BACKGROUND OF THE INVENTION The invention relates to antagonists of the neuropeptide neurokinin-1 (NK1 or NK-1) receptor.

Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in a variety of biological processes. They can be found in a mammal's nervous and circulatory systems, as well as in peripheral tissues. Consequently, the modulation of these types of receptors have been studied to potentially treat or prevent various mammalian disease states. For instance, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion. Representative types of neurokinin receptor antagonists and the disorders that can be treated with them include, for example, sleep, pain, migraine, emesis, nociception and inflammation, see, for example, U. S. 6, 329, 401, U. S. 5,760, 018, U. S. 5,620, 989, WO 95/19344, WO 94/13639, and WO 94/10165. Cyclobutyl heterocyclic compounds can be found in: WO 99/52848, WO 99/21824 and WO 98/57940.

It would be beneficial to provide a NK1 antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to provide a NK1 antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases, while minimizing side effects. This invention provides such NK1 antagonists.

SUMMARY OF THE INVENTION This invention is directed to compounds of formula (I) :

or the pharmaceutically-acceptable salts or solvates thereof, wherein: Ar1 and Ar2 are each independently selected from the group consisting of: (a) heteroaryl, (b) heteroaryl substituted with (R21) r, and (c) is selected from the group consisting of-0-,-S-,-SO-,-S02-,-NR -N(COR20)- and -N(SO2R17)-; and when X1 is selected from the group consisting of-SO-,-SO2-, -N(COR20)- and -N(SO2R17)-, then R1 and R2 are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy (Ci-C3 alkyl)-, C3-C8 cycloalkyl, -CH2F, -CHF2 and -CF3 ; or R1 and R2, together with the carbon atom to which they are both attached, form a Cs-Ce cycloalkyl ring; and when X1 is selected from the group consisting of-O-,-S-and -NR20-, then R'and R2 are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy (C1-C3 alkyl)-, C3-C8 cycloalkyl, -CH2F,-CHF2 and-CF3 ; or R'and R2, together with the carbon atom to which they are both attached, form a C3-C6 cycloalkyl group; or R1 and R2, together with the carbon atom to which they are both attached, form a-C (=O) group;

R3 is selected from the group consisting of H, Ci-Ce alkyl, hydroxy (Ci-C3 alkyl)-, C3-C8 cycloalkyl,-CH2F,-CHF2 and-CF3 ; R4 and R5 are each independently selected from the group consisting of H, C1-C6 alkyl-, -halogen, -OR20, -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16 and -SR20 ; or R4 and R5, together with the carbon atom to which they are both attached, form a-C (=O)- or -C(=NR13)- group ; R6 is-(CH2) n1-G wherein ni is 0 to 5, wherein G is selected from the group consisting of: H, -OH, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16, -C(O)NR15R16, -C (O) OR20,-C3-C8 cycloalkyl, is selected from the group consisting of-O-,-S-, and R7 is -(CR40R41)n6-J wherein R40 and R41 are each independently selected from the group consisting of H and-Ci-C2 alkyl, and n6 is 0 to 5, and J is selected from the group consisting of -H, -CF3, -CHF2, -CH2F, -OH, -O-(C1-C6 alkyl), -SO2R15, -O-(C3-C8 cycloalkyl), -O-C(O)NR15R16, -NR15R16, -SO2NR15R16, -NR15SO2R17, - C (O) R14, -NR20C(O)NR15R16, -C(O)NR15R16, -C(O)OR20, C3-C8 cycloalkyl,

(examples of R7 include, but are not limited to,- (CH2) n6-J and-C (CH3) 2-J) ; provided that : (a) when R6 is-(CH2) n1-G, where ni is 0, then G is selected from the group consisting of :-OH,-O-(C1-C6 alkyl),-O-(C3-C8 cycloalkyl), -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16, (b) R7 is-(CR4°R41) n6-J, wherein n6 is 0, then J is selected from the group consisting of-H,-CF3,-CHF2,-CH2F,-C (O) NR15R16, -C(O)OR20,

(c) when ni for R6 is 0, and n6 for R7 is 0, and one of R6 and R 7 is bound through a heteroatom (e. g., O or N) to the ring carbon of the cyclobutane ring then the other of R6 and R 7 is bound through a carbon atom to the ring carbon of the cyclobutane ring (i. e., only one of R6 or R7 can be bound through a heteroatom to the carbon atom of the cyclobutane ring, i. e. , the ring carbon atom to which R6 and R7 are bound does not have two heteroatoms bound to said ring carbon); or and R, together with the carbon atom to which they are both attached, form a-C (=O)-,-C (=CH2) -, or-C (=NR'3)- group ; or R6 and R7, taken together with the carbon atom to which they are bound, form: (a) a 4-to 7-membered carbon ring (e. g. , a C4to C7 cycloalkyl ring); (b) a 4-to 7-membered heterocycloalkyl ring; or (c) a 4 to 7-membered heterocycloalkenyl ring; wherein said heterocycloalkyl or said heterocycloalkenyl comprises from 1 to 4 heteroatoms independently selected from the group consisting of : -O-,-S-, -S (O)-, -SO2-, -N=, and -NR20- (wherein R20 is defined below), provided that a ring-S-in said heterocycloalkyl and said heterocycloalkenyl rings is not bound to another ring-S-or ring-S (O)- or ring -O-, and provided that a ring-O-in said heterocycloalkyl and said heterocycloalkenyl rings is not bound to another ring -O-; said 4-to 7-membered rings being optionally substituted with from 1 to 4 R45 substituents wherein each R45 substituent is independently selected ; R8 and R9 are each independently selected from the group consisting of H, Ci-Ce alkyl-, halogen, -OR20, -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16 and -SR20 ; or R5 and R9, taken together with the carbon atom to which they are both attached, form a-C (=O)- group ;

R10, R11 and R12 are each independently selected from the group consisting of H, Ci-Ce alkyl, C8-C8 cycloalkyl, -OR20, halogen, -CN, -NO2, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -C(O)OR20,-C(O)NR23R24, -NR23C(O)R20, -NR23CO2R17, -NR23C(O)NR23R24, -NR23SO2R17, -NR23R24, -SO2NR23R24, -S(O)n5R17, aryl, aryl substituted with (R21) r wherein each R21 substitutent is independently selected, heteroaryl, and heteroaryl substituted with (R21) r wherein each R21 substituent is independently selected; each R13 is independently selected from the group consisting of-OH and -0- (Cl-C6 alkyl) ; each R14 is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl,-C1-C6 alkylNH2 and-Ci-Ce alkylNHC (O) OC1-C6 alkyl ; R15 and R16 are each independently selected from the group consisting of H, benzyl, Ci-Ce alkyl, and C3-C8 cycloalkyl ; or R15 and R16, together with the nitrogen atom to which they are both attached, form a 4-to 7-membered ring that is optionally substituted with -OR20, and wherein one of the carbon atoms in said 4-to 7-membered ring is optionally replaced by a heteroatom selected from the group consisting of-0-,-S-and-NR each R17 is independently selected from the group consisting of Ci-Ce alkyl, C3-C8 cycloalkyl and-CF3 ; each R20 is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl, -(C1-C6)alkylNH2 (e. g.,-CH2CH2NH2), (C1-C6) alkoxy (C2- C6) alkyl, and hydroxy (C2-C6) alkyl ;<BR> <BR> each R2 is a substituent on the aryl or heteroaryl ring to which it is attached and is independently selected from the group consisting of Ci-Ce alkyl, C3-C8 cycloalkyl, -OH, -halogen, -CN, -NO2, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -C(O)OR20, -C(O)NR23R24, -NR23R24, -NR23C(O)R20, -NR23CO2R20, -NR23C(O)NR23R24, -NR23SO2R17 and -S(O)n5R17; R22 is selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl and - (CH2)n4-heterocycloalkyl ; R23 and R24 are each independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl and benzyl ; or R23 and R24, together with the nitrogen atom to which they are both attached, form a 4-to 7-membered ring that is optionally

substituted with-OR, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of -O-, -S- and -NR20-; R25 and R26 are each independently selected from the group consisting of H and Ci-Ce alkyl ; or R25 and R26, together with the carbon atom to which they are both attached, form a-C (=O)- or cyclopropyl group; R7 and R28 are each independently selected from the group consisting of H and Ci-Ce alkyl ; or R27 and R28, together with the carbon atom to which they are both attached, form a-C (=O)- or cyclopropyl group; each R29 is independently selected from the group consisting of H, Ci-Ce alkyl and C3-C8 cycloalkyl ; R30 and R31 are each independently selected from the group consisting of H, C1-C6 alkyl (e. g., C1-C2 alkyl), -CH2F, -CHF2, -CF3, -OH, and -O(C1 to C3) alkyl ; or R30 and R31, together with the carbon atom to which they are both attached, form a- C (=O)- group ; R38 and R39 are each independently selected from the group consisting of H and Ci-Ce alkyl ; or R38 and R39, together with the carbon atom to which they are both attached, form a cyclopropyl group; each R45 is independently selected from the group consisting of: C1-C6 alkyl (e. g., Ci-C2 alkyl),-CH2F,-CHF2,-CF3,-OH, and-O (Ci to C3) alkyl ; or two R45 substitutents, together with the carbon atom to which they are both attached, form a -C(=O)- group ; X2 is selected from the group consisting of-CH2-,-NR22-,-N (C (O) NR15R16)-, -N(CO2R15)-,-N(SO2R17)-, -N(C(O)R20)-, -N(SO2NHR20)-,-O-, -S-, -S(O)-, -SO2-, -CF2- and -CR20F- ; r is from 1 to 3; n2 is from 1 to 4; n3 is from 0 to 2; n4 is from 0 to 3; n5 is from 0 to 2; n8 is from 0 to 4; and n9 is from 1 to 3;

provided that, when n3 is 0, and R27 and R28 are each H, then x2 is selected from the group consisting of-CH2-,-S (O)-,-S02-,-CF2-and-CR20F-.

This invention is also directed to a pharmaceutical composition comprising an effective amount of at least one (e. g. , one) compound of formula (1) and a pharmaceutical acceptable carrier.

This invention is also directed to a method for effecting an NK1 receptor in a patient comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method for treating an NK1 receptor mediated disease (i. e. , a disease associated with an NK1 receptor, or a disease involving an NK1 receptor in part of the disease process) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein said disease is selected from the group consisting of: respiratory diseases (e. g. , chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), inflammatory diseases (e. g., arthritis and psoriasis), skin disorders (e. g. , atopic dermatitis and contact dermatitis), ophthalmalogical disorders (e. g. , retinitis, ocular hypertension and cataracts), central nervous system conditions, such as depressions (e. g. , neurotic depression), anxieties (e. g. , general anxiety, social anxiety and panic anxiety disorders), phobias (e. g., social phobia), and bipolar disorder, addictions (e. g., alcohol dependence and psychoactive substance abuse), epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AID's related dementia, Towne's disease, stress related disorders (e. g. , post tramautic stress disorder), obsessive/compulsive disorders, eating disorders (e. g., bulemia, anorexia nervosa and binge eating), sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders (e. g. , irritable bowel syndrome, Crohn's disease, colitis, and emesis), atherosclerosis, fibrosing disorders (e. g. , pulmonary fibrosis), obesity, Type II diabetes, pain related disorders (e. g. , headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), bladder and genitourinary

disorders (e. g., interstitial cystitis and urinary incontinence), emesis (e. g., chemotherapy-induced (e. g., cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and nausea, comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein said disease is selected from the group consisting of: respiratory diseases (e. g. , cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulemia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders, bladder disorders, genitourinary disorders, emesis and nausea, comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method of treating a disease wherein there is microvascular leakage and mucus secretion in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one (e. g., one) compound of formula (I).

This invention is also directed to a method of treating asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method of treating emesis, depression, anxiety and cough in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site in a patient in need of such treatment, comprising administering to said patient at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method for the blockade of neurokinin-1 receptors in a patient in need of such treatment, comprising administering to said patient at least one (e. g. , one) compound of formula (I).

This invention is also directed to a method for treating depression and/or anxiety in a patient in need of such treatment comprising administering to said patient an effective amount of one or more (e. g. , one) compounds of formula (I) in combination with an effective amount of one or more (e. g. , one) anti-depressant agents and/or one or more (e. g. , one) anti-anxiety agents.

This invention is also directed to a method of treating an NK1 receptor mediated disease in a patient in need of such treatment comprising administering to said patient an effective amount of one or more (e. g. , one) compounds of formula (I) in combination with an effective amount of one or more (e. g. , one) selective serotonin reuptake inhibitors ("SSRis").

This invention is also directed to a method of treating depression and/or anxiety in a patient in need of such treatment comprising administering to said patient an effective amount of one or more (e. g. , one) compounds of formula (I) in combination with an effective amount of one or more (e. g. , one) selective serotonin reuptake inhibitors.

This invention is also directed to a method of treating an NK1 receptor mediated disease in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I) in combination with at least one (e. g. , one) therapeutic agent selected from the group consisting of: other types of NK1 receptor antagonists (e. g. , those that are disclosed in the neurokinin receptor antagonist patents cited in the above Background Section), prostanoids, H1 receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin 11 receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists (e. g., ondansetron), serotonin 5-HT2r, receptor agonists, nociceptin receptor agonists,

glucocorticoids (e. g. , dexamethasone), rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5.

This invention is also directed to a method for treating an NK1 mediated disease in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of formula (I) in combination at least one (e. g. , one) therapeutic agent selected from the group consisting of: prostanoids, such as prostaglandin Ei ; a-adrenergic agonists, such as phentolamine mesylate ; dopamine receptor agonists, such as apomorphine; angiotensin 11 antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA antagonists, such as bosentan and ABT-627; serotonin 5-HT3 receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone.

This invention is also directed to a method for treating an NK1 mediated disease in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I) in combination with and effective amount of at least one (e. g. , one) therapeutic agent selected from the group consisting of: other types of NK1 receptor antagonists, SSR ! s, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multi-drug resistance protein 5.

This invention is also directed to a method for treating emesis, nausea and/or vomiting in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e. g. , one) compound of formula (I) in combination with and effective amount of at least one (e. g. , one) serotonin 5-HT3 receptor antagonist (e. g., ondansetron) and/or at least one glucocorticoid (e. g., dexamethasone).

DETAILED DESCRIPTION OF THE INVENTION Unless indicated otherwise, the following definitions apply throughout the specifications and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with

other terms, unless otherwise indicated. Hence, the definition of"alkyl"applies to "alkyl"as well as the"alkyl"portions of"hydroxyalkyl,""haloalkyl,""alkoxy,"etc.

Unless otherwise incicated, when a substituent can be present more than once in a formula, each selection for that substituent is made independently of any other selections (e. g. , for (R21) r each R21 substituent is independently selected).

"At least one", examples include 1-3,1-2 or 1.

"Heteroatom"means a nitrogen, sulfur, or oxygen atom. Multiple heteroatoms in the same group may be the same or different.

"One or more", examples include 1-3, or 1-2 or 1.

"Patient"means a mammal, such as a human, and preferably a human.

"Alkyl"means an unsubstituted or substituted, straight or branched, hydrocarbon chain having, preferably, from one to twenty-four carbon atoms, more preferably, from one to twelve carbon atoms, and even more preferably, from one to six carbon atoms.

"Cycloalkyl"or"cycloalkane"means an unsubstituted or substituted, saturated, stable, non-aromatic, carbocyclic ring, having, preferably, from three to fifteen carbon atoms, more preferably, from three to eight carbon atoms, most preferably 5 to 6 carbon atoms. The cycloalkyl ring can be fused with one to two cycloalkyl, aromatic (e. g. , a benzofused ring), heterocyclic or heteroaromatic rings. The cycloalkyl ring can be attached at any endocyclic carbon atom that results in a stable structure.

Examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Aryl"means a substituted or unsubstituted aromatic carbocyclic ring system comprising, for example, from one to two aromatic rings. The aryl moiety generally comprises from 6 to 14, preferably 6 to 10, carbon atoms with all available substitutable carbon atoms of the aryl moiety being intended as possible points of attachment. Representative examples include phenyl, tolyl, xylyl, cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The carbocyclic ring can optionally be substituted with from one to five, preferably one to three, moieties, such as mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy, amino,

monoalkylamino, dialkylamino, and the like, said moieties being independently selected.

"Heteroaryl"means an aromatic ring system comprising, for example, one or two aromatic rings and at least one nitrogen, oxygen or sulfur hetero atom in an aromatic ring. The heteroaryl group typically comprises 5 to 10 ring atoms (e. g. , 5-6 or 9-10).

The heteroaryl groups can be unsubstituted or substituted with a one or more substituents, preferably, one to five substituents, more preferably, one, two or three substituents (e. g. , mono-through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino, dialkylamino, and the like). Representative heteroaryl (heteroaromatic) groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3, 5-triazinyl and indolyl groups.

"Heterocycloalkyl"means an unsubstituted or substituted, saturated, cyclic ring system comprising from three to fifteen ring atoms, preferably, from three to eight ring atoms, and comprising carbon atoms and at least one heteroatom as part of the ring.

"Heterocycloalkenyl"means an unsubstituted or substituted, non-aromatic cyclic ring system comprising at least one (e. g. , one) double bond, said ring system comprising from three to fifteen ring atoms, preferably, from three to eight ring atoms, and comprising carbon atoms and at least one heteroatom as part of the ring, and comprising.

"Heterocyclic ring"or"heterocycle"means an unsubstituted or substituted, saturated, unsaturated or aromatic mono cyclic or polycyclic ring, comprising carbon atoms and one or more heteroatoms in the ring. Monocyclic rings preferably contain from three to eight atoms in the ring structure, most preferably, five to seven atoms.

Polycyclic ring systems comprising two rings preferably comprise from six to sixteen atoms, most preferably, ten to twelve atoms. Polycyclic ring systems comprising three rings comprise, preferably, from thirteen to seventeen atoms, most preferably, fourteen to fifteen atoms. Each heterocyclic ring has at least one heteroatom.

Unless otherwise stated, the heteroatoms are each independently selected from the group consisting of: nitrogen, sulfur and oxygen atoms.

"Carbocyclic ring"or"carbocycle"means an unsubstituted or substituted, saturated, unsaturated or aromatic (e. g., aryl) hydrocarbon ring. Carbocycles may be monocyclic or polycyclic. Monocyclic rings, preferably, contain from three to eight atoms, more preferably, five to seven atoms. Polycyclic rings having two rings, preferably, contain from six to sixteen atoms, more preferably, ten to twelve atoms, and those having three rings, preferably, contain from thirteen to seventeen atoms, more preferably, fourteen to fifteen atoms.

"Alkoxy"means an oxygen atom bonded to an alkyl group (-O-alkyl).

Representative alkoxy groups include methoxy, ethoxy and isopropoxy groups.

"Hydroxyalkyl"means an alkyl group, as defined above, comprising at least one hydroxy substituent (-alkyl-OH). Additional substituents to the alkyl group may also be present. Representative hydroxyalkyl groups include hydroxymethyl, hydroxyethyl and hydroxypropyl groups.

"Halo,""halogen"or"halide"means a chloro, bromo, fluoro or iodo atom radical. Chlorides, bromides and fluorides are preferred halides.

"Sulfonyl"represents a group having the formula-S (O) 2-.

"Prodrug"represents compounds that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process (e. g. , a prodrug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form). A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of A. C. S.

Symposium Series (1987), and in Bioreversible Carriers in Drug Design, E. B. Roche, ed. , American Pharmaceutical Ass'n and Pergamon Press (1987), each of which is incorporated herein by reference thereto.

"Effective amount"means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g. , provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and the particular active ingredient (s)

being employed, and like factors within the knowledge and expertise of the attending physician.

This invention is directed to compounds having the formula (I) or la (defined below), including any and all isomers, such as enantiomers, stereoisomers, diastereomers, rotomers, and tautomers, and prodrugs of the compounds having the formula (I) or (la), and the isomers thereof, and their corresponding salts, solvates (e. g. , hydrates), esters, and the like.

The invention is also directed to pharmaceutical compositions comprising one or more compounds of formula (I) or (la) and one or more pharmaceutical acceptable excipients/carriers, or salts, solvates, and esters thereof.

The compounds of formula (I) or (la) can be useful for treating a variety of diseases, symptoms and physiological disorders, such as emesis, depression, anxiety and cough. Thus, the invention is also directed to methods of treating such types of diseases, symptoms and disorders by administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising at least one compound having the formula (I) or (la) and at least one pharmaceutically acceptable excipient/carrier.

Another aspect of the invention is to provide a kit comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically- acceptable carriers to treat a variety of physiological disorders, symptoms and diseases.

Compounds having the formula (I) or (la) can have at least one asymmetrical carbon atom. All isomers, including stereoisomers, diastereomers, enantiomers, tautomers and rotational isomers, are contemplated as being part of the invention.

Prodrugs, salts, solvates, esters, etc. , derived from the compounds having the formula (I) or (la), or precursors thereof, are also within the scope of the invention.

The invention includes d-and 1-isomers in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by

reacting optically pure or optically enriched starting materials or by separating isomers of a compound having the formula (I) or (la).

The inventive compounds can exist in unsolvated as well as solvate forms, including hydrated forms. In general, the solvate forms, with pharmaceutically- acceptable solvents, such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.

The inventive compounds may form pharmaceutically-acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Acidic compounds of the invention (e. g. , those compounds which possess a carboxyl group) form pharmaceutically-acceptable salts with inorganic and organic bases. Representative examples of such types of salts are sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically-acceptable amines, such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, and the like. Many such types of salts are known in the art, for example, those that are described in WO 87/05297, which is incorporated in its entirety by reference herein.

Preferred cationic salts include alkali metal salts (e. g. , sodium and potassium) and alkaline earth metal salts (e. g. , magnesium and calcium). Preferred anionic salts include halide (e. g., chloride), acetate and phosphate salts.

For compounds of formula (I), n8 is preferably 0-2 and most preferably 0-1.

For compounds of formula (I), t is preferably 1-2.

For compounds of formula (I) R30 and R31 are preferably selected from the group consisting of: H, and (Ci-C6) alkyl, and most preferably H and -CH3.

For compounds of formula (I) R45 is preferably selected from the group consisting of: H, and (Ci-Ce) alkyl, and most preferably H and -CH3.

For compounds of formula 9I) R20 is preferably H in the substitutent -NR20-.

Examples of moieties formed as a result of R6 and R7 being taken together with the carbon atom to which they are bound include :

wherein t is from 1 to 4, and X4 is selected from the group consisting of-O-,-S-or -NR20- (wherein R'O, R'O, R31, R45, and n8 are as defined for formula (1)).

Examples of moieties formed as a result of R6 and R7 being taken together with the carbon atom to which they are bound also include:

wherein t is 1 to 4.

One embodiment of the invention is directed to compounds wherein R6 and R7 taken together with the carbon atom to which they are bound form a ring selected from the group consisting of:

wherein t is 1 to 4.

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

wherein X4 is selected from the group consisting of :-O-,-S-and-NR20-, and wherein R20, R30 and R31 are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

wherein t is 1-4, and R20, R45 and n8 are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring :

wherein X4 is selected from the group consisting of :-O-,-S-and-NR20-, and wherein R20, R45 and n8 are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

wherein R20, R30, and R31 are as defined for formula (1).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring :

wherein R30 is as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

wherein t is 1 to 4.

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring: One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring: One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring:

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring: One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 taken together with the carbon to which they are bound form the ring: One embodiment of the invention is directed to compounds of formula (I) wherein R6 or R7 is wherein n8 is 0-1 and R45 is selected from the group consisting of-OH and -O(C1-C6)alkyl, and all other substituents are as defined for formula (I), One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 together with the carbon to which they are bound form the ring

wherein R30 is selected from the group consisting of-OH and-O (Ci-C3) alkyl, and R3 is H, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R4 is H and R5 is-OH, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 or R7 is wherein n8 is 0-1, R45 is selected from the group consisting of-OH and -O(C1-C3)alkyl, R4 is H and R5 is-OH, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 together with the carbon to which they are bound form the ring wherein R30 is selected from the group consisting of-OH and-O (Ci-C3) alkyl, R31 is H, R4 is H and R5 is-OH, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R8 is H and R9 is-OH, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 or R7 is wherein n8 is 0-1, R45 is selected from the group consisting of-OH and -O(C1-C3)alkyl, R8 is H and R9 is-OH, and all other substituents are as defined for formula (I).

One embodiment of the invention is directed to compounds of formula (I) wherein R6 and R7 together with the carbon to which they are bound form the ring wherein R30 is selected from the group consisting of-OH and-O (Ci-C3) alkyl, R31 is H, R8 is H and R9 is-OH, and all other substituents are as defined for formula (I).

Preferred embodiments of this invention are directed to compounds of formula (I) comprising one of, or any two or more of, the groups of substituents defined in (1) to (7) below : (1) Ar1 and Ar2 are each independently (i. e., Ar1 and Ar2 are the same or different

10 Rio d eR1 R12 group) wherein R10, R"and R 12 are as defined for formula (1); more preferably, RIO, R11 and R12 are each independently selected from the group consisting of H, Ci-Ce alkyl, C3- C8 cycloalkyl, -OR20, halogen, -CN, -NO2, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, heteroaryl, and heteroaryl substituted with (R21) r; even more preferably, R10, R11 and R12 are each independently selected from the group consisting of H, Ci-Ce alkyl, halogen,-CF3,-CHF2 and-CH2F ; and still more preferably, when X1 is -O-, R10, R11 and R12 are each independently selected from the group consisting of H, halogen,-CF3,-OH, C1-C6alkyl and-O (Ci-Ce) alkyl ; (2) X1 is selected from the group consisting of -O- and -NR20-; and more preferably Xl is-0--, (3) R'and R2 are each independently selected from the group consisting of H, Ci-Ce alkyl, hydroxy (Ci-C3 alkyl)-, C3-C8 cycloalkyl,-CH2F,-CHF2 and-CF3 ; more preferably R'and R2 are each independently selected from the group consisting of H and Ci-Ce alkyl ; and even more preferably R1 and R2 are each independently selected from the group consisting of H and-CH3 ; (4) R 3is selected from the group consisting of-H, Ci-Ce alkyl,-CH2F, -CHF2 and -CF3 ; more preferably R3 is selected from the group consisting of H and Ci-Ce alkyl ; and even more preferably R3 is H; (5) R4 and R5 are each independently selected from the group consisting of H, Ci-Ce alkyl.-OH and halogen (e. g., CI) ; more preferably R4 and R5 are each independently selected from the group consisting of H and Ci-Ce alkyl ; and even more preferably R4 and R5 are each H; (6) ni is 0,1, or 2 for R6, G for R6 is selected from the group consisting of: H, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16, -C(O)NR15R16, -C(O)OR20, C3-C8 cycloalkyl,

wherein R14, R'5, R16, R17, R20 R25, R26, R27, R28, R29, X2, R45, n2, n3, and n8 are as defined for formula (I) ; and (7) R7 is -(CH2) n6-J (i. e., R40 and R41 are H) wherein n6 is 0,1 or 2, and J is, selected from the group consisting of H, -CF3, -CHF2, -CH2F, -NR15R16, -NR15SO2R17, -NR15C(O)R14, -NR20C(O)NR15R16, -C(O)NR15R16, -C(O)OR20, C3-C8 cycloalkyl,-0-C (O) NR15R16,

wherein R14, R15, R16, R17, R20, R25, R26, R27, R28, R29, X2, R45, n2, n3 and n3 are as defined for formula (I).

In another preferred embodiment of the invention, R6 and R7, together with the carbon atom to which they are both attached, form a 4-to 7-membered ring comprising from, preferably, 0 to 2 heteroatoms that are each independently selected from the group consisting of -O-, -S-, -S (O)-,-S02-,-N= and -NR20-, the 4-to 7- membered ring being optionally substituted with from 1 to 4 R45 substituents wherein each R45 substituent is independently selected. More preferably, the ring is selected from the group consisting of:

wherein t is 1 to 4, X4 is selected from the group consisting of :-O-,-S-, and-NR, and R02, R30, R31, R45, and n8 are as defined for formula (I). Even more preferably the ring is selected from the group consisting of: wherein t is 1 to 4. Still more preferably the ring is selected from the group consisting of:

wherein t is 1 to 4.

In another preferred embodiment of the invention, R6 is as defined for formula (I) (and most preferably ni for R6 is 0 to 3, and R7 is selected from the group consisting of -NR15R16 (e.g., -NH2), -NR15C(O)R14 and -NR20C(O)NR15R16, wherein R14, R15, R16 and R20 are as defined for formula (l). In still another preferred embodiment of the invention, R6 is selected from the group consisting of-CH3,-CF3, -CHF2, -CH2F, -OH, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -NR15R16, -NR15C(O)R14, - C (O) NR15R16, -C(O)NR15R16 and-C (O) OR20, wherein R, R, R16 and R are as defined for formula (I). In yet another preferred embodiment of the invention, R6 and R7, together with the carbon atom to which they are both attached, form a -C (=O)-,-C (=CH2) -, or-C (=NR13)- group.

Preferably R8 and R9 are each independently selected from the group consisting of H,-OH, Ci-Ce alkyl and halogen (e. g. , F or Cl), or R8 and R9, together with the carbon atom to which they are both attached, form a-C (=O)- group. More

preferably, R8 and R9 are each independently selected from the group consisting of H and Ci-Ce alkyl. Even more preferably, R'3 and R9 are each H.

Preferably each R13 is independently selected from the group consisting of -OH and -OCH3.

Preferably each R14 is independently selected from the group consisting of H, Ci-Ce alkyl (e. g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc. ), -C1-C6 alkylNH2 and -C1-C6 alkylNHC(O)OC1-C6 alkyl. More preferably, each R14 is independently selected from the group consisting of H and -CH3.

Preferably R15 and R16 are each independently selected from the group consisting of H, Ci-Ce alkyl and C3-C8 cycloalkyl, or R15 and R16, together with the nitrogen atom to which they are both attached form a 4-to 7-membered ring that is optionally substituted with-OR, wherein one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of-O-,-S- and -NR20-, and wherein R20 is as defined for formula (I). In one preferred embodiment of the invention, R15 and R'6 are each independently selected from the group consisting of H and CH3.

Preferably each R17 is selected from the group consisting of Ci-Ce alkyl and -CF3. More preferably, each R17 is C1-C6 alkyl (e. g.,-CH3).

Preferably each R20 is independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, each R20 is independently selected from the group consisting of H and -CH3.

Preferably each R21 is independently selected from the group consisting of H, C1-C6 alkyl,-CF3,-CHF2,-CH2F,-OCF3,-OCHF2 and-OCH2F. More preferably, each R21 is selected from the group consisting of H and Ci-Ce alkyl.

Preferably R22 is selected from the group consisting of H and Ci-Ce alkyl.

More preferably, R22 is selected from the group consisting of H and-CH3.

Preferably R23 and R24 are each independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, R23 and R24 are each independently selected from the group consisting of H and-CH3.

Preferably R25 and R26 are each independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, R25 and R26 are each independently selected from the group consisting of H and -CH3.

Preferably R27 and R28 are each independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, R27 and R28 are each independently selected from the group consisting of H and -CH3.

When n3 is 0, and R27 and R28 are each H, and n3 is 0, then X2 is selected from the group consisting of -CH2, -CF2- and -CR20F-, where R20 is defined the same as above in the summary of the invention.

Preferably R29 is selected from the group consisting of H and Ci-Ce alkyl.

More preferably R29 is selected from the group consisting of H and -CH3.

Preferably R30 and R31 are each independently selected from the group consisting of H and Cl-C2 alkyl (e. g.,-CH3), or R30 and R31, together with the carbon atom to which they are both attached form a-C (=O)- group.

Preferably R38 and R39 are each independently selected from the group consisting of H and C1-C2 alkyl ; or R38 and R39, together with the carbon atom to which they are both attached, form a cyclopropyl group.

Preferably each R45 is independently a C1-C2 alkyl (e. g.,-CH3), or two R45 substitutents, together with the carbon atom to which they are both attached, form a -C(=O)- group.

Preferably X2 is selected from the group consisting of -NR22, -O-, -S-, -S(O)-, -SO2-, -CH2-, -CF2- and -CR12F-. More preferably, X2 is selected from the group consisting of -NR22, -O- and -CH2-.

Preferably r is 1 or 2, and more preferably 1.

Preferably n2 is 2 or 3.

Preferably n3 is 0,1 or 2, and more preferably 1.

Preferably n4 is 1,2 or 3, and more preferably 1.

Preferably n5 is 0 or 1.

Preferably n8 is 0-2, and more preferably 0-1.

Preferred embodiments of the invention are also directed to compounds of formula (I) having one, or a combination of any two or more, of the groups of substituents defined in (1) to (8) below : (1) X1 is -O- or -NR20-; (2) Ar1 and Ar2 are each independently: (i. e., Ar1 and Ar2 are the same or different group) wherein (a) R10, R11 and R12 are as defined for formula (I) ; or (b) For Ar1 : (i) R10, R11 and R12 are each H; or (ii) at least one (e. g. , 1) of R10, R and R is halogen, preferably, F; or (c) For Ar2 : (i) at least two (e. g. , 2) of R10, R11 and R12 are each -CF3 ; or (ii) at least two (e. g. , 2) of R10, R11 and R12 are each independently selected from the group consisting of F and Cl ; (3) (a) R1 and R2 are each independently selected from the group consisting of H and Ci-Ce aiky) (e. g.,-CH3) ; or (b) One of R1 and R2 is C1-C6 alkyl, preferably-CH3 ; (4) R3 is H ; (5) (a) R4 and R5 are each H; or

(b) R4 and R5 are each Cl ; or (c) R4 and R5, together with the carbon atom to which they are both attached, form a-C (=O)- group ; (6) (a) R8 and R9 are each H; or (b) R8 and R9, together with the carbon atom to which they are both attached, form a-C (=O)- group ; (7) (a) R6 is -NH2, and R7 is selected from the group consisting of H, -CH3, -C(O)NH2,-C(O)NHCH3, -C(O) N (CH3) 2 and-C (O) OH; (b) R6 is -NH2, and R7 is selected from the group consisting of H, C1-C6alkyl (e. g.,-CH3,-CH2CH3,-CH2CH2CH3,-CH2CH2CH2CH3, and-CH2CH2CH2CH2CH3),-C (O) NR15R16 and-C (O) OR wherein R15, R16 and R20 are as defined for formula (I) ; (c) R6 is H, and R7 is selected from the group consisting of-NH2, -NHC(O) CH3, -NHC (O) C (NH2) (CH3) 2, (d) R6 is H, and R7 is selected from the group consisting of -NR15R16, -NR15C(O)R14 and NR20C(O)NR15R16, wherein R14, R15 and R16 are as defined for formula (I) ; (e) R6 and R7, together with the carbon atom to which they are both attached, form a 4-to 7-membered ring selected from the group consisting of:

wherein t is from 1 to 4, X4 is selected from the group consisting of :-0-,-S-and-NR-, and R20 R30, R31, R45 and ns are as defined for formula (I) ; (f) R6 and R7, together with the carbon atom to which they are both attached, form a 4-to 7-membered ring selected from the group consisting of:

wherein t is from 1 to 4; or (g) R6 and R7, together with the carbon atom to which they are both attached, form a 4-to 7-membered ring selected from the group consisting of: wherein t is from 1 to 4; and (8) X1 is -O- or -NR20-; Ar1 and Ar2 are each independently represented by the formula:

(i. e., AR1 and Ar2 are the same or different group)

wherein R10, R11 and R12 are each independently selected from the group consisting of H, F, Cl, C1-C6 alkyl, -CF3, -CHF2, -CH2F, -OR20, -OCF3, -OCHF2, heteroaryl, and heteroaryl substituted with (R21) r; R1 and R2 are each independently selected from the group consisting of H, Ci-Ce alkyl and hydroxy (C1-C3alkyl)-; or R1 and R2, together with the carbon atom to which they are both attached, form a -C(=O)- group ; R3 is selected from the group consisting of H and Ci-Ce alkyl ;

R4 and R5 are each independently selected from the group consisting of H, -OH, Ci-C6 alkyl and halogen ; or R4 and R5, together with the carbon atom to which they are both attached, form a-C (=O)- group; and R3 and R9 are each independently selected from the group consisting of H, -OH, Ci-Ce alkyl and halogen; or R3 and R9, together with the carbon atom to which they are both attached, form a-C (=O)- group.

Another preferred embodiment of the invention is directed to a compound of formula (I) having formula (la) :

(la) or pharmaceutically acceptable salts or solvates thereof, wherein: Arbis represented by the following formula : wherein R10, R11 and R12 are each independently selected from the group consisting of H, halogen,-OH,-O (Ci-C6) alkyl, C1-C6alkyl and -CF3 (preferably R10, R11 and R12 are each H); Ar 2a is represented by the following formula :

wherein R10, R11 and R12 are independently selected from the group consisting of: H, Ci-Ce alkyl, C3-C8 cycloalkyl,-OR20 (wherein R20 is as defined for formula (I)), halogen,-CN,-N02,-CF3,-CHF2,-CH2F,-CH2CF3,-OCF3,-OCHF2,-OCH2 F, -OCH2CF3, heteroaryl, and heteroaryl substituted with (R21) r wherein each R21 substituent is independently selected and R21 is as defined for formula (I) (preferably R'O, R11 and R12 are each independently selected from the group consisting of H, halogen,-OH,-O (Ci-Ce) alkyl, C1-C6alkyl and -CF3) ; R1a and R2a are each independently selected from the group consisting of H, C1-C6 alkyl and hydroxy (C1-C3alkyl)-; and R6 and R7 are as defined for formula (I).

R6 is-NR15R16, and R7 is selected from the group consisting of H, Ci-Ce alkyl (e. g., -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, and)-CH2CH2CH2CH2CH3), -C(O)NR15R16 and-C (O) OR20, wherein R15, R16 and R20 are as defined for formula (I).

More preferably, R6 is-NH2, and R7 is selected from the group consisting of H,-CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -C(O)NH2, -C(O) NHCH3, -C (O) N (CH3) 2 and-C (O) OH. In another preferred embodiment, R6 and R7, together with the carbon atom to which they are both attached, form a 4-to 7- membered ring, and preferably a 4-to 7-membered ring having 0 to 2 heteroatoms, said ring being as defined for formula (I). More preferably, the 4-to 7-membered ring is selected from the group consisting of: wherein t is from 1 to 4, X4 is selected from the group consisting of :-0-,-S-and -NR20-, and R20, R30, R31, R45 and n8 are as defined for formula (I). Most preferably the 4-to 7-membered ring is selected from the group consisting of:

wherein t is 1 to 4. Still more preferably the ring is selected from the group consisting of:

wherein t is 1 to 4.

Representative compounds of the invention include, but are not limited to, the compounds in Table I. In the structures in Table I,"Me"represents methyl.

TABLE I EXAMPLE STRUCTURE 1a F 0 F F cri ci F tOF $ JS S F 0 2fez F 1 b F cl ce O I F I'F F F F F - F /I 2 FFF 0 \y 3 F FF if 0 0 1 F 'I CH3 F 4 F F F NOME F O \ F F F F NOS 0 F NOS / 0 F F F CL3 F F I 0 F F '/cl3 F H\NH F F F p F F CH3 F l 8a 0 F F F Han,,, F ''/ I F F F 8b 0 F FI HO : 0 9a o F F F 9a H F F zon Hic 0 F F CH 3 F 9b F F F H F F zon H3c /I F 9C ; H3 F F H F F 9c H F F F 0 F H3C p F W Cl 3 '/CH3 F 10a F F F F ,,,,/O \ F F CH3 F 10b F F °'je "tel, ." c3 F F F H F F F "-O CH3 F ,...,"/ \ F CH3 F 11b j-N F F N HN.",,. ,."r0 \ F c 3 F 12a O F F F HN 11 b F 12a F CH3 F 12b o. H p N F F HN p F 1XX F CH3 F 13 0 H N /F F F zon HN- F '/cl3 F 14 ooh NEZ 14 0 H N, N HAN I 0 F F 4 Oß N, N 15a 0 Cl3 f-I s N Hs H ß FiF H F cl3 C H 3 F 15b cl3 NCHg H V F Ho /I .,,,.,/O \ F F CH3 F 16a CH H2N 3 F F F han HAN F CH3 F CH3 F 16b C H3 H2N 3 F F F p F F F ,,,,/O \ F F CH3 F 0 17a F F F HN,,, au 0 IF F 17b F A /N--, F / 0 18"P F 18 F F H2N,,, C H3 19 _ 19 F CH3 F 19 HAN O CF3 Han 'erz 20 o F 0"' F /CH3 21a o. H F O N 0"' IF CH3 21b r 0 22a Wo VS HAN 0 F CL3 22a H F O N »",. HUI F F Ht JL N H F dz HUI F F 23a po HAN 23a °NH F 0 CH3 F 23b 0 H w o HN.", F F CH3 F 24 F HO F F HOO F HAN 0 F F ,. ,,/ \ F F HN F F un 25 F H F O w F F 26a F F , oh oh F FEZ F F 27 26b HAN F , 0 H F 's/ \ I F 27 / HAN CF3 HZN X 28 28 Han Han CAF3 29 Meat HAN HAN - 30 HAN HAN 'n/ C ON 0 cl3 H2N 0 cl3 ''/ 'CF3 0 caf3 c N =0 P H J H2N 33 / HN O CF3 Non,,. /1-1 CF, 34 HAN HAN O Han,,. 35 HO ho caf3 Ho 1/--, ! CAF3 36 36 36 '\ pu HN/, spi ' 37 o 0 (\ CFs Ni. 38 Yv C Caf3 hui. ou G3 HAN ''i/ \ Caf3 HN. 1 ou y_ O CF3 nui,, \ IT CFs 40 ON 0 CF3 4D/ ''i/ \ C F3 41 o ! CFg HN/./'t Han/, o D CF 0 HN) NH CL3 43 CF3 Zon 'n/ fl-CF3 N/. 0 44 Me Mye cl3 N/, 0 -10 cl3 Me CF3 Ni, 0 CF3 45 Me ZON 'n 46 01 NII NO CFs ''i/ \ d' 46 Me ZON Mye r N CF, cA CAF3 48 mye 47 Me P 'OkAcF, 48 Me r N CF3 r \ CFs HN/. 0 /I 49 H N CF3 Han 3 .., 1 '% 50 50 ZON H Hui, I A 1 p ne 51 0 Me N F o CF HO I 52 pane ZON ° N 53 H2N \ CF3 HzN \ CFs ''i \ caf3 54 HAN CF3 . \ CFs HzN/. HN -, CL 55 0 HO HAN HzN s, /I a,/of X 56 'je han HAN CF3 H2N/, '/ 57 zu han"" HN \ CFs 58 4, r (\ a CF3 58 el o 58 han HAN Han \ caf3 I 59 'i/ \ Caf3 cl3 Ho N 60 o 60 0 NH d'' HN. 1' HN 'i/ \ caf3 61 0 NH CF3 HN/. ''i/ \ caf3 62 NHz HZ Zu '°i/ \ 63a 63a nu NU CF3 ' 63b 0 NH a/," ''i/ \ . I 64 0 CF, HN /I rA ops CAF3

Preferred compounds of the invention are compounds of Examples 7,8a, 8b, 9c, 10a, 11a, 11b, 12a, 12b, 14,16b, 17a, 17b, 18,26b, 27-36,39, 43-54,57, 63b, and 64 in Table I.

More preferred compounds of the invention are compounds of Examples 11a, 11 b, 12a, 12b, 27-29,39, 43,44-50 in Table I.

Even more preferred compounds of the invention are compounds of Examples 11a, 11b, 12b, 27,28, 46 and 49 in Table I.

ASSAY The in vítro and in vivo NK1, NK2 and NK3 activities of the compounds having the formulas (I) and (la) can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the NK1 agonist Substance P.

The percent inhibition of neurokinin agonist activity is the difference between the percent of maximum specific binding ("MSB") and 100%. The percent of MSB is defined by the following equation, wherein"dpm"represents"disintegrations per minute" : <BR> <BR> <BR> <BR> <BR> <BR> % MSB (dpm of unknown) - (dpm of nonspecific binding)<BR> <BR> O _ X 100 (dpm of total binding) - (dpm of nonspecific binding) The concentration at which a compound having the formula (I) or (la) produces 50% inhibition of binding is then used to determine an inhibition constant ("ksi") using the Chang-Prusoff equation.

The Ksi values can be determined following the procedure of Duffy, Ruth A. et al.,"Correlation of Neurokinin (NK) 1 Receptor Occupancy in Gerbil Striatum with

Behavioral Effects of NK1 Antagonists", J Pharmacol Exp Ther, 2002,301 : 536-542, the disclosure of which is incorporated herein by reference thereto.

In vivo activity may be measured by inhibition of an agonist-induced foot tapping in a gerbil, as described in Science, 281, 1640-1695 (1998), the disclosure of which is incorporated herein by reference thereto.

The compounds of Examples 1 a, 1 b, 2-7,8a, 8b, 9a, 9b, 9c, 1 Oa, 1 Ob, 11 a, 11b, 12a, 12b, 13,14, 15a, 15b, 16a, 16b, 17a, 17b, 18-20, 21 a, 21 b, 22a, 22b, 23a, 23b, 24,25, 26a, 26b, 27-62,63a, 63b, and 64 in Table I had a K ; in the range of 0.02 to 93.20 nM The compounds of Examples 7,8a, 8b, 9c, 10a, 11a, 11b, 12a, 12b, 14,16b, 17a, 17b, 18,26b, 27-36,39, 43-54,57, 63b, and 64 in Table I had a Ki in the range of 0. 02 to 5. 32 nM.

The compounds of Examples 11 a, 11 b, 12a, 12b, 27-29,39, 43, and 44-50 in Table I had a Ki in the range of 0.11 to 5.32 nM.

The compounds of Examples 11 a, 11 b, 12b, 27,28, 46 and 49 in Table I had a Ki in the range of 0.13 to 1. 78 nM.

The compound of Example 49 had a Kj of 0. 2 nM.

Compounds having the formula (I) or (la) can be effective antagonists of the NK1 receptor, and of an effect of its endogenous agonist, Substance P, at the NK1 receptor site, and therefore, can be useful in treating conditions caused or aggravated by the activity of said receptor Compounds having the formulas (I) or (la) have a number of utilities. For instance, the inventive compounds can be useful as antagonists of neurokinin receptors, particularly, NK1 receptors in a mammal, such as a human. As such, they may be useful in treating and preventing one or more of a variety of mammalian (human and animal) disease states (physiological disorders, symptoms and diseases) in a patient in need of such treatment, for instance, respiratory diseases (e. g. , chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), inflammatory diseases (e. g. , arthritis and psoriasis), skin disorders (e. g. , atopic dermatitis and contact dermatitis), ophthalmalogical disorders (e. g. , retinitis, ocular hypertension and cataracts), central nervous system conditions, such as depressions

(e. g. , neurotic depression), anxieties (e. g., general anxiety, social anxiety and panic anxiety disorders), phobias (e. g., social phobia), and bipolar disorder, addictions (e. g., alcohol dependence and psychoactive substance abuse), epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia, Towne's disease, stress related disorders (e. g., post tramautic stress disorder), obsessive/ compulsive disorders, eating disorders (e. g., bulemia, anorexia nervosa and binge eating), sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders (e. g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), atherosclerosis, fibrosing disorders (e. g., pulmonary fibrosis), obesity, Type II diabetes, pain related disorders (e. g. , headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), bladder and genitourinary disorders (e. g., interstitial cystitis and urinary incontinence), and nausea.

Preferably, the inventive compounds can be useful in treating and preventing one of the following mammalian (e. g. , human) disease states in a patient in need of such treatment: respiratory diseases (e. g. , cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulemia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders, bladder disorders, genitourinary disorders and nausea. In particular, the compounds having the formulas (I) and (la) are useful for treating disease states related to microvascular leakage and mucus secretion. Consequently, the compounds of the invention are especially useful in the treatment and prevention of asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders, more especially, emesis, depression, anxiety and cough.

In another aspect, the invention relates to pharmaceutical compositions comprising at least one compound (e. g. , one to three compounds, preferably, one compound) represented by the formula (I) or (la) and at least one pharmaceutically- acceptable excipient/carrier. The invention also relates to the use of such pharmaceutical compositions in the treatment of mammalian (e. g. , human) disease states, such as those listed above.

In still another aspect of the invention, a method is provided for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for the blockade of one or more neurokinin-1 receptors in a mammal (i. e. , a patient, e. g. , a human) in need of such treatment, comprising administering to the mammal an effective amount of at least one (e. g. , one) compound having the formula (I) or (la).

In another embodiment of the invention, an effective amount of one or more of the inventive NK1 receptor antagonists may be combined with an effective amount of one or more anti-depressant agents and/or one or more anti-anxiety agents (e. g., gepirone (e. g. , gepirone hydrochloride), and nefazodone (e. g. , nefazodone hydrochloride, e. g. , Serzone @) to treat depression and/or anxiety. U. S. 6,117, 855 (2000) which is incorporated herein by reference thereto, discloses a method for treating or preventing depression or anxiety with a combination therapy of a specific NIC receptor antagonist together with an anti-depressant and/or anti-anxiety agent.

Thus, anti-depressant and/or anti-anxiety agents, such as those disclosed in U. S.

6, 117, 855 (2000), can be combined with one or more (e. g. , one) compounds having the formulas (I) and/or (la) to treat depression and/or anxiety disease states in a mammal, preferably, a human.

In still another embodiment of the invention, an effective amount of one or more (e. g. , one) of the inventive NK1 receptor antagonists may be combined with an effective amount of one or more (e. g. , one) selective serotonin reuptake inhibitors ("SSRis") to treat a variety of mammalian disease states, such as those described above. SSRls alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. U. S. 6,162, 805 (2000), which is incorporated herein by reference thereto, discloses a method for treating obesity with a combination therapy of a NIC receptor antagonist and an SSRI. An inventive compound (s) having the formula (I) or (la) can be combined together with an SSRI (s) in a single pharmaceutical composition, or it can be administered simultaneously, concurrently or sequentially with an SSRI. This combination may be useful in the treatment and prevention of obesity or another of the above-identified human and animal disease states. In particular, an effective amount of at least one (e. g. , one) compound having the formula (I) or (la), alone or together with an effective

amount of at least one (e. g. , one) selective serotonin reuptake inhibitor, can be useful in the treatment and prevention of emesis, depression, anxiety and/or cough.

Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. Representative SSRIs include, without limitation, the following : fluoxetine (e. g., fluoxetine hydrochloride, e. g. , Prozac @), fluvoxamine (e. g., fluvoxamine maleat, e. g. Luvox @), paroxetine (e. g. , paroxetine hydrochloride, e. g., Paxil @), sertraline (e. g., sertraline hydrochloride, e. g., Zoloft @), citalopram (e. g., citalopram hydrobromide, e. g., Celexa), duloxetine (e. g.., duloxetine hydrochloride), and venlafaxine (e. g., venlafaxine hydrochloride, e. g. , Effexor @). Further SSRIs include those disclosed in U. S. 6,162, 805 (2000). Other compounds can readily be evaluated to determine their ability to selectively inhibit serotonin reuptake. Thus, one aspect of the invention relates to a pharmaceutical composition comprising at least one (e. g. , one) NK1 receptor antagonist having the formula (I) or (la), at least one (e. g. , one) SSRI, and at least one pharmaceutically-acceptable excipient/carrier.

Another aspect of the invention relates to a method of treating the above identified mammalian (e. g. , human) disease states, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising at least one (e. g. , one) NK1 receptor antagonist having the formula (I) or (la) in combination with at least one (e. g. , one) SSRI, such as one of those recited above, and at least one pharmaceutically-acceptable excipient/carrier.

In a preferred aspect, the invention relates to a method of treating emesis, depression, anxiety and/or cough, the method comprising administering to a patient in need of such treatment an effective amount of at least one (e. g. , one) NK1 receptor antagonist having the formula (I) or (la) in combination with at least one (e. g. , one) SSRI, such as one of those described above. When an inventive NK1 receptor antagonist is combined with an SSRI for administration to a patient in need of such treatment, the two active ingredients can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the two active ingredients are administered consecutively or sequentially, the inventive

NK1 receptor antagonist is, preferably, administered before the administration of the SSRI.

Thus, the compounds of the invention may be employed alone or in combination with other active agents. Combination therapy includes the administration of two or more active ingredients to a patient in need of treatment. In addition to the above described NK1 receptor antagonist/SSRI combination therapy, the compounds having the formula (I) and (la) may be combined with one or more other active agents, such as the following : other types of NK1 receptor antagonists (e. g. , those that are disclosed in the neurokinin receptor antagonist patents cited above in the related art description section), prostanoids, H1 receptor antagonists, a- adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin 11 receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists (e. g. , ondansetron (e. g. , ondansetron hydrochloride, e. g., Zolfran @), palonosetron and granisetron (e. g. , granisetron hydrochloride, e. g., Kytril @)), serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids (e. g. , dexamethasone), rho kinase inhibitors, potassium channel modulators and/or inhibitors of multi-drug resistance protein 5.

Preferable therapeutic agents for combination therapy with compounds of the invention are the following : prostanoids, such as prostaglandin Ei ; a-adrenergic agonists, such as phentolamine mesylate ; dopamine receptor agonists, such as apomorphine; angiotensin 11 antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA antagonists, such as bosentan and ABT-627; serotonin 5-HT3 receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of the invention, the inventive compounds can be combined with: other types of NK1 receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and/or inhibitors of multi-drug resistance protein 5. A preferred embodiment of the invention is directed to a combination therapy comprising the administration to a patient of an effective

amount of at least one (e. g. , one) compound having the formula (I) or (la) in combination with an effective amount of at least one (e. g. , one) serotonin 5-HT3 receptor antagonist (e. g. , ondansetron) and/or at least one (e. g. , one) glucocorticoid (e. g. , dexamethasone).

Pharmaceutical compositions may contain from about 0.1 to about 99.9 weight percent, or from about 5 to about 95 weight percent, or from about 20 to about 80 weight percent of active ingredient (compound having the formula (I) or (la)).

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutical acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e. g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed. ), Remington: The Science and Practice of Pharmacy, 20t Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e. g. nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or

emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e. g. , an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 4000 mg, preferably from about 0.02 mg to about 1000 mg, more preferably from about 0.3 mg to about 500 mg, and most preferably from about 0.04 mg to about 250 mg according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutical acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.02 mg/day to about 2000 mg/day, in two to four divided doses.

The pharmaceutical compositions of the invention may be administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

The quantity of NK1 receptor antagonist in combination with a selective serotonin reuptake inhibitor ("SSRI") in a unit dose of preparation may be from about 10 to about 300 mg of NK1 receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another combination the quantity of NK1 receptor antagonist in combination with a SSRI in a unit dose of preparation may be from about 50 to about

300 mg of NK1 receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another combination the quantity of NK1 receptor antagonist in combination with SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NK receptor antagonist combined with from about 20 to about 50 mg of SSRI.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of the invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the judgment of the treating physician.

Determination of the proper dosage regimen for a particular situation is within the skill of the art.

Compounds having the formula (I) or (la) can be prepared using methods known to those skilled in the art. Typical procedures are described below, although a skilled artisan will recognize that other procedures may be applicable, and that the procedures may be suitably modified to prepare the same or other compounds within the scope of formula (I) or (la).

Definitions for abbreviations disclosed in the experimental section are as follows : Me is methyl ; Bu is butyl ; OH is hydroxyl ; Ac is acetyl ; Et is ethyl ; Ph is phenyl ; THF is tetrahydrofuran; OAc is acetate; Et20 is diethyl ether; (Boc) 20 is di- ter-butyl dicarbonate; (Boc) is tert-butoxy carbonyl ; TLC is thin layer chromatography; LDA is lithium diisopropyl amine; DCC is 1, 3-dicyclohexylcarbodiimide ; HATU is 0- (7- azabenzotriazol-1-yl)-N, N, N'N',-tetramethyluronium hexafluorophosphate ; TFA is trifluoroacetic acid; DIBAL or DIBAL-H is diisobutylaluminum hydride; DIEA or i- Pr2EtN is diisopropylethyl amine; UNCA is Urea protected N-carboxy Anhydrides; IPA is 2-propanol ; DMF is dimethylformamide ; TBAF is tetrabutylammonium fluoride ; TASF is tris (dimethylamino) sulfur (trimethylsilyl) difluoride ; and equiv is equivalents.

Compounds having the formula (I) or (la) may be generally prepared from the corresponding ketone A1 (described in WO 01/44200, which is incorporated herein by reference thereto) as shown under the following conditions: wherein: Ar1, Ar2, X1, R1 through R3 and R10through R35 are as defined for formula (I) ; R4 and R5 are independently selected from the group consisting of-H and-Cl ; and R, together with the carbon atom to which they are both attached, form a-C (=O) group; and R3 and R9 are each-H.

Wittig olefination of ketone A1 with the methyltriphenylphosphonium bromide and a suitable base, such as sodium amide or n-butyllithium, in THF provides alkene A2. Cycloaddition of the alkene with dichloroketene, which is generated in situ with trichloroacetylchloride and zinc-copper couple, in a suitable solvent, such as diethyl ether or ethylene glycol dimethyl ether ("DME"), affords dichlorocyclobutanone A3.

The ketene may also be prepared in situ with dichloroacetylchloride, triethylamine, and a suitable solvent such as hexane. Additionally, the zinc-copper couple can be replaced with zinc dust when the cycloaddition is performed using ultrasound.

Reduction of the dichlorides using a suitable reducing agent, such as sodium iodide and zinc dust in acetic acid gives cyclobutanone A4. 0 0 0 dichloroketene ci R'R' R'R'.. " cycloaddition A1 A2 R A3 0 o Zn, HOAc A3 x Ar n D D Ro A A A4

For derivatives where R1 through R5, R8, and R9 are equal to hydrogen an alternative cyclobutane synthesis can be utilized. Deprotonation of the benzyl nitrile A5 with sodium hydride in DMF is followed by the addition of 3-chloro-2-chloromethyl- 1-propene to afford cyclobutane A6. Reduction of the nitrile preferably with DiBAL-H in THF yields the aldehyde A7. Additional methods for the reduction of the nitrile are with Raney nickel and sodium hypophosphate in aqueous acetic acid-pyridine or formic acid and with other hydride reducing agents such as LiAIH4 and NaAIH4.

Those skilled in the art will recognize that the aldehyde can be converted to an alcohol (Q = OH) by reduction with a hydride reducing agent, a sulfide (Q = SH) by standard alkylation methods from the alcohol, or the amine (Q = NH2) by reductive amination. Alkylation of A8 with an electrophile containing the second aryl moiety, Ar2, further functionalizes the side chain to provide cyclobutane A9. Ozonolysis of the alkene in dichloromethane is the method of choice for the formation of ketone A10. NaH, DMF Reduction Standard Ar CN A5 CCI Ar CN Ar CHO Functionalization A5 C ! ! C ! Ar CN Ar CHO Ar -0 A6 A7 Q = OH, SH, or NH2 A8 0 base Ozonolysis XI Ar2 X'Ar2 Ar Ar LG = leaving group such A9 A10 as Cl, Br, OMs, OTf

Further derivatization of cyclobutanone A4 may be performed through deprotonation with a suitable base, such as LDA or KHMDS, followed by the addition of an electrophile to provide the substituted cyclobutanone A11. Appropriate electrophiles can be, but are not limited, to alkyl halides, peroxide reagents, trisylazide, and disulfides. Those skilled in the art can elaborate these derivatives to prepare compounds, where R4, R5, R8, and R9 are independently selected from H, C1- C6 alkyl, -OR20, -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15COR14, - NR14CONR15R16, or-SR ; or R4 and R5 together are =O or =NR13 0 0 0 Ru 8 8 ba/ Rz Stan R R5 z hil, - X Functional R9 1 Ar R3 R1 Ar2 Ar1 R3 R1 Ar2 Ar R3 R1 Ar2 A4 E represents attachment A12 to-C,-O,-N, or-S A11 To those skilled in the art, manipulation of the ketone moiety in A12 to the reported functional groups represented in R6 and R7 may require certain additional protection and deprotection steps. Accordingly, the order of synthetic operations may be different in order to maintain functional group compatibility with the operational steps in the synthesis.

The following modifications to ketone A12 can provide compounds of the type A13 where R6 is H, and R7 is either -OH, -O-(C1-C6 alkyl), -SO2R15, -O-(C3-C8 cycloalkyl), -O-C(O)NR15R16, -NR15R16, -SO2NR15R16, -NR15SO2R17, -NR15COR14, -NR14CoNR15R16 or one of the structures below :

Reduction of the ketone A12 with a hydride reducing agent, such as lithium aluminum hydride or sodium borohydride, will provide a secondary alcohol.

Conversion of the alcohol to ethers, thioethers, sulfones, carbamates and sulfonamides as defined above can be performed with standard methods.

Preferably, reductive amination of ketone A12 with a primary or secondary amine and sodium triacetoxyborohydride readily afford amines. Alternatively, reductive aminations can be accomplished with sodium cyanoborohydride, sodium borohydride, zinc/HCI, or BH3-pyridine as the reducing agent. Additional functionalization of the amines by standard alkylation, acylation, sulfonylation, addition to isocyanates, or coupling with an appropriate carboxylic acid to the above analogs can be recognized by those skilled in the art. Ra 1. Hydride reduction orHR7 R4 Rs reductive amination Ra R5 1 2 f25 1 2 RRs XR 2. Standard Methods Rs 1 Ar 1 1 ^ 2 A 1 > R3 RI A r R3 R R Ar- R A A12 A13 The synthesis of compounds where R6 or R together are =CH2, =NR13, or =NR15 originates with ketone A12. Wittig olefination of A12 with triphenylphosphonium bromide and n-butyllithium affords alkene A14. Oximes and oxime ethers, A15, are readily obtained from the reaction of the ketone with a hydroxyl-or alkoxyl-amine hydrochloride salt in pyridine as the solvent. Preferentially, imines are formed from ketones and primary amines in the presence of catalytic acid, such as para-toluenesulfonic acid, with the removal of water by a Dean-Stark apparatus. \\ C), NRs 0 R3s9R5 Witug R8 5 2 Hydroxylamine R8 R5 2 R5 XI R2 R XI R or Amine Xi R 9 9 9 1 Ar r2 Ar Addition Ar R3 Rl A, RI Ar2 R RI Ar2 A14 A12 A15

In cases where R6 or R7 is not hydrogen, a quaternary center may be generated from ketone A12 to provide compound A17 where R7 is-(CH2) n6-J, where n6 is 0-5, J is H,-CF3,-CHF2,-CH2F,-C3-C8 cycloalkyl, and R6 is-OH,-O-(C1-C6 alkyl),-0- (C3-Cs cycloalkyl), -O-C(O)NR15R16, -NR15R16, -NR15SO2R17, -NR15COR14, -NR14CoNR15R16} or one of the structures below.

Incorporation of an alkyl group in the R7 position of A12 to afford a tertiary alcohol can be completed with the addition of a Grignard reagent to the ketone.

Organometallic reagents such as alkyllithiums and alkylzincs may also be employed for this transformation. For-CF3 and-CHF2 moieties where the organometallic reagent cannot be generated the following protocol is applied. The method of choice for introducing a trifluoromethyl group to a ketone is with trimethylsilyltrifluoromethane (Ruppert's Reagent) and catalytic tetrabutylammonium fluoride in THF. Subsequent addition of aqueous mild acid hydrolyzes the silylether to the desired carbinol A16. In instances where acid sensitive functionality is present, basic hydrolysis with potassium carbonate and methanol or TBAF in THF can be used. The difluoromethyl group can be incorporated in a similar manner using (difluoromethyl) phenyidimethylsilane and catalytic TASF or potassium fluoride in DMF followed by mild acid hydrolysis. Functionalization of the alcohol A16 to ethers, thioethers, sulfones, and sulfonamides can be performed with standard methods. 0, R. a6 R. R4 fro 5 Nucleophilic R8 * R5 Xi R 2 Standard R R R R9 rl Addition Functionalization [9 1 R9 1 A I ri A12 A16 A17

Additionally, the incorporation of alkyl groups, particularly-CH2F, could be obtained through conversion of the ketone to an epoxide A18 with dimethyloxosulfonium methylide or diazomethane. Nucleophilic addition to the epoxide would provide an alternate route to tertiary alcohol derivative A16. R O R e R8 R8 Nucleophilic 5 - R s R X R or Rg X R2 Addition R9 R X R2 Ar \Ar'iazomethane Ar R3 Ri Ai. 2 A12 A18 A16

Preferentially, the formation of a quaternary center at R6 and R7, where R6 is an amine, commences with the conversion of the ketone to a nitrone. Thus, formation of the nitrone with N-hydroxylbenzylamine and subsequent addition of a Grignard reagent generates the benzyl-protected hydroxylamine A19. Reduction to the secondary amine with zinc dust in acetic acid affords the benzylamine, which can be derivatized to nitrogen-containing analogs by the previously listed methods.

Those skilled in the art will recognize that an imine, iminium salt, or a chiral sulfoxylimine is also a viable intermediate. Grignard reagents add to iminium salts, however, when using a sulfoxylimine or imine, alkyllithiums are the reagents of choice. The previously described chemistry to incorporate a-CF3 or-CHF2 can be applied to imines with the addition of trimethylsilylimidazole to the reaction and the use of stoichiometric cesium fluoride. 7 7 R4 Bn (HO) N R R4 R6<R7 4 R8 i. BnNH (OH) R8 1. Zn, HOAc Ra R R9 RS X RZ ii. R7MgBr R 2. Standard R9 R3 RI Ar2 R3 RI A 3 R'Ar2 A12 A19 A17 Analogous to the chemistry described with epoxide A18, the-CH2F moiety, along with other alkyl analogs, are accessible through an aziridine A20. Aziridination of the alkene A8 can be accomplished with chloramine-T or (N- (p- toluenesulfonyl) imino)-phenyliodinane. Nucleophilic addition to A20 followed by further functionalization will provide the previously listed nitrogen-containing derivatives. RXX1 4 Rs Ft R4 1. Nucleo hilic Azir'idlnation Ra. 5 Addition 5 2. Standard R R3 \ArZ RAr 3 RXA2 Methods A R3 R''Ar2 r'' A14 A20 A17

Spirocyclic analogs can be prepared where R6 and R 7together with the carbon to which they are attached form a four to seven-member heterocycloalkyl or heterocycloalkenyl ring, which includes but is not limited to hydantoins, ureas, lactams, imidazolones, imidazolidinones, piperazines, morpholines, and cyclic amines. Ketone A12 is converted to hydantoin A21 with potassium cyanide and ammonium carbonate in aqueous ethanol with heating. Reduction of the hydantoin to the cyclic urea A22 occurs with the addition of lithium aluminum hydride and aluminum trichloride in THF. 0. 0 N R4 O H N Ra HN 4 RB 5 2 KCN, (NH4) 2C03 Re RS LiAIH4, AICI3'RB R R9 rl 50% aq. EtOH, heat g/E-XRt-THF R9 1 X1>R2 R Ar Ar R3 R Ar2 Rs R Ar r A12 A21 A22 The above transformation of ketone A12 to a hydantoin may also be accomplished through a stepwise process using the Strecker reaction. Initial formation of an aminonitrile from ketone A12 is obtained with sodium cyanide, and a suitably protected-primary amine, such as benzylamine, in methanol and acetic acid.

Preferential basic hydrolysis of the nitrile with hydrogen peroxide and sodium hydroxide in ethanol provides the amino amide A23. Deprotection of the amine can be performed by methods known to those skilled in the art. The addition of triphosgene to the amino amide affords the spirocyclic hydantoin A21. con42 0 CONS2 1. Strecker Reaction 1. Deprotection HN 4 'R R R RArl --Ar2 2 R R 1, p2 air A12 Pg = protecting group R3 A12 A23 A21 The spirocyclic beta-lactam is synthesized from alkene A14 by a [2+2] addition with N-chlorosulfonylisocyanate to afford lactam A24. Ring expansion of the beta-to the gamma-lactam may be achieved through the following route where the lactam nitrogen is protected preferably as the t-butyl carbamate. Opening of the imide system with trimethylsilyldiazomethane, a safer alternative to diazomethane, generates a diazoketone. Wolff rearrangement of the diazoketone is carried out

photolytically in benzene or in the presence of a catalytic amount of silver benzoate and triethylamine in THF. Deprotection of the lactam nitrogen with TFA in dichloromethane provides the desired lactam A25. As represented with beta-lactam A26, reduction of a lactam to the cyclic amine derivative A27 is completed with lithium aluminum hydride and aluminum trichloride. 0 R4 1. N-Chlorosulfonyl BocN HN R4 R8 isocyanate, Et2O 8 R4 1. TMSCHN2, THF R8 R5 RS R5 X'2. (Boc), O, DMAP-R vi p2 2. Wolff Rearrangement R 9 xl . \ Ar R3 R1 Ar2 Ar R3 Rl Ar2 3. TFA, CH2CI2 R3Rl"A'r2 R Ar A14 A24 A25 O R8 N R4 LiAIH4, AICI3 R$ N Ra //R 1 R2 THF </R 1 2 Ruz tif 0 A _'X Arl ; lKA Ar R3 R1 Ar2 Ar1 13 R1 Ar2 'CX R THF /RY R ', RA Ar A26 A27 An alternative method for the preparation of lactam A25 involves hydrolysis of the hydantoin A 21 by protection of the hydantoin with Boc-anhydride and the subsequent addition of lithium hydroxide solution to form the amino acid A28. An alternate method for the basic hydrolysis of the hydantoin is with sodium hydroxide in aqueous ethanol at elevated temperatures. Protection of the nitrogen as the tert-butyl carbamate A29 followed by cyclization with triphosgene then affords the UNCA derivative A30. Hydride reduction of the UNCA to the alcohol, preferably with lithium borohydride, and subsequent oxidation to the aldehyde with the Swern protocol generates Boc-amino aldehyde A31. Homologation of the aldehyde by aldol condensation or preferably by Horner-Wadsworth-Emmons olefination provides ester A32. Subsequent hydrogenation and removal of the Boc-protecting group with trifluoroacetic acid will provide the desired lactam A25. 0 H N C02H C02H 0 2 R4 BocHN R R8 R i. (BOC) 20 R5 XI Ar2 (BOC) 20 o R Xl Ar2 R5 2 ii. LIOH x) < R9 Ar 3 R ^R R9 Ar 3 R2 \R / Ar Ri \Ar R R A28 A29 A21 0 0 CHO ß O BocHN R4 R triphosgene BoCNtR4 1. Reduction R 5 Horner-Emmons R5 R5 1 Ar R Ar'Rs RArz A30 A31 N COsMe 0 BocHN R4 1. Hydrogenation R89Z (R4 R8 2. Deprotection R Rk r2 Arl R A32 A25

The spirocyclic gamma-lactam positional isomer is prepared from cyclobutanone A12. An initial Horner-Wadsworth-Emmons reaction with an ester phosphonate is followed by a Michael addition with nitromethane in the presence of a suitable base, such as TBAF, in refluxing THF to provide nitro ester A33. The nitro group is reduced by hydrogenation in the presence of Raney nickel to the amine which spontaneously cyclizes to afford the lactam A34. 0 H R4 MeOC Ra Ra 5 1. Horner-Emmons Re Raney Ni R R4 2. MeNO s R5 XR2 Ar R3 R \A RAr R3 R \A RAr R1 \Arz A12 A33 A34 R T R A12 ASS A34 The following route can be applied in cases when R7is- (CH2) n6-J, where n6 = 0, J is-C (O) NR R or-C (O) OR14 and R6 is -NR15R16, -NR15SO2R17, -NR15COR14, or -NR14CoNR15R16. Starting with the Boc-protected UNCA derivative A30, addition of an alkoxide or amine would provide an ester or amide analog. Preferentially, the Boc- protecting group is removed with trifluoroacetic acid in dichloromethane to afford A35.

Functionalization of the amine by standard alkylation, acylation, sulfonylation, addition to isocyanates, or coupling with an appropriate carboxylic acid can be recognized by those skilled in the art. H J R4 R6 J R4 BocB R4 1. Nucleophile Ra R5 Xi RZ Standard Amine R5 R5xl R2 2. TFA, CH2CI2 R9 r2 Functionalization 9 R 9 R ru R A30 A35 A36

In addition to the formation of amino amides through the UNCA derivative A30, the following route can be applied in cases when R7 is- (CH2) n6-J, where n6 = 0, J is -C(O)NR15R16 and R6 is -NR15R16, -NR15SO2R17, -NR15COR14, or -NR14CONR15R16.

The Boc-protected amino acid A29 can undergo a coupling reaction with ammonia, primary or secondary amines, preferably in the presence of PyBOP to activate the carboxylic acid, to provide Boc-amino amide A37. Those who are skilled in the art recognize other coupling reagents, such as CDI, DCC, EDC/HOBt, and HATU, can be used in the conversion of carboxylic acids to amides. Removal of the Boc-protecting group preferably with TFA in dichloromethane can be followed by elaboration of the amine by the previously described methods to afford derivatives of the type A36. C02H 1 4 R6 J 4 BocHN-./-R4 BocHN R-TFA, CH2CI2 R Ru Ra R5 Ar Am R Xi R R 2 Arl 1. TFA, CH2cl2 R9I R Ar1 ~< R> (R1 Reagent Ar1 t R1 Ar2 2. Standard Amine Ar R3 R1 Ar2 R3 R Functionalization A29 A37 A36 Nitrogen-substituted analogs of hydantoin A21 can be prepared from secondary amino amides A38 where R20 is Ci-Ce alkyl, C3-C8 cycloalkyl, hydroxy (C2- C8) alkyl, or (Ci-C6) alkoxy (Ci-Ce) alkyl. The addition of triphosgene in the presence of an amine base affords substituted hydantoin A39. R20HN Ot_NR20 H2N R4 triphosgene HN 4 R8 R5 4-10R8 R5 R3 R1 \Ar2 R Ar1 R3 RXAr Z R5 9 y Xl R 2 Xi R 2 A38 A39 In addition to the above method, N-alkyl substituted hydantoins can be prepared from hydantoin A21 by standard alkylation conditions with potassium carbonate and an alkyl bromide in DMF to obtain A39. Alkylation of the less reactive nitrogen of the hydantoin to provide analog A40 could be accomplished through protection of the more reactive nitrogen, standard alkylation, and subsequent removal of the protecting group.

oNR °\-°r R R4 1. Protection R RB R5 5 Rs 5 Xl R2 R 2 2. Alkylation R 2 9 s, X<, R 9/, 9 < R9 R9 3. Deprotection R x R1 \Ar2 A39 A21 A40 Spirocyclic imidazolones and imidazolidinones can be prepared from primary and secondary amino amides A41, where R15 is the same as defined in the summary of the invention. Condensation of the amino amide with an orthoformate, preferably triethylorthoformate, in refluxing toluene with catalytic acetic acid affords the imidazolone A42. Reduction to the imidazolone is accomplished preferably with sodium borohydride in methanol to give imidazolidinone A43. The imidazolone can also be reduced by hydrogenation over platinum oxide, Raney nickel, or palladium on carbon. R15 HN 0 ri-NR150 rNR'5 0 Hp23NtRo4 CH (OEt) 3 N 4 Reduction HN 4 S R5 2 R5 2 R5 2 9 y XI R y Xl R Xi R R ri 1XAr2 R9r1 1X r2 R9 r1 3 r2 Ar1/< R ; 8Ar2 Ar1< R ; 8Ar2/< A41 A42 A43 Those skilled in the art will also recognize that the addition of an orthoester in place of an orthoformate to an amino amide would provide alkyl-or aryl-substituted imidazolones A44. Likewise, condensation of the amino amide with acetone in methanol with acid, such as para-toluenesulfonic acid, would afford the dimethyl- substituted imidazolidinone A45. °\NR RHN \. NR Q -NR 15 R'5HN NR 15 11) C=o 0 HN 04 N R4 Hq R4 'T" Ty CX. 3 rthoester acetone R s Rs X R2, s Rs XRz s Rs XR2 R Ar R1 \A2 R Ar R A R Ar Ra qr A44 A41 A45 (Q is alkyl or aryl)

For derivatives when R7 is- (CH2) n6-J, where n6 = 1-5, J is-C (O) NR15R16, or -C(O)OR14 and R6 is -NR15R16, -NR15SO2R17, -NR15COR14, or -NR14CONR15R16 the following route can be used. One carbon homologation of aldehyde A31 can be obtained using Wittig reagents such as methoxymethyl triphenylphosphonium bromide or cyanomethyltriphenylphosphonium bromide. Additionally, formation of an acid chloride followed by the Arndt-Eistert protocol will afford the homologated ester or amide analogs. Further chain extensions can be obtained through Wittig and Horner-Wadsworth-Emmons chemistry. Functionalization of the amine to afford derivatives of the type A47 is analogous to the previously reported procedures. CHO i i R4 4 6 4 R8 1. Homologation RaN R Standard Amine _ R8 R 5 Z 2 TFA, CH2C12 gR5x1 R2 Functionalization jSXtXR2 1 A31 A31 A46 A47 For derivatives where R7 is -(CH2)n6-J, where n6 = 1, J is is-NR15R16, <BR> <BR> -NR15SO2R17,-NR15COR14, or-NR14CONR15R16 and R6 is-NRl5R16,-NR15SO2R17 -NR15CoR14, or-NR14CoNR15R16 the following route can be used. Initial formation of an amino nitrile from ketone A12 is obtained with sodium cyanide, and a suitable protected primary amine, such as benzylamine, in methanol and acetic acid.

Reduction of the nitrile, preferably with lithium aluminum hydride, in ether affords the protected diamine A48. Those who are skilled in the art will recognize other methods to reduce nitriles to amines with other hydride reducing agents or hydrogenation with a catalyst. Deprotection of the amine or further functionalization followed by deprotection will afford derivatives with the structure A49. Han O R4 PgHN R4 1. Deprotection R6 R4 Ré 1. Strecker Reaction RB or R8 5 R5 p2 R5 I p2 R5 Vl p2 Ar Ar Functionalization Arl R R 2. Deprotection R3 A12 A48 A49 In addition to the A49 analogs, R6 and R7, together with the carbon atom to which they are both attached, can form a piperazine ring. Deprotection of diamine A48 followed by cyclization with chloroacetyl chloride will provide the keto-piperazine derivative A50. Han O PGHN R4 NH B 1. Deprotection R4 R R5 X R 2. Chloroacetyl R N s t3 R2<Ar2 ArXXR11XARr2 R Art y A50

Cyclic carbamates and morpholine analogs can be prepared from amino acid A28. Reduction of the carboxylic acid with lithium borohydride in the presence of trimethylsilyl chloride in THF provides amino alcohol A51. Cyclization to carbamate A52 and keto-morpholine A53 is accomplished with triphosgene or phenylbromoacetate addition, respectively, to the amino alcohol in the presence of diisopropylethylamine. 0 0 triphosgene Ra C02H H RS XAr2 Ra R9 Ar R3 R R R s LiBH a Arz R s Ark R3 R R9 Ar1 R2 Ri 0 R ru A28 0 phenylbromo-HN R4 acetate R5 Xl Ar2 Ruz R y A53

For derivatives where R7 is-(CR4°R41) n6-J, where R40 and R41 are not hydrogen and n6 = 1, J is is-OH,-O-(C1-C6 alkyl),-O-(C3-C8 cycloalkyl),-o-C (o) NR15R16 and R6 is -NR15R16, -NR15SOR17, -NR15COR14, or -NR14CONR15R16 the following route can be used. Esterification of the Boc-amino acid A29 with trimethylsilyldiazomethane, a safer alternative to diazomethane, followed by addition of methyl magnesium bromide affords a mixture of the Boc-amino alcohol A54 and cyclic carbamate A55. Derivative A54 can afford an amino alcohol upon deprotection of the Boc-moiety with TFA or with further functionalization of the alcohol followed by deprotection afford amino ethers or amino carbamates. A ketomorpholine derivative analogous to A53 can be prepared by the previously defined conditions. ho BocHN R4 1. Deprotection R6 R4 or R5 XPr R R5 Arz R9 X 1. Standard Alcohol x COZY Ar Ar R2 Ri Functionalization R9 Ar 2 BoctHN,,/-R4 R3 2. Deprotection 3 R R R8 1. TMSCHN2 Ara A54 A56 2. MeMgBr 0 Zu io HN R4 A29 R8vyR5 x1Ar2 IR9 Arl _R2 RI R3 A55

In examples where R4 and R5 together with the carbon atom to which they area attached, form a-C (=O) group and R6 through R9 is hydrogen, the following preparation of the core cyclobutanone employs ketone A1. Using a protocol reported by Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. , 95,5321 (1973), which is incorporated by reference in its entirety, the addition of diphenylcyclopropyl ylide to the ketone A1 initially affords an oxaspiropentane. This intermediate rearranges to the cyclobutanone upon treatment with lithium perchlorate or lithium tetrafluoroborate.

The chemistry described for the elaboration of the cyclobutanone A4 is applicable to the functionalization of cyclobutanone A57.

The invention disclosed herein is exemplified by the following examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.

Preparation of Examples 1 a and 1b Example 1 a Example 1 b

CF3 I CF3 i 1. Tf02, t-Bu N t-Bu HO F3 2. I CF3 Oh w Compound 1 Compound 2 (82%) Step 1 : Procedures for preparing Compound 1 and Compound 2 are shown in WO 01/44200.

Step 2: CFs CFs 0 0 1 Ph3PCH3Br/NaNH2. CFg (92%) \ I O Compound 2 Compound 2 Compound 3

To methyltriphenylphosphonium bromide/sodium amide ("Instant Ylide" reagent) (20.9 g, 50.1 mmol, 1.3 equiv) in a 500 mL RBF under N2 was added anhydrous THF (210 mL). The yellow suspension became warm and was allowed to stir for 20 minutes. Compound 2 (14.5 g, 38.5 mmol, 1.0 equiv) as a solution in anhydrous THF (50 mL) was added via cannula over 20 minutes. The reaction mixture was allowed to stir at rt for 24 h. The solution was filtered through a 1"plug

of silica gel and rinsed with 1 L of 5% EtOAc/hexane. The solution was concentrated in vacuo to provide a solid/oil mixture. The crude material was using a 5"silica plug in a glass-fritted funnel eluting with 2% EtOAc/hexane to afford pure alkene Compound 3 (13.2 g, 92.2%) as a bright yellow oil.

Step 3 : Compound 3 Example 1a Example 1b To Compound 3 (5.2 g, 13.9 mmol, 1.0 equiv) in a 200 mL RBF was added anhydrous Et20 (50 mL) and anhydrous DME (7 mL) under N2. Zinc copper couple (2.7 g, 41.3 mmol, 3.0 equiv) was added to the reaction mixture followed by dropwise addition of trichloroacetylchloride (4.7 mL, 42 mmol, 3.0 equiv) over 5 minutes. The reaction mixture was allowed to stir for 48 hours. After this time additional zinc copper couple (2.0 g) and trichloroacetylchloride (2.0 mL) was added. After 65 h, hexane (100 mL) was added and the brown suspension was allowed to cool to room temperature. After 2 h, the suspension was filtered through celite washing with 5% Et2O/hexane (3 x 200 mL). The solution was concentrated in vacuo to afford a brown oil (9.6 g). The crude material was purified using a Si02 plug eluting with a solvent gradient of hexane to 5% EtOAc/hexane to 10% EtOAc/hexane to afford the desired isomers Example 1 a and 1b (5.8 g, 86% yield). The ratio of Isomer A : B is 1: 1.

Electrospray MS [M+Na] + 507.1 for Example 1a.

Electrospray MS [M+Na] + 507.1 for Example 1b.

Preparation of Example 2 Example 2

To the dichloroketene Example 1a and 1b (4.3 g, 8.86 mmol, 1.0 equiv) in acetic acid (39 mL) was added zinc dust (4.46 g, 70.9 mmol, 8.0 equiv) followed by Nal (2.65 g, 17.7 mmol, 2.0 equiv). The reaction mixture was allowed to stir for 48 h.

The solution was allowed to cool to room temperature and was filtered through a plug of celite washing with EtOAc. The reaction mixture was taken up in EtOAc and washed with saturated NaHC03 (1x100mL) followed by brine (1x100mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using a biotage eluting with a solvent gradient of 5% EtOAc/hexane to 10% EtOAc/hexane to afford Example 2 as yellow oil (3.0 g, 82% yield).

Electrospray MS [M+1] + 417.1 for Example 2.

Preparation of Example 3 Example 3 To Compound 2 (1.17 g, 3.1 mmol, 1.0 equiv) in anhydrous DMSO (10mL) was added cyclopropyldiphenylsulfonium tetrafluoroborate (1.07 g, 3.4 mmol, 1.1 equiv). The reaction mixture was degassed well with N2 and potassium hydroxide flakes (0.37 g, 7.0 mmol, 2.25 equiv) were added. After 18 h, the red reaction mixture was poured into hexane. The red oil was not soluble in hexane and was diluted with

of ether (100 mL). The aqueous layer was extracted with (3x50 mL) ether. The combined organics were rinsed with saturated NaHC03 solution (2x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 1.8 g of orange oil. The oil was diluted with benzene (8 mL) and lithium perchlorate (14 mg) was added. The suspension was heated to reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, washed once with H20 and saturated NaHC03 solution, dried over Na2SO4 filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using a biotage eluting with 3% EtOAc/hexane to give Example 3 (0.65 g, 52% yield) as yellow oil.

Electrospray MS [M+1] + 417.1 for Example 3.

Preparation of Example 4 Example 4 To Example 2 (0.091 g, 0.22 mmol, 1.0 equiv) in pyridine (1 mL) was added methoxylamine hydrochloride (0.22 g, 0.26 mmol, 1.2 equiv) and the reaction mixture was allowed to stir at room temperature for 24 hours. The reaction was quenched with H20 and diluted with EtOAc. The organic layer was washed twice with H2O, and once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude material was purified by flash chromatography using a biotage eluting with 5% EtOAc/hexane to afford the desired product Example 4 (0.10 g, 100% yield) as a colorless oil.

Electrospray MS [M+1] + 446.1 for Example 4.

Preparation of Example 5 Example 5

The title compound was prepared by a method analogous to that described for Example 4, using hydroxylamine hydrochloride in place of methoxylamine hydrochloride.

Electrospray MS [M+1] + 432.1 for Example 5.

Preparation of Example 6 Example 6 To Example 2 (2.9 g, 7.0 mmol, 1.0 equiv) in 1, 2-dichloroethane (28 mL) under N2 was added benzylamine (6.0 g, 56 mmol, 8.0 equiv). After 20 minutes, sodium triacetoxyborohydride (3.0 g, 14 mmol, 2.0 equiv) was added followed by acetic acid (0.5 g, 8. 4 mmol, 1.2 equiv). The reaction was monitored by TLC and showed the presence of starting material after 6 hours. An additional 1.5 g of sodium triacetoxyborohydride was added and the reaction mixture was allowed to stir for an additional 18 h. The reaction was quenched with saturated NaHC03 solution and diluted with EtOAc. The organic layer was washed once with H20 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude

material was purified by flash chromatography using a biotage eluting with 40% EtOAc/hexane to afford Example 6, a 1: 1 mixture of diastereomers, as a light yellow oil (3.33 g, 94% yield).

Electrospray MS [M+1] + 508.1 for Example 6.

Preparation of Example 7 Example 7

To Example 6 (1.9 g, 3.7 mmol, 1.0 equiv) in EtOH (30 mL) under N2 was added 20% Pd (OH) 2 on carbon. The reaction mixture was allowed to stir overnight under H2. The TLC indicated the presence of starting material, and an additional 0.3 g of 20% Pd (OH) 2 on carbon was added. After 36 h, the reaction mixture was filtered through celite and washed with EtOAc. The crude material was purified by flash chromatography using a biotage eluting with 5% Et3N/EtOAc to afford Example 7, a 1: 1 mixture of diastereomers, as a pale yellow oil (1.25 g, 81 % yield).

Electrospray MS [M+1] + 418.1 for Example 7.

Preparation of Examples 8a and 8b Example 8a Example 8b

Step1 : 0 CF3 CF3 nBuLi /\ O \ CF3 PhsPCH3Br Example 2 Compound 4

To methyltriphenylphosphonium bromide (0.86 g, 2.4 mol, 2.0 equiv) in anhydrous THF (50 mL) at 0 °C was added butyl lithium (1.5 mL, 2.4 mmol, 2.0 equiv) dropwise. After 30 minutes, the ice bath was removed and Example 2 (0.51 g, 1.2 mmol, 1.0 equiv) was added in THF (5 mL) via cannula over a period of 5 minutes.

After 1 h, the solution was cooled to 0 °C, quenched with saturated NH4CI solution, and diluted with EtOAc. The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford an orange residue. The crude material was purified by flash chromatography using a biotage eluting with the solvent gradient 5% EtOAc/hexane to 10% EtOAc/hexane to afford Compound 4 (0.036 g, 77% yield).

Step 2: 0 0 CF3 CF3 K CF3 Han,, I GIS02N=C=O 16-A CF3 '' I CF Compound 4 Example 8a Example 8b

To Compound 4 (0.49 g, 1.2 mmol, 1.0 equiv) in anhydrous ether (2.6 mL) at 0 °C was added chlorosulfonylisocyanate (0.018 g, 1.3 mmol, 1.1 equiv) dropwise.

After 1 h the reaction mixture was allowed to warm to room temperature. After 19 h, additional isocyanate (55 p. L) was added. After 4 h, the reaction mixture was concentrated in vacuo. The residue was diluted with ether (12 mL) and was added to a flask containing 25% sodium sulfate solution (12 mL) and ether (6 mL). The solution was adjusted to pH 8 with 2.0 M KOH solution. The biphasic mixture was allowed to stir for 1.5 hours. The organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as an oil/solid mixture. The crude material was purified by flash chromatography using a biotage eluting with the solvent gradient 15% EtOAc/hexane to 50% EtOAc/hexane to afford the desired product (0.033 g, 60% yield) as a mixture of two isomers. The isomers were separated by HPLC on a Chiralcel AD column using 9/1 hexane/IPA to afford Examples 8a and 8b.

Electrospray MS [M+1] + 536.2 for Example 8a.

Electrospray MS [M+1] + 536.2 for Example 8b.

Preparation of Examples 9a, 9b and 9c Examples 9a, 9b and 9c

0 0 0 ANH CF3 ANH CF3 ANH CF3 i i CF3 Y'' CF3 '' I CF /\/\/\ Example 9a Example 9b Example 9c To Example 7 (0.1 g, 0.24 mmol, 1.0 equiv) in 1, 2-dichloroethane (2 mL) under N2 at 0 °C was added triethyl amine (0.61 g, 0.6 mmol, 2.5 equiv) followed by acetyl chloride (0.020 g, 0.26 mmol, 1.1 equiv). After 2 h at 0 °C, the solution was concentrated under vacuo to afford the crude product as a white solid. The crude material was purified by flash chromatography using a biotage eluting with 70% EtOAc/hexane to afford Example 9a as a 1: 1 diastereomeric mixture of isomers (0.102 g, 93% yield).

Separated 0.90 g of Example 9a by HPLC on a Chiralcel OD column using 9/1 hexane/IPA. Isomer A as Example 9b (0.042 g) and Isomer B as Example 9c (0.041 g) were obtained.

Electrospray MS [M+1] + 460.1 for Example 9a.

Electrospray MS [M+1] + 460.1 for Example 9b.

Electrospray MS [M+1] + 460.1 for Example 9c.

Preparation of Examples 10a and 10b Example 10a Example 10b p'N CF3 O'-N_ CF3 'ACF3 X ACF3 0)

To Example 7 (0.097 g, 0.23 mmol, 1.0 equiv) in 1, 2-dichloroethane (1.7 mL) under N2 at 0 °C was added triethyl amine (0.81 mL, 0.58 mmol, 2.5 equiv) followed by 4-chlorobutyryl chloride (0.035 g, 0.25 mmol, 1.1 equiv). After 3 hours at 0 °C, the reaction mixture was quenched with saturated NH4CI solution and diluted with CH2CI2.

The aqueous layer was extracted twice with CH2CI2, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil. The oil was diluted with anhydrous THF (2 mL) and cooled to 0 °C. Sodium hydride as a 60% dispersion in mineral oil (0.019 g, 0.46 mmol, 2.0 equiv) was then added to the solution. The reaction mixture was allowed to warm to room temperature and stir for 14 h. The reaction was quenched with saturated NH4CI solution and diluted with EtOAc. The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil. The crude material was purified by flash chromatography using a biotage eluting with 80% EtOAc/hexane to afford the desired product as mixture of isomers (0.090 g, 80% yield). Separated 0.90 g of the mixture by HPLC on a Chiralcel AD column using 9/1 hexane/IPA. Isomer A as Example 10a (0.034 g) and Isomer B as Example 10b (0.035 g) were obtained.

Electrospray MS [M+1] + 486. 1 for Example 10a.

Electrospray MS [Ms1] + 486.1 for Example 10b.

Preparation of Examples 11a and 11b Example 11a Example 11b To Example 2 (1.35 g, 3.2 mmol, 1.0 equiv) in 50% EtOH (20 mL) was added KCN (0.42 g, 6.4 mmol, 2.0 equiv) and ammonium carbonate (1.25 g, 13 mmol, 4.0).

The reaction mixture was heated in a steel bomb to 90 °C. After 36 h, the bomb was allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a white foam. The crude material was purified by flash chromatography using a biotage eluting with the solvent gradient 30% EtOAc/hexane to 40% EtOAc/hexane to afford Example 11 a (0.71 g, 46% yield) as a white foam and Example 11b (0.66 g, 43% yield) as a white foam.

Electrospray MS [M+1] + 487.1 for Example 11 a.

Electrospray MS [M+1] + 487. 1 for Example 11 b.

Preparation of Example 12a Example 12a The title compound was prepared by a method analogous to Example 12b, using Example 11 a in place of Example 11 b.

Electrospray MS [M+1] + 473. 1 for Example 12a.

Preparation of Example 12b Example 12b

A flame-dried, 50 mL RBF under N2 was charged with AICI3 (0. 45 g, 3.4 mmol, 4.0 equiv). The solid was cooled to 0 °C in an ice bath and a 1 M solution of LiAIH4 (2.6 mL, 2.6 mmol, 3.0 equiv) in Et2O was added dropwise over 3 minutes. After 30 minutes, a solution of Example 11b (0.42 g, 0. 86 mmol, 1.0 equiv) in dry THF (8 mL) was added via a cannula over a period of 2 minutes. After 1 h, the reaction mixture was allowed to warm to room temperature and was allowed to stir for an additional 24 h. The reaction mixture was cooled to 0 °C and quenched slowly with saturated sodium/potassium tartrate solution. After 1 h, the biphasic solution was diluted with EtOAc and the aqueous layer was extracted twice with EtOAc. The combined organics were washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a white solid. The crude material was purified by flash chromatography using a biotage eluting with 90% EtOAc/hexane to afford the desired product (0.34 g, 84% yield) as white solid.

Electrospray MS [M+1] + 473.1 for Example 12b.

Preparation of Example 13 Example 13 To a solution of Example 6 (0.4 g, 0.79 mmol, 1.0 equiv) and potassium carbonate (0.12 g, 0.87 mmol, 1.1 equiv) in DMF (1.0 mL) at 0 °C was added a solution of the chlorotriazolinone (0.1 g, 0.79 mmol, 1.0 equiv) in DMF (1.7 mL). After 5 h, an additional amount (0. 01g) of chlorotriazolinone was added to the reaction.

After 4 h, the solution was concentrated in vacuo to afford a yellow oil. The crude

material was purified by flash chromatography using a biotage eluting with the solvent gradient 50% EtOAc/hexane (2% Et3N) to 75% EtOAc/hexane (2% Et3N) to afford a diastereomeric mixture of isomers Example 13 (0.3 g, 77% yield) as colorless oil.

Electrospray MS [M+1] + 605.1 for Example 13.

Preparation of Example 14 Example 14 To Example 13 (0. 31 g, 0. 51mmol, 1. Oequiv) in MeOH (5.0 mL) under N2 was added 10% Pd/C (0.3 g) followed by ammonium formate (0.16 g, 2.6 mmol, 5.0 equiv). The reaction mixture was refluxed for one hour and then was allowed to cool to room temperature. The suspension was filtered through celite washing with EtOAc. The solution was concentrated in vacuo to afford a white solid (0.24 g, 92% yield) Example 14.

Electrospray MS [M+1] + 515.1 for Example 14.

Preparation of Examples 15a and 15b Example 15a Example 15b

To a solution of Example 7 (0.47 g, 1.1 mmol, 1.0 equiv) in CH2CI2 (5.5 mL) under N2 was added Boc-a-methylalanine (0.1 g, 0.79 mmol, 1.0 equiv) followed by DCC (0.23 g, 1.1 mmol, 1.0 equiv). The reaction was complete after 18 h. The suspension was diluted with CH2CI2 (20 mL) and filtered through a fritted-glass funnel.

The reaction mixture was concentrated to afford a 0.74 g of a yellow solid. The crude material was purified by flash chromatography using a biotage eluting with the solvent gradient 25% EtOAc/hexane to 50% EtOAc/hexane to afford the desired product (0.56 g, 85% yield) as colorless oil. The isomers (0.56 g) were separated by HPLC on a Chiralcel OD column using 9/1 hexane/IPA. Isomer A as Example 15a (0. 028 g) and Isomer B as Example 15b (0.021 g) were obtained.

Electrospray MS [M+1] + 603.1 for Example 15a.

Electrospray MS [M+1] + 603.2 for Example 15b.

Preparation of Example 16a Example 16a To a solution of Example 15a (0.26 g, 0.43 mmol, 1.0 equiv) in anhydrous CH2CI2 (5.0 mL) under N2 at 0 °C was added TFA (0.1 mL). The reaction mixture was monitored by TLC and showed a small amount of starting material after 4 hours. An excess amount of TFA (0.4 mL) was added and the reaction was allowed to warm to room temperature. After 2 h, the reaction mixture was cooled to 0 °C, and quenched with saturated NaHC03 solution. The biphasic mixture was diluted with EtOAc, washed once with H20 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford Example 16a (0.22 g, 100 % yield) as a colorless oil. Electrospray MS [M+1] + 503. 2 for Example 16a.

Preparation of Example 16b

Example 16b The title compound was prepared by a method analogous to Example 16a, using Example 15b.

Electrospray MS [M+1] + 503.3 for Example 16b.

Preparation of Examples 17a and 17b Example 17a Example 17b The title compounds were prepared by a method analogous to Example 12b, using Examples 8a and 8b. The isomers were separated by HPLC on a Chiralcel AD column using 9/1 hexane/IPA to afford Examples 17a and 17b.

Electrospray MS [M+1] + 444.2 for Example 17a.

Electrospray MS [M+1] + 444.2 for Example 17b.

Preparation of Example 18 Example 18 Step 1 : Bon i 1) BnNHOH, MgS04 HO, O w O I CF3 "'CF3 2) MeMgBr, Et20 0-40 OC Compound 4 Compound 5 To Compound 4 (0.5 g, 1.2 mmol, 1.0 equiv) in anhydrous toluene (2 mL) was added sodium bicarbonate (0.092 g, 1.1 mmol, 0.95 equiv), N-benzyl hydroxylamine hydrochloride (0.18 g, 1.1 mmol, 0.95 equiv) and magnesium sulfate (0.05g). The yellow suspension was allowed to stir for 4 hours, before being filtered and concentrated in vacuo to afford a yellow oil. The yellow oil was diluted with anhydrous ether (4 mL) and was cooled the solution to-78 °C. Methyl magnesium bromide (0.43 mL, 1.3 mmol, 1.1 equiv) was added over 1 minute. The resulting yellow solution was allowed to warm to room temperature after 10 minutes. The reaction mixture was monitored by TLC and after 45 minutes indicated the presence of starting material. The solution was recooled to-78 °C and (0.43 mL) of MeMgBr was added. The cold bath removed after 10 minutes and the reaction mixture was allowed to stir for 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated NH4CI solution and diluted with EtOAc. The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude material was purified by flash chromatography using a biotage eluting

with the solvent gradient 5% EtOAc/hexane to 40% EtOAc/hexane to afford Compound 5 (0.25 g, 38% yield).

Electrospray MS [M+1] + 538.1 for Compound 5.

Step 2: Bn CF Bn F3C HO'N,, 3 HN,,,, < rfi zn, HoAc r ! t Zn, HOAc . 1, /\ 3/\ Compound 5 Compound 6 To a solution of Compound 5 (0.29 g, 0.54 mmol, 1.0 equiv) in acetic acid (3 mL) under N2 was added zinc dust (0.35 g, 5.4 mmol, 10.0 equiv). The reaction mixture was heated to 70 °C. After 30 minutes, the reaction mixture was allowed to cool to room temperature, filtered through celite, neutralized with 10% NaOH solution, and diluted with EtOAc. The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil. The crude material was purified by flash chromatography using a biotage eluting with the solvent gradient 25% EtOAc/hexane to 75% EtOAc/hexane to 10% MeOH/EtOAc to afford Compound 6 (0.28 g, 100% yield).

Electrospray MS [M+1] + 522.1 for Compound 6.

Step 3: gon caf HN,/CF3 H2N, CF3 ri] io% pc < j, Y 10% Pd/C o NH40aCH MeOH Compound 6 Example 18 To a solution of Compound 6 (0.13 g, 0.25 mmol, 1.0 equiv) in MeOH (5 mL) under N2 was added 10% Pd/C (0.12 g) and ammonium formate (0.082 g, 1.3 mmol, 5.0 equiv). The reaction mixture was heated to reflux. After 1.5 h, the reaction mixture was allowed to cool to room temperature and the suspension was filtered through celite washing with EtOAc. The solution was concentrated in vacuo to afford Example 18 (0.097 g, 92% yield).

Electrospray MS [M+1] + 432. 1 for Example 18.

Preparation of Example 19 Example 19 Step 1 : ) 4 > NC NHBn CF3 NHBn CF3 NaCN, BnNH2 H202 CF3 MeOH, AcOH d 4 8 CF3 /\/\ Example 2 Compound 7 Compound 8 To Example 2 (0.21 g, 0.5 mmol, 1.0 equiv) in anhydrous MeOH (1.5 mL) under N2 was added sodium cyanide (0.03 g, 0.6 mmol, 1.2 equiv) and benzylamine (0.07 g, 0.65 mmol, 1.3 equiv). The reaction mixture was cooled to 0 °C and acetic acid (70 ! 11) was added dropwise. The ice bath was removed after 30 minutes and the reaction was heated to reflux. After 19 h, the reaction mixture was quenched with saturated NaHC03 solution and diluted with EtOAc. The organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford Compound 7 (0.26 g), a 1: 1 mixture of diastereomers, as a yellow oil. To the crude Compound 7 (0.26 g, 0.49 mmol, 1.0 equiv) in EtOH (8 mL) was added a 1 M NaOH solution (5 mL) followed by a dropwise addition of a 30% H202 solution over 10 minutes. After 4 h, the reaction was quenched with saturated NaHC03 solution and diluted with EtOAc. The organic layer was washed twice with brine, dried over

Na2SO4, filtered, and concentrated in vacuo to afford Compound 8 (0.14 g, 50% yield) as a yellow oil.

Electrospray MS [M+1] + 551.1 for Compound 8.

Step 2 : O H2N 2 9/; H24 CF 10% Pd t mCF3 NH402CH 4 mCF3 Compound 8 Example 19 To Compound 8 (0.114 g, 0.21 mmol, 1.0 equiv) in MeOH (4 mL) was added 10% Pd/C (0.11 g) followed by ammonium formate (0.069 g, 1.1 mmol, 5.0 equiv).

After 3 h, the suspension was allowed to cool to room temperature and filtered through celite to afford a colorless oil (0. 1 g). The crude material was purified on biotage eluting with 95: 5 CH2CI2/MeOH to afford a 1: 1 diastereomeric mixture of Example 19 (0.044 g, 45% yield) as a colorless oil.

Electrospray MS [M+1] + 446.1 for Example 19.

Preparation of Example 20 Example 20 Step 1 : Compound 9

Compound 9 was prepared using similar procedure as for Compound 2 using 3, 5-difluoromethylbenzyl alcohol instead of 3, 5-bistrifluoromethylbenzyl alcohol.

Step 2: p F O CI Zn, Et O F Cl Nal, HOAc cri CIgCCOCI Compound 9 Compound 10 Example 20 Compound 9 Compound 10 Examp) e20 To Compound 9 (1.73 g, 6.3 mmol, 1.0 equiv) in a flame-dried 100 mL RBF in anhydrous Et20 (45 mL) was added zinc dust (0.83 g, 12.6 mmol, 2.0 equiv). An addition funnel containing a solution of trichloroacetylchloride (1.1 mL, 9.46 mmol, 1.5 equiv) in anhydrous Et2O (20 mL) was attached on top of the reaction flask which was emerged in the water bath of a sonicater to the level where it experienced the maximum agitation. The solution was added dropwise over a period of 50 minutes.

After the addition was complete, the reaction mixture was sonicated vigorously for an additional 5 h. The TLC (EtOAc/Hexane=10%) indicated the presence of starting material and an additional portion of trichloroacetylchloride (0.8 mL, 7.17 mmol, 1.1 equiv) was added over 10 minutes. The reaction mixture was sonicated for another 6 h. The reaction was almost complete by TLC and the solvent was evaporated in vacuo. The crude product, mainly Compound 10 and zinc dust, was treated with HOAc (30mL), zinc dust (3.3 g, 50.5 mmol, 8 equiv) and Nal (1.88 g, 12.5 mmol, 2.0 equiv). The black mixture was heated at 90 °C for 1 hour. The TLC (EtOAc/Hexane=10%) showed the Compound 10 was almost completely consumed.

The reaction mixture was diluted with EtOAc and the dark brown solution was filtered through a fritted funnel containing celite and was washed thoroughly with EtOAc. The filtrate was cooled to 0 °C and neutralized carefully with saturated NaHC03 aqueous solution, separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and

concentrated in vacuo to afford the crude product. The crude material was purified by flash chromatography using a biotage to afford Example 20 (0.43 g, 21 % yield).

Example 20 : 1H NMR (500MHz, CDCI3) 8 1. 37 (d, J=6.305 Hz, 3 H), 3.35-3. 43 (m, 4 H), 3.48 (s, 2 H), 4.25 (q, J=6.305 Hz, 1 H), 6.62-6. 68 (m, 3 H), 7.25-7. 39 (m, 5 H).

Preparation of Examples 21 a and 21 b Example 21 a Example 21 b A solution of Example 20 (0.38 g, 1.2 mmol, 1.0 equiv) in EtOH/H20 (v/v=1/1) (2.25 mL) was treated with (NH4) 2CO3 (0.34 g, 4.43 mmol, 3.7 equiv) and KCN (0.12 g, 1.90 mmol, 1.58 equiv). The resulting orange solution was heated to 60 °C for 36 h. The reaction mixture was diluted with water, and carefully extracted with EtOAc.

The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified on a biotage eluting with the solvent gradient 10% EtOAc/hexane to 30% EtOAc/hexane to afford a mixture of diastereomers, which was further purified on a Chiralcel OD column (I PA/hexane=10/90) to obtain Examples 21 a and 21 b.

Electrospray MS [M+1] + 387.1 Example 21 a.

Electrospray MS [M+1] + 387. 1 Example 21 b.

Preparation of Examples 22a and 22b Example 22a Example 22b Step 1 : t3,, c, Acl X CN > X KCN NaH, DMF CN Compound 11

A three-necked RBF under N2 was charged with anhydrous DMF (1L), 1,3- dichloro-2-butene (30 mL, 0.259 mmol) and a 60% dispersion of NaH in mineral oil (30.6 g). To the above suspension under vigorous stirring was added dropwise benzylcyanide (30.45 mL) in anhydrous DMF (30 mL) over 15 minutes. After 30 minutes, the reaction was quenched with saturated NH4CI and extracted with ether.

The organic layer was washed with water, brine, dried with Na2SO4 filtered, and concentrated in vacuo. The crude product was purified using a flash silica gel column to afford Compound 11 (10-15g, 23-35% yield). DIBAL-H CN CHO Compound 11 Compound 12 Step 2: A flame-dried 250mL flask containing a 1.0 M solution of DIBAL-H in hexane (60 mL, 60 mmol, 2.0 equiv) was diluted with anhydrous THF (15 mL) and cooled to - 50 °C. To this solution was added via cannula a solution of Compound 11 (5 g, 30 mmol, 1.0 equiv) in dry THF (10 mL). After 3 h at-50 °C, the reaction was quenched with saturated NH4CI and was allowed to stir at room temperature for 30 minutes. The layers were separated and the aqueous layer was further extracted with EtOAc. The organic layers were combined and concentrated in vacuo. The crude product was purified using a silica plug, eluting with EtOAc to afford Compound 12 (4.31 g, 83% yield).

Step 3: EtOH, NaBH4 /\ CHO OOC U Compound 12 Compound 13

A solution of Compound 12 (4.31 g, 25 mmol, 1.0 equiv) in absolute EtOH (50 mL) was cooled to 0 °C and treated with NaBH4 (1.89 g, 50 mmol, 2.0 equiv). The reaction mixture was quenched with MeOH after stirring for one hour, then concentrated in vacuo to dryness. The residue was taken up in ether and washed with saturated sodium bicarbonate and brine. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product which was purified via flash chromatography using a biotage to give Compound 13 (3. 81 g, 87% yield). foc NaH, DMF OH F3C I Br i Compound 13 CF3 Compound 14 Step 4: A solution of Compound 13 (2.5 g, 14.4 mmol) in DMF (50 mL) was cooled to 0 °C and treated with a 60% dispersion of NaH in mineral oil (1.0 g, 25.2 mmol). After stirring for 10 minutes, 3, 5-bistrifluoromethylbenzylbromide (4.7 mL, 23 mmol) was added dropwise and the solution was allowed to warm to 23 °C. After 18 h, the reaction was quenched with saturated NH4CI and taken up in ether. The organic layers were combined washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product which was purified by flash chromatography using a biotage to give Compound 14 (5.45 g, 95% yield).

Step 5: F3C O CF3 / Os i TBA) "C3 CAF3 U Compound 14 Compound 15

A solution of Compound 14 (1.7 g, 4.25 mmol, 1.0 equiv) in CH2CI2 (42 mL) was cooled to-78 °C and treated with 03. After 1 h, the reaction mixture was quenched with tetrabutylammonium iodide (1.88 g, 5.1 mmol) and was allowed to warm to 23 °C. The solution was concentrated in vacuo and the crude product was purified by flash chromatography using a biotage to give Compound 15 (0.85 g, 49%).

Step 6 : 0" 0 CF3 N 0 CF3 NH42C3 @z/° CF3 KCN d CF3 Compound 15 Example 22a O N H N HN : / I' , il/O \ CF3 Example 22b

To a solution of Compound 15 (0.85 g, 2.1 mmol, 1.0 equiv) in EtOH-H20 (4: 1; v/v) (10 mL) was added (NH4) 2CO3 (0.7 g, 7.3 mmol, 3.5 equiv) and KCN (0.25 g, 3.8 mmol, 1. 8 equiv). The reaction vessel was sealed and heated at 90 °C for 12 hours.

The EtOH was then removed under reduced pressure and residue was partitioned

between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column to give (0.62 g, 62% yield) Examples 22a and 22b.

Electrospray MS [M+1] +473. 1 for Example 22a.

Electrospray MS [M+1] +473. 1 for Example 22b.

Preparation of Examples 23a and 23b Example 23a Example 23b Step i : Compound 16 Compound 16 was prepared using a similar procedure as for Compound 2 using 3-trifluoromethylbenzyl alcohol instead of 3, 5-bistrifluoromethylbenzyl alcohol.

Step 2: o H N KCN N,,, I-HN / rl HN.,/°' HN'° . 11 KCN _, 7 o-CFs (NHzCOg T'0 -°YCF3 Compound 16 Example 23a Example 23b

Examples 23a and 23b were prepared using similar procedure as for Examples 11 a and 11 b using Compound 16 instead of Compound 2.

Example 23a: 1H NMR (500MHz, Cd13) 8 7.47-7. 15 (m, 9H); 5.69 (s, 1H) ; 4.38 (dd, 1H) ; 3.84, (d, 1H) ; 3.54 (d, 1H) ; 3.14 (m, 1H) ; 3.03 (m, 1H) ; 2.67 (m, 2H); 1.34 (d, 1H).

Example 23b :'H NMR (500MHz, Ceci3) 6 7.54 (m, 4H); 7.48 (m, 3H); 7.00 (m, 2H); 6.53 (s, 1H) ; 4.53 (m, 1H) ; 3.25, (m, 2H); 3.10 (m, 2H); 2.76 (dd, 1H) ; 2.65 (dd, 1H) ; 1.61 (d, 1H) Preparation of Example 24 Example 24 In a sealed tube, Example 22b (0.120 g, 0.254 mmol, 1.0 equiv) was dissolved in MeOH (2 mL) and water (3 mL) and was treated with a 50% aqueous solution NaOH (0.5 mL). The suspension was sealed and heated at 100-110 °C for 20 hours.

The volatiles were blown away with N2 at 100 °C. The residue was diluted with MeOH (10 mL) and neutralized with 1 M HCI in ether to pH 7. The mixture was filtered and the residue was washed with MeOH. The filtrate was concentrated in vacuo and the resulting residue was diluted with water and EtOAc. The aqueous layer was further extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The material was dissolved in DMSO and subjected to Gilson (RP C18) to provide Example 24 (0.064 g, 56% yield).

Electrospray MS [M+1] + 448.1 for Example 24.

Preparation of Example 25 Example 25

To a solution Example 24 (0.056 g, 0.123 mmol, 1.0 equiv) in DMF (1 mL), was added a 2.0 M solution of methylamine in MeOH (0.135 mL, 0.27 mmol, 2.2 equiv) followed by the addition of HATU (0.052 g, 1.35 mmol, 11 equiv). The reaction mixture was allowed to stir at 23 °C overnight. The reaction mixture was diluted with DMF (1 mL) and subjected to separation by Gilson (RP C18) to give Example 25 (0.001 g, 2% yield).

Electrospray MS [M+1] + 461.1 for Example 25.

Preparation of Examples 26a and 26b Example 26a Example 26b To a solution of Example 2 (0.39 g, 0.93 mmol, 1.0 equiv) in dry ether (10 mL) at-78 °C was added methylmagnesium bromide (0.34 mL, 1.005 mmol, 1.07 equiv).

After 10 minutes at-78 °C, the reaction mixture was allowed to warm to room temperature. After 16 h, no progress in the reaction was observed by TLC. The solution was cooled to-78 °C and methylmagnesium bromide (1.0 equiv) was added.

The solution was allowed to warm to room temperature and stir for 5 h. The reaction mixture was quenched with saturated NaHC03 solution (20 mL) and was extracted

with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 95: 5 hexane/EtOAc to 9: 1 hexane/EtOAc to afford a mixture of two isomers (0.2 g, 50% yield). The isomers were separated by HPLC using a semi-prep Chiralcel OD column (IPA/hexane=10/90) to afford Examples 26a and 26b.

Electrospray MS [M-17] + 451.1 for Example 26a.

Electrospray MS [M+1] + 433.1 for Example 26b.

Preparation of Example 27 Example 27 Step 1 : HA -N\-o CF3 HO_o CF3 HC_o CF3 HN. i. Boc20 2 r Boc20 _ i yO. ii. 1M LiOH yOA THF/NaHCOg O. J 0' (3') Example 11a Compound 17 Compound 18 To a solution of Example 11 a (7.5 g, 15.4 mmol, 1.0 equiv) in anhydrous THF (200 mL) under N2 was added di-tert-butyl dicarbonate (6.7 g, 30.8 mmol, 2.0 equiv) and catalytic DMAP (50 mg, 0.41 mmol, 0.03 equiv). After 3 hours, 1 M LiOH solution (150 mL) was added to the reaction mixture and the resulting suspension was allowed to stir for 24 h. The reaction mixture was diluted with water (200 mL) and EtOAc (700 mL). The organic layer was washed with brine, dried over Na2SO4,

filtered, and concentrated in vacuo to afford Compound 17 (10.5 g, > 100% yield) as a yellow foam. [Note: The crude material was carried forward based on a quantitative yield from the first step. ] To a solution of Compound 18 (7.1 g, 15.4 mmol, 1.0 equiv) in THF (80 mL) and saturated aqueous NaHC03 solution was added di-tert- butyl dicarbonate (8.4 g, 38.5 mmol, 2.5 equiv). After 24 h, the solution was cooled to 0 °C and was acidified with 10% citric acid solution to ph 3-4. The solution was extracted with EtOAc (700 mL). The organic layer was washed once with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a foam (11.4 g). The crude product was purified by flash chromatography using a biotage eluting with 7% MeOH/CH2CI2 to afford Compound 18 (7.6 g, 88% yield) as a white solid foam.

Electrospray MS [M+1] + 562.1 for Compound 18.

Step 2: HO MeHN BocHN i. PyBOP, CH2CI2 BocNN. t i. PyBOP, CH2C12 > d wO<CF3 ii-MeNH2/o<CF /\/\ Compound 18 Compound 19 To a solution of Compound 18 (5.0 g, 8.9 mmol, 1.0 equiv) in anhydrous CH2CI2 (100 mL) under N2 at 0 °C was added diisopropylethylamine (4.6 mL, 26.7 mmol, 3.0 equiv) and PyBOP (5.1 g, 9.8 mmol, 1.1 equiv). After 30 minutes the ice bath was removed and the solution was allowed to stir for 1 h at room temperature. A 2M solution of methylamine in THF (44 mL, 89 mmol, 10 equiv) was added to the reaction mixture and the resulting suspension was allowed to stir for 24 h. The reaction was quenched with water and diluted with EtOAc (400 mL). The organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow foam (8.5 g). The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 30% EtOAc/hexane

to 40% EtOAc/hexane to 50% EtOAc/hexane to afford Compound 19 (4.2 g, 82% yield) as a white solid foam.

Electrospray MS [M+1] + 575. 1 for Compound 19.

Step 3: MeHN MeHN BocHN. TFA, CH2C12 H2N i yoAA/ok4L Compound 19 3 3 Compound 19 Example 27

To a solution of Compound 19 (3.0 g, 5.2 mmol, 1.0 equiv) in anhydrous CH2CI2 (35 mL) under N2 at was added excess TFA (4.0 mL, 52 mmol, 10 equiv).

After 24 h, the reaction mixture was cooled to 0 °C and quenched with saturated NaHC03 solution. The biphasic mixture was diluted with EtOAc, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford Example 27 (2.4 g, 98 % yield) as a colorless gum.

Electrospray MS [M+1] + 475.1 for Example 27.

Preparation of Example 28 Example 28

The title compound was prepared by a method analogous to Example 27 from Compound 18, using ammonia gas in place of methylamine.

Electrospray MS [M+1] + 461. 1 for Example 28.

Preparation of Example 29 Example 29

Step 1 : a BocHN CF3 BocHN N CF3 i. triphosgene d Me2NH ., I CF /\ Compound 18 Compound 20 To a solution of Compound 18 (0.15 g, 0.27 mmol, 1.0 equiv) in anhydrous CH2CI2 (2 mL) under N2 was added diisopropylethylamine (0.14 mL, 0.81 mmol, 3.0 equiv) and triphosgene (0.040 g, 0.14 mmol, 0.5 equiv). After 3 h, a 2M solution of dimethylamine in THF (0.7 mL, 1.4 mmol, 5 equiv) was added to the reaction mixture and the resulting suspension was allowed to stir for 60 h. The reaction was quenched with water and diluted with EtOAc (25 mL). The organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow foam (0.094 g). The crude product was purified by flash chromatography using a biotage eluting with 30% EtOAc/hexane to afford Compound 20 (0.036 g, 23% yield) as a white solid.

Electrospray MS [M i 11+ 589. 1 for Compound 20.

Step 2: Me2N ; CF3 Me2Nv CF3 BocHN TFA, CH2C (2, H2N--I ",/,-o I CF3",,, o r6 CF3 d zO<CF3 < zO<CF Compound 20 Example 29

Example 29 was prepared from Compound 20 by a method analogous to Example 27 from Compound 19.

Electrospray MS [M+1] + 489.1 for Example 29.

Preparation of Example 30 Example 30

The title compound was prepared by a method analogous to Example 29 from Compound 18, using pyrrolidine in place of dimethylamine.

Electrospray MS [M+1] + 515.1 for Example 30.

Preparation of Example 31 Example 31

The title compound was prepared by a method analogous to Example 29 from Compound 18, using piperidine in place of dimethylamine.

Electrospray MS [M+1] + 529.1 for Example 31.

Preparation of Example 32 Example 32 The title compound was prepared by a method analogous to Example 29 from Compound 18, using morpholine in place of dimethylamine.

Electrospray MS [M+1] + 531.1 for Example 32.

Preparation of Example 33 Example 33

The title compound was prepared from Example 11b by a method analogous to Example 27 from Example 11 a.

Electrospray MS [M+1] + 475.3 for Example 33.

Preparation of Example 34 Example 34 The title compound was prepared from Example 11b by a method analogous to Example 27 from Example 11a.

Electrospray MS [M+1] + 461.3 for Example 34.

Preparation of Example 35 Example 35

Step 1 : Compound 21 Compound 21 was prepared from Example 11b by a method analogous to Compound 17 from Example 11a.

Electrospray MS [M+1] + 462. 1 for Compound 21.

Step 2: HO HO H Ho 0 CF3 H2 Ho CF3 i LiBH4, TMSCI i THE Compound 21 Example 35 To a solution of lithium borohydride (0.033 g, 1.5 mmol, 2.0 equiv) in anhydrous THF (1.0 mL) under N2 was added TMSCI (0.39 mL, 3.0 mmol, 4.0 equiv).

After 10 minutes, a solution of Compound 21 (0.0035 g, 0.76 mmol, 1.0 equiv) in anhydrous THF (2 mL) was cannulated into the reaction flask over 8 minutes. After 4

h, the solution was cooled to 0 °C and carefully quenched with MeOH (1 mL) and 1 M KOH solution (1 mL). The reaction mixture was diluted with EtOAc (40 mL), washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford Example 35 (0.31 g, 91 % yield) as a colorless gum.

FAB MS [M+1] + 448. 3 for Example 35.

Preparation of Example 36 Example 36 To a solution of Example 35 (0.12 g, 0.27 mmol, 1.0 equiv) in anhydrous CH2CI2 (2 mL) under N2 was added diisopropylethylamine (0.24 mL, 1.4 mmol, 5.0 equiv) and triphosgene (0.042 g, 0.14 mmol, 0.5 equiv). After 4 h, the reaction mixture was concentrated in vacuo to afford a yellow foam (0.2 g). The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 10% EtOAc/hexane to 50% EtOAc/hexane to afford Example 36 (0.10 g, 78% yield) as a white solid.

Electrospray MS [M+1] + 474.1 for Example 36.

Preparation of Example 37 Example 37

To a solution of Example 35 (0.14 g, 0.31 mmol, 1.0 equiv) in CH3CN (3 mL) under N2 was added diisopropylethylamine (0.13 mL, 0. 78 mmol, 2.5 equiv) and a solution of phenyl bromoacetate (0.073 g, 0.34 mmol, 1.1 equiv) in CH3CN (1 mL).

After 24 h, the reaction mixture was concentrated in vacuo to afford a colorless oil (0.2 g). The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 20% EtOAc/hexane to 80% EtOAc/hexane to afford Example 37 (0.10 g, 68% yield).

FAB MS [M+1] + 488.2 for Example 37.

Preparation of Example 38 Example 38 Step 1 : HO MeO BocHNO C BocHNO boche TMSCHN MeOH, toluene '' CF3 Compound 18 Compound 22

To a solution of Compound 18 (0.20 g, 0.36 mmol, 1.0 equiv) in MeOH (1.2 mL) and toluene (3.0 mL) under N2 at 0 °C was added a 2. 0M solution of trimethylsilyl diazomethane in hexane (0.9 mL, 1.8 mmol, 5.0 equiv). After 30 minutes, the reaction mixture was concentrated in vacuo to afford a yellow oil (0.2 g). The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 10% EtOAc/hexane to 25% EtOAc/hexane to afford Compound 22 (0.10 g, 47% yield).

Electrospray MS lM+1] + 576.1 for Compound 22.

Step 2 : MeO t° Boche CF3 HN : BocHN. MeMgBr 99/OCF3 THF 9"'ACF3 3 Compound 22 Example 38 To a solution of Compound 22 (0.10 g, 0.17 mmol, 1.0 equiv) in THF (2 mL) under N2 at 0 °C was added a 3.0 M solution of MeMgBr in Et2O (0.14 mL, 0.41 mmol, 2.4 equiv). The reaction mixture was slowly allowed to warm to room temperature. After 24 h, the reaction mixture was cooled to 0 °C and quenched with saturated NH4CI solution. The solution was diluted with EtOAc, washed once with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product (0.093 g) as a yellow oil. The crude material was subjected to purification on a Gilson (RP C18) to give Example 38 (0.035 g, 41 % yield).

Electrospray MS [M+1] + 502.1 for Example 38.

Preparation of Example 39 Example 39 Step 1 : Compound 24 Compound 24 was prepared from Compound 21 by a method analogous to Compound 18 from Compound 17.

Electrospray MS [M+1] + 562.1 for Compound 24.

Step 2: HO 0 0 Cl3 CF3 BocHN,, 0 HN,,, 0, J- /\/\ Compound 24 Example 39 Example 39 was prepared from Compound 24 by a method analogous to Example 38 from Compound 18.

Electrospray MS [M+1] + 502. 1 for Example 39.

Preparation of Example 40 Example 40

Step 1 : 0 C) WN 0 CF3 CIN CF3 BnHN. BnN, I- X CF3 1, 2-dichloroethane < CF3 -. 11 Compound 6 Compound 25

To a solution of Compound 6 (0.14 g, 0.27 mmol, 1.0 equiv) in 1,2- dichloroethane (1 mL) under N2 was added diisopropylethylamine (0.12 mL, 0.68 mmol, 2.5 equiv) followed by 1-pyrrolidinecarbonyl chloride (0.60 mL, 0.54 mmol, 2.0 equiv). After 60 h the reaction was not complete by TLC and was heated to 60°C for 36 h. The reaction mixture was allowed to cool to room temperature and was quenched with water. The solution was diluted with EtOAc, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil (0.17 g).

The crude product was purified by flash chromatography using a biotage eluting with 30% EtOAc/hexane to afford Compound 25 (0.10 g, 59% yield) as a colorless gum.

Electrospray MS [M+1] + 619.1 for Compound 25.

Step 2: ( N o N0 r. CFt' CPg CFg 20% Pd (OH) 2/C, HN. BnN,, , o 16 CF3 AcOH, MeOH/."o 1-6 CF3 Example 40 Compound 25 Example 40

To a solution of Compound 25 (0.096 g, 0.16 mmol, 1.0 equiv) in MeOH (4 mL) under N2 was added 20% Pd (OH) 2 on carbon (0.2 g) and AcOH (4 mL). The reaction mixture was allowed to stir for 5 h under H2. The suspension was filtered through celite, washed with EtOAc and concentrated in vacuo to afford a colorless oil (0.071 g). The crude product was purified by flash chromatography using a biotage eluting with 40% EtOAc/hexane to afford Example 40 (0.040 g, 47% yield) as a white solid.

Electrospray MS [M+1] + 529.1 for Example 40.

Preparation of Example 41 Example 41 The title compound was prepared from Compound 6 by a method analogous to Example 40 from Compound 6 using trimethylsilyl isocyanate in place of 1- pyrrolidinecarbonyl chloride.

Electrospray MS [M+1] + 475. 1for Example 41.

Preparation of Example 42 Example 42

Step 1 : 0 . CFg H HN. NH BnHN. C N CF3 ZO CF N-NH p BnN, *t \3 /\ 3 K2C03, DMF v CF3 Compound 6/\ Compound 26

To a solution of Compound 6 (0.083 g, 0.16 mmol, 1.0 equiv) and potassium carbonate (0.029 g, 0.21 mmol, 1.3 equiv) in DMF (1.0 mL) at 0 °C was added chlorotriazolinone (0.026 g, 0.19 mmol, 1.2 equiv). The reaction mixture was allowed to warm to room temperature and stir for 20 h. The suspension was filtered through a plug of glass wool and concentrated in vacuo to afford a colorless oil. The crude material was purified on a Gilson (RP C18) to afford Compound 26 (0.033 g, 33% yield).

Electrospray MS [M+1] + 619. 1 for Compound 26.

Step 2: 0 0 HN*ßtH HN. NH N iq= CF3 10% Pd/C, NH402CH HN,/CF3 BnN,,-U114" mesh ce 3 3 Compound 26 Example 42

Example 42 was prepared from Compound 26 by a method analogous to Example 18 from Compound 6.

Electrospray MS [M+1] + 529.1 for Example 42.

Preparation of Example 43 Example 43 To a solution of Example 34 (0.058 g, 0.13 mmol, 1.0 equiv) in toluene (1.6 mL) under N2 was added triethylorthoformate (0.027 mL, 0.16 mmol, 1.2 equiv) followed by AcOH (0.010 mL). The solution was reftuxed for 4.5 h. The reaction mixture was allowed to cool to room temperature and was quenched with water. The solution was diluted with EtOAc, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil (0.058 g). The crude product was purified by flash chromatography using a biotage eluting with 2% MeOH/CH2CI2 to afford Example 43 (0.038 g, 62% yield) as a colorless gum.

Electrospray MS [M+1] + 471.1 for Example 43.

Preparation of Example 44 Example 44

The title compound was prepared from Example 33 by a method analogous to Example 43 from Example 34.

Electrospray MS [M+1] + 485.1 for Example 44.

Preparation of Example 45 Example 45 The title compound was prepared from Example 27 by a method analogous to Example 43 from Example 34.

Electrospray MS [M+1] + 485.1 for Example 45.

Preparation of Example 46 Example 46 To a solution of Example 28 (1. 8 g, 3.9 mmol, 1.0 equiv) in toluene (96 mL) under N2 was added triethylorthoformate (0.77 mL, 4.68 mmol, 1.2 equiv) followed by AcOH (0.3 mL). The solution was refluxed for 3 h. The reaction mixture was allowed to cool to room temperature and was quenched with water. The solution was diluted with EtOAc, washed once with saturated NaHC03 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil (1. 89 g). The crude product was purified by flash chromatography using a biotage eluting with the

solvent gradient 2% MeOH/CH2CI2 to 5% MeOH/CH2CI2 to afford Example 46 (1.26 g, 68% yield) as a white foam.

Electrospray MS [M+1] + 471.1 for Example 46.

Preparation of Example 47 Example 47

To a solution of Example 45 (0.080 g, 0. 17 mmol, 1.0 equiv) in MeOH (1.0 mL) under N2 was added sodium borohydride (0.013 g, 0.34 mmol, 2.0 equiv). After 7 h, the solution was neutralized with AcOH and concentrated in vacuo. The residue was dissolved with EtOAc, washed once with saturated sodium bicarbonate solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a colorless oil (0.076 g). The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 60% EtOAc/hexane to 90% EtOAc/hexane to 5% MeOH/EtOAc to afford Example 47 (0.047 g, 59% yield).

Electrospray MS [M+1] + 487.1 for Example 47.

Preparation of Example 48 Example 48

The title compound was prepared from Example 44 by a method analogous to Example 47 from Example 45.

Electrospray MS [M+1] + 487.1 for Example 48.

Preparation of Example 49 Example 49 To a solution of Example 46 (1.21 g, 2.57 mmol, 1.0 equiv) in MeOH (15 mL) under N2at 0 °C was added sodium borohydride (0.19 g, 5.14 mmol, 2.0 equiv). After 2.5 h at 0 °C, the solution was neutralized with AcOH (2 mL) and concentrated in vacuo. The residue was dissolved with EtOAc, washed once with saturated sodium bicarbonate solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a white solid. The crude product was purified by flash chromatography using a biotage eluting with the solvent gradient 80% EtOAc/hexane to EtOAc to 5% MeOH/EtOAc to afford Example 49 (1.15 g, 95% yield) as a white solid.

Electrospray MS [M+1] + 473.1 for Example 49.

Preparation of Example 50 Example 50 The title compound was prepared from Example 43 by a method analogous to Example 47 from Example 45.

Electrospray MS [M+1] + 473.1 for Example 50.

Preparation of Example 51 Example 51

To a solution of Example 27 (0.054 g, 0.114 mmol, 1.0 equiv) in anhydrous CH2CI2 (2.5 mL) under N2 was added diisopropylethylamine (0.044 mL, 0.25 mmol, 2.2 equiv) and triphosgene (0. 010 g, 0.034 mmol, 0.3 equiv). After 2 h, the reaction mixture was diluted with CH2CI2, washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a biotage eluting with 75% EtOAc/hexane to afford Example 51 (0. 028 g, 49% yield) as a white solid.

Electrospray MS [M+1] + 501.1 for Example 51.

Preparation of Example 52 Example 52

The title compound was prepared from Example 33 by a method analogous to Example 51 from Example 27.

Electrospray MS [M+1] + 501.1 for Example 52.

Preparation of Example 53 Example 53 Step 1 : r) = HzN BnHN xCN CF3 H2NX BAHN. 1 M LiAIH4 CF3 Et20 Compound 7a Compound 27 To a solution of Compound 7a, the less polar diastereomer, (1.4 g, 2. 7mmol, 1.0 equiv) in dry ether (15 ml) at 0 °C was added 1.0 M lithium aluminum hydride in ether (2.7 ml, 2.7 mmol, 1.0 equiv). After 3 h at 0 °C, the reaction was quenched with sodium-potassium tartrate solution. The solution was diluted with EtOAc, washed with saturated aqueous NaHC03 solution, dried over Na2SO4, filtered and concentrated in vacuo to provide the crude Compound 27 (1.3 g, 90% yield).

Step 2 : BnHNH CF3 H2Ny CF3 10% Pd/C H2N. 48o,/°<cF3 NH402CH 9O/CF3 Compound 27 Example 53 Example 53 was prepared from Compound 27 by a method analogous to Example 18 from Compound 6.

Electrospray MS [M+1] + 447.1 for Example 53.

Preparation of Example 54 Example 54

The title compound was prepared from Compound 7b, the more polar diastereomer, by a method analogous to Example 53 from Compound 7a.

Electrospray MS [M+1] + 447.1 for Example 54.

Preparation of Example 55 Example 55 Step 1: Compound 28

Compound 28 was prepared from Compound 7b by a method analogous to Compound 27 from Compound 7a.

Step 2: O\\ H2N BNHN,. CF3 CIN HN CF3 BnHN, I ''i CF3 CH2CI2 'oi '3 /\ v CF Compound 29

To a solution of Compound 28 (0.105 g, 0.20 mmol, 1.0 equiv) in CH2CI2 (2 mL) at 0 °C under N2 was added diisopropylethylamine (0.052 mL, 0.30 mmol, 1.5 equiv) followed by 1-pyrrolidinecarbonyl chloride (0.024 mL, 0.22 mmol, 1.1 equiv).

The solution was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride solution and washed with EtOAc (3x). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo to afford Compound 29 as a white foam. The crude product was carried forward without purification.

Step 3: HNN HNN HN HN BnHN 1'10% C N HN CF3 10% Pd/C, H2N, BnHN. NHq. 4 2C X ° ce 3 3 Compound 29 Example 55

Example 55 was prepared from Compound 29 by a method analogous to Example 18 from Compound 6.

Electrospray MS [M+1] + 544.1 for Example 55.

Preparation of Example 56 Example 56

The title compound was prepared from Compound 28 by a method analogous to Example 55 from Compound 28 using isobutyryl chloride in place of 1- pyrrolidinecarbonyl chloride.

Electrospray MS [M+1] + 517.1 for Example 56.

Preparation of Example 57 Example 57

The title compound was prepared from Compound 27 by a method analogous to Example 55 from Compound 28.

Electrospray MS [M+1] + 544.1 for Example 57.

Preparation of Example 58 Example 58

The title compound was prepared from Compound 27 by a method analogous to Example 55 from Compound 28 using isobutyryl chloride in place of 1- pyrrolidinecarbonyl chloride.

Electrospray MS [M+1] + 517. 1 for Example 58.

Preparation of Example 59 Example 59 Step 1 : CI-O0 O H2Ny CF3 BnHN. BnHN N° CF3 NaH BnHN N\ CF3 BNHN i . 1,. 1, 3 3 Compound 27 Compound 30 Compound 31 To a solution of Compound 27 (0.133 g, 0.25 mmol, 1.0 equiv) in MeOH (2 mL) at-78 °C under N2 was added 4-chlorobutyryl chloride (0.031 mL, 0.27 mmol, 1.1 equiv). The solution was allowed to warm to room temperature and stir for 5 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and

washed with EtOAc (3x). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo to afford Compound 30 as a colorless oil. To a solution of the oil in anhydrous THF (2 mL) was added sodium hydride (0.011 g, 0.27 mmol, 1.1 equiv) as a 60% dispersion in mineral oil. After 4 h at reflux, the solution was allowed to cool to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and washed with EtOAc (3x). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo to afford Compound 31.

Step 2: ro Oo -N N N N BAHN. 10% Pd/C H2N.' r -2 r6-a Compound 30 Example 59 Example 59 was prepared from Compound 30 by a method analogous to Example 18 from Compound 6.

Electrospray MS [M+1] + 515. 1 for Example 59.

Preparation of Example 60 Example 60 The title compound was prepared from Compound 27 by a method analogous to Example 59 from Compound 27 using 2-chloroacetyl chloride in place of 4- chlorobutyryl chloride.

Electrospray MS [M+1] + 487. 1 for Example 60.

Preparation of Example 61 Example 61

The title compound was prepared from Compound 28 by a method analogous to Example 59 from Compound 27 using 2-chloroacetyl chloride in place of 4- chlorobutyryl chloride.

Electrospray MS [M+1] + 487.1 for Example 61.

Preparation of Example 62 Example 62 To a solution of a 1: 1 diastereomeric mixture of Examples 26a and 26b (0.060 g, 0.14 mmol, 1.0 equiv) in CH2CI2 (1.0 mL) under N2 was added trichloroacetyl isocyanate (0.020 mL, 0.17 mmol, 1.2 equiv). After 16 h, the solution was concentrated in vacuo. To the residue in MeOH (3 mL) and water (3 mL) was added potassium carbonate (0.058 g, 0.42 mmol, 3 equiv). After 6 h, the reaction mixture was diluted with water and CH2CI2. The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 30% EtOAc/hexane to afford Example 62 (0.054 g, 81 % yield) as a 1: 1 mixture of diastereomers.

Electrospray MS [M+1] + 476. 1 for Example 62.

Preparation of Examples 63a and 63b Example 63a Example 63b

ß CF3 ) CF3 I CF'r, I CF f)' (3 Minor Diastereomer Major Diastereomer Step 1 : 0 CF3 C02Me O C02Me \ (Et0) 2P- i I CF3 THF CF3 Example 2 Compound 32 To a suspension of sodium hydride (0. 12 g, 3.0 mmol, 1.5 equiv) as a 60% dispersion in mineral oil in anhydrous THF (8 mL) at 0 °C was added methyl diethylphosphonoacetate (0.62 mL, 3.4 mmol, 1.7 equiv) dropwise. After 10 minutes, the ice bath was removed and Example 2 (0.82 g, 2.0 mmol, 1.0 equiv) was added in THF (8 mL) via cannula over a period of 5 minutes. After 4 h, the solution was cooled to 0 °C, quenched with saturated NH4CI solution, and diluted with EtOAc. The organic layer was washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude material was purified by flash chromatography using a biotage eluting with 5% EtOAc/hexane to afford Compound 32 (0.53 g, 55% yield).

Electrospray MS [M+1] + 473.1 for Compound 32.

Step 2: cyme CF3 C02Me CF3 MeN02, TBAF CF3 THF Compound 32 Compound 33

To a solution of Compound 32 (0.063 g, 0.13 mmol, 1. 0 equiv) in anhydrous THF (5 mL) was added nitromethane (0.015 mL, 0.27 mmol, 2.0 equiv) followed by a 1M solution of tetrabutylammonium fluoride in THF (0.20 mL, 0.20 mmol, 1.5 equiv).

After 20 h at reflux, the solution was allowed to cool to room temperature and diluted with 10% citric acid solution. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo.

The crude material was purified by flash chromatography eluting with 20% Et2O/hexane to afford Compound 33 as a colorless oil.

Step 3: NH NH C02Me CF3 CF3 CF3 02N ; Raney Ni i CF3 CF3-. 1, CF3 Compound 33 Example 63a Example 63b To a solution of Compound 33 in MeOH (5 mL) was added Raney Ni. After 5 h at 50 psi of H2, the suspension was filtered through celite washing with MeOH. The crude material was purified by flash chromatography eluting with 80% EtOAc/hexane to afford a 1: 4 mixture of diastereomers, Examples 63a and 63b, as a colorless oil.

The mixture was separated by HPLC on a Chiralcel OD column using 9/1 hexane/IPA. Example 63a, the first eluted isomer, was obtained as a white foam and Example 63b, the second eluted product, was obtained as a white foam.

Electrospray MS [M+1] + 472.1 for Example 63a.

Electrospray MS [M+1] + 472.1 for Example 63b.

Preparation of Example 64 Example 64 Step 1: HC H 0 HOv CF3 BocHN » ° CF3 B N CF3 ? > A A, A triphosgene oc ><eo, $\ i i triphosgene O w Compound 18 Compound 34

To a solution of a 1: 1 diastereomeric mixture of Compound 18 and Compound 24 (3.48 g, 6.2 mmol, 1.0 equiv) in anhydrous CH2CI2 (50 mL) under N2 was added diisopropylethylamine (0.32 mL, 18.5 mmol, 3.0 equiv) and a solution of triphosgene (0.92 g, 3.1 mmol, 0.5 equiv) in anhydrous CH2CI2 (10 mL). After 16 h, the reaction mixture was filtered through a plug of silica gel washing with CH2CI2. The solution was concentrated in vacuo to afford the crude product as a yellow oil (3.5 g, 100% yield).

Step 2: 0 Ho BocN O CF3 BocHN Lib4 I CF3 r, I CF3 /\/ Compound 34 Compound 35 To a solution of Compound 34 (3.5 g, 6.2 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added lithium borohydride (0.268 g, 12.3 mmol, 2.0 equiv) in small portions. After 16 h, the reaction mixture was quenched with saturated NaHC03 solution and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 25% EtOAc/hexane to afford Compound 35 (1.5 g, 44% yield) as a colorless oil.

Electrospray MS [M+1] + 548. 1 for Compound 35.

Step 3: Ho CF3 0 H CF3 BocHN BocHN Stern CF 3 3 O] <CF3 4//O<CF Compound 35 Compound 36

To a solution of DMSO (1.6 mL, 22 mmol, 8.0 equiv) in CH2CI2 (50 mL) at-78 °C under N2 was added oxalyl chloride (0.96 mL, 11 mmol, 4.0 equiv) dropwise. After 15 minutes, Compound 35 (1.5 g, 2.7 mmol, 1.0 equiv) in CH2CI2 (10 mL) was added to the solution. After 6 h at-78 °C, triethylamine (5.3 mL, 38 mmol, 14.0 equiv) was added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NaHC03 solution and diluted with CH2CI2. The layers were separated and the aqueous layer was extracted with CH2CI2 (2x). The combined organic layers were dried over MgS04, filtered through a plug of silica gel, and concentrated in vacuo to afford Compound 36 as a yellow oil (1.47 g, 100% yield).

Step 4: O C02Me BocHN_+H CF3 ° CO2Me i CF3 I CF THF'r / Compound 36 Compound 37 To a suspension of sodium hydride (0.342 g, 8.1 mmol, 3.0 equiv) as a 60% dispersion in mineral oil in anhydrous THF (50 mL) at 0 °C was added methyl dimethylphosphonoacetate (1.7 g, 8.1 mmol, 3.0 equiv) dropwise. After 15 minutes, a solution of Compound 36 (1.47 g, 2.7 mmol, 1.0 equiv) in THF (10 mL) was added dropwise. After the addition was complete, the ice bath was removed and the solution was allowed to warm to room temperature. After 1 h, the reaction was quenched with saturated NH4CI solution, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgS04, filtered through a pad of silica gel, and

concentrated in vacuo. The crude material was purified by flash chromatography on a biotage eluting with 20% EtOAc/hexane to afford Compound 37 (1.0 g, 62% yield) as a colorless oil.

Electrospray MS [M+1] + 602.1 for Compound 37.

Step 5: COsMe COzMe \\ CFs \ CFs C02Me C02Me 9 g ; H2, Pd/C > z I CF -, I CF 3 3 Compound 37 Compound 38

To a solution of Compound 37 (1.0 g, 1.7 mmol, 1.0 equiv) in EtOH (20 mL) under N2 was added 10% Pd on carbon (0.177 g, 0.17 mmol, 0.1 equiv). The reaction mixture was placed under H2 atmosphere with a balloon. After 2 days, the reaction mixture was filtered through celite and concentrated in vacuo to afford crude Compound 38 (1.0 g, 100% yield).

Step 6:

02mye 0 CF3 CF3 BocHN TFA, CH2C12 H 3 I 3/\ 3 Compound 38 Example 64 Example 64 was prepared from Compound 38 by a method analogous to Example 27 from Compound 19.

Electrospray MS [M+1] + 472.1 for Example 64.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.