter integrity was tested with the ultra short-acting barbiturate Brevital (methohexital sodium; Eli Lilly) at the end of the experiment.
[1200] Generation of Lentivirus and Titer Estimation. For Hcrt-Rl re-expression studies, the human Hcrt-Rl gene was cloned into the pCDFl lentivirus expression vector containing copGFP (GFP cloned from copepod Pontellina plumata) from Systems Biosciences. To generate lentivirus supernatant, HEK293FT packaging cells (3.75 x 106293TN cells per 10- cm plate) were transfected with the vectors, along with the pPACLFlTM Lenti viral Packaging Kit using lipofectamine reagent and plus reagent (Invitrogen) according to the manufacturer's instructions. Medium containing virus particles (-10 ml) was harvested 48- 60 h after transfection by centrifugation at 76,755g at rt (22 °C) for 5 min to pellet cell debris and was filtered through 0.45 mm PVDF (polyvinylidene difluoride) filters (Millex-HV). To concentrate the viral supernatant for intrastriatal administration, supernatants were centrifuged at 32,000g for 90 min at 4 °C, and the precipitate re-suspended in 100 μΐ cold PBS. Supernatants were aliquoted into 100 μΐ volumes and stored at -80 °C until use. Viral supernatant titres were determined using the Lentivector Rapid Titer Kit from System
Biosciences, according to the manufacturer's instructions. The number of infectious units per ml of supernatant (IFU ml-1) was calculated as follows: multiplicity of infection (MOI) of the sample x the number of cells in the well upon infection x 1,000 / μΐ of viral supernatant used.
[1201] Results. Results of the assay are shown in Figure 1. As shown in Figure 1A, knockout (KO) and wild-type (WT) mice showed very stable acquisition of learning to lever press for food pellets, demonstrating that genetic deletion of the Hcrt-IR had no effect on learning the task. As shown in Figure IB, systemic administration (i.p.) of Example 11 (racemic, see PCT Publ. No. WO2011/119639) 30 min prior to the self administration (SA) session had no effect on food SA in KO and WT mice. As shown in Figure 1C, WT (n=12) and KO (n=10) were evenly divided and were given a virus to site-specifically restore Hcrt-IR expression or an empty vector (control) in the dorsal thalamus three weeks prior to the initiation of the experiment. There were no effects on food SA in any group. As shown in Figure ID, lentiviral restoration of Hcrt-IR expression in the dorsal thalamus of KO mice restored nicotine SA. Mice that received systemic pretreatment of Example 11 (7.5 and 15.0 mg/kg) exhibited decreased nicotine SA in the WT and virally-rescued mice, with no significant reduction in KO mice that received the control virus.
[1202] Comparison of Results to Orexin-2 Selective Agent. The assay was repeated with JNJ 10397049, a commercially available orexin-2 selective receptor antagonist. Results of this assay are shown in Figure 2. Figure 2A shows that systemic administration of JNJ 10397049 30 min prior to the experimental session had no effect on SA of food pellets in both WT (n=6) and KO (n=6) mice. Figure 2B shows that JNJ 10397049 had no effect on nicotine SA at any of the doses tested (0, 5 and 10 mg/kg) in the WT mice. JNJ 10397049 induced a marginal decrease in nicotine SA in KO mice.
Biological Example 3B. Nicotine Self-Administration Assay (Rats) [1203] For all experiments, rats weighing 250-300 g were housed in groups of 1-23 per cage, in a temperature-controlled vivarium under a reversed 12-h light/dark cycle (lights off at 8 am). Food and water were provided ad libitum until behavioral training commences. During training, rats were food-restricted to maintain -85-90% of their free-feeding body weight. Behavioral testing occured during the dark portion of the light/dark cycle between the hours of 9 am-1 pm, during the early portion of the dark phase of the cycle. All procedures were conducted in strict adherence with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and are approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute.
[1204] Rats were anesthetized by inhalation of 1-3% isoflurane in oxygen and silastic catheters were inserted into the jugular veins. Briefly, the catheters consist of a 14 cm length of silastic tubing fitted to a guide cannula (Plastics One, Wallingford, CT), bent at a curved right angle and encased in dental acrylic. The catheter tubing was passed subcutaneously from each animal's back to the right jugular vein, and 1 cm length of the catheter tip was inserted into the vein. After surgery, catheters were flushed daily with 0.1 mL of a heparinized (30 USP units/ml) sterile saline solution. Following 7 d of surgical recovery, rats were mildly food restricted to 85-90% of their free-feeding body weight and trained to press a lever in an operant chamber (Med Associates, St. Albans, VT) for food pellets (20 mg;
TestDiet, Richmond, IN) under a fixed-ratio 5, time out 20-s (FR5TO20 s) schedule of reinforcement prior to catheter implantation. Once stable responding was achieved (> 25 pellets per session), rats were permitted to acquire IV nicotine self-administration by autoshaping during 1-h daily sessions, 7 days per week. Nicotine was delivered through the tubing into the IV catheter by a Razel syringe pump (Med Associates). Each nicotine self- administration session was performed using two retractable levers (1 active; 1 inactive). Completion of the response criteria on the active lever resulted in the delivery of an IV nicotine infusion (0.03 mg/kg/infusion). After 1 week, the nicotine dose was increased to 0.1 mg/kg/inf for the remainder of the experiment, including subsequent training and test sessions. Delivery of all nicotine infusions coincided with the initiation of a 20-s time-out (TO) period, signaled by a light cue located above the lever. During the TO period, responding on the lever was recorded but without scheduled consequence. Catheter integrity was tested with the ultrashort-acting barbiturate Brevital (methohexital sodium; Eli Lilly) at the end of the experiment.
[1205] Data for Example Al is presented in Figures 3 and 4. Figure 3 A shows that Example Al produced a dose-dependent reduction in nicotine self-administration, while Figure 3B shows that Example Al does not have a significant effect on food intake. Figure 4 shows the percent baseline responding for food or nicotine using Example Al at several doses.
[1206] Data for Example Bl is presented in Figures 5 and 6. Figure 5A shows that Example Bl produced a dose-dependent reduction in nicotine self-administration, while Figure 5B shows that Example Bl does not have a significant effect on food intake. Figure 6 shows the effect of Example Bl in a model of relapse measuring the extinction (Figure 6A) and reinstatement (Figure 6B) of nicotine- seeking behavior in rats.
[1207] Figure 7 shows the results for the dual OXi/OXi antagonist, suvorexant, in the nicotine self-administration assay, and demonstrates that this dual antagonist has little effect on nicotine self-administration at 20 mg/kg, but a significant reduction in food intake. In contrast, the selective OXi antagonist of Example Bl does not have a negative effect on food intake.
[1208] Figure 8 shows the results for varenicline, which is a marketed drug for nicotine addiction, in the nicotine self-administration assay. Varenicline is a nicotinic receptor partial agonist and functions by a different mechanism than the compounds described herein. In the nicotine self-administration assay, this compound caused an increase in food intake, while Example B 1 did not.
[1209] While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.
[1210] All patents and publications referred to herein are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
[1211] The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. [1212] Data for Example A259 is presented in Figures 9 and 10. Figure 9 shows the results of the nicotine self-administration assay for Example A259. Figure 9A shows the effect of Example A259 on nicotine self-administration with oral dosing. Figure 9B shows no effect on responding for food at the same doses. Figure 10 shows the effect of Example A259 on nicotine self-administration with chronic oral dosing on days 4-8.
Biological Example 4: Microsome stability Assay
[1213] Compounds were tested for stability in mouse, rat, and human liver microsomes (Xenotech, Lenexa, Kansas). Microsome stability was evaluated by incubating 1 μΜ test compound with 1 mg/mL hepatic microsomes in 100 mM KPi, pH 7.4. The reaction was initiated at 37°C by adding NADPH (1 mM final concentration). After 30 minutes, acetonitrile (5X v:v) was added to stop the reaction and precipitate the protein. At the end of the assay, the samples were centrifuged through a Millipore Multiscreen Solvinter 0.45 micron low binding Polytetrafluoroethylene (PTFE) hydrophilic filter plate and analyzed by LC-MS/MS to calculate percent remaining. Results are shown in Table 9. Compounds from Tables 1A and IB described herein displayed significantly higher metabolic stability in mouse, rat, and human liver microsomes than compounds 11, 12, 75, 82, and 97 from PCT Publ No. WO2013/119639.
Table 9: Microsomal Stability
Figure imgf000510_0001
A268 20 2 1
A319 53 33 20
A321 61 51 52
A322 31 21 15
A323 30 37 9
A389 34 50 13
B33 15 16 8
B130 33 25 81
B132 17 16 35
B273 29 30 3
B274 14 13 1
B319 53 46 44
B343 69 35 2

Claims

What is claimed is:
A compound of Formula (VI):
Figure imgf000512_0001
wherein
R10 is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Rn)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C^alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof; or a compound of Formula (VII):
Figure imgf000513_0001
wherein
R10 is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Rn)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C^alkoxy, halo, -CN, and -CF ;
or a pharmaceutically acceptable salt thereof; or a compound of Formula (IX):
Figure imgf000514_0001
wherein
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
wherein the CH groups are optionally substituted with B and (Rn)t as shown;
each R11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2;
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C^alkyl, C^alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound is a compound of Formula (VIA)
Figure imgf000515_0001
wherein
B is phenyl, pyridyl, or pyrimidinyl, each unsubstituted or substituted with one or two
substituents selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
X2 is CH or N;
R10 is H or methyl;
R200 is H, -CF3, or chloro; and
(a) one of R 20 and R 22 is methyl, chloro, or fluoro, the other of R 20 and R 22 is H, and R 102 is H; or
(b) R21 is H, chloro, or fluoro, and R20 and R22 are both H;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein Het is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally fused to phenyl or a monocyclic heteroaryl, and each optionally substituted with one or two substituents Rx.
4. The compound of claim 1, wherein Het is thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzoxazolyl, quinazolinyl, or triazolo-pyrimidinyl, each optionally substituted with one or two substituents Rx.
5. The compound of claim 1, wherein each Rx is independently selected from the group consisting of -F, -CI, -Br, methyl, methoxy, -CN, -CF , cyclopropyl, and cyano-cyclopropyl.
6. The compound of claim 1, wherein X is N, Y is CH, and Z is S; or X is N, Y is CHCH, and Z is CH; or X is CH, Y is CHCH, and Z is CH; wherein the CH groups are optionally substituted with B and (Ru)t as shown.
7. The compound of claim 1, wherein each R is independently methyl, chloro, fluoro, or -CN.
The compound of claim 1, wherein the group (XX):
Figure imgf000516_0001
(XX)
is a grou of Formula (Xa), or is a group of Formula (Xb), or is a group of Formula (Xc):
Figure imgf000516_0002
(Xa) (Xb) (Xc)
wherein X1 is CH or N and B is unsubstituted or is substituted as described in claim 1.
9. The compound of claim 1, wherein the roup (XX)
is a group of Formula (Xd):
Figure imgf000516_0003
where (a) one of R101 and R103 is methyl, chloro, or fluoro, the other of R101 and R103 is H, and R102 is H; or (b) R102 is H, chloro, or fluoro, and R101 and R103 are both H.
10. The compound of claim 1, wherein ring B is phenyl, or is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally substituted with one or two substituents Ry.
11. The compound of claim 1, wherein ring B is pyrazolyl or triazolyl.
12. The compound of claim 1, wherein each Ry is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, isopropoxy, -F, -CI, -Br, -CN, or -CF3.
13. A compound selected from the group consisting of compounds as shown in Table 1A and Table IB, and pharmaceutically acceptable salts thereof.
14. The compound of claim 1, wherein the compound is not a compound in Table 1, wherein the compounds in Table 1 are racemic compounds.
15. A pharmaceutical composition comprising a compound of claim 1 or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16. A method of treating a malcondition in a patient wherein modulation of an orexin receptor is medically indicated, comprising administering to the patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein modulating an orexin receptor is antagonism of the orexin receptor.
18. The method of claim 16, wherein the compound is a selective modulator of an orexin receptor OX\.
19. The method of claim 16, wherein the malcondition comprises an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, or renal disease.
20. A compound of Formula (la):
Figure imgf000518_0001
wherein
X is NH, N(C1_4alkyl), or O;
R1 is pyridinyl, pyrimidinyl, benzoxazolyl, benzothiazolyl, or quinazolinyl, each
unsubstituted or substituted with one or more substituents selected from the group consisting of Ci^haloalkyl or halo; or
X and R1 taken together form pyrrolyl or dihydropyrrolyl, unsubstituted or substituted with C^haloalkyl or halo;
R 2" and R 3J are defined as in (a) or (b):
(a) R 2 is thiazolyl substituted with C1-4alkyl; and R 3 is phenyl substituted with halo; or
(b) R is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1-4alkyl, -OC1-4alkyl, or halo; and R is triazolyl or pyrimidinyl;
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising (a) at least one compound of Formula (la) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
22. A method of treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (la) or a pharmaceutically acceptable salt thereof.
23. A compound of Formula (lb):
Figure imgf000519_0001
wherein
A is aryl, wherein A can be unsubstituted or can be mono- or multi- substituted with halo or CF3;
B is heteroaryl, wherein B can be unsubstituted or can be mono- or multi-substituted;
D comprises aryl or heteroaryl, wherein D can be unsubstituted or can be mono- or independently multi- substituted with halo, C1-4 alkyl, C1-4 alkoxy, -CN, -CF3, or C3_6 cycloalkyl;
Z is N or O, provided that when Z is O, R is absent; and
R is H or methyl;
or any salt or hydrate thereof.
24. The compound of claim 23, wherein A is phenyl.
25. The compound of claim 23 or 24, wherein A is substituted with F or CI.
26. The compound of claim 23, wherein D is thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzoxazolyl, quinazolinyl, or triazolo-pyrimidinyl.
27. The compound of claim 23, wherein D is pyrimidinyl.
28. The compound of any one of claims 23-27, wherein D is substituted with CI or CF .
29. The compound of claim 23, wherein B is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
30. The compound of claim 23, wherein B is triazolyl or pyrimidinyl.
31. A compound of Formula
Figure imgf000520_0001
wherein
R10 is H or methyl;
Het is a monocyclic heteroaryl comprising one N and one or two additional heteroatoms selected from the group consisting of N, O, and S;
wherein Het is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C1_4alkyl, C1-4alkoxy, -CN, -CF3, and C3_ 6cycloalkyl, wherein said cycloalkyl is optionally substituted with halo, methyl, or cyano; or two adjacent substituents taken together with the atoms to which they are attached form a fused phenyl or monocyclic heteroaryl;
each R11 is independently selected from the group consisting of cyano, chloro, fluoro, and methoxy;
t is 0, 1, or 2; and
B is phenyl or a monocyclic heteroaryl comprising one N and one or two additional
heteroatoms selected from the group consisting of N, O, and S;
wherein ring B is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, C^alkoxy, halo, -CN, and -CF3;
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 31, wherein Het is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally fused to phenyl or a monocyclic heteroaryl, and each optionally substituted with one or two substituents.
33. The compound of claim 31, wherein Het is pyrimidinyl, optionally substituted with one or two substituents. 34. The compound of any one of claims 31-33, wherein Het is substituted with CI or CF3.
35. The compound of claim 31, wherein R11 is F or CI.
36. The compound of claim 31, wherein B is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
37. The compound of claim 31, wherein B is triazolyl or pyrimidinyl.
38. A pharmaceutical composition comprising a compound of any one of claims 23-37 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
39. A method of treating a disease, disorder, medical condition, or malcondition wherein the modulation of an orexin receptor is medically indicated, comprising administering to the patient an effective amount of a compound of any one of claims 23-37 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38.
40. The method of claim 39, wherein modulating an orexin receptor is antagonism of the orexin receptor.
41. The method of claim 39, wherein the compound is a selective modulator of an orexin receptor 0X1.
42. The method of claim 39, wherein the disease, disorder, medical condition, or
malcondition comprises an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, or renal disease.
43. Use of a compound of any one of claims 1-14, 20, and 23-37 or a pharmaceutical composition of any one of claims 15, 21, and 38 for the manufacture of a medicament for treating a disease, disorder, medical condition, or malcondition, wherein the modulation of an orexin receptor is medically indicated.
44. The use of claim 43, wherein modulating an orexin receptor is antagonism of the orexin receptor.
45. The use of claim 43, wherein the compound is a selective modulator of an orexin receptor OXi.
46. The use of claim 43, wherein the disease, disorder, medical condition, or malcondition comprises an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, or renal disease.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
WO2017139603A1 (en) * 2016-02-12 2017-08-17 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
CN108239019A (en) * 2016-12-27 2018-07-03 浙江医药股份有限公司新昌制药厂 The synthetic method of one kind (2S, 5S or 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
JP2019503390A (en) * 2016-01-29 2019-02-07 シー４エックス・ディスカヴァリー・リミテッド Therapeutic compounds
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
CN111138413A (en) * 2018-11-01 2020-05-12 江苏豪森药业集团有限公司 Preparation method and intermediate of cyclin-dependent kinase inhibitor
JP2020518573A (en) * 2017-05-03 2020-06-25 イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivative
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
CN112745316A (en) * 2016-04-01 2021-05-04 里科瑞尔姆Ip控股有限责任公司 Estrogen receptor modulators
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
WO2023218023A1 (en) * 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026866A1 (en) * 2002-09-18 2004-04-01 Glaxo Group Limited N-aroyl cyclic amines as orexin receptor antagonists
WO2013119639A1 (en) * 2012-02-07 2013-08-15 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US20140364433A1 (en) * 2012-02-07 2014-12-11 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026866A1 (en) * 2002-09-18 2004-04-01 Glaxo Group Limited N-aroyl cyclic amines as orexin receptor antagonists
WO2013119639A1 (en) * 2012-02-07 2013-08-15 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US20140364433A1 (en) * 2012-02-07 2014-12-11 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIANG, R ET AL.: "Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 12, 2012, pages 3890 - 3894, XP029121646 *

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* Cited by examiner, † Cited by third party
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