The present invention relates to dihydrospiroindene modulators of muscarinic receptors. The present invention also provides compositions comprising such dihydrospiroindene modulators, and methods therewith for treating muscarinic receptor mediated diseases.

Description

91 parts

›CLAIM OF PRIORITY

This application is a continuation-in-part of U.S. patent application Ser. No. 11/208,386 filed on Aug. 19, 2005, which claims the benefit of U.S. provisional patent application No. 60/602,731, filed on Aug. 19, 2004, both of which are hereby incorporated by reference.

›TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of muscarinic receptors. The present invention also provides compositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.

›BACKGROUND OF THE INVENTION

The neurotransmitter acetylcholine binds to two types of cholinergic receptors: the ionotropic family of nicotinic receptors and the metabotropic family of muscarinic receptors. Muscarinic receptors belong to the large superfamily of plasma membrane-bound G protein coupled receptors (GPCRs). To date, five subtypes of muscarinic receptors (M 1 -M 5 ) have been cloned and sequenced from a variety of species, and show a remarkably high degree of homology across species and receptor subtype. These M 1 -M 5 muscarinic receptors are predominantly expressed within the parasympathetic nervous system which exerts excitatory and inhibitory control over the central and peripheral tissues and participate in a number of physiologic functions, including heart rate, arousal, cognition, sensory processing, and motor control.

Muscarinic agonists such as muscarine and pilocarpine, and antagonists, such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, thereby making it difficult to assign specific functions to the individual receptors. See, e.g., DeLapp, N. et al., “Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System,” J. Med. Chem., 43 (23), pp. 4333-4353 (2000); Hulme, E. C. et al., “Muscarinic Receptor Subtypes,” Ann. Rev. Pharmacol. Toxicol., 30, pp. 633-673 (1990); Caulfield, M. P. et al., “Muscarinic Receptors-Characterization, Coupling, and Function,” Pharmacol. Ther., 58, pp. 319-379 (1993); Caulfield, M. P. et al., International Union of Pharmacology. XVII. “Classification of Muscarinic Acetylcholine Receptors,” Pharmacol. Rev., 50, pp. 279-290 (1998), the disclosures of which are incorporated herein by reference.

The Muscarinic family of receptors is the target of a large number of pharmacological agents used for various diseases, including leading drugs for COPD, asthma, urinary incontinence, glaucoma, Alzheimer's (AchE inhibitors). Despite the large therapeutic value of this family, cholinergic drugs are limited by the lack of selectivity of these agents, with significant activation of the parasympathetic autonomous system and elevated incidence of adverse effects. The molecular cloning of the muscarinic receptors and the identification of the physiological role of specific isoforms using knock-out mice, has recently delineated novel opportunities for selective muscarinic ligands, and has helped to define the selectivity profile that is required for enhanced efficacy and reduced side effects.

There is a need for modulators of muscarinic receptors M 1 -M 5 . There is also a need for methods for treating muscarinic receptor-mediated diseases.

There is also a need for modulators of muscarinic receptors that are selective as to subtypes M 1 -M 5 .

›SUMMARY OF THE INVENTION

The present invention provides methods of modulating activity of a muscarinic receptor using compounds of formula (I):

and pharmaceutically acceptable salts thereof.

Each of R 1 , R 2 , R 3 is independently Q 1 or Q 2 , or R 2 and R 3 together form oxo.

Z 1 is —C(Q 1 ) 2 -, —C(H)(Q 1 )-, —C(H)(Q 5 )-, —C(O)—, —CH 2 —, —N(Q 1 )-, —N(Q 2 )-, or O.

Z 2 is N.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloaliphatic group, the monocycloheteroalipahtic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X 1 and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ 4 , fluorine, Q 2 , —C(O)—X 2 -aliphatic in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring; and ring B is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 .

X 1 is —(CH 2 ) i —, —O—, —S—, —N(Q 2 )—, —N(C(O)—X 2 -aliphatic)-in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ;

Each Q 1 is independently halo, —CN, —NO 2 , —OQ 2 , —S(O) z Q 2 , —S(O) z N(Q 2 ) 2 , —N(Q 2 ) 2 , —C(O)OQ 2 , —C(O)-Q 2 , —C(O)N(Q 2 ) 2 , —C(O)N(Q 2 )(OQ 2 ), —N(Q 2 )C(O)-Q 2 , —N(Q 2 )C(O)N(Q 2 ) 2 , —N(Q 2 )C(O)O-Q 2 , —N(Q 2 )S(O) z -Q 2 or aliphatic optionally including 1-3 substituents independently selected from Q 2 or Q 3 .

Each Q 2 is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally substituted with 1-3 substituents independently selected from Q 3 . In several examples, Q 2 is a heteroaryl ring optionally substituted with 1-3 of Q 3 . In other examples, Q 2 is a pyrazole-yl, a thiadiazole-yl, or a pyrazine-yl, each of which is optionally substituted with 1-3 of C 1-4 aliphatic.

Each Q 3 is halo, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, —S(O) z Q 4 , —N(Q 4 ) 2 , —COOQ 4 , —C(O)Q 4 , —OQ 4 , or C 1 -C 4 alkyl optionally substituted with 1-3 halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , or —COOH.

Each Q 4 is aliphatic, cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , or COOH.

Each Q 5 is a heterocyclic ring optionally substituted with 1-3 substituents selected from halo, C 1 -C 4 alkyl, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , COOH; and each i is independently 1, 2, or 3; each m and n is independently 1, 2, 3, or 4 provided that m+n is at least 4; each p is 0 or 1; each y is independently 0 or 1; t is 1 to 4; and each z is independently 0, 1, or 2.

Additional aspects of the present invention provide compounds of formula (II), pharmaceutical compositions that are useful modulators of muscarinic receptors, and methods of treating muscarinic receptor mediated diseases using compounds of formulae (I and II).

Advantageously, the compounds of the invention are generally selective for M 1 and M 4 muscarinic receptors. Unexpectedly, the compounds of the invention exhibit increased activity and/or efficacy for M 1 and/or M 4 muscarinic receptors relative to other muscarinic receptors.

›DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following definitions shall apply unless otherwise indicated.

›I. DEFINITIONS · 1 of 6

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 th 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”, 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

The term “muscarinic receptor,” without a prefix specifying the receptor subtype, refers to one or more of the five receptor subtypes M 1 -M 5 .

The term “modulating” as used herein means increasing or decreasing, e.g. activity, by a measurable amount. Compounds that modulate muscarinic activity by increasing the activity of the muscarinic receptors are called agonists. Compounds that modulate muscarinic activity by decreasing the activity of the muscarinic receptors are called antagonists. An agonist interacts with a muscarinic receptor to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with a muscarinic receptor and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

The phrase “treating or reducing the severity of a muscarinic receptor mediated disease” refers both to treatments for diseases that are directly caused by muscarinic activities and alleviation of symptoms of diseases not directly caused by muscarinic activities. Examples of diseases whose symptoms may be affected by muscarinic activity include, but are not limited to, CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances and wound healing.

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.

As used herein the term “aliphatic” encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.

As used herein, an “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocyc loalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-SO 2 —], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as halo, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO 2 —, cycloaliphatic-SO 2 —, or aryl-SO 2 —], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.

›I. DEFINITIONS · 2 of 6

As used herein, an “alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO 2 —, aliphaticamino-SO 2 —, or cycloaliphatic-SO 2 —], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refers to an amido group such as —N(R X )—C(O)—R Y or —C(O)—N(R X ) 2 , when used terminally, and —C(O)—N(R X )— or —N(R X )—C(O)— when used internally, wherein R X and R Y are defined below. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR X R Y wherein each of R X and R Y is independently hydrogen, alkyl, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by —NR X —. R X has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C 4-8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO 2 — or amino-SO 2 —]; sulfinyl [e.g., aliphatic-S(O)— or cycloaliphatic-S(O)—]; sulfanyl [e.g., aliphatic-S—]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. An example of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocyc loalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

›I. DEFINITIONS · 3 of 6

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. A “cycloalkenyl” group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO 2 — and aryl-SO 2 —], sulfinyl [e.g., alkyl-S(O)—], sulfanyl [e.g., alkyl-S—], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” includes cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been defined previously.

As used herein, the term “heterocycloaliphatic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad 2,6-dioxa-tricyclo[3.3.1.0 3,7 ]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety such as tetrahydroisoquinoline. A “heterocycloalkenyl” group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicycloheteroaliphatics are numbered according to standard chemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

›I. DEFINITIONS · 4 of 6

Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

A heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. “Aliphatic,” “alkyl,” and “heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above. A heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “acyl” group refers to a formyl group or R X —C(O)— (such as -alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R X and “alkyl” have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or a heteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where “alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having the structure —O—CO—NR X R Y or —NR X —CO—O—R Z wherein R X and R Y have been defined above and R Z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR X , —OC(O)H, —OC(O)R X when used as a terminal group; or —OC(O)— or —C(O)O— when used as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group —CF 3 .

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO 3 H or —SO 3 R X when used terminally or —S(O) 3 — when used internally.

As used herein, a “sulfamide” group refers to the structure —NR X —S(O) 2 —NR Y R Z when used terminally and —NR X —S(O) 2 —NR Y — when used internally, wherein R X , R Y , and R Z have been defined above.

As used herein, a “sulfamoyl” group refers to the structure —S(O) 2 —NR X R Y or —NR X —S(O) 2 —R Z when used terminally; or —S(O) 2 —NR X — or —NR X —S(O) 2 — when used internally, wherein R X , R Y , and R Z are defined above.

As used herein a “sulfanyl” group refers to —S—R X when used terminally and —S— when used internally, wherein R X has been defined above. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—, aryl-S—, or the like.

›I. DEFINITIONS · 5 of 6

As used herein a “sulfinyl” group refers to —S(O)—R X when used terminally and —S(O)— when used internally, wherein R X has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)—, aryl-S(O)—, (cycloaliphatic(aliphatic)) —S(O)—, cycloalkyl-S(O)—, heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O) 2 —R X when used terminally and —S(O) 2 — when used internally, wherein R X has been defined above. Exemplary sulfonyl groups include aliphatic-S(O) 2 —, aryl-S(O) 2 —, (cycloaliphatic(aliphatic))-S(O) 2 —, cycloaliphatic-S(O) 2 —, heterocycloaliphatic-S(O) 2 —, heteroaryl-S(O) 2 —, (cycloaliphatic(amido(aliphatic)))-S(O) 2 — or the like.

As used herein, a “sulfoxy” group refers to —O—SO—R X or —SO—O—R X , when used terminally and —O—S(O)— or —S(O)—O— when used internally, where R X has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine, chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure (R X ) 2 N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure —NR X —CO—NR Y R Z and a “thiourea” group refers to the structure —NR X —CS—NR Y R Z when used terminally and —NR X —CO—NR Y — or —NR X —CS—NR Y — when used internally, wherein R X , R Y , and R Z have been defined above.

As used herein, a “guanidine” group refers to the structure —N═C(N(R X R Y ))N(R X R Y ) wherein R X and R Y have been defined above.

As used herein, the term “amidino” group refers to the structure —C═(NR X )N(R X R Y ) wherein R X and R Y have been defined above.

In general, the term “vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., R X O(O)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent to at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

As used herein, the term “amidino” group refers to the structure —C═(NR X )N(R X R Y ) wherein R X and R Y have been defined above.

As used herein, “cyclic group” includes mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure —[CH 2 ] v —, where v is 1-6. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure —[CHQ] v - where Q is hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” As described herein, compounds of the invention can 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. As described herein, the variables in formula I and other variables contained encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables in formula I and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.

›I. DEFINITIONS · 6 of 6

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. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

The phrase “stable or chemically feasible,” 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 chemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used herein, “patient” refers to a mammal, including a human.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, 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 13 C- or 14 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

›II. COMPOUNDS · 1 of 2

The present invention provides methods of modulating muscarinic receptor activity using compounds of formulae (I and II), described above, that are useful in modulating activity of a muscarinic receptor.

Methods of modulating muscarinic receptors according to one aspect of the present invention involve compounds of formula (I):

or pharmaceutically acceptable salts thereof.

Each of R 1 , R 2 , R 3 is independently Q 1 or Q 2 , or R 2 and R 3 together form oxo.

Z 1 is —C(Q 1 ) 2 —, —C(H)(Q 1 )-, —C(H)(Q 5 )-, —C(O)—, —CH 2 —, —N(Q 1 )-, —N(Q 2 )-, or O.

Z 2 is N.

L is a bond, an aliphatic group, C 3 -C 6 cycloaliphatic, —O—, —S(O) zl —, —S(O) z —(C 1 -C 4 )alkyl-, —C(O)N(Q 2 )-, or —S(O) z N(Q 2 )-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 .

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of the formula (III)

X 1 is —(CH 2 ) i —, —O—, —S—, —N(Q 2 )-, —N(C(O)—X 2 -aliphatic)- in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .

Each Q 1 is independently halo, —CN, —NO 2 , —OQ 2 , —S(O) z Q 2 , —S(O) z N(Q 2 ) 2 , —N(Q 2 ) 2 , —C(O)OQ 2 , —C(O)-Q 2 , —C(O)N(Q 2 ) 2 , —C(O)N(Q 2 )(OQ 2 )—N(Q 2 )C(O)-Q 2 , —N(Q 2 )C(O)N(Q 2 ) 2 , —N(Q 2 )C(O)O-Q 2 , —N(Q 2 )S(O) z -Q 2 or aliphatic optionally including 1-3 substituents independently selected from Q 2 or Q 3 .

Each Q 2 is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q 3 .

Each Q 3 is halo, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, —S(O) z Q 4 , —N(Q 4 ) 2 , —COOQ 4 , —C(O)Q 4 , —OQ 4 , or C 1 -C 4 alkyl optionally substituted with 1-3 of halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , or —COOH.

Each Q 4 is aliphatic, cycloaliphatic, aryl, aralkyl, heterocyclic, heteroaralyl, or heteroaryl ring, each optionally substituted with 1-3 substituents selected from halo, oxo, CN, NO 2 , CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , —COOH.

Each m and n is independently 1, 2, 3, or 4 provided that m+n is at least 4.

Each p is 0 or 1.

Each y is independently 0 or 1; each t is 1 to 4; and each z is independently 0, 1, or 2.

Another aspect of the invention provides compounds of formula (II) including:

or pharmaceutically acceptable salts thereof.

Each of R 1 , R 2 , R 3 is independently Q 1 or Q 2 , or R 2 and R 3 together form oxo.

Z 1 is —C(Q 1 ) 2 —, —C(H)(Q 1 )—, —C(H)(Q 5 )—, —C(O)—, —CH 2 —, —N(Q 1 )—, —N(Q 2 )—, or O.

Z 2 is N.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of formula (III)

in which the monocycloaliphatic group, the monocycloheteroaliphatic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X 1 and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ 4 , fluorine, Q 2 , —C(O)—X 2 -aliphatic in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring, and is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 .

Each Q 2 is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally substituted with 1-3 substituents independently selected from Q 3 .

Each Q 3 is halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —S(O) z Q 4 , —N(Q 4 ) 2 , —COOQ 4 , —C(O)Q 4 , —OQ 4 , or C 1 -C 4 alkyl optionally substituted with 1-3 halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , or —COOH.

Each Q 5 is a heterocyclic ring optionally substituted with 1-3 substituents selected from halo, oxo, C 1 -C 4 alkyl, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , and —COOH.

›II. COMPOUNDS · 2 of 2

Each i is independently 1, 2, or 3.

Each p is 0 or 1.

Each y is independently 0 or 1.

Each z is independently 0, 1, or 2.

›III. SPECIFIC EMBODIMENTS · 1 of 2

a. Substituent G

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of formula (III)

In certain embodiments, G is an optionally substituted monocycloaliphatic group.

In several embodiments, G is an optionally substituted cycloaliphatic. In examples of this embodiment, G is an optionally substituted monocycloaliphatic. Specific examples of G include, but are not limited to, 5 to 8 membered monocycloalkyls or a 5 to 8 membered monocycloalkenyls. In other examples, G can be an optionally substituted cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cyclooctyl.

In several embodiments, G is optionally substituted with Q 2 , or —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 . In examples of these embodiments, G can be substituted with carbonyl, sulfonyl, alkoxy, combinations thereof, or the like.

In several embodiments, G is optionally substituted with 1 to 3 of carbonyl, sulfonyl, or combinations thereof. Examples of G include, but are not limited to, alkoxycarbonyl, aliphaticcarbonyl (e.g., alkylcarbonyl, alkenylcarbonyl, or alkynylcarbonyl), aliphatic, alkoxyalkoxycarbonyl, cycloalkoxycarbonyl, heterocycloalkoxycarbonyl, aminoaliphatic, aliphaticamino, arylcarbonyl, or heteroarylcarbonyl, each of which is optionally substituted.

In several embodiments, G is substituted with alkyl, aryl, haloalkyl, alkoxycarbonyl, or alkoxyamino.

In several embodiments, G is selected from

In several embodiments, G is an optionally substituted monoheterocycloaliphatic group. Examples of G include, but are not limited to, optionally substituted 5 to 7 membered monoheterocycloaliphatic groups.

In several embodiments, G includes at least 1 nitrogen atom. G can be substituted with 1 to 3 substituents independently selected from Q 2 , and —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .

In several embodiments, G is optionally substituted with 1 to 2 substituents independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.

In other embodiments, G is one selected from

In several embodiments, G includes at least one O atom. In several examples, G is optionally substituted with 1 to 3 substituents independently selected from independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl. In other examples, G is unsubstituted.

In several embodiments, G is one selected from

In other embodiments, G is an optionally substituted bicyclic group of formula (III). In one group of examples, ring B is absent from the bicyclic group of formula (III).

In several embodiments, X 1 is —(CH) 2i —.

In several alternative embodiments, the bicyclic group of formula (III) includes 7 to 9 ring atoms. In specific examples, G is an optionally substituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl. In yet another group of the examples, G can be substituted with 1 to 3 substituents independently selected from Q 2 , and —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .

In several embodiments, G is one selected from

In other embodiments, G is optionally substituted adamantly.

In several embodiments, X 1 is —N(Q 2 )- or —N(C(O)—X 2 -aliphatic), where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 . In one group of examples, G is an optionally substituted tropane.

In other examples, G is substituted with Q 2 , and —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .

In several embodiments, G is substituted with alkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl, cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxycarbonyl, alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl.

In several embodiments, G is one selected from

b. Substituent Z 1

Z 1 is —C(Q 1 ) 2 -, —C(H)(Q 1 )-, —C(H)(Q 5 )-, —C(O)—, —CH 2 —, —N(Q 1 )-, —N(Q 2 )-, or O.

In several embodiments, Z 1 is optionally substituted carbon or nitrogen atom. In one group of examples, Z 1 is substituted with amino, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl, alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl, alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.

›III. SPECIFIC EMBODIMENTS · 2 of 2

In several embodiments, Z 1 is one selected from

c. Substituents R 1 , R 2 , and R 3

Each of R 1 , R 2 , R 3 is independently Q 1 or Q 2 , or R 2 and R 3 together form oxo.

In several embodiments, R 1 is hydrogen, halo, or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, or alkoxyaryl. R 1 groups can be optionally substituted with 1 to 3 substituents selected from amino, carbonyl, alkoxycarbonyl, aminocarbonyl, aryl, aliphatic, alkoxy, and sulfonyl.

In other embodiments, R 1 is one selected from hydrogen, halo, methyl, —OCH 3 ,

In several embodiments, R 2 and R 3 are independently hydrogen, alkyl, arylalkyl, or R 2 and R 3 together form an oxo or amino.

In still other embodiments, R 2 and R 3 are independently hydrogen, alkyl, or R 2 and R 3 together form an oxo.

d. L Groups

L is a bond, an aliphatic group, C 3 -C 6 cycloaliphatic, —O—, —S(O) z —, —S(O) z —(C 1 -C 4 )alkyl-, —C(O)N(Q 2 )-, or —S(O) z N(Q 2 )-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 . In some embodiments, L is a bond or an aliphatic group in which the aliphatic group is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 . In other embodiments, L is a bond. In still further embodiments, L is an aliphatic group optionally substituted with 1-3 of oxo, Q 1 , or Q 2 . L is CH 2 .

e. Combinations of Embodiments

Other embodiments include any combination of the aforementioned substituents G, Z 1 , L, R 1 , R 2 , and R 3 .

f. Excluded Compounds

In several embodiments, when Z 1 is —CH 2 — or —N(CH 3 )—, L is a bond, and G is an optionally substituted monocycloaliphatic, an optionally substituted monocycloheteroalipahtic group, or a norbornanyl group, then the R 1 substituent on the indane or indole is other than H.

In several embodiments, when L is —C(O)—CH 2 — and Z 1 is —N(Q 1 )-, and Q 1 on Z 1 is —S(O) 2 -optionally substituted phenyl, then the R 1 substituent on the indole is other than H.

In several embodiments, when L is —S(O) 2 —(C 1 -C 4 )alkyl-, Z 1 is —CH 2 —, then the R 1 substituent on the indane or tetrahydronaphthyl is other than H.

In several embodiments, when L is —S(O) 2 —(C 1 -C 4 )alkyl-, R 2 and R 3 form ═O, Z 1 is —N(Q 1 )-, and Q 1 is aliphatic or —S(O) 2 -aliphatic, then the R 1 substituent on the indole is other than H.

In several embodiments, when L is aliphatic, and R 2 and R 3 form ═O, and Z 1 is —N(Q 1 )-, Q 1 is aliphatic, G is a substituted monocycloheteroaliphatic group, then the R 1 substituent on the indole is other than H.

In certain embodiments, L is not —S(O) 2 —(C 1 -C 4 )alkyl-.

g. Specific Embodiments

Specific compounds of formulae (I or II) are shown below in Table 1.

›IV. SYNTHETIC SCHEMES

The compounds of formulae (I and II) may be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of formulae (I and II), are provided below in Preparations A-F and Schemes 1-10. For simplicity of illustration, schemes 1-11 depict only a single R 1 substituent on the fused phenyl ring of formulae I and II, the compounds of this invention may include 1 to 4 R 1 substituents on the fused phenyl ring.

›Scheme 1 below depicts general conditions for the synthesis of compounds of formula (I) · 1 of 2

The reaction of amine 1a with an appropriate aldehyde or ketone under reductive amination conditions (step a), typically using NaBH(OAc) 3 in DCE/AcOH/TEA at room temperature, may be used to provide the desired compounds of formula I. For less reactive ketones, more forcing conditions may be used. For example, the treatment of the amine 1a and the ketone in a neat solution of Ti(O i Pr) 4 , followed by treatment with NaBH 4 in MeOH, may be used to provide the desired compounds of formula I. See Abdel-Magid, A. F. et al., “Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures,” J. Org. Chem., 61, pp. 3849-3862 (1996) and the references sited therein.

Alternatively, the spiroamine of type 1a may be alkylated with an alkyl halide in the presence of an appropriate base to provide the desired compounds of formula I. Typically, the amine 1a is reacted with an alkyl iodide, bromide, or chloride in the presence of an appropriate base to yield compounds of formula I. Bases may be organic such as triethylamine, or inorganic such as Na 2 CO 3 or Cs 2 CO 3 . Typical reaction solvents include but are not limited to DMF, acetone, and acetonitrile.

Scheme 2 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —C(H) 2 — and R 2 and R 3 are hydrogen (Synthetic route A), or in which Z 1 is —C(O)— (Synthetic route B).

Compounds of type 2a in Scheme 2 may be prepared using procedures as described in Evans, B. E, et al., J. Med. Chem. 1992, 35, 3919 and M. S. Chambers J. Med. Chem. 1992, 35, 2033. Intermediate compounds may be produced from compound of type i using the following conditions: (a) KMnO 4 oxidation, TBAB, aqueous KOH (b) NaH, X—R 2 and/or X—R 3 , THF (c) when PG is Cbz or Bz, ammonium formate, MeOH, Pd/C, room temperature or heat; or Pd/C, MeOH, H 2 ; or if PG=Boc, then TFA, CH 2 Cl 2 , −10° C.; (d) NaBH(OAC) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(O i Pr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat.

Scheme 3 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —O— and R 2 and R 3 are hydrogen.

Amines of type 3e in Scheme 3 were prepared using procedures analogous to those found in the following references: WO 96/11934 “Tricyclic spiro compounds process for their preparation” and US006013652A “Spiro-substituted azacyclics as neurokinin antagonists”. Conditions: (a) Ph 3 P/DEAD (b) Bu 3 SnH, AIBN (c) ammonium formate, MeOH, Pd/C, room temperature or heat; or Pd/C, MeOH, H 2 ; or if PG=Boc, then TFA, CH 2 Cl 2 , −10° C.; (d) NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(O i Pr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat.

Scheme 4 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —N(Q1)- and R 2 and R 3 are hydrogen.

Amines of type i in Scheme 4 may be prepared from methods known in the art and by using procedures analogous to those found in the following references: WO 03/106457 “Spiroindolinepiperidine Derivatives”; Maligres, P. E., et al., Tetrahedron, 1997, 53, 10983-10992; Cheng, Y. and Chapman, K. T., Tet. Lett. 1997, 38, 1497-1500; US006013652A “Spiro-substituted azacyclics as neurokinin antagonists”. Conditions: (a) amine protection orthoganol to PG 1 ; (b) amine deprotection of PG 1 (e.g. PG 1 =Boc: TFA, CH 2 Cl 2 , −10° C.); (c) NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat; (d) Q 2 X (Q 2 may be, for example, H and aliphatic, X is halogen), K 2 CO 3 , DMF/THF, RT to 60° C.; or electrophile (e.g. RSO 2 Cl, RCOCl, ROC(═O)Cl, where R is H or Q 2 , TEA, CH 3 CN.

Reaction of i with intermediate under palladium cross coupling conditions (step a) Pd(dppf)Cl2 or (Ph 3 P) 4 Pd, 2M K 2 CO 3 , and acetonitrile under microwave irradiation at 150° C. for 10-20 minutes yields compound ii. Unsaturated compounds of type ii may be further elaborated (e.g. reduction; oxidation) to provide additional compounds of formula (I).

Scheme 6 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —N(Q 1 )- or —N(Q 2 )-, R 2 and R 3 together form oxo, and p=1.

Compound i may be produced by methods disclosed above and by those known in the art. Intermediate compounds may be produced from compounds of type i using the following conditions: (a) NH 2 OH.HCl; (b) 2,4,6-trichloro-1,3,5-triazine; (c) PG=Bn or Cbz; Ammonium formate, MeOH, Pd/C, room temperature; or Pd/C, MeOH, H 2 ; (d) NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat; (e) optional alkylation, NaH, THF, appropriate alkyl halide.

Scheme 7 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —CH(Q 1 )- and R 2 and R 3 are hydrogen.

Compound i may be produced by methods disclosed above and by those known in the art. Compounds ii through ix may be produced from compound i using the following conditions: (a) ZnCl 2 or other Lewis acid, (R)— or (S)-1-phenylethanamine, PhCH 3 reflux, Dean-Stark; (b) NaBH 4 , MeOH, −30° C.; (c) Q 2 ′X (Q 2 ′ may be, for example, H and aliphatic, X is halogen), K 2 CO 3 , DMF/THF, RT to 60° C. (d) Ammonium formate, MeOH, Pd/C, room temperature; or Pd/C, MeOH, H 2 ; (e) electrophile (e.g. RSO 2 Cl, RCOCl, ROC(═O)Cl, where R is H or alkyl, and Q 2 ″ is RSO 2 —, RC(O)—, ROC(O)—, TEA, CH 3 CN; (f) PG=Boc: TFA, CH 2 Cl 2 , −10° C.; (g) NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat.

›Scheme 1 below depicts general conditions for the synthesis of compounds of formula (I) · 2 of 2

Scheme 8 illustrates alternative conditions as example for the synthesis of compounds of formula I in which Ring G contains or is substituted with a protected functionality which may be either be retained, deprotected and retained, or deprotected and further elaborated to produce additional compounds of formula I.

Compound i may be produced by methods disclosed above and by those known in the art. Compounds ii through iv may be produced from compound i using the following conditions: (a) e.g. PG=ketal: AcOH/H 2 O, heat; PG=Boc: TFA, CH 2 Cl 2 ; (b) e.g. if ring G is substituted by oxo, the compound of formula I may be further elaborated to the oxime: NH 2 —O-Q 2 , pyridine; (c) e.g. if ring G contains or is substituted by —NH— or —N(Q 2 )-, it may be elaborated with an appropriate electrophile to produce iv.

Scheme 9 illustrates alternative conditions for the synthesis of compounds of formula I in which Z 1 is —N(Q 1 )- or —N(Q 2 )-, and R 2 and R 3 are oxo, and p=0.

Compounds of type i may be purchased commercially or produced by methods known in the art. Conditions: (a) NaH/HMDS/THF; (b) e.g. PG=Bn: Pd(OH) 2 ; (c) NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr) 4 , appropriate ketone; ii. NaBH 4 , MeOH; or the appropriate alkyl halide, Cs 2 CO 3 , acetonitrile, heat.

Scheme 10 outlines the general preparation of the appropriate aldehydes from the corresponding ketone.

Ketone electrophiles of type i may be purchased commercially or produced by methods disclosed above and by those known in the art. Aldehydes of type ii may be purchased commercially or produced from compounds of type i using the following conditions: (a) Ph 3 P + CH 2 OMeCl − , NaN(SiMe 3 ) 2 ; (b) aqueous HCl, CH 3 CN. The following conditions may be used for the synthesis of compounds of formula I using ketones of type i and aldehydes of type ii: (c) Spiro-amine of type A (see Scheme 1), NaBH(OAc) 3 , DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr) 4 , appropriate ketone; ii. NaBH 4 , MeOH.

Scheme 11 illustrates conditions for the synthesis of compounds of formula I in which Z 1 is NH and Q 2 is aryl or heteroaryl.

›V. FORMULATIONS, ADMINISTRATIONS, AND USES · 1 of 3

The present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention. A “pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention 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, 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, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C 1-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic 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 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 may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

›V. FORMULATIONS, ADMINISTRATIONS, AND USES · 2 of 3

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. 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.”

According to a preferred embodiment, the compounds of formulae (I and II) are selective modulators of M 1 , M 2 and M 4 . More preferably, the compounds of formulae (I and II) are selective modulators of M 1 and/or M 4 . Yet more preferably, certain compounds of formulae (I and II) are selective modulators of M 1 . Or, preferably, certain compounds of formulae (I and II) are selective modulators of M 4 .

Applicants believe that the ability of the compounds of the present invention to modulate the activity of muscarinic receptors is derived from the affinity of these compounds to the muscarinic receptors. Such affinity, applicants believe, activates a muscarinic receptor (i.e., an agonist) or inhibits the activity of a muscarinic receptor.

The term “selective” as used herein means a measurably greater ability to modulate one muscarinic receptor subtype when compared to the other muscarinic receptor subtypes. E.g., the term “selective M 4 agonist” means a compound that has a measurably greater ability to act as an M 4 agonist when compared to that compound's agonist activity with the other muscarinic receptor subtype(s).

According to an alternative embodiment, the present invention provides a method of treating a muscarinic receptor mediated disease in a mammal, such as a human, including the step of administering to said mammal a composition comprising a compound of formulae I and II, or an embodiment thereof as set forth herein.

According to another embodiment, the present invention provides a method of treating a disease mediated by a muscarinic receptor including the step of administering to said mammal a composition comprising a compound of formulae (I and II), or other embodiments thereof as set forth above. Preferably, said disease is mediated by M 1 , or said disease is mediated by M 4 .

According to yet another embodiment, the present invention provides a method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, sudden infant death syndrome, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, wherein said method comprises the step of contacting said patient with a compound according to the present invention.

›V. FORMULATIONS, ADMINISTRATIONS, AND USES · 3 of 3

According to an alternative embodiment, the present invention provides a method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from pain, psychosis (including schizophrenia, hallucinations, and delusions), Alzheimer's disease, Parkinson's disease, glaucoma, bradhycardia, gastric acid secretion, asthma, or GI disturbances.

According to a preferred embodiment, the present invention is useful for treating or reducing the severity of psychosis, Alzheimer's disease, pain, or Parkinson's disease.

All references cited within this document are incorporated herein by reference.

›VII. PREPARATIONS AND EXAMPLES · 1 of 4

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.

Preparation A: Synthesis of N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde

Sodium bis(trimethylsilyl)amide (6 mmol, 6 mL of 1 M solution in THF) was added to a suspension of 2.06 g (6.0 mmol) of methoxymethyltriphenylphosphonium chloride in 6 mL of THF at 0° C. under argon. After stirring at 0° C. for 15 min, the resulting dark red solution was added via syringe to a solution of 0.79 g (4.0 mmol) of N-(ethoxycarbonyl)tropinone (6) in 8 mL of THF at 0° C. and then stirred at room temperature for 4 h (an orange color persisted). The reaction mixture was quenched by adding sat. aq. NaCl (15 mL) and then extracted with ether (25 mL×3). The combined organic extracts were dried over Na 2 SO 4 . The solid residue obtained after solvent evaporation was loaded onto a short silica gel column (3.5 cm×4 cm) to remove the phosphorous impurities. The product was eluted with ether. After the solvent was evaporated, the product enol ether was obtained as a brown oil which was used in the next step without further purification.

The enol ether intermediate was dissolved in a solution of 12 mL of 2 N HCl and 20 mL of acetonitrile, and stirred at room temperature for 16 h. After removing the acetonitrile on a rotary evaporator, the aqueous solution was extracted with ether (25 mL×3). The combined organic extracts were washed with sat. aq. NaHCO 3 (15 mL×2), sat. aq. NaCl (15 mL) and then dried over Na 2 SO 4 . After the solution was evaporated to dryness, the residue was purified by chromatography (SiO 2 , 10%-20% EtOAc in Hexane as eluent). N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde was obtained as a colorless oil in an approximately 1:1 ratio of endo and exo isomers (77%). ESI-MS m/z 212.1 (MH + ); 1 H NMR (300 MHz, CDCl 3 ) δ 9.53 (s, 1H), 4.54 (br s, 1H), 4.38 (br s, 1H), 4.16 (m, 2H), 2.72 (m, 2H), 2.38 (s, 1H), 2.32 (s, 1H), 2.10 (m, 3H), 1.69 (m, 2H), 1.29 (m, 3H).

Preparation B: Synthesis of bicyclo[3.2.1]octane-2-carbaldehyde

Bicyclo[3.2.1]octane-2-carbaldehyde was prepared using an analogous procedure as for Intermediate 1 from commercially available bicyclo[3.2.1]octan-2-one. The crude products were used in the next step without further purification.

Preparation C: Synthesis of 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde

To a stirred solution of furan (9) (15 mL, 200 mmol) and acrolein (13) (6.7 mL, 100 mmol) in DCM (25 mL) was slowly added AlCl 3 (666 mg, 5 mmol) under argon at −43° C. (dry ice/isopropanol bath). The reaction mixture was stirred at −43° C. under argon for 30 min, and then quenched with sat. aq. K 2 CO 3 (50 mL). After the reaction mixture was gradually warmed to room temperature, it was extracted with ether (200 mL×5). The combined ether extracts were washed with sat. aq. K 2 CO 3 (200 mL×2) and sat. aq. NaCl (200 mL×2), dried over MgSO 4 , filtered, and concentrated to give an oily crude product 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde which was used in the next step without further purification. See references Laszlo, P.; Lucchetti, J. Tetrahedron Lett. 1984, 25, 4387-4388. Moore, J. A., Partain, E. M. III. J Org Chem. 1983, 48, 1105-1106. Dauben, W. G.; Krabbenhoft, H. O. J. Am. Chem. Soc. 1976, 98, 1992-1993. Nelson, W. L.; Allen, D. R.; Vincenzi, F. F. J. Med. Chem. 1971, 14, 698-702.

To a stirred solution of crude product 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (2.6 g. 20 mmol) in 95% EtOH (200 mL) was added 10% Pd—C (0.25 g) at room temperature under argon. The mixture was shaken on a Parr hydrogenation apparatus for 4 h at room temperature under 30 psi of hydrogen. After the Pd catalyst was removed by filtration through a Celite pad, the Celite was washed with MeOH (15 mL×2), the combined extracts were concentrated under vacuum to yield a crude 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde as a pale yellow oil, which was used in the next step without further purification.

Preparation D: Synthesis of ethyl 4-formylpiperidine-1-carboxylate

1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H 2 O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ˜0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H 2 O, 0.1 N HCl (aq) (×2), saturated brine, then dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); t R =1.56 min [10-99% CH 3 CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 9 H 17 NO 3 =188.1; Found 188.0.

A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H 2 O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).

›VII. PREPARATIONS AND EXAMPLES · 2 of 4

Preparation E: Synthesis of ethyl 4-formyl-4-methylpiperidine-1-carboxylate

Diisopropylamine (3.14 mL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to −78° C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at −78° C. Ethyl 1-benzylpiperidine-4-carboxylate (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at −78° C. The solution was stirred at −78° C. for 30 minutes and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room temperature and stirred at room temperature for 1 hour. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the product as an oil. The product was analytically pure and used without further purification. LC/MS m/z (M+1) 262.0, Retention time 1.78 minutes; (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, CDCl 3 ) δ 7.24-7.14 (m, 5H), 4.08 (q, J=7.1 Hz, 2H), 3.40 (s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 1.10 (s, 3H).

1-Benzyl-4-methylpiperidine-4-carboxylate (5.0 g; 19.15 mmol) was dissolved in Et 2 O (50 mL) and cooled to 0° C. LiAlH 4 (1.0 g; 26.3 mmol) was slowly added portion-wise to the solution. After the addition was complete, the solution was slowly warmed to room temperature and stirred for 1 h. The solution was then cooled to 0° C. and slowly quenched with 1N NaOH (6 mL). The resultant white precipitates were filtered and washed with EtOAc (100 mL). The combined organic layers were concentrated under reduced pressure to provide the product as an oil that was used without further purification. LC/MS m/z M+1 220.0, retention time 0.64 minutes; (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, CDCl 3 ) δ 7.25-7.16 (m, 5H), 3.46 (s, 2H), 3.30 (d, J=3.9 Hz, 2H), 2.51-2.46 (m, 2H), 2.26-2.20 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.25 (m, 2H), 0.87 (s, 3H).

(1-benzyl-4-methylpiperidin-4-yl)methanol (3.9 g; 17.8 mmol) was dissolved in MeOH (50 mL) and NH 4 CO 2 H (12.5 g; 178.0 mmol) was added. Pd/C (10% by weight, wet; 5.5 g) was then added and the system was flushed with nitrogen and then with hydrogen. The reaction was stirred at room temperature overnight (18 hours) and then filtered through a pad of Celite. The solvent was removed under high vacuum to provide a solid that was a mixture of the amino alcohol and NH 4 CO 2 H. The crude product (2.4 g as a mixture with NH 4 COOH) was used in the next step without further purification. LC/MS m/z (M+1) 130.0, retention time 0.35 min; (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, CDCl 3 ) δ 3.17 (s, 2H), 3.03-2.98 (m, 2H), 2.95-2.88 (m, 2H), 1.64-1.57 (m, 2H), 1.36-1.31 (m, 2H), 0.89 (s, 3H).

(4-methylpiperidin-4-yl)methanol (2.4 g, a mixture of the amino alcohol and NH 4 CO 2 H) was suspended in DCM (70 mL). Et 3 N (5 mL; 37.2 mmol) was then added followed by the drop-wise addition of ethyl chloroformate (1.05 mL, 13 mmol, 1.4 eq.). After 1 hour at room temperature, 1N HCl (70 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (70 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under high vacuum. The product is obtained as an analytically pure oil and used without further purification. LC/MS m/z (M+1) 202.2, retention time 1.89 minutes; (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.05 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.32 (s, 2H), 3.11 (t, J=5.2 Hz, 1H), 3.11 (dd, J=23.9, 3.5 Hz, 1H), 1.44-1.37 (m, 3H), 1.26-1.22 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 0.93 (s, 3H).

To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to −78° C. and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at −78° C. for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at −78° C. and then treated with Et 3 N (3.53 mL; 25.32 mmol). The solution was stirred at −78° C. for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 hours. The solution was then treated with saturated aqueous NaHCO 3 (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the product as an oil that was used without further purification. LC/MS m/z (M+1) 200.0, retention time 2.23 minutes; (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.09 (dd, J=10.1, 3.5 Hz, 1H), 3.06 (dd, J=10.2, 3.4 Hz, 1H), 1.86 (dt, J=13.6, 4.4 Hz, 2H), 1.42-1.30 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 1.02 (s, 3H).

Preparation F: Synthesis of benzyl 4-oxotropane-N-carboxylate

Tropinone (10.0 g; 71.84 mmol) was dissolved in DCE (60 mL) and treated drop-wise with 1-chloroethyl chloroformate ACE-Cl (14.5 mL; 19.11 g; 133.7 mmol). The reaction was allowed to stir at room temperature overnight and was then diluted with Et 2 O (400 mL) and filtered. The filtrate was concentrated under reduced pressure to provide the crude chloroethyl carbamate. This compound was taken in MeOH (200 mL) and stirred at room temperature for 1 h, then concentrated under reduced pressure (at 55° C.) to provide the crude des-methyltropinone as the HCl salt (tan solid). The crude material was recrystallized from acetonitrile to furnish the pure product as a white crystalline solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.79 (dd, J=15.0, 6.9 Hz, 2H), 2.09 (m, 2H), 2.40 (d, J=16.7 Hz, 2H), 3.02 (dd, J=17.1, 4.3 Hz, 2H), 4.23 (s, 2H), 10.00 (br s, 2H)

›VII. PREPARATIONS AND EXAMPLES · 3 of 4

Des-methyl tropinone (5.10 g; 31.55 mmol) was dissolved in CH 2 Cl 2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH 2 Cl 2 . The organic phase was washed with 1 N HCl (2×100 mL), dried on Na 2 SO 4 and concentrated to provide the crude product. 1 H NMR (400 MHz, CDCl 3 ) δ 1.71 (dd, J=15.0, 7.2 Hz, 2H), 2.12 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.67 (m, 2H), 4.62 (s, 2H), 5.22 (s, 2H), 7.38 (m, 5H).

Preparation G: Synthesis of 5-chloro-3-methyl-1,2,4-thiadiazole

Dry chlorine gas was bubbled into CS 2 (1000 mL, containing about 1.0 g of iodine) at 5° C. for 48 hours. The excess CS 2 was evaporated and the residue was fractionally distilled to give perchloromethyl mercaptan (bp 144-145° C./1 atm, 300 g, 10%). 13 C-NMR (300 MHz, CDCl 3 ) δ 96.69 (1 C).

To a mixture of perchloromethyl mercaptan (60 g, 323 mmol) and acetamidine hydrochloride (30.6 g, 323 mmol) in dichloromethane (200 mL) was added dropwise a solution of NaOH (64.8 g in water (200 mL) at −5° C. The resulting mixture was stirred at −5° C. for 30 min and then allowed to warm to room temperature. The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (50 mL×2) and brine (100 mL), dried over Na 2 SO 4 , and the solvent was removed. The residue was distilled under reduced pressure to give 5-chloro-3-methyl-1,2,4-thiadiazole (bp 70° C./0.85 Mpa, 18 g, 41.8%). 1 H-NMR (300 MHz, CDCl 3 ) δ 2.59 (s, 3H).

Preparation H: Synthesis of 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one

To a mixture of piperidin-4-one HCl salt (4.08 g, 30 mmol) and Et 3 N (20 mL, 78.6 mmol) in EtOH (50 mL) was added 5-chloro-3-methyl-1,2,4-thiadiazole (4.05 g, 30 mmol). The mixture was heated to reflux for 1.5 hours and then concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with water (30 mL×3) and brine (30 mL), dried over Na 2 SO 4 , and concentrated to dryness. The residue was recrystalled from ether to give 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (510 mg, 8.6%). 1 H-NMR (300 MHz, CDCl 3 ) δ 3.86 (t, J=6.3 Hz, 4H), 2.62 (t, J=6.3, Hz, 4H), 2.44 (s, 3H).

Preparation I: Synthesis of 1-(3-ethyl-1,2,4-thiadiazol-5-yl)piperidin-4-one

1-(3-ethyl-1,2,4-thiadiazol-5-yl)piperidin-4-one was made in a manner analogous to that found in Preparation B in 54% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 3.95 (t, J=6.4 Hz, 4H), 2.84 (q, J=7.6 Hz, 2H), 2.68 (t J=6.4, Hz, 4H), 1.36 (t, J=7.6 Hz, 3H).

Preparation J: Synthesis of 5-chloro-1,2,4-thiadiazole

5-chloro-1,2,4-thiadiazole was made in a manner analogous to that found in Preparation A in 36% yield after distillation (bp 124° C./1 atm). 1 H-NMR (300 MHz, CDCl 3 ) δ 8.45 (s, 1H).

Preparation K: Synthesis of 1-(1,2,4-thiadiazol-5-yl)piperidin-4-one

1-(1,2,4-thiadiazol-5-yl)piperidin-4-one was made in a manner analogous to that found in Preparation B in 9% yield. 1 H-NMR (300 MHz, CDCl 3 ) δ 8.00 (s, 1H), 3.92 (t, J=4.5 Hz, 4H), 2.65 (t, J=4.8 Hz, 4H).

Preparation L: Synthesis of 5-chloro-2,3-dimethylpyrazine

A mixture of 2,3-dimethylpyrazine (25 g, 0.23 mol) and 30% H 2 O 2 (52.4 g, 0.46 mol) in acetic acid (74 mL) was stirred for two days at 35° C. The solvent was removed under vacuum. Water was added and the mixture evaporated again. The residue was basified with aqueous K 2 CO 3 and extracted with EtOAc. The organic phases were dried over Na 2 SO 4 and concentrated. The resulting solid combined from two batches was recrystallized from cyclohexane to give 2,3-dimethylpyrazine 1-oxide (27 g, 47%). 1 HNMR (CDCl 3 , 300 MHz) δ 8.18 (d, J=3.9 Hz, 1H), 8.02 (d, J=4.2 Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H).

2,3-Dimethyl-pyrazine 1-oxide (25 g, 0.2 mol) was dissolved in POCl 3 (200 mL) under cooling. The mixture was gradually heated to reflux and stirred for 2 hours. After cooling, the reaction mixture was poured onto ice, basified to pH 8 with a saturated KOH solution under cooling and extracted with EtOAc. The combined organics were dried over Na 2 SO 4 and concentrated. The residue was purified by column (P.E./EtOAc 100:1-60:1) to obtain 5-chloro-2,3-dimethylpyrazine. 1 HNMR (CDCl 3 , 300 MHz) δ 8.31 (s, 1H), 2.53 (s, 6H). MS (ESI) m/e (M+H + ) 143.2.

Preparation M: Synthesis of (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate

A mixture of itaconic acid (6.5 g, 50 mmol) and S-(−)-α-methylbenzylamine (6.05 g, 50 mmol) was heated at 160° C. (oil bath) for 4 hours. Upon cooling, methanol (25 mL) was added and the resulting solid was collected by filtration. The solid was treated with ethanol (75 mL) and warmed using a steam bath until ˜40 mL solvent remained. After cooling to room temperature, the solid was collected and dried to afford (S)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid as a white crystalline solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.6 (br s, 1H), 7.23-7.36 (m, 5H), 5.21 (q, J=6.9 Hz, 1H), 3.43-3.48 (m, 1H), 3.11-3.19 (m, 2H), 2.41-2.58 (m, 2H), 1.43 (d, J=6.9 Hz, 3H).

(S)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (1.16 g, 5 mmol) was treated with CH 3 OH/HCl (10 mL, 1 M) for 3 h. The excess CH 3 OH/HCl was removed under reduced pressure. The residue was basified with saturated aqueous NaHCO 3 to pH 8. The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to give (S)-methyl 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate, which was used directly in the next step. 1 H NMR (300 MHz, CDCl 3 ) δ 7.24-7.37 (m, 5H), 5.48 (q, J=7.2 Hz, 1H), 3.72 (s, 3H), 3.51-3.56 (m, 1H), 3.03-3.21 (m, 2H), 2.62-2.79 (m, 2H), 1.53 (d, J=7.2 Hz, 3H).

To a suspension of LAH (20 g, 0.526 mol) in dried THF (400 mL) was added dropwise a solution of (S)-methyl 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate (50 g, 0.202 mol) in dried THF (50 mL) at 0° C. The mixture was heated to reflux overnight. The reaction mixture was cooled to 0° C. and treated with water (20 mL) and aqueous NaOH (10%, 20 mL). The slurry formed was filtered off and washed with THF. The combined filtrate was evaporated to give compound ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)methanol, which was used directly in the next step.

›VII. PREPARATIONS AND EXAMPLES · 4 of 4

To a solution of ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)methanol (42.2 g, 0.194 mol) and (Boc) 2 O (69.4 g, 0.292 mol) in methanol (300 mL) was added Pd(OH) 2 /C (5 g). The resultant mixture was heated to 50° C. at 50 psi under H 2 and stirred overnight then cooled to room temperature. Pd(OH) 2 /C was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate. 1 H NMR (300 MHz, CDCl 3 ) δ 3.60-3.63 (m, 2H), 3.29-3.52 (m, 3H), 3.07-3.13 (m, 1H), 2.37-2.42 (m, 1H), 1.94-1.98 (m, 1H), 1.62-1.70 (m, 1H), 1.45 (s, 9H).

To a solution of oxalyl chloride (22.17 g, 0.176 mol) in CH 2 Cl 2 (200 mL) was added dropwise a solution of DMSO (20.59 g, 0.264 mol) in CH 2 Cl 2 (50 mL) at −78° C. The mixture was stirred for 0.5 hours at this temperature. A solution of (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (11.8 g, 58.7 mmol) in CH 2 Cl 2 (50 mL) was added dropwise to the reaction mixture at −78° C. The mixture was continued to stir for 1 hour at that temperature. Et 3 N (29.7 g, 0.294 mol) was added at −78° C. The resultant mixture was warmed to room temperature and stirred for 3 hours. The mixture was poured into saturated aqueous NaHCO 3 and shaken. The organic layer was separated, washed twice with water, dried and evaporated to give a residue, which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate. 1 H NMR (CDCl 3 , 300 MHz): δ 9.68 (d, J=1.8 Hz, 1H), 3.67-3.68 (m, 1H), 3.51-3.55 (m, 1H), 3.35-3.40 (m, 2H), 2.99-3.04 (m, 1H), 2.04-2.18 (m, 2H), 1.46 (s, 9H).

Preparation N: Synthesis of (R)-tert-butyl 3-formylpyrrolidine-1-carboxylate

(R)-tert-butyl 3-formylpyrrolidine-1-carboxylate was synthesized in a manner analogous to that of (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate above by using the R-(+)-α-methyl benzylamine chiral auxillary. Intermediates are characterized below:

(R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylic acid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.6 (br s, 1H), 7.25-7.36 (m, 5H), 5.21 (q, J=7.2 Hz, 1H), 3.43-3.51 (m, 1H), 3.08-3.19 (m, 2H), 2.48-2.58 (m, 2H), 1.43 (d, J=7.2 Hz, 3H).

(R)-methyl 5-oxo-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylate: 1 H NMR (300 MHz, CDCl 3 ) δ 7.23-7.35 (m, 5H), 5.47 (q, J=7.2 Hz, 1H), 3.70 (s, 3H), 3.50-3.55 (m, 1H), 3.02-3.20 (m, 2H), 2.60-2.78 (m, 2H), 1.51 (d, J=7.2 Hz, 3H).

Preparation O: Synthesis of 1-benzylazocan-5-one

A mixture of benzylamine (83.7 g, 0.78 mol), 4-bromo-butyric acid ethyl ester (304.6 g, 1.56 mol) and K 2 CO 3 (215.8 g, 1.56 mol) in anhydrous EtOH (970 mL) was refluxed overnight. The mixture was filtered, and the filtrate was concentrated and dissolved into dichloromethane, which was washed with water, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (P.E.) to provide diethyl 4,4′-(benzylazanediyl)dibutanoate (123 g, 47%). 1 H NMR (CDCl 3 , 400 MHz) δ 7.16-7.22 (m, 5H), 4.03 (q, J=7.2, 14.4 Hz, 4H), 3.47 (s, 2H), 2.36 (br s, 4H), 2.24 (t, J=7.6 Hz, 4H), 1.71 (br s, 4H), 1.17 (t, J=7.2 Hz, 6H).

To a stirred boiling slurry made from potassium (1.28 g, 32.8 mmol) and t-BuOH (2.43 g, 32.8 mmol) in xylene (182.5 mL) under N 2 was added diethyl 4,4′-(benzylazanediyl)dibutanoate (5 g, 14.9 mmol) over 5 hours in xylene (37.25 mL). The mixture was stirred and heated at reflux for 1 hour. After being cooled, the reaction mixture was neuturalized with 6N HCl (100 mL) and then was extracted with 6N HCl (3×50 mL). The combined acid solutions were filtered and the filtrate was heated under reflux for 1 hour. After cooling, the mixture was basified with concentrated KOH solution to pH 10 with cooling and extracted with dichloromethane. The combined organics were dried over Na 2 SO 4 and concentrated to give a residue. Another 17 batches were done in parallel. The combined residue from 18 batches was purified together by column (P.E./EtOAc 5:1) to give 1-benzylazocan-5-one. 1 H NMR (CDCl 3 , 400 MHz) δ 7.30-7.33 (m, 2H), 7.21-7.25 (m, 3H), 3.56 (s, 2H), 2.55 (t, J=6.0, 4H), 2.24 (t, J=6.4 Hz, 4H), 1.86-1.91 (m, 4H).

›Examples66

›Example 1

To a solution of compound N-Boc Spiroindane 1a (60.0 g, 0.21 mol) in CH 2 Cl 2 (1000 mL) was added H 2 O (500 mL), TBAB (6.9 g, 0.02 mol) and KOH (3.5 g, 0.06 mol) and followed by addition of KMnO 4 (70.0 g, 0.45 mol) in several portions. After stirring for two days at 35° C., another quantity of KMnO 4 (70.0 g, 0.45 mol) was added and the mixture was continued to stir for 2 days. After Na 2 SO 3 (103.0 g, 1.0 mol) was added in portions at 5° C., the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 and evaporated under vacuum. The residue was purified by column chromatography (PE/EtOAc: 5/1) to yield 1b. 1 H NMR (CDCl 3 ) δ: 7.74-7.72 (m, 1H), 7.66-7.64 (m, 1H), 7.62-7.61 (m, 1H), 7.49-7.38 (m, 1H), 4.22-4.20 (m, 2H), 2.89-2.82 (m, 2H), 2.63 (s, 2H), 2.02-1.94 (m, 2H), 1.56-1.52 (m, 2H), 1.49 (s, 9H). MS (ESI) m/z (M+H + ) 246.0/202.1.

Boc-protected starting material 1b (400.0 mg; 1.33 mmol) was dissolved in CH 2 Cl 2 (1.5 mL) and treated with TFA (1.5 mL). The reaction was allowed to stir at room temperature for 1 h and was then quenched by adding H 2 O (5 mL) and Et 2 O (7 mL). The layers were separated, and the aqueous layer was brought to a basic pH by addition of solid KOH. The resulting emulsion was extracted with Et 2 O (3×10 mL). The combined organic extracts were dried on Na 2 SO 4 and concentrated to yield the desired product 1c as a colorless oil that solidifies upon standing. LC/MS m/z 202.2 [M+H] + , retention time 0.72 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min).

Intermediate 1c (40 mg; 0.2 mmol) was suspended in DCE (1 mL) and treated with (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg; 0.26 mmol; 1.300 eq.) in DCE (0.5 mL), followed by portion-wise addition of NaBH(OAc) 3 (127 mg; 0.6 mmol) The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (1 mL) and allowed to stir for another 30 min. The crude reaction mixture was purified by HPLC (10-99% CH 3 CN gradient with 0.03% TFA, 15 min) to provide the purified compound no. 237. LC/MS m/z 308.2 [M+H] + , retention time 2.08 (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (br s, 1H), 7.81-7.77 (m, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.59 (d, J=7.8 Hz, 7.53-7.49 (m, 1H), 6.27 (dd, J=5.7, 3.0 Hz, 1H), 6.05 (dd, J=5.7, 2.8 Hz, 1H), 3.60 (t, J=12.7 Hz, 3H), 3.11-2.90 (m, 4H), 2.85-2.74 (m, 4H), 2.29 (t, J=13.0 Hz, 2H), 2.05-1.99 (m, 1H), 1.76 (d, J=14.2 Hz, 2H), 1.39-1.35 (m, 1H), 1.29 (d, J=8.2 Hz, 1H), 0.71-0.66 (m, 1H).

›Example 2

1.0 eq of the Boc-protected spiroindanone 2a (2.06 g, 6.84 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and added drop-wise, under nitrogen, to an ice-cold (˜0° C.) suspension of 2.2 eq sodium hydride (600 mg, 60% dispersion in mineral oil, 15.0 mmol) in anhydrous tetrahydrofuran (10 mL). A solution of 10.0 eq iodomethane (9.71 g, 68.4 mmol) in anhydrous tetrahydrofuran (5 mL) was then added drop-wise over 20 min. The reaction was warmed to room temperature and stirred for 2 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and slowly treated with H 2 O (25 mL). The product was extracted with ethyl acetate (2×50 mL) and the pooled extracts washed with saturated sodium bicarbonate and saturated brine, then dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo to afford crude product 2b as a viscous, pale yellow oil. 1 H-NMR (400 MHz, acetone-d 6 ) δ 7.90 (d, J=6.8 Hz, 1H), 7.71 (m, 2H), 7.49 (t, J=7.4 Hz, 1H), 3.75 (m, 2H), 3.56 (br m, 2H), 1.89 (m, 2H), 1.64 (br m, 2H), 1.48 (s, 9H), 1.12 (s, 6H); t R =3.50 min [10-99% CH 3 CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 20 H 27 NO 3 =330.2; Found 330.2.

The gem-dimethyl spiroindanone 2b (379 mg, 1.15 mmol) was dissolved in dichloromethane (2.5 mL), cooled in an ice-H 2 O bath and treated slowly with trifluoroacetic acid (2.5 mL). The reaction was stirred for 30 min at ˜0° C., then concentrated under reduced pressure. The oil obtained was dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was treated with 1.0 N NaOH (5 mL) and extracted with ethyl acetate (2×30 mL). The pooled extracts were washed with H 2 O and saturated brine, then dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo to afford 210 mg of the crude free base 2c as a colorless semi-solid. t R =1.52 min [10-99% CH 3 CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)+m/z for C 15 H 19 NO=230.2; Found 230.2

The crude free base 2c (53 mg, 0.23 mmol) was dissolved in anhydrous 1,2-dichloroethane (1.0 mL) and treated with N-(carbethoxy)-4-tropinone (55 mg, 0.28 mmol), followed by titanium tetraisopropoxide (202 μL, 196 mg, 0.69 mmol). The vial was flushed with nitrogen and stirred at room temperature for 2.5 days. The reaction was diluted with methanol (1.0 mL), cooled in an ice-H 2 O bath and treated with sodium borohydride (17 mg, 0.46 mmol). The reaction was warmed to room temperature and stirred thereafter for 30 min. The reaction was then quenched with 1.0 N NaOH (750 μL), diluted with methanol (1.5 mL) and stirred at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in DMSO:methanol (1.5 mL, 1:1 v/v), filtered, and purified by reverse-phase HPLC (2-40% CH 3 CN gradient over 10 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected) to produce the compound no. 277 as a TFA salt. t R =2.12 min [10-99% CH 3 CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 25 H 34 N 2 O 3 =411.3; Found 411.2.

›Example 3

The starting Spiroindane 3a (45 mg, 0.2 mmol) was suspended in DCE (1 mL) and treated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (25 mg, 0.2 mmol) in DCE, followed by the addition of NaBH(OAc) 3 (63 mg, 0.3 mmol). The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (0.5 mL) and allowed to stir for another 30 min (until gas evolution stopped). The crude reaction mixture was filtered, then purified by HPLC (10-99% CH 3 CN/0.05% TFA gradient) to yield compound no. 312. LC/MS m/z 294.4 [M+H] + , retention time 2.33 min (RP—C 18 , 10-99% CH 3 CN/0.05% TFA); 1 H NMR MHz, DMSO-d 6 ) δ 9.33 (br s, 1H), 7.25-7.17 (m, 3H), 7.13 (d, J=6.9 Hz, 1H), 6.27-6.26 (m, 1H), 6.06-6.04 (m, 1H), 3.56-3.40 (m, 3H), 3.11-3.03 (m, 2H), 2.98-2.78 (m, 6H), 2.09-1.98 (m, 5H), 1.67 (d, J=13.9 Hz, 2H), 1.36 (t, J=8.0 Hz, 1H), 1.29 (d, J=8.2 Hz, 1H), 0.70-0.66 (m, 1H).

›Example 4

To a solution of 2-amino-4-chloro-phenol 4a (50 g, 0.35 mol) in HCl (2.5 mol, 500 mL) was added drop-wise a solution of sodium nitrite (25.25 g, 0.35 mol) in water (50 mL) at 0° C. The mixture was stirred at this temperature for 30 min. Then a cooled solution of KI (70 g, 0.42 mol) in H 2 O (100 mL) was slowly added at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and the separated aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic fraction was washed with Na 2 S 2 O 3 (10%, 100 mL), water (100 mL×2) and brine (200 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column on silica gel to afford 4-chloro-2-iodo-phenol 4b as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.67 (d, J=2.4 Hz, 1H), 7.21 (dd, J=2.4, 8.4, Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.33 (s, 1H).

To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol), (1-benzyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na 2 CO 3 solution (10% 100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (200 mL), dried over Na 2 SO 4 , concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c. 1 H NMR (400 MHz, CDCl 3 ): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).

To a refluxing solution of 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c (26.7 g, 0.06 mol) and AIBN (0.05 g, 0.003 mol) in dry benzene was added a solution of Bu 3 SnH (40 g, 0.137 mol) in benzene (100 mL) over 1 h under nitrogen atmosphere. After addition, the mixture was refluxed for 3 hr and additional AIBN (0.5 g, 0.003 mol) and Bu 3 SnH (20 g, 0.68 mol) were added. After refluxing for 4 hr, the mixture was concentrated to dryness, and EtOAc (100 mL) and HCl (10%, 40 mL) were added. The precipitate was filtered and washed with petroleum ether to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) as its HCl salt, which was basified by NaHCO 3 solution to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 68%).

To a solution of 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 0.04 mol) in CH 2 Cl 2 (130 mL) was added drop-wise 1-chloroethyl chloroformate (7.2 g, 0.05 mol). The mixture was stirred for 3 hr at room temperature and then concentrated to dryness. The residue was dissolved in CH 3 OH (30 mL) and the solution was heated to reflux for 30 min. After removing of the solvent, ether was added. The resulted solid was filtered and washed with ether to the debenzylated product 4e as the HCl salt (5.5 g, yield 48%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.08 (br s, 1H), 7.16-7.19 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.25-9.29 (m, 2H), 2.98-2.92 (m, 2H), 2.12-2.05 (m, 2H), 1.83-1.8 (m, 2H).

The chloro-dihydrobenzofuran spiro amine 4e (3.18 mmol) was dissolved in anhydrous DCE (15 mL) and treated with triethylamine (322 mg, 3.18 mmol), followed by (+)-2-norcamphor (421 mg, 3.82 mmol), acetic acid (382 mg, 6.36 mmol) and NaBH(OAc) 3 (1.35 g, 6.37 mmol). The reaction was stirred vigorously under nitrogen at room temperature for ˜36 hours. The reaction was quenched with methanol (15 mL) and stirred vigorously for 10 min at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue obtained dissolved in a mixture of DMSO:CH 3 OH (20 mL, 1:3 v/v). The solution was filtered and purified by reverse-phase HPLC (2-99% CH 3 CN/0.05% TFA, 35 mL/min). The combined pure fractions were concentrated under reduced pressure until ˜25 mL of solvent remained. The suspension was treated with 1 N NaOH (25 mL) and extracted with CH 2 Cl 2 (3×50 mL). The combined organic extracts were washed with H 2 O, saturated brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford 522 mg pure free base (1.64 mmol) as a crystalline white solid. The free base was readily dissolved in anhydrous diethyl ether (10 mL) and treated with 1.0 eq 1 N ethereal HCl (1.7 mL). The thick, gelatinous suspension obtained was cooled in an ice/H 2 O bath for 1 hour, filtered, rinsed with Et 2 O (3×10 mL), and dried overnight under reduced pressure to yield compound no. 1 as a fine white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.1 (br s, 1H), 7.77 (d, J=2.2 Hz, 0.2H), 7.21 (dd, J=2.3 Hz, 8.5 Hz, 1H), 7.08 (d, J=2.3 Hz, 0.8H), 6.85 (d, J=8.5 Hz, 0.8H), 6.84 (d, J=8.5 Hz, 0.2H), 4.52 (s, 1.6H), 4.45 (s, 0.4H), 3.41 (m, 1.8H), 3.24 (m, 0.8H), 3.01 (br m, 1.6H), 2.63 (br m, 2H), 2.44 (m, 0.9H), 2.27 (br s, 1.1H), 1.86 (br m, 4H), 1.51 (br m, 3.3H), 1.39 (br m, 2.7H), 1.24 (br m, 0.7H); LC/MS m/z 318.0 [M+H] + , retention time 2.14 min (RP—C 18 , 10-99% CH 3 CN/0.05% TFA).

›Example 5

The starting material 5a (54 mg, 0.2 mmol, 1.0 eq) was suspended in DCE (1 mL) and treated with (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg, 0.26 mmol, 1.3 eq) in DCE (0.5 mL), followed by portion-wise addition of NaBH(OAc) 3 (127 mg, 0.6 mmol). The reaction was allowed to stir at room temperature for 3 h and was then quenched with MeOH (2 mL) and allowed to stir for another hour (until gas evolution stopped). The reaction mixture was then diluted with H 2 O (5 mL) and extracted with Et 2 O (10 mL). The organic layer was treated with 1 N HCl (5 mL) and formation of an insoluble precipitate was observed. The biphasic emulsion was filtered, and the white precipitate was washed with Et 2 O (3×5 mL) and hexanes (2×10 mL) and dried under vacuum to provide the pure HCl salt of compound no. 64 as white shiny platelets. LC/MS m/z 344.0 [M+H] + , retention time 2.56 min (RP—C 8 , 10-99% CH 3 CN/0.05% TFA). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.18 (q, J=2.8 Hz, 1H), 6.02 (q, J=2.7 Hz, 1H), 4.05-4.03 (m, 2H), 3.37-3.32 (m, 2H), 3.08-2.97 (m, 3H), 2.85-2.77 (m, 2H), 2.72-2.65 (m, 1H), 2.49-2.45 (m, 3H), 1.98-1.90 (m, 3H), 1.72-1.70 (m, 2H), 1.26 (dd, J=33.4, 7.3 Hz, 2H), 0.63 (d, J=10.5 Hz, 1H).

›Example 6

The fluoroindoline 6a (1.22 g; 4.0 mmol) was suspended in DCE (10 mL) and cooled to −30° C. A solution of (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (635 mg; 5.2 mmol) in dry DCE (2 mL) was added, followed by portion-wise addition of NaBH(OAc) 3 (1.18 g; 5.6 mmol). The reaction was stirred at −30° C. under nitrogen for 90 min then at room temperature until complete consumption of starting material was observed by LC/MS (30 h). The reaction was quenched with MeOH (10 mL) and allowed to stir vigorously for 30 min (until gas evolution stopped). The reaction was diluted with 1N HCl (80 mL) and Et 2 O (50 mL). Formation of a white precipitate can be observed as the HCl salt of the desired product is insoluble in both phases. The biphasic mixture was filtered, and the precipitate was washed with Et 2 O (2×20 mL) and hexanes (2×30 mL) and dried under high vacuum to provide the product 6b as the corresponding HCl salt (white powder).

The HCl salt 6b (1.4 g; 3.1 mmol) was dissolved in CH 2 Cl 2 (10 mL) and TFA (10 mL) was added. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction was quenched with water (100 mL) and diluted with hexanes (40 mL) and Et 2 O (50 mL). The layers were separated, and the organic layer was extracted with H 2 O (2×100 mL). The combined aqueous layers were washed with Et 2 O (50 mL) then neutralized with solid KOH (under dry-ice bath cooling) until formation of an oily suspension was observed. The suspension was extracted with EtOAc (3×100 mL) and CH 2 Cl 2 (100 mL), and the combined organic extracts were dried over Na 2 SO 4 and concentrated to provide the crude product as a light brown oil. The amine was dissolved in 15 mL Et 2 O and treated with 2 N HCl in ether (1.5 mL, 3.0 mmol, 0.96 eq). After 20 min of stirring the resulting precipitate was vacuum filtered under a nitrogen atmosphere, washed with 50 mL Et 2 O, 30 mL Et 2 O:CH 3 CN (5:1) and 40 mL hexanes and dried under high vacuum to provide the HCl salt of compound no. 147 as an off-white powder. LC/MS m/z 313.30 [M+H] + , retention time 1.73 min (RP—C 18 , 10-99% CH 3 CN/0.05% TFA). 1 H NMR (400 MHz, MeOD) δ 0.83 (ddd, J=5.8, 2.6 Hz, 1H), 1.41 (d, J=8.4 Hz, 1H), 1.54 (m, 1H), 2.01 (s, 1H), 2.05 (d, J=3.9 Hz, 1H), 2.15 (ddd, J=6.1, 3.1 Hz, 1H), 2.23 (m, 2H), 2.60 (m, 1H), 2.86 (dd, J=13.0, 7.4 Hz, 1H), 2.93 (s, 1H), 3.11 (m, 4H), 3.66 (m, 4H), 6.09 (d, J=2.8 Hz, 1H), 6.33 (d, J=3.0 Hz, 1H), 6.90 (m, 3H).

›Example 7

Starting material 7a hydrochloride (2.17 g, 6.40 mmol) was suspended in anhydrous DCE (30 mL) and treated with triethylamine (648 mg, 6.40 mmol), followed by (−)-2-norcamphor (706 mg, 6.40 mmol), acetic acid (770 mg, 12.8 mmol) and NaBH(OAc) 3 (2.72 g, 12.8 mmol). The reaction was stirred vigorously under nitrogen at room temperature for ˜72 hours (˜77% conversion by LC/MS at 220 nm). The reaction was quenched with methanol (10 mL) and stirred vigorously for 10 min at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue obtained dissolved in a 1:1 mixture of DMSO:CH 3 OH (30 mL). The mixture was centrifuged (3,000 rpm, 10 min) and the supernatant filtered and purified by reverse-phase HPLC (10-99% CH 3 CN/0.05% TFA, 50 mL/min). The combined pure fractions were concentrated under reduced pressure to afford 2.25 g of the N-Boc intermediate 7b (isolated as the TFA salt) as an off-white solid. LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 397.4 [M+H] + , retention time 2.70 min.

The N-Boc intermediate 7b (2.25 g, 4.41 mmol) was dissolved in dichloromethane (25 mL) and slowly treated with trifluoroacetic acid (15 mL). The reaction was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The oil obtained was slowly treated with 1 N NaOH (100 mL) and extracted with CH 2 Cl 2 (2×75 mL). The combined extracts were washed with H 2 O, saturated brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford a free base as a yellow oil. The free base was dissolved in a minimal volume of anhydrous diethyl ether and treated with 0.95 eq 1 N ethereal HCl. The suspension was cooled in an ice/H 2 O bath for 1 hour, filtered, rinsed with Et 2 O, and dried overnight under reduced pressure to yield the desired product 7c as a fine, off-white to very pale yellow powder. LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 297.2 [M+H] + , retention time 1.72 min.

The deprotected amine HCl salt 7c (33 mg, 0.10 mmol) was suspended in anhydrous CH 3 CN (1.0 mL) and treated with triethylamine (20 mg, 0.20 mmol), followed by methanesulfonyl chloride (14 mg, 0.12 mmol). The reaction was stirred at room temperature for 10 min, then quenched with DMSO:CH 3 OH (1.0 mL, 1:1 v/v) and centrifuged (4000 rpm, 7 min). The supernatant was filtered and purified by reverse-phase HPLC (2-99% CH 3 CN, 50 mL/min, 2.0 mL injected) to yield the desired compound no. 231 as the TFA salt. LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 375.0 [M+H] + , retention time 2.08 mm.

›Example 8

Boc-protected fluoroindoline 8a (1.41 g; 4.11 mmol) and benzyl 4-oxotropane-N-carboxylate (1.07 g; 4.11 mmol) were dissolved in a mixture of DCE (5 mL) and DME (5 mL) and placed under a nitrogen atmosphere. TEA (0.57 mL; 0.42 g; 4.11 mmol) was added, followed by Ti(OiPr) 4 (1.21 mL; 1.17 g; 4.11 mmol) and the reaction was allowed to stir at room temperature for 60 hours. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH 4 (0.6 g; 13.45 mmol) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. to −20° C. until bubbling subsided (3 hours), then warmed slowly to room temperature and was stirred for 2 hours. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et 2 O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et 2 O (2×50 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated to provide the crude product as a white foam. This material was dissolved in Et 2 O (400 mL) and treated with 1 N aq. HCl (500 mL) and the mixture was vigorously stirred for 20 min. The resulting biphasic suspension was filtered, the precipitate was washed with HCl 1N (2×30 mL), H 2 O (2×30 mL) and Et 2 O (3×30 mL) and dried. To remove the unreacted starting material by conversion to the corresponding ethyl carbamate, the crude HCl salt was suspended in acetonitrile (10 mL) and treated sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et 2 O (300 mL) and poured onto 1 N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H 2 O (2×30 mL) and Et 2 O (3×30 mL) and dried to provide the desired product 8b hydrochloride salt. LC/MS m/z [M+H] + 550.4 retention time 2.93 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min).

Cbz-protected starting material 8b (1.140 g; 1.945 mmol) was dissolved in methanol (20 mL) and treated with 10% wet Pd/C (1.14 g) and NH 4 COOH (2.45 g; 38.9 mmol). The mixture was allowed to stir vigorously overnight under an empty balloon (for venting). LC/MS analysis showed complete conversion to the desired product. The reaction mixture was filtered through a pad of Celite under a nitrogen atmosphere, and the filter cake was rinsed with methanol (4×30 mL). The filtrate was concentrated to provide the crude product, which was taken up in a mixture of EtOAc (100 mL) and NaHCO 3 sat. (100 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2×100 mL), Et 2 O (100 mL), and CH 2 Cl 2 (2×100 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated to provide the crude product 8c as a white foam (707 mg, 87% yield). LC/MS m/z 416.4 [M+H] + , retention time 2.26 (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min)

Compound 8c (250.0 mg; 0.60 mmol) was dissolved in DCM (15 mL) and treated sequentially with methoxyethyl chloroformate (138.4 uL; 166.1 mg; 1.203 mmol) and TEA (401.7 uL; 291.7 mg; 2.89 mmol). After 10 min. the reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with DCM (30 mL) and the combined organic extracts were dried on Na 2 SO 4 and concentrated to provide the desired product 8d which was taken to the next step without further purification. LC/MS m/z 518.0 [M+H] + , retention time 2.43 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min).

Intermediate 8d was dissolved in a mixture of DCM (15 mL) and TFA (20 mL) and allowed to stir at room temperature for 2 h. The reaction mixture was concentrated, dissolved in water (20 mL) and the pH was adjusted to basic by portion-wise addition of solid KOH. The resulting suspension was extracted with DCM (3×30 mL) and Et 2 O (30 mL) and the organic extracts were dried over Na 2 SO 4 , and then concentrated to provide the free base of the desired product. The material was dissolved in Et 2 O (20 mL) and treated with excess 1N HCl in ether (2 mL). The resulting suspension was filtered under nitrogen and the filtrate was washed with Et 2 O (3×10 mL) and dried under vacuum to provide the desired product 8e as an off white solid (232 mg, 85% yield over 2 steps). LC/MS m/z 418.2 [M+H] + , retention time 1.16 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min).

Intermediate 8e (230.0 mg; 0.51 mmol) was suspended in DCM (15 mL) and treated sequentially with dimethyl carbamoyl chloride (931.3 uL; 1089.7 mg; 10.13 mmol) and TEA (704.8 uL; 511.70 mg; 5.07 mmol). The reaction was allowed to stir overnight at room temperature, and then the mixture was diluted with DCM (30 mL) and washed with saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with DCM (30 mL) and the combined organic extracts were dried over Na 2 SO 4 and concentrated to provide the free base of the desired product. This material was dissolved in Et 2 O (20 mL) and treated with excess 1N HCl in ether (3 mL). The resulting suspension was filtered under nitrogen and the filtrate was washed with Et 2 O (3×10 mL) and dried under vacuum to provide the desired compound no. 119 as an off-white solid. LC/MS m/z 489.4 [M+H] + , retention time 2.20 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.66 (d, J=7.0 Hz, 2H), 1.82 (s, 4H), 1.86 (s, 2H), 1.92 (s, 2H), 2.07 (s, 2H), 2.22 (t, J=12.1 Hz, 2H), 2.87 (s, 6H), 3.05 (q, J=11.1 Hz, 2H), 3.28 (s, 3H), 3.53 (m, 4H), 3.73 (m, 1H), 4.15 (d, J=4.4 Hz, 2H), 4.27 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (m, 2H), 10.41 (s, 1H).

Example 9

›Example 9

Bromo-spiroindoline 9a (1.5 g, 4.08 mmol) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0° C. To the rapidly stirring solution was added acetyl chloride (0.481 g, 6.13 mmol) followed by triethylamine (0.853 mL, 6.13 mmol). The reaction mixture was stirred at room temperature for 1 h. Then mixture was concentrated under reduced pressure to afford desired product 9b as viscous pale yellow oil and carried to the next step without further purification. LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 411.0 [M+H] + , retention time 3.39 min.

The intermediate 9b was dissolved in 10 mL of dichloromethane and treated with trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The oil obtained was re-dissolved in acetonitrile, re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were washed with saturated NaHCO 3 , saturated brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford crude free base 9c as a pale yellow oil. LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 309.7 [M+H] + , retention time 2.07 min.

Intermediate 9c (1.260 g, 4.08 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with 2 eq of 1-carbethoxy-4-piperidone (1.393 g, 8.16 mmol), followed by glacial acetic acid (0.490 g, 8.16 mmol) and sodium triacetoxyborohydride (1.721 g, 8.16 mmol). The reaction was stirred at room temperature under nitrogen for 48 h. The reaction was diluted with dichloromethane (50 mL), quenched with 1.0 N NaOH (20 mL) and stirred vigorously at room temperature for 30 min. The layers were separated and the aqueous layer extracted with DCM (2×20 mL). The pooled organic layers were washed with H 2 O (20 mL), brine (20 mL), then dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford 1.8 g crude product 9d as pale yellow oil (˜95% yield). An analytical sample was subjected to reverse-phase HPLC purification (2-50% CH 3 CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected). The remainder of the material was taken to the next step without purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.13 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.54-3.46 (m, 3H), 3.16 (q, J=11.0 Hz, 2H), 2.83 (bs, 2H), 2.21 (s, 3H), 2.17-2.07 (m, 4H), 1.93 (d, J=15.6 Hz, 2H), 1.66-1.55 (m, 2H), 1.20 (t, J=7.0 Hz, 3H). LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min) m/z 467.2 [M+H] + , retention time 1.97 min.

Product 9d (46.4 mg, 0.1 mmol) was mixed with 4-methylphenyl boronic acid (14 mg, 0.1 mmol) in 1 mL of CH 3 CN and 1 mL of 2 M aq. Na 2 CO 3 . The microwave tube was purged with N 2 and 7 mg (10 mol %) of PdCl 2 (dppf) was added and tube was again purged with N 2 , then sealed and microwaved for 20 min at 150° C. After reaction was complete, organic layer was separated, filtered through silica gel plug, concentrated and was subjected to reverse-phase HPLC purification (RP—C 18 , 2-50% CH 3 CN/0.1% aq. TFA gradient over 13 min, 35 mL/min) to yield compound no. 58. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.5 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 4.14 (s, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58 (m, 3H), 3.19 (q, J=11.1 Hz, 2H), 2.85 (bs, 2H), 2.34 (s, 3H), 2.29-2.23 (m, 5H), 2.09 (d, J=12.9 Hz, 2H), 1.96 (d, J=13.9 Hz, 2H), 1.67-1.57 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). LC/MS (RP—C 18 , 10-99% CH 3 CN/0.05% TFA gradient over 5 min): m/z 476.2 [M+H] + , retention time 2.36 min.

›Example 10

1.0 eq of the amine hydrochloride 10a (416 mg, 1.46 mmol) was suspended in anhydrous 1,2-dichloroethane: 1,2-dimethoxyethane (6.0 mL, 1:1 v/v) and treated with 1.0 eq triethylamine (148 mg), followed by 1.5 eq tert-butyl 4-oxoazepane-1-carboxylate (467 mg, 2.19 mmol) and 3.0 eq titanium tetraisopropoxide (1.3 mL, 1.26 g, 4.4 mmol). The reaction vial was flushed with nitrogen and stirred at room temperature for 3 days. The reaction was diluted with methanol (6.0 mL), cooled in an ice-H 2 O bath and treated with sodium borohydride (110 mg, 2.92 mmol). The reaction was slowly warmed to room temperature and stirred thereafter for 90 min. The reaction was then further diluted with methanol (10 mL), quenched with 1.0 N NaOH (5.0 mL) and stirred vigorously at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in dichloromethane (75 mL) and washed successively with H 2 O, saturated sodium bicarbonate, and saturated brine, then dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to afford 704 mg crude product 10b as a viscous, pale yellow oil. The crude product was used in the next step without further purification. t R =2.14 min [10-99% CH 3 CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 25 H 36 FN 3 O 3 =446.3; Found 446.4.

The Boc-protected amine 10b (573 mg) was dissolved in dichloromethane (5 mL), cooled in an ice-H 2 O bath and treated slowly with ice-cold trifluoroacetic acid (5 mL). The reaction was stirred at ˜0° C. for 1 h, then concentrated under reduced pressure. The oil obtained was dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was dissolved in methanol (6.0 mL) and purified by reverse-phase HPLC (2-25% CH 3 CN/0.1% TFA gradient over 10 min, 6×1.0 mL injected, 35 mL/min). The combined pure fractions were concentrated in vacuo to afford 291 mg amine 10c as the di-TFA salt, as a viscous, colorless oil. Yield (over 2 steps)=35%. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.83 (br s, 1H), 8.74 (br s, 2H), 8.06 (dd, J=8.8 Hz, 5.0 Hz, 1H), 7.06 (br m, 1H), 6.97 (br m, 1H), 4.12 (s, 2H), 3.59 (br s, 1H), 3.13 (br m, 6H), 2.36 (m, 1H), 2.20 (s, 3H), 2.13 (m, 5H), 1.89 (m, 5H), 1.71 (m, 1H); t R =1.06 min [10-99% CH 3 CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 20 H 28 FN 3 O=346.2; Found 346.0.

Deprotected amine 10c (46 mg, 0.080 mmol, di-TFA salt) was dissolved in anhydrous acetonitrile (750 μL) and treated with 3.0 eq triethylamine (24 mg, 0.24 mmol). The mixture was then treated with ethyl chloroformate (9 μL, 10 mg, 0.096 mmol) and stirred at room temperature for 30 min. The reaction was quenched with methanol (500 μL) and purified by reverse-phase HPLC to provide compound no. 308 (2-40% CH 3 CN/0.1% TFA gradient over 10 min, 1.0 mL injected, 35 mL/min). t R =1.90 min [10-99% CH 3 CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H) + m/z for C 23 H 32 FN 3 O 3 =418.2; Found 418.4.

›Example 11

Spiroindoline 11a (300.0 mg; 1.21 mmol) and 4-oxocyclohexane spirodioxolane (283.1 mg; 1.81 mmol) were dissolved in DCE (5 mL). After 10 min, NaBH(OAc) 3 (512.1 mg; 2.42 mmol) was added, followed by AcOH (69.7 uL; 72.5 mg; 1.208 mmol) and the mixture was allowed to stir at room temperature for 75 h. The reaction was quenched by adding MeOH (10 mL) and was allowed to stir for 24 h. The resulting suspension was diluted with DCM (30 mL) and NaOH 1 N (5 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic extracts were dried on Na 2 SO 4 and concentrated. The white solid residue was suspended in ether, the ethereal suspension was filtered and the precipitate was washed with ether (3×20 mL) and dried to provide the acetate salt of the desired product 11b (400 mg, 74% yield). The material was used for the next step without further purification. LC/MS m/z 389.2 [M+H] + , retention time 1.73 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.49 (m, 4H), 1.60 (d, J=13.0 Hz, 2H), 1.72 (d, J=9.4 Hz, 4H), 1.81 (td, J=13.4, 2.5 Hz, 2H), 2.19 (s, 3H), 2.28 (t, J=11.5 Hz, 2H), 2.37 (m, 1H), 2.80 (d, J=11.5 Hz, 2H), 3.85 (t, J=2.3 Hz, 4H), 3.95 (s, 2H), 6.97 (td, J=8.3, 1.8 Hz, 1H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 8.02 (dd, J=8.8, 5.0 Hz, 1H)

The ketal 11b (350.0 mg; 0.82 mmol) was dissolved in 80% aq. acetic acid (20 mL) and the solution was refluxed overnight. LC/MS analysis shows complete deprotection of the ketal, along with some deacetylation of the indoline nitrogen. The reaction mixture was diluted with water (20 mL), cooled on an ice bath and neutralized by addition of solid KOH. The resulting suspension was filtered and the precipitate was washed with water (3×10 mL) and dried to provide the crude product as a tan powder. This material was dissolved in DCM (10 mL) and treated with excess AcCl (1 mL) and triethylamine (1 mL). After stirring at room temperature for 3 h, the mixture was diluted with DCM (30 mL) and washed with saturated NaHCO 3 . The organic layer was dried on Na 2 SO 4 and concentrated to provide the product 11c as a yellow oil (253 mg, 89% yield), which was used for the next step without further purification. LC/MS m/z 345.0 [M+H] + , retention time 1.43 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min); 1 H NMR (400 MHz, CDCl 3 ) δ 1.68 (d, J=13.3 Hz, 2H), 1.82 (m, 2H), 1.91 (m, 2H), 2.07 (m, 2H), 2.18 (s, 3H), 2.29 (m, 6H), 2.45 (m, 2H), 2.78 (t, J=9.5 Hz, 1H), 2.97 (d, J=11.6 Hz, 2H), 3.81 (s, 2H) 6.88 (m, 2H), 8.16 (dd, J=8.5, 4.8 Hz, 1H).

The crude ketone 11c (100.0 mg; 0.29 mmol) was dissolved in pyridine (1 mL) and treated with O-ethyl hydroxylamine hydrochloride (21.3 mg; 0.35 mmol). The vial was sealed and heated to 60° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (2 mL) and the product oxime compound no. 86 purified by reverse phase HPLC (2-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 15 min. run). LC/MS m/z 388.4 [M+H] + , retention time 1.87 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min); 1 H NMR (free base, 400 MHz, CDCl 3 ) δ 1.25 (t, J=7.0 Hz, 3H), 1.55 (m, 2H), 1.71 (d, J=13.1 Hz, 2H), 1.94 (m, 5H), 2.14 (m, 1H), 2.25 (s, 3H), 2.30 (td, J=11.9, 5.6 Hz, 2H), 2.50 (d, J=14.3 Hz, 1H), 2.62 (t, J=9.6 Hz, 1H), 2.94 (d, J=11.8 Hz, 2H), 3.25 (d, J=14.7 Hz, 1H), 3.86 (s, 2H), 4.07 (q, J=7.0 Hz, 2H), 6.88 (m, 2H), 8.16 (dd, J=8.5, 4.8 Hz, 1H).

›Example 12

The N-Boc protected indanone 12a (6.5 g, 21.6 mmol), (S)-1-phenylethanamine (2.875 g, 23.72 mmol, 1.1 eq), and anhydrous ZnCl 2 (88 mg, 0.647 mmol, 0.03 eq) were brought up in 35 mL dry toluene in a 100-mL flask under N 2 atmosphere. The flask was fitted with a Dean-Stark trap and reflux condenser for the removal of water. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled, diluted with EtOAc (200 mL), and washed with 0.1 N NaOH (2×30 mL), 20% saturated NH 4 Cl (1×100 mL), and brine (1×100 mL). The organic layer was then dried over Na 2 SO 4 , filtered, and dried down to afford imine (S)-12b as a light orange solid. LC/MS analysis of the crude product indicated complete conversion to the desired product. LC/MS (10-99%) m/z 405.2 [M+H] + , retention time 2.76 min.

The crude imine (S)-12b (21.6 mmol) was dissolved in anhydrous MeOH (30 mL) and cooled to −40° C. under N 2 atmosphere. NaBH 4 (816 mg, 21.6 mmol, 1.0 eq) was added in one portion. The reaction mixture was allowed to warm to −20° C. over 2 h, then warmed to −5° C. for 3 h. The reaction mixture was then diluted with EtOAc (200 mL), then washed with 50% saturated NaHCO 3 (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over Na 2 SO 4 , filtered, and dried down to yield (S, S)-12c as a colorless oil. The oil was brought up in anhydrous diethyl ether, and 1 eq of ethereal HCl was added to precipitate the product as a fine white solid. The solid was filtered, washed with ether (100 mL), and dried under vacuum to obtain 7.2 of (S,S)-12c HCl salt as a white powder (75% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.08 (m, 1H), 9.49 (m, 11H), 8.01 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.1 Hz, 2H), 7.29-7.47 (m, 6H), 4.91 (m, 1H), 4.62 (m, 1H), 3.94 (m, 2H), 2.87 (bs, 2H), 2.62 (dd, J=13.5, 8.0 Hz, 11H), 1.99 (dd, J=13.5, 7.5 Hz, 1H), 1.92 (dt, J=12.9, 4.4 Hz, 11H), 1.76 (d, J=6.7 Hz, 3H), 1.58 (d, J=12.9 Hz, 1H), 1.42 (s+obscured m, 1H); LC/MS (10-99%) m/z 407.4 [M+H] + , retention time 2.70 min.

(S,S)-12c (3.0 g, 6.8 mmol), ammonium formate (8.5 g, 135.4 mmol, 20 eq), and 800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH (30 mL) in a 100-mL flask fixed with a N 2 balloon. The mixture was stirred at room temperature for 28 h. The reaction mixture filtered through packed Celite and concentrated in vacuo to ˜10 mL. The concentrate was diluted with 50% saturated NaHCO 3 (200 mL), and the product extracted into EtOAc (3×100 mL). The combined extracts were washed with brine (50 mL), dried over Na 2 SO 4 , and concentrated in vacuo to obtain (S)-12d as a colorless oil (2.0 g, 98% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.34 (m, 1H), 7.02-7.21 (m, 3H), 4.23 (t, J=7.7 Hz, 1H), 3.99 (m, 2H), 2.90 (br s, 2H), 2.57 (dd, J=12.7, 7.3 Hz, 11H), 2.00 (bs, 2H), 1.92 (dt, J=12.9, 4.5 Hz 11H), 1.42 (s+obscured m, 13H); LC/MS (10-99%) m/z 303.2 [M+H] + , 286.2 [m/z−NH 3 ] + , retention time 2.31 min.

(S)-12d (300 mg, 0.99 mmol) was dissolved in 1.5 mL anhydrous CH 3 CN and cooled to 0° C., followed by ethyl chloroformate (118 mg, 1.09 mmol, 1.1 eq) and triethylamine (200 μL). White precipitate formed upon addition of the triethylamine. The reaction was allowed to warm to room temperature and then stirred for 1 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with 50% saturated NaHCO 3 (20 mL), water (20 mL), and brine (20 mL). The solution was dried over Na 2 SO 4 , filtered, and dried in vacuo to obtain product (S)-12e as a light yellow oil (>90% pure). LC/MS (10-99%) m/z 375.2 [M+H] + , retention time 3.43 min.

The crude (S)-12e was dissolved 5 mL CH 2 Cl 2 and cooled to 0° C., followed by the addition of 5 mL TFA. The reaction mixture was stirred at 0° C. for 1 h, diluted with CH 3 CN (20 mL), and dried in vacuo to obtain the (S)-12f TFA salt. The oil was dissolved in CH 2 Cl 2 (30 mL), washed with 0.1 N NaOH (2×10 mL), brine (10 mL), dried over Na 2 SO 4 , filtered, and dried in vacuo to obtain the product (S)-12f as a light yellow oil (269 mg, 98% yield over 2 steps). LC/MS (10-99%) m/z 275.2 [M+H] + , retention time 1.42 min.

(S)-12f (269 mg, 0.98 mmol) was dissolved in cold DCE (1.5 mL) and treated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (119 mg, 0.98 mmol, 1.0 eq), followed by portion-wise addition of NaBH(OAc) 3 (300 mg, 1.4 mmol, 1.4 eq). The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (1 mL) and allowed to stir for another 30 min (until gas evolution stopped). The crude reaction mixture was purified by HPLC (10-99 CH 3 CN gradient, 0.05% TFA) to provide the desired product (S)-12 g as the TFA salt. LC/MS (10-99%) m/z 381.2 [M+H] + , retention time 2.28 min.

The combined HPLC fractions (˜10 mL) were treated with 10% Pd/C (50 mg, wet, 50% by weight) under H 2 atmosphere with to cleanly provide (S)-12 g after 2 h of rapid stirring at room temperature. The solution was filtered through a 0.2 micron nylon filter and concentrated to provide 114 mg of compound no. 274 TFA salt (23% over 2 steps). LC/MS (10-99%) m/z 383.2 [M+H] + , retention time 2.28 min; 1 H-NMR (HCl salt, 400 MHz, DMSO-d 6 ) δ 10.39 (br s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.25 (m, 4H), 5.11 (m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.45 (m, 2H), 3.09 (m, 4H), 2.64 (m, 2H), 2.33 (br s, 2H), 2.15 (m, 2H), 1.84 (m, 1H), 1.67 (m, 3H), 1.48 (m, 2H), 1.34 (m, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.14 (m, 1H), 0.88 (m, 1H).

Spiroindane (R)- compound no. 274 was produced utilizing an analogous synthetic route with the substitution of (R)-1-phenylethanamine for (S)-1-phenylethanamine in the synthesis of intermediate imine 12b (step 1).

›Example 13

To a flask containing (S,S)-13a (See Example 12, 1.5 g, 3.39 mmol) and K 2 CO 3 (1.87 g, 13.54 mmol, 4 eq) was added 2 mL anhydrous DMF followed by 8 mL anhydrous THF. The mixture was treated with MeI (2.40 g, 16.93 mmol, 5 eq) and heated to 45° C. for 6 h, followed by stirring at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with 20% saturated NH 4 Cl (50 mL), 50% saturated NaHCO 3 (50 mL), brine (50 mL). The solution was dried over Na 2 SO 4 , filtered, and dried in vacuo to yield a reddish oil. The oil was dissolved in diethyl ether and filtered to remove insoluble material, followed by treatment with 1 eq of ethereal HCl. The resulting solution was dried down in vacuo to yield crude (S)-13b as a light orange solid. LC/MS (10-99%) m/z 421.0 [M+H] + , retention time 2.77 min.

Crude (S)-13b was dissolved in CH 2 Cl 2 (50 mL) and cooled to −10° C., followed by the addition of 10 mL TFA. The reaction mixture was stirred at −10° C. for 1 h, diluted with CH 3 CN (20 mL), and dried in vacuo to obtain the (S)-13c TFA salt. The oil was dissolved in CH 2 Cl 2 (30 mL), washed with 50% saturated NaHCO 3 (2×10 mL), brine (10 mL), dried over Na 2 SO 4 , filtered, and dried in vacuo to obtain the product (S)-13c as a colorless oil (673 mg, 67% yield over 2 steps). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.46 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.16-7.25 (m, 5H), 4.66 (t, J=8.0 Hz, 1H), 3.79 (q, J=6.7 Hz, 1H), 2.99 (app t, J=12.0 Hz, 2H), 2.79 (dt, J=12.4, 2.5 Hz, 1H), 2.69 (dt, J=12.7, 2.3 Hz, 1H), 2.07 (q, J=8.0 Hz, 1H), 1.97 (dt, J=13.3, 4.2 Hz, 1H), 1.85 (s, 3H), 1.73 (m, 1H), 1.52 (dt, J=12.7, 4.2 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H), 1.36 (app t, J=12.9 Hz, 3H); LC/MS (10-99%) m/z 321.2 [M+H] + , retention time 1.60 min.

(S)-13c (650 mg, 2.03 mmol) and (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (262 mg, 2.15 mmol) were dissolved in DCE (13 mL) and the mixture cooled to −30° C., followed by portion-wise addition of NaBH(OAc) 3 (646 mg, 3.05 mmol). The reaction was stirred at −30° C. for 2 h and was the allowed to come to room temperature and stirred for 16 h. The reaction was quenched with MeOH (5 mL) and diluted with EtOAc (200 mL). The crude reaction was washed with 50% saturated NaHCO 3 (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over Na 2 SO 4 , filtered and dried in vacuo to yield the product (S)-13d as a colorless oil (802 mg, 93% yield).

(S)-13d (800 mg, 6.8 mmol), ammonium formate (2.36 g, 37.5 mmol), and 800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH (8 mL) in a 25-mL flask fixed with a N 2 balloon. The mixture was stirred at room temperature for 24 h. 1.18 g of ammonium formate were added and the mixture stirred for an additional 24 h. The reaction mixture was filtered through packed Celite, diluted with 50% saturated NaHCO 3 (200 mL), and the product (S)-13e extracted into EtOAc (5×75 mL). The combined extracts were washed with brine (50 mL), dried over Na 2 SO 4 , and concentrated in vacuo to obtain (S)-13e as a colorless oil (493 mg, 81% yield). LC/MS (10-99%) m/z 325.4 [M+H] + , retention time 1.52 min.

(S)-13e (123 mg, 0.38 mmol) was dissolved in 1.5 mL anhydrous CH 3 CN and cooled to 0° C., followed by the additional of acetyl chloride (33 mg, 0.42 mmol) and triethylamine (200 μL). White precipitate formed upon addition of the triethylamine. The reaction was allowed to warm to room temperature and then stirred for 1 h. The crude reaction mixture was purified by HPLC (10-99 CH 3 CN gradient, 0.05% TFA) to provide the desired compound no. 190 as the TFA salt (65 mg, 47% yield). LC/MS (10-99%) m/z 367.2 [M+H] + , retention time 1.99 min.

Spiroindane (R) form of compound no. 190 was produced utilizing an analogous synthetic route with the substitution of (R)-1-phenylethanamine for (S)-1-phenylethanamine in the synthesis of intermediate 13a (See Example 12).

›Example 14

Intermediate 14a (49 mg; 0.2 mmol) and 4-formyl-4-methylpiperidine-1-carboxylate (40 mg; 0.2 mmol) were dissolved in DCE (2 mL) and NaBH(OAc) 3 (85 mg; 0.4 mmol) was added. The reaction was stirred at room temperature for 20 hours. The reaction was diluted with DCM (10 mL) and 1N HCl (20 mL), the layers were separated, and the organic layer was discarded. The aqueous layer was washed with DCM (10 mL) and then was basified with NaOH. The aqueous layer was then washed with EtOAc (3×20 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under high vacuum. The crude product compound no. 314 was purified using reversed-phase chromatography (2-99% CH 3 CN/H 2 O gradient with 0.05% TFA). LC/MS m/z [M+H] + 428.2, retention time 1.85 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min); 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.50 (br s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.27 (m, 4H), 5.35 (m, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.69 (m, 2H), 3.53 (m, 2H), 3.31 (m, 2H), 3.18 (m, 5H), 2.69 (m, 1H), 2.07 (m, 1H), 1.89 (s, 3H), 1.66 (m, 3H), 1.50 (m, 4H), 1.19 (overlapping q and s, 6H).

›Example 15

The mixture of N-Boc protected spiroindanone 15a (20 g, 66.4 mmol) and MeOH/HCl (2.5 mol/L, 100 mL) were stirred overnight. After evaporation the residue was washed by petroleum ether to gave the corresponding amine hydrochloride 15b (15.4 g, 97.6%).

To a solution of compound 15b (5.0 g, 24.84 mmol) and Et 3 N (7.54 g, 74.53 mol) in CH 2 Cl 2 (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 Et 2 O and dried to furnish compound 15c (6.1 g, yield 99%).

A solution of compound 15c (3 g, 10.3 mmol) in EtOH (30 mL) containing NH 2 OH.HCl (1.43 g, 20.6 mmol) and NaOAc (1.52 g, 18.53 mmol) was heated under reflux for 1.5 hours. The solvent was removed by evaporation and the residue was partitioned between CH 2 Cl 2 and water. The organic phase was washed with brine, dried over Na 2 SO 4 , and concentrated to give compound 15d (3.14 g, yield 99%), which could be used directly in the next step.

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 compound 15d (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 saturated Na 2 CO 3 , followed by 1N HCl and brine, dried over Na 2 SO 4 and concentrated. The residue was purified by prep HPLC to obtain compound 15e (260 mg, yield 16%).

The mixture of compound 15e (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 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC twice to give 15f (110 mg, 11%) as a TFA salt. 1 H NMR (CDCl 3 ) δ 7.65 (d, J=7.5 Hz, 1H), 7.29-7.45 (m, 3H), 3.45 (d, J=12.3 Hz, 2H), 3.20 (t, J=12.3 Hz, 2H), 2.96 (s, 2H), 2.10-2.21 (m, 2H), 1.70 (d, J=14.1 Hz, 2H). MS (ESI) m/z 217.06 [M+H] + .

Amine 15f (22 mg, 0.1 mmol) and ethyl 4-formylpiperidine-1-carboxylate (28 mg, 0.15 mmol) were dissolved in DCE (1 mL) and NaBH(OAc) 3 (42 mg; 0.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted methanol (0.5 mL), filtered, and compound no. 34 was purified using reversed-phase chromatography (10-99% CH 3 CN/H 2 O gradient with 0.05% TFA). LC/MS m/z 386.2 [M+H] + , retention time 2.05 min (10-99% CH 3 CN—H 2 O gradient with 0.03% TFA, 5 min); 1 H NMR (free base, 400 MHz, DMSO-d 6 ) δ 7.71 (d, J=3.9 Hz, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.47-7.41 (m, 1H), 4.05-3.96 (m, 4H), 2.86-2.67 (m, 4H), 2.56 (d, J=9.7 Hz, 2H), 2.18 (s, 2H), 2.01 (d, J=7.7 Hz, 4H), 1.73 (d, J=11.1 Hz, 4H), 1.45 (d, J=8.7 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.03-0.96 (m, 2H).

›Example 16

A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. 1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hours. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hours. After cooling to room temperature, the reaction mixture was washed with water, dried over Na 2 SO 4 , and concentrated under reduced pressure to afford 1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.23-7.31 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 3.52 (s, 2H), 3.21 (s, 3H).

A suspension of NaH (60%, 70 g, 0.48 mol) in THF (300 mL) was stirred for 10 min at 0° C. Then a solution of 1-methyl-1,3-dihydro-indol-2-one 16b (70 g, 2.88 mol) in THF (200 mL) was added at 0° C., and the mixture was stirred for 1 hour at room temperature. Benzyl-bis-(2-chloro-ethyl)-amine (129 g, 0.48 mol) was added in portions at 0° C. The mixture was stirred overnight at room temperature, and then was poured into ice-water, extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column on silica gel (P.E./E.A. 2:1) to give compound 16c (24 g, 16.3%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.25-7.42 (m, 7H), 7.02-7.07 (m, 1H), 6.83 (d, J=7.5, 1H), 3.68 (s, 2H), 3.19 (s, 3H), 2.74-2.99 (m, 2H), 2.66-2.72 (m, 2H), 1.93-2.01 (m, 2H), 1.79-1.85 (m, 2H).

To a solution of compound 16c (12 g, 39.2 mmol) in MeOH (100 mL) was added Pd(OH) 2 /C (1.5 g, 20%) under N 2 . The suspension was hydrogenated under H 2 (50 psi) at room temperature for 4.5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the deprotected spiroindolone product 16d (8 g, 94.5%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.46 (d, J=7.2, 1H), 7.23-7.27 (m, 1H), 6.96-7.03 (m, 2H), 3.04-3.14 (m, 5H), 2.83-2.89 (m, 2H), 1.61-1.67 (m, 2H), 1.45-1.51 (m, 2H). MS (ESI) m/z 217.1 [M+H] + .

1.0 eq of deprotected spiroindolone 16d (22 mg, 0.10 mmol) was dissolved in anhydrous 1,2-dichloroethane: 1,2-dimethoxyethane (1.0 mL, 1:1 v/v) and treated with 1.5 N-Carbethoxy-4-tropinone (30 mg, 0.15 mmol), followed by titanium tetraisopropoxide (88 μL, 85 mg, 0.30 mmol). The vial was flushed with nitrogen and stirred at room temperature ˜70 hours. The reaction was then diluted with methanol (1.0 mL), cooled in an ice-H 2 O bath and treated with sodium borohydride (8 mg, 0.20 mmol). After warming to room temperature and stirring for 90 min, the reaction was further diluted with methanol (2.0 mL), quenched with 1.0 N NaOH (500 μL) and stirred vigorously at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in MeOH: acetonitrile (1250 μL, 1:1 v/v), filtered, and purified by reverse-phase HPLC (2-40% CH 3 CN/0.1% TFA gradient over 10 min) to yield product compound no. 149. LC/MS (10-99%) m/z [M+H] + 398.2, retention time 1.93 min.

›Example 17

A suspension of 1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 17a (1.7 g, 5.8 mmol), 10% Pd/C (1 g), and ammonium formate (4.8 g, 76 mmol) in MeOH (50 ml) was stirred under N 2 for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated. The filtrate was dissolved in CH 2 Cl 2 , washed with diluted NaOH, and the aqueous phase was re-extracted with CH 2 Cl 2 . The combined organic phase was dried (Na 2 SO 4 ) and concentrated to give 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 17b. LC-MS: m/e=202.1 (M+H). R t =1.61 min. 1 H-NMR (500 MHz, CDCl 3 ): 9.74 (s, 2H), 7.58 (d, J=7.9, 1H), 7.22 (t, J=7.8, 1H), 7.14 (t, J=7.9, 1H), 7.08 (d, J=8.0, 1H), 3.47 (d, J=12.4, 2H), 3.22-3.18 (m, 2H), 2.88 (t, J=4.9, 2H), 2.81 (t, J=6.2, H), 2.60 (td, 2H), 1.93-1.89 (m, 2H), 1.83-1.77 (m, 2H).

A solution of cyclohexanecarbaldehyde (40 mg, 0.35 mmol) and 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 17b (33 mg, 0.16 mmol) in 1,2-dichloroethane (2 mL) was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and treated with sodium triacetoxyborohydride (44 mg, 0.2 mL), followed by acetic acid (1 drop) and methanol (1 mL). The reaction mixture was stirred for another 5 hours and concentrated under a stream of N 2 . The residue was dissolved in methanol (1 mL) and purified by reverse phase HPLC to give compound no. 802 as a TFA salt. LC-MS: m/e=298.0 (M+H). R t =2.09 min. 1 H-NMR (500 MHz, DMSO-d 6 ): 8.70 (s, 1H), 7.39 (d, 1H), 7.22 (t, 1H), 7.14 (t, 1H), 7.06 (d, 1H), 3.40 (d, 2H), 3.14 (dd, 2H), 3.00 (t, 2H), 2.72 (t, 2H), 2.28 (td, 2H), 1.89-1.87 (m, 2H), 1.83-1.66 (m, 10H), 1.28 (q, 2H), 1.21-1.13 (m, 1H), 1.03-0.96 (m, 2H).

A solution of 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 18a (33 mg, 0.16 mmol) and cycloheptanone (86 mg, 0.76 mmol) in dichloromethane (2 ml) was stirred in a sealed vial for 90 min and treated with titanium (IV) propoxide (60 ul, 0.21 mmol) for 24 hours. Sodium borohydride (10 mg, 0.27 mmol) was added to the reaction mixture and the resulting mixture was stirred for 5 hours then treated with methanol (1 mL) and acetic acid (1 drop) for 1 hour. The solvents were evaporated and the residue was dissolved in methanol (1 ml) and acidified with TFA and purified by HPLC to give compound no. 738. LC-MS: m/z=298.3 (M+H). R t =2.05 min. 1 H-NMR (500 MHz, DMSO-d 6 ): 9.01 (s, H), 7.38 (d, 1H), 7.21 (t, 1H), 7.14 (t, 1H), 7.05 (d, 1H), 3.40 (m, 1H), 3.27-3.17 (m, 4H), 2.72 (t, 2H), 2.26 (td, 2H), 2.12-2.05 (m, 2H), 1.88-1.86 (m, 2H), 1.76-1.67 (m, 8H), 1.57-1.46 (m, 6H).

›Example 18

A solution of (S)—N—(1′-(2-(piperidin-4-yl)ethyl)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-4-yl)acetamide 18a (18 mg, 0.048 mmol), Et 3 N (0.2 ml) in 1,2-dichloroethane (2 ml) was treated acetyl chloride (2 drops, ca. 0.05 ml) for 2 hours. The solvent was evaporated. The residue was dissolved in MeOH (1 ml), acidified with CF 3 COOH and purified with HPLC to give compound no. 832 as a TFA salt. LC-MS: m/z=412.20 (M+H). R t =1.48 min. 1 H-NMR (500 MHz, DMSO-d 6 ): 9.03 (s, 1H), 8.17 (d, 1H), 7.34 (t, 1H), 7.30 (d, 1H), 7.20 (t, 1H), 7.17 (d, 1H), 4.92 (q, 1H), 4.35 (d, 1H), 3.80 (m, 2H), 3.43 (m, 2H), 3.16 (t, 4H), 3.00 (t, 1H), 2.22-2.14 (m, 2H), 2.06 (ddd, 1H), 1.98 (s, 3H), 1.87 (s, 3H), 1.82 (m, 3H), 1.75-1.53 (m, 7H), 1.13 (m, 1H), 1.00 (m, 1H).

›Example 19

Compound no. 364 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CDCl 3 ) δ 1.27 (t, J=6.3 Hz, 3H), 1.56 (d, J=11.5 Hz, 2H), 1.67 (q, J=7.0 Hz, 4H), 1.82 (m, 2H), 1.97 (m, 6H), 2.29 (t, J=11.5 Hz, 2H), 2.82 (m, 1H), 2.89 (dd, J=13.7, 6.5 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 4.35 (d, J=24.4 Hz, 2H), 7.17 (m, 4H).

›Example 20

Compound no. 413 was synthesized using known methods and those described above.

1 H NMR (free base, 400 MHz, DMSO-d 6 ) δ 7.20-7.10 (m, 4H), 4.02 (q, J=7.1 Hz, 2H), 3.99-3.96 (m, 2H), 2.84 (t, J=7.3 Hz, 2H), 2.81-2.77 (m, 4H), 2.16 (d, J=4.9 Hz, 2H), 2.06 (t, J=12.2 Hz, 2H), 1.94 (t, J=7.3 Hz, 2H), 1.80 (t, J=11.3 Hz, 2H), 1.74-1.70 (m, 3H), 1.43 (d, J=12.5 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.02-0.93 (m, 2H).

›Example 21

Compound no. 375 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 6.99 (dt, J=12.8, 4.5 Hz, 1H), 6.91 (dd, J=8.0, 2.7 Hz, 1H), 6.82 (dd, J=8.7, 4.1 Hz, 1H), 6.25 (q, J=2.9 Hz, 1H), 6.07 (q, J=2.7 Hz, 1H), 4.50 (s, 2H), 3.51 (t, J=13.2 Hz, 2H), 3.04-2.96 (m, 3H), 2.91-2.84 (m, 2H), 2.74-2.68 (m, 1H), 2.40-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.88 (d, J=14.2 Hz, 2H), 1.32 (dd, J=33.8, 7.1 Hz, 2H), 0.69 (d, J=11.4 Hz, 1H).

›Example 22

Compound no. 181 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.03 (br s, 1H), 7.21 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 3.41 (m, 2H), 3.25 (m, 1H), 3.01 (m, 2H), 2.63 (m, 2H), 2.44 (m, 1H), 2.27 (m, 1H), 1.86 (m, 4H), 1.51 (m, 3H), 1.39 (m, 2H), 1.24 (m, 1H).

›Example 23

Compound no. 23 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.27 (br s, 1H), 8.53 (br s, 1H), 6.93 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 6.72 (d, J=7.9 Hz, 1H), 3.48 (s, 2H), 3.40 (m, 3H), 3.04 (m, 2H), 2.64 (m, 1H), 2.57 (br s, 1H), 2.38 (m, 1H), 2.26 (m, 1H), 2.24 (s, 3H), 1.94 (m, 2H), 1.78 (m, 2H), 1.55 (m, 3H), 1.39 (m, 3H).

›Example 24

Compound no. 367 was synthesized using known methods and those described above.

1 H-NMR (300 MHz, CDCl 3 ): δ 7.08 (m, 1H), 6.95 (m, 2H), 4.28 (br s, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.62 (m, 2H), 3.00 (m, 2H), 2.91 (m, 2H), 2.49 (m, 3H), 1.95-2.02 (m, 6H), 1.69 (m, 2H), 1.48 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).

›Example 25

Compound no. 370 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.65 (br s, 1H), 8.05 (dd, J=8.9, 4.9 Hz, 1H), 7.06 (td, J=9.0, 2.7 Hz, 1H), 6.92 (dd, J=8.3, 2.7 Hz, 1H), 4.27 (br s, 2H), 4.08 (m, 4H), 3.74 (m, 1H), 3.55 (br s, 2H), 3.06 (m, 2H), 2.30 (m, 2H), 2.20 (s, 3H), 2.07 (m, 2H), 1.86 (m, 6H), 1.67 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).

›Example 26

Compound no. 422 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.61 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.96 (s, 1H), 4.06 (s, 2H), 3.96 (m, 3H), 3.59 (s, 3H), 3.51 (m, 2H), 3.11 (m, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.83 (br s, 2H), 2.47 (m, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 2.11 (m, 1H), 1.88 (m, 2H), 1.77 (m, 2H), 1.13 (m, 2H).

›Example 27

Compound no. 92 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.97 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.95 (s, 1H), 4.13 (m, 2H), 4.06 (m, 4H), 3.45 (m, 3H), 3.12 (m, 2H), 2.83 (br s, 2H), 2.43 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.17 (m, 2H), 1.82 (m, 2H), 1.64 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

›Example 28

Compound no. 412 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 8.05 (q, J=4.6 Hz, 1H), 7.06 (dt, J=12.9, 4.5 Hz, 1H), 6.94 (dd, J=8.3, 2.6 Hz, 1H), 4.13-4.09 (m, 4H), 4.05 (q, J=7.1 Hz, 2H), 3.50-3.39 (m, 3H), 3.13 (q, J=11.4 Hz, 2H), 2.83 (bs, 2H), 2.46 (t, J=13.5 Hz, 2H), 2.20 (s, 3H), 2.16 (d, J=11.6 Hz, 2H), 1.88 (d, J=13.8 Hz, 2H), 1.67-1.59 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

›Example 29

Compound no. 361 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 1.22 (t, J=7.2 Hz, 3H), 1.66 (d, J=6.5 Hz, 2H), 1.87 (m, 6H), 2.05 (s, 2H), 2.21 (t, J=12.3 Hz, 2H), 2.87 (s, 6H), 3.05 (m, 2H), 3.52 (d, J=11.6 Hz, 2H), 3.73 (m, 1H), 3.84 (s, 2H), 4.08 (q, J=7.1 Hz, 2H), 4.26 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (m, 2H), 10.38 (br s, 1H).

›Example 30

Compound no. 39 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.25 (t, J=7.1 Hz, 3H), 1.66 (qd, J=12.3, 4.5 Hz, 2H), 1.98 (s, 2H), 2.10 (d, J=11.8 Hz, 2H), 2.28 (td, J=14.2, 3.7 Hz, 2H), 2.81 (t, J=15.9 Hz, 2H), 2.92 (s, 6H), 3.08 (q, J=11.3 Hz, 2H), 3.38 (dd, J=13.4, 10.5 Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.26 (d, J=12.1 Hz, 2H), 6.97 (m, 3H).

›Example 31

Compound no. 91 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 0.96 (t, J=7.4 Hz, 3H), 1.66 (m, 4H), 1.98 (s, 2H), 2.10 (d, J=11.3 Hz, 2H), 2.28 (dt, J=19.9, 7.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.2 Hz, 2H), 3.38 (t, J=12.2 Hz, 1H), 3.52 (d, J=11.9 Hz, 2H), 3.87 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 4.27 (d, J=12.8 Hz, 2H), 6.97 (m, 3H).

›Example 32

Compound no. 54 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.24 (d, J=6.2 Hz, 6H), 1.65 (dq, J=12.3, 4.5 Hz, 2H), 1.99 (s, 2H), 2.09 (d, J=11.9 Hz, 2H), 2.25 (td, J=14.2, 3.7 Hz, 2H), 2.81 (t, J=11.4 Hz, 2H), 2.93 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.39 (m, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.26 (d, J=12.8 Hz, 2H), 4.86 (heptet, J=6.2 Hz, 1H), 6.98 (m, 3H).

›Example 33

Compound no. 208 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.67 (dq, J=12.2, 4.2 Hz, 2H), 2.15 (m, 4H), 2.27 (t, J=14.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.39 (t, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 2H), 3.82 (m, 6H), 3.87 (s, 2H), 4.25 (d, J=11.2 Hz, 2H), 5.19 (s, 1H), 6.96 (m, 3H).

›Example 34

Compound no. 120 was synthesized using known methods and those described above.

›Example 35

Compound no. 48 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.69 (dq, J=12.3, 4.1 Hz, 2H), 1.99 (s, 2H), 2.12 (d, J=11.5 Hz, 2H), 2.28 (t, J=14.1 Hz, 2H), 2.87 (brs, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.40 (t, J=11.9 Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.27 (m, 3H), 4.34 (m, 1H), 4.56 (t, J=3.9 Hz, 1H), 4.68 (t, J=3.9 Hz, 1H), 6.97 (m, 3H).

›Example 36

Compound no. 352 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.68 (qd, J=12.3, 4.5 Hz, 2H), 1.85 (t, J=2.3 Hz, 3H), 1.98 (s, 2H), 2.12 (d, J=12.1 Hz, 2H), 2.30 (td, J=14.1, 3.7 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.0 Hz, 2H), 3.39 (t, J=12.1 Hz, 1H), 3.51 (d, J=11.8 Hz, 2H), 3.87 (s, 2H), 4.25 (br s, 2H), 4.65 (d, J=2.1 Hz, 2H), 6.98 (m, 3H).

›Example 37

Compound no. 127 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.68 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H), 2.11 (d, J=12.3 Hz, 2H), 2.27 (m, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H), 2.85 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.1 Hz, 2H), 3.39 (t, J=11.9 Hz, 1H), 3.51 (d, J=12.4 Hz, 2H), 3.87 (s, 2H), 4.15 (t, J=6.6 Hz, 2H), 4.26 (d, J=13.2 Hz, 2H), 6.97 (m, 3H).

›Example 38

Compound no. 264 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.67 (qd, J=12.3, 4.3 Hz, 2H), 1.99 (s, 2H), 2.11 (d, J=10.6 Hz, 2H), 2.29 (t, J=14.1 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=10.9 Hz, 2H), 3.34 (s, 3H), 3.40 (t, J=6.6 Hz, 1H), 3.52 (d, J=6.3 Hz, 2H), 3.57 (t, J=4.6 Hz, 2H), 3.86 (s, 2H), 4.18 (dd, J=5.1, 4.0 Hz, 2H), 4.26 (d, J=12.7 Hz, 2H), 6.96 (m, 3H).

›Example 39

Compound no. 172 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H), 2.14 (d, J=14.4 Hz, 2H), 2.22 (s, 3H), 2.35 (td, J=14.2, 3.4 Hz, 2H), 2.89 (br s, 2H), 3.10 (q, J=10.6 Hz, 2H), 3.41 (t, J=11.4 Hz, 1H), 3.53 (d, J=12.6 Hz, 2H), 4.06 (s, 2H), 4.28 (m, 2H), 4.35 (t, J=4.0 Hz, 1H), 4.57 (t, J=4.0 Hz, 1H), 4.69 (t, J=4.0 Hz, 1H), 7.01 (m, 2H), 8.14 (dd, J=8.8, 4.9 Hz, 1H).

›Example 40

Compound no. 102 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.85 (t, J=2.4 Hz, 3H), 1.99 (s, 2H), 2.13 (d, J=12.2 Hz, 2H), 2.22 (s, 3H), 2.35 (td, J=14.1, 3.6 Hz, 2H), 2.88 (br s, 2H), 3.09 (q, J=11.2 Hz, 2H), 3.40 (t, J=12.0 Hz, 1H), 3.53 (d, J=12.7 Hz, 2H), 4.06 (s, 2H), 4.26 (br s, 2H), 4.66 (d, J=2.2 Hz, 2H), 6.99 (td, J=9.0, 2.7 Hz, 1H), 7.05 (dd, J=8.6, 2.6 Hz, 1H), 8.14 (dd, 8.7, 4.8, 1H).

›Example 41

Compound no. 62 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.70 (qd, J=12.2, 4.3 Hz, 2H), 1.99 (s, 2H), 2.13 (d, J=11.1 Hz, 2H), 2.22 (s, 3H), 2.27 (t, J=2.6 Hz, 1H), 2.36 (td, J=14.0, 3.5 Hz, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H), 2.87 (br s, 2H), 3.09 (q, J=10.4 Hz, 2H), 3.40 (t, J=12.1 Hz, 1H), 3.53 (d, J=12.3 Hz, 2H), 4.06 (s, 2H), 4.16 (t, J=6.6 Hz, 2H), 4.28 (d, J=12.6 Hz, 2H), 6.99 (td, J=9.0, 2.6 Hz, 1H), 7.05 (dd, J=8.6, 2.6 Hz, 1H), 8.13 (dd, J=8.8, 4.9 Hz, 1H).

›Example 42

Compound no. 32 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.72 (d, J=7.3 Hz, 2H), 1.91 (d, J=2.5 Hz, 2H), 1.99 (s, 2H), 2.10 (m, 2H), 2.31 (td, J=14.0, 3.7 Hz, 2H), 2.91 (s, 6H), 2.96 (m, 2H), 3.36 (m, 2H), 3.57 (d, J=12.4 Hz, 2H), 3.63 (br s, 1H), 3.84 (s, 2H), 4.29 (t, J=4.0 Hz, 1H), 4.37 (m, 3H), 4.58 (t, J=3.9 Hz, 1H), 4.70 (t, J=3.9 Hz, 1H), 6.96 (m, 3H).

›Example 43

Compound no. 200 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.72 (d, J=7.2 Hz, 2H), 1.85 (t, J=2.4 Hz, 3H), 1.98 (m, 4H), 2.11 (m, 2H), 2.30 (td, J=14.0, 3.6 Hz, 2H), 2.91 (s, 6H), 2.96 (br s, 2H), 3.08-3.72 (m, 5H), 3.84 (s, 2H), 4.37 (s, 2H), 4.67 (d, J=16.6 Hz, 2H), 6.96 (m, 3H).

›Example 44

Compound no. 229 was synthesized using known methods and those described above.

1 H NMR (400 MHz, CD 3 CN) δ 1.66 (br s, 2H), 1.84 (br s, 2H), 1.92 (br s, 2H), 1.98 (br s, 2H), 2.23 (m, 3H), 2.50 (dd, J=6.4, 2.5 Hz, 2H), 2.84 (s, 6H), 2.93 (m, 2H), 3.08 (m, 2H), 3.50 (d, J=10.9 Hz, 2H), 3.65 (br s, 1H), 3.77 (s, 2H), 4.11 (s, 2H), 4.30 (s, 2H), 6.90 (m, 3H).

›Example 45

Compound no. 165 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) d 9.73 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.74 (q, J=1.3 Hz, 1H), 7.65 (q, J=2.6 Hz, 1H), 7.60 (dd, J=8.4, 1.7 Hz, 1H), 7.49 (dd, J=5.0, 1.2 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 4.16-4.10 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.56-3.49 (m, 3H), 3.19 (q, J=11.3 Hz, 2H), 2.85 (br s, 2H), 2.28-2.23 (m, 5H), 2.10 (d, J=12.9 Hz, 2H), 1.96 (d, J=13.9 Hz, 2H), 1.66-1.57 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

›Example 46

Compound no. 406 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J=10.3 Hz, 1H), 5.78-5.69 (m, 1H), 4.15-4.10 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58-3.49 (m, 3H), 3.16 (q, J=10.8 Hz, 2H), 2.84 (br s, 2H), 2.21 (s, 3H), 2.16-2.07 (m, 4H), 1.93 (d, J=13.9 Hz, 2H), 1.87 (d, J=7.2 Hz, 3H), 1.63-1.55 (m, 2H), 1.20 (t, J=7.1 Hz, 3H

›Example 47

Compound no. 158 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.40 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.27 (m, 4H), 5.34 (m, 1H), 3.40 (m, 3H), 3.13 (m, 1H), 2.97 (m, 2H), 2.65 (m, 1H), 2.57 (br s, 1H), 2.30 (m, 2H), 1.97 (m, 2H), 1.88 (s, 3H), 1.65 (m, 4H), 1.46 (m, 5H).

›Example 48

Compound no. 182 was synthesized using known methods and those described above.

1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.43 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.28 (m, 4H), 5.34 (m, 1H), 3.96 (br m, 2H), 3.59 (s, 3H), 3.50 (m, 2H), 3.07 (m, 4H), 2.72 (m, 4H), 2.28 (m, 1H), 2.08 (m, 1H), 1.88 (s, 3H), 1.85 (m, 2H), 1.66 (m, 3H), 1.12 (m, 2H).

›Example 49

Compound no. 358 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.34-7.31 (m, 1H), 7.27 (dt, J=10.1, 3.7 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 5.33 (q, J=7.8 Hz, 1H), 4.26 (m, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.77-3.70 (m, 1H), 3.52 (t, J=13.0 Hz, 2H), 3.06 (q, J=11.5 Hz, 1H), 2.97 (q, J=11.8 Hz, 1H), 2.61 (dd, J=13.2, 8.0 Hz, 1H), 2.54-2.47 (m, 1H), 2.15-2.04 (m, 3H), 1.91-1.81 (m, 7H), 1.71-1.66 (m, 5H), 1.22 (t, J=7.1 Hz, 3H).

›Example 50

Compound no. 191 was synthesized using known methods and those described above.

1 H NMR (free base, 400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4, 3.8 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 4.03 (q, J=7.1 Hz, 4H), 2.94-2.88 (m, 2H), 2.79 (s, 2H), 2.72-2.66 (m, 2H), 2.58-2.51 (m, 1H), 1.82-1.75 (m, 4H), 1.64-1.59 (m, 2H), 1.43-1.33 (m, 2H), 1.18 (t, J=7.1 Hz, 3H).

›Example 51

Compound no. 199 was synthesized using known methods and those described above.

1 H NMR ((free base, 400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.17 (dt, J=10.5, 3.8 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 4.18 (m, 2H), 4.05 (q, J=6.5 Hz, 2H), 2.94-2.84 (m, 3H), 2.63 (t, J=8.1 Hz, 2H), 1.97-1.83 (m, 3H), 1.78-1.70 (m, 5H), 1.62-1.58 (m, 4H), 1.19 (t, J=7.1 Hz, 3H).

›Example 52

Compound no. 318 was synthesized using known methods and those described above.

Compound was prepared using reductive amination conditions described above. 1 H NMR ((free base, 400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 7.46 (d, J=7.4 Hz, 1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4, 3.8 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.97 (m, 2H), 2.82-2.77 (m, 4H), 2.56-2.52 (m, 1H), 2.27 (d, J=6.8 Hz, 2H), 1.84-1.72 (m, 5H), 1.63-1.59 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.04-0.94 (m, 2H).

›Example 53

Compound no. 104 was synthesized using known methods and those described above.

1 H NMR (free base, 400 MHz, DMSO-d 6 ) δ 7.74-7.68 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.46-7.42 (m, 1H), 6.17-6.15 (m, 1H), 5.97-5.95 (m, 1H), 2.95-2.76 (m, 4H), 2.55 (s, 2H), 2.36-2.28 (m, 1H), 2.09-1.99 (m, 6H), 1.87-1.81 (m, 1H), 1.45 (d, J=3.9 Hz, 2H), 1.34-1.20 (m, 2H), 0.55-0.51 (m, 1H)

›Example 54

Compound no. 186 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.44 (br s, 1H), 7.07-6.95 (m, 2H), 6.85-6.82 (m, 1H), (tt, J=28.8, 18.1 Hz, 1H), 4.51 (s, 2H), 4.40-4.31 (m, 4H), 3.74 (q, J=5.5 Hz, 1H), 3.59-3.40 (m, 4H), 2.98 (q, J=10.8 Hz, 2H), 2.07-1.93 (m, 8H), 1.68 (d, J=5.5 Hz, 4H).

›Example 55

Compound no. 275 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (br s, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.16 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 4.11 (t, J=5.1 Hz, 2H), 3.38-3.34 (m, 2H), 3.25-3.13 (m, 3H), 2.31-2.23 (m, 2H), 2.08-2.04 (m, 4H), 1.85 (d, J=13.7 Hz, 4H), 1.63 (d, J=12.6 Hz, 1H), 1.49-1.39 (m, 2H), 1.34-1.29 (m, 2H), 1.21 (m, 1H)

›Example 56

Compound no. 258 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 9.20 (bs, 1H), 7.30-7.15 (m, 2H), 7.07-6.87 (m, 2H), 3.65-3.35 (m, 5H), 2.66-2.64 (m, 1H), 2.40-2.30 (m, 3H), 2.07-1.98 (m, 1H), 1.92 (d, J=14.7 Hz, 1H), 1.79 (d, J=14.3 Hz, 1H), 1.68-1.51 (m, 3H), 1.47-1.38 (m, 3H), 1.27-1.20 (m, 1H).

›Example 57

Compound no. 152 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.41 (br s, 1H), 7.04-6.93 (m, 2H), 6.84-6.80 (m, 1H), 4.53 (s, 2H), 3.47 (d, J=12.1 Hz, 1H), 3.40-3.38 (m, 1H), 3.24-3.17 (m, 1H), 3.06 (q, J=11.3 Hz, 2H), 2.19-2.11 (m, 2H), 2.05 (d, J=10.2 Hz, 2H), 1.94 (d, J=14.1 Hz, 2H), 1.84 (d, J=12.9 Hz, 2H), 1.63 (d, J=12.5 Hz, 1H), 1.46-1.23 (m, 4H), 1.17-1.07 (m, 1H).

›Example 58

Compound no. 288 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (br s, 1H), 7.05-6.92 (m, 2H), 6.85-6.80 (m, 1H), 6.34-6.31 (m, 1H), 4.50 (s, 2H), 4.33 (d, J=13.4 Hz, 2H), 3.83-3.74 (m, 1H), 3.67-3.51 (m, 3H), 2.95 (q, J=1.0 Hz, 2H), 2.07-1.85 (m, 8H), 1.74-1.58 (m, 4H), 1.08 (d, J=6.6 Hz, 6H).

›Example 59

Compound no. 211 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 7.65 (br s, 1H), 7.06-6.95 (m, 2H), 6.85-6.80 (m, 1H), 5.18 (s, 1H), 4.51 (s, 2H), 4.25 (s, 2H), 3.81-3.71 (m, 5H), 3.58 (d, J=12.1 Hz, 2H), 2.98-2.93 (m, 2H), 2.13-1.94 (m, 10H), 1.65 (d, J=7.4 Hz, 4H).

›Example 60

Compound no. 156 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.56 (br s, 1H), 7.06-6.95 (m, 2H), 6.86-6.80 (m, 1H), 4.51 (s, 2H), 4.26 (s, 2H), 3.57-3.44 (m, 6H), 2.97 (q, J=11.1 Hz, 2H), 2.08-2.02 (m, 4H), 1.94 (d, J=13.5 Hz, 4H), 1.70-1.65 (m, 4H).

›Example 61

Compound no. 181 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (br s, 1H), 7.21 (dd, J=8.5, 2.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 3.47-3.21 (m, 3H), 3.10-2.94 (m, 2H), 2.66-2.40 (m, 3H), 2.27 (s, 1H), 1.96-1.83 (m, 4H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 3H).

›Example 62

Compound no. 178 was synthesized using known methods and those described above.

1 H NMR (400 MHz, DMSO-d 6 ) δ 9.42 (br s, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.18-7.16 (m, 1H), 6.84-6.81 (m, 1H), 4.14-3.99 (m, 2H), 3.46 (d, J=12.1 Hz, 4H), 3.36-3.31 (m, 2H), 3.20-3.11 (m, 3H), 2.28-2.20 (m, 2H), 2.07-2.00 (m, 4H), 1.88 (d, J=14.4 Hz, 2H), 1.75-1.64 (m, 2H).

›Example 63

Physical Characteristics of Compounds of Formulae (I and II)

Additional compounds having the structures shown in Table 2 were synthesized using known methods and those described above.

›Example 62 · 1 of 2

Assays

Functional Mobilization of Intracellular Calcium to Determine Muscarinic Receptor Activity:

CHO cells expressing muscarinic receptors (M 1 to M 5 ) are grown as monolayers in tissue culture flasks at 37° C. in a humidified atmosphere containing 5% CO 2 and passaged every 3-5 days. The growth media is Dulbecco's modified eagles medium (DMEM, Gibco Cat# 12430-054), containing 25 mM Hepes and supplemented with Fetal Bovine Serum (Hyclone, cat# SH30071.03), 0.1 mM of MEM non-essential amino acids (GIBCO, Cat# 11140-050), 1 mM MEM Sodium Pyruvate (GIBCO Cat# 11360-070) and 100 units/ml of Penicillin G and 100 μg/ml of Streptomycin (GIBCO Cat# 15140-122). The recombinant muscarinic receptor cell lines are grown under antibiotic pressure with media containing 25 μg/ml zeocin and 500 μg/ml G418 (M1-CHO), 4 μg/ml puromycin, 50 μg/ml zeocin and 2.5 μg/ml blasticidin (M2 and M4-CHO) or 50 μg/ml zeocin and 4 μg/ml puromycin (M3 and M5-CHO).

Cells are harvested at 80-90% confluence using Versene (GIBCO Cat# 15040-066), collected by centrifugation and seeded 18-24 hrs prior to running the calcium assay at a density of 5,000 cells/well in back-walled, clear-bottomed 384-well plates (BD Biocoat, poly-D-lysine, Cat#356663). The day of the experiment, the cells are washed with a plate washer (Bioteck Instruments, ELX 405) using bath 1 buffer (140-mM NaCl, 4.5-mM KCl, 2-mM CaCl 2 , 1-mM MgCl 2 , 10-mM Hepes-Na, 10-mM Glucose, pH 7.4, with NaOH) containing 1 mM Probenecid. Next, the calcium dye Fluo-3 (25 μl/well of Fluo-3 AM at 4 μM, Molecular Probes F-1241, in Bath 1 buffer containing 1 mM Probenecid) is added to the 25 μl of Bath 1 remaining in each well after the plate wash and the dye is loaded at 37° C. in the tissue culture incubator for 60-90 min. The fluorescent dye is removed using the plate washer with Bath 1 containing 1 mM Probenecid, leaving 25 μl/well of this solution after the wash. Alternatively, cells can be loaded with the calcium indicator from Molecular Devices (Calcium 3 Assay Reagents, Cat # R7181) adding 5 μl of a 5× solution dye in Bath 1 containing 1 mM Probenecid (10 ml per dye flask cat# R7182 to generate a solution 20×) to 20 μl of the same buffer. After loading for 60 min, the experiment can be run without having to remove the dye.

Compounds are prepared at a 2× fold concentration in a 96-well plate (round bottom, Costar Corning cat# 3656), by reconstituting the pre-spotted compounds in bath 1 containing 1 mM probenecid. The final concentration DMSO is 0.5%, and the amount of DMSO is normalized across the assay plate. To determine an agonist action of the compounds on muscarinic receptors, the reconstituted compounds are added (25 μl compound/well) to the cell assay plate (containing 25 μl/well) using the multi-channel robotic system of the FLIPR 3 Instrument (Molecular Devices, Sunnyvale, Calif.). To determine a functional inhibitory action of the compounds on muscarinic receptors, the reconstituted compounds are added (25 μl compound/well) to the assay plate and pre-incubated for 15 min prior to adding 25 μl of Carbachol at 3× the EC80 for each muscarinic subtype. Alternatively, the compounds can be co-applied simultaneously with the agonist. In both assay modes, the fluorescence is recorded for 60 sec (excitation wavelength is 488 nM and emission wavelength 540 nm) using the FLIPR 3 instrument.

The potency, efficacy and selectivity of the muscarinic compounds were evaluated by screening the compound activity across the whole family (M 1 to M 5 cells). Compounds were also screened for activity on other proteins such as other GPCRs and ion channels to determine selectivity on M4 receptors.

The compounds of the present invention were found to modulate the M 1 and/or M 4 muscarinic receptors selectively over the other receptor types.

Examples of activities and efficacies of the muscarinic compounds of formulae (I and II) on modulating M 1 and M 4 receptors are shown below in Table 2. The compound activity for the M 1 and M 4 receptor is illustrated with “xxx” if activity was measured to be less than 0.1 μM, “xx” if activity was measured to be between 0.1 μM and 1.0 μM, and “x” if activity was measured to be greater than 1.0 μM. The efficacy for M 1 and M 4 modulation is illustrated with “xxx” if efficacy was calculated to be greater than 85%, “xx” if efficacy was calculated to be between 85% and 65%, and “x” if efficacy was calculated to be less than 65%.

Table 2. Compound activities and efficacies for modulating M 1 and M 4 receptors

Additional examples of activities and efficacies of the muscarinic compounds of formulae (I and II) on modulating M 1 and M 4 receptors are shown below in Table 4. The compound activity for the M 1 and M 4 receptor is illustrated with “xxx” if activity was measured to be less than 2.0 μM, “xx” if activity was measured to be between 2.0 μM and 5.0 μM, and “x” if activity was measured to be greater than 5.0 μM. The efficacy for M 1 and M 4 modulation is illustrated with “xxx” if efficacy was calculated to be greater than 100%, “xx” if efficacy was calculated to be between 100% and 25%, “x” if efficacy was calculated to be less than 25%, and “−” if no data was available. It should be noted that 100% efficacy is the maximum response obtained with the Carbachol control.

Additional examples of activities and efficacies of the muscarinic compounds of formulae (I and II) on modulating M 1 and M 4 receptors are shown below in Table 5. The compound activity for the M 1 and M 4 receptor is illustrated with “xxx” if activity was measured to be less than 2.0 μM, “xx” if activity was measured to be between 2.0 μM and 10 μM, and “x” if activity was measured to be greater than 10 μM. The efficacy for M 1 and M 4 modulation is illustrated with “xxx” if efficacy was calculated to be greater than 100%, “xx” if efficacy was calculated to be between 100% and 25%, “x” if efficacy was calculated to be less than 25%, and “−” if no data was available. It should be noted that 100% efficacy is the maximum response obtained with the Carbachol control.

›Example 62 · 2 of 2

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

›Tables in the description — 4

TABLE 2 — Physical Characteristics of Compounds in Table 1.

Cmd	LCMS	LCMS
No.	Plus	RT	NMR
2	327.3	2.8
3	309	1.88
4	379.2	1.99
5	306.2	2.32
6	476.2	2.34
7	309.4	1.93
8	353.3	2.16
9	426.2	1.94
10	519.4	1.92
11	412.2	1.98
12	397.5	2.48
13	328.2	2.05
14	460.5	2.13
15	369.2	2.19
16	508.5	2.2
17	458.4	2.35
18	286	2.13
19	378.2	1.94
20	336.4	2.23
21	484.2	2.2
22	459.4	2.04
23	297.4	1.26
24	524.5	2.44
25	496.5	2.35
26	448.5	2.18
27	359.2	2.09
28	502.2	2.15
29	367.2	2.31
30	462.4	2.53
31	372.2	1.83
32	477.2	2.2
33	476.5	2.29
35	357.2	1.99
36	428.2	2.08
37	307.2	1.01
38	464.2	2.1
39	433.2	2.14
40	546.4	2.53
41	496.4	2.28
42	389.2	2.22
43	411.4	2.31
44	496.5	2.31
45	496.4	2.29
46	414.5	2.26
47	472.3	2.08
48	451.2	2.1
49	476.2	2.08
50	510.5	2.12
51	365.2	2.11
52	345.2	1.91
53	480.2	2.35
54	447.2	2.22
55	381.2	2.21
56	398.2	2.07
57	498.5	2.28
59	514.4	2.2
60	418.3	2.22
61	400.5	1.89
62	428.2	2.12
63	476.4	2.63
65	448.2	1.77
66	550.4	2.6
67	472.3	2.06
68	395	2.6
69	512.5	2.41
70	387.2	2.02
71	414.2	1.98
72	325.5	1.94
73	510.3	2.4
74	428.2	2.19
75	347	1.57
76	460.5	2.11
77	484.2	2.3
78	476	2.34
79	418.3	2.24
80	532.5	2.33
81	410.3	2.27
82	460.5	2.12
83	526.6	2.09
84	480.2	2.28
85	331.3	1.98
87	498.5	2.29
88	483.3	2.15
89	547.4	2.49
90	490.4	2.16
91	447.2	2.23
92	400.3	2.16
93	544.5	2.29
94	444.5	2.29
95	399.2	2.31
96	488.7	2.25
97	460.5	2.95
98	432.5	2.33
99	405.2	2.36
100	467.4	2.41
101	351.2	2.11
102	428.2	2.18
103	466.4	2.09
104	308.2	2.08
105	463.4	1.45
106	516.5	2.61
107	377.4	2.29
108	473.4	2.35
109	384.3	1.72
110	297.5	1.7
111	315.3	1.65
112	544.5	2.3
113	390.2	1.76
114	448.4	2.37
115	516.5	2.51
116	397.3	2.59
117	520.5	2.33
118	353.4	2.62
120	475.2	2.05
122	492.5	2.53
123	415.2	2.29
124	443	2.33
125	528.3	2.6
126	462.4	2.23
127	457.4	2.19
128	452.2	2.06
129	404.5	2.09
130	501.3	2.21
131	373.2	2.31
132	404.4	1.76
133	429	2.39
134	399.2	2.02
135	333.2	1.47
136	430.2	2.07
137	414.4	1.99
138	339.3	1.97
139	398.2	2.21
140	430.5	2.29
141	420.2	1.95
142	432.4	2.08
143	341.2	1.78
144	467.4	1.78
145	448.2	2.36
146	480.2	2.24
148	494.5	2.56
150	492.4	2.25
151	426.3	2.32
152	290	2.16
153	370.3	1.6
154	419.2	2.03
155	305.2	1.88
156	375	1.92
157	319.2	2
158	339.3	1.92
159	341.3	2.96
160	417.5	2.35
161	353.3	2.25
162	532.5	2.33
163	343	2.03
164	344	2.56
165	468.2	1.16
166	500.5	2.78
167	446.4	2.12
168	436.2	1.84
169	495.4	2.27
170	480.3	2.93
171	339.3	1.92
172	422.2	2
173	420.2	2.07
174	456.5	2.4
175	302.3	2.16
176	393.2	2.42
177	540.4	2
178	322.4	2.17
179	470.5	2.51
180	351.3	2.22
181	318	2.38
182	400.2	1.86
183	313	1.46
184	341.2	1.87
185	351.4	1.86
186	425	2.15
187	331	1.89
188	501.3	2.19
189	552.6	2.52
191	358	1.68
192	488.3	2.25
193	492.4	2.25
194	460.4	2.49
195	516.5	2.56
196	327.2	1.62
197	525.6	2.44
198	544.5	2.3
199	384.2	2.06
200	483.4	2.35
202	432.5	2.31
203	388.2	2.12
204	302.3	2.14
205	412	1.86
206	329.5	0.92
207	316.2	2.45
208	406.4	2.29
209	475.2	2.04
210	345.2	1.94
211	419.4	2.12
212	431.4	1.96
213	351.2	2.11
214	456.5	2.38
215	491.2	2.25
216	532.5	2.33
217	410.2	2.26
218	351.2	2.11
219	388.2	2.04
220	462.4	2.54
221	504.4	2.14
222	510.4	2.35
223	461.4	2.24
224	317	1.8
225	470.5	2.43
226	373	2.23
227	389.2	2.28
228	403.2	1.93
229	446.2	2.21
230	483.4	2.3
232	375	2.08
233	552.5	2.25
234	463.2	1.49
235	432.5	2.24
236	399.2	2.03
238	308.2	2.09
239	303.3	1.73
240	345.2	2.28
241	NA	NA
242	313.2	1.88
243	544.5	2.31
244	297.5	1.59
245	426.2	2.05
246	395.2	2.28
247	431.5	2.46
248	359.2	2.08
249	418.4	1.98
250	414.4	1.91
251	357.2	1.99
252	414.5	2.35
253	487.4	2.18
254	444.4	2.23
255	459.4	2.02
256	434.4	2.05
257	308.2	2.09
258	409.2	2.68
259	297.2	1.78
260	467.4	1.74
261	355.4	1.94
262	496.4	2.25
263	294.4	2.33
264	297.4	1.24
265	463.2	2.04
266	432.4	2.04
267	484.2	2.27
268	333.5	1.84
269	418.3	2.23
270	446.4	2.29
271	424.2	2.38
272	283.3	1.34
273	403.4	2.17
275	383	2.47
276	320.2	2.37
278	411.2	2.12
279	442.5	2.08
280	341.2	1.85
281	472.4	2.44
282	446.4	2.24
283	403.5	2.21
284	434.5	2.05
285	383.2	2.53
286	417.5	2.36
287	474.3	2.58
288	336.4	2.17
289	402.4	2.16
290	475.2	1.89
291	339.5	0.51
292	392.2	2.13
293	430.5	2.14
294	480.5	2.48
295	530.2	2.55
296	473.4	2.11
297	516.5	2.65
298	526.6	2.57
299	291	0.45
300	316.2	1.44
301	426.2	1.98
302	484.5	2.61
303	432.5	2.13
304	532.3	2.31
305	351.3	2.22
306	428.5	2.38
307	418.4	1.84
309	418.4	1.9
310	388.5	1.66
311	486.5	2.3
313	294	2.33
315	428	1.85
316	428.2	1.95
317	418.6	1.97
318	426.3	2.1
319	372.2	1.79
320	403.2	2.23
321	457.2	2.07
322	430.2	1.94
323	339.1	1.92
324	432.4	2.14
325	289.2	0.77
326	383.2	2.3
327	386	1.92
328	331.2	2.11
329	500.3	2.86
330	480.2	2.38
331	467.4	2.01
332	397.27	1.79
333	319.2	1.86
334	313	2.01
335	484.2	2.34
336	426	1.96
337	353.2	1.84
338	431.4	1.97
339	367.3	2.3
340	416.2	1.76
341	347	2.41
342	285.3	1.65
343	316.8	1.64
344	502.4	2.17
345	470.5	2.48
346	458.4	2.35
347	397.2	2.47
348	331.3	1.96
349	494.3	2.3
350	297.3	1.04
351	404.5	1.9
352	344	0.7
353	457.4	2.22
354	437.2	2.48
355	411.4	2.31
356	417.4	1.94
357	403	2.19
358	341.2	1.77
359	426	1.79
360	473.4	2.35
361	516.5	2.5
362	459.2	1.96
363	445.3	2.08
364	424	1.8
365	369.2	2.41
366	369.2	2.14
367	355.2	2.02
368	401.25	1.75
369	332.2	2.4
370	452.2	2.19
371	430.2	1.94
372	313.1	1.55
373	487.4	2.19
374	390.3	1.98
375	271.2	0.59
376	314	2.39
377	315.3	1.66
378	419.2	1.97
379	482.5	2.55
380	414.5	2.28
381	404.4	1.75
382	411.4	2.75
383	452.3	2.17
384	466.4	2.23
385	369	2.19
386	460.5	2.51
387	331	1.78
388	508.5	2.21
389	470.5	2.5
390	458.5	2.12
391	420.3	2.08
392	351.2	2.11
393	345.2	2.03
394	408.2	1.72
395	432.4	2.01
396	502.2	2.34
397	311.3	1.72
398	442.5	2.08
399	428.2	2.06
400	368	1.97
401	510.4	2.27
402	516.5	2.51
403	456.5	2.17
404	428.3	2.36
405	504.5	2.53
406	505.4	1.81
407	426	2.1
408	351.2	2.11
409	486.5	2.7
410	484.2	2.3
411	552.5	2.25
412	444.4	1.81
413	404.5	2.11
414	357.2	2.39
415	322.4	2.15
416	301.2	1.23
417	446.2	2.04
418	446.3	2.02
419	444.5	2.18
420	297.5	1.61
421	351.2	2.11
422	504.5	2.51
423	400.5	2.16
424	446.3	2.01
425	399.2	2.31
426	452.4	2.28
427	434.4	2.21
428	476.2	2.09
429	316.2	1.4
430	400.3	1.88
431	422.2	1.78
432	381.2	2.38
433	463.2	2.19
434	492	2.2
435	455.2	1.78
436	356.3	1.6
437	329.5	0.88	H NMR(500MHz,
			DMSO) 8.97(s,
			1H), 7.32-7.15(m,
			4H), 6.52(d, J=8.5Hz,
			1H), 6.27(dd, J=3.0,
			5.5Hz, 1H),
			6.05(dd, J=2.6,
			5.5Hz, 1H),
			5.26(dd, J=8.0, 16.4Hz,
			2H), 3.54(d, J=11.6Hz,
			2H),
			3.25-2.58(m,
			13H),
			2.40-2.36(m, 1H),
			2.04-2.01(m, 1H),
			1.85-1.68(m, 4H),
			1.40-1.23(m, 2H),
			0.72-0.67(m, 1H),
438	379.3	1.9
439	438.2	1.97
440	400.2	1.8
441	374.2	1.02	CD3OD:6.85(s, 1H),
			6.77(s, 1H),
			5.36(t, 1H),
			4.30(m, 2H),
			4.13(q, 2H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.45(m, 3H),
			3.20(m, 1H),
			2.72(dd, 1H),
			2.35(m, 1H),
			2.10(m, 2H),
			2.00(s, 3H),
			1.59-1.90(m, 14H)
442	401.6	1.85
443	443.4	1.9
444	426.2	1.93
445	424.2	2.31
446	495.2	1.91	NMR(500MHz,
			DMSO-d6)
			8.98(br. s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.32(t, 1H), 7.22(t,
			1H), 7.19(d, 1H),
			6.27(dd, 1H),
			6.17-6.15(m, 1H),
			6.05(q, 1H),
			4.94-4.92(m, 1H), 3.45(m,
			2H), 3.20-3.13(m,
			2H), 2.98(br.s,
			1H), 2.95(m, 1H),
			2.86(br.s, 1H),
			2.85-2.79(m, 1H),
			2.28-2.22(m, 2H),
			2.07-1.99(m, 2H),
			1.87(s, 3H),
			1.83-1.78(m, 3H), 1.73(d,
			1H), 1.65-1.61(m,
			1H), 1.39-1.29(m,
			3H), 0.70(dt, 1H).
447	365.32	1.63	:
448	395.5	2.69	1H NMR(500MHz,
			DMSO(d6)):
			8.98(s, 1H),
			7.37(d, 1H), 7.22(t, H),
			7.10(t, 1H),
			7.07(d, 1H), 6.27(q, 0.7H),
			6.18-6.14(m,
			0.6H), 6.05(q,
			0.7H), 3.43(m,
			2H), 3.30-3.21(m,
			1H), 3.22-3.10(m,
			2H), 2.98(s, 1H),
			2.95-2.90(m, 1H),
			2.85(s, 1H),
			2.85-2.80(m, 1H),
			2.73(t, 2H),
			2.28-2.22(m, 2H), 2.00(ddd,
			1H), 1.89-1.87(m,
			2H), 1.78-1.67(m,
			4H), 1.39-1.29(m,
			2H), 0.72-0.67(m,
			1H).
449	308.6	2.01
450	400.1	1.81
451	494.4	1.97	DMSO(d6):
			9.53(br. s), 8.18(d, 1H),
			7.40(d, 1H),
			7.30(t, 1H), 7.19(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.40(m,
			2H), 3.14(t, 2H),
			3.07(m, 2H),
			2.27(m, 2H), 2.05(dd,
			1H), 1.87(s, 3H),
			1.81(m, 3H),
			1.74-1.59(m, 9H),
			1.27-1.12(m, 6H),
			0.89(m, 2H).
452	383.44	1.96
453	410.2	2.19
454	416.6	1.3
455	438.4	2.44
456	485.4	2.22
457	386.3	1.2
458	438.4	1.39
459	416.4	1.62
460	438.4	1.95
461	486.2	2.2
462	371.2	2.12
463	447.2	1.6
464	417.4	1.66
465	444.4	1.98
466	496.5	2.57
467	492.4	2.24
468	396.2	1.95
469	404.4	2.26
470	324.2	2.08
471	411.2	2
472	440.4	1.99
473	404.4	1.97
474	390.4	1.03
475	469.3	1.78
476	454.2	2.23
477	448.4	2.13
478	400.2	1.84
479	471.4	2.13
480	372.3	1.2
481	424.4	1.98
482	386.2	1.73
483	324.2	2.05
484	383.2	1.94
485	471.4	2.16	DMSO(d6):
			9.06(br. s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			6.27(dd, 1H),
			6.05(m, 1H), 4.92(q,
			1H), 3.47(m, 3H),
			3.15(m, 2H),
			2.98(s, 1H), 2.93(dd,
			1H), 2.85(s, 1H),
			2.80(ddd, 1H),
			2.25(m, 2H), 2.20(m,
			2H), 1.87(s, 3H),
			1.81(m, 3H),
			1.71(d, 1H), 1.62(m,
			1H), 1.35(t, 1H),
			1.30(d, 1H),
			0.68(dq, 1H).
486	365.3	1.61
487	394.5	2
488	328.2	1.7
489	406.4	1.65
490	353.3	1.8
491	504	2.28
492	442.4	1.66
493	396	1.71
494	428.6	1.89
495	412.3	2.3
496	428.2	2.11
497	464.4	1.92	(CDCl3, ppm)
			11.89(br s, 1H),
			7.47(m, 3H),
			6.22(s, 2H) 5.98(s, 1H),
			3.75(br s, 2H),
			3.00(s, 2H), 2.86(s,
			1H), 2.58(m, 5H),
			2.57(m, 3H),
			2.38(s, 3H), 2.06(m,
			1H), 1.65(m, 2H),
			1.48(m, 1H),
			1.27(m, 1H), 0.72(d, J=11Hz,
			1H).
498	321.9	1.76
499	480	2.43
500	509.4	2
501	343.2	1.9
502	400.2	1.84	DMSO(d6):9.03(s,
			1H), 7.31(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.47(d, 1H),
			4.81(m, 1H),
			4.39(m, 1H), 4.34(m,
			1H), 4.26(m, 1H),
			4.10(q, 2H),
			3.45(m, 2H),
			3.21-3.08(m, 2H), 2.82(s,
			6H), 2.68-2.61(m,
			3H), 2.23(m, 1H),
			2.03-1.92(m, 5H),
			1.79(m, 1H),
			1.73-1.62(m, 5H),
			1.57(d, 1H), 1.51(t,
			1H), 1.19(t, 3H).
503	469.3	1.87	DMSO(d6):
			9.17(br.s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.16(d, 1H),
			4.93(m, 1H),
			3.55(td, 1H), 3.43(d,
			2H), 3.19(m, 2H),
			2.29(td, 1H),
			2.24(td, 1H), 2.06(dd,
			1H), 1.87(s, 3H),
			1.83(m, 6H),
			1.63(m, 1H), 1.27(t,
			3H), 1.08(d, 1H),
			1.04(s, 6H),
			0.97(s, 6H).
504	397.4	1.94
505	392.2	1.62
506	353.3	1.5
507	426.2	1.91
508	430.2	2.12
509	400.2	1.83
510	447.4	2	CD3OD:
			6.85(s, 1H),
			6.78(s, 1H),
			5.36(t, 1H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.60(m, 2H),
			3.10-3.20(m, 2H),
			3.02(d, 2H),
			2.72(dd, 1H),
			2.25(m1H),
			2.03(m, 1H),
			2.00(s, 3H),
			1.65-1.95(m, 8H),
			1.38(m, 2H),
			1.26(m, 1H),
			1.07(m, 2H)
511	401.5	1.8
512	361.4	2.2
513	484.4	2.17	DMSO(d6):
			9.25(m, 1H), 8.19(d,
			1H), 7.39(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.93(ddd, 1H),
			3.49(t, 2H), 3.18(m,
			2H), 3.05(t, t, 2H),
			2.25(ddd, 2H),
			2.06(dd, 1H), 1.87(s,
			3H), 1.83(m, 3H),
			1.75(d, 1H),
			1.63(m, 1H), 1.10(m,
			1H), 0.68(m, 2H),
			0.39(m, 2H).
514	313.2	1.27
515	450	2.04
516	422.2	1.79
517	439.4	1.44
518	400.2	1.88
519	403.5	2.1
520	459.2	1.67	CD3OD:6.86(s, 1H),
			6.77(s, 1H),
			5.36(t, 1H),
			4.30(m, 2H),
			4.13(q, 2H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.54(m, 2H),,
			3.15(m, 3H),
			2.70(m, 1H),
			2.30(m, 1H),
			2.15(m, 2H), 2.00(s, 3H),
			1.70-2.009m, 7H0,
			1.25-1.60(m, 5H)
521	387	1.46
522	446.3	2.41
523	528.3	2.6
524	416.2	1.8
525	408.21	1.89
526	424.2	2.29
527	485.4	2.32
528	439.4	1.66
529	468.2	2.1
530	325.2	1.3
531	467.4	1.61
532	444.5	2.37
533	354.3	1.3
534	455	2.02
535	438.4	1.46	500mHz, MeOH-
			d4; 7.36(d, 1H),
			7.30-7.22(m, 3H),
			5.20-5.17(m, 1H),
			3.01(br s, 2H),
			2.52-2.48(m, 1H),
			2.39(s, 2H),
			2.25-2.0(m, 4H),
			1.95-1.49(m, 6H),
			1.45-1.29(m, 5H),
			0.99-0.97(m, 1H)
536			DMSO(d6):
			9.50(br.s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			4.12(d, 2H), 4.05(q,
			2H), 3.40(m, 3H),
			3.19(m, 2H),
			2.82(m, 2H), 2.25(m,
			2H), 2.09(d, 2H),
			2.03(td, 1H),
			1.86(s, 3H), 1.82(m,
			4H), 1.61(m, 3H),
			1.19(t, 3H).
537	414.3	1.46	DMSO-d6:
			9.95-9.58(m, 1H),
			8.30-8.26(m, 1H),
			7.53-7.40(m, 1H),
			7.21-7.18(m, 1H),
			7.03-6.98(m, 1H),
			5.36-5.28(m, 1H),
			4.08-4.05(m, 4H),
			3.78(s, 1H),
			3.68-3.65(m, 2H), 2.80(br s,
			2H), 2.72(s, 1H),
			2.69-2.63(m, 1H),
			2.58(s, 2H),
			2.20-2.07(m, 1H),
			2.03(s, 2H),
			1.97-1.90(m, 3H),
			1.82-1.77(m, 1H),
			1.51-1.47(m, 2H),
			1.21-1.18(m, 3H)
538	404.5	1.65
539	416.4	1.57
540	419.4	1.75
541	448.2	1.65
542	300.2	1.46
543	446.3	2.13
544	485.4	1.78
545	447.2	2.4	CD3OD:
			6.86(s, 1H),
			6.79(s, 1H),
			5.37(m, 1H),
			3.84(s, 3H),
			3.82(m, 3H),
			3.40(m, 2H),
			3.55(m, 3H),
			3.00-3.20(m, 2H),
			2.70(m, 1H),
			2.48(m, 2H),
			1.77-2.10(m, 19H
			including 3H
			singlet at 2.00)
546	439.6	1.9
547	332.2	0.75
548	314.2	1.64
549	410.2	1.81
550	456.5	2.17
551	454.2	2.03
552	467.4	1.76
553	441.4	1.76
554	428.4	2.4
555	442.4	2.24
556	486.8	2.23
557	349.2	2.03
558	447.4	1.99
559	451.8	2.24
560	416.4	1.82
561	443.2	1.93
562	413.2	1.48
563	410.4	1.91
564	410.2	2.2
565	444.4	2.08	CD3OD:
			6.86(s, 1H),
			6.78(s, 1H),
			5.36(m, 1H),
			3.83(s, 3H),
			3.82(m, 3H),
			3.55(m, 3H),
			3.15-3.25(m, 2H),
			2.25(m, 1H),
			2.35(m, 1H),
			2.00(s, 3H),
			1.80-1.90(m, 5H),
			1.36(m, 2H),
			1.12(s, 6H),
			1.04(s, 6H)
566	442.3	2.1
567	440.4	2.17	DMSO(d6):
			9.40(br. s), 8.18(d, 1H),
			7.38(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.41(m,
			2H), 3.13(m, 4H),
			2.24(m, 2H),
			2.05(dd, 1H), 1.87(s,
			3H), 1.84-1.76(m,
			3H), 1.74-1.65(m,
			5H), 1.64-1.56(m,
			4H), 1.33-1.12(m,
			4H), 0.96(m, 2H).
568	369.43	1.82	DMSO-d6:
			7.69(d, 1H), 7.52(d,
			2H), 7.43(d, 2H),
			7.25(d, 2H),
			7.01(d, 2H),
			6.26(m, 1H),
			6.06(d, 1H),
			4.95(m, 1H),
			4.49(m, 1H),
			3.77(s, 3H),
			3.55(m, 2H),
			2.42(m, 1H),
			2.79-3.15(m, 7H),
			1.94-2.11(m, 3H),
			1.71(d, 3H),
			0.68-0.70(m, 2H)
569	477	1.58
570	444.4	1.5
571	434	2.14
572	484.2	1.76
573	410.2	2.21
574	413	1.68	DMSO(d6):
			9.25(br. s), 8.17(d, 1H),
			7.37(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.93(d,
			2H), 3.42(m, 3H),
			3.15(m, 4H),
			2.71(m, 1H), 2.20(m,
			2H), 2.04(dd, 1H),
			1.87(s, 3H),
			1.82(m, 3H), 1.72(d,
			1H), 1.63(m, 5H),
			1.49(m, 1H),
			1.39(s, 9H), 1.04(ddd,
			1H).
575	470.4	1.82	DMSO(d6):
			8.92(br.s, 1H), 8.39(d,
			1H), 7.39(d, 1H),
			7.32(t, 1H), 7.21(t,
			1H), 7.16(d, 1H),
			6.27(dd, 1H),
			6.05(m, 1H), 4.95(q,
			1H), 3.45(m, 3H),
			3.28-3.10(m, 3H),
			2.98(s, 1H),
			2.94(ddd, 1H), 2.85(s,
			1H), 2.81(ddd,
			1H), 2.25(m, 2H),
			2.03(ddd, 2H),
			1.82(m, 3H),
			1.71(d, 1H), 1.65(m,
			1H), 1.58(m, 1H),
			1.38(dd, 1H),
			1.29(d, 1H),
			0.78-0.63(m, 4H).
576	391.38	1.83
577	303.2	1.93
578	424.2	1.99
579	422.2	1.79
580	490.2	1.79	DMSO(d6):
			9.14(br. s), 8.17(d, 1H),
			7.36(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.4(m,
			2H), 3.18-3.01(m,
			4H), 2.21(m, 3H),
			2.04(dd, 1H),
			2.00(s, 1H), 1.87(s,
			3H), 1.82(m, 3H),
			1.72(d, 1H),
			1.64(m, 2H), 1.47(m,
			4H), 1.35(m, 2H),
			1.17-1.02(m, 4H).
581	381.4	1.89
582	357.2	2.1
583	480.2	2.2
584	459.4	2.08
585	439.2	1.95
586	355.23	1.59
587	418.4	1.9
588	495.4	2.01
589	424.2	1.95
590	445.6	1.88	H NMR(500MHz,
			DMSO(d6)):
			9.14(s, H), 7.36(d, 1H),
			7.22(t, 1H), 7.09(t,
			1H), 7.07(d, 1H),
			4.10(d, 2H),
			4.05(q, 2H),
			3.48-3.39(m, 4H), 3.19(q,
			2H), 2.83(m, 2H),
			2.71(t, 2H),
			2.27(td, 2H), 2.09(d,
			2H), 1.87(m, 2H),
			1.77(d, 2H),
			1.72-1.68(m, 2H),
			1.58(qd, 2H), 1.22(t,
			3H).
591	357.4	1.87
592	471.4	1.83
593	468.3	1.61
594	453.4	1.4
595	459.4	2.01
596	434	2.14
597	391.2	2.16
598	473.4	2.28	CD3OD:
			6.86(s, 1H),
			6.77(s, 1H),
			5.35(m, 1H),
			3.83(s, 3H),
			3.82(m, 3H),
			3.15-3.25(m, 3H),
			2.25(m, 1H),
			2.35(m, 1H),
			2.00(s, 3H),
			1.40-1.90(m, 26H)
599	471.6	2.3
600	383.4	2.28
601	404.4	1.86	DMSO(d6):
			9.09(m, 1H), 8.18(d,
			1H), 7.38(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.16(d, 1H),
			4.92(ddd, 1H),
			3.86(t, 1H), 3.78(ddd,
			1H), 3.67(q, 1H),
			3.43(m, 3H),
			3.19(m, 4H), 3.66(m,
			1H), 2.25(m, 2H),
			2.12(m, 1H),
			2.05(dd, 1H), 1.87(s,
			3H), 1.82(m, 3H),
			1.73(d, 1H),
			1.63(m, 2H).
602	343.1	0.97
603	454.2	2.13
604	440.4	2.08	DMSO(d6):
			8.85(br.s, 1H), 8.18(d,
			1H), 7.41(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.42(m, 2H), 3.14(m,
			2H), 3.00(t, 2H),
			2.29(m, 2H),
			2.05(m, 1H), 1.86(s,
			3H), 1.85-1.58(m,
			11H), 1.26(m, 2H),
			1.17(m, 1H),
			0.99(m, 2H).
605	355.3	1.71
606	454.2	2.24
607	442.4	1.69
608	439.4	1.73	CD3OD:
			7.73(dd, 1H),
			7.67(d, 1H), 7.63(d,
			1H), 3.50(, .2H),
			3.26(m, 2H),
			2.83(s, 2H),
			2.37(m, 2H),
			2.13(m, 2H),
			1.60-1.90(m, 12H)
609	332	1.84
610	414.4	1.96
611	432.4	1.86
612	314.2	1.59
613	412.2	2.01
614	471.4	2
615	454.2	1.98	DMSO(d6):8.76(s,
			1H), 8.17(d, 1H),
			7.39(t, 1H),
			7.31(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.88(dd, 2H), 3.44(m,
			2H), 3.34(t, 2H),
			3.17(m, 2H),
			3.06(t, 2H),
			2.31-2.14(m, 2H),
			2.11-2.02(m, 2H), 1.86(s,
			3H), 1.81(m, 3H),
			1.71(d, 1H),
			1.64(m, 3H), 1.27(ddd,
			2H).
616	357.2	1.48
617	384.2	1.91
618	450.4	2.08
619	456.2	1.72
620	438.2	2.12
621	411.2	2.38
622	324.3	2.07
623	454.2	1.69	DMSO(d6):8.29(s,
			1H), 8.17(d, 1H),
			7.45(d, 1H),
			7.31(t, 1H), 7.20(t, 1H),
			7.17(d, 1H),
			4.93(m, 1H), 3.38(m,
			2H), 3.20-3.09(m,
			3H), 2.34(qd, 2H),
			2.25-2.13(m, 2H),
			2.08-2.03(m, 1H),
			1.87(s, 3H),
			1.83(m, 4H),
			1.74-1.60(m, 4H), 1.55(d,
			2H), 1.33-1.22(m,
			4H), 0.82(s, 6H),
			0.79(t, 3H).
624	411.3	2.34
625	469.2	2.32
626	386.2	1.72	DMSO(d6):
			9.06(br.s, 1H), 7.47(d,
			1H), 7.45(d, 1H),
			7.32(t, 1H), 7.24(t,
			1H), 6.26(dd, 1H),
			6.04(dd, 1H),
			4.45(q, 1H), 3.38(m,
			2H), 3.15(m, 2H),
			3.05(s, 3H),
			2.98(s, 1H), 2.93(ddd,
			1H), 2.85(s, 1H),
			2.80(ddd, 1H),
			2.23(m, 2H), 2.07(m,
			1H), 2.01(ddd,
			1H), 1.94(m, 1H),
			1.86(dd, 1H),
			1.78(m, 2H), 1.69(d,
			1H), 1.38(d, 1H),
			1.35(d, 1H),
			1.29(d, 1H), 0.68(dq,
			1H).
627	401.35	1.79
628	433.4	1.78
629	505.4	2.03
630	487	2.31
631	442.3	1.52
632	404.4	1.9
633	485.4	1.94
634	404.4	1.88
635	398.3	2.2	DMSO(d6):
			9.16(br. s, 1H), 8.18(d,
			1H), 7.36(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.91(q, 1H),
			3.31(m, 2H), 3.20(t,
			2H), 3.13(t, 2H),
			2.74(m, 1H),
			2.25-2.09(m, 4H),
			2.04(dd, 1H), 1.91(m,
			1H), 1.87(s, 3H),
			1.82(m, 6H),
			1.71(d, 1H), 1.62(m,
			1H).
636	327.3	1.42
637	410.2	1.86
638	383.4	2.28
639	393.5	2.1	CD3CN:
			7.50-7.35(m, 1H),
			7.12-7.05(m, 1H),
			7.02-6.99(m, 1H),
			6.86-6.77(m, 1H),
			5.42-5.35(m, 1H),
			3.88-3.84(m, 2H),
			3.36-3.13(m, 4H),
			2.72(dd, J=7.5, 12.7Hz,
			1H),
			2.63-2.54(m, 1H), 2.32(s,
			1H), 2.29(s, 1H),
			2.23-2.18(m, 4H),
			2.12-1.93(m, 1H),
			1.89-1.79(m, 1H),
			1.57-1.34(m, 5H),
			1.27-1.21(m, 2H),
			0.87-0.75(m, 1H)
640	357.1	1.71
641	383.4	2.24	1H NMR(500MHz,
			DMSO(d6)):
			8.50(br. s, 1H),
			7.41(d, 1H),
			7.22(t, 1H), 7.13(t, 1H),
			7.06(d, 1H),
			3.50(m, 2H), 3.38(m,
			1H), 3.30(m, 1H),
			3.22-3.10(m, 2H),
			2.72(t, 2H),
			2.37-2.25(m, 4H),
			2.01(t, 1H),
			1.90-1.87(m, 2H),
			1.75-1.59(m, 8H),
			1.52-1.37(m, 2H),
			1.30-1.15(m, 2H).
642	296.3	1.9	CD3OD:
			7.38-7.63(m, 5H),
			6.66(s, 1H),
			6.45(m, 1H),
			5.70(s, 1H),
			5.40(m, 1H),
			3.73(s, 3H),
			3.54(m, 2H),
			3.47(s, 3H),
			2.33(s, 3H),
			2.16(m, 4H),
			1.96(m, 4H),
			1.20-1.75(m, 13H)
643	491.6	2.2
644	347.4	1.91
645	471.4	2.17	DMSO(d6):8.35(s,
			1H), 8.18(d, 1H),
			7.45(d, 1H),
			7.31(t, 1H), 7.21(t, 1H),
			7.17(d, 1H),
			4.93(m, 1H), 3.55(m,
			2H), 3.37(m, 1H),
			3.20-3.09(m, 2H),
			2.34(qd, 2H),
			2.24-2.13(m, 2H),
			2.06(m, 1H), 1.87(s,
			3H), 1.90-1.81(m,
			3H), 1.74-1.58(m,
			5H), 1.30(q, 2H),
			1.15(m, 2H),
			0.88(s, 9H).
646	397.2	2.2	DMSO-d6:9.12(s,
			1H), 7.49(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.14(dd, 1H),
			3.39(dd, 2H),
			3.24-3.07(m, 3H), 2.98(t,
			2H), 2.88(ddd,
			1H), 2.59(td, 1H),
			2.41-2.29(m, 3H),
			2.19(td, 1H),
			1.95-1.59(m, 13H),
			1.27(m, 2H), 1.17(tt,
			1H), 0.99(m, 2H).
647	381.4	1.78
648	492.4	2.22
649	471.4	1.85	H NMR(500MHz,
			DMSO) 8.60(br s,
			1H, from TFA),
			8.44(d, J=8.0Hz,
			1H), 7.32(dt, J=25.2,
			8.1Hz, 2H),
			7.21(dd, J=7.3,
			18.5Hz, 2H),
			5.39(q, 1H),
			4.07-2.97(m, 4H, partially
			obscured by
			solvent),
			2.70-2.60(m, 2H),
			2.45-2.31(m, 2H),
			2.07-1.91(m, 2H),
			1.72-1.55(m, 8H),
			1.46-1.41(m, 3H),
			1.25-1.17(m, 1H),
			0.77-0.66(m, 4H)
650	365.3	1.9
651	459.4	2.06	NMR(500MHz,
			DMSO-d6)
			8.98(br. s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.32(t, 1H), 7.22(t,
			1H), 7.19(d, 1H),
			6.27(dd, 1H),
			6.17-6.15(m, 1H),
			6.05(q, 1H),
			4.94-4.92(m, 1H), 3.45(m,
			2H), 3.20-3.13(m,
			2H), 2.98(br.s,
			1H), 2.95(m, 1H),
			2.86(br.s, 1H),
			2.85-2.79(m, 1H),
			2.28-2.22(m, 2H),
			2.07-1.99(m, 2H),
			1.87(s, 3H),
			1.83-1.78(m, 3H), 1.73(d,
			1H), 1.65-1.61(m,
			1H), 1.39-1.29(m,
			3H), 0.70(dt, 1H).
652	365.32	1.63
653	530	2.65
654	371.1	2.75	DMSO(d6):
			9.28(br.s, 1H), 8.19(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.42(m, 2H),
			3.25-3.08(m, 4H),
			2.34-2.14(m, 5H), 2.05(t,
			1H), 1.87(s, 3H),
			1.81(m, 4H),
			1.70(d, 1H), 1.63(m,
			1H), 1.49(m, 2H),
			1.37(m, 2H),
			1.30(d, 1H), 1.14(m,
			2H) 0.81(m, 1H).
655	367.4	1.71
656	424.2	1.98	1H NMR(500MHz,
			DMSO(d6)):
			8.82(s, 1H),
			7.33(d, 1H), 7.22(t,
			1H), 7.14(t, 1H),
			7.06(d, 1H),
			3.43-3.35(m, 3H),
			3.14-3.03(m, 2H),
			2.72(t, 2H),
			2.45-2.39(m, 2H), 2.32(m,
			2H), 2.18(td, 2H),
			1.87-1.84(m, 2H),
			1.76-1.67(m,
			4H), 1.60(t, 2H),
			1.56-1.46(m, 1H),
			1.42(d, 2H),
			1.30(t, 2H), 1.02(dt,
			1H).
657	310.3	2.05
658	450	1.93
659	467.4	1.87
660	439.2	1.74
661	480.2	2.4
662	447.4	1.57	DMSO(d6):
			9.16(br.s, 1H), 8.39(d,
			1H), 7.43(d, 1H),
			7.31(t, 1H), 7.21(t,
			1H), 7.15(d, 1H),
			4.95(q, 1H),
			3.27(m, 3H), 2.31(m,
			2H), 2.07(m, 3H),
			1.85-1.26(m, 18H),
			0.78-0.63(m, 4H).
663	381.44	1.79
664	466.43	1.72
665	431.4	1.78
666	355.4	1.57
667	382.4	2.11	DMSO(d6):
			8.93(br.s, 1H), 7.46(d,
			1H), 7.44(d, 1H),
			7.35(d, 1H),
			7.32(t, 1H), 7.21(t, 1H),
			4.45(q, 1H),
			3.11(m, 2H), 3.04(s,
			3H), 2.35(m, 2H),
			2.15(m, 2H),
			2.05(dd, 1H), 1.97(m,
			2H), 1.86-1.62(m,
			6H), 1.56-1.26(m,
			7H), 1.15(t, 1H).
668	403.34	1.79
669	440.3	1.57
670	355	2.51
671	356.3	1.3
672	410.2	1.82	DMSO(d6):8.68(s,
			1H), 7.38(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.48(d, 1H),
			4.82(q, 1H),
			3.42(d, 2H), 3.15(m,
			2H), 3.00(t, 2H),
			2.82(s, 6H),
			2.41(td, 1H), 2.22(dd,
			1H), 2.15(td, 1H),
			1.89(d, 1H),
			1.82-1.63(m, 10H),
			1.28(q, 2H), 1.17(m,
			1H), 0.99(q, 2H).
673	384.3	2
674	433.2	1.6
675	471.4	2.17
676	418.2	2.07
677	463.2	0.96
678	482.4	2.24
679	398.2	1.64
680	372.2	1.56
681	416.4	1.62
682	299.1	1.8
683	414.4	1.99
684	456.4	1.81
685	361.2	1.32
686	480.2	2.08
687	396.5	2.1
688	455.4	2.09
689	502.2	2.27
690	384.3	2.1	DMSO-d6:
			10.16-9.77(m, 1H),
			8.28(m, 1H),
			7.54-7.42(m, 1H), 7.19(m,
			1H), 7.03-6.97(m,
			1H), 5.37-5.28(m,
			1H), 3.79-3.74(m,
			1H), 3.69-3.47(m,
			1H), 3.30-3.16(m,
			1H), 2.74-2.62(m,
			1H), 2.58(s, 3H),
			2.19-2.04(m, 3H),
			1.89(m, 3H),
			1.82-1.77(m, 3H),
			1.63(m, 1H),
			1.40-1.35(m, 2H),
			1.28-1.23(m, 2H), 1.10(td, J=12.7,
			9.5Hz, 1H)
691	331.4	1.71	DMSO-d6:
			9.65-9.45(m, 1H),
			8.27(d, J=7.5Hz, 1H),
			7.54-7.45(m, 1H),
			7.50(s, 1H),
			7.22-7.15(m, 1H),
			7.04-6.99(m, 1H),
			6.25(dd, J=3.1, 6.9Hz,
			1H), 6.06-6.04(m,
			1H), 5.34-5.28(m,
			1H), 3.86(d, J=4.1Hz,
			1H),
			3.77-3.69(m, 2H),
			3.31-3.21(m, 2H),
			3.03-3.01(m, 1H),
			2.98-2.94(m, 2H), 2.90(s,
			1H), 2.58(s, 2H),
			2.36(t, J=1.8Hz,
			1H), 2.18-2.12(m,
			1H), 2.02-1.94(m,
			1H), 1.83(s, 3H),
			1.38-1.28(m, 2H)
692	355.4	1.87
693
694	471.4	2.06
695	433.2	1.87	DMSO(d6):
			8.64(m, 1H), 8.18(t,
			1H), 7.43(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(m, 1H),
			3.49(m, 1H), 3.41(t,
			1H), 3.33(t, 1H),
			3.17(m, 2H),
			2.61(s, 1H), 2.31(m,
			3H), 2.02(m, 2H),
			1.86(s, 3H),
			1.85-1.60(m, 8H),
			1.40(m, 3H), 1.20(dd,
			1H).
696	353.3	1.54
697	388.2	0.95
698	447.4	1.89
699	374.2	0.92
700	442.2	2.36
701	429.4	1.71	CD3OD:
			7.63(d, H),
			7.39(d, 1H),
			7.35(d, 1H),
			4.21(q, 2H),
			3.63(m, 2H),
			3.30(m, 2H),
			3.17(d, 2H),
			2.98(s, 2H),
			2.24(m, 2H),
			1.75-1.90(m, 8H),
			1.29-1.39(m, 5H),
			1.09(m, 2H)
702	375	2.18
703	342.2	1.7
704	461.4	2.01	1H-NMR(300MHz,
			DMSO-d6):?
			6.87(d, J=8.7Hz,
			1H), 6.69(t, J=7.5Hz,
			1H), 6.40(dd, J=8.7Hz,
			J=4.5Hz,
			1H), 4.42(m,
			2H), 3.28(s, 2H),
			2.78(d, J=11.1Hz,
			1H), 2.58(d, J=11.7Hz,
			1H),
			3.38(m, 1H),
			1.85-2.05(m, 4H),
			1.70-1.85(m, 3H),
			1.40-1.60(m, 4H),
			1.09(dd, J=11.7Hz, J=4.8Hz,
			1H).
705	302.2	1.33
706	447.4	2.01
707	431.2	2.41
708	423.4	1.6	DMSO(d6):9.00(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.85(dd, 2H), 3.4(m,
			2H), 3.29(t, 2H),
			3.15(m, 4H),
			2.22-2.14(m, 2H),
			2.04(dd, 1H), 1.87(s,
			3H), 1.81(m, 3H),
			1.73(d, 1H),
			1.65-1.55(m, 6H),
			1.21(ddd, 2H).
709	371.2	1.52
710	382.4	1.4
711	455.2	2.15
712	477.4	2.15
713	371.2	2.1
714	448.3	2.18	CD3OD:
			7.71(d, 1H),
			7.62(d, 1H),
			7.52(dd, 1H),
			3.68(m, 2H),
			3.48(m, 1H),
			3.30(m, 2H),
			2.80(s, 2H),
			2.40(m, 2H),
			2.15(m, 1H),
			1.88(m, 2H),
			1.56-1.91(m, 4H),
			1.30(m, 1H)
715	318	1.71	DMSO(d6):
			9.20(m, 1H), 8.19(d,
			1H), 7.41(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.38(m, 2H), 3.20(m,
			2H), 2.26(m, 2H),
			2.10(m, 1H),
			2.03(dd, 1H), 1.87(s,
			3H), 1.85-1.68(m,
			6H), 1.63(m, 3H),
			1.44(q, 2H),
			1.29(q, 2H), 1.12(m,
			2H).
716	341.2	1.46
717	468.4	2.48
718	466	1.67
719	464.2	1.66
720	438.2	1.44
721	443.4	2.03
722	436.2	1.91	DMSO(d6):
			9.07(br.s, 1H), 7.46(d,
			1H), 7.44(d, 1H),
			7.41(d, 1H),
			7.32(t, 1H), 7.23(t, 1H),
			4.45(q, 1H),
			3.04(s, 3H), 2.26(m,
			2H), 2.06(m, 3H),
			1.93(m, 3H),
			1.87-1.67(m, 8H),
			1.59-1.38(m, 8H),
			1.30(m, 1H).
723	391.36	1.76
724	412	1.88
725	440.3	2.5
726	422.5	2.3
727	497.4	1.92
728	463.2	1.04
729	428	1.63
730	448.3	2.18
731	456.3	1.95	H NMR(500MHz,
			MeOD)
			7.72-7.64(m, 3H),
			7.45-7.41(dt, 1H), 3.05(t,
			2H), 2.62(s, 2H),
			2.42-2.38(m, 2H),
			2.27-2.15(m, 3H),
			2.12-2.0(m, 2H),
			1.85-1.77(m, 2H),
			1.60-1.32(m, 7H),
			1.00-0.97(m, 1H),
732	296.2	1.46
733	443.2	1.69
734	398.2	2.19
735	467	2.05
736	426.3	2.4
737	355.4	2.38	1H NMR(500MHz,
			DMSO(d6)):
			9.01(s, H), 7.38(d,
			1H), 7.21(t, 1H),
			7.14(t, 1H),
			7.05(d, 1H), 3.40(m,
			1H), 3.27-3.17(m,
			4H), 2.72(t, 2H),
			2.26(td, 2H),
			2.12-2.05(m, 2H),
			1.88-1.86(m, 2H),
			1.76-1.67(m, 8H),
			1.57-1.46(m, 6H).
739			DMSO(d6):
			9.12(br.s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			6.27(m, 1H),
			6.04(m, 1H), 4.92(m,
			1H), 3.44(m, 2H),
			3.14(m, 2H),
			2.98(s, 1H), 2.94(m,
			1H), 2.84(s, 1H),
			2.80(m, 1H),
			2.26(m, 2H), 2.03(m,
			2H), 1.86(s, 3H),
			1.81(m, 3H),
			1.70(d, 1H), 1.62(m,
			1H), 1.37(t, 1H),
			1.29(d, 1H),
			0.68(m, 1H).
740	365.3	1.67	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.79(m, 1H), 3.42(m,
			3H), 3.16(m, 7H),
			2.89(m, 1H),
			2.22-2.14(m, 2H),
			2.05(m, 1H), 1.87(s,
			3H), 1.83(m, 5H),
			1.74(d, 1H),
			1.63(m, 3H), 1.46(m,
			1H), 1.35(m, 1H),
			1.17(q, 1H),
			0.90(d, 6H).
741	470.3	2.13
742	426.2	1.93
743	424.2	1.8	DMSO(d6):
			9.05(br.s, 1H), 8.39(d,
			1H), 7.38(d, 1H),
			7.30(t, 1H), 7.21(t,
			1H), 7.15(d, 1H),
			4.95(q, 1H),
			3.11(m, 2H), 2.35(m,
			2H), 2.25-2.12(m,
			3H), 2.07-1.96(m,
			2H), 1.82(m, 3H),
			1.72(m, 2H),
			1.65(m, 2H),
			1.60-1.25(m, 9H), 1.16(t,
			1H), 0.78-0.63(m,
			4H).
744	393.4	1.83
745	455.3	1.74
746	444.6	1.99
747	436.4	1.89
748	457.2	2
749	461.4	2.01
750	443.2	2.08
751	458.6	2.31
752	440.4	2.13
753	372.2	1.53
754	442.5	2.23
755	396.62	1.7
756	444.6	2.19
757	440.5	2.41
758	324.2	2.04
759	369.2	2.15
760	469.4	1.5
761	457.2	1.96
762	467.4	2.21
763	436.3	2.4	DMSO(d6):
			9.38(m, 1H), 8.19(d,
			1H), 7.37(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(m, 1H),
			3.53(m, 2H), 3.22(m,
			2H), 3.04(m, 2H),
			2.42(m, 2H),
			2.21(qd, 2H), 2.10(dd,
			1H), 1.91(t, 2H),
			1.87(s, 3H),
			1.84(m, 3H), 1.74(d,
			1H), 1.64(s, 3H).
			1.63(m, 1H),
			1.54(m, 2H), 1.41(m,
			2H), 1.01(s, 6H).
764	409.4	2.09	CDCl3(ppm):
			7.93(1H, br s),
			7.43(1H, m), 7.36(1H,
			m), 4.35(2H, br s),
			4.12(2H, m),
			3.98(1H, br s),
			3.21(1H, br s),
			3.08(2H, br s),
			2.76(4H, m), 2.05(3H,
			m), 1.62(1H, br s),
			1.28(6H, m).
765	360.9	1.68	DMSO-d6:9.16(s,
			1H), 7.55(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.15(dd, 1H),
			3.47(m, 1H), 3.34(t,
			2H), 3.24-3.11(m,
			3H), 2.88(q, 1H),
			2.60(t, 2H),
			2.41-2.26(m, 5H),
			2.08-1.33(m, 13H),
			1.28-1.14(m, 2H).
766	379.35	1.63
767	483.4	1.93
768	476	2.5
769	464.5	1.67
770	495.4	1.95
771	376.2	1.59
772	465.2	1.86	DMSO(d6):
			8.74(br.s, 1H), 7.47(d,
			1H), 7.45(d, 1H),
			7.32(t, 1H), 7.23(t,
			1H), 4.45(q, 1H),
			3.43(m, 2H),
			3.15(q, 2H), 3.05(s,
			3H), 3.00(t, 2H),
			2.28(m, 2H),
			2.07(dd, 1H), 1.95(m,
			1H), 1.88-1.63(m,
			10H), 1.28(q, 2H),
			1.18(tt, 1H),
			0.99(q, 2H).
773	391.38	1.79	CD3OD:6.86(s, 1H),
			6.77(s, 1H),
			5.36(t, 1H),
			4.30(m, 2H),
			4.13(q, 2H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.60(m, 2H),
			3.45(m, 1H),
			3.15(m, 2H),
			2.85(brm, 4H),
			2.70(m, 2H),
			2.40(m, 2H),
			2.20(m, 2H),
			2.00(s, 3H),
			1.60-1.90(m, 5H),
			1.26(t, 3H)
774	460.1	1.45
775	443.4	1.9
776	456.4	1.81
777	436.2	1.93
778
779	353.2	1.8
780	371.3	0.9
781	523.6	2.08
782	400.3	1.4
783	371.2	1.82	in DMSO-d6
784	395.6	2.39
785	414.2	1.92
786	414.2	1.98	CD3OD:
			7.70(d, 1H),
			7.66(d, 1H),
			7.52(dd, 1H),
			3.62(m, 2H),
			3.23(m, 3H),
			2.81(s, 2H),
			2.33(m, 2H),
			2.18(m, 2H),
			1.90-1.99(m, 4H),
			1.75(s, 1H),
			1.56(m, 2H),
			1.44(m, 2H),
			1.25(m, 1H)
787	330	1.74	CD3OD:
			7.61(d, 1H),
			7.45(m, 1H),
			7.37(s, 1H),
			6.29(m, 2H),
			6.05(m, 2H),
			4.93(m, 1H),
			3.65(m, 2H),
			2.90-3.10(m, 10H),
			2.40-2.60(m, 3H),
			1.70-2.10(m, 7H),
			1.55(m, 2H),
			1.40(m, 2H),
			0.65-0.80(m, 2H)
788	449	1.38	DMSO(d6):8.51(s,
			1H), 7.40(d, 1H),
			7.28(t, 1H),
			7.24(d, 1H), 7.19(t,
			1H), 6.48(d, 1H),
			4.82(q, 1H),
			3.50(m, 1H), 3.42(d,
			1H), 3.33(d, 1H),
			3.16(m, 2H),
			2.82(s, 6H), 2.61(m,
			1H), 2.41(dd, 1H),
			2.31(m, 1H),
			2.22(dd, 1H), 2.19(td,
			1H), 2.01(m, 1H),
			1.89(d, 1H),
			1.80(m, 1H),
			1.71-1.56(m, 6H), 1.41(m,
			3H), 1.17(dd, 1H).
789	382.1	1.87
790	439.4	1.75
791	466.4	1.46
792	370.3	1.98
793	438.4	2.44
794	411.2	2.04
795	466.4	1.57
796	345.2	1.95	H NMR(500MHz,
			DMSO) 8.79(s,
			1H), 8.16(d, J=8.2Hz,
			1H),
			7.34-7.16(m, 4H),
			5.37(q, J=7.9Hz,
			2H),
			3.53-3.47(m, 2H),
			3.07-2.98(m, 4H),
			2.69-2.63(m, 1H),
			2.40-2.34(m, 1H),
			2.11(dt, 2H),
			1.90-1.54(m, 12H),
			1.31-1.13(m, 3H),
			1.02-0.96(m, 2H),
			0.89(t, J=7.4Hz, 3H),
797	369.5	2.1
798	419.5	2.1
799	492.2	2.36
800	447.3	1.98
801	379.5	2	1H NMR(500MHz,
			DMSO(d6)):
			8.70(s, 1H),
			7.39(d, 1H), 7.22(t,
			1H), 7.14(t, 1H),
			7.06(d, 1H),
			3.40(d, 2H), 3.14(dd, 2H),
			3.00(t, 2H),
			2.72(t, 2H),
			2.28(td, 2H),
			1.89-1.87(m, 2H),
			1.83-1.66(m, 10H), 1.28(q,
			2H), 1.21-1.13(m,
			1H), 1.03-0.96(m,
			2H).
803	328.2	1.7
804	470.2	1.81
805	465	1.98
806	413.3	0.5
807	419.2	1.75
808	456.2	2.56	DMSO(d6):
			9.09(br.s, 1H), 7.46(d,
			1H), 7.45(t, 1H),
			7.31(d, 2H),
			7.23(m, 1H), 7.21(t,
			1H), 4.45(q, 1H),
			4.26(br.s, 2H),
			4.08(m, 4H), 3.89(m,
			1H), 3.76(m, 1H),
			3.10(q, 2H),
			3.05(s, 3H), 2.11(m,
			3H), 1.93(m, 2H),
			1.87-1.59(dd, 7H),
			1.34(m, 1H),
			1.21(t, 3H), 1.16(q,
			2H).
809	476.35	1.68	DMSO(d6):
			9.51(m, 0.62H),
			9.29(m, 0.38H), 8.18(d,
			1H), 7.36(d, 0.64H),
			7.33(d, 0.36H),
			7.28(t, 1H),
			7.19(t, 1H),
			7.16(d, 1H), 4.92(m,
			1H), 4.33-4.26(m,
			2H), 4.06(q, 2H),
			4.05(m, 1H),
			3.45(m, 2H), 3.13(m,
			2H), 2.66(m, 1H),
			2.26-1.98(m, 4H),
			1.92(m, 2H),
			1.86(s, 3H),
			1.85-1.58(m, 9H), 1.54(t,
			1H), 1.24(t, 3H),
			1.20(m, 1H).
810	440.3	1.57
811	439.2	1.52
812	471.4	1.81
813	402.2	2.04
814	485.4	2.12
815	398.2	2.19
816	396.2	1.73
817	447.5	2.5
818	440	2.1	DMSO(d6):
			9.15(br. s), 8.17(d, 1H),
			7.36(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.17(d, 1H),
			4.92(q, 1H), 3.76(m,
			2H), 3.42(m, 3H),
			3.18(m, 4H),
			2.80(t, 1H), 2.20(m,
			2H), 2.05(dd, 1H),
			1.87(s, 3H),
			1.81(m, 4H), 1.73(d,
			1H), 1.67-1.52(m,
			4H), 1.45-1.29(m,
			2H), 1.40(s, 9H),
			1.15(m, 1H).
819	470.43	1.85
820	464.2	2.24	DMSO-d6:
			9.48-9.05(m, 1H),
			8.28-8.25(m, 1H),
			7.58-7.40(m, 1H),
			7.22-7.19(m, 1H),
			7.05-7.00(m, 1H),
			5.32-5.29(m, 1H),
			3.90-3.88(m, 1H),
			3.73(d, J=9.6Hz, 1H),
			3.69-3.63(m, 2H),
			2.63(t, J=1.8Hz,
			1H), 2.51(s, 4H),
			2.28(t, J=5.1Hz,
			1H), 2.19-2.10(m,
			1H), 2.02-1.98(m,
			1H), 1.95-1.89(m,
			3H), 1.61-1.52(m,
			3H), 1.38(d, J=9.7Hz,
			3H), 1.12(t, J=12.7Hz,
			1H)
821	343.4	1.71
822	420.2	1.81	DMSO-d6:
			10.17-9.82(m, 1H),
			8.31-8.23(m, 1H),
			7.55-7.50(m, 1H),
			7.21-7.16(m, 1H),
			7.03-6.99(m, 1H),
			5.35-5.29(m, 1H),
			4.92-4.85(m, 1H),
			3.76-3.66(m, 1H),
			3.53-3.30(m, 3H),
			2.75-2.61(m, 1H),
			2.58(s, 2H),
			2.31-2.20(m, 1H),
			2.18-2.00(m, 3H),
			1.86-1.77(m, 3H),
			1.74-1.60(m, 4H),
			1.53-1.40(m, 5H)
823	345.4	1.86
824	428.2	1.57
825	438.4	2.42
826	342.2	1.91
827	440.4	2.07	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.93(q, 1H),
			4.10(m, 2H), 3.43(m,
			3H), 3.18(m, 4H),
			2.92(m, 1H),
			2.20(m, 2H), 2.06(m,
			1H), 1.87(s, 3H),
			1.83(m, 4H),
			1.74(d, 1H), 1.66(m,
			3H), 1.55(m, 1H),
			1.44(m, 1H),
			1.35(m, 1H), 1.24(m,
			1H), 1.20(s, 9H).
828	454.3	1.91
829	436.4	1.87
830	327.1	2.1
831	496.5	2.68
833	412.2	1.48	in DMSO-d6
834	339.22	2.7
835	408.3	2.2	CD3OD:
			7.70(d, 1H),
			7.65(s, 1H), 7.52(d,
			1H), 4.45(m, 2H),
			4.17(m, 3H),
			3.76(m, 2H),
			3.13(m, 2H),
			2.79(s, 2H),
			1.60-2.30(m, 13H),
			1.27(m, 3H),
836	417	1.76
837	498.4	2.18
838	468.2	2.56
839	540	2.16
840	402.2	1.81
841	472.3	2.56
842	382.5	2
843	386.2	1.71
844	414.2	2.2
845	383.2	2.33	MeOD:7.86(m,
			1H), 7.55(d, J=2.4Hz,
			1H), 7.40(d, J=7.3Hz,
			1H),
			4.02(m, 1H), 3.89(m,
			1H), 3.25-3.15(m,
			2H), 3.58(m, 1H),
			3.47(m, 1H),
			3.05(m, 1H), 2.84(d, J=6.9Hz,
			1H),
			2.65(br m, 1H), 2.32(m,
			1H), 1.89(m, 1H),
			1.82-1.79(m, 4H),
			1.73-1.71(m, 1H),
			1.34-1.23(m, 3H),
			1.10-1.04(m, 2H)
846	302.4	2.04
847	487.2	2.33
848	469.4	2.44
849	375.4	2.4
850	414.2	1.98
851	460.4	2.4
852	444.4	1.5
853	444.4	2.14	DMSO-d6:9.58(s,
			1H), 7.46(d, 1H),
			7.29(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.14(dd, 1H),
			3.47-3.36(m, 3H),
			3.21(q, 2H), 3.01(m,
			2H), 2.88(ddd,
			1H), 2.44-2.29(m,
			6H), 2.11(td, 1H),
			2.00-1.87(m, 5H),
			1.84-1.69(m, 2H),
			1.66-1.52(m, 5H),
			1.48-1.34(m, 3H).
854	393.36	1.74
855	440.4	1.85	DMSO-d6:9.46(s,
			1H), 7.48(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			6.26(dd, 1H),
			6.06(dd, 1H), 5.14(dd,
			1H), 3.43(m, 2H),
			3.21(q, 1H),
			3.13(m, 2H), 3.00(s,
			1H), 2.95-2.74(m,
			3H), 2.84(s, 1H),
			2.57(m, 1H),
			2.41-2.29(m, 3H),
			2.16(m, 1H), 2.00(m,
			1H), 1.91(m, 3H),
			1.80(t, 1H),
			1.74(m, 1H), 1.62(t,
			2H), 1.37(d, 1H),
			1.29(d, 1H),
			0.69(m, 1H).
856	391.38	1.74
857	462	2.42
858	402.4	1.98
859	414	2.26
860	406.4	1.99	DMSO(d6):
			9.05(m, 1H), 8.18(d,
			1H), 7.35(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.42(m, 3H), 3.06(m,
			2H), 2.42(m, 2H),
			2.34(m, 2H),
			2.18(m, 2H), 2.01(m,
			1H), 1.86(s, 3H),
			1.81(m, 3H),
			1.72({m, 3H), 1.63(m,
			1H), 1.54(d, 1H),
			1.41(m, 2H),
			1.32(t, 2H), 1.01(dt,
			1H).
861	367.4	1.65
862	411.2	1.81	(DMSO-d6, ppm)
			9.03(br s, 1H),
			7.59(d, J=8Hz, 1H),
			7.45(m, 2H),
			3.43(m, 2H), 3.16(q, J=10Hz,
			23Hz, 2H),
			2.77(s, 2H),
			2.39(s, 3H), 2.03(m,
			3H), 1.72(m, 6H),
			1.53(m, 8H).
863	311.2	1.99
864	400.2	1.84	CD3OD:
			7.64(d, 1H),
			7.35-7.39((m, 2H),
			4.21(q, 2H),
			3.64(m, 2H),
			3.46(m, 1H),
			3.30(m, 2H),
			3.17(d, 2H),
			2.98(s, 2H),
			2.10-2.30(m, 3H),
			1.49-1.80(m, 10H),
			1.29-1.35(m, 4H)
865	373	2.06
866	455.2	2.19
867	357.2	2
868	390.2	2.1
869	428	2.02
870	528.3	2.56
871	422	1.79
872	428.2	2.14	:
873	449.5	2.69	DMSO(d6):9.02(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			4.14(m, 1H), 3.66(m,
			2H), 3.43(m, 3H),
			3.18(m, 4H),
			3.07(t, 1H), 2.18(m,
			2H), 2.05(m, 1H),
			2.00(s, 3H),
			1.87(s, 3H), 1.82(m,
			4H), 1.74(d, 1H),
			1.69-1.50(m, 4H),
			1.41(m, 1H),
			1.22(m, 1H).
874	412.2	1.52	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.96(d, 2H), 3.58(s,
			3H), 3.42(m, 2H),
			3.16(m, 4H),
			2.79(m, 2H),
			2.22-2.14(m, 2H), 2.04(dd,
			1H), 1.87(s, 3H),
			1.83(m, 3H),
			1.74(d, 1H),
			1.68-1.60(m, 5H), 1.51(m,
			1H), 1.07(ddd,
			2H).
875	428.2	1.69
876	426.3	2.4
877	369	2.15
878	353	2.3
879	445.2	2.2
880	403.4	1.62	DMSO(d6):
			9.35(m, 1H), 8.19(d,
			1H), 7.42(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.15(d, 1H),
			4.91(m, 1H),
			3.39(m, 1H),
			3.32-3.15(m, 4H), 2.28(m,
			2H), 2.06(m, 3H),
			1.87(s, 3H),
			1.82(m, 3H), 1.71(m,
			5H), 1.62(m, 1H),
			1.51(m, 5H).
881	355.4	1.57	DMSO(d6):
			8.89(br. s, 1H), 8.18(d,
			1H), 7.41(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(q, 1H),
			3.42(t, 2H), 3.15(t, 2H),
			2.99(t, 2H),
			2.36-2.25(m, 2H),
			2.04(dd, 1H), 1.87(s,
			3H), 1.85-1.57(m,
			11H), 1.27(q, 2H),
			1.18(t, 1H),
			1.00(q, 2H).
882	355.4	1.65
883	422.3	1.9
884	373.2	2.29
885	469.2	1.89
886	410.2	1.83
887	483.2	1.9	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.44(m, 5H), 3.18(m,
			4H), 2.89(m, 1H),
			2.72(s, 6H),
			2.18(m, 2H), 2.05(dd,
			1H), 1.87(s, 3H),
			1.82(m, 4H),
			1.73(d, 1H),
			1.66-1.48(m, 5H), 1.42(m,
			1H), 1.13(m, 1H).
888	441.3	1.69	DMSO(d6):
			8.74(br.s, 1H), 8.39(d,
			1H), 7.41(d, 1H),
			7.31(t, 1H), 7.21(t,
			1H), 7.16(d, 1H),
			4.95(q, 1H),
			3.41(t, 2H), 3.16(t, 2H),
			3.16(t, 2H),
			2.29(ddd, 2H), 2.06(dd,
			1H), 1.86-1.61(m,
			11H), 1.88(ddd,
			1H), 1.28(q, 2H),
			1.18(tt, 1H),
			1.00(q, 2H),
			0.78-0.63(m, 4H).
889	381.4	1.83
890
891	444.4	2.47
892	401	2.51
893	448.4	2.11
894	397	1.99
895	439.4	1.76
896	470.4	2
897	448	1.93
898	483.4	1.78
899	481.3	1.78
900	455.2	1.78	CD3OD:
			7.74(dd, 1H),
			7.68(d, 1H), 7.61(d,
			1H), 3.69(m, 2H),
			3.48(m, 1H),
			3.30(m, 2H),
			2.81(s, 2H),
			2.46(m, 3H),
			2.15(m, 1H),
			1.88(m, 2H),
			1.49-1.75(m, 7H),
			1.30(m, 1H)
901	330	1.75
902	369	2.28
903	457.2	1.75	1H NMR-MeOD:
			7.46(d, J=7.3Hz,
			1H), 7.30(dd, J=7.2,
			15.1Hz, 2H),
			7.21(d, J=7.2Hz,
			1H), 4.18-4.15(m,
			1H), 3.62(m, 2H),
			3.50(m, 1H),
			3.22-3.18(m, 2H),
			2.71(m, 1H),
			2.49-2.41(m, 3H), 2.4-2.1(m,
			3H), 1.99(m, 1H),
			1.80-1.65(m, 3H),
			1.58-1.5(m, 4H),
			1.22(d, 1H)
904	326.2	1.6
905	422.2	1.81
906	442.6	2.23
907	476.2	2.53
908	468.2	2.51
909	528.3	2.56
910	400.2	1.84
911	476	2.46	DMSO(d6):8.15(d,
			1H), 7.41(d, 1H),
			7.21(ddd, 1H),
			7.12(m, 2H), 4.81(m,
			1H), 3.95(d, 2H),
			2.61(m, 4H),
			2.42(m, 3H), 1.94(m,
			3H), 1.86(s, 3H),
			1.76(m, 3H),
			1.67(t, 1H), 1.61(d,
			1H), 1.47(d, 1H),
			1.39(s, 9H),
			1.30(ddd, 2H).
912	442.4	1.68
913	406.4	2.01
914	489.2	2.03
915	342.2	1.91
916	303.2	1.56
917	495.4	1.93
918	454.4	2.52
919	356.3	1.94
920	483.2	1.99
921	449.2	1.77
922	313.4	1.5
923	372.2	1.56
924	303.2	1.21
925	347	2.11	in DMSO-d6
926	371.4	1.6
927	398.2	1.8	DMSO-d6:
			9.93-9.62(m, 1H),
			8.30-8.24(m, 1H),
			7.53-7.32(m, 1H),
			7.22-7.17(m, 1H),
			7.04-6.96(m, 1H),
			5.35-5.27(m, 1H),
			4.39(br s, 3H), 4.32(s,
			2H), 4.13-4.03(m,
			2H), 3.96(m, 1H),
			3.75-3.73(m, 1H),
			3.68-3.63(m, 1H),
			2.62-2.58(m, 3H),
			2.30-2.20(m, 2H),
			2.08(s, 1H),
			2.00(s, 2H),
			1.95-1.88(m, 2H),
			1.69-1.63(m, 3H), 1.57(d, J=7.9Hz,
			1H),
			1.24-1.15(m, 3H)
928	430.5	1.74
929	424.2	2.23
930	452	2.44	CD3OD:
			7.30-7.63(m, 5H),
			6.61(s, 1H),
			6.35(m, 1H),
			5.65(s, 1H),
			5.43(m, 1H),
			3.73(s, 3H),
			3.56(m, 2H),
			3.47(s, 3H),
			3.20(m, 1H),
			3.03(m, 2H),
			2.33(s, 3H),
			1.10-1.95(brm, 21H)
931	505.6	2.3
932	428.2	1.57
933	401	2.27	in DMSO-d6
934	327.4	1.7
935	339.2	2.08	DMSO(d6):9.01(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.85(d, 2H), 3.59(s,
			3H), 3.42(m, 3H),
			3.17(m, 4H),
			2.87(m, 1H), 2.18(m,
			2H), 2.05(dd, 1H),
			1.87(s, 3H),
			1.83(m, 4H), 1.74(d,
			1H), 1.63(m, 3H),
			1.55(m, 1H),
			1.46(m, 1H), 1.35(q,
			1H), 1.16,(q, 1H)
936	428.2	1.74
937	512.5	2.81
938	487.4	2.04
939	457.4	2
940	400.2	2.19
941	439.4	1.55
942	454.2	1.54
943	430	1.71
944	415.2	1.74	DMSO-d6:9.24(s,
			1H), 7.48(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.14(dd, 1H),
			3.47(m, 2H),
			3.31-3.12(m, 5H), 2.88(m,
			1H), 2.53(m, 1H),
			2.40-2.30(m, 4H),
			2.17-2.04(m, 2H),
			1.91(m, 3H),
			1.84-1.59(m, 7H),
			1.57-1.42(m, 5H).
945	381.36	1.71
946	396.5	2.1
947	396.2	1.68
948	478.2	1.77
949	397.2	1.91
950	480.2	2.23
951	458.4	2.07
952	362.4	1
953	420.2	2.09
954	477.4	1.8
955	367.3	2
956	468	1.04
957	444.4	1.53
958	361.2	2.24
959	441.2	1.93
960	424.27	2.04	DMSO(d6):9.12(s,
			1H), 7.35(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.48(d, 1H),
			4.82(q, 1H),
			4.12(d, 2H), 4.05(q,
			2H), 3.43(m, 4H),
			3.20(m, 2H),
			2.82(s, 6H),
			2.38-2.31(m, 2H), 2.20(dd,
			1H), 2.13-2.06(m,
			2H), 1.95(d, 1H),
			1.83-1.78(m, 1H),
			1.73-1.65(m, 3H),
			1.63-1.53(m, 2H),
			1.19(t, 3H).
961	443.2	1.74	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.29(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.98(d, 2H), 3.77(d,
			2H), 3.42(m, 2H),
			3.16(m, 4H),
			2.79(m, 2H),
			2.22-2.14(m, 2H), 2.05(dd,
			1H), 1.87(s, 3H),
			1.82(m, 3H),
			1.75-1.52(m, 10H),
			1.07(m, 2H), 0.89(d,
			6H).
962	470.3	2.08
963	449.2	1.56
964	455.2	1.65
965	495.4	1.51	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			4.26(d, 2H), 3.42(m,
			2H), 3.16(m, 4H),
			2.77(t, 2H),
			2.22-2.14(m, 2H),
			2.04(m, 1H), 1.87(s,
			3H), 1.83(m, 3H),
			1.72(t, 3H),
			1.65-1.59(m, 4H),
			1.19(s, 9H), 1.05(q,
			2H).
966	454.3	1.82
967	467.4	1.96
968	371.2	2.24
969	448.2	1.65
970	454.2	1.69
971	519	2.15
972	483.2	1.95
973	398.2	2.1
974	433.4	1.88
975	458.4	2.17
976	415	1.43
977
978	500.3	1.7
979	410.19	1.6	MeOD:7.86(m,
			1H), 7.55(d, J=2.5Hz,
			1H), 7.40(dd, J=2.4,
			7.5Hz, 1H),
			4.17(q, J=7Hz,
			2H), 4.10(br s,
			2H), 3.89(br s,
			2H), 3.81(br s,
			2H), 3.02(s, 2H),
			2.94(s, 1H),
			2.79(s, 1H), 2.50(m,
			1H), 2.37(br s,
			1H), 2.32(br d, J=13.0Hz,
			5H),
			2.14(d, J=9.0Hz, 2H),
			1.27(t, J=7Hz,
			3H)
980	387.5	1.91
981	485.2	2.31
982	423	2.2	CD3OD:
			7.70(d, 1H),
			7.67(d, 1H),
			7.52(dd, 1H),
			3.53(m, 2H),
			3.48(m, 1H),
			3.28(m, 2H),
			2.81(s, 2H),
			2.34(m, 2H),
			2.12(m, 4H),
			1.58-1.95(m, 10H)
983	332	1.8
984	355	2.5
985	365.2	2
986	432.4	2.08
987	465.2	1.86
988	467.4	1.58
989	410.2	1.78
990	467.4	1.73
991	456.4	2.51
992	480.2	2.24	DMSO(d6):
			8.80(m, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.16(d, 1H),
			4.93(ddd, 1H),
			3.46(m, 2H), 3.14(m,
			4H), 2.27(m, 3H),
			2.04(dd, 1H),
			1.87(s, 3H), 1.82(m,
			5H), 1.71(d, 1H),
			1.68-1.51(m, 5H),
			1.24(m, 2H).
993	341.2	1.56
994	468.2	2.28
995	464	1.95
996	400.2	1.84
997	475.2	1.61	DMSO(d6):8.85(s,
			1H), 7.36(d, 1H),
			7.28(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.48(d, 1H),
			6.27(dd, 0.8H),
			6.16(m, 0.6H),
			6.04(dd, 0.8H),
			4.82(q, 1H),
			3.45(m, 2H),
			3.19-3.09(m, 2H), 2.98(br.s,
			1H), 2.97-2.90(m,
			1H), 2.85(s, 1H)
			2.82(s, 6H),
			2.79(m, 1H), 2.36(m,
			1H), 2.22(dd, 1H),
			2.11(m, 1H),
			2.02(td, 1H), 1.90(d,
			1H), 1.81-1.64(m,
			4H), 1.37(dd, 2H),
			1.30(d, 1H),
			0.68(d, 1H).
998	394.3	1.95	DMSO(d6):9.03(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.54(d, 2H), 3.42(m,
			2H), 3.16(m, 4H),
			2.71(s, 6H),
			2.67(m, 2H),
			2.22-2.14(m, 2H), 2.04(m,
			1H), 1.87(s, 3H),
			1.82(m, 3H),
			1.73(d, 1H), 1.64(m,
			5H), 1.48(m, 1H),
			1.13(q, 2H).
999	441.3	1.61
1000	398.4	1.68
1001	429.2	1.56	CD3OD:6.86(s, 1H),
			6.75(s, 1H),
			5.35(t, 1H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.60(m, 2H),
			3.45(m, 1H),
			3.10(m, 2H),
			2.71(m, 2H),
			2.45(m, 2H),
			2.00(s, 1H),
			1.50-2.20(brm, 11H0,
			1.25(m, 1H),
1002	399.6	1.78
1003	432.4	1.98
1004	448.2	1.91	in DMSO-d6
1005	368.5	1.9
1006	459.4	1.66
1007	485.3	2.2
1008	430.4	2.2
1009	359	2.09	DMSO(d6):9.01(s,
			1H), 7.32(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.48(d, 1H),
			4.82(q, 1H),
			3.42(d, 2H),
			3.18-3.02(m, 4H), 2.82(s,
			6H), 2.30(t, 1H),
			2.21(m, 2H),
			2.01(m, 2H), 1.92(d,
			1H), 1.80(m, 1H),
			1.73-1.63(m, 4H),
			1.52-1.43(m, 4H),
			1.39-1.32(m, 2H),
			1.17-1.03(m, 4H).
1010	410.3	2.21
1011	412.3	1.9
1012	420.2	1.66
1013	410.2	1.78	DMSO-d6:9.78(s,
			1H), 7.43(d, 1H),
			7.29(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.14(dd, 1H),
			4.05(m, 2H), 3.74(m,
			1H), 3.45(dd, 2H),
			3.21(q, 1H),
			3.08(m, 2H), 2.88(ddd,
			1H), 2.42-2.29(m,
			3H), 2.09(m, 4H),
			1.97-1.60(m, 16H),
			1.15(t, 3H).
1014	466.37	1.67
1015	422.2	1.78
1016	379.5	2
1017	367.5	1.9
682	422.2	1.78
683	381.2	2.38
684	463.2	2.19
685	492	2.2
686	455.2	1.78
687	356.3	1.6
688	329.5	0.88	H NMR(500MHz,
			DMSO) 8.97(s,
			1H), 7.32-7.15(m,
			4H), 6.52(d, J=8.5Hz,
			1H), 6.27(dd, J=3.0,
			5.5Hz, 1H),
			6.05(dd, J=2.6,
			5.5Hz, 1H),
			5.26(dd, J=8.0, 16.4Hz,
			2H), 3.54(d, J=11.6Hz,
			2H),
			3.25-2.58(m,
			13H),
			2.40-2.36(m, 1H),
			2.04-2.01(m, 1H),
			1.85-1.68(m, 4H),
			1.40-1.23(m, 2H),
			0.72-0.67(m, 1H),
689	379.3	1.9
690	438.2	1.97
691	400.2	1.8
692	374.2	1.02	CD3OD:6.85(s, 1H),
			6.77(s, 1H),
			5.36(t, 1H),
			4.30(m, 2H),
			4.13(q, 2H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.45(m, 3H),
			3.20(m, 1H),
			2.72(dd, 1H),
			2.35(m, 1H),
			2.10(m, 2H),
			2.00(s, 3H),
			1.59-190(m, 14H)
693	401.6	1.85
694	443.4	1.9
695	426.2	1.93
696	424.2	2.31
697	495.2	1.91	NMR(500MHz,
			DMSO-d6)
			8.98(br. s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.32(t, 1H), 7.22(t,
			1H), 7.19(d, 1H),
			6.27(dd, 1H),
			6.17-6.15(m, 1H),
			6.05(q, 1H),
			4.94-4.92(m, 1H), 3.45(m,
			2H), 3.20-3.13(m,
			2H), 2.98(br.s,
			1H), 2.95(m, 1H),
			2.86(br.s, 1H),
			2.85-2.79(m, 1H),
			2.28-2.22(m, 2H),
			2.07-1.99(m, 2H),
			1.87(s, 3H),
			1.83-1.78(m, 3H), 1.73(d,
			1H), 1.65-1.61(m,
			1H), 1.39-1.29(m,
			3H), 0.70(dt, 1H).
698	365.32	1.63	:
699	395.5	2.69	1H NMR(500MHz,
			DMSO(d6)):
			8.98(s, 1H),
			7.37(d, 1H), 7.22(t, H),
			7.10(t, 1H),
			7.07(d, 1H), 6.27(q, 0.7H),
			6.18-6.14(m,
			0.6H), 6.05(q,
			0.7H), 3.43(m,
			2H), 3.30-3.21(m,
			1H), 3.22-3.10(m,
			2H), 2.98(s, 1H),
			2.95-2.90(m, 1H),
			2.85(s, 1H),
			2.85-2.80(m, 1H),
			2.73(t, 2H),
			2.28-2.22(m, 2H), 2.00(ddd,
			1H), 1.89-1.87(m,
			2H), 1.78-1.67(m,
			4H), 1.39-1.29(m,
			2H), 0.72-0.67(m,
			1H).
700	308.6	2.01
701	400.1	1.81
702	494.4	1.97	DMSO(d6):
			9.53(br. s), 8.18(d, 1H),
			7.40(d, 1H),
			7.30(t, 1H), 7.19(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.40(m,
			2H), 3.14(t, 2H),
			3.07(m, 2H),
			2.27(m, 2H), 2.05(dd,
			1H), 1.87(s, 3H),
			1.81(m, 3H),
			1.74-1.59(m, 9H),
			1.27-1.12(m, 6H),
			0.89(m, 2H).
703	383.44	1.96
704	410.2	2.19
705	416.6	1.3
706	438.4	2.44
707	485.4	2.22
708	386.3	1.2
709	438.4	1.39
710	416.4	1.62
711	438.4	1.95
712	486.2	2.2
713	371.2	2.12
714	447.2	1.6
715	417.4	1.66
716	444.4	1.98
717	496.5	2.57
718	492.4	2.24
719	396.2	1.95
720	404.4	2.26
721	324.2	2.08
722	411.2	2
723	440.4	1.99
724	404.4	1.97
725	390.4	1.03
726	469.3	1.78
727	454.2	2.23
728	448.4	2.13
729	400.2	1.84
730	471.4	2.13
731	372.3	1.2
732	424.4	1.98
733	386.2	1.73
734	324.2	2.05
735	383.2	1.94
736	471.4	2.16	DMSO(d6):
			9.06(br. s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			6.27(dd, 1H),
			6.05(m, 1H), 4.92(q,
			1H), 3.47(m, 3H),
			3.15(m, 2H),
			2.98(s, 1H), 2.93(dd,
			1H), 2.85(s, 1H),
			2.80(ddd, 1H),
			2.25(m, 2H), 2.20(m,
			2H), 1.87(s, 3H),
			1.81(m, 3H),
			1.71(d, 1H), 1.62(m,
			1H), 1.35(t, 1H),
			1.30(d, 1H),
			0.68(dq, 1H).
737	365.3	1.61
738	394.5	2
739	328.2	1.7
740	406.4	1.65
741	353.3	1.8
742	504	2.28
743	442.4	1.66
744	396	1.71
745	428.6	1.89
746	412.3	2.3
747	428.2	2.11
748	464.4	1.92	(CDCl3, ppm)
			11.89(br s, 1H),
			7.47(m, 3H),
			6.22(s, 2H) 5.98(s, 1H),
			3.75(br s, 2H),
			3.00(s, 2H), 2.86(s,
			1H), 2.58(m, 5H),
			2.57(m, 3H),
			2.38(s, 3H), 2.06(m,
			1H), 1.65(m, 2H),
			1.48(m, 1H),
			1.27(m, 1H), 0.72(d, J=11Hz,
			1H).
749	321.9	1.76
750	480	2.43
751	509.4	2
752	343.2	1.9
753	400.2	1.84	DMSO(d6):9.03(s,
			1H), 7.31(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.47(d, 1H),
			4.81(m, 1H),
			4.39(m, 1H), 4.34(m,
			1H), 4.26(m, 1H),
			4.10(q, 2H),
			3.45(m, 2H),
			3.21-3.08(m, 2H), 2.82(s,
			6H), 2.68-2.61(m,
			3H), 2.23(m, 1H),
			2.03-1.92(m, 5H),
			1.79(m, 1H),
			1.73-1.62(m, 5H),
			1.57(d, 1H), 1.51(t,
			1H), 1.19(t, 3H).
754	469.3	1.87	DMSO(d6):
			9.17(br.s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.16(d, 1H),
			4.93(m, 1H),
			3.55(td, 1H), 3.43(d,
			2H), 3.19(m, 2H),
			2.29(td, 1H),
			2.24(td, 1H), 2.06(dd,
			1H), 1.87(s, 3H),
			1.83(m, 6H),
			1.63(m, 1H), 1.27(t,
			3H), 1.08(d, 1H),
			1.04(s, 6H),
			0.97(s, 6H).
755	397.4	1.94
756	392.2	1.62
757	353.3	1.5
758	426.2	1.91
759	430.2	2.12
760	400.2	1.83
761	447.4	2	CD3OD:
			6.85(s, 1H),
			6.78(s, 1H),
			5.36(t, 1H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.60(m, 2H),
			3.10-3.20(m, 2H),
			3.02(d, 2H),
			2.72(dd, 1H),
			2.25(m1H),
			2.03(m, 1H),
			2.00(s, 3H),
			1.65-1.95(m, 8H),
			1.38(m, 2H),
			1.26(m, 1H),
			1.07(m, 2H)
762	401.5	1.8
763	361.4	2.2
764	484.4	2.17	DMSO(d6):
			9.25(m, 1H), 8.19(d,
			1H), 7.39(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.93(ddd, 1H),
			3.49(t, 2H), 3.18(m,
			2H), 3.05(t, t, 2H),
			2.25(ddd, 2H),
			2.06(dd, 1H), 1.87(s,
			3H), 1.83(m, 3H),
			1.75(d, 1H),
			1.63(m, 1H), 1.10(m,
			1H), 0.68(m, 2H),
			0.39(m, 2H).
765	313.2	1.27
766	450	2.04
767	422.2	1.79
768	439.4	1.44
769	400.2	1.88
770	403.5	2.1
771	459.2	1.67	CD3OD:6.86(s, 1H),
			6.77(s, 1H),
			5.36(t, 1H),
			4.30(m, 2H),
			4.13(q, 2H),
			3.83(s, 3H),
			3.81(s, 3H),
			3.54(m, 2H),,
			3.15(m, 3H),
			2.70(m, 1H),
			2.30(m, 1H),
			2.15(m, 2H), 2.00(s, 3H),
			1.70-2.009m, 7H0,
			1.25-1.60(m, 5H)
772	387	1.46
773	446.3	2.41
774	528.3	2.6
775	416.2	1.8
776	408.21	1.89
777	424.2	2.29
778	485.4	2.32
779	439.4	1.66
780	468.2	2.1
781	325.2	1.3
782	467.4	1.61
783	444.5	2.37
784	354.3	1.3
785	455	2.02
786	438.4	1.46	500mHz, MeOH-
			d4; 7.36(d, 1H),
			7.30-7.22(m, 3H),
			5.20-5.17(m, 1H),
			3.01(br s, 2H),
			2.52-2.48(m, 1H),
			2.39(s, 2H),
			2.25-2.0(m, 4H),
			1.95-1.49(m, 6H),
			1.45-1.29(m, 5H),
			0.99-0.97(m, 1H)
787			DMSO(d6):
			9.50(br.s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			4.12(d, 2H), 4.05(q,
			2H), 3.40(m, 3H),
			3.19(m, 2H),
			2.82(m, 2H), 2.25(m,
			2H), 2.09(d, 2H),
			2.03(td, 1H),
			1.86(s, 3H), 1.82(m,
			4H), 1.61(m, 3H),
			1.19(t, 3H).
788	414.3	1.46	DMSO-d6:
			9.95-9.58(m, 1H),
			8.30-8.26(m, 1H),
			7.53-7.40(m, 1H),
			7.21-7.18(m, 1H),
			7.03-6.98(m, 1H),
			5.36-5.28(m, 1H),
			4.08-4.05(m, 4H),
			3.78(s, 1H),
			3.68-3.65(m, 2H), 2.80(br s,
			2H), 2.72(s, 1H),
			2.69-2.63(m, 1H),
			2.58(s, 2H),
			2.20-2.07(m, 1H),
			2.03(s, 2H),
			1.97-1.90(m, 3H),
			1.82-1.77(m, 1H),
			1.51-1.47(m, 2H),
			1.21-1.18(m, 3H)
789	404.5	1.65
790	416.4	1.57
791	419.4	1.75
792	448.2	1.65
793	300.2	1.46
794	446.3	2.13
795	485.4	1.78
796	447.2	2.4	CD3OD:
			6.86(s, 1H),
			6.79(s, 1H),
			5.37(m, 1H),
			3.84(s, 3H),
			3.82(m, 3H),
			3.40(m, 2H),
			3.55(m, 3H),
			3.00-3.20(m, 2H),
			2.70(m, 1H),
			2.48(m, 2H),
			1.77-2.10(m, 19H
			including 3H
			singlet at 2.00)
797	439.6	1.9
798	332.2	0.75
799	314.2	1.64
800	410.2	1.81
801	456.5	2.17
802	454.2	2.03
803	467.4	1.76
804	441.4	1.76
805	428.4	2.4
806	442.4	2.24
807	486.8	2.23
808	349.2	2.03
809	447.4	1.99
810	451.8	2.24
811	416.4	1.82
812	443.2	1.93
813	413.2	1.48
814	410.4	1.91
815	410.2	2.2
816	444.4	2.08	CD3OD:
			6.86(s, 1H),
			6.78(s, 1H),
			5.36(m, 1H),
			3.83(s, 3H),
			3.82(m, 3H),
			3.55(m, 3H),
			3.15-3.25(m, 2H),
			2.25(m, 1H),
			2.35(m, 1H),
			2.00(s, 3H),
			1.80-1.90(m, 5H),
			1.36(m, 2H),
			1.12(s, 6H),
			1.04(s, 6H)
817	442.3	2.1
818	440.4	2.17	DMSO(d6):
			9.40(br. s), 8.18(d, 1H),
			7.38(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.41(m,
			2H), 3.13(m, 4H),
			2.24(m, 2H),
			2.05(dd, 1H), 1.87(s,
			3H), 1.84-1.76(m,
			3H), 1.74-1.65(m,
			5H), 1.64-1.56(m,
			4H), 1.33-1.12(m,
			4H), 0.96(m, 2H).
819	369.43	1.82	DMSO-d6:
			7.69(d, 1H), 7.52(d,
			2H), 7.43(d, 2H),
			7.25(d, 2H),
			7.01(d, 2H),
			6.26(m, 1H),
			6.06(d, 1H),
			4.95(m, 1H),
			4.49(m, 1H),
			3.77(s, 3H),
			3.55(m, 2H),
			2.42(m, 1H),
			2.79-3.15(m, 7H),
			1.94-2.11(m, 3H),
			1.71(d, 3H),
			0.68-0.70(m, 2H)
820	477	1.58
821	444.4	1.5
822	434	2.14
823	484.2	1.76
824	410.2	2.21
825	413	1.68	DMSO(d6):
			9.25(br. s), 8.17(d, 1H),
			7.37(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.93(d,
			2H), 3.42(m, 3H),
			3.15(m, 4H),
			2.71(m, 1H), 2.20(m,
			2H), 2.04(dd, 1H),
			1.87(s, 3H),
			1.82(m, 3H), 1.72(d,
			1H), 1.63(m, 5H),
			1.49(m, 1H),
			1.39(s, 9H), 1.04(ddd,
			1H).
826	470.4	1.82	DMSO(d6):
			8.92(br.s, 1H), 8.39(d,
			1H), 7.39(d, 1H),
			7.32(t, 1H), 7.21(t,
			1H), 7.16(d, 1H),
			6.27(dd, 1H),
			6.05(m, 1H), 4.95(q,
			1H), 3.45(m, 3H),
			3.28-3.10(m, 3H),
			2.98(s, 1H),
			2.94(ddd, 1H), 2.85(s,
			1H), 2.81(ddd,
			1H), 2.25(m, 2H),
			2.03(ddd, 2H),
			1.82(m, 3H),
			1.71(d, 1H), 1.65(m,
			1H), 1.58(m, 1H),
			1.38(dd, 1H),
			1.29(d, 1H),
			0.78-0.63(m, 4H).
827	391.38	1.83
828	303.2	1.93
829	424.2	1.99
830	422.2	1.79
831	490.2	1.79	DMSO(d6):
			9.14(br. s), 8.17(d, 1H),
			7.36(d, 1H),
			7.30(t, 1H), 7.20(t, 1H),
			7.16(d, 1H),
			4.92(q, 1H), 3.4(m,
			2H), 3.18-3.01(m,
			4H), 2.21(m, 3H),
			2.04(dd, 1H),
			2.00(s, 1H), 1.87(s,
			3H), 1.82(m, 3H),
			1.72(d, 1H),
			1.64(m, 2H), 1.47(m,
			4H), 1.35(m, 2H),
			1.17-1.02(m, 4H).
832	381.4	1.89
833	357.2	2.1
834	480.2	2.2
835	459.4	2.08
836	439.2	1.95
837	355.23	1.59
838	418.4	1.9
839	495.4	2.01
840	424.2	1.95
841	445.6	1.88	H NMR(500MHz,
			DMSO(d6)):
			9.14(s, H), 7.36(d, 1H),
			7.22(t, 1H), 7.09(t,
			1H), 7.07(d, 1H),
			4.10(d, 2H),
			4.05(q, 2H),
			3.48-3.39(m, 4H), 3.19(q,
			2H), 2.83(m, 2H),
			2.71(t, 2H),
			2.27(td, 2H), 2.09(d,
			2H), 1.87(m, 2H),
			1.77(d, 2H),
			1.72-1.68(m, 2H),
			1.58(qd, 2H), 1.22(t,
			3H).
842	357.4	1.87
843	471.4	1.83
844	468.3	1.61
845	453.4	1.4
846	459.4	2.01
847	434	2.14
848	391.2	2.16
849	473.4	2.28	CD3OD:
			6.86(s, 1H),
			6.77(s, 1H),
			5.35(m, 1H),
			3.83(s, 3H),
			3.82(m, 3H),
			3.15-3.25(m, 3H),
			2.25(m, 1H),
			2.35(m, 1H),
			2.00(s, 3H),
			1.40-1.90(m, 26H)
850	471.6	2.3
851	383.4	2.28
852	404.4	1.86	DMSO(d6):
			9.09(m, 1H), 8.18(d,
			1H), 7.38(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.16(d, 1H),
			4.92(ddd, 1H),
			3.86(t, 1H), 3.78(ddd,
			1H), 3.67(q, 1H),
			3.43(m, 3H),
			3.19(m, 4H), 3.66(m,
			1H), 2.25(m, 2H),
			2.12(m, 1H),
			2.05(dd, 1H), 1.87(s,
			3H), 1.82(m, 3H),
			1.73(d, 1H),
			1.63(m, 2H).
853	343.1	0.97
854	454.2	2.13
855	440.4	2.08	DMSO(d6):
			8.85(br.s, 1H), 8.18(d,
			1H), 7.41(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.42(m, 2H), 3.14(m,
			2H), 3.00(t, 2H),
			2.29(m, 2H),
			2.05(m, 1H), 1.86(s,
			3H), 1.85-1.58(m,
			11H), 1.26(m, 2H),
			1.17(m, 1H),
			0.99(m, 2H).
856	355.3	1.71
857	454.2	2.24
858	442.4	1.69
859	439.4	1.73	CD3OD:
			7.73(dd, 1H),
			7.67(d, 1H), 7.63(d,
			1H), 3.50(,.2H),
			3.26(m, 2H),
			2.83(s, 2H),
			2.37(m, 2H),
			2.13(m, 2H),
			1.60-1.90(m, 12H)
860	332	1.84
861	414.4	1.96
862	432.4	1.86
863	314.2	1.59
864	412.2	2.01
865	471.4	2
866	454.2	1.98	DMSO(d6):8.76(s,
			1H), 8.17(d, 1H),
			7.39(t, 1H),
			7.31(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.88(dd, 2H), 3.44(m,
			2H), 3.34(t, 2H),
			3.17(m, 2H),
			3.06(t, 2H),
			2.31-2.14(m, 2H),
			2.11-2.02(m, 2H), 1.86(s,
			3H), 1.81(m, 3H),
			1.71(d, 1H),
			1.64(m, 3H), 1.27(ddd,
			2H).
867	357.2	1.48
868	384.2	1.91
869	450.4	2.08
870	456.2	1.72
871	438.2	2.12
872	411.2	2.38
873	324.3	2.07
874	454.2	1.69	DMSO(d6):8.29(s,
			1H), 8.17(d, 1H),
			7.45(d, 1H),
			7.31(t, 1H), 7.20(t, 1H),
			7.17(d, 1H),
			4.93(m, 1H), 3.38(m,
			2H), 3.20-3.09(m,
			3H), 2.34(qd, 2H),
			2.25-2.13(m, 2H),
			2.08-2.03(m, 1H),
			1.87(s, 3H),
			1.83(m, 4H),
			1.74-1.60(m, 4H), 1.55(d,
			2H), 1.33-1.22(m,
			4H), 0.82(s, 6H),
			0.79(t, 3H).
875	411.3	2.34
876	469.2	2.32
877	386.2	1.72	DMSO(d6):
			9.06(br.s, 1H), 7.47(d,
			1H), 7.45(d, 1H),
			7.32(t, 1H), 7.24(t,
			1H), 6.26(dd, 1H),
			6.04(dd, 1H),
			4.45(q, 1H), 3.38(m,
			2H), 3.15(m, 2H),
			3.05(s, 3H),
			2.98(s, 1H), 2.93(ddd,
			1H), 2.85(s, 1H),
			2.80(ddd, 1H),
			2.23(m, 2H), 2.07(m,
			1H), 2.01(ddd,
			1H), 1.94(m, 1H),
			1.86(dd, 1H),
			1.78(m, 2H), 1.69(d,
			1H), 1.38(d, 1H),
			1.35(d, 1H),
			1.29(d, 1H), 0.68(dq,
			1H).
878	401.35	1.79
879	433.4	1.78
880	505.4	2.03
881	487	2.31
882	442.3	1.52
883	404.4	1.9
884	485.4	1.94
885	404.4	1.88
886	398.3	2.2	DMSO(d6):
			9.16(br. s, 1H), 8.18(d,
			1H), 7.36(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.91(q, 1H),
			3.31(m, 2H), 3.20(t,
			2H), 3.13(t, 2H),
			2.74(m, 1H),
			2.25-2.09(m, 4H),
			2.04(dd, 1H), 1.91(m,
			1H), 1.87(s, 3H),
			1.82(m, 6H),
			1.71(d, 1H), 1.62(m,
			1H).
887	327.3	1.42
888	410.2	1.86
889	383.4	2.28
890	393.5	2.1	CD3CN:
			7.50-7.35(m, 1H),
			7.12-7.05(m, 1H),
			7.02-6.99(m, 1H),
			6.86-6.77(m, 1H),
			5.42-5.35(m, 1H),
			3.88-3.84(m, 2H),
			3.36-3.13(m, 4H),
			2.72(dd, J=7.5, 12.7Hz,
			1H),
			2.63-2.54(m, 1H), 2.32(s,
			1H), 2.29(s, 1H),
			2.23-2.18(m, 4H),
			2.12-1.93(m, 1H),
			1.89-1.79(m, 1H),
			1.57-1.34(m, 5H),
			1.27-1.21(m, 2H),
			0.87-0.75(m, 1H)
891	357.1	1.71
892	383.4	2.24	1H NMR(500MHz,
			DMSO(d6)):
			8.50(br. s, 1H),
			7.41(d, 1H),
			7.22(t, 1H), 7.13(t, 1H),
			7.06(d, 1H),
			3.50(m, 2H), 3.38(m,
			1H), 3.30(m, 1H),
			3.22-3.10(m, 2H),
			2.72(t, 2H),
			2.37-2.25(m, 4H),
			2.01(t, 1H),
			1.90-1.87(m, 2H),
			1.75-1.59(m, 8H),
			1.52-1.37(m, 2H),
			1.30-1.15(m, 2H).
893	296.3	1.9	CD3OD:
			7.38-7.63(m, 5H),
			6.66(s, 1H),
			6.45(m, 1H),
			5.70(s, 1H),
			5.40(m, 1H),
			3.73(s, 3H),
			3.54(m, 2H),
			3.47(s, 3H),
			2.33(s, 3H),
			2.16(m, 4H),
			1.96(m, 4H),
			1.20-1.75(m, 13H)
894	491.6	2.2
895	347.4	1.91
896	471.4	2.17	DMSO(d6):8.35(s,
			1H), 8.18(d, 1H),
			7.45(d, 1H),
			7.31(t, 1H), 7.21(t, 1H),
			7.17(d, 1H),
			4.93(m, 1H), 3.55(m,
			2H), 3.37(m, 1H),
			3.20-3.09(m, 2H),
			2.34(qd, 2H),
			2.24-2.13(m, 2H),
			2.06(m, 1H), 1.87(s,
			3H), 1.90-1.81(m,
			3H), 1.74-1.58(m,
			5H), 1.30(q, 2H),
			1.15(m, 2H),
			0.88(s, 9H).
897	397.2	2.2	DMSO-d6:9.12(s,
			1H), 7.49(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.14(dd, 1H),
			3.39(dd, 2H),
			3.24-3.07(m, 3H), 2.98(t,
			2H), 2.88(ddd,
			1H), 2.59(td, 1H),
			2.41-2.29(m, 3H),
			2.19(td, 1H),
			1.95-1.59(m, 13H),
			1.27(m, 2H), 1.17(tt,
			1H), 0.99(m, 2H).
898	381.4	1.78
899	492.4	2.22
900	471.4	1.85	H NMR(500MHz,
			DMSO) 8.60(br s,
			1H, from TFA),
			8.44(d, J=8.0Hz,
			1H), 7.32(dt, J=25.2,
			8.1Hz, 2H),
			7.21(dd, J=7.3,
			18.5Hz, 2H),
			5.39(q, 1H),
			4.07-2.97(m, 4H, partially
			obscured by
			solvent),
			2.70-2.60(m, 2H),
			2.45-2.31(m, 2H),
			2.07-1.91(m, 2H),
			1.72-1.55(m, 8H),
			1.46-1.41(m, 3H),
			1.25-1.17(m, 1H),
			0.77-0.66(m, 4H)
901	365.3	1.9
902	459.4	2.06	NMR(500MHz,
			DMSO-d6)
			8.98(br. s, 1H), 8.18(d,
			1H), 7.40(d, 1H),
			7.32(t, 1H), 7.22(t,
			1H), 7.19(d, 1H),
			6.27(dd, 1H),
			6.17-6.15(m, 1H),
			6.05(q, 1H),
			4.94-4.92(m, 1H), 3.45(m,
			2H), 3.20-3.13(m,
			2H), 2.98(br.s,
			1H), 2.95(m, 1H),
			2.86(br.s, 1H),
			2.85-2.79(m, 1H),
			2.28-2.22(m, 2H),
			2.07-1.99(m, 2H),
			1.87(s, 3H),
			1.83-1.78(m, 3H), 1.73(d,
			1H), 1.65-1.61(m,
			1H), 1.39-1.29(m,
			3H), 0.70(dt, 1H).
903	365.32	1.63
904	530	2.65
905	371.1	2.75	DMSO(d6):
			9.28(br.s, 1H), 8.19(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.42(m, 2H),
			3.25-3.08(m, 4H),
			2.34-2.14(m, 5H), 2.05(t,
			1H), 1.87(s, 3H),
			1.81(m, 4H),
			1.70(d, 1H), 1.63(m,
			1H), 1.49(m, 2H),
			1.37(m, 2H),
			1.30(d, 1H), 1.14(m,
			2H) 0.81(m, 1H).
906	367.4	1.71
907	424.2	1.98	1H NMR(500MHz,
			DMSO(d6)):
			8.82(s, 1H),
			7.33(d, 1H), 7.22(t,
			1H), 7.14(t, 1H),
			7.06(d, 1H),
			3.43-3.35(m, 3H),
			3.14-3.03(m, 2H),
			2.72(t, 2H),
			2.45-2.39(m, 2H), 2.32(m,
			2H), 2.18(td, 2H),
			1.87-1.84(m, 2H),
			1.76-1.67(m,
			4H), 1.60(t, 2H),
			1.56-1.46(m, 1H),
			1.42(d, 2H),
			1.30(t, 2H), 1.02(dt,
			1H).
908	310.3	2.05
909	450	1.93
910	467.4	1.87
911	439.2	1.74
912	480.2	2.4
913	447.4	1.57	DMSO(d6):
			9.16(br.s, 1H), 8.39(d,
			1H), 7.43(d, 1H),
			7.31(t, 1H), 7.21(t,
			1H), 7.15(d, 1H),
			4.95(q, 1H),
			3.27(m, 3H), 2.31(m,
			2H), 2.07(m, 3H),
			1.85-1.26(m, 18H),
			0.78-0.63(m, 4H).
914	381.44	1.79
915	466.43	1.72
916	431.4	1.78
917	355.4	1.57
918	382.4	2.11	DMSO(d6):
			8.93(br.s, 1H), 7.46(d,
			1H), 7.44(d, 1H),
			7.35(d, 1H),
			7.32(t, 1H), 7.21(t, 1H),
			4.45(q, 1H),
			3.11(m, 2H), 3.04(s,
			3H), 2.35(m, 2H),
			2.15(m, 2H),
			2.05(dd, 1H), 1.97(m,
			2H), 1.86-1.62(m,
			6H), 1.56-1.26(m,
			7H), 1.15(t, 1H).
919	403.34	1.79
920	440.3	1.57
921	355	2.51
922	356.3	1.3
923	410.2	1.82	DMSO(d6):8.68(s,
			1H), 7.38(d, 1H),
			7.27(t, 1H),
			7.24(d, 1H), 7.18(t,
			1H), 6.48(d, 1H),
			4.82(q, 1H),
			3.42(d, 2H), 3.15(m,
			2H), 3.00(t, 2H),
			2.82(s, 6H),
			2.41(td, 1H), 2.22(dd,
			1H), 2.15(td, 1H),
			1.89(d, 1H),
			1.82-1.63(m, 10H),
			1.28(q, 2H), 1.17(m,
			1H), 0.99(q, 2H).
924	384.3	2
925	433.2	1.6
926	471.4	2.17
927	418.2	2.07
928	463.2	0.96
929	482.4	2.24
930	398.2	1.64
931	372.2	1.56
932	416.4	1.62
933	299.1	1.8
934	414.4	1.99
935	456.4	1.81
936	361.2	1.32
937	480.2	2.08
938	396.5	2.1
939	455.4	2.09
940	502.2	2.27
941	384.3	2.1	DMSO-d6:
			10.16-9.77(m, 1H),
			8.28(m, 1H),
			7.54-7.42(m, 1H), 7.19(m,
			1H), 7.03-6.97(m,
			1H), 5.37-5.28(m,
			1H), 3.79-3.74(m,
			1H), 3.69-3.47(m,
			1H), 3.30-3.16(m,
			1H), 2.74-2.62(m,
			1H), 2.58(s, 3H),
			2.19-2.04(m, 3H),
			1.89(m, 3H),
			1.82-1.77(m, 3H),
			1.63(m, 1H),
			1.40-1.35(m, 2H),
			1.28-1.23(m, 2H), 1.10(td, J=12.7,
			9.5Hz, 1H)
942	331.4	1.71	DMSO-d6:
			9.65-9.45(m, 1H),
			8.27(d, J=7.5Hz, 1H),
			7.54-7.45(m, 1H),
			7.50(s, 1H),
			7.22-7.15(m, 1H),
			7.04-6.99(m, 1H),
			6.25(dd, J=3.1, 6.9Hz,
			1H), 6.06-6.04(m,
			1H), 5.34-5.28(m,
			1H), 3.86(d, J=4.1Hz,
			1H),
			3.77-3.69(m, 2H),
			3.31-3.21(m, 2H),
			3.03-3.01(m, 1H),
			2.98-2.94(m, 2H), 2.90(s,
			1H), 2.58(s, 2H),
			2.36(t, J=1.8Hz,
			1H), 2.18-2.12(m,
			1H), 2.02-1.94(m,
			1H), 1.83(s, 3H),
			1.38-1.28(m, 2H)
943	355.4	1.87
944
945	471.4	2.06
946	433.2	1.87	DMSO(d6):
			8.64(m, 1H), 8.18(t,
			1H), 7.43(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(m, 1H),
			3.49(m, 1H), 3.41(t,
			1H), 3.33(t, 1H),
			3.17(m, 2H),
			2.61(s, 1H), 2.31(m,
			3H), 2.02(m, 2H),
			1.86(s, 3H),
			1.85-1.60(m, 8H),
			1.40(m, 3H), 1.20(dd,
			1H).
947	353.3	1.54
948	388.2	0.95
949	447.4	1.89
950	374.2	0.92
951	442.2	2.36
952	429.4	1.71	CD3OD:
			7.63(d, 1H),
			7.39(d, 1H),
			7.35(d, 1H),
			4.21(q, 2H),
			3.63(m, 2H),
			3.30(m, 2H),
			3.17(d, 2H),
			2.98(s, 2H),
			2.24(m, 2H),
			1.75-1.90(m, 8H),
			1.29-1.39(m, 5H),
			1.09(m, 2H)
953	375	2.18
954	342.2	1.7
955	461.4	2.01	1H-NMR(300MHz,
			DMSO-d6):?
			6.87(d, J=8.7Hz,
			1H), 6.69(t, J=7.5Hz,
			1H), 6.40(dd, J=8.7Hz,
			J=4.5Hz,
			1H), 4.42(m,
			2H), 3.28(s, 2H),
			2.78(d, J=11.1Hz,
			1H), 2.58(d, J=11.7Hz,
			1H),
			3.38(m, 1H),
			1.85-2.05(m, 4H),
			1.70-1.85(m, 3H),
			1.40-1.60(m, 4H),
			1.09(dd, J=11.7Hz, J=4.8Hz,
			1H).
956	302.2	1.33
957	447.4	2.01
958	431.2	2.41
959	423.4	1.6	DMSO(d6):9.00(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.85(dd, 2H), 3.4(m,
			2H), 3.29(t, 2H),
			3.15(m, 4H),
			2.22-2.14(m, 2H),
			2.04(dd, 1H), 1.87(s,
			3H), 1.81(m, 3H),
			1.73(d, 1H),
			1.65-1.55(m, 6H),
			1.21(ddd, 2H).
960	371.2	1.52
961	382.4	1.4
962	455.2	2.15
963	477.4	2.15
964	371.2	2.1
965	448.3	2.18	CD3OD:
			7.71(d, 1H),
			7.62(d, 1H),
			7.52(dd, 1H),
			3.68(m, 2H),
			3.48(m, 1H),
			3.30(m, 2H),
			2.80(s, 2H),
			2.40(m, 2H),
			2.15(m, 1H),
			1.88(m, 2H),
			1.56-1.91(m, 4H),
			1.30(m, 1H)
966	318	1.71	DMSO(d6):
			9.20(m, 1H), 8.19(d,
			1H), 7.41(d, 1H),
			7.29(t, 1H), 7.19(t,
			1H), 7.16(d, 1H),
			4.92(m, 1H),
			3.38(m, 2H), 3.20(m,
			2H), 2.26(m, 2H),
			2.10(m, 1H),
			2.03(dd, 1H), 1.87(s,
			3H), 1.85-1.68(m,
			6H), 1.63(m, 3H),
			1.44(q, 2H),
			1.29(q, 2H), 1.12(m,
			2H)
967	341.2	1.46
968	468.4	2.48
969	466	1.67
970	464.2	1.66
971	438.2	1.44
972	443.4	2.03
973	436.2	1.91	DMSO(d6):
			9.07(br.s, 1H), 7.46(d,
			1H), 7.44(d, 1H),
			7.41(d, 1H),
			7.32(t, 1H), 7.23(t, 1H),
			4.45(q, 1H),
			3.04(s, 3H), 2.26(m,
			2H), 2.06(m, 3H),
			1.93(m, 3H),
			1.87-1.67(m, 8H),
			1.59-1.38(m, 8H),
			1.30(m, 1H).
974	391.36	1.76
975	412	1.88
976	440.3	2.5
977	422.5	2.3
978	497.4	1.92
979	463.2	1.04
980	428	1.63
981	448.3	2.18
982	456.3	1.95	H NMR(500MHz,
			MeOD)
			7.72-7.64(m, 3H),
			7.45-7.41(dt, 1H), 3.05(t,
			2H), 2.62(s, 2H),
			2.42-2.38(m, 2H),
			2.27-2.15(m, 3H),
			2.12-2.0(m, 2H),
			1.85-1.77(m, 2H),
			1.60-1.32(m, 7H),
			1.00-0.97(m, 1H),
983	296.2	1.46
984	443.2	1.69
985	398.2	2.19
986	467	2.05
987	426.3	2.4
988	355.4	2.38	1H NMR(500MHz,
			DMSO(d6)):
			9.01(s, H), 7.38(d,
			1H), 7.21(t, 1H),
			7.14(t, 1H),
			7.05(d, 1H), 3.40(m,
			1H), 3.27-3.17(m,
			4H), 2.72(t, 2H),
			2.26(td, 2H),
			2.12-2.05(m, 2H),
			1.88-1.86(m, 2H),
			1.76-1.67(m, 8H),
			1.57-1.46(m, 6H).
989	298.3	2.05
990			DMSO(d6):
			9.12(br.s, 1H), 8.18(d,
			1H), 7.39(d, 1H),
			7.30(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			6.27(m, 1H),
			6.04(m, 1H), 4.92(m,
			1H), 3.44(m, 2H),
			3.14(m, 2H),
			2.98(s, 1H), 2.94(m,
			1H), 2.84(s, 1H),
			2.80(m, 1H),
			2.26(m, 2H), 2.03(m,
			2H), 1.86(s, 3H),
			1.81(m, 3H),
			1.70(d, 1H), 1.62(m,
			1H), 1.37(t, 1H),
			1.29(d, 1H),
			0.68(m, 1H).
991	365.3	1.67	DMSO(d6):9.04(s,
			1H), 8.17(d, 1H),
			7.34(t, 1H),
			7.30(d, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(q, 1H),
			3.79(m, 1H), 3.42(m,
			3H), 3.16(m, 7H),
			2.89(m, 1H),
			2.22-2.14(m, 2H),
			2.05(m, 1H), 1.87(s,
			3H), 1.83(m, 5H),
			1.74(d, 1H),
			1.63(m, 3H), 1.46(m,
			1H), 1.35(m, 1H),
			1.17(q, 1H),
			0.90(d, 6H).
992	470.3	2.13
993	426.2	1.93
994	424.2	1.8	DMSO(d6):
			9.05(br.s, 1H), 8.39(d,
			1H), 7.38(d, 1H),
			7.30(t, 1H), 7.21(t,
			1H), 7.15(d, 1H),
			4.95(q, 1H),
			3.11(m, 2H), 2.35(m,
			2H), 2.25-2.12(m,
			3H), 2.07-1.96(m,
			2H), 1.82(m, 3H),
			1.72(m, 2H),
			1.65(m, 2H),
			1.60-1.25(m, 9H), 1.16(t,
			1H), 0.78-0.63(m,
			4H).
995	393.4	1.83
996	455.3	1.74
997	444.6	1.99
998	436.4	1.89
999	457.2	2
1000	461.4	2.01
1001	443.2	2.08
1002	458.6	2.31
1003	440.4	2.13
1004	372.2	1.53
1005	442.5	2.23
1006	396.62	1.7
1007	444.6	2.19
1008	440.5	2.41
1009	324.2	2.04
1010	369.2	2.15
1011	469.4	1.5
1012	457.2	1.96
1013	467.4	2.21
1014	436.3	2.4	DMSO(d6):
			9.38(m, 1H), 8.19(d,
			1H), 7.37(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 7.17(d, 1H),
			4.92(m, 1H),
			3.53(m, 2H), 3.22(m,
			2H), 3.04(m, 2H),
			2.42(m, 2H),
			2.21(qd, 2H), 2.10(dd,
			1H), 1.91(t, 2H),
			1.87(s, 3H),
			1.84(m, 3H), 1.74(d,
			1H), 1.64(s, 3H).
			1.63(m, 1H),
			1.54(m, 2H), 1.41(m,
			2H), 1.01(s, 6H).
1015	409.4	2.09	CDCl3(ppm):
			7.93(1H, br s),
			7.43(1H, m), 7.36(1H,
			m), 4.35(2H, br s),
			4.12(2H, m),
			3.98(1H, br s),
			3.21(1H, br s),
			3.08(2H, br s),
			2.76(4H, m), 2.05(3H,
			m), 1.62(1H, br s),
			1.28(6H, m).
1016	360.9	1.68	DMSO-d6:9.16(s,
			1H), 7.55(d, 1H),
			7.31(t, 1H), 7.20(t,
			1H), 6.93(d, 1H),
			5.15(dd, 1H),
			3.47(m, 1H), 3.34(t,
			2H), 3.24-3.11(m,
			3H), 2.88(q, 1H),
			2.60(t, 2H),
			2.41-2.26(m, 5H),
			2.08-1.33(m, 13H),
			1.28-1.14(m, 2H).
1017	379.35	1.63
1018	392.2	1.62
1019	415	1.43
1020	400	1.7
1021	430	1.71
1022	467.4	1.87
1023	467.4	1.96
1024	455.2	2.15
1025	455.2	2.19
1026	455	2.02
1027	467.4	1.76
1028	467	2.05
1029	467.4	1.73
1030	485.4	2.12
1031	439.4	1.76
1032	439.4	1.75
1033	439.4	1.66
1034	444.4	1.53
1035	439.2	1.74
1036	439.4	1.73
1037	444.4	1.5
1038	444.4	1.5
1039	438.2	1.44
1040	438.4	1.46
1041	443.2	1.93

TABLE 3 — Compound activities and efficacies for modulating M 1 and M 4 receptors.

Cmd	M 1	M 4	M 1	M 4
No.	Activity	Activity	Efficacy	Efficacy
1	xx	xx	xx	xxx
2	x	x	x	x
3	xxx	xx	xx	xx
4	xxx	x	x	x
5	xxx	xxx	xx	xxx
6	xxx	xx	xx	xx
7	xxx	xx	xx	xxx
8	xx	xx	x	xx
9	xxx	x	xx	xx
10	xx	xx	xx	xx
11	x	x	x	x
12	xxx	xx	x	x
13	xx	x	xx	x
14	xxx	xxx	xx	xxx
15	xxx	xx	xx	xxx
16	xxx	xxx	xx	xx
17	xx	xx	x	xx
18	xxx	xx	x	xxx
19	xxx	xx	xx	xx
20	x	xx	x	x
21	xx	x	x	x
22	xxx	x	xx	x
23	xx	x	x	x
24	xx	x	x	x
25	xxx	xxx	xx	xxx
26	xxx	xx	xx	x
27	xxx	xxx	xx	xx
28	xxx	xx	xxx	xx
29	xxx	xxx	xxx	xxx
30	xxx	xxx	xxx	xxx
31	xxx	xxx	xxx	xx
32	xxx	xxx	xxx	xx
33	xxx	xxx	xxx	xxx
34	xxx	xx	xx	xxx
35	xxx	xx	xxx	xxx
36	xxx	xx	xx	xxx
37	xxx	xx	xx	xxx
38	xxx	xxx	xxx	xxx
39	xxx	xx	xx	xxx
40	xxx	xx	xx	xxx
41	xxx	xxx	xxx	xxx
42	xxx	xx	xxx	xxx
43	xxx	x	xxx	xxx
44	xxx	xx	xx	xxx
45	xxx	xxx	xxx	xx
46	xxx	xxx	xxx	xx
47	xxx	xx	xx	xx
48	xxx	xx	xxx	xx
49	xxx	xxx	xxx	xx
50	xxx	xx	xxx	xxx
51	xxx	xx	xx	xx
52	xxx	xxx	xxx	xx
53	xx	xx	x	xx
54	xxx	xx	xxx	xx
55	xxx	xxx	xxx	xx
56	xxx	xxx	xx	xx
57	xxx	xxx	xx	xx
58	xxx	xx	xx	xx
59	xxx	xx	x	xx
60	xx	x	xx	xx
61	xxx	xx	xx	xx
62	xxx	xx	x	xx
63	xxx	x	x	x
64	xxx	xx	x	x
65	xx	x	xx	x
66	xxx	xxx	xxx	xxx
67	xxx	xx	x	x
68	xx	x	x	x
69	xx	xx	x	x
70	xx	x	xx	xx
71	xxx	xx	x	x
72	xxx	xx	xx	xx
73	xxx	xx	xx	xx
74	xxx	xx	xx	xx
75	xxx	xx	x	xx
76	xxx	xx	xx	xx
77	xxx	xx	xx	x
78	xxx	xx	xx	x
79	xx	x	x	x
80	xx	xx	x	x
81	xx	x	x	x
82	xxx	xx	xx	xx
83	xxx	x	x	x
84	xxx	xx	xx	xx
85	xxx	xx	xx	xx
86	xxx	x	xx	x
87	xxx	x	xx	x
88	xxx	xx	xx	x
89	xxx	xx	xx	x
90	xx	x	xx	x
91	xxx	xx	xx	x
92	xxx	xx	xx	x
93	xx	xx	x	x
94	xxx	xx	x	x
95	xxx	xx	xx	x
96	xx	x	xx	x
97	xxx	x	xx	x
98	xxx	xx	xx	x
99	xxx	x	x	x
100	xxx	xx	xx	xx
101	xxx	xx	xx	xx
102	xxx	xx	xx	xx
103	xxx	xx	xx	x
104	xxx	x	xx	x
105	xx	x	x	x
106	xxx	xx	xx	x
107	xxx	x	xx	x
108	xxx	xx	xx	x
109	xxx	xx	xx	x
110	xxx	xx	x	x
111	xxx	xx	xx	x
112	xxx	xx	xx	x
113	xxx	x	xx	x
114	xx	x	xx	x
115	xxx	xx	xx	x
116	xxx	xx	xx	x
117	xxx	xx	xx	x
118	xxx	x	xx	x
119	xxx	x	x	x
120	xx	x	x	x
122	xxx	xx	xx	x
123	xx	x	x	x
124	xxx	xx	x	x
125	xxx	xx	xx	x
126	xxx	x	x	x
127	xxx	xx	xx	x
128	xxx	xx	x	x
129	xxx	x	xx	x
130	xxx	xx	x	x
131	xxx	xx	xx	xxx
132	xxx	xxx	xxx	xxx
133	xxx	xx	xxx	xx
134	xxx	xx	xxx	x
135	xxx	xx	xxx	xxx
136	xxx	xxx	xxx	xxx
137	xxx	x	xxx	xxx
138	xxx	x	xx	xx
139	xxx	xxx	xxx	xxx
140	xxx	xxx	xxx	xxx
141	xxx	xx	xxx	xxx
142	xxx	x	xx	xxx
143	xxx	xxx	xx	xxx
144	xxx	xxx	xxx	xxx
145	xxx	x	xxx	xxx
146	xxx	xxx	xxx	xxx
147	xxx	xx	xx	xxx
148	xxx	xx	xx	xxx
149	xxx	x	xxx	xxx
150	xxx	x	xx	xxx
151	xxx	xxx	xxx	xxx
152	xx	x	xx	xxx
153	xxx	xxx	xxx	xxx
154	xxx	xxx	xx	xxx
155	xxx	x	xxx	xxx
156	xxx	xxx	xx	xxx
157	xxx	x	xx	xxx
158	xxx	x	xxx	xxx
159	xx	x	xxx	xxx
160	xxx	xx	xxx	xxx
161	xx	x	xxx	xxx
162	xxx	x	xx	xxx
163	xxx	xx	xx	xxx
164	xx	x	xxx	xxx
165	x	x	xx	xxx
166	xxx	x	xxx	xxx
167	xxx	xx	xx	xxx
168	xx	xx		xxx
169	xxx	x	xx	xxx
170	xx	x	xx	xxx
171	xx	x	xxx	xx
172	x	x	xxx	xx
173	xxx	xx	xx	xxx
174	xxx	x	xxx	xx
175	xxx	xx	xx	xx
176	xx	xx	xxx	xx
177	xxx	xx	xx	xx
178	xx	x	xxx	xx
179	xx	x	xxx	xx
180	xxx	xxx	xx	xx
181	xx	x	xx	xx
182	x	x	xx	xx
183	xx	x	xx	xx
184	xx	x	xxx	xx
185	x	x	xx	xx
186	xxx	x	xxx	xx
187	xx	x	xx	xx
188	x	x	x	xx
189	xxx	x	xx	xx
190	x	x	xxx	xx
191	xxx	x	xx	xx
192	xxx	x	xx	xx
193	x	x	x	x
194	xxx	x	xxx	xx
195	xx	x	x	x
196	xxx	x	xx	x
197	xx	x	x	x
198	xx	x	xx	x
199	xx	x	xx	x
200	xx	x	xx	x
202	xx	x	xx	x
203	xxx	xx	xx	x
204	xxx	x	xx	x
205	x	x	x	x
206	xxx	x	xx	x
207	xx	x	xx	x
208	xx	x	x	x
209	xx	x	xxx	x
210	xx	x	xx	x
211	x	x	xx	x
212	x	x	x	x
213	xx	x	xx	x
214	x	x	x	x
215	xx	x	x	x
216	xxx	x	xxx	x
217	xx	x	x	x
218	xx	x	x	x
219	x	x	xx	x
220	x	x	xx	x
221	xx	x	xx	x
222	x	x	x	x
223	x	x	x	x
224	x	x	xx	x
225	x	x	x	x
226	x	x	x	x
227	xxx	xxx	xxx	xxx
228	x	x	x	x
229	xx	xxx	x	xxx
230	x	xx	x	xxx
231	x	x	xx	xxx
232	xx	xxx	x	xxx
233	xxx	xxx	xx	xxx
234	xxx	xxx	xx	xx
235	xx	x	xx	xx
236	xxx	xx	xx	xx
237	xxx	xx	x	x
238	x	x	x	x
239	x	x	xx	xx
240	xx	x	xx	xxx
241	xx	x	x	xxx
242	xxx	xx	xx	xxx
243	xxx	x	xx	xx
244	xx	x	xx	xx
245	xx	xx	x	xxx
246	xx	xx	x	xxx
247	xx	x	xx	xxx
248	xx	x	xx	x
249	x	x	xx	xx
250	xx	x	xx	xx
251	xx	x	xx	xx
252	x	x	x	xx
253	xx	x	xx	xx
254	x	x	xx	xx
255	x	x	x	x
256	xx	xx	x	x
257	x	x	xxx	x
258	x	x	xx	x
259	x	x	xx	x
260	xxx	x	xx	x
261	xx	x	x	x
262	x	x	x	x
263	xxx	xxx	x	x
264	x	x	x	x
265	xx	xx	x	x
266	x	x	x	x
267	x	x	x	x
268	x	x	x	x
269	xxx	xxx	xx	xxx
270	xxx	xxx	xx	xxx
271	xxx	xxx	xx	x
272	xxx	xxx	xx	xxx
273	xxx	xx	xxx	xxx
274	xxx	x	xx	xxx
275	xxx	xx	xx	xxx
276	xxx	x	xx	xx
277	xxx	x	xx	x
278	xx	xx	xx	xx
279	xx	xx	x	x
280	x	x	xx	xx
281	xx	xx	x	xx
282	xxx	xx	x	xx
283	xx	x	xx	xx
284	xx	xx	x	x
285	xx	x	x	x
286	xx	x	x	x
287	xx	x	x	x
288	x	x	x	x
289	xxx	x	x	x
290	xxx	x	x	x
291	xx	x	xx	xx
292	xx	x	xx	xx
293	xx	xxx	xxx	xxx
294	xx	xx	xxx	xx
295	xxx	xxx	xx	xx
296	x	x	xx	xx
297	x	x	xx	xx
298	x	x	x	xx
299	x	x	xx	xx
300	xx	x	xx	x
301	x	x	x	x
302	x	x	x	x
303	xx	x	xxx	x
304	xxx	x	xx	x
305	x	x	x	x
306	x	x	x	x
307	xx	x	xx	x
308	xxx	x	xxx	x
309	xx	x	xxx	x
310	xx	x	x	x
311	xxx	x	xx	xx
312	x	x	x	x
313	x	x	x	x
314	xx	x	x	x
315	x	x	x	x
316	x	x	x	x
317	x	x	x	x
318	xxx	xxx	xx	xxx
319	xx	x	x	x
320	xx	x	xx	x
321	xx	x	xx	xx
322	xx	xxx	x	xxx
323	xx	x	xx	xx
324	xx	x	xx	xx
325	x	x	xx	x
326	x	x	x	x
327	x	x	x	x
328	xx	x	x	xx
329	xxx	x	xx	x
330	x	x	x	x
331	xx	x	x	x
332	x	x	x	x
333	x	x	x	x
334	x	x	x	x
335	x	x	x	x
336	x	x	x	x
337	x	x	x	x
338	x	x	x	x
339	x	x	x	x
340	xx	x	x	x
341	x	x	x	x
342	xxx	xx	xx	xx
343	xxx	xxx	xx	x
344	xxx	xx	xx	x
345	xxx	xx	x	x
346	xxx	x	x	x
347	xxx	xx	xx	xxx
348	xxx	xx	xxx	xxx
349	xx	xx	xxx	xxx
350	xxx	xxx	xxx	xxx
351	xxx	xx	xx	xxx
352	xxx	x	xxx	xxx
353	xxx	x	xxx	xx
354	x	x	xx	xx
355	xx	xx	xx	xx
356	xxx	x	xxx	xx
357	xx	x	x	x
358	xxx	xx	xx	xx
359	xx	xx	x	x
360	xx	x	xx	x
361	xx	x	x	x
362	xx	x	xx	x
363	xx	x	x	x
364	xxx	x	xxx	x
365	xxx	x	xx	x
366	xx	x	x	x
367	x	x	x	x
368	xxx	xx	x	x
369	xxx	xx	xxx	xxx
370	xxx	xx	xx	xxx
371	xxx	x	xx	xxx
372	xxx	xx	xx	xxx
373	xxx	xx	xx	xxx
374	xx	x	xx	xx
375	xxx	xxx	xxx	xx
376	xxx	x	xx	xx
377	xxx	xx	xx	xx
378	xx	x	xx	xx
379	xxx	xx	xx	xx
380	xxx	xx	xx	xx
381	xxx	x	xx	x
382	xxx	x	xx	xx
383	xxx	xx	xx	x
384	xx	x	x	x
385	xx	x	xx	x
386	xx	xx	x	x
387	xxx	xx	xx	x
388	xxx	x	xx	x
389	xx	x	xx	x
390	xxx	x	xx	x
391	xx	x	x	x
392	xxx	x	xx	x
393	xxx	x	xx	x
394	xxx	xx	x	x
395	xxx	x	x	x
396	xx	x	x	x
397	xx	x	xx	x
398	xx	x	x	x
399	xx	xx	xx	x
400	x	x	x	x
401	xxx	x	xx	x
402	xx	x	xx	x
403	xxx	x	xx	x
404	xx	x	x	x
405	xx	x	x	x
406	xx	x	x	x
407	xx	x	x	x
408	xxx	xxx	xx	xx
409	xxx	xxx	xxx	xxx
410	xx	xx	x	x
411	xxx	xx	x	x
412	xx	x	x	x
413	xxx	xx	x	x
414	x	x	x	x
415	x	x	x	x
416	x	x	x	x
417	xx	x	x	x
418	x	x	x	x
419	x	x	x	x
420	xx	x	x	x
421	x	x	x	x
422	xxx	x	x	x
423	xx	x	x	x
424	x	x	x	x
425	x	x	x	x
426	x	x	x	x
427	xx	x	x	x
428	xx	x	x	x
429	xx	x	x	x
430	xx	x	x	x

TABLE 4 — Additional exemplary compounds of formulae (I and II).

Cmd	M 1	M 4	M 1	M 4
No.	Activity	Activity	Efficacy	Efficacy
431	xx	xx	xx	xx
432	x	x	x	x
433	xxx	xxx	xxx	xx
434	x	xxx	xx	xx
435	xxx	xxx	xx	xx
436	x	x	x	x
437	x	x	x	x
438	xxx	xxx	xx	x
439	xxx	xxx	xx	xx
440	xxx	xxx	xx	xx
441	x	x	x	x
442	x	x	x	x
443	xxx	xxx	xxx	xxx
444	xx	xx	xx	xx
445	xxx	xxx	xx	xx
446	x	x	xx	x
447	xxx	xxx	xx	xx
448	x	xxx	x	x
449	xx	xxx	xx	xx
450	xxx	x	xx	x
451	xxx	xxx	xx	xx
452	xxx	x	xx	x
453	xxx	x	xx	x
454	x	x	x	x
455	xxx	xxx	xx	xx
456	xxx	xxx	xx	xx
457	x	x	x	x
458	x	x	x	x
459	x	xx	xx	x
460	xxx	xxx	xx	xx
461	xx	x	xx	x
462	xxx	xxx	xx	xx
463	x	x	xx	x
464	xx	xx	xx	xx
465	—	—	—	—
466	xxx	xxx	xx	xx
467	xx	xx	xx	xx
468	xx	xxx	xx	xx
469	xxx	xxx	xx	xx
470	xx	xx	xx	xx
471	xx	xx	xx	xx
472	xxx	xxx	xxx	xx
473	x	x	xx	x
474	x	x	x	x
475	—	—	—	—
476	x	x	x	x
477	x	x	x	x
478	x	x	x	x
479	xxx	xxx	xx	x
480	x	x	x	x
481	xxx	xxx	xx	xx
482	xxx	xxx	xx	xx
483	x	x	x	x
484	xxx	xxx	xx	xx
485	xx	xxx	xx	x
486	x	xxx	x	xx
487	x	xxx	x	xx
488	x	x	xx	xx
489	xxx	xxx	xx	xx
490	x	xxx	xx	xxx
491	xx	xx	xx	x
492	x	x	xx	x
493	xxx	xxx	xxx	xxx
494	xx	xxx	xx	xx
495	—	—	—	—
496	x	x	x	x
497	xx	xx	xx	xx
498	xxx	xxx	xx	xx
499	x	x	xx	x
500	x	x	x	x
501	—	—	—	—
502	xxx	xx	xx	xx
503	xxx	xxx	xx	xx
504	x	x	x	x
505	xxx	xxx	xx	xx
506	x	xx	x	xx
507	xxx	xxx	xx	xx
508	xxx	xxx	xx	xx
509	xx	x	xx	xx
510	xxx	xxx	xx	xx
511	x	x	x	x
512	x	x	x	x
513	xxx	xxx	xx	xx
514	xx	x	xx	xx
515	xxx	xxx	xx	xx
516	xxx	xxx	xx	xx
517	xxx	xxx	xx	xx
518	x	x	x	x
519	xxx	x	xx	x
520	x	x	xx	x
521	x	x	x	x
522	xxx	xxx	xxx	xx
523	—	—	—	—
524	—	—	—	—
525	x	xxx	x	xx
526	xxx	x	xx	x
527	xxx	xxx	xx	xx
528	xx	xxx	xx	xx
529	x	xx	xx	xx
530	x	x	x	x
531	x	x	x	x
532	x	x	x	x
533	x	x	x	x
534	xx	xxx	xx	x
535	xxx	xxx	xx	xx
536	xxx	xxx	xx	xx
537	xxx	xxx	xx	xx
538	xx	x	xx	x
539	xx	xx	xx	xx
540	xxx	xxx	xx	xx
541	xxx	x	xx	x
542	x	x	x	x
543	xxx	xxx	xxx	xx
544	xx	xx	xx	x
545	x	x	x	x
546	x	x	xx	xx
547	xx	x	xx	xx
548	x	x	x	x
549	x	x	x	x
550	x	x	x	x
551	x	x	x	xx
552	x	x	xx	xx
553	xxx	xxx	xx	x
554	—	—	—	—
555	xxx	xx	xx	xx
556	x	x	xx	x
557	—	—	—	—
558	xxx	xxx	xx	xx
559	xxx	x	xx	xx
560	xxx	x	xx	x
561	x	xx	xx	xx
562	—	—	—	—
563	xxx	xxx	xxx	xx
564	xxx	xxx	xx	xx
565	xxx	xxx	xx	xx
566	x	x	x	x
567	xxx	xxx	xx	xx
568	xxx	xxx	xx	x
569	xx	xx	xx	xx
570	xx	xxx	xx	xx
571	xxx	xxx	xx	xx
572	xx	x	xx	x
573	xxx	xxx	xx	xx
574	xx	xxx	xx	xx
575	x	x	x	x
576	xxx	xxx	xx	xx
577	x	x	x	x
578	xxx	xxx	xx	xx
579	xxx	xxx	xx	xx
580	xxx	x	xx	xx
581	xxx	xxx	xx	x
582	—	—	—	—
583	xxx	xxx	xx	xx
584	xxx	xxx	xx	xx
585	xxx	xxx	xx	xx
586	xxx	xxx	xx	xx
587	xxx	xxx	xx	xx
588	x	x	x	x
589	x	x	x	x
590	xx	xx	xx	x
591	xxx	xxx	xxx	xx
592	xx	x	xx	x
593	—	—	—	—
594	x	xx	xx	x
595	xxx	xxx	xx	xx
596	xxx	xxx	xx	xx
597	x	x	xx	x
598	xxx	xxx	xx	xx
599	x	x	xx	xx
600	x	x	x	x
601	—	—	—	—
602	xxx	xx	xx	xx
603	xxx	xxx	xx	xx
604	x	xxx	x	xx
605	xxx	xxx	xx	xx
606	xxx	xxx	xx	xx
607	xxx	xxx	xx	xx
608	xxx	xxx	xx	xx
609	xx	xxx	xx	xx
610	xxx	xxx	xx	xx
611	xxx	x	xx	x
612	x	x	x	xx
613	—	—	—	—
614	xxx	xxx	xx	xx
615	xxx	xx	xx	x
616	xxx	x	xxx	xx
617	xx	xxx	xx	xxx
618	xxx	xxx	xx	xx
619	xx	xxx	xx	xx
620	x	x	xx	x
621	xx	xxx	xx	xx
622	x	x	x	x
623	xxx	xxx	xx	xx
624	xxx	x	xx	x
625	xxx	xxx	xx	xxx
626	xxx	xxx	xx	xx
627	xxx	xxx	xx	xx
628	xxx	xxx	xx	xx
629	xx	xx	xx	xx
630	x	xxx	xx	xx
631	—	—	—	—
632	x	x	x	x
633	xx	x	xx	x
634	x	x	x	x
635	—	—	—	—
636	xxx	xxx	xx	xx
637	xxx	xxx	xxx	xx
638	x	x	x	x
639	x	x	xx	x
640	xxx	xxx	xx	xx
641	x	x	x	x
642	x	xxx	xx	xxx
643	x	x	x	x
644	x	x	x	x
645	xxx	xxx	xx	xx
646	xxx	x	xx	x
647	xxx	xxx	xx	xx
648	xx	x	xx	x
649	xxx	xxx	xx	x
650	xxx	xxx	xx	xx
651	xxx	xxx	xx	xx
652	xxx	xxx	xx	xx
653	x	x	xx	xx
654	—	—	—	—
655	xxx	xxx	xx	xx
656	xxx	xxx	xx	xx
657	xx	xxx	xx	xx
658	xxx	xxx	xx	xx
659	xxx	xxx	xx	xx
660	xxx	xxx	xxx	xxx
661	x	x	xx	x
662	x	xx	xx	xx
663	xxx	xxx	xx	xx
664	xxx	xxx	xx	xx
665	x	x	xx	x
666	x	xxx	x	xx
667	x	x	x	xx
668	xxx	xxx	xx	xx
669	xxx	xxx	xx	xx
670	x	xx	xx	xx
671	x	x	x	x
672	xxx	xxx	xx	xx
673	x	xx	x	xx
674	x	x	xx	xx
675	xxx	xxx	xx	xx
676	—	—	—	—
677	x	x	xx	x
678	xxx	x	xx	x
679	xxx	xxx	xx	xx
680	xx	xxx	xx	xx
681	x	x	xx	x
682	x	x	x	x
683	xx	x	xx	x
684	x	x	x	x
685	x	xxx	x	xx
686	x	x	x	x
687	x	x	x	x
688	xxx	xxx	xx	xx
689	xxx	xxx	xxx	xx
690	—	—	—	—
691	x	x	xx	x
692	xxx	xxx	xx	xx
693	x	x	xx	x
694	xxx	xxx	xx	xx
695	xxx	xxx	xx	xx
696	xx	xxx	xx	xx
697	x	x	xx	x
698	xxx	xxx	xxx	xxx
699	x	x	x	x
700	xxx	xxx	xxx	xxx
701	xxx	xxx	xx	xx
702	x	x	xx	xx
703	x	x	x	x
704	xxx	xxx	xx	xx
705	x	x	x	x
706	xxx	xxx	xx	xx
707	—	—	—	—
708	xxx	xxx	xx	xx
709	xxx	xxx	xx	x
710	x	x	xx	xx
711	xx	x	xx	x
712	xxx	xxx	xx	xx
713	—	—	—	—
714	xxx	xxx	xxx	xx
715	xxx	xxx	xx	xx
716	xxx	xxx	xx	xx
717	xxx	xxx	xx	xx
718	x	x	x	x
719	xxx	x	xx	x
720	xx	xxx	xx	xx
721	xxx	xxx	xx	xx
722	xxx	xxx	xx	xx
723	xxx	xxx	xx	xx
724	xx	x	xx	x
725	—	—	—	—
726	x	x	x	x
727	x	xxx	xx	xx
728	xx	x	xx	x
729	x	x	x	x
730	xxx	xxx	xx	xx
731	xxx	x	x	x
732	x	xx	xx	xx
733	—	—	—	—
734	xxx	xxx	xx	xx
735	xx	xxx	xx	xx
736	—	—	—	—
737	xx	xxx	xx	xx
738	xx	xxx	xx	xx
739	x	xx	xx	x
740	xxx	xxx	xx	xx
741	x	x	x	x
742	xxx	xxx	xx	xx
743	x	x	x	x
744	xxx	xxx	xx	xx
745	—	—	—	—
746	xxx	xxx	xx	xx
747	xxx	xxx	xx	xx
748	—	—	—	—
749	xxx	xxx	xx	xx
750	xxx	xxx	xx	xx
751	xxx	xxx	xx	xx
752	xxx	xxx	xx	xx
753	xx	xx	xx	xx
754	xxx	xxx	xx	xx
755	x	xxx	x	xx
756	xxx	xxx	xx	xx
757	x	x	x	x
758	x	x	x	x
759	x	x	x	x
760	x	xxx	xx	xx
761	xxx	xxx	xx	xx
762	xxx	xxx	xx	xx
763	—	—	—	—
764	xxx	xxx	xx	x
765	x	x	xx	x
766	xxx	xxx	xx	xx
767	x	x	xx	x
768	x	x	xx	x
769	xxx	xxx	xx	xx
770	xxx	xx	xx	x
771	x	x	x	x
772	xxx	xxx	xx	xx
773	xxx	xxx	xx	xx
774	x	x	xx	xx
775	xxx	xxx	xx	xx
776	x	x	x	x
777	xxx	xxx	xx	xx
778	x	x	x	x
779	xx	xxx	xx	x
780	x	x	x	x
781	x	x	xx	x
782	x	x	x	x
783	xxx	xx	xx	xx
784	x	x	x	x
785	xx	xxx	xx	xx
786	—	—	—	—
787	xxx	xxx	xx	xx
788	xx	xx	xx	xx
789	x	x	xx	xx
790	xx	xxx	xx	xx
791	xx	x	xx	x
792	x	x	xx	xx
793	xxx	xxx	xx	xx
794	x	x	x	x
795	xx	x	x	x
796	xxx	xxx	xx	xx
797	x	xxx	xx	xx
798	x	x	x	x
799	x	x	x	x
800	xxx	xxx	xx	xx
801	x	x	x	x
802	x	xxx	xx	xx
803	x	x	x	x
804	x	x	x	x
805	xxx	xxx	xx	xx
806	x	x	x	x
807	xxx	xxx	xx	xx
808	xxx	xxx	xx	xx
809	xxx	xxx	xx	xx
810	xxx	xxx	xx	xx
811	—	—	—	—
812	xx	x	xx	x
813	x	x	xx	x
814	x	xx	xx	xx
815	xx	xxx	xx	xx
816	xxx	xxx	xxx	xxx
817	x	x	x	x
818	x	x	x	x
819	xxx	x	xx	x
820	xxx	xxx	xx	xx
821	x	x	xx	x
822	xxx	xxx	xx	xx
823	xx	xx	xx	xx
824	x	x	xx	x
825	xxx	x	xx	x
826	xxx	xxx	xx	xx
827	xxx	xxx	xx	xx
828	xxx	x	xx	x
829	xxx	xxx	xx	xx
830	x	xx	xx	xx
831	—	—	—	—
832	xxx	xxx	xx	xx
833	xxx	xxx	xx	xx
834	xxx	xxx	xx	xx
835	—	—	—	—
836	xxx	xxx	xx	xx
837	x	x	x	x
838	xxx	xxx	xx	xx
839	xx	x	x	x
840	x	x	x	x
841	—	—	—	—
842	x	xxx	x	x
843	xxx	xxx	xx	xx
844	xxx	xxx	xx	xx
845	x	x	x	x
846	xx	xx	x	x
847	xxx	x	xx	x
848	xxx	xxx	xx	xxx
849	x	x	x	x
850	—	—	—	—
851	xxx	xxx	xx	xx
852	xx	xxx	xx	xx
853	xxx	xxx	xx	xx
854	xxx	xxx	xx	xx
855	xxx	xxx	xx	xx
856	xxx	xxx	xx	xx
857	x	x	xx	x
858	—	—	—	—
859	x	x	xx	xx
860	xxx	xxx	xx	xx
861	xxx	xxx	xx	xx
862	xxx	xxx	xx	xx
863	x	xx	xx	xx
864	x	x	x	x
865	xx	xxx	xx	xx
866	xx	xxx	xx	xx
867	—	—	—	—
868	x	xxx	x	xx
869	xx	xxx	xx	xx
870	—	—	—	—
871	x	xx	xx	xx
872	xxx	xxx	xx	xx
873	x	x	x	x
874	xx	x	xx	x
875	xxx	x	xx	x
876	—	—	—	—
877	xxx	xxx	xx	xx
878	xxx	xxx	xx	xx
879	xxx	xxx	xx	xx
880	x	x	x	x
881	xxx	xxx	xx	xx
882	x	x	x	x
883	—	—	—	—
884	xxx	xxx	xx	xx
885	xxx	xxx	xx	xx
886	xxx	xxx	xx	xx
887	xx	x	xx	x
888	xxx	x	xx	x
889	xxx	xxx	xx	xx
890	xxx	xxx	xx	xx
891	xxx	xxx	xx	xx
892	x	x	x	x
893	x	x	x	x
894	x	x	xx	x
895	xxx	xxx	xx	xx
896	xxx	xxx	xx	xx
897	xxx	xxx	xx	xx
898	x	x	x	x
899	—	—	—	—
900	xx	x	x	x
901	xx	xx	xx	xx
902	x	x	xx	x
903	xx	xxx	xx	xx
904	x	x	x	x
905	xxx	xxx	xx	xx
906	—	—	—	—
907	x	x	xx	x
908	xxx	xxx	xx	xx
909	—	—	—	—
910	xxx	xx	xx	x
911	x	x	x	x
912	xxx	x	xx	x
913	x	x	xx	x
914	xxx	xxx	xx	xx
915	x	x	xx	xx
916	x	x	x	x
917	x	x	x	x
918	x	x	xx	x
919	x	x	x	x
920	xxx	xxx	xx	xx
921	x	x	xx	x
922	x	x	xx	xx
923	xx	xxx	xx	xx
924	—	—	—	—
925	xxx	xxx	xx	xx
926	x	x	xx	x
927	—	—	—	—
928	xxx	xxx	xx	xx
929	xxx	xxx	xx	xx
930	x	x	x	x
931	x	x	x	x
932	x	x	xx	x
933	x	x	x	x
934	xx	xxx	xx	xx
935	x	xxx	xx	xx
936	xxx	x	xx	x
937	—	—	—	—
938	xxx	xxx	xx	xx
939	xxx	xxx	xx	xx
940	xxx	xxx	xx	xx
941	xxx	xxx	xx	xx
942	xxx	xxx	xxx	xx
943	xxx	xxx	xx	xx
944	xxx	xxx	xx	xx
945	xxx	xxx	xx	xx
946	x	xxx	x	x
947	xxx	xxx	xxx	xx
948	x	x	x	x
949	xxx	xxx	xx	xx
950	xx	xx	xx	xx
951	xxx	xxx	xx	xx
952	xxx	xxx	xx	xx
953	xx	xxx	xx	xx
954	xxx	xxx	xx	xx
955	xxx	xxx	xx	xx
956	x	x	xx	x
957	xxx	xxx	xx	xx
958	xxx	xxx	xx	xx
959	xx	xxx	xx	xx
960	x	xx	x	xx
961	xxx	xxx	xx	xx
962	x	x	x	x
963	—	—	—	—
964	—	—	—	—
965	x	xxx	xx	xx
966	xxx	x	xx	x
967	xx	xx	xx	xx
968	x	x	x	x
969	xxx	x	xx	x
970	xxx	xxx	xx	xx
971	xx	xx	xx	xx
972	xx	x	xx	x
973	x	x	xx	x
974	xxx	xxx	xx	xx
975	x	x	x	x
976	xxx	xxx	xx	xx
977	xxx	xxx	xx	xx
978	x	x	x	x
979	x	xxx	xx	xx
980	xxx	xxx	xxx	xx
981	xxx	xxx	xx	xx
982	x	x	x	x
983	xxx	xxx	xx	xx
984	xx	xxx	xx	xx
985	x	xx	xx	xx
986	xxx	xxx	xx	xx
987	xxx	xxx	xx	xx
988	xxx	xxx	xx	xx
989	xxx	x	xx	x
990	xx	x	xx	xx
991	xxx	xxx	xx	xx
992	x	x	xx	xx
993	xxx	xxx	xx	xx
994	xxx	xxx	xx	xx
995	x	xx	xx	xx
996	x	x	x	x
997	—	—	—	—
998	x	xxx	x	xx
999	xxx	x	xx	x
1000	x	x	xx	xx
1001	—	—	—	—
1002	x	x	x	x
1003	xxx	xxx	xx	xx
1004	xxx	xxx	xx	xx
1005	x	xxx	x	xx
1006	x	x	xx	x
1007	—	—	—	—
1008	—	—	—	—
1009	xxx	xxx	xx	xx
1010	x	x	x	x
1011	—	—	—	—
1012	x	x	x	x
1013	x	x	x	x
1014	xxx	xxx	xx	xx
1015	xx	xxx	xx	x
1016	xxx	xxx	xx	xx
1017	x	xxx	xx	xx

TABLE 5 — Additional compound activities and efficacies for modulating M 1 and M 4 receptors.

Cmd	M 1	M 4	M 1	M 4
No.	Activity	Activity	Efficacy	Efficacy
1018	—	—	—	—
1019	xxx	xxx	xx	xx
1020	xx	xx	xx	x
1021	—	—	—	—
1022	—	—	—	—
1023	—	—	—	—
1024	xx	xx	xx	x
1025	xx	xxx	xx	xx
1026	xx	xxx	xx	x
1027	xx	xx	xx	xx
1028	xx	xxx	xx	xx
1029	xx	xx	xx	xx
1030	xx	xx	xx	xx
1031	xxx	xxx	xx	xx
1032	xx	xxx	xx	xx
1033	xx	xxx	xx	xx
1034	xxx	xxx	xx	xx
1035	xxx	xxx	xxx	xx
1036	xxx	xxx	xx	xx
1037	xx	xxx	xx	xx
1038	xx	xxx	xx	xx
1039	xx	xxx	xx	xx
1040	xxx	xxx	xx	xx
1041	xx	xx	xx	xx

Claims as granted

2 claims

Classifications

13 codes

IPC · International Patent Classification

Section A — Human necessities

A01N43/40
A61K31/445

Section C — Chemistry; metallurgy

C07D413/00
C07D405/00
C07D211/08
C07D419/00
C07D401/00
C07D411/00
C07D421/00
C07D409/00
C07D417/00

USPC · US Patent Classification

514/317546/192

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4.5 y

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1 RCE

Examiner

James O Wilson

art unit 1624 · TC 1600

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