CA2655085A1 - Cgrp receptor antagonists - Google Patents

Abstract

The present invention relates to CGRP receptor antagonists, pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions. The present invention relates to CGRP receptor antagonists of formula 1, wherein: X is S, SO, or SO2; pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions.

Description

CGRP RECEPTOR AN.TAGONISTS

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to CGRP receptor antagonists, pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions.

BACKGROUND OF THE INVENTION

[0002] CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA
and is widely distributed in the central and peripheral nervous system. CGRP
is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP
initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth inuscle origin.

[0003) CGRP is a potent vasodilator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187). CORP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to be the major source of headache pain during migraine attacks (Lance, Headache Pathogenesis:
Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery, the principle artery in the dura inater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP.
Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988, 23, 193-196).

Page 1 of 153 Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP
(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).
Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP (8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist. In recently reported clinical trials, the CGRP receptor antagonist BIBN
4096 BS was reported to be effective in treating acute attacks of migraine (Olesen et al., N.
Engl. J. Med. 2004, 350:1104-1110).
[00041 CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson-et al., The CGRP
Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extra-cranial pain and facial allodynia, maybe the result of sensitized trigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.
[00051 The ability of the compounds of the present invention to act as CGRP
antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders include migraiine and cluster headache (Doods, Curr. Opin. Inves. Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988, 24, 739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;
Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May et al.
Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993, 67, 5786-5791);
shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal Page 2 of 153 syndrome (Salmon et al., Nature Neurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis;
encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffinan et al.
Scandinavian Journal of Gastroenterology, 2002, 37(4) 4I4-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.
[00061 The present invention relates to compounds that are useful as ligands for CGRP
receptors, in particular antagonists of CGRP receptors, pharmaceutical compositions thereof, and uses therewith.
SUMMARY OF THE INVENTION
[0007] The present invention provides compounds of formula I:
Rz Rw RW m , Z1 Rx x g R6 RX~ N
/N O )n RY

or a pharmaceutically acceptable salt thereof.
These compounds are useful as antagonists of CGRP receptors and thus treating CGRP-mediated conditions. The present invention also provides pharmaceutical compositions thereof and uses therewith.

DETAILED DESCRIPTION OF THE INVENTION
1000812. Compounds and Definitions:
[0009] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.

Page 3 of 153 [00101 For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75`h Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5h Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0011] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally"
or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 C or less, in the absence of moisture or other che2nically reactive conditions, for at least a week.
[00121 The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle"
"cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms.
In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other Page 4 of 153 embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "eycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or bicyclic or tricyclic C8-C14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl.
[0013] The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.
[0014] The tenn "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring atom is an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
[0015] The term "heteroatom" means one or more of oxygen, sulfur, or nitrogen (including, any oxidized forms thereof, e.g., S=O, SO2, etc.; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR-' (as in N-substituted pyrrolidinyl)).
[0016] The terms "haloaliphatic" and "haloalkoxy" means aliphatic or alkoxy, as the case may be, subsfituted with one or more halo atoms. The term "halogen" or "halo"
means F, Cl, Br, or I. Examples of haloaliphatic include -CHF2, -CH2F, -CF3, -CF2-, or perhaloalkyl, such as, -CF2CF3.
[0017] The terny "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and Page 5 of 153 wherein each ring in the system contains 3 to 7 ring members. The term "aryl"
may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow.
[0018] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at Ieast one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
[00191 An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halo; -R ; -OR ; -SR ; 1,2-methylene-dioxy; 1,2-ethylenedioxy;
phenyl (Ph) optionally substituted with R ; -O(Ph) optionally substituted with R ; -(CH2)1_ 2(Ph), optionally substituted with R ; -CH=CH(Ph), optionally substituted with R ; -NO2; -CN; -N(R )2; -NR C(0)R ; -NR C(O)N(R )2; -NR C02R ; -NR NR C(O)R ; -NR NR C(O)N(R )2; -NR NR CO2R ; -C(O)C(O)R ; -C(O)CH2C(O)R ; -C02R ; -C(O)R ;
-C(O)N(R )2i -OC(0)N(R )2i -S(0)2R ; -SO2N(R )2i -S(O)R ; -NR SO2N(R )2; -NR
S02R ;
-C(=S)N(R )a; -C(=NH)-N(R )2; or -(CH2)0_2NHC(0)R wherein each independent occurrence ofR is selected from hydrogen, optionally substituted C1_6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, notwithstanding the definition above, two independent occurrences of R , on the same substituent or different substituents, taken together with the atom(s) to which each R group is bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R are selected from NH2, NH(C1_4aliphatic), N(C1_4aliphatic)2, halo, CI-4aliphatic, OH, O(Ci-4aliphatic), NO2a CN, COaH, CO2(Q_4aliphatic), O(haloCi4 aliphatic), or haloC .aliphatic, wherein each of the foregoing Ci-4aliphatic groups of R is unsubstituted.
[0020] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may coritain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the Page 6 of 153 following: =0, =S, =NNHR*, =NN(R*)a, =NNHC(O)R*, =NNI-iCO2(alkyl), =NNHSO2(alkyl), or =NR", where each R* is independently selected from hydrogen or an optionally substituted C1_6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NH2, NH(CI-4 aliphatic), N(C14 aliphatic)2, halo, C14 aliphatic, OH, O(Ci4 aliphatic), NO2, CN, CO2H, CO2(C14 aliphatic), O(halo CI4 aliphatic), or halo(C[4 aliphatic), wherein each of the foregoing CI.4aliphatic groups of R* is unsubstituted.
[0021] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -NW)a, -C(O)R+, -COaR+, -C(O)C(O)R, -C(O)CH2C(O)R+, -SOZR+, -SO2N(R+)2, -C(=S)N(R})2, -C(=NH)-N(R+)2, or -NR+SOZR+; wherein R+ is hydrogen, an optionally substituted C1.6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CHZ(Ph), optionally substituted -(CH2)i_2(Ph);
optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R+, on the sarne substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(C1 -4 aliphatic), N(CI-4 aliphatic)z, halo, CI-4 aliphatic, OH, O(Ct4 aliphatic), NO2, CN, CO2H, C02(C14 aliphatic), O(halo C14 aliphatic), or halo(CI-4 aliphatic), wherein each of the foregoing Ci-4aliphatic groups of R+ is unsubstituted.
[0022] The term "spirocyclic ring'system" refers to a moiety comprising two or more rings, wherein at least one ring has two points of attachment to another ring through a common carbon ring atom.
[0023] As detailed above, in some embodiments, two independent occurrences of R (or R+, or aiiy other variable similarly defined herein), are taken together with the atom(s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Exemplary rings that are formed when two independent occurrences of R (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R (or R+, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R )2, where both occurrences of R are taken together with the nitrogen atom to form a piperidin-l-yl, Page 7 of 153 piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R (or R, or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is ~ OR
OR
substituted with two occurrences of ORo I ~ ~- , these two occurrences of R
are taken together with the oxygen atoms to which they are bound to form a fused 6-membered " 1 o) oxygen containing ring: d. It will be appreciated that a variety of other rings can be formed when two independent occurrences of R (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.
[0024] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereorneric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[0025] The term "aryl-Cl-C6 aliphatic-" and similar such terms mean that the aryl group is linked to the core molecule by a CI to C6 aliphatic linker. For instance, the term "aryl-C2--alkyl- means a-CH2CHaPh group or a phenylethyl group is attached to the core molecule.
[0026] In one embodiment, the present invention provides compounds of formula 1:

Page 8 of 153 A
RW
Rz Rw _.. Z1 Rx X B R6 RX--V N
/N 0 )n RY

wherein:
X is S, SO, or SO2;
Z' is a bond or NR7,0, S, CH2, C(O), orNR7 C(O)NR7, wherein R7 is hydrogen, C1-C4 aliphatic or C(O)C1-C4 aliphatic;
Z2 is a bond', 0, CHaO, or C(O);
ring A is phenyl or a 4-7 membered heterocyclic or heteroaryl ring or a 10-14 membered bicyclic heteroaryl or heterocyclic ring, wherein said heterocyclic or heteroaryl ring has 1-4 heteroatoms selected from 0, N, or S; wherein ring A is optionally substituted with up to 5 R' substituents;
wherein:
Z2 is a bond, Z' is a bond, NR', 0, S, CH2, C(O), or NR7C(O)NR7; or wherein:
Z', Z2, and R6 are absent, ring A is not aromatic, and ring A together with ring B
form a spirocyclic ring system;
R6 is hydrogen or C1-C4 aliphatic;
m is 1-3;
n is 1-3; provided that m+n is S4;
RY is aryl, heteroaryl, cycloaliphatic, Cl -C6 aliphatic, aryl-C1-C6 aliphatic-, heteroaryl-Ci-C6 aliphatic-, heterocyclyl-C1-C6 aliphatic- or cycloaliphatic-Cl -C6 aliphatic-; wherein RY is optionally substituted with up to 5 R2 substituents;
Rx is hydrogen, aryl, heteroaryl, C l-C6 aliphatic, aryl-C 1 -C6 aliphatic-, heteroaryl-Cl-C6 aliphatic-, wherein Rx is optionally substituted with up to 5 R3 substituents;
or two Rx, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-14 membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring system formed by two Rx is optionally substituted with up to 5 R4 substituents;

Page 9 of 153 RZ is absent, hydrogen, CN, C1-C6 aliphatic, halo-C1-C6 aliphatic, O-Cl-C6 aliphatic, O-(halo-C1-C6 aliphatic), halo, aryl-C1-C6 aliphatic, orheteroaryl-Cl-C6 aliphatic;
-= is a single or a double bond; provided that when it is a double bond, then Rz and one of RW is absent;
each RW is independently absent, hydrogen, halo, oxo, C1-C6 aliphatic, halo-C1-aliphatic, -O-Cl-C6 aliphatic, -O-(halo-Cl-C6 aliphatic), aryl, aryl-C1-C6 aliphatic-, C3-C7 cycloaliphatic; or two Rw taken together form an optionally substituted C3-C7 cycloaliphatic or heterocyclic ring, wherein said heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring formed by two Rti'' is optionally substituted with up to 5 R5 substituents;
wherein each occurrence of R', R2, R3, R4, and RS is independently Q-R"';
wherein Q is a bond or is a C1-C6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by CO, C02, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SOa, NRSOa, SOzNR, NRSO2NR, 0, S, or NR;
wherein each occurrence of RM is independently selected from R', halogen, NO2, CN, OR', SR', N(R')2, NR'C(O)R', NR'C(O)N(R')Z, NR'CO2R', C(O)R', CO2R', OC(O)R', C(O)N(R')z, OC(O)N(R')2, SOR', SO2R', SO2N(R')2, NR'SOaR', NR'SO2N(R')2a C(O)C(O)R', or C(O)CH2C(O)R';
wherein each occurrence of R is independently selected from hydrogen or a CI_6 aliphatic group optionally substituted with 0-5 occurrences of RK ; and each occurrence of RK
is independently selected from -RV, halogen, -NO2, -CN, -ORv, -SRV, -N(RV)2, -NRvCORV, -NRYCON(Rv)2, -NR'COaRv, -CORV, -CO2RV, -OCORV, -CON(RV)Z, -C(=N-CN), -OCON(Rv)2, -SORv, -SOaRv, -SO2N(Rv)2, -NRvSOaRv, -NRVSO2N(Rv)2, -COCORV, -COCH2CORv, -OP(O)(ORV)2, -P(O)(ORV)a, -OP(O)2ORV, -P(O)20Rv, -PO(RV)2, or -OPO(Rv)Z, wherein Rv is hydrogen or unsubstituted C1_6 aliphatic; and wherein each occurrence of R' is independently hydrogen, a C1_6 aliphatic group optionally substituted with 0-5 occurrences of R"' 1; and each occurrence of RM 1 is independently selected from -RT, halogen, -NO2, -CN, -ORT, -SRT, --N(RT)2, -NRTCORT, -NRTCON(RT)2, -NRTCOaRT, -CORT, -CO2RT, -OCORT, -CON(RT)a, -C(=N-CN), -OCON(RT)2, -SORT, -SO2RT, -SOzN(RT)a, -NRTSO2RT, -NRTSO2N(RT)2, -COCORT, -COCH2CORT, -OP(O)(ORT)a, -P(O)(ORT)2, -OP(O)aORT, -P(O)2ORT, -PO(RT)2, or -OPO(RT)2, wherein RT

Page 10 of 153 is hydrogen or unsubstituted C1_6 aliphatic; or R' is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 5-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein said monocyclic or bicyclic ring is optionally substituted with 0-5 occurrences of RU; and each occurrence of Ru is independently selected from a: 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring optionally substituted with 0-3 occurrences of -RQ' and having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or e is -RQ, halogen, =0, =NRQ, -N02, -CN, -ORQ, -SRQ, -N(RQ)2, -NRQCORQ, -NReCON(RQ)a, -NRQC02RQ, -CORQ, -COzRQ, -OCORQ, -CON(RQ)Z, -C(=N-CN), -OCON(RQ)2, -SORQ, -SO2RQ, -SO2N(RQ)2, -NRQSOzRe, -NRQSOzN(RQ)z, -COCORQ, -COCHaCORQ, -OP(O)(ORQ)Z, -P(O)(ORQ)2, -OP(0)20RQ, -P(O)2ORQ, -PO(RQ)Z, or -OPO(RQ)Z, wherein RQ and RQ 1 are hydrogen or unsubstituted C1_6 aliphatic; or R and R', two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to fonn a 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein said monocyclic or bicyclic ring is optionally substituted with 0-5 occurrences of RT'; and each occurrence ofRT' is independently selected from -Rs, halogen, =0, =NRs, -NOz, -CN, -ORS, -SRs, -N(RS)a, -NRSCORs, -NR5CON(Rs)a, -NRsCOzRs, -CORs, -C02Rs, -OCORs , -CON(RS)2a -C(=N-CN), -OCON(RS)a, -SORS, -SOZRs, -SO2N(Rs)z, -NRsSO2Rs, -NRSSOzN(Rs)2, -COCORs, -COCHZCORs, -OP(O)(ORS)2, -P(O)(ORs)2, -OP(O)2ORs, -P(O)20RS, -PO(Rs)2, or -OPO(Rs)2, wherein Rs is hydrogen or unsubstituted C1_6 aliphatic.
[0027] In one embodiment of formula 1, Z2 is a bond, R6 is hydrogen, and Z' is a bond.
[0028] In another embodiment of formula I, Z2 is a bond, R6 is hydrogen, and Z' is NR7,0, S, CH2, C(O), or NR7C(O)NR'.
[0029] In one embodiment of formula I, ZZ-Rb is other than hydrogen and Z, is a bond.
[0030] In one embodiment of formula I, Z2-R6 is other than hydrogen and Z, is NR', O, S, CH2, C(O), or NR7C(O)NR'.
[0031] In one embodiment of forcnula I, is a single bond.
[0032] In one embodiment of formula I, is a single bond and both of Rw are hydrogen.
[0033] In one embodiment of formula 1, Rz, if present, is C1-C6 alkyl, halo-CI-C6 alkyl- or -O-C 1-C6 alkyl.

Page I 1 of 153 [0034] In one embodiment of formula I, Rz, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[0035] In one embodiment of formula 1, at least one Rw is C1-C6 alkyl, halo-Cl-C6 alkyl or -O-C l -C6 alkyl.
[0036] In one embodiment of formula I, at least one RW is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[0037] In one embodiment of formula I, one Rw is hydrogen and the other Rw is alkyl, halo-Cl-C6 alkyl- or -O-C1-C6 alkyl.
[0038] In one embodiment of formula I, one of RW is hydrogen and the other Rw is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[0039] In one embodiment of formula I, RY is C1-C6 aliphatic optionally substituted with one or more halo, OH, -Cl-C4 alkoxy, -Cl-C4 alkoxy carbonyl, or di-(Cl-C4 alkyl) amino-.
[0040] In one embodiment of formula I, RY is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxy carbonyl)-3-methyl-butyl, 1-(hydroxy methyl)-3-methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.
j0041] In one embodiment of formula I, RY is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.
[0042] In one embodiment of formula 1, RY is C3-C8 cycloaliphatic or a C3-C8 cycloaliphatic substituted Cl-C6 aliphatic-.
100431 In one embodiment of formula I, RY is C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted C1-C6 alkyl-.
[0044] In one embodiment of formula I, RY is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl-, or cyclohexylethyl-.
[0045] In one embodiment of formula I, RY is pyridyl (C1-C6)- alkyl-, tetrahydrofuranyl (C1-C6 alkyl)-, orN-(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl)-.
[0046] In one embodiment of formula I, tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, I H-indazol-5-yl, or 2-(N-m ethyl)-pyrroli din-2-yl-ethyl -.
100471 In one embodiment of formula I, RY is phenyl or (phenyl)-substituted C1-aliphatic- each optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, 0, or S.

Page 12 of 153 [0048] In one embodiment of formula I, RY is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl-, 2-piperidinylphenyl- or phenylethyl-.
[0049] In one embodiment of formula I, one Rx is hydrogen and the other Rx is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 3 Ru substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
[0050] In one embodiment of formula I, one Rx is hydrogen and the other RX is phenyl or pyridyl with up to 2 R3 substituents independently selected from halogen or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 2 Ru substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
[0051] In one embodiment of formula I, one Rx is hydrogen and the other Rx is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.
[0052] In one embodiment of formula I, one Rx is hydrogen and the other Rx is phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-lyl, 4-propyl-piperazin-1 yl, 4-butyl-piperazin-1 yl, 4-isopropyi-piperazin-l yl, 4-t-butylpiperazin-1 yl, 4-cyclopropylpiperazin-l-yl, 4-t-butoxycarbonyl-piperazin-l-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-l-yI, morpholin-4-yl, 1-H-pyrazol-l-yl, irnidazol-l-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-l-yl, 4-(piperidin-l-yl)piperidine, pyridyl (1 -methylpiperidin-4-yl)piperazin- 1 -yl, or 1-(2,2,2-trifluoroethyl)piperazin-l-yl.
[0053] In one embodiment of formula I, one Rx is hydrogen and the other Rx is pyridyl, or pyridyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-lyl, 4-propyl-piperazin-lyl, 4-butyl-piperazin-lyl, 4-isopropyl-piperazin-lyl, 4-t-butylpiperazin-lyl, 4-cyclopropylpiperazin-l-yl, 4-t-butoxycarbonyl-piperazin-l-y1, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, 1-HHpyrazol-1-yl, imidazol-1-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-l-yl)piperi dine, pyridyl (1-methylpiperidin-4-y1)piperazin-1-yl, or 1-(2,2,2-trifluoroethyl)piperazin-l-yl.
[0054] In one embodiment of formula I, one RX is hydrogen and theother Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from Cl-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 Page 13 of 153 aliphatic-, aralkyloxy, di(Cl-C6 aliphatic)amino-, -0-Cl-C6 aliphatic, -S(O)-aliphatic, or -S(O)a-C 1-C6 aliphatic.
[0055] In one embodiment of formula I, one Rx is hydrogen and the other Rx is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from 0, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.
[0056] In one embodiment of formula I, said Rx is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-' yl or piperidinyl.
[00571 In one embodiment of formula I, two RX, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-14 membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring system formed by two Rx is optionally substituted with up to 5 R4 substituents.
[0058] In one embodiment of formula i, said ring system is selected from 9H-fluroen-9-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl, or 1-benzyl-piperidin-4-yl.
[0059] In another embodiment of formula I, said compound is of formula I-A:
O
1 N.R-RZ Rw Rw CaA
RX
RX--~x N~
RY N O O

I-A;
wherein:
ring A is a 4-7 membered heterocyclic ring that forms a spirocyclic ring system with said piperidine ring through carbon atom CA, wherein ring A is optionally fused with a phenyl or heteroaryl ring that is optionally substituted with up to 5 R1 substituents;
wherein said ring A, in addition to the nitrogen ring atom, has up to two additional ring heteroatoms selected from 0, N, or S;
wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R, substituents;
R', Rx, RY, RZ, R"", and X are as defined herein.
Page -14 of 153 [0060] In one embodiment of formula I-A, is a single bond and Rz, if present, is hydrogen.
[0061] In one embodiment of formula I-A, is a single bond and Rz is CI-C6 alkyl, halo-Cl-C6 alkyl-, or -O-Cl-C6 alkyl.
[0062] In one embodiment of formula I-A, Rz, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[00631- In one embodiment of formula I-A, at least one RW is C1-C6 alkyl, halo-C1-C6 alkyl-or -O-C1-C6 alkyl.
[00641 In one embodiment of formula I-A, at least one Rw is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[00651 In one embodiment of formula I-A, - is a single bond, one RW is hydrogen and the other Rw is C1-C6 alkyl, halo-CI-C6 alkyl or -O-C1-C6 alkyl.
10066] In one embodiment of forinula I-A, one R`N is hydrogen and the other Rw is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.
[00671 In one embodiment of formula I-A, - is a single bond and each RW is hydrogen.
[00681 In one embodiment of formula I-A, RY is Cl-C6 aliphatic optionally substituted with one or more halo, OH, C 1-C4 alkoxy, C 1-C4 alkoxy carbonyl, or di-(C 1-C4 alkyl) amino-.
[00691 In one embodiment of formula I-A, RY is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1 -(methoxy carbonyl)-3 -methyl-butyl, 1-(hydroxy methyl)-3-methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, l-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.
[0070] In one embodiment of formula I-A, RY is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.
[0071] In one embodiment of formula I-A, RY is C3-C8 cycloaliphatic or a C3-C8 cycloaliphatic substituted C1-C6 aliphatic-.
[0072] In one embodiment of formula I-A, RY is C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted C 1-C6 alkyl-.
[00731 In one embodiment of formula I-A, RY is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl-, or cyclohexylethyl-.
[0074J In one embodiment of forrnula I-A, RY is pyridyl (Cl -C6) alkyl-, tetrahydrofuranyl (C1-C6 alkyl)-, N-(C1-C4 alkyl)-pyrrolidinyl-(Cl -C6 alkyl)-.

Page15of153 [0075] In one embodiment of formula I-A, RY is tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, 1H-indazol-5-yl, or 2-(N-methyl)-pyrrolidin-2-yl-ethyl-.
[0076] In one embodiment of formula I-A, R'r is phenyl or (phenyl)-substituted aliphatic- optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, 0, or S.
[0077] In one embodiment of fornula I-A, Ry is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl-, 2-piperidinylphenyl- or phenylethyl-.
[0078] In one embodiment of formula I-A, - is a single bond, one RX is hydrogen and the other Rx is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic or a 4-7 membered heterocyclic ring with up to 3 RU substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
[0079] In one embodiment of formula I-A, one Rx is hydrogen and the other RX
is phenyl or pyridyl with up to 2 R5 substituents independently selected from halogen or a 4-7 membered heterocyclic ring with up to 2 RU substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
[0080] In one embodiment of formula I-A, one Rx is bydrogen and the other Rx is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.
[0081] In one embodiment of formula I-A, one Rx is hydrogen and the other Rx is phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-lyl, 4-propyl-piperazin-lyl, 4-butyl-piperazin-lyl, 4-isopropyl-piperazin-lyl, 4-t-butylpiperazin-lyl, 4-cyclopropylpiperazin-l-yl,. 4-t-butoxycarbonyl-piperazin-l-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, l-HHpyrazol-l-yl, imidazol-l-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-l-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-l-yl, or 1-(2,2,2-trifluoroethyl)piperazin-l-yl.
[0082] In one embodiment of formula I-A, one Rx is hydrogen and the other Rx is pyridyl, or pyridyl substituted with piperazine, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-1 yl, 4-propyl-piperazin-lyl, 4-butyl-piperazin-lyl, 4-isopropyl-piperazin-lyl, 4-t-butylpiperazin-lyl, 4-cyclopropylpiperazin-l-yl, 4-t-butoxycarbonyl-piperazin-l-yl, 4-hydroxy-piperidinyl, 4-etlioxyearbonyl-piperidin-1-yl, morpholin-4-yl, l-HHpyrazol-l-yl, imidazol-l-yl, pyrrolidin-Page 16 of 153 1-yl, 3-dimethylamino-pyrroiidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-l-yl, 1-(2,2,2-trifluoroethyl)piperazin-1-yl.
[0083] In one embodiment of formula I-A, one Rx is hydrogen and the other Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-Cl-C6 aliphatic-, heteroaryl-Cl-C6 aliphatic-, aralkyloxy, di(C1-C6 aliphatic)amino-, -O-C1-C6 aliphatic, -S(O)-aliphatic, or -S(O)2-C1-C6 aliphatic.
[0084] In one embodiment of formula I-A, at least one Rx is hydrogen and the other Rx is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from 0, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.
[0085] In one embodiment of formula I-A, said Rx is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl or piperidinyl.
[0086] In one embodiment of formula I-A, - is a single bond, two RX, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring system formed by two Rx is optionally substituted with up to 5 R4 substituents.
[0087] In one embodiment of formula I-A, said ring system is selected from 9H-fluroen-9-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl, or 1-benzyl-piperidin-4-yl.
[00881 In one embodiment of formula I or I-A, ring A is selected from:
A A
D
SWA ~ ~ WAP
WE (WB) q (WB~q ``, ,~ ~
W~-N O N O
' I I
Ri Ri A-i A-ii;

Page 17 of 153 .r~ i'z k i'"
A
(,V1/A P { WA P /a W~ (W B )(WB) ~"F___TrN / Q B1N/ q ,Ri ,R' A-iii or A-iv;
wherein:
p is 0-2;
q is 0-2; provided that p+q <2;
each of WA and WB is independently selected from NR', 0, S, SO, SOZ, C(R')Z, or =CR' (when p or q is 2);
WE is -C(R')2, =C(R')-, N-, or -N(R' )-;
WF is absent or is selected from -C(R')2, =C(R')-, =N-, or -N(R')-; provided that both of WE and Wr are not simultaneously =N- or -N(R')-;
ring B I is a phenyl or 5-6 membered heteroaryl ring optionally substituted with up to R' substituents; and R' is as defined herein.
[0089] In another embodiment of formula I or I-A, ring A has formula A-i.
[0090] In one embodiment of formula I or I-A, ring A has formula A-ii.
[0091] In one embodiment of formula I or I-A, ring A has formula A-iii.
[0092] In one embodiment of formula I or I-A, ring A has formula A-iv.
10093] In one embodiment of formula I or I-A, both, WE and WF are =C(R').
[0094] In one embodiment of formula I or I-A, WE is =C(R')- and WF is =N-.
(0095] In one embodiment of formula I or I-A, p is 0 and q is 0.
[0096] In one embodiment of formula I or I-A, p is 1 and q is 0.
[0097] In one embodiment of formula I or I-A, p is 0 and q is 2.
[0098] In one embodiment of formula I or I-A, WA is NR'.
[0099] In one embodiment of formula I or I-A, WA is O.
[00100] In one embodiment of formula I or I-A, WA is C(R')2.
[00101] In one embodiment of formula I or I-A, WA is C(R')2 and R' is hydrogen.
[00102] In one embodiment of formula I or I-A, WB is NR'.
[00103] In one embodiment of formula I or I-A, Wg is O.
1001041 In one embodiment of formula I or I-A, WB is C(R')2.
Page 18 of 153 [00105] In one embodiment of formula I or I-A, WB is C(R')2 and R' is hydrogen.
[00106] In one embodiment of formula I or I=A, p is 2 and WA is C(RI)2-C(RI)2 or -CR1=CRt-.
[00107] In one embodiment of formula I or I-A, q is 2 and WB is C(RI)Z-C(RI)2 or -CR'=CR'-.
[00108] In one embodiment of formula I or I-A, ring A is selected from:
~ `'~.
CCA ~ ~ / CA
, C~ ~ A
I O ~ NH cLo Ii~ ~
O n1 O N ~O N ~~O
H H H
A-i-a A-i-b A-i-c A-i-d A-i-h ~ ~ ~ ~ ,, / ~`
,.~` i/~.. : . .~.~ ;'',/~
CA ~ , , ~ , ~ NH HN O
H ~ NH O
N~O H

A-i-i A-i-j A-i-k or A-i-I;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00109] In one embodiment of forniula I or I-A, ring A is selected from:
~ H
CO
/ /
'-, CN
C y v ~~` A
H~O H ~ H~o A-i-e A-i-f or A-i-g;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00110] In one embodiment of formula I or I-A, ring A is selected from:
X 1/11/1 'k, 1/7-11 1)113 1/h,"
NH CA
CA C__O CA

N O N"~O \ N~O ~ N~O
H H H H
A-ii-a A-ii-b A-ii-c or A-ii-d;
wherein said ring system is optionally substituted with up to 4 R' substituents.
[001111 In one embodiment of formula I or I-A, ring A is selected from:
Page 19 of 153 O N V CA ~

\ ~ CAs`s' C(N- CA CA ~ ~ I ~O
N0 O N~sO'` N
H H H H
A-ii-e A-ii-f A-ii-g A-ii-h O

~ 'k ~ ~
N N O N N 'tO
H H
A-ii-i or A-ii-j;
wherein said ring system is optionally substituted with up to 4 R' substituents.
[00112] In another embodiment of formula I or I-A, the compound is of formula I-B:
O
(LRN"
A
R-__,'X N
~N_~~` 0 r{Y O
I-B;
wherein ring A is a 4-7 membered heterocyclic ring optionally fused with an phenyl or heteroaryl ring that is optionally substituted with up to 5 R' substituents;
wherein said ring A, in addition to the nitrogen ring atom, contains up to two additional ring heteroatoms selected from 0, N, or S;
wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R' substituents;
R', Rx, RY, and X are as defined herein.
[00113] In one embodiment of formula I-B, RY is C1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C 1-C4 alkoxy carbonyl, or di-(C 1-C4 alkyl) amino-.
[00114] In one embodiment of formula I-B, RY is inethyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3 -dimethyl -butyl, 3-methyl-butyl, 2-methyl-propyl, 2-1nethoxy-ethyl, 3-_ ethoxypropyl, 1-(methoxy carbonyl)-3 -m ethyl -butyl, 1-(hydroxy methyl)-3-methyl-butyl, Page 20 of 153 allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.
[00115) In one embodiment of formula I-B, RY is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.
[001161 In one embodiment of formula I-B, RY is C3-C8 cycloaliphatic or a C3-cycloaliphatic substituted C1-C6 aliphatic-.
[00117] In one embodiment of formula I-B, RY is C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted C1-C6 alkyl-.
[001181 In one embodiment of formula I-B, RY is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl-, or cyclohexylethyl-.
[00119] In one embodiment of formula I-B, RY is pyridyl (C1-C6) alkyl-, tetrahydrofuranyl (C1-C6 alkyl)-, N-(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl)-.
[001201 In one embodiment of formula I-B, RY is tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, 1H-indazol-5-yl, or 2-(N-methyl)-pyrrolidin-2-yl-ethyl-.
[001211 In one embodiment of formula I-B, RY is phenyl or (phenyl)-substituted aliphatic each optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, 0, or S.
[00122] In one embodiment of formula I-B, RY is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl-, 2-piperidinylphenyl- or phenylethyl-.
[001231 In one embodiment of formula I-B, Rx is an aryl or heteroaryl ring optionally substituted witli up to 5 R3 substituents independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic or a 4-7 membered heterocyclic ring with up to 3 Ru substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
[00124] In one embodiment of formula I-B, Rx is phenyl or pyridyl with up to 2 substituents independently selected from halogen or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 2 Ru substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, 0, or S.
1001251 In one embodiment of formula I-B, Rx is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.
[001261 In one embodiment of formula I-B, RX is pyridyl, phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-l--yl, 4-ethyl-piperazin- I yl, 4-propyl-piperazin-1yl, 4-Page 21 of 153 butyl-piperazin-lyl, 4-isopropyl-piperazin-1yl, 4-t-butylpiperazin-1y1, 4-cyclopropylpiperazin-l-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-l-yl, morpholin-4-yl, 1-HHpyrazol-1-yl, imidazol-1-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-l-yl, 4-(piperidin-l-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin- I -yi, or 1-(2,2,2-trifluoroethyl)piperazin-l-yl.
[00127] In one embodiment of formula I-B, Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from Cl -C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-Cl-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aralkyloxy, di(C1-C6 aliphatic)amino-, -0-C1-C6 aliphatic, -S(O)-C1-C6 aliphatic, or -S(0)2-C1-C6 aliphatic.
[001281 In one embodiment of formula I-B, RX is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from 0, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.
[00129] In one embodiment of formula I-B, said fused ring is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl or piperidinyl.
[00130] In one embodiment of formula I-B, ring A is selected from:
c WE~W W ~! ~ r ~z WpF
(1 /
N
WN/Y

A-v or A-vi;
wherein:
Wc is -C(Rl)2, C(O), or =CRl-;
r is 0-2;
WD is N or =C-;
WE is -C(R')2, =C(R')-, =N-, or -N(R')-;
WF is absent or is selected from -C(R')2, =C(R')-, =N-, or -N(R)-; provided that=both of WE and WF are not siinultaneously =N- or -N(Rl)-;
Y is C(O), S(O), or S(O)2;
ring B 1 is a phenyl or 5-6 membered heteroaryl ring optionally substituted with up to Ri substituents; and =- is a single or a double bond;

Page 22 of 153 R' is as defined herein. ..
[001311 In one embodiment of formula I-B, W' is -C(R')2.
[00132] In another embodiment of formula I-B, Wc is =CR'-.
[00133] In one embodiment of formula I-B, Wc is C(O).
.[00134] In one embodiment of formula I-B, r is 0.
[00135) In one embodiment of formula I-B, r is 1.
[00136] In one embodiment of formula I-B, r is 2.
[00137] In one embodiment of formula I-B, WD is N.
[001381 In one embodiment of formula I-B, WD is -C-.
[00139] In one embodiment of formula I-B, Y is C(O).
[001401 In one embodiment of formula I-B, Y is S(O).
[00141] In one embodiment of formula I-B, Y is S(O)2.
[00142] In one embodiment of formula I-B, ring A is selected from:
O
Ni~z a NA Ni~
C CS 2 ~
H O H NO H H O
A-v-a A-v-b A-v-c A-v-d N~O c ~NO ~NO ;>=
A-v-e A-v-f A-v-g A-v-h N/~ N/~
' \H O H~O N ~O
N
H
A-v-i A-v-j or A-v-k;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00143] In one embodiment of formula I-B, ring A is selected from:

Page 23 of 153 O
~x N N N
~ s0 H 0 H 0 \ H 2 H
A-vi-a A-vi-b A-vi-c A-vi-d ~1,.
~ r~
3>= 1j_-zo H O N H
A-vi-e A-vi-f A-vi-g A-vi-h C H

or A-vi-I;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00144] In one embodiment of formula I-B, ring A is optionally substituted with up to 5 substituents selected from C1-C6 aliphatic, Cl-C6 aliphatic-oxy, Cl-C6 haloaliphatic, CN, halo, oxo, optionally substituted C3-C7 cycloaliphatic, or an optionally substituted ring selected from phenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imadazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, or morpholinyl.
[00145] In one embodiment of formula I-B, in R', Q is a bond.
[00146] In one embodiment of formula I-B, in R', Q-R"' is Q-R'.
[00147] In one embodiment of formula I-B, Q is present and R is hydrogen.
[00148] In one embodiment of formula I-B, Q is present and R is Cl-C6 aliphatic.
[00149] In one embodiment of formula I-B, R is methyl, ethyl, propyl, or butyl.
(00150] In one embodiment of formula I-B, R' is hydrogen.
[00151] In one embodiment of formula I-B, R' is a C1-C8 aliphatic group, optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, wherein up to two methylene units of said C1-C8 aliphatic is optionally replaced with -CO-, -CONH(C 1-C4 alkyl)-, -COz-, -OCO-, -N(C l-C4 alkyl)C02-, -0-, -N(C 1-C4 alkyl)CON(C 1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(Cl-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SOaN(C1-C4 alkyl)-, N(C 1-C4 alkyl)SOz.-, or -N(C I -C4 alkyl)SO2N(C1-C4 alkyl)-.

Page 24 of 153 [00152] In one embodiment of formula I-B, R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(Cl-C4 alkyl)-, N(C1-C4 alkyl)S02-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.
[00153) In one embodiment of formula I-B, R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said Cl-C6 alkyl is optionally replaced with -CO-, -CONH(CI-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(Cl-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SOZ-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.
[00154] In one embodiment of formula I-B, two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said Cl-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(CI-C4 alkyl)C02-, -0-, -N(C1-alkyl)CON(C'1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.
[001551 In one embodiment, compounds of the present invention include those in Table I
and Table 1 A.
[001561 In another embodiment, compounds of the present invention include those in Table 1.
[00157] In another embodiment, compounds of the present invention include those in Table lA.
[00158] In another embodiment, compounds of the present invention include those in Table IA and Table I except for compound numbers 85, 97, and 105.

Page 25 of 153 [00159] In another embodiment, compounds of the present invention include those in Table 1 except for compound numbers 85, 97, and 105.
[001601 In one embodiment, the present invention provides compounds of formula I':
"'C~A.
Rz Rw W m "Z"
R
Rx B
RX-~X N
/N O n RY

I, .
wherein:
X is S, SO, or SO2;
Z is present or absent;
wherein:
when Z is present, then ring A is attached to ring B through a single bond;
when Z is absent, then ring A together with ring B forms a spirocyclic ring system;
ring A is a 4-7 membered heterocyclic or heteroaryl ring or a 10-14 membered bicyclic heterocyclic ring, wherein ring A has 1-4 heteroatoms selected from 0, N, or S;
wherein ring A is optionally substituted with up to 5 R' substituents;
m is 1-3;
n is 1-3; provided that m+n is --54;
RY is aryl, heteroaryl, cycloaliphatic, CI-C6 aliphatic, aryl-aliphatic, or cycloaliphatic-aliphatic; wherein RY is optionally substituted with up to 5 R2 substituents;
Rx is hydrogen, halo, aryl, heteroaryl, CI-C6 aliphatic, aryl-C1-C6 aliphatic, heteroaryl-C1-C6 aliphatic, whereiti Rx is optionally substituted with up to 5 R3 substituents;
or two RX, taken together with the carbon atom that they are attached to, form a 3-9 membered cycloaliphatic or heterocyclic ring, wherein said heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring is optionally substituted with up to 3 R3 substituents;
wherein said ring formed by two RX is optionally substituted with up to 5 R4 substituents;

Page 26 of 153 RZ is absent, hydrogen, CN, C 1-C6 aliphatic, halo-C 1-C6 aliphatic, O-C 1-C6 aliphatic, O-(halo-C 1-C6 aliphatic), halo, aryl-Cl -C6 aliphatic, or heteroaryl-C 1-C6 aliphatic;
- is a single or a double bond; provided that when it is a double bond, then RZ
and one of RW is absent;
Rw is independently hydrogen, halo, oxo, C1-C6 aliphatic, halo-C1-C6 aliphatic, 0-C1-C6 aliphatic, O-(halo-Cl-C6 aliphatic), aryl, aryl-Cl-C6 aliphatic, C3-C7 cycloaliphatic;
or two Rw taken together form an optionally substituted C3-C7 cycloaliphatic or heterocyclic ring, wherein said heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring formed by two RW is optionally substituted with up to substituents;
wherein each occurrence of R', R2, R3, R4, and RS is independently Q-Rm;
wherein Q is a bond or is a CI-C6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, C02, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, 0, S, or NR;
wherein each occurrence of RM is independently selected from R', halogen, NOz, CN, OR', SR', N(R')2, NR'C(O)R', NR'C(O)N(R')Z, NR'COaR', C(O)R', COZR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, SOR', SOZR', SOzN(R')Z, NR'SOZR', NR'SO2N(R')2, C(O)C(O)R', or C(O)CH2C(O)R', wherein each occurrence of R is independently selected from hydrogen or an optionally substituted CI_6 aliphatic group;
wherein each occurrence of R' is independently selected from hydrogen or an optionally substituted group selected from CI_$ aliphatic, C6_1o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R
and R' taken together with the atom(s) to which they are bound, or two occurrences of R' taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00161] In one embodiment, - is a double bond and Rz and one of RW is absent;
[00162] In another embodiment, - is a single bond. In another embodiment, one or RW is hydrogen and the other is not. In another embodiment, both of Rw are hydrogen.
[00163] In one embodiment, m is I and n is 1. In another embodiment, m is I
and n is 2. Or,mis2andnisl. Or,mis2andnis2.

Page 27 of 153 [00164] In another embodiment, Rz.is C1-C6 alkyl or halo.-C1-C6 alkyl. Or, RZ
is -O-C1-C6 alkyl. Exemplary Rz include fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc.
[00165] In another embodiment, Rw is Cl-C6 alkyl or halo-Cl-C6 alkyl. Or, Rw is -O-C1-C6 alkyl. Exemplary Rw include fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc.
[00166] In another embodiment, two Rw, taken together with the carbon atom they are attached to, form an optionally substituted C3-C9 cycloalkyl or a 3-9 membered heterocyclyl ring. Exemplary such rings include cyclopropyl, cyclopentyl, or cyclohexyl.
[00167] In one embodiment, RY is C 1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, or di-(Cl-C4 alkyl) amino.
Exemplary embodiments include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxy carbonyl)-3-rnethyl-butyl, 1 -(hydroxy methyl)-3 -methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.
[00168] In another embodiment, RY is C3-C8 cycloaliphatic or C3-C8 cycloaliphatic substituted C1-C6 aliphatic. In one embodiment, Ry is C3-C6 cycloalkyl or C3-cycloalkyl substituted Cl-C6 alkyl. Exemplary embodiments include cyclopropyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, or cyclohexylethyl.
[00169] In another embodiment, RY is pyridyl (C1-C6) alkyl, tetrahydrofuranyl (C1-C6 alkyl), N-(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl). Exemplary embodiments include tetrahydrof-uran-2-ylmethyl, pyridin-3-yl-methyl, pyridin-4-yl-ethyl, pyridin-2-yl-ethyl, pyridin-4-yl-methyl, I H-indazol-5-yl, or 2-(N-methyl)-pyrrolidin-2-yl-ethyl.
[00170] In another embodiment, RY is optionally substituted phenyl or (optionally substituted phenyl)-substituted C1-C6 aliphatic. Exemplary embodiments include phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyhnethyl, or phenylethyl.
[00171] In one embodiment, both Rx are hydrogen.
[00172] In one embodiment, Rx is a phenyl or a heteroaryl, such as pyridyl, wherein said phenyl or heteroaryl is optionally substituted with an optionally substituted 3-7 membered heterocyclic or heteroaryl ring having up to three heteroatoms selected from 0, S, or N. Exemplary Rx include phenyl, pyridyl, or phenyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-l-yl, morpholin-4-yl, 1-HHpyrazol-l-yl, imidazol-I-yl or pyridyl.

Page 28 of 153 [00173] In another embodiment, Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 aliphatic, cyano, halo, halo-Cl-C6 aliphatic, aryl-Cl-C6 aliphatic, heteroaryl-C1-C6 aliphatic, aralkyloxy, di (C1-C6 aliphatic)amino, O-Cl-C6 aliphatic, S(O)-Cl-C6 aliphatic, or S(O)2-C1-C6 aliphatic.
[00174] In another embodiment, Rx is an optionally substituted C3-C7 cycloaliphatic or a heterocycloaliphatic ring having up to three heteroatoms selected from 0, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl ring. Exemplary rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2F1 pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl, piperidinyl, etc.
[001751 In another embodiment, two RX, taken together with the carbon atom that they are attached to, form an optionally substituted 3-9 membered cycloaliphatic or heterocyclic, monocyclic, bicyclic, or tricyclic ring. Exemplary embodiments include 9H-fluroen-9-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl, or 1-benzyl-piperidin-4-yl.
[001761 In another embodiment, the present invention provides compounds of formula O
(LNR
RZ Rw Rw A
RRX C,a X --~-X N,,) = _--RY N O
wherein:
ring A is a 4-7 membered heterocyclic ring that forms a spirocyclic ring system with said piperidine ring through carbon atom CA, wherein said heterocyclic ring is optionally fused with an optionally substituted phenyl or heteroaryl ring;
wherein said ring A, in addition to the nitrogen ring atom, up to two additional ring heteroatoms selected from 0, N, or S;
wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R~
substituents;
R~, RX, RY, Rz, Rw, and X are as defined above.
[00177] In one embodiment, - is a double bond and RZ and one of Rw is absent;
[00178] In another embodiment, - is a single bond.

Page29of153 [00179] In another embodiment, RZ is C1-C6 alkyl or halo-Cl-C6 alkyl. Or, Rz is -0-Cl-C6 alkyl. Exemplary Rz include methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc.
[00180] In another embodiment, Rw is C1-C6 alkyl or halo-Cl-C6 alkyl. Or, RW
is -O-Cl-C6 alkyl. Exemplary Rw include methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc.
[00181] In another embodiment, two Rw, taken together with the carbon atom they are attached to, form an optionally substituted C3-C9 cycloalkyl or a 3-9 membered heterocyclyl ring. Exemplary such rings include cyclopropyl, cyclopentyl, or cyclohexyl.
[00182] In one embodiment, ring A is selected from:
i ~. k :4-~ A= / -- A
~WA P CC B) a l WA p C( B) a ~
T'_4B1 F-N O N O
I I
R' R1 A-i A-ii;
~
Ii''+iz-A A
(A)-' ('N ~'"C
~ C 8) A p w V1/E ~
q \ /= q WF--_ir N, R' N`R' O
A-iii or A-iv;
wherein:
p is 0-2;
q is 0-2; provided that p+q <?;
each of WA and WB is independently selected from NR', 0, S, SO, S02, C(R')Z, or =CR' (when p or q is 2);-WE is -C(R')2, =C(R')-, =N-, or -N(R')-;
WF is absent or is selected from -C(R')2, =C(R')-, =N-, or -N(R')-; provided that both of WE and WF are not simultaneously =N- or -N(R')-;
ring BI is an optionally substituted phenyl or 5-6 membered heteroaryl ring;
R' is as defined above.
[00183] In one embodiment, ring A has formula A-i. In another embodiment, ring A
has formula A-ii. Or, ring A has formula A-iii. Or, ring A has formula A-iv.

Page 30 of 153 [00184] In one embodiment, both, WE and WF are =C(R'). In another embodiment, WE.1S =C(Rl)- and WF is =N-.
[00185] In one embodiment, p is 0 and q is 0. In another embodiment, p is 1 and q is 0. In another embodiment, p is 0 and q is 1. In yet another embodiment, both p and q are 1.
Or, p is 0 and q is 2. Or,pis2 andqis0.
[00186] In one embodiment, WA is NR1. In another embodiment, WA is O. Or, WA
is C(R')2. In one einbodiment Rl is hydrogen.
[00187] In one embodiment, W~ is NR': In another embodiment, WB is O. Or,-WB
is .. .
C(R])2. In one embodiment R' is hydrogen.
[00188] In another embodiment, p is 2 and WA is C(R')2-C(R')2 or -CR'=CR'-.
[00189] In another embodiment, q is 2 and WB is C(RI)2-C(R1)2 or -CR1=CR!-.
[001901. In one embodiment, ring A is selected from:

(CA CA CA

O NH cc ~O O C~H H H H H

A-i-a A-i-b A-i-c A-i-d A-i-h ~ ~^. i'1s ~ ~ i ~
N_ A A
CA ~NH CNH HN y O
H
\ N ~O
H ~ ~ 0 A-i-i . A-i-j A-i-k or A-i-l;
wherein said ring is optionally substituted with up to 4 Ri substituents.
[00191] In another embodiment, ring A is selected from:

O : L H

~ NA~-I CA~~ I CA C C
-~ -K ~
H ~ H H. O
A-i-e A-i-f or A-i-g;
wherein said ring is optionally substituted with up to 4 R' substituents.
1001921 In another embodiinent, ring A is selected from:

Page 31 of 153 ~ i ~ i ~
C'A CA C'4 I \O \NH CA
N O N'k-O N--tz'--O N~O
H H H H

A-ii-a A-ii-b A-ii-c or A-ii-d;
wherein said ring system is optionally substituted with up to 4 Rl substituents.
[00193] In another embodiment, ring A is selected from:

N
NO N N N/}c OCNLO CA~` CA/ ~ I \ 0 H H H H
A-ii-e A-ii-f A-ii-g A-ii-h ~.. ~i `~

OCA ~ rN C A N N~O N ~O
H H
A-ii-i or A-ii-j;
wherein said ring system is optionally substituted with up to 4 R' substituents.
[001941 In another embodiment, the compounds of the present invention have formula O
R' RXX N B 4A) N_Z

O .
1'-B;
wherein said ring A, in addition to the nitrogen ring atom, contains up to two additional ring heteroatoms selected from 0, N, or S;
wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R, substituents;
R', Rx, RY, and X are as defined above.
[00195] In one embodiment, ring A is selected from:
Page 32 of 153 (_WC .
WE W W~
wD.
F B1 ' WN__-Y N--Y
A-v or A-vi;
wherein:
W'- is -C(R')Z, C(O), or =CR'-;
r is 0-2;
W is N or =C-;
WE is -C(R')z, =C(R')-, N-, or -N(R')-;
WF is absent or is selected from -C(R')2, =C(R')-, =N-, or -N(R')-; provided that both of WE and WF are not simultaneously. N- or -N(R')-;
Y is C(O), S(O), or S(O)2;
ring BI is an optionally substituted phenyl or a heteroaryl ring;
--- is a single or a double bond;
R' is as defined above.
[00196] In one embodiment, Wc is -C(R')2. Or, WC is =CR'-. Or, Wc is C(O).
[00197] In one embodiment, r is 0. Or, r is 1. Or, r is 2.
[00198] In another embodiment, W is N. Or, W is =C-_ [00199] ln one embodiment, Y is C(O). Or, Y is S(O). Or, Y is S(O)2.
[00200j In one einbodiinent, ring A is selected from:

O
N~~ N~x.
I
C aO ft02 N~O N
N~O
H H H H
A-v-a A-v-b A-v-c A-v-d N~O CN ~N~O O

A-v-e A-v-f A-v-g A-v-h Page 33 of 153 ~ ciN ~ a ~ o . vO

A-v-i A-v-j or A-v-k;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00201] In one embodiment, ring A is selected from:
O
N~~4 / I \ . N~~ N
SO
! ~ \ I ~
H O \ H O Hi 2 H
A-vi-a A-vi-b A-vi-c A-vi-d N oc., N N~O
N ~HH~O N
H
A-vi-e A-vi-f A-vi-g A-vi-h or aNN" O
H
A-vi-I;
wherein said ring is optionally substituted with up to 4 R' substituents.
[00202] In one embodiment, ring A is optionally substituted with up to 5 substituents selected from Cl-C6 aliphatic, Cl-C6 aliphatic-oxy, Cl-C6 haloaliphatic, CN, halo, oxo, optionally substituted C3-C7 cycloaliphatic, or an optionally substituted ring selected from phenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imadazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, or morpholinyl.
[00203] In one embodiment Q is absent. In another embodiment, Q-RM is R'.
[00204] In one embodiment, R is hydrogen. Or, R is C1-C6 aliphatic. Exemplary R
includes CI-C6 alkyl, e.g., methyl, ethyl, propyl, or butyl.
[00205] In one embodiment, R' is hydrogen.
[00206] In one embodiment, R' is a Cl-C8 aliphatic group, optionally'substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, wherein up to two Page 34 of 153 methylene units of said Cl-C8 aliphatic is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)CO2-, -0-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(Cl-C4 alkyl)-, -SO2N(Cl-C4 alkyl)-, N(Cl-C4 alkyl)SO2-, or -N(C1-C4 alkyl)SO2N(Cl-C4 alkyl)-.
[00207] In one embodiment, R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said Cl-C6 alkyl is optionally replaced with -CO-, -CONH(Cl-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(Cl-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(Cl-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02-, or -N(C1-C4 alkyl)SO2N(Cl-C4 alkyl)-.
[00208] In one embodiment, R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or Cl-C6 alkyl, wherein up to two methylene units of said Cl-C6 alkyl is optionally replaced with -CO-, -CONH(C1-alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C 1-C4 alkyl)-, -N(C 1-C4 alkyl)CO-, -S-, -N(C 1-C4 alkyl)-, -SO2N(C 1-C4 alkyl)-, N(C1-C4 alkyl)SOa-, or -N(Cl-C4 alkyl)SO2N(C1-C4 alkyl)-.
[002091 In one embodiment, two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C
1-C6 alkyl, wherein up to two methylene units of said Cl -C6 alkyl is optionally replaced with -CO-, -CONH(C 1-C4 alkyl)-, -COa-, -OCO-, -N(C 1-C4 alkyl)C02-, -0-, -N(C 1-C4 alkyl)CON(C 1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(CI-C4 alkyl)-, N(Cl-C4 alkyl)S02-, or-N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.
[00210] Exemplary compounds of the present invention are shown in Table I and Table lA below.
Table 1:

Page 35 of 153 ICN
N p S N
tJ
~ U10 S N
Q N~ d ~
O
p H ' p 5 l?~p N,,~,~o,, ., N O
VO

N S
N S
O
N N O N
0 ~
o:`N
H

1 ~
i ~
~J s rJ s N~

0 ~cl)o O NaN N

~O ~O N
~ r'y-i ,~ P}i p~=,N ~ .~
H

p Nl N^~'~
/ S ~
pp UO ~ S .
N
Q O
N-r- O N~--O tJ I
NH pJ, N
H
Page 36 of 153 F
F t r ~ ,~ ~ \ f S s N
O
!-~ N
o a S. )( 0 ~J ~s N i tJ

~O HN~N N

q Fr0F eoo ~ A. `~N` F ~\s N O N ~"U ^
a "
}FO N N
O--~'N I~ OPL=N
H H

~
tJ o S-'J ~ g N
Q Ns ~O ~O
~~ $ a 'N N
O O
~ ~ . =h~t ~ ~
~ 0+

22 .23 24 F
F
F
N H ~. t S rl ~ 5 tJ ~
O 5 j~N 1 ~a UO
LNJ
~-N` t ~ C ) (> ~/] -a 0 CN
H~O

Page 37 of 153 F
, rN S 0 N O

N S
~10 N

N \
N S

R
t,00 N EJ S Q p S O O N

N'F~,O N +
d=H -32 33 ~

Ci o rJ o ~
s~s ~s N s O EJ O O O ON
NxrJH aNANH N
ON

~ ~ F F F
~'Nt `~ F F
rN/ s rJ~ F F
a E=J
o S
o m o N"p- o '}i H
H

Page 38 of 153 S g N N.= t g N

~010 ~1O ~100 N

O NFlO NIiO

i~~ S PJ~ ~ C3 S N
O y ~NJ~S O UO
yil O ti fl ma !~ N;=p 0%N' NH
N

F . N ~
N_ 1~ 0 1 ~ ./ .
O S
`O
O O S
S N
O t14,'3'~yI`N
N v;, N
H &'Ilfo ~ O

F

~ / T'H S ~J
S O $ R ~
N
N N F:;O
N ItH
Q H N N~o H

Page 39 of 153 S NN O

ks ~ " OlN
~ O N
~Nit,, O N
ON
H H

F
~ N` ^ ~
~N f S N `~ \ ~~O S 'N~
'r ~Ioo O

r'; NP~ s n~i o ri} 'FZ-'o e12 b'N' N-I

Q
1 ~ c N O S O~s s 0 I N o r~' 1 ;+' 0 N .,. ~,J=,N ~ `..,~N~r~
O~~H
H

ra X 14 ~J
~s N r~ s ~ N
N rl ~
O rd N
~=o N H H
Page 40 of 153 F
tv Nt~FO

S' ~tJ~

~N
O
O aN
P! N ~ O ! \ ~ oi~ pN
H

/ = i ~ F

N.ko ttF
"Q
to S' N
N N
d ~ o tJ
g4 N~ ~N
N
NH H
67 68 69.
N`( ~
CI ~
~S S
N N p~~
N N
~ O N

H ~=o H N rH

q-, O...J~
a J S C t ~
o O N
Q s tJ S L~
PJ
N
~Q 0~1 H
Page 41 of 153 s N 0 to 1S
O N Q Q N~

O ~.
. O H

S ri^..~
C~ S s N
~
~100 O.Q N~ N O O N, I O
O N I'~

F
i1 ~rt_ ci U10 tJ UO
N N
~ O Ni~ Y
Ny-O N'Ir- 0 Ni NH

t S tJ `~i ~1 N 0 RS }1O
--.N N (}..O HN

O Q N~ Q ~
O
O tJApiti O

Page 42 of 153 d IsU
\-ps O N ?~
~N 1 $ N~~H g~yd ..*~ ~ d oi y~! ~ ~ Gi H
S r~ g r~~.~=, ~

UO H O

N
t~i tJ O N IP, O O

F L f \ 1 aml'~ d p i t~ ~ O^1J 94 96 ~, N $ N ~S
O

N NF=o N"
Page 43 of 153 N1 ~
N ~ ~!/ 3 !~
U = ~ ~ ~-t~
o $ H 14 ~-,O
-'" 102 \ 1 =' 1 / ~t~.~
s ~s s ox ~ O N
O~ti I ~ ~ = ~~~
, 103 't(}5 ON
Q
. ,~ ~s a r~ S -i s .~/~, v 4~=N^~ ~ L~,N
I [ t! ~' ~
0tiN
3!N H

106 107 4 ~
N s _ N S ~

ti Q
0 r=J i =
~/'N = ~tF = ~~
td )=O
H

Page 44 of 153 F F ~ ~ tJH
~F O N~p O

\I s ~ N

O N~ p p N I g O
O ~%H N~ ~ ~.

ko ~ ~ ~J
$ s N
Q rJ ~NO C7"
O O j~
g N `./ `N I "
O~r, f ~ ~ O~" 11 CI

ri rJ,~ Hpc s s H p N ~rJ
~ s N H o N o N
V `N ~N aN -4N O%' N f"H
H H

C1 N rJt S
Hoc ~J~ ~p p N
O p N O N ~
N N~O
~. it J
Q H p H `i Page 45 of 153 fi \/O S N
N N S O Q
O
-QQ FJ ~O O N
N ~
~FJ
O PJ' 0~,~
FI ttll N, N / \
O~ S N
~O F N S
O

Q d O O N
M N
)=O N
NH
O.H r ~ i O N

i=
O i /
~ F S
S
N
N~ N
"
N S O '=N Q OIN
~
I .~ O tJ
`/`~N
O~ ~N
O~õ
F

F / N
F ~
F S FJ' O O

/N O!
~f S O
~Q N O

Page 46 of 153 133 134 11,15 F
-- ~N

aN" ~ p N~ .
a O~

F
'F ~ r \
&' F s N
~ = ~ ~' ~~~
rJ~

o0 IN aQ ti a =- ~ -e +y. ~
O \ ~ ~rt S 40 `'~
p O IN $ 0 rJ ~. M~p N

~~H ' ' ~ ~ =P~ r , ........
IL

M,,~ ,,~= HO= " 0 O
~,j ~ ~ O P1 IJ S~d 'F;p td Page 47 of 153 H
N
qs S N
dN ~
N
O
-~

N ?:-- o N I ~ ~N
H

q S
, a SH O ~N4O `O ~100 N~p N)r-"p p IN
H

~ !i t ry s N,~~ 1 / f r~
s o s N
'o o o N ~ .~~ O N
N NH &)--o o: ~

F
F~= ~
D ~ N 0 tJ ~ N S

o l-~ ~
rJ 0 ~--j Q o tJ ~tJH N~O
N ll~~

H
Page 48 of 153 O--r- cl N _ ~ \ r Q~ O O TJ~
ri'1 S o 1~,=~ N~
160 9:61 162 h QQth QCO ~ H.
N N S. N N S
O~

v 'N \ N v`N \
Jl ( H I ~d OtN
H

N
N F
S N~
q s N
d .~*~
~, 7 0 r7 N~O I~N~
NH H
0i ~"`~ /

/
Qci F S -ti H ~ S
N
O
~NO O N O ~N00 S
N I `~ p~ v "N ' ~=
H `=%' ~ J H
Page 49 of 153 ;
FIP 1l . ~O
S N

~100 Y
~00~ N 00 N

N)--O
O~,N
H i p tN O
N~( N S~
l__/ 'S
~ \ /
O~N p N p O
~N 114I-l N r'`kNH
i H `t \ r Nc S N \ fN RS
~/ HS O N H ~N
tJ ~
~ O v VJ p O N
t~
~O ~N

H

H ~
11..~0 g g }~

O ~O
t~tJ O ~I+N

H

Page 50 of 153 S N S
q ~
O
~1100 N ~N to N)ZO `-,='=N I tJ,,:O
{ ~i p pi.'~,./
H

No s s Q O N ~100 N\`t H
ON ~
N
~ 0 { ~ ~O 0 Ol" NH
nn i N N S N~Q
O td O O

N~~ NN O S
N
H~~=~~
'Ft'^' ~

F F `

Fp `.~
S ~S
S F N N
O~M
O N
aO aN
~ti N 0~ H
D~.
Page 51 of 153 193'^

~/ ~N-~ ~ F FS N.~ p O

N

O ri a o s S ~ra~
a- N o= a o ta oJIM

1 f N
-..~
N~ ~ N S
00 N N p ~ ~N
~N *Jd H

F. F
F-q , F e y S =0 ~O O N ~~ Ot 1 a O M

~~ci Page 52 of 153 o~
O s S
HN O O O
S N ~10 N O
O N 2 ~
N PO )--O

H

F
F
N N$ S
O O~'N ON ON
I~(~
F ~I ~/ ~N"
o~`
H ''~i o~H~.!~

Q4( HN
, qO 8 F s ~NoN ~r s ~r~
O O N
N ONy ~.
0~~, N 4~
p~.F{ H
H p~r H

~~ r t F
F
g O ~100 S
OlN
N~o j_0 r'i H
Page 53 of 153 F
F F
Ftii.F ~N F F
S N~ S F
~0 F 5 ~010 N
~ N \r- J
O N~
N~O r\JT~ 10/LN-,,, 1 ~=o H
H

Oli F c~

~ ~ 5 N
O N O J

tJ N
O
OJ'H I " ; ~ O~H /

H
~
O - ~
\ f NJ O N

r7 g 1:0 O ^-~
O S O N Q
N tJ ~ ~ N-r- O

.

F N O O / ~
S rJ~ tJ ; S
O O
o N

0 r~'1 `,=L1J
H
I ~.
H O~N i H
Page 54 of 153 N ~
b ~
S ~oo ~10 ~N
b b N ( ) ~ \ Y
N1=-! ~ 1 N~O
~ ~b O H Ni ~

F F.~ F
F F 1 I ti b (O ~ \ = N
O F $
g }}}~~~ D
N
~ ~Y? -V O
~ p O"N O N
N
O~ri O N ~N H
~ ~ 6ko H

N
S ( N ra' ~ o~ N p\~o _e' ~ p N l~ rJ S
L

O H . ~
F

F
F F
HO qtj,-,k F O

O
~p N
O N Y ~NON

~O ~/`N H 6I~i p~H

Page 55 of 153 1 k O~

g tJ ~S
p ~ O
tilINH
N I `' ~p p%~N

N
F,r $ NN~~

~100 g J ~ N
r~ N O
l~
(~-~ Q 00, M, ~ip N~p N I `
Nd p F
F IF
NH
F p ~ p \ /
Sfff...N 5 S
~O p N
O ~
N
~ p (YI p O tJ

N'rp ~ ~
1r p H /

p `_ d ~
=='C
' F
_ fJ p N

0 J N ~ ~N
Lv ~
p f~'~` AI ~F! ~ `= N ~=
p~N ~ = ~ p H O P! '~
H H
Page 56 of 153 N a RS
F-~--~( g F S ~N

O N
O N
r' O O N ~
NxNH f\/I`
N f ~
O~H O
H

~ tJ S N ~
F (( a O
N ON
Fg 0 O ;i I
F F
O N
N =,N=^1 S N rJ~a o ~. ~ ~N ~ Nr~
~ `r ~
a~N \ N ` t N .i ~. S N J, O O N N
N ~010 Q p p )::, ~
a S N~~,.
~ \ 1 S

to 100 ~ ~ O O N

N~o Nr o ~/ `r! I
~ N o~
~i H
Page 57 of 153 e\ =
C
N~ N S N S N S
ON ~

~-s q,,, / ~ Br S S
~ N ~-N o ril ~PfJ ~ ~= v N ~ ~
o~` C~ O
H H

Qr RS b S
O Na O N~ O N
C
O PJ
o %'~~ N ' ~ N `+ D~
/ H
H O H

r~ ~ .= ` l ~s O S " ~,i 0 C~ [[[~.~~ N ~ S
N
O N
N

~=p N H p~.H
N H

Page 58 of 153 277 -` 78 ~ 279 9~ ` ~-.
s N'~-k , iz N
1a tloo N
j;ts N ..~
aI
lr H (i 280 28'1 282 '. .""
F N-ri ~
g a n ~

~1.1 'N
a N
r{t ` ~
F
283 284 2$5'i _ f4is ~ ~ ~010 Fd ri N

O
r~ i ~= .. r~j o~`~
H
H

28Ei 287 ~i= H
rN

taV=0 ~.
O O t~

54 $
, ~ 0 -o Table 1A:

Page 59 of 153 .

t H l O p N z>~) O p N N N
~ ~ H
O~v ~=O U
291 292 Fi 293 N `t ~ `- 1 N M o ~
N`
pY~

Q Q Q
aN )= )=Q %i=p H H NH

`4 -<--, -, -lc-\
N ~ ~1 H
~5s C~ S NNl pO
~ Q
NO ~ /rN~ ~5oH

aN\ p \ I N,,. O
O
H H

N O O
p S N N O leN`
~ ! ~'`/J

N N
\~= )C=
Page 60 of 153 o Q-1 o \1 H
Q~S pS N Q~ CNJ
Q
N N
P H
\ ~ N O O
H
li 303 304 li 305 N N._ N S
~ O S N N1 -S
QN
N OH (~
Q N ' Y
N
=U.I~

_ ~-N "
~ \ s N~ S N
N S ScO vo Q
N
~ N
N
o ON ~ ?-~
HN)~-N

op S N~ S N---~ S N
O Q
_~, ~ ,_..N (010 O
)~..'_'/~ 0 HN N O ON NP

Page 61 of 153 qm-" N

~ I s N v\ SN

-KNO N 0 N p O N~

`~`N ~ N N Np~o .~ + ~ ~i ~s 3'15 316 317 s N g N Q HN/`
~
O~-N
O b O ~041 N N
O ~ O O
O
HN H Nt g 1 ~
~N O ~ B N~ / /N-..
S S
N
~N
bN
O O`r" N O ~<OYOIN
~ ~

0 N O~N ' N11 H

F

\ /H ~N cH-/ ~
S
H N H
o O~ ~ O ~~ ~
N ~ N O N
a I~
N ~/'~N
O~N ~ i' O~N ~.-H H H
Page 62 of 153 r N-~
nt..1 s H1t . ~
a Q ~N ~
N ON ~Q

~O \N~ NN~ S N
L..N ~õ~N

O Q' iJH
O O O

N N N
O O
O S~ ~ ) O t) S( ~ ~`S , N
N N/ N N~ N N~

O

N N N
p i p ~
p N
~N
A1 N~ N~ N t3 \ / ~ \ t / ``\ I

14 (<,o ~p H
N SH
~
O N `~Q N O
~ 1~., O N
O ~;1 N ~ ~
~ ~
H

Page 63 of 153 QO-S N H 0s ~ S
<
N N !! !
0 (N

N~o SN
H N H

ti N

s N VNo N N F
O
a N
~
N
N f ~. ~=o N
)==o F
ck&o A:, S N qs ~l N
N
N ~ ~ O N

OF ~Qh K

vN~ S N" HN H1V
UO O~-N O O~-}ON

,~~ ~
N
~ ~
-. N S N~ N S N~
~-Fy ~ N F
-~ ~ I .~~I
Page 64 of 153 F
F

p {N~ 4 \~ L.N N
N } N ~ ,-Nt 1 N N
O
j 1 O ~fl ~
` ` N}{ 'N ~ N ti F
~.
'1 N~. JN N 1 "
~100 ~ C~
~N YC
O trt Q N S
o 354 r r-_ 355 356 F Ct Ci f} 1 f N N- N - ~! õ S
O.< N eo N
'a (Y'}
N N ~
357 358 39 ~
O
N } ON}~
~~ '.,p~ sYN t)"'"=J
N
CI ` %
-f I 0 N ' ~ 1 `=O L . ............

Page 65 of 153 F F
~ ~
EICN N S N ~ {
UO O
N S p (~`1 " J
t ~ N
O Nv`
l~ ~3' ~ `Fd N
ON ~H I / (io 363 364 tl 365 1 ~ N.~fl "
N ~! ~/N ~~,N~ s N
s O
N N ~co ~ N
ST-YN-f Q
LI N N nj=p ~j ~
NH
=^
H
366. 367 368 -1c, -- r--~ _ -, N NJ S N~
~.
p S N N S /, ~(>
N
N ~ 0 N
N
H ~~ -~, N p ~ ~ ~}CO ~ r N

S ~'\
'p r.,.', p N S

0' N ~ ) 0 U N
Y ~
`-p N
O~`~
H
Page 66 of 153 t qxCNI, ` , f N
J S N~--f H~--~
~S

~N O H NH
N
IN O
N
l~
v `N
I i O, N
H
H

Q1 N N/ ~N `i ~,,. O~ N
~, Sl~, ! \ N /1 5 N`~''\

~O n O ~O
N ~ N
N
%- O N ~--O
1r 1~ -.r-~ 1 t !"` N N ~ I
rN H 1dJ S N"l O p...
O
(-~ N

~`GJO O N U
Ni Ni th o N~ O N~ S
N g N ~O
N~ ~ A-I N
N.r N '-O

N N NH

Page 67 of 153 Nw N N S N

~ ~100 ~00 O NIN~
~-N ~N
~/ ~,~ 1 ~ FO Ny~.O (}- ') N
N O
H

`1 F `1 , / S / S
N N N N NN"
P-24 N O Voo ~clo0 ~ ) N ~ Y
N.r- O
N

ti F
t,-~1 F `1 ~ ` 1 N~T,^
N~F ~1~,.~

O a O~S O 0 ~~ ,-N
N
~ -r- 0 N O

N Fi 393 .394 395 F F ' H
H..`~ 4 N N N
N
1. ~ H~ v\ N

OS O C
"~~HS
N
N F N

N
N 'F~=.F N

Nf O N
~O

Page 68 of 153 F .~ F

N H N
r .~,~ r. S
N ~ `.-FO O H = ~ H."O
~O O H ~c0 N C , Y N N N
Y
,F:O Q )--O
i % ' ~ O Mi N Fi s_ F~ 1 F _ 1 `
41 H N f^N~tN ~N H N ~ 'i iN-f ~N/ ~~ ~N/ 'v \
N O N O N O

N.F~O N.--O N.~--O
(5N, 402 403 404 O N UO
~ 5 `~'~
N N H N--Nr-O ~
N O
H~ ~ I ~
405 .406 Fi 407 N"~JN g NH"V
~010 O g N O
O ~O
N }~ ~ r N
N ~
)FO Q N'FO
N
N

Page 69 of 153 [V, RNN '''\ N S N O=rl N
s 'N '--~N ~- U O ~100 N
Q ~ ~ Y Q
/ ~ N,~0 N~O
, O
FI r ~ ' N

N~
16~N -k, F S O S N~ N~N
~ dO
N
Q
N
1F0 N.r-O
&Nki L ~ ~ ~ ~ ~ O
N H

RN~ 1 0 N
O O S N
~ O O
rN) ~N?
~ YH ~Y
1r0 Y-- O
JNf i I .;.-O 4{
N r vl O N N~ -N S N
S O N
O ~100 M
N ~
p N, N '- O
N
)=O =~ ~ O t~i N NH

Page 70 of 153 O
O N O
O
%S O N~ ~
N ~O O
~) N N
Y
N'T-- O N)--O N~pO

O
~N N
/
N O ~ S N
O ~ o~O
~O

N O P
Q
N~ ~O N~ N O
i N

o rDo 0-~
O=
~N
N f~ 5 N
s N ~ OO
S N
O

Np N, N
~ N"`TT~~Y" ~
N
~=O `' H Q

N N
pl N NF O N NF O N NF
jO / \ illo ~y./ \ 0 n 'PO NNP~

Page 71 of 153 ~ C N cf õ N~ N J 5 N" N /) O N

p ~p ~ p );::O Q ~IF- -I0 ..

-l ~ 1 ~ {V ~ y~ 1 1 r F
N F N

t3 ~N~ a N ( ~ t~, (x ~ ~ -A-No N
)==O ~=O

F ~ 1 F dL
o -1c, C, H ~OO

`` ~HS ~ 0 ~ O

7 tV
~ ~ ~

.~ N Nd N

.- A-t y Nhl ~ 1 F N~~N
0 `~tHi' O H O }1 O N

N a N
~ j=o f I '.~o ! )1=0 N 3'1 NN L N

Page 72 of 153 ....,~, .~~,_._.,.... ~
F F

rd td g t; ~ 0 ~I ~ a ~1 ra __ .. ....~. ~. ~..... -.................Y~. _._~___.. ~,.~ _. ,,,._..

H ~.,,.N Ct ! \ N F ~ \ .
O ~ .
H N
fl HNI
~ ) `~~~ ~/' `~H~ S N
14 ./ / ` / ' .__..~....._..,.....
~
Q
O
O ~ l. N
O o! t,t ~
O ~
i ~' ~.~- ~`'N
v N F ~.

F

HO HO X'I H F
o~
hT N O H
~, 0 ~
~
\/ \~ F M~ ~Q

Page 73 of 153 Br 1 f \ ~1 H,, H ooo4~~~F
O N
N
O li -~ N M
11~Q Pi H
r0xt K
r Q ~ fl O }- H
o d S N
N
v,-~ ,~
F

ti s H
d ~UH ~Q O
~ ~
~
r ~ ~Q y ~ "~i Q~N ~ =,,,.
=" -F~ ~ H

i H F H -\ ~
H fi~H S t H
o H a ~H

o- =^1 = - ~a ~J-N ~ ~
ti H ~ -~~~ ` F~ ~~~ /
Page74of153 H
o X-~ tt ~ t F
H~( H
qs Q~
~ N O H S
__ /
H N H
N oH N~--^ H N
O Q
/ O N FI
f N
N` ~o d-H I - N H
~O

F
h'I `N~N qH~ N~ XHH O HS N
f ~O N H 0~
,-N o N N H H
~N
Ni d~'~f N N=O
H

F
F~_ = i, ' r 1 yV ~N N ~. F N
~-- Q N

N o '~.--~ c ~~H.N O
Y p Q
N-y-O N 'r-4 )~=O
ti S.
O N~
N I \
fl~N 'r' H

Page 75 of 153 [00211) Compounds of the present invention may be readily prepared by methods well known in the art. Synthetic schemes for preparing the compounds of the present invention are shown below for illustrative purposes.
[00212] Scheme 1: Preparation of compounds of formula I:

Rx x X~Rx B NH X~Rx 0 N_RY
, a Z + O N-RY N Rz O
HO z O . Z' Rw Rw R
Rw Rw Amine Core Thiazolidinone Acid I' Core a) HATU, D`PEA, DMF, RT, 16 h.
[00213] Compounds of formula I are prepared as shown in Scheme 1 above, wherein an axnine core, containing the ring A, and the thiazolidinone acid core are combined under suitable conditions to provide compounds of formula I.
[00214] Scheme lA: Preparation of compounds of formula I:
Rx 6 X~ Rx RZz NH R~Rx R6 0 N-RY
X
+ O N-RY a ,z2,~ NI ~,'' Rz O
Rw w HO Z
z 0 Rw w R

Amine Core Thiazolidinone Acid (I) Core [00215] Scheme 2: Preparation of thiazolidinone core acid (Acid-I):

Rx -O ~Rx Rx ~ R" + RY-NHz HO" a, b O S N_RY

0 (Acid-I) a) DMF or Toluene or benzene, 4A molecular sieves, 80 C, 1-2 h b) Mercaptosuccinic acid, 80 C, 16 h (00216] Scheme 3: Preparation of thiazolidinone core acid (Acid-II):
Page 76 of 153 O Sj~,Rx a O S~Rx b O S~Rx N-RY -'" N-RY N-(~v HO ~~0~~ ~~O~U~
O O RW O
ic Rx Rx O S
N-RY
HO
Rw 0 (Acid-II) a) EtOH / H2SO4, 80 C, 24 h b) LiHMDS, THF, 15 min, then RW-LG, 0 C to RT, 16 h NaOH (aq.), MeOH; wherein LG is a suitable leaving group.
[00217] Scheme 4: Preparation of thiazolidinone core acid (Acid-III):
x x Rx ~ x ~Rx R
R X b S:" NR RY a N-RY Rz s N-RY

HO'~~ HO_ t~ HO~~\

lc Rx Rx O Rz S N`RY
HO~
0 (Acid-III) a) BOP, D'PEA, THF, 6 h, then NaBH4, RT
b) LiCI, LiHMDS, RZ-LG, -78 C C to -40 C; wherein LG is a suitable leaving group c) Jones oxidation, 0 C

[00218] Scheme 5: Preparation of thiazolidinone core acid (Acid-IV):
Page 77 of 153 O Rx ~ Rx Rx Rx a S
R'~~Rx + Rv-NH2 N-Rv b O/S N"Rv ~~0J~
~ = ~
O O
1 c Rx Rx O S
N`Rv HO ~
0 (Acid-IV) a) THF / trimethoxyorthoformate, thioacetic acid, 80 C, 16 h or DMF, 2 h, 80 C, then thioacetic acid, 80 C, 16 h.
b) LDA, -78 C C to RT, then ethyl glyoxalate, RT, 16 h c) NaOH (aq.), MeOH.

[00219] Scheme 6: Preparation of thiazolidinone core acid (Acid V):

O S~Rx a O O~S-~ Rx O ~ S~(~x HO N-Ry HO N-Rv + HO J~N-Rv ~~~
O O O
(Acid-V-a) (Acid-V-b) a) mCPBA, CHC13i 0 C to RT, 16 h [00220] Scheme 7: Preparation of Amine core (C-A-i-d):
-O N
) O a N b,c ~ ---H O
H

(A-i-d) & (A-i-h);
a) 4-Methoxybenzylchloride, TEA, DMF
b) tert-butyl bis(2-chloroethyl)carbamate, LDA, THF
c) TFA / DCM

[00221] Amine core C-A-i-e, wherein ring A is A-i-e (see, supra) can be prepared using the method of Scheme 7.
[00222] Scheme 8: Preparation of Amine core C-A-ii-c:
Page78of153 Bz O N H
a b -- -~.
N NH I~ NH
Bz H --QO N --~-O
H (C-A-ii-c) a) Polyphosphoric acid, 100 C, then, phenylurea, 150 C
b) MeOH, HCI, Pd / C, H2 [00223] Scheme 9: Preparation of Amine core C-A-ii-d:

Boc H
Boc N N
O:N~=O + CI f NICI a O b O
H N N
H H (C-A-ii-d) a) LiHMDS
b) TFA / DCM

1002241 Scheme 10: Preparation of Amine core C-A-ii-e:
Boc, N Br + a Boc'N NO2 O--,,-0 NOa O0 O
1 b HN Boc-N

O H O H
(C-A-ii-e) a) NaHMDS
b) H2, Pd/C
c) HCI

Page 79 of 153 [002251 Scheme 11: Preparation of Amine core C-A-v-e:
Boc H
Boc N N
+ HzN NHz a b, c C J N
HN N
~ YD/

(C-A-v-e) a) NaBH4CN
b) CDI or SOC12 or 1,1'-Sulfonyldiimidazole c) TFA / DCM

[00226] Amine cores C-A-v-a, C-A-v-c, and C-A-v-f, containing ring A
embodiments, A-v-a, A-v-c, and A-v-f, respectively, can be readily prepared using the method of Scheme 11.

[002271 Scheme 12: Alternative Preparation of Amine core C-A-v-e:
Boc Boc Boc B ac N N
a b c -- -- -r N ~~ ~!N~O
N H2 C ~
p NH NH (C-A-v-e) a) COC12 b) Aminoacetaldehyde dimethylacetal c) TFA / DCM

[00228] Scheme 13: Preparation of Amine Core C-A-vi-a:

Boc j --N-Boc NH
c~0 ~ Br + a H ~
zNOZ H O
NH2 (C-A-vi-a) a) TEA, DCM, RT, 16 h b) CDI; THF / DCM, 16 h.
c) TFA / DCM

[00229] Scheme 14: Preparation of Amne core C-A-vi-c:
Page 80 of 153 Boc "Boc NH
Br + --- ~ ' ~ a ~ H bc ~\ N
~S\ O

NH2 (C-A-vi-c) a) TEA, DCM, RT, 16 h b) 1, i'-Sulfonyldiirnidazole, THF / DCM.
c) TFA / DCM

[00230] Scheme 15: Preparation of Amine Core C-A-vi-f:

Boc OH Br NHZ
d NH a (/ - ~ / -- ~ /

le i Boc N
N--CINH 9 NN-Boc f ~ NH
H.,.~O N~~JJ (~' H \`O NHz (C-A-vi-f) a) PPh3, CBr4, DCM, 0 C to RT, overnight b) NaN3, H20, CH3CN
c) 1) PPh3, toluene, RT, 16 hours;
2) Acetic acid / 48% HBr in Acetic acid, 100 C 1h.
d) tert-butyl 4-oxopiperidine-l-carboxylate, NaBH(OAc)3, AcOH, DMF
e) CDI, THF
t) TFA / DCM

[002311 Scheme 16: Preparation of Amine Core A-v-e:
Page 81 of 153 Boc N ~N.Boc N ~NH
/ + a b N c Br J
O NH2 HN'"~Q HN~O
(A-v-e) a) DCM, D'PEA
b) NaOCN, AcOH, c) TFA / DCM

[00232] Scheme 17: Preparation of Amine Core A-v-f:

JJH NH
N a N
HN--,~O HN-'~O
(A-v-f) a) H2, Pd/C, MeOH

[00233] Scheme 18: Preparation of Amine Core A-v-g:

Fmoc Fmoc Fmoc s O
N t a~ N b,c + e N~Oi~
H
0 HN, N, NHBoc NH2 d JD H N,Fmoc N'N e N,N
t-iN--~
O HN--~O
(A-v-g) a) H2NNHBoc, EtOH
b) Pt02, AcOH, H2 c) TFA
d) D`PEA, THF
e) Et2NH, THF

[00234] Scheme 19: Preparation of Amine Core A-vi-h:
Page 82 of 153 Boc H
O N N

+ a b,c --- N
N~ NH2 CN NH
Boc ~ ~, al~ N
N NHz N H (A-vi-h) a) NaBH(OAc)3, DCE
b) CDI, CH3CN
c) HCI, Et20 1002351 Scheme 20: Preparation of Amine Core A-vi-i:

\ CN I~ CN NH2 ~~ -- N H N N H a N C! Dao / ~ ~
i O O
Boc ~
N 0,Boc NH ~ N~' \./ .. N N 0 r--- ccrl H
N N \
N H O I\
H ~, O O
O
I I
(A-vi-i) a) 2,4-Dimethoxybenzylamine, DMA, TEA
b) LiAIH3, THF
c) tert-butyl 4-oxopiperi dine-l-carboxylate, NaBH(OAc)3, AcOH, DCE
d) CDI, DMF
e) TFA / DCM

[00236] Scheme 21: Preparation of Amine Core A-ii-h:
Page 83 of 153 HO
OH

a, c O a' e` O f- ~
N H N N N N (~ O
SEM H N H
9, h yH
N
N N
H
h) a) NaH, SEM-Cl, DMF.
b) Pyridinehydrobromide perbromide, dioxane c) Zn, AcOH
d) cis- 1, 4-dichl orobut-2-ene, Cs2CO3, DMF
e) TFA / DCM
f) Os04, Me3N-O, DCM
g) Na104, EtOH, H20 h) NH4OH, H2, Pd/C

[00237] Scheme 22: Preparation of Amine Core A-ii-i:
Cbz H
N N
nc,_ a ajC~ b CINH CI N8oc O O

CI N H O N H
(A-a) NaHMDS, BOC2O, THF
b) nBuLi, TMEDA, benzyl 4-oxopiperidine-l-carboxylate, THF
c) H2, Pd/C
d) EtOH

[00238] Scheme 23: Preparation of Amine Core A-i-h:
Page 84 of 153 Npc Noc Boc Boc a b N c N
-' i'= O
O O ~S
O f O i O i N
O O O O

i d HN e Boc, N

\ / \ /
O NH O NH
A-i-h a) KHMDS, allylbromide, THF
b) 03, MeOH, DCM, then Me2S
c) `BuSONH2, CuSO4, DCE
d) PhLi, EtzO
e) HCl, MeOH

[00239] Scheme 24: Preparation of Amine Core A-ii-j:
O O
O O Cbz.N O N ~
a b c ~
-- / N ~
N H Br Cbz N N
Cbz Cbz Cbz H I N N

N'' f,g e Cbz,N ~O/~ N ~ , l~.%
~
N N 0 N N O SEM Br H SEM
A-ii-j a) (2-Methoxy-2-oxoethyl)(triphenyl)phosphonium chloride, benzene b) DBU, DMF
c) 3-Bromo-2-aminopyridine, A1Me3, DCE
d) NaH, SEM-Cl, THF
e) Pd(`Bu3)2, dicyclohexylmethylamine, dioxane f j TFA
g) H2, Pd/C

[00240] Scheme 25: Preparation of Amine Core A-i-x:
Page 85 of 153 Boc, N a Boc, N 0 Boc.N

COOH b - VNH2 NHCbz NHCL~H2 lc NH N,goc o-~ o H 0 A-i-i a) EDC, HOBt, NH3, TEA, DMF
b) H2, Pd/C, EtOH
c) 1-(Trimethoxymethyl)benzene, toluene d) TFA / DCM

[002411 Scheme 26: Preparation of Amine Core A-i-j:
Bn Bn.N~ 0 .N O a N b CN Bn-N (::)eNH2 ~~ Bn, -0 HN N
d,e ~ ~ 0 NH N
N_O N1-O
H H
A-i-j a) 2,4-Dimethoxybenzylamine, TMSCN
b) H2, Rh/alumina c) CDI
d) TFA / DCM
e) H2, Pd/C

[00242] Scheme 27: Preparation of Amine Core A-i-k:
Page 86 of 153 O / O . O / O
Bn.N a Bn b Bn`N
~N NH
O NH

n .
I I
O o Bn, O' o/ o N
e Bn`N NH d Bn~N
N NH
O O
OH
f HN

NH
O~O
A-i-k a) 2,4-Dimethoxybenzylamine, TMSCN
b) H2SO4 c) 1) KOH
2) HZSO4: KOH
d) LiAIH4 e) CDI
fl 1)TFA/DCM
2) H2, Pd/C

Page 87 of 153 [002431 Scheme 28: Preparation of Amine Core A-i-I:

Bn.N a b Bn, - Bn.N TMS
O ``^--~r6 _C OH

c Bn,N
HCLO d O)=
O
N O H
H
A-i-I

a) TMSCN
b) LiA1H4 c) COC12 d) 1)TFA/DCM
2) H2, Pd/C

[00244] Amine core A-i-a may be prepared according to the method disclosed in W02005097795. Amine core A-ii-a may be prepared according to the method disclosed in US2006293281. Amine core A-ii-a wherein the fused 6-membered ring is pyridyl may be prepared according to the method disclosed in W02007016087. Amine core A-v-b may be prepared according to the method disclosed in W02006044504. Amine core A-v-i may be prepared according to the method disclosed in W02006044504. Amine core A-vi-b as the HCI salt may be prepared according to the method disclosed in W02005056550.
Amine core A-vi-d may be prepared according to the method disclosed in Chem. Pharm.
Bull., 34(5), pp.
1907-1916 (1986). Amine core A-vi-e is commercially available. Amine core A-v-h may be prepared according to the method disclosed in W02007016087. Other amine cores not described in the schemes, experimentals, or referenced herein, can be prepared by methods known to one of skill in the art.
[00245] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present ilivention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need Page 88 of 153 is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
[002461 As used herein, the term "pharmaceutically acceptable salt" refers to those salts wliich are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A
"pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof. As used herein, the term "active metabolite or residue thereof' ineans that a metabolite or residue thereof is also an antagonist of CGRP.

[002471 Pharmaceutically acceptable salts are well known in the art. For example, S.
M. Berge, et al. describe pharmaceutically acceptable salts in detail in J.
Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-yalkyl)4 salts. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quateniization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic Page 89 of 153 axnmonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[00248] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes, any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Reinington's Pharmaceutical Sciences, Sixteenth Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose;
starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Page 90 of 153 [00249] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisterrrnally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 rng/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[00250] Liquid dosage fonns for oral administfation include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[002511 Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00252] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Page 91 of 153 (00253] In order to prolong the effect of a compound of the present invention, it is often desirable to slow'the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00254] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
(00255] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharnzaceutically acceptable excipient or carrier such as.sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for exainple, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00256] Solid corripositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, Page 92 of 153 dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
They may optionally contain opacifying agents and can also be of a composition that they release the.
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00257] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[00258] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00259] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, Page 93 of 153 that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one=or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a coinbination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as ';
appropriate for the disease, or condition, being treated". For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics= (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone;
oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin;
salicylates such as Asprin, Choline magnesium trisalicylate, Diflunisal;
fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H.
Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, www.fda.~ov, the entire contents of which are hereby incorporated by reference.

[002601 The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range Page 94 of 153 from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
[00261] The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. =-Accordingly, the present inveiition, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes-an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by-a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
[00262] The compounds of the present invention are useful in a method of antagonism of CGRP receptors in a patient such as a mainmal iri need of such antagonism comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.
[00263] Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP
receptors.
[00264] The present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the preserit invention with a phannaceutical carrier or diluent.
[00265] The subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired.
The term "therapeutically effective amount" means the amount of the subject compound that Page 95 of 153 will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. -[00266] The ability of the compounds of the present invention to act as CGRP
antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
[00267] The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache;
pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders;
inflammation;
arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome;
morphine tolerance; hot flashes in men and women; allergic dermatitis;
encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus; infla.mmatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.
[00268] The coinpounds of the present invention are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and. .
conditions noted herein.
[00269] The compounds of the present invention are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
[00270] The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a -compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the Page 96 of 153 compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
[00271] For example, the present compounds may be used in conjunction with an anti-inflammatory or analgesic agent or -an anti-migraine agent, such as an ergotamine or 5-HT_l agonists, especially a 5-HT_1B/ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as aspirin, ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanereept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or a steroidal analgesic. Similarly, the instant compounds may be administered with a pain reliever such as acetaminophen, phenacetin, codeine, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
[00272] Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example-aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin- 1 receptor antagonist; an adenosine A 1 receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; a tricyclic antidepressant, for example amitriptyline, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene Page 97 of 153 antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.
[00273] Also, the present compounds may be used in conjunction with ergot alkaloids, for example ergotamine, ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-I-ergocryptine, dihydro-.theta.-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, 1-ergocryptine, .theta.-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
[00274] Additionally, the present compounds may be used in conjunction with a beta-adrenergic antagonist such as timolol, propanolol, atenolol, or nadolol, and the like; a MAO
inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin;
neuroleptics such as olanzapine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat or divalproex sodium; an angiotensin II antagonist, for example losartan and candesartan cilexetil; an angiotensin converting enzyme inhibitor such as lisinopril; or botulinum toxin type A.
[00275] The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magn.esium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone, and a sedating or non-sedating antihistamine.

In a particularly preferred embodiment the present compounds are used in conjunction with an anti-migraine agent, such as: an ergotamine; a 5-HT_l agonist, especially a 5-HT_1B/1D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan and rizatriptan; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, meloxicam, valdecoxib or paracoxib.
[00276] The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of Page 98 of 153 risk of the diseases or conditions for which compounds of the present invention are useful. ' Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
[00277] The weight ratio of the compound of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
[00278] In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.
[00279] The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous; ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the invention are effective for use in humans.
[00280] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
Page 99 of 153 EXAMPLES
[00281] General .LC/MS Methods [00282] LC/MS data.were acquired using a PESciex API-1'50-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215 autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 10-99% CH3CN (0.035 % TFA) / H20 (0.05 % TFA) gradient, Phenomenex Luna 5u C18 column (50 x 4.60 mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD
detector.
[00283] Mass Spec Method for separating diasteromeric mixtures:
[00284] A Semi-Prep Gilson HPLC was used to purify various diastereomeric mixtures in the present invention using Gilson 322 pumps, a Gilson 215 liquid handler, a Gilson 819 injection module. Flow rate was 15.0 mL/min using a gradient of 20-70% CH3CN
(0.1 Oo TFA) / H20 (0.1 % TFA) on an Agilent Zorbax, SB-C18 column (21.2 x 100 mm, 5um) monitoring with a Gilson 156 UV/Vis detector.
[002851 tert-Buty14-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-l-carboxylate .Boc [00286] HN__~\o [002871 tert-Butyl 4-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-l-carboxylate was synthesised as described in J. Med. Chem., 2005, 48, 5921. A solution of 2-bromo-l-phenylethanone (5 g, 25 mmol) in DCM (10 ml) was added dropwise to a stirred solution of tert-butyl 4-aminopiperidine-l-carboxylate.(6 g, 30 mmol) and D'PEA (9.84 ml, 57.5 ml) in DCM (50 ml)'over I hour, the reaction mixture was then stirred at room temperature for 16 hours. Sodium cyanate (3_41 g, 52.5 nimol) was added, the reaction mixture was then cooled to 0 C, the pH was brought to pH 4 with acetic acid and the reaction mixtures was stirred from 0 C to RT over 16 hours. The reaction mixture was poured into water and extracted with DCM (3x). Organics combined, washed with water (3x), brine, dried (MgSO4) and evaporated to dryness. The residue was triturated with ether, filtered and the solid was washed with ether to give a pale yellow solid (4.04 g, 47%). LC/MS (10% to 99%): M/Z
(M+H)+ (obs) = 344 ; tR = 3.01.
[002881 5-Phenyl-3-(piperidin-4-yl)-1H-imidazol-2(3H)-one ~NH
N
[00289] HN~O

Page 100 of 153 1002901 To a solution of tert-buty.l 4-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine- 1 -carboxylate (4 g) in DCM (20 ml) was added TFA (4 ml) and the reaction mixture was stirred at RT for 4 hours. Evaporation gave the TFA salt of the desired product (Quant.). LC/MS (10% to 99%): MIZ (M+H)+ (obs) = 244 ; tR = 1.06.
[00291] tert-Butyl4-(2-nitrobenzylamino)piperidine-l-carboxylate Boc, N

=
NH

[00292] No2 [002931 A solution of 1-(bromomethyl)-2-nitrobenzene (13.2 g, 61 mmol) in DCM
(60 ml) was added dropwise to a solution of tert-butyl 4-aminopiperi dine-l-carboxylate (14.6 g, 73 mmol) and TEA (13.4 ml, 91 mmol) in DCM (100 ml), followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was then poured into water, and the layers separated. The aqueous layer was then extracted with DCM (2x). The organic layers were combined, washed with water (2x), brine, dried (MgSO4) and evaporated to dryness.
The residue was taken up in EtOAc and filtered through a large plug of silica.
= The silica was washed with EtOAc until TLC analysis show no further material was eluting.
Evaporation gave the product as an orange oil (24g, 74%). LC/MS (10% to 99%): M/Z (M+H)+
(obs) _ 336;tR=2.23.
[002941 tert-Butyl4-(2-aminobenzylamino)piperidine-l-carboxylate N,Boc I~ H
[00295] NH2 [00296] A solution of tert-Buty14-(2-nitrobenzylamino)piperidine-l-carboxylate (24g, 71.6 mmol) in MeOH (150 ml) was stirred under an atmosphere of hydrogen for 24 hours.
The reaction mixture was filtered and evaporated to give the crude amine, which was used without further purification.

[002971 tert-Buty14-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-l-carboxylate N,Boc \

N ---O
[00298] H

Page 101 of 153 [00299] To a solution of tert-butyl 4-(2-nitrobenzylamino)piperidine-l-carboxylate (13.2g, 43.2 mmol) in THF (400 ml) was added a solution of CDI (7.7g, 47.5 mmol) in 1:
1 DCM :
THF (100 ml) dropwise over 1 hour followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was evaporated to give an oil that, when treated with EtOAc, precipitated the desired product. The precipitate was washed with cold EtOAc and dried to give a yellow solid (3.5g). LC/MS (10% to 99%):. M/Z (MtH)+ (obs) = 332 ;. tR
=..3..01.
[00300] 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one OH
c~x0 [00301] H
[00302) To a solution of tert-Butyl 4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (3.5 g,-10.6 mmol) in DCM (20 ml) was added TFA (15 ml) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated, then co-evaporated with EtOH (2x), to give the TFA salt of the desired product (Quant.). LC/MS
(10% to 99%):
M/Z (M+H)} (obs) = 232 ; tR = 0.38.
[00303] 1-(2-Bromoethyl)-2-nitrobenzene Br [00304] (:) N02 [00305] To a solution of 1-(2-hydroxyethyl)-2-nitrobenzene (21 ml, 150 mmol) and triphenylphosphine (39.2 g, 150 mmol) in DCM (400 -ml) at 0 C was add CBr4 (49.5 g, 150 mmol) in portions and the reaction mixture was stirred from 0 C to RT
overnight. The reaction mixture was quenched with sat. aq. Na2CO3, the layers were separated and the organic layer was washed with brine, dried (MgSO4) and evaporated to dryness.
The residue was treated with EtOAc and the precipitated Ph30 was filtered and the solvent removed. This was repeated twice more. Purification by column chromatography (0% to 10%
EtOAc in Hx) gave an oil that solidified on standing.
[00306] 2-(2-Nitrophenyl)ethanamine ~ NH2 ( /
[00307] NO2 [00308] To a solution of l-(2-Bromoethyl)-2-nitrobenzene (6.96 g, 30.5 mmol) in CH3CN
was added a solution of NaN3 (6 g, 91.6 mmol) in water (20 ml) and the reaction mixture was refluxed for 20 hours. The solution was cooled and extracted with DCM (3x).
The organics Page 102 of 153 were combined, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in toluene (160 ml) and to this was added PPh3 (8 g, 30.5 mmol) and the reaction mixture was stirred at =RT for 16 hours. The solvent was evaporated to dryness and the residue was treated with acetic acid (30 ml) and 48% HBr in acetic acid (30 ml) at 100 C
for 1 h. The reaction mixture was cooled, concentrated =and extracted with DCM. The aqueous was brought to pH -10 with NaOH (aq.) and extracted with EtOAc (3x).
The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness (4.2 g)=
[00309] tert-Butyl 4-(2-nitrophenethylamino)piperidine-l.-carboxylate Boc ~~ NH
[003101 NO~
[00311] A stirred solution of 2-(2-nitrophenyl)ethanamine (4 g, 24 mmol) and tert-butyl 4-oxopiperidine-l-carboxylate (4.8 g, 24 mmol) in MeOH (48 ml) was brought to pH
5 by the addition of acetic acid. NaBH3CN (2.3 g, 36 mmol) was added and the reaction mixture was stirred at RT for 3 hours. The solvent was evaporated and the residue was taken up in EtOAc and sat. aq. Na2CO3. The layers were separated and the organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (0% to 7% MeOH in DCM) gave the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs) =
350;tR=2.22.

[00312] tert-Buty14-(2-aminophenethylamino)piperidine-l-carboxylate pyBoc [00313] NH2 H
[00314] To a solution of tert-butyl 4-(2-nitrophenethylamino)piperidine-l-carboxylate (10.5 g) in EtOH (180 ml) was added 10% Pd/C (1.05 g) and the reaction mixture was stirred at RT under an atmosphere of H2 overnight. The reaction mixture was filtered and the resulting solution was evaporated to dryness giving the desired product (9.6 g). LC/MS (10%
to 99%): Ivl/Z (M+H)+ (obs) = 320 ; tR = 2.06.
[00315] tert-Butyl 4-(1,2,4,5-tetrahydro-2-oxobenzo[d] [1,3]diazepin-3-yl)piperidine-1-carboxylate Page 103 of 153 N~N-Boc [00316] H O
[00317] To a solution of tert-butyl4-(2-aminophenethylamino)piperidine-l-carboxylate (6.9 g, 30 mmol) in DMF (110 ml) was added CDI (4.86 g, 30 mmol) in portions followed by stirring the reaction mixture at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organics were combined, washed with water, brine, and evaporated to dryness to give the desired product. LC/MS (10% to 99%): M/Z
(M+H)+ (obs) =346; tR=3.24.
[00318] 4,5-Dihydro-3-(piperidin-4-yl)-1H-benzo[d][1,3]diazepin-2(3H)-one ~NH
C~D) N
[00319] H O
[00320] To a solution of tert-butyl 4-(1,2,4,5-tetrahydro-2-oxobenzo[d][1,3]diazepin-3-yl)piperidine-l-carboxylate (10 g, 2.89 mmol) in DCM (5 ml) was added TFA (5 ml) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was evaporated, then co-evaporated with EtOH (2x), to give the TFA salt of the desired product (Quant.). LClMS
(10% to 99%): M/Z (M+H)+ (obs) = 246 ; tR = 1.75.
[00321] tert-Butyl4-(2-atninopyridin-3-ylamino)piperidine-l-carboxylate Boc NH = =
[00322] N NH2 [00323] To a solution of 2,3 -di aminopyri dine (3.0 g, 27.5 inmol) in DCE (45 ml) was added tert-butyl 4-oxopiperidine-l-carboxylate (5.75 g, 28.8 mmol) and the reaction mixture stirred for 5 min at RT before the portion-wise addition of NaBH(Oac)3 (8.7 g, 41.7 nunol) and continued stirring at RT until the reaction judged complete by LCMS. The reaction was quenched with 5% NaOH, the layers separated and the organic layer was dried over Na2SO4.
Evaporation gave the desired product as a brown solid (4.96 g). LC/MS (10% to 99%): M/Z
(M+H)+ (obs) = 293 ; tR = 2.31.
[00324] ' tert-Butyl 4-(2,3-dihydro-2-oxoimidazo [4,5-b] pyridin-1-yl)piperidine-l-carboxylate Page 104 of 153 Boc ~
I i N
>=
[00325] N H =
[00326] To a solution of tert-Butyl 4-(2-aminopyridin-3-ylamino)piperi dine- 1 -carboxyl ate (3.0 g, 10.3 mmol) in CH3CN (206 ml) at RT was added CDI (4.2 g, 25.7 mmol) in portions and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and the residue was take up in DCM and water. The layers were separated and the organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness.
Purification by column chromatography (1-10% MeOH in DCM) gave the desired solid as a beige solid (3.55 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs) = 319 ; tR = 2_31.
[00327] 1-(Piperidin-4-yl)-1H-irnidazo[4,5-b]pyridin-2(3H)-one H
N
N>==O
[00328] N H
[003291 A solution of tert-butyl 4-(2,3-dihydro-2-oxoimidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate (3.39 g, 10.7 mmol) in 2N HCI in Et20 (20 ml) was stirred from 0 C to RT over 2 h. The solvent was evaporated and the residue triturated with Et20, filtered washed with -Et20 and dried to give the bis-HCI Salt of the desired product (2.62 g). LC/MS
(10% to 99%): M/Z (M+H)+ (obs) = 219 ; tp, = 0.36.
[00330] 2-(2,4-Dimethoxybenzylaniina)pyridine-3-carbonitrile CN

N H ~
~
O ~ O
[00331] 1 [00332] To a solution of 2-chloro-3-cyanopyridine (4.0 g, 28.9 mmol) in DMA
(58 ml) was added 2,4-dimethoxybenzealdehyde (5.2 mi, 34.6 mmol) and TEA (4.8 ml (34.6 mmol) and the reaction mixture stirred at 80 C for 4 hours. The reaction mixture was poured into water and extracted with Et20. The organics were combined, dried (NaySO4) and evaporated to dryness. Column chromatography (0.5% to 5% EtOAc (with 0.1% TEA) in DCM) gave the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs) = 270; tR = 3.05.

Page 105 of 153 [00333] N-(2,4-Dimethoxybenzyl)-3-(aminomethyl)pyridin-2-annine I ~ NH2 ~

N H 0 I/ Oi [00334] 1 [00335] A solution of 2-(2,4-Dimethoxybenzylamino)pyridine-3-carbonitrile (0.55 g, 2.04 mmol) and LiAlH4 (2.2 ml of 1N, 4.4 mmol) was stirred at RT until the reaction was judged complete by LCMS. The reaction was quenched with sat. aq. Na2CO3 and the layers were separated. The organic layer was dried (Na2SO4) and the solvents removed under reduced pressure giving the desired product which was used without further purification. LC/MS
(10% to 99%): M/Z (M+H)a- (obs) = 274 ; tR = 0.28.
[00336] tert-Butyl-4-((2-(2,4-dimethoxybenzylamino)pyridin-3-yl)methylamino)piperidine-l-carboxylate N N,Boc -"~/
N ~ - ) O Oi a H

[00337] 1 [00338] To a stirred solution of N-(2,4-Dimethoxybenzyl)-3-(arninomethyl)pyridin-2-amine (2.04 mmol) and tert-butyl 4-oxopiperidine-1 -carboxylate (0.41 g, 2.04 mmol) in DCE
(8 ml) and AcOH (115 L, 2.04 mmol) was added NaBH(OAc)3 (0.43 g, 2.04 mmol) and the reaction stirred at RT until judged complete by LCMS. The reaction mixture was diluted with DCM and sat. aq. Na2CO3, the layers were separated and the organic layer was dried (Na2SO3) and evaporated to dryness. Purificaion by column chromatography (MeOH/DCM) gave the desired product (0.64g, 69%). LC/MS (10% to 99%): M/Z (M+H) + (obs) =
457 ; tR
= 2.19.
[00339] tert-Butyl 4-(1-(2,4-dimethoxybenzyl)-1,2-dihydro-2-oxopyrido[2,3-d] pyrimidin-3 (4H)-yl)piperidine-l-carboxylate N O
~-O
O [00340] I I

Page 106 of 153 [00341] To a solution of tert-butyl 4-((2-(2,4-dimethoxybenzylamino)pyridin-3-yl)methylamino)piperidine-l-carboxylate (2.89 g, 6.33 mmol) in DMF (42 ml) was added CDI (1.23 g, 7.6 mmol) in portions and the reaction mixture was stirred at 120 C for 2 hours.
A further portion of CDI was added (0.82 g) was added and the reaction mixture stirred at 130 C for 6 hours, followed by stirring at RT for 16 hours. The reaction was diluted with water and extracfed with DCM. The organics were combined, dried (NaSO4) and evaporated to dryness. Purification by col.umn chromatography (10 to 80% EtOAc in Hx) gave the desired product (1.17 g). LC/MS (10% to 99%): M/Z (M+H)+(obs) = 483 ; tR =
3.58.
[00342] 3,4-Dihydro-3-(piperidin-4-yl)pyrido[2,3-d]pyrimidin-2(IH)-one ~NH
N N O
[00343] H
[00344]
[00345] 2-(4-Oxo-2-phenyl-3-((pyridin-4-yl)methyl)thiazolidin-5-yl) acetic acid P
O S
HO N
O ~ ~

[00347] A solution of benzaldehyde (0.75 mmol, 79.6 n7g) and 2-(pyridin-4-yl)ethanamine (97.3 mg, 0.9 mmol) in DMF (0.5 ml) with 4A molecular sieves was heated at 80 C for 2 hours. A solution of mercaptosuccinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the reaction was heated at 80 C for an additional 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with IN HCI, water and evaporated to dryness to give the desired product which was used without further purification. LC/MS (10% to 99%): M/Z (M+H)+ (obs) = 329 ; tR = 1.95.
[00348] 1-(1-(2-(4-Oxo-2-phenyl-3-((pyridin-4-yl)methyl)thiazolidin-5-yI)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound # 45) Page 107 of 153 ~ ~
`
~ S N
O
N N

[00349] H
[00350] To a solution of 2-(4-oxo-2-phenyl-3-((pyridin-4-yl)methyl)thiazolidin-5-yl)acetic acid (0.15 mmol, 49 mg), 1-(piperidin-4-yl)-1 H-benzo[d]imidazol-2(3H)-one (0.15 mmol, 33 mg) and D'PEA (0.375 mmol, 65.3 }rl) in 4:1 CH3CN:DMF (0.5 ml) was added HATU
(0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H20 (0.05%
TFA) gave the title compound. LC/MS (10% to 99%): 1VI/Z (M+H)} (obs) = 528.1 ;
tR = 2.28.
H NMR (400 MHz, CDC13) 8 9.00 (s, 1H), 8.60 (d, J = 6.3 Hz, 2H), 7.40 - 7.38 (in, 2H), 7.33 - 7.29 (m, 5H), 7.06 - 6.92 (m, 4H), 5.55 - 5.53 (m, IH), 4.55 (d, J =
4.4 Hz, 2H), 4.45 -4.42 (m, 3H), 4.07 (d, m, 2H), 3.42 - 3.41 (m, 1 H), 3.20 - 3.15 (m, 1H), 3.01 - 2.90 (m, 1 H), 2.66 (m, 2H), 1.88 (m, 2H) ppm.
[00351] 2-(3-Methyl-4-oxo-2-phenylthiazolidin-5-yi)acetic acid ~ ~

O S
N--HO
[00352] O
[00353) A solution of benzaldehyde (0.75 mmol, 79.6 mg) and methylamine hydrochloride (60.8 mg, 0.9 mmol) in DMF (0.5 ml) with 4A molecular sieves was heated at 80 C for 2 hours. A solution of inercaptosuccinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the reaction was heated at 80 C for an additional 16 hours. The reaction-mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N HCI, water and evaporated to dryness to give the desired product which was used without further purification.
[003541 3,4-Dihydro-3-(I-(2-(3-methyl-4-oxo-2-ph enylthiazolidin-5-yl)acetyl)piperidin-4-yl)quinazolin-2(1H)-one (Compound # 273) Page 108 of 153 (a: ~N

O N
1.003551 0 [003561 To a solution of 2-(3-methyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (0.2 mmol, 50 mg), 3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one TFA salt (0.15 mmol, 49 mg) and D'PEA (0.375 mmol, 65.3 p,l) in 4:1 CH3CN:DMF (0.5 ml) was added HATU
(0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10 Jo-99 Jo CH3CN (0.035% TFA)/H20 (0.05%
TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs) = 465.5 ;
eR = 2.18.
'H NMR (400 MHz, CDC13) S 7.34 - 7.22 (m, 5H), 7.12 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H), 6.95 - 6.89 (in, 2H),6.61 (d, J = 7.8 Hz, 2H), 5.46 - 5.41 (m, 1 H), 4.70 (m, 1 H), 4.56 (m, 1H), 4.26 (m, 3H), 3.86 (m, 1H), 3.50 (m, 1H), 3.32 (m, iH), 3.12 - 3.08 (m, 1H), 2.89 -2.73 (m, 114), 1.69 (m, 3H) ppm.
[003571 2-(3-Isopropyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid O S !
P
N--f\
HO
[00358] 0 [003591 A solution of benzaldehyde (0.75 mmol, 79.6 mg) and isopropylamine (53.1 mg, 0.9 mmol) in DMF (0.5 ml) with 4A molecular sieves was heated at 80 C for 2 hours. A
solution of inercaptosuccinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the reaction was heated at 80 C for an additional 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with IN HCI, water and evaporated to dryness to give the desired product which was used without further purification.
[003601 3,4-Dihydro-3-(1-(2-(3-isopropyl-4-oxo-2-ph enylthiazolidin-5-yl)acetyl)piperidin-4-yl)quinazolin-2(1H)-one (Compound #255) Page 109 of 153 O S ~
N
N~Jj~

(DO"
N O
[00361] H
[00362] To a solution of 2-(3-isopropyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (0.2 mmol, 56 mg), 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (0.15 mmol, 33 mg) and D'PEA (0.375 mmol, 65.3 l) in 4:1 CH3CN:DMF (0.5 ml) was added HATU (0.18 inmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h.
Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H20 (0.05%
TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs) = 493.5 ; tR =
3.1. H
NMR (400 MHz. CDC13) S 7.31 - 7.25 (m, 5H), 7.14 - 7.10 (m, 1H), 7.05 (s, 1H), 7.00 (m, 1 H), 6.93 - 6.89 (m, 1 H), 6.62 (d, J = 7.8 Hz, IH), 5.56 (m, I H), 4.72 (m, 1 H), 4.47 - 4.41 (m, 2H), 4.27 - 4.19 (m, 2H), 4.02 - 3.96 (m, 1 H), 3.87 (m, 1 H), 3.36 - 3.29 (m, IH), 3.13 - 3.10 (m, 1H), 2.70 (m, 2H), 1.70 - 1.60 (m, 3H), 1.20 (dd, J = 2.0, 6.9 Hz, 3H), 0.94 (m, 3H).
[003631 2-(3 Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid HO~~ " ~~~
[00364]
1003651 A solution of benzealdehyde (5.06 ml, 50 mmol) and isopentylamine (5.82 ml, 50 mmol) was stirred at 80 C for 2 hours before the addition of inercaptosuccinic acid (7.51 g, 50 mmol) and a further 16 hours of stirring at 80 C. The reaction mixture was poured into water and extracted with EtOAc. The organics combined, dried and evaporated to dryness.
Purification by column chromatography (EtOAc / Hx) gave the desired product as a yellow oil (11.3 g).
[00366] Ethy12-(3-isopentyl-4-oxo-2-phez+ylthiazolidin-5-yl)acetate ~ ~
.--O S
/'- " N-\--~
[00367] 0 Page 110 of 153 [00368] A solution of 2-(3-lsopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (2.2 g, 7.2 mmot) in EtOH (20 ml) and H2SO4 (1 ml) was refluxed for 16 hours. The solution was evaporated to dryness and the residue was taken up in EtOAc and washed with sat. aq.
Na2CO3 (3x), brine and evaporated to give the desired product as an oil.
[00369] Ethyl2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoate [00370] O No [00371] To a stirred solution of ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetate (84 mg; 0.25 mmol) in THF at 0 C was added LiHMDS (0.28 ml of I N, 0.28 mmol) dropwise and the reaction mixture was stirred from 0 C to RT over 16 hours. The reaction mixture was poured in to 1 N HCl and extreacted with EtOAc (4x). The organics were combined, dried (MgSO4) and evaporated to dryness. Purification by preparative TLC
(7 : 1; Hx : EtOAc) gave the the desired product as an oil (12 ing).
[00372] 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoic acid ~ \
_-HO ~~
[00373]
[00374] A solution 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoic acid (12 mg, 0.034 mmol) and NaOH aq. (0.068 ml of 1N, 0.068 mmol) in MeOH (0.2 ml) was stirred at 60 C for 16 hours. The solution was neutralized with 1 N-HCi (0.068 ml of I
N), the solvents removed and the crude product used with out further purification.
[00375] 3-(1-(2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoyl)piperidin-4-y1)-3,4-dihydroquinazolin-2(1H)-one (Compound #156) ,/~~ p ~ 1 .
N--( ,N S
N--~ t-- / N
O
[00376] O
[00377] To a solution of 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoic acid (11 mg, 0.034 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one'TFA (17 mg, 0.051 mmol) and D'PEA (24 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (17 mg, 0.044 Page 111 of 1 S3 mmol) and the reaction mixture was stirred at RT for 16 hours. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/Ha0 (0.05% TFA) gave the title compound.
[00378] 3-Isopentyl-2-phenylthiazolidin-4-one ~ ~ ~
.---S
.[003791 0 [00380] A solution of isopentylamine (0.58 ml, 5 mmol), benzealdehyde (1 ml, 10 mmol) and mercaptoacetic acid (1.05 ml g, 15 mmol) in THF (7 ml) and trimethoxyorthoformate (2 ml) was stirred at 75 C for 16 hours. The RM was poured in to water and extracted with EtOAc (3x). The organics were combined, washed with IN HCl (2x), brine, dried (MgSO4) and evaporated to dryness. Purification by column chromatography (10 - 25 1o EtOAc in Hx) gave the desired product as an oil (1.07 g, 86%).
[003811 Ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetate O S N

[00382] O
[003831 To a stirred solution of 3-isopentyl-2-phenylthiazolidin-4-one (0.25 g, I mmol) in THF was added LDA (1.1 ml of - I M in THF; freshly prepared from nBuLi and Diisopropylamine) at -78 C and the reaction mixture was allowed to warm to room temperature. Ethyl glyoxalate (0.24 ml of --50% w / v in toluene, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for'16 hours. The reaction mixture was poured into I N HC1 and extracted with EtOAc (3x). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. Purification by column chromatography (5 to 15% EtOAc in Hx) gave the desired product as an oil.
[00384] 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetic acid .--O S N
00385l HO
0 [

Page 112 of 153 [00386] To a solution of ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetate (0.031 g, 0.1 mmol) and aq. NaOH (0.3 ml of 1 N) in MeOH was stirred at 40 C
for 2 hours.
HCI (0.5 ml of 1 N) was added and the MeOH was evaporated. Water and EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc (2x), all organic layers were combined, dried (MgSO4) and evaporated to dryness to give the desired product as an orange oil (11 mg, 36%).
[00387] 3,4-Dihydro-3-(1-(2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetyl)piperid.in-4-yl)quinazolin-2 (1H)-one O
HN--<\ ~-/ - N
(00388] o [00389] To a solution of 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetic acid (11 mg, 0.036 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one'TFA
(18 mg, 0.054 mmol) and D`PEA (22 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (16 mg, 0.043 mmol) and the reaction mixture was stirred at RT for 16 hours.
Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H20 (0.05%
TFA) gave the title compound.

[00390] Preparation A: Synthesis of 1'H-spiro[piperidine-4,4'-quinolin]-2'(3'H)-one N c N N Cbz HCI/MeOH CbzCI
/ I ---' /
\ HCf O O O
15a 15b 95c Cbz CIN` GI Cbz H
Y N iN

NH2OH.t-ICI C' HN Pd/C

N"OH DMF H O ~ \ I N O
H
15d 15e 15f [00391] The mixture of tert-butyl 3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (20 g, 66.4 mmol) and MeOH/HCl (2.5 mol/L, 100 mL) were stirred overnight_ Page 113 of 153 After evaporation the residue was washed by petroleum ether to provide spiro[indene-1,4'-piperidin]-3(2H)-one hydrochloride (15.4 g, 97.6%).
100392] To a solution spiro[indene-1,4'-piperidin]-3(2H)-one hydrochloride (5.0 g, 24.84 mmol) and Et3N (7.54 g, 74.53 mol) in CH2CI2 (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33 mmol) at 0 C. The reaction was allowed to warm to room temperature and stirred, overnight. The precipitate was filtered, washed with Et20 and dried to fizrnish benzyl 3-oxo-2,3-dihydrospiro[indene-1;4'-piperi dine]-1'-carboxylate (6.1 g, yield 99%).
[00393] A solution of benzyl 3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (3 g, 10.3 mmol) in EtOH (30 mL) containing NHzOH.HCI (1.43 g, 20.6 inmol) and NaOAc (1.52 g, 18.53 mmol) was heated under reflux for 1.5 h. The solvent was removed by evaporation and the residue was partitioned between CHZCl2 and water. The organic phase was washed with brine, dried over Na2SO4, and concentrated to provide benzyl 3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (3.14 g, yield 99%), which was used= directly in the next step.
[00394] 2,4,6-trichloro-[1,3,5]-triazine (1.32 g, 7.16 mmol) was added to DMF
(9.6 mL) maintained at 25 C. The reaction was monitored by TLC until TCT was consumed.
Then benzyl3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (1.6 g, 4.77 mmol) in DMF (17 mL) was added. After the addition, the mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. NaaCO3, followed by 1N HCI and brine, dried over Na2SO4 and concentrated. The residue was purified by prep HPLC to obtain benzyl 2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-carboxylate (260 mg, yield 16%).

(00395] The mixture of benzyl 2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-I-carboxylate (1.2 g, 3.4 mmol) and Pd/C (200 mg) in MeOH (20 mL) was hydrogenated under atmosphere pressure at room temperature for 3 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC twice to give 1'H-spiro[piperidine-4,4'-quinolin]-2'(3'H)-one (110 mg, 11 %) as a TFA salt. 'H NMR (CDC13) S 7.65 (d, J=7.5 Hz,1 H), 7.29-7.45 (m, 3 H), 3.45 (d, J
= 12.3 Hz, 2 H), 3.20 (t, J= 12.3 Hz, 2 H), 2.96 (s, 2 H), 2.10-2.21 (m, 2 H), 1.70 (d, J= 14.1 Hz, 2 H). MS (ESI) m/z 217.06 [M+H]'.

[00396] Preparation B: Synthesis of spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1FI)-one Page 114 of 153 Boc H
Boc N
HN"Boc I\ + N 2.3 eq tBuLi I\ O TFA O
700C to RT CH2CI2 --__O THF F { H O

[003971 N-Boc-aniiine (16.12 g, 83.4 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to -70 C. To this solution was added dropwise, under nitrogen, a 1.7 M solution of tert-butyllithium in pentane (110 mL, 187 mmol) at -70 C.
After 30 min at -70 C, the solution was warmed to -20 C and maintained at that temperature for 2 h. The solution was again cooled to -70 C and treated dropwise with a solution of N-Boc-4-piperidone (15.98 g, 80.2 mmol) in anhydrous tetrahydrofuran (50 mL).
The solution was slowly warmed to room temperature, treated with potassium tert-butoxide (25 mg) and stirred at room temperature overnight under nitrogen. The solution was diluted with diethyl ether (300 mL), cooled in an ice-H20 bath and adjusted to pH 7 with 1.0 N HCl (aq). The layers were separated and the aqueous layer extracted once with diethyl ether (100 mL). The pooled organic layers were washed with H20 and saturated brine, then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 39.09 g crude product as a viscous pale yellow oil. The crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes) to afford tert-butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4'-piperidine]-1'-carboxylate as a pale yellow solid (8.687 g, 34% yield). LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-C18,10-99%
CH3CN/0.05% TFA); 'H-NMR (400 MHz, CDC13) & 9.06 (br s, 1 H), 7.28 (m, 1 H), 7.12 (m, 2H), 6.91 (d, J= 8.5 Hz, 1 H), 4.12 (br d, J= 9.9 Hz, 2H), 3.36 (br t, J= 12.4 Hz, 2H), 2.13 (br d, J= 13.1 Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).
[003981 tert-Butyl 2-oxo-1,2-dihydrospiro[benzo[d] [ 1,3]oxazine-4,4'-piperidineJ-1'-carboxylate (6.71 g, 21.1 mmol) was dissolved in dichloromethane (50 inL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice-H20 bath, dissolved in ice-cold saturated brine (20 mL) and H20 (50 mL) and basified with ice-cold 35%
NaOH'(aq). A
small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H20 bath, filtered, rinsed with ice-cold H20 and dried to afford 3.071 g Page 115 of 153 spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one free base as a white crystalline solid.
An additional 800 mg free base was obtained via extraction of the mother liquor with ethyl acetate (10 x 50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield = 84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP-C18,10-99%
CH3CN/0.05% TFA); 'H-NMR (400 MHz, DMSO-d6) S 10.17 (br s, 1H), 7.23 (m, 2H), 7.02 (m, 1 H), 6.87 (dd, J= 8.2, 1.2 Hz, IH), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
1003991 1-B enzyl-4- (2-chloro qu inolin-3-yl) piperidin-4-ol Bn, N
OH
CI N

To a solution of LDA (3.4 ml of 2 M in Hept / THF) at -78 C in THF (5 ml) was added a solution of 2-chloroquinoline (1.0 g. 6.11 mmol) in THF (10 ml) dropwise, and the reaction mixture stirred at -78 C for 1 hour before a solution of 1-benzylpiperidin-4-one (1.22 g, 6.22 mmol) in THF (2 ml) was added dropwise. The reaction mixture was stirred from -78 C to RT over two hours, cooled to -20 C, quenched with water and extracted with EtOAc. The organics combined, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (1 to 15% MeOH in DCM) gave the desired product. LC/MS (10% to 99%):
M/Z (M+H)+ (obs) = 353; tR = 2.24.

[00400] 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one Bn, N

O N !-!
X~O
A solution of 1-Benzyl-4-(2-chloroquinolin-3-yl)piperidin-4-ol (1 g, 2.84 mmol) in 6 N HCI
(9 ml) was heated at 100 C for 8 h. The reaction mixture was cooled, water was added and the precipitated product was filtered and dried (0.27 g). LC/MS (10% to 99%):
M/Z (M+H)+
(obs) = 317; tR = 2.18.
[00401] 3-(Piperidin-4-yl)quinolin-2(1H)-one Page 116 of 153 HN

r)O
O N H

A solution of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-y1)quinolin-2(IH)-one (0.25 g. 0.29 mmol) and 10% Pd/C (130 mg) in MeOH (20 ml) was stirred at 40 C for 6 hours.
The catalysis was filtered and solvent evaporated affording the desired product.
LC/MS (10% to 99%): M/Z (M+H)" (obs) = 229; tR = 1.27.

[00402] Analytical data for certain compounds of the present invention are shown below in Table 2.
[004031 Table 2 Page 117 of 153 .: .~.R . =
LC1MS :.:LC/RT'=, , =LC/MS .' LC/RT ;
Grnpd.# tiM+~'` ` ~~n,' mpd~#;;`..=~:M*1 rtii 1 533.5 3.36 45 542.5 2.13 2 633. 1.45 46 542.5 2.39 3 603.5 3.35 .. 47 620.5 1.27 4 551.5 3.22 48 585.3 3.82 599.5 3.07 49 634.5 1.74 6 549.5 1.98 50 632.7 1.49 7 632.7 2.34 51 563.7 2.08 8 549.5 3.63 52 661.7 1.47 9 507.5 3.24 53 568.5 2.22 620.5 1.89 54 585.3 3.84 11 563.5 3.77 55 619.5 3.68 12 521. 3.31 56 612.5 1.52 13 621.5 3.77 57 555.5 2.13 14 595.5 3.8 58 555.3 3.37 559.3 3.72 59 606.4 2.39 16 597.5 3.62 60 601.5 1.37 17 633. 1_47 61 563.5 3.34 18 569.5 3.37 62 573.4 3.06 19 593.5 3.17 63 546.5 3.27 615.5 3.23 64 563.5 3.36 21 577.7 3.94 65 641.3 3.89 22 619.7 1.39 66 573.4 3.05 23 621.5 3.8 67 539.5 3.45 24 507.3 3_25 68 667.5 1.42 571.5 3.72 69 508.6 3.1 26 567.5 3.72 70 634.5 1.93 27 562.4 3.28 71 543.5 2.31 28 615.7 1.41 72 690.5 2.16 29 506.4 2.96 73 563.5 3.82 509.7 2.91 74 557.5 4.15 31 545.7 3.64 75 501.5 3.5 32 527.3 1_98 76 589.5 1.98 33 555.3 3_55 77 562.5 2.41 34 647. 1.46 78 535.5 3.51 529.3 3.12 79 587.3 3.79 36 583.3 1.86 80 551.5 3.47 37 541.7 3.8 81 665.7 . 1.46 38 507.5 3.25 82 550.5 2.42 39 626.7 1.53 83 549.5 3.12 633.5 1.42 84 531. 1.78 41 535.5 3.54 85 517.5 1.21 42 704.7 2.23 86 513.3 3.53 43 536.3 2.24 87 525.5 3.5 44 571.3 3.57 88 615.5 1.88 Page 118 of 153 LC/MS.. LGI~iT :LGlMS LG'LRT
;Crnpd '#
iriin 89 603.5 3.77 133 551.5 3.22 90 551.5 3.22 134 549.5 1.98 91 541.5 2.05 135 597.5 3.65 92 583.5 3.6 136 607.3 1.96 93 535.5 3.51 137 583.5 3.58 94 574.5 2. 138 519.5 3.28 95 527.3 1.96 139 551.5 3.44 96 505.3 3.2 140 626.5 1.58 97 487.5 1.41 141 493.1 3.76 98 549.7 3.63 142 681.7 1.47 99 733.7 2.26 143 538.7 3.52 100 553.5 2.08 144 620.7 1.68 101 549.5 1.89 145 601.5 3.15 102 619.5 2.58 146 469.5 2.56 103 579.5 3.64 147 561.5 3.7 104 507. 3.22 148 522. 1.52 105 487.5 1.37 ' 149 553.5 3.57 106 604.7 2.21 150 648.7 1.79 107 507.5 3.27 151 515.7 1.96 108 528.1 2.28 152 578.5 1.89 109 533.3 3.11 153 612.5 1.46 110 533. 3.28 154 541.7 2.06 111 492.5 3.43 155 571.5 3.6 112 567.5 3.53 156 535. 3.52 113 535.5 2.95 157 534.4 2.77 114 587.5 1.32 158 555.3 3.6 115 601.5 1.84 159 537.5 3.06 116 489.5 3. 160 620.5 1.89 117 551.5 3.12 161 619.7 1.38 118 537.4 2.95 162 619.7 1.36 119 633. 1.41 163 633.5 1.37 120 634.5 1.74 164 579.5 3.62 121 564.7 1.84 165 571.5 3.75 122 553,6 3.16 166 573.5 1.91 123 563.7 3.79 167 477.3 4.08 124 564.7 2.91 168 574.5 2.05 125 621.5 3.22 169 605.5 3.61 126 565.5 3.55 170 539.5 3.38 127 569.5 3.44 171 549.5 3.62 128 556.5 2.39 172 535.5 3,45 129 651.5 1.39 173 618.7 1.41 130 588.5 2.13 174 531.5 3.37 131 588.4 3.22 175 586.5 3.47 132 479.3 3.02 176 522. 1.52 Page 119 of 153 ~ -:LG/M.S LCXRT: ~L~C%MS.. ILCIRT'=-:
Cmpd # Cmpd # .
__-~ = `M 1 ' .'min '' M+1 min 177 479.5 3. 221 587.5 3.7 178 579.5 3.39 222 549.5 1.98 179 589.5 3.3 223 508.2 2.53 180 563.7 3.67 224 587.5 1.78 181 567.5 3.95 225 593.5 3,53 182 522.5 2.54 226 513.3 3.29 183 601.7 1.83 227 546.5 3.28 184 606.5 1.83 228 581.3 3.27 185 556.5 2.48 229 647.7 1.42 186 521.6 2.67 230 491.3 2.97 187 527.3 3.19 231 569.5 3.5 188 513.5 3.52 232 592.5 3.38 189 559.3 3.13 233 597.3 1.91 190 547.3 3.15 234 571.5 3.77 191 547.5 1.74 235 618.7 2.28 192 487.5 1.82 236 556.5 2.2 193 719.7 2.21 237 569.5 3.43 194 621.5 3.79 238 551.5 3.13 195 525.5 3.41 239 543.5 3.3 196 515.7 3.07 240 637.4 3.61 197 577.7 3.84 241 539.5 3.57 198 578.5 1.64 242 601.3 3.64 199 647.7 1.41 243 633.5 3.8 200 510.8 2.76 244 567.5 3.79 201 529.5 1.56 245 550.5 2.53 202 557.5 3.44 246 627.5 2.06 203 589.4 3.21 247 651.5 3.69 204 549.5 3.58 248 587.5 3.02 205 579.5 3.39 249 518.2 3.49 206 589.7 3.15 250 523.5 3.04 207 529.5 3.79 251 507.5 3.24 208 559.5 3.38 252 553.3 3.72 209 529.5 1.61 253 581.3 3.6 210 583.5 3.53 254 491.3 3.06 211 578.5 1.92 255 493.5 3.1 212 557.5 3.44 256 607.5 1.98 213 578.4 2.95 257 645.7 1.38 214 565.5 3.22 258 543.5 3.25 215 618.7 2.28 259 519. 3.07 216 589.5 3.57 260 601.5 1.34 217 585.3 3.77 261 446.5 3.03 218 471.3 2.79 262 563.7 3.75 219 607.5 1.99 263 592.7 1.98 220 537.5 3. 264 647.5 3.57 Page 120 of 153 :_- _ _... ..
C/M:S LC/RT:, LCl:M.S: LGZRT
;Cmp'd #'; .jyM+1 !min ':Cmpd # . M+1 min 265 572.7 3.4 309 609.5 2.18 266 522.5 2.96 310 623.7 2.23 267 553.5 1.91 311 595.5 2.12 268 601.3 3.61 312 549.7 2 269 493.3 3.13 313 539.5 1.32 270 506.4 2.77 314 539.6 4.31 271 505.5 3.14 315 575.7 2.08 272 551.5 3.41 316 561.5 2.02 273 465.5 2.88 317 561.5 2.04 274 620.7 1.24 318 575.5 2.09 275 485.5 3.31 319 620.4 1.61 276 515.7 1.98 320 634.4 1.68 277 588.7 2.05 321 633.7 1.47 278 542.5 2.35 322 633.7 1.5 279 597.5 3.65 323 651.5 1.42 280 561.5 1.78 324 665.5 1.48 281 499.1 3.98 325 663.7 1.42 282 575.5 3.05 326 663.7 1.45 283 569.5 3.45 327 620,5 1.32 284 493.5 3.13 328 634.7 1.41 285 607.5 1.54 329 620.5 1.3 286 563.5 3.32 330 634.5 1.35 287 567.5 2.85 331 605.5 1.48 288 570.5 1.33 332 619.7 1.56 289 573.5 1.27 333 647.7 1.41 290 606.5 1.62 334 647.7 1.49 291 573.5 1.73 335 633.5 1.45 292 590.7 2.16 336 633.5 1.47 293 550.5 = 1.79 337 638.5 1.26 294 592.7 1.79 338 637.5 1.39 295 587.5 1.34 339 679.7 1.49 296 620.7 1.71 340 693.7 1.52 297 587.5 1.79 341 666.5 1.34 298 604.5 2.23 342 691.5 1.51 299 564.5 1.88 343 665.7 1.41 300 606.5 1.86 344 665.5 1.42 301 620.7 1.78 ' 345 679.7 1.46 302 619 1.42 346 677.7 1.44 303 630 1.49 347 663.7 1.39 304 606.5 1.71 348 637.7 1.34 305 525.5 1.24 349 652.5 1.26 306 525.5 1.25 350 638.5 1.18 307 649.7 1.41 351 651.5 1.46 308 589.5 2.13 352 665.5 1.49 Page 121 of 153 .~Cm `d' .LC%MS T ;LCLMS ;<LC1R7:
=p;#~ -,.. ,Cmp~,~' .~ ..,..::.. .
M+1` min M*1 in353 638.5 1.26 397 638.5 1.24 354 637.7 1.42 398 651.7 1.47 355 667.5 1.47 399 651.7 1.47 356 681.7 1.52 400 707.7 1.58 357 654.7 1.29 401 707.7 1.53 358 679.7 1.46 402 710.9 1.5 359 653.7 1.41 403 737.7 1.68 360 651.5 1.45 404 634.5 1.32 361 665.5 1.5 405 661.7 1.49 362 638.5 1.29 406 634.5 1.3 363 663.7 1.44 407 661.5 1.49 364 675.7 1.56 408 710.7 1.51 365 689.5 1,63 409 737.7 1.69 366 662.5 1.38 410 633.5 1.4 367 695.7 2.02 411 680.7 2.29 368 709 2.01 412 647.7 1.5 369 647.7 1.52 413 620.5 1.27 370 661.7 1.55 414 630 1.5 371 663.7 1.45 415 621.6 1.59 372 677.7 1.5 416 535.5 1.92 373 633 1.42 417 508.6 1.62 374 633 1.42 418 648.7 1.3 375 661.6 1.53 419 675.7 1.52 376 707 1.56 420 549.6 1.51 377 661.6 1.61 421 632.4 1.88 378 634.6 1.26 422 634.6 1.44 379 730.9 1.31 423 620.6 1.83 380 634.6 1.37 424 520.4 1.65 381 703.9 1.16 425 605.4 1.52 382 636.7 1.33 426 607.4 1.12 383 649:7 1.48 427 593.4 1.52 384 715.7 1.61 428 591.6 1.7 385 663.7 1.54 429 707.4 1.77 386 622.7 1.28 430 707.4 1.91 387 688.7 1.43 431 707.4 1.77 388 647.7 1.43 432 707.4 1.87 389 691.7 1.53 433 709 1.49 390 664.7 1.32 434 709 1.49 391 651.7 1.47 435 623 1.21 392 733.7 2.07 436 680 1.29 393 706.7 1.82 437 680 1.29 394 638.5 0.95 438 682 1-3 395 693.6 1.63 439 733.6 1.68 396 693.6 1.7 440 733.6 1.7 Page 122 of 153 .. . .
. ., . .
Q%Ftl' '~ :.Y,:= .- . LC/MS 'LC/.RT
CInpd. # = {. . :=
M+1':i: min~s, . . . . . . ., ,.
441 706.6 1.45 460 695.2 2.3 442 706.4 1.5 461 681.3 2.45 443 649.7 1.21 462 625.4 2.87 444 676.5 1.44 463 652.4 3.31 445 680 1.48 464 637.3 3.29 446 680 1.33 465 624.5 1.91 447 645.5 1.98 466 651.2 2.13 448 672.6 2.42 467 637.5 1.97 449 669.5 3.2 468 625.4 2.94 450 693.6 2.75 469 638.5 3.2 451 664.5 2.98 470 624.5 1.98 452 694.7 3.12 471 651.2 2.21 453 657 3.05 472 637.2 2.13 454 657.5 . 3.1 473 652.5 1.94 455 652.5 1.98 474 679.5 2.13 456 652.5 1.98 475 652.5 1.98 457 717.1 2.68 476 679.5 2.16 458 638.5 1.94 477 605 1.36 459 638.5 2 100404J Measuring CGRI' functional antagonism using SK-N-MC-BLA (4C10):
[004051 CGRP functional antagonism was characterized in a cell based transcriptional assay using a recombinant SK-N-MC line. To introduce the transcriptional reporter system, SK-N-MC cell line was transduced with a retroviral vector containing P-lactamase gene downstream of cAMP responsive promoter. The expression of P-lactamase is triggered by cAMP increase that is a downstream event of activation of endogenous CGRP receptor. Single clones were separated using Fluorescent Activated Cell Sorting (FACS) based on CGRP
induced P-lactamase activity. (3-lactamase activity was measured using a fluorescence energy transfer (FRET) dye, CCF4. CCF4 is a substrate of P-lactama.se (Zlokarnik G, et al., Science, 279 (5347): 84-88, 1998) and cleaved into a product with different fluorescent signal from that of the parent. .4C10 clone was selected for dose dependent (3-lactamase expression to different concentrations of CORP and consistent pharmacology with previously published values. To evaluate functional antagonist activity of compounds in SK-N-MC (4C10) line, compounds were evaluated for their inhibition of (3-lactamase expression in the presence of CGRP.

[004061 SK-N-MC (4C10) was cultured in Minimal Essential Media (MEM) (Invitrogen) supplemented with 1mM non-essential amino acids solution (Invitrogen),100 units/ml Penicillin-Page 123 of 153 , = .

Streptomycin (Invitrogen), ImM sodiuin pyruvate (Invitrogen) and 10% fetal bovine serum. For the (3-lactamase assay, low serum, 1% FBS in MEM was used. 30,000 cells were plated into each wells of poly-D-lysine coated 384-well plate (Becton Dickinson) a day prior to the assay.
SK-N-MC (4C 10) was preinciubated with compounds for 30 min before the addition of 200 pM
CGRP. The assay was incubated for 3 hours at 37 C to allow P-lactamase expression. CCF4 dye was added and incubated for 2 hours at room temperature. The fluorescent signals were read using a fluorescence plate reader, Topology Compensatory Plate Reader (tcPR) at excitation wavelength, 400 nm and emission wavelengths, 460 nm for the product and 535 nm for the parent. The ratio of values at 460 to 535 nm was used to calculate percent of activation. Curve fitting and ICSO calculation were carried about using MOD3.

[004071 I125-CGRP binding displacement assay to calculate K; of compounds.
[004081 Purified SK-N-MC membrane was purchased from Perkin Elmer. The membrane was thawed quickly and placed on ice. The compounds were diluted with CGRP
binding solution (25 mM Tris-HCI, pH7.4, 5 mM MgC12, 0.1% BSA and 0.05% Tween). The membrane was diluted 1:20 with the binding solution and homogenized with Tissue Matster-Homogenizer (Omni International) for 30 sec. The homogenized membrane was added to compounds in the binding solution. After 10 minutes incubation at room temperature, the final concentration of 46 pM, 1125-iodotyrosyl-Calcitonin-Gene-Related Peptide (GE
healthcare) was added to the membrane and compounds. After 2 hour incubation at room temperature, the reaction was stopped by rapid filtration through 0.5% PEI treated GF/C filter plate (Perkin Elmer) and the filter plate was washed with ice-cold washing solution (50 mM
Tris HC1, pH7.4, mM MgC12 and 0.1 %BSA) using cell harvestor (Tomtec). The radioactivity of the filter plates were read on Topcount (Packard). The nonspecific binding was determined in the control reaction where I uM unlabelled CGRP was preincubated with the membrane prior to 1125-CGRP addition. The total binding was determined in the control reaction of the membrane and 1125-CGRP in the absence of compound. The percent displacement of 1125-CGRP
with compounds was calculated using nonspecific and total binding controls. The curve fitting was carried out using MOD3. Ki of compound was calculated by the equation of Cheng and Prusoff (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22: 3099-3108, 1973) using Kd of CGRP for the membrane and the amount of I125-CGRP used for the assay.
Page 124 of 153 [00409] Exemplary compounds of the present invention in Table 1 were found to be antagonists of CGRP in the I125-CGRP binding assay and in the CGRP functional antagonism assay described above.
[00410] IC5o and Ki data for selected compounds of the present invention are shown below in Table 3. Tn Table 3, for both the IC5o column and the Ki column, the symbols have the following meaning: "A" means <1 M; "B" means between l M and 5 M; "C" means >5 M
and "ND" means no data.
[00411] Table 3 IFC t`~' ~ ~~ r .r .
G~ mpcl~ ~ r.
_~_,~ ~Crn d #~~ r'a `,#~ ~I;C'50A K~
.,.....:, P...~.. e~ },..._._,._;......;r Se:.. Sy 11 A ND . 50 ND ND 89 A ND

16 A A 55 B 'ND 94 C ND

36 . A ND 75 B- ND 114 A A

Page 125 of 153 ~Gm ;d=,~~ ~IC'50r~ ~Ki~~ ~CmpdH#~ i k I ,C5U~ ~~~KiN , IC;50~
118 B A 170 A A 222 ~A~ ND

130 B ND 182. A A 234 A ND

Page 126 of 153 ,.. .~~ .

Page 127 of 153 ~C ~ 4 ~' FrCm "dE#e~ 1:C:50~ FKii~s~ ~Gmpd~#?~ ~IC50 ' a Ki mpd~~ s~I,C.;50.~ ~Ki,~ ~ P.,. ~. _..
~.'' _ 438 = A ND 454 C ND 470 A A

442 A N D. 458 A A 474 B A

Page 128 of 153

Claims (140)

1. A compound of formula I:

wherein:
X is S, SO, or SO2;
Z1 is a bond or NR7, O, S, CH2, C(O), or NR7(O)NR7, wherein R7 is hydrogen, C1-aliphatic or C(O)C1-C4 aliphatic;
Z2 is a bond, O, CH2O, or C(O);
ring A is phenyl or a 4-7 membered heterocyclic or heteroaryl ring or a 10-14 membered bicyclic heteroaryl or heterocyclic ring, wherein said heterocyclic or heteroaryl ring has 1-4 heteroatoms selected from O, N, or S; wherein ring A is optionally substituted with up to 5 R1 substituents;
wherein:
Z2 is a bond, Z1 is a bond, NR7, O, S, CH2, C(O), or NR7C(O)NR7; or wherein:
Z1, Z2, and R6 are absent, ring A is not aromatic, and ring A together with ring B form a spirocyclic ring system;
R6 is hydrogen or C1-C4 aliphatic;
m is 1-3;
n is 1-3; provided that m+n is <=4;
R Y is aryl, heteroaryl, cycloaliphatic, C1-C6 aliphatic, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, heterocyclyl-C1-C6 aliphatic- or cycloaliphatic-C1-C6 aliphatic-;
wherein R Y is optionally substituted with up to 5 R2 substituents;

R X is hydrogen, aryl, heteroaryl, C1-C6 aliphatic, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, wherein R X is optionally substituted with up to 5 R3 substituents;
or two R X, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-14 membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from O, S, and N; wherein said ring system formed by two R X is optionally substituted with up to 5 R4 substituents;
R Z is absent, hydrogen, CN, C1-C6 aliphatic, halo-C1-C6 aliphatic, O-C1-C6 aliphatic, O-(halo-C1-C6 aliphatic), halo, aryl-C1-C6 aliphatic, or heteroaryl-C1-C6 aliphatic;
is a single or a double bond; provided that when it is a double bond, then R Z and one of R W is absent;
each R W is independently absent, hydrogen, halo, oxo, C1-C6 aliphatic, halo-aliphatic, -O-C1-C6 aliphatic, -O-(halo-C1-C6 aliphatic), aryl, aryl-C1-C6 aliphatic-, C3-C7 cycloaliphatic; or two R W taken together form an optionally substituted C3-C7 cycloaliphatic or heterocyclic ring, wherein said heterocyclic ring has up to 3 heteroatoms selected from O, S, and N; wherein said ring formed by two R W is optionally substituted with up to 5 R5 substituents;
wherein each occurrence of R1, R2, R3, R4, and R5 is independently Q-R M;
wherein Q is a bond or is a C1-C6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
wherein each occurrence of R M is independently selected from R', halogen, NO2, CN, OR', SR', N(R')2, NR'C(O)R', NR'C(O)N(R')2, NR'CO2R', C(O)R', CO2R', OC(O)R', C(O)N(R')2, OC(O)N(R')2, SOR', SO2R', SO2N(R')2, NR'SO2R', NR'SO2N(R')2, C(O)C(O)R', or C(O)CH2C(O)R';
wherein each occurrence of R is independently selected from hydrogen or a C1-6 aliphatic group optionally substituted with 0-5 occurrences of R K; and each occurrence of R K is independently selected from -R V, halogen, NO2, -CN, -OR V, -SR V, -N(R V)2, -NR V COR V, -NR V CON(R V)2, -NR V CO2R V, -COR V, -CO2R V, -OCOR V, -CON(R V)2, -C(=N-CN), -OCON(R V)2, -SOR V, -SO2R V, -SO2N(R V)2, -NR V SO2R V, -NR V SO2N(R V)2, -COCOR V, -COCH2COR V, -OP(O)(OR V)2, -P(O)(OR V)2, -OP(O)2OR V, -P(O)2OR V, -PO(R V)2, or -OPO(R V)2, wherein R V is hydrogen or unsubstituted C1-6 aliphatic; and wherein each occurrence of R' is independently hydrogen, a C1-6 aliphatic group optionally substituted with 0-5 occurrences of R M1; and each occurrence of R
M1 is independently selected from -R T, halogen, -NO2, -CN, -OR T, -SR T, -N(RT)2, -NR T COR T, -NR T CON(R T)2, -NR T CO2R T, -COR T, -CO2R T, -OCOR T, -CON(R T)2, -C(=N-CN), -OCON(R T)2, -SOR T, -SO2R T, -SO2N(R T)2, -NR T SO2R T, -NR TSO2N(R T)2, -COCOR T, -COCH2COR T, -OP(O)(OR
T)2, -P(O)(OR T)2,-OP(O)2OR T, -P(O)2OR T, -PO(R T)2, or -OPO(R T)2; wherein R T is hydrogen or unsubstituted C1-6 aliphatic; or R' is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein said monocyclic or bicyclic ring is optionally substituted with 0-5 occurrences of R U; and each occurrence of R U is independently selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring optionally substituted with 0-3 occurrences of -R Q1 and having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R U is -R Q, halogen, =O, NR Q, -NO2, -CN, -OR Q, -SR Q, N(R
Q)2, -NR Q COR Q, -NR Q CON(R Q)2, NR Q CO2R Q, -COR Q, -CO2R Q, -OCOR Q, -CON(R Q)2, -C(=N-CN), -OCON(R Q)2, -SOR Q, -SO2R Q, -SO2N(R Q)2, -NR Q SO2R Q, -NR Q SO2N(R Q)2, -COCOR Q, -COCH2COR Q, -OP(O)(OR Q)2, -P(O)(OR Q)2, -OP(O)2OR Q, -P(O)2OR Q, -PO(R Q)2, or -OPO(R Q)2, wherein R Q and R Q1 are hydrogen or unsubstituted C1-6 aliphatic;
or R and R', two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form a 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein said monocyclic or bicyclic ring is optionally substituted with 0-5 occurrences of R T1;
and each occurrence of R T1 is independently selected from -R S, halogen, =O, =NR S, -NO2, -CN, -OR S, -SR S, -N(R S)2, -NR S COR S, -NR S CON(R S)2, -NR S CO2R S, -COR S, -CO2R S, -OCOR S, -CON(R S)2, -C(=N-CN), -OCON(R S)2, -SOR S, -SO2R S, -SO2N(R S)2, -NR S SO2R
S, -NR S SO2N(R S)2, -COCOR S, -COCH2COR S, -OP(O)(OR S)2, -P(O)(ORS)2, -OP(O)2OR
S, -P(O)2OR S, -PO(R S)2, or -OPO(R S)2, wherein R S is hydrogen or unsubstituted C1-6 aliphatic.

2. The compound according to claim 1, wherein Z2 is a bond, R6 is hydrogen, and Z1 is a bond.

3. The compound according to claim 1, wherein Z2 is a bond, R6 is hydrogen, and Z1 is NR7, O, S, CH2, C(O), or NR7C(O)NR7.

4. The compound according to claim 1, wherein Z2-R6 is other than hydrogen and Z1 is a bond.

5. The compound according to claim, wherein Z2-R6 is other than hydrogen and Z1 is NR7, O, S, CH2, C(O), or NR7C(O)NR7.

6. The compound according to claim 1, wherein is a single bond.

7. The compound according to claim 1, wherein is a single bond and both of R W are hydrogen.

8. The compound according to any one of claims 1-7, wherein R Z, if present, is C1-C6 alkyl, halo-C1-C6 alkyl- or -O-C1-C6 alkyl.

9. The compound according to claim 8, wherein R Z, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

10. The compound according to any one of claims 1-6, wherein at least one R W
is C1-C6 alkyl, halo-C1-C6 alkyl- or -O-C1-C6 alkyl.

11. The compound according to claim 10, wherein at least one R W is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

12. The compound according to any one of claims 1-8, wherein one R W is hydrogen and the other R W is C1-C6 alkyl, halo-C1-C6 alkyl- or -O-C1-C6 alkyl.

13. The compound according to claim 12, wherein one R W is hydrogen and the other R W is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

14. The compound according to any one of claims 1-13, wherein R Y is C1-C6 aliphatic optionally substituted with one or more halo, OH, -C1-C4 alkoxy, -C1-C4 alkoxy carbonyl, or di-(C1-C4 alkyl) amino-.

15. The compound according to claim 14, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxy carbonyl)-3-methyl-butyl, 1-(hydroxy methyl)-3-methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.

16. The compound according to claim 15, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.

17. The compound according to any one of claims 1-13, wherein R Y is C3-C8 cycloaliphatic or a C3-C8 cycloaliphatic substituted C1-C6 aliphatic-.

18. The compound according to claim 17, wherein R Y is C3-C6 cycloalkyl or a cycloalkyl substituted C1-C6 alkyl-.

19. The compound according to claim 18, wherein R Y is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl-, or cyclohexylethyl-.

20. The compound according to any one of claims 1-13, wherein R Y is pyridyl (C1-C6)-alkyl-, tetrahydrofuranyl (C1-C6 alkyl)-, or N-(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl)-.

21. The compound according to claim 20, wherein tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, 1H-indazol-5-yl, or 2-(N-methyl)-pyrroli din-2-yl-ethyl-.

22. The compound according to any one of claims 1-13, wherein R Y is phenyl or (phenyl)-substituted C1-C6 aliphatic- optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, or S.

23. The compound according to claim 22, wherein R Y is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl-, 2 piperidinylphenyl- or phenylethyl-.

24. The compound according to any one of claims 1-23, wherein one R X is hydrogen and the other R X is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 3 RU substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, O, or S.

25. The compound according to claim 24, wherein one R X is hydrogen and the other R X is phenyl or pyridyl with up to 2 R3 substituents independently selected from halogen or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 2 RU substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, O, or S.

26. The compound according to claim 25, wherein one R X is hydrogen and the other R X is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.

27. The compound according to claim 24, wherein one R X is hydrogen and the other R X is phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-1 yl, 4-propyl-piperazin-1 yl, 4-butyl-piperazin-1 yl, 4-isopropyl-piperazin- 1 yl, 4-t-butylpiperazin-1 yl, 4-cyclopropylpiperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-I-yl, morpholin-4-yl, 1-H-pyrazol-1-yl, imidazol-1-yl, pyrrolidin- 1 -yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-1-yl, or 1-(2,2,2-trifluoroethyl)piperazin-1-yl.

28. The compound according to claim 24, wherein one R X is hydrogen and the other R X is pyridyl, or pyridyl substituted with piperazine, 4-methyl-piperazin- 1 -yl, 4-ethyl-piperazin-1yl, 4-propyl-piperazin-1yl, 4-butyl-piperazin-1yl, 4-isopropyl-piperazin-1yl, 4-t-butylpiperazin- 1 yl, 4-cyclopropylpiperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1 -yl, morpholin-4-yl, 1-H-pyrazol-1-yl, imidazol- 1 -yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-1-yl, or 1-(2,2,2-trifluoroethyl)piperazin-1-yl.

29. The compound according to any one of claims 1-23, wherein one R X is hydrogen and the other R X is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C 1-C6 aliphatic, cyano, halo, halo-C 1-C6 aliphatic-, aryl-C 1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aralkyloxy, di(C1-C6 aliphatic)amino-, -O-C1-C6 aliphatic, -S(O)-C 1-C6 aliphatic, or -S(O)2-C 1-C6 aliphatic.

30. The compound according to any one of claims 1-23, wherein one R X is hydrogen and the other R X is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from O, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.

31. The compound according to claim 30, wherein said R X is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl or piperidinyl.

32. The compound according to any one of claims 1-23, wherein two R X, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-14 membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from 0, S, and N; wherein said ring system formed by two R X is optionally substituted with up to 5 R4 substituents.

33. The compound according to claim 32, wherein said ring system is selected from 9H-fluroen-9-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl, or 1-benzyl-piperidin-4-yl.

34. The compound according to claim 1, wherein said compound is of formula I-A:
wherein:
ring A is a 4-7 membered heterocyclic ring that forms a spirocyclic ring system with said piperidine ring through carbon atom CA, wherein ring A is optionally fused with a phenyl or heteroaryl ring that is optionally substituted with up to 5 R1 substituents;
wherein said ring A, in addition to the nitrogen ring atom, has up to two additional ring heteroatoms selected from O, N, or S; and wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R1 substituents.

35. The compound according to claim 34, wherein is a single bond and R
z, if present, is hydrogen.

36. The compound according to claim 34, wherein is a single bond and R z is C 1-C6 alkyl, halo-C 1-C6 alkyl-, or -O-C 1-C6 alkyl.

37. The compound according to claim 36, wherein R Z, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

38. The compound according to any one of claims 34-37, wherein at least one R
W is C 1-C6 alkyl, halo-C 1-C6 alkyl- or -O-C 1-C6 alkyl.

39. The compound according to claim 38, wherein at least one R W is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

40. The compound according to any one of claims 37, wherein ~ is a single bond, one R W
is hydrogen and the other R W is C1-C6 alkyl, halo-C1-C6 alkyl- or -O-C1-C6 alkyl.

41. The compound according to claim 40, wherein one R W is hydrogen and the other R W is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt.

42. The compound according to any one of claims 37, wherein ~ is a single bond and each R W is hydrogen.

43. The compound according to any one of claims 34-42, wherein R Y is C1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, or di-(C 1-C4 -alkyl) amino-.

44. The compound according to claim 43, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxy carbonyl)-3-methyl-butyl, 1-(hydroxy methyl)-3-methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl,-3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.

45. The compound according to claim 44, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.

46. The compound according to any one of claims 34-42, wherein R Y is C3-C8 cycloaliphatic or a C3-C8 cycloaliphatic substituted C1-C6 aliphatic-.

47. The compound according to claim 46, wherein R Y is C3-C6 cycloalkyl or a cycloalkyl substituted C 1-C6 alkyl-.

48. The compound according to claim 47, wherein R Y is cyclopropyl, cyclohexyl, cyclohexylmethyl , cyclopropylmethyl-, or cyclohexylethyl-.

49. The compound according to any one of claims 34-42, wherein R Y is pyridyl (Cl-C6) alkyl-, tetrahydrofuranyl (C 1-C6 alkyl)-, or N-(C 1-C4 alkyl)-pyrrolidinyl-(C
1-C6 alkyl)-.

50. The compound according to claim 49, wherein R Y is tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, 1H-indazol-5-yl, or 2-(N-methyl)-pyrrolidin-2-yl-ethyl-.

51. The compound according to any one of claims 34-42, wherein R Y is phenyl or (phenyl)-substituted C 1-C6 aliphatic optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O or S.

52. The compound according to claim 51, wherein e is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl, 2-piperidinylphenyl- or phenylethyl-.

53. The compound according to any one of claims 43-52, wherein is a single bond, one R X is hydrogen and the other R X is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents independently selected from C 1-C6 aliphatic, phenyl, halogen, cycloaliphatic or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 3 R U substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, O, or S.

54. The compound according to claim 53, wherein one R X is hydrogen and the other R X is phenyl or pyridyl with up to 2 R5 substituents independently selected from halogen or a 4-7 membered heterocyclic ring with up to 2 R U substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, O, or S.

55. The compound according to claim 54, wherein one R X is hydrogen and the other R X is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.

56. The compound according to claim 54, wherein one R X is hydrogen and the other R X is phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1 yl, 4-propyl-piperazin-1yl, 4-butyl-piperazin-1yl, 4-isopropyl-piperazin-1yl, 4-t-butylpiperazin-1yl, 4-cyclopropylpiperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, 1-H-pyrazol-1-yl, imidazol-1-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-1-yl, or 1-(2,2,2-trifluoroethyl)piperazin-1-yl.

57. The compound according to claim 54, wherein one R X is hydrogen and the other R X is pyridyl, or pyridyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1yl, 4-propyl-piperazin-1yl, 4-butyl-piperazin-1yl, 4-isopropyl-piperazin-1yl, 4-t-butylpiperazin-1yl, 4-cyclopropylpiperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, 1-H-pyrazol-1-yl, imidazol-1-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-1-yl, 1-(2,2,2-trifluoroethyl)piperazin-1-yl.

58. The compound according to any one of claims 34-52, wherein one R X is hydrogen and the other R X is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aralkyloxy, di(C1-C6 aliphatic)amino-, -O-C1-C6 aliphatic, -S(O)-C1-C6 aliphatic, or -S(O)2-C1-C6 aliphatic.

59. The compound according to any one of claims 34-52, wherein at least one R
X is hydrogen and the other R X is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from O, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.

60. The compound according to claim 59, wherein said R X is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl or piperidinyl.

61. The compound according to any one of claims 34-52, wherein ~ is a single bond, two R X, taken together with the carbon atom that they are attached to, form a 3-9 membered monocyclic, a 9-14 membered bicyclic, or a 12-14 membered tricyclic aryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from O, S, and N; wherein said ring system formed by two R X is optionally substituted with up to 5 R4 substituents.

62. The compound according to claim 61, wherein said ring system is selected from 9H-fluroen-9-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl, or 1-benzyl-piperidin-4-yl.

63. The compound according to any one of claims 34-62, wherein ring A is selected from:
wherein:
p is 0-2;
q is 0;2; provided that p+q <=2;
each of W A and W B is independently selected from NR1, O, S, SO, SO2, C(R1)2, or =CR1 (when p or q is 2);
W E is -C(R1)2, =C(R1)-, =N-, or -N(R1)-;
W F is absent or is selected from -C(R1)2, =C(R1)-, =N-, or -N(R1)-; provided that both of W E and W F are not simultaneously =N- or -N(R1)-;
ring B1 is a phenyl or 5-6 membered heteroaryl ring optionally substituted with up to 5 R1 substituents; and R1 is as defined in claim 34.

64. The compound according to claim 63, wherein ring A has formula A-i.

65. The compound according to claim 63, wherein ring A has formula A-ii.

66. The compound according to claim 63, wherein ring A has formula A-iii.

67. The compound according to claim 63, wherein ring A has formula A-iv.

68. The compound according to claim 64 or 66, wherein both, W E and W F are =C(R1).

69. The compound according to claim 64 or 66, wherein W E is =C(R1)- and W F
is =N-.

70. The compound according to any one of claims 63-69, wherein p is 0 and q is 0.

71. The compound according to any one of claims 63-69, wherein p is 1 and q is 0.

72. The compound according to any one of claims 63-69, wherein p is 0 and q is 2.

73. The compound according to any one of claims 63-72, wherein W A is NR1.

74. The compound according to any one of claims 63-72, wherein W A is O.

75. The compound according to any one of claims 63-72, wherein W A is C(R1)2.

76. The compound according to any one of claims 63-72, wherein W A is C(R1)2 and R1 is hydrogen.

77. The compound according to any one of claims 63-72, wherein W B is NR1.

78. The compound according to any one of claims 63-72, wherein W B is O.

79. The compound according to any one of claims 63-72, wherein W B is C(R1)2.

80. The compound according to any one of claims 63-72, wherein W B is C(R1)2 and R1 is hydrogen.

81. The compound according to any one of claims 63-72, wherein p is 2 and W A
is C(R1)2-C(R1)2 or -CR1=CR1-.

82. The compound according to any one of claims 63-72, wherein q is 2 and W B
is C(R1)2-C(R1)2 or -CR1=CR1-.

83. The compound according to claim 63, wherein ring A is selected from:
wherein said ring is optionally substituted with up to 4 R1 substituents.

84. The compound according to claim 63, wherein ring A is selected from:
wherein said ring is optionally substituted with up to 4 R1 substituents.

85. The compound according to claim 63, wherein ring A is selected from:
wherein said ring system is optionally substituted with up to 4 R1 substituents.

86. The compound according to claim 63, wherein ring A is selected from:

wherein said ring system is optionally substituted with up to 4 R1 substituents.

87. The compound according to claim 1, wherein said compound is of formula I-B:
wherein ring A is a 4-7 membered heterocyclic ring optionally fused with an phenyl or heteroaryl ring that is optionally substituted with up to 5 R1 substituents;
wherein said ring A, in addition to the nitrogen ring atom, contains up to two additional ring heteroatoms selected from O, N, or S; and wherein ring A, in addition to the oxo group, is optionally substituted with up to 5 R1 substituents.

88. The compound according to claim 87, wherein R Y is C1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, or di-(C1-C4 alkyl) amino-.

89. The compound according to claim 88, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxy carbonyl)-3-methyl-butyl, 1-(hydroxy methyl)-3-methyl-butyl, allyl, acetenyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl, or 2,2,3,3,3-pentafluoro-propyl.

90. The compound according to claim 89, wherein R Y is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl.

91. The compound according to claim 87, wherein R Y is C3-C8 cycloaliphatic or a C3-C8 cycloaliphatic substituted C1-C6 aliphatic-.

92. The compound according to claim 87, wherein R Y is C3-C6 cycloalkyl or a cycloalkyl substituted C1-C6 alkyl-.

93. The compound according to claim 92, wherein R Y is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl-, or cyclohexylethyl-.

94. The compound according to claim 87, wherein R Y is pyridyl (C1-C6) alkyl-, tetrahydrofuranyl (C1-C6 alkyl)-, or N-(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl)-.

95. The compound according to claim 94, wherein R Y is tetrahydrofuran-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl-ethyl-, pyridin-4-yl-methyl-, 1H-indazol-5-yl, or 2-(N-methyl)-pyrrolidin-2-yl-ethyl-.

96. The compound according to claim 87, wherein R Y is phenyl or (phenyl)-substituted C1-C6 aliphatic optionally substituted with up to 5 R2 substituents independently selected from halogen or a 5-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, or S.

97. The compound according to claim 96, wherein R Y is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morpholinophenyl-, 2-piperidinylphenyl- or phenylethyl-.

98. The compound according to any one of claims 87-97, wherein R X is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 3 R U substituents wherein said heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, O, or S.

99. The compound according to claim 98, wherein R X is phenyl or pyridyl with up to 2 R3 substituents independently selected from halogen or a 4-7 membered heterocyclic ring wherein said heterocyclic ring is optionally substituted with up to 2 R U substituents wherein said heterocyclic ring has up to three heteroatoms selected from N, O, or S.

100. The compound according to claim 99, wherein R X is phenyl substituted with a 4-7 membered heterocyclic ring in the 2 position and a halogen in the 3 position.

101. The compound according to claim 99, wherein R X is pyridyl, phenyl, or phenyl substituted with piperazine, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1yl, 4-propyl-piperazin-1yl, 4-butyl-piperazin-1yl, 4-isopropyl-piperazin-1yl, 4-t-butylpiperazin-1yl, cyclopropylpiperazin-1-yl, 4-t-butoxycarbonyl-piperazin-1-yl, 4-hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, 1-H-pyrazol-1-yl, imidazol-1-yl, pyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-(piperidin-1-yl)piperidine, pyridyl (1-methylpiperidin-4-yl)piperazin-1-yl, or 1-(2,2,2-trifluoroethyl)piperazin-1-yl.

102. The compound according to any one of claims 87-97, wherein R X is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aralkyloxy, di(C1-C6 aliphatic)amino-, -O-C1-C6 aliphatic, -S(O)-C1-C6 aliphatic, or -S(O)2-C1-C6 aliphatic.

103. The compound according to any one of claims 87-97, wherein R X is a C3-C7 cycloaliphatic or a heterocycloaliphatic ring optionally substituted with up to five R3 substituents and having up to three heteroatoms selected from O, N, or S, wherein said ring is optionally fused to one or more phenyl or heteroaryl rings.

104. The compound according to claim 103, wherein said R X is selected from cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 9H-fluoren-9-yl or piperidinyl.

105. The compound according to claim 87, wherein ring A is selected from:
wherein:
W C is -C(R1)2, C(O), or =CR1-;
r is 0-2;
W D is N or =C-;
W E is -C(R1)2, =C(R1)-, =N-, or -N(R1)-;
W F is absent or is selected from -C(R1)2, =C(R1)-, =N-, or -N(R1)-; provided that both of W E and W F are not simultaneously =N- or -N(R1)-;
Y is C(O), S(O), or S(O)2; and ring B1 is a phenyl or 5-6 membered heteroaryl ring optionally substituted with up to 5 R1 substituents; and ~ is a single or a double bond.

106. The compound according to claim 105, wherein W c is -C(R1)2.

107. The compound according to claim 105, wherein W c is =CR1-.97.

108. The compound according to claim 105, wherein W c is C(O).

109. The compound according to any one of claims 105-108, wherein r is 0.

110. The compound according to any one of claims 105-108, wherein r is 1.

111. The compound according to any one of claims 105-108, wherein r is 2.

112. The compound according to any one of claims 105-111, wherein W D is N.

113. The compound according to any one of claims 105-111, wherein W D is =C-.

114. The compound according to any one of claims 105-113, wherein Y is C(O).

115. The compound according to any one of claims 105-113, wherein Y is S(O).

116. The compound according to any one of claims 105-113, wherein Y is S(O)2.

117. The compound according to claim 105, wherein ring A is selected from:

A-v-i A-v-j or A-v-k;
wherein said ring is optionally substituted with up to 4 R1 substituents.

118. The compound according to claim 105, wherein ring A is selected from:
wherein said ring is optionally substituted with up to 4 R1 substituents.

119. The compound according to claim 105, wherein ring A is optionally substituted with up to 5 substituents selected from C1-C6 aliphatic, C1-C6 aliphatic-oxy, C1-C6 haloaliphatic, CN, halo, oxo, optionally substituted C3-C7 cycloaliphatic, or an optionally substituted ring selected from phenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imadazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, or morpholinyl.

120. The compound according to any one of claims 105-119, wherein in R1, Q is a bond.

121. The compound according to any one of claims 105-119, wherein in R1, Q-R M
is Q-R'.

122. The compound according any one of claims 105-119, wherein Q is present and R is hydrogen.

123. The compound according to any one of claims 105-119, wherein Q is present and R is C1-C6 aliphatic.

124. The compound according to claim 123, wherein R is methyl, ethyl, propyl, or butyl.

125. The compound according to claim 121, wherein R' is hydrogen.

126. The compound according to claim 121, wherein R' is a C1-C8 aliphatic group, optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, wherein up to two methylene units of said C1-C8 aliphatic is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

127. The compound according to claim 121, wherein R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

128. The compound according to claim 121, wherein R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

129. The compound according to claim 121, wherein two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2-, or -N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

130. A compound selected from Table 1 or Table IA.

131. A pharmaceutical composition comprising a compound according to any one of claims 1-130, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

132. The pharmaceutical composition according to claim 131, further comprising an additional therapeutic agent.

133. A method of treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases in a subject: headache; migraine;
cluster headache;
chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;
vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis;
opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women;
allergic dermatitis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases;
skin diseases;
neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus;
inflammatory bowel disease, irritable bowel syndrome, or cystitis, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable composition comprising said compound to said subject in need thereof.

134. The method according to claim 133, wherein said method is used in the acute or prophylactic treatment of headache, including migraine and cluster headache.

135. The method according to claim 133 or claim 134, further comprising an additional agent.

136. The method according to claim 135, wherein said additional agent is selected from an anti-inflammatory agent, an analgesic agent, or an anti-migraine agent.

137. The method according to claim 136, wherein said additional agent is selected from an interleukin inhibitor, an NK-1 receptor antagonist an NMDA antagonist, an NR2B
antagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptor agonist; a sodium channel blocker, an opiate against, a lipoxygenase inhibitor, an alpha receptor antagonist, an alpha receptor agonist, a vanilloid receptor antagonist, an mGluR5 agonist, antagonist or potentiator, a GABA
A receptor modulator, nicotinic antagonists or agonists, muscarinic agonists or antagonists, a selective serotonin reuptake inhibitor, a tricyclic antidepressant, a leukotriene antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.

138. The method according to claim 135, wherein said additional agent is selected from an ergot alkaloid.

139. The method according to claim 135, wherein said additional agent is selected from a beta-adrenergic antagonist, a MAO inhibitor, a calcium channel blocker, an anticonvulsant, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, or botulinum toxin type A.

140. The method according to claim 135, wherein said additional agent is selected from a potentiator such as caffeine, an H2-antagonist, a decongestant, an antitussive, a diuretic; a prokinetic agent, or a sedating or non-sedating antihistamine.