Therapeutic isoxazole compounds

THERAPEUTIC ISOXAZOLE COMPOUNDS

BACKGROUND OF THE INVENTION

10001] Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-dependent metabolic enzyme responsible for the oxidative deamination of both endogenous, aminergic neurotransmitters and xenobiotic amines. There are two reported isoforms of MAO, MAO-A and MAO-B, which arise from two independent genes (Bach, et. al., Proc. Natl. Acad. Sci., 1988, 85, 4934-4938). Both forms of MAO are distributed in a variety of tissues in varying amounts throughout the body; in the human brain, MAO-B is present to a greater extent then MAO-A (Saura, et. al.. Neuroscience, 1996, 70, 755-774).

[0002) MAO-A has greater selectivity for serotonin and adrenalin while MAO-B is selective for tyramine and phenethyl amine while both isoforms will metabolize dopamine. Studies have shown that the level of MAO-B activity in the brain increases with age (Fowler. et.al., J. Neural Transm., 1980, 49, 1-20). The process of oxidative deamination, which produces both peroxide and aldehydes as byproducts, has also been associated with an increase in oxidative damage in the brain, especially to dopaminergic neurons, potentially exacerbating the neuronal degeneration associated with diseases such as Alzheimer’s Disease and Parkinson’s Disease. There are also reports that the level of MAO-B activity present is greater in patients with Alzheimer’s disease which may be linked to the increased cognitive impairment of Alzheimer patients (Doslert, et.al, Biochem. Pharmacol., 1989, 38, 555-561; and Emilsson, et.al., Neuroscience Letters, 2002, 326, 56-60). This link between oxidative stress and progression of neuronal damage suggests that inhibition of MAO-B will minimize the degenerative effects of both of these diseases, presumably by preventing the metabolism of monoamines in the brain. Furthermore, the relative increase in dopamine levels, due to inhibition of its metabolism, may have effects on downstream regulation of plasticityassociated cognitive function, which may help repair, not just impede the progression of these diseases.

CA 2S74477 2017-07-21

[0003] The use of selective MAO-B inhibitors for neurological diseases has been known for some time (Bentue-Ferrer, et.al., CNS Drugs, 1996, 6, 217-236). Most early MAO inhibitors for the treatment of depression were irreversible inhibitors with minimal selectivity for MAO-B versus MAO-A. This can be problematic due to potential side effects associated with both the subsequent inability of the irreversibly inhibited enzyme to effectively metabolize dietary amines associated with cardiovascular events (the “cheese effect”) and the potential for drug-drug interactions with other drugs that are metabolized by MAO-B. More recent drugs, including selegiline and rasagiline, while still irreversible inhibitors, have greater selectivity for MAO-B, and have better side-effect profiles (Chen & Swope, JC/m Pharmacol. 2005 45,87894). There is currently a need for compounds that are useful for enhancing cognitive function and for treating cognitive deterioration in Parkinson’s Disease and Alzheimer’s Disease, as well as compounds that can generally improve cognition in normal, diseased, and aging subjects. Preferably, such agents will have higher potency and/or fewer side-effects than current therapies.

SUMMARY

[0004] This disclosure provides MAO-B inhibiting compounds.

[0004A] Various aspects of the disclosure are directed to a compound of formula I:

<img file="CA2974477C_D0001.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

R* is H (hydrogen), or is selected from the group consisting of aryl and (Ci-Cé)alkyl, each optionally substituted with one or more R_h;

each Rh is independently selected from the group consisting of halo, cyano, nitro, and -OH;

-2CA 2974477 2017-07-21

A¹ is CR²;

A and A are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is O, A³ is N and when A² is N, A³ is 0;

R² is H (hydrogen), (Ci-Côjalkyl, aryl(C₍-C6)alkyl, (C2-C₆)alkenyl, (Ca-Côjalkynyl, or aryl optionally substituted with one or more halo;

B is thiophene optionally substituted with one or more R³;

each R³ is independently aryl(C_t-C6)alkyl;

X is -C(=0)-, -C(=S)-, or -S-;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0, 1, and 2;

Y is R⁴, -N(R⁴)2, -OR⁴, -SR⁴, or -C(R⁴)3, each optionally substituted with one or more R&lt;i;

each R⁴ is independently selected from the group consisting of hydrogen, (Ci-Cé)alkyl, (Ci-Côjalkenyl, (C2-C6)alkynyl, (Ci-Cé)alkanoyl, (Ci-Cé)alkoxycarbonyl, (C3-C8)cycloalkyl, -(CH2)n(C3-C8)cycloalkyl, heteroaryl, aryl, aryl(C]-C6)alkyl, heterocycle, heterocycle(C|-C6)alkyl, heterocyde(C|-C6)alkanoyl, and NR,Rb; or when Y is -N(R⁴)2, then two R⁴ groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)Z, and NR&lt; wherein each ring system is optionally substituted with one or more Rj;

each R» and Rb is independently hydrogen or (Ci-C₆)alkyl, or R. and R_b are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-Céalkyl groups;

each R&lt; is independently selected from the group consisting of hydrogen, (Ci-Céjalkyl, aryl, heteroaryl, (Ci-Céjalkylsulfonyl, arylsulfonyl, (C_t-C6)alkylC(0)-, arylC(O)~, hydroxyl(C|-C₆)alkyl, alkoxy(Ci-C₆)alkyl, heterocycle, (Ci-C6)alkylOC(O)-, (Ci-C₆)alkylaminocarbonyl, and arylaminocarbonyl;

-2aCA 2974477 2017-07-21 each R&lt;j is independently halo, cyano, nitro, oxo, RfRgN(Ci-C6)alkyl, -(CH₂)_nNR_fRg, -C(O)NRfRg, -NR_tC(O)R_g, arylC(O)NR_fR_g, -C(O)OH, (CrC₆)alkyl, (Cj-Cgjcycloalkyl, (C|-C₆)alkoxy, halo(C)-C₆)alkoxy, (C_rC6)alkylC(O)-, (C|-C6)alkylOC(O)-, (Ci-Cé)alkylC(O)O-, heterocycle, aryl, heterocycle(Ci-Cé)alkyl, aryl(C|-C₆)alkyl, -NR_tS(O)_ICCi-C₆)alkyl, -NR&lt;S(O)_zaryl, -NR«C(O)NRfRg, -NR«C(O)ORf, or -OC(O)NR_fRg;

each R» is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl;

each R_f and R_g is independently hydrogen, (C]-C₆)alkyl, aryl or heteroaryl, or R_fand Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NR_C wherein each ring system is optionally substituted with one or more Rq;

each R&lt;, is independently halo, cyano, nitro, oxo, -NRjRj, R,RjN(Ci-C₆)alkyl, -(CH₂)_BNRiRj, -C(O)NRiRj, -NR_kC(O)Rj, arylQOjNRjRj, -C(O)OH, (C!-C₆)alkyl, (C₃-C₈)cycloalkyl, -(CH₂)_BOH, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-Cé)alkylC(O)-, (Cj-C6)alkylOC(O)-, (Ci-Cé)alkylC(O)O-, heterocycle, aryl, heterocycle(Ci-C₆)alkyl, aryl(CrC₆)alkyl, -NReSiOUCi-CôJalkyl, -NR_kS(O)_zaryl, -NR_kC(O)NRjRj, -NR_kC(O)ORj, or -OC(O)NRjRj;

each R_k is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl;

each Rj and Rj is independently hydrogen, (Ci-C6)alkyl, aryl or heteroaryl; and the dashed line represents an optional double bond wherein the ring comprising A¹, A², and A³ is heteroaromatic;

with the proviso that the compound of formula I is not selected from the group consisting of:

2bCA 2974477 2017-07-21

<img file="CA2974477C_D0002.tif" />

In some embodiments, such a compound is of (la) or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

Z¹ is S (sulfur), Z², and Z³ are each independently CR⁵;

each R^s is independently H (hydrogen), or aryl(Ci-C6)alkyl;

each Rf and Rg is independently hydrogen, (Ci-C6)alkyl, aryl or heteroaryl, or R_fand Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NR_C wherein each ring system is optionally substituted with one or more R_q;

each R&lt;] is independently halo, cyano, nitro, oxo, COOH, RjRjN(Ci-C₆)alkyl, -(CH₂)_BNRiRj, -QOJNRiRj, -NR_kC(O)Rj, arylCiOjNRiRj, -C(O)OH, (C|-C₆)alkyl, (C₃-C₈)cycloalkyl, -(CH₂)_aOH, (C_rC₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-Ci)alkylC(O)-, (Ci-Cô)alkylOC(O)-, (C]-Cé)alkylC(O)O-, heterocycle, aryl, heterocycle(C_rC₆)alkyl, aryl(C|-C₆)atkyl, -NR^OMCrCôjalkyl, -NR_kS(O)_zaryl, -NR_kC(O)NRjRj, -NR_kCrO)OK, or -OC(O)NRiRj;

each R_k is independently hydrogen, (C]-C6)alkyl, aryl or heteroaryl; and each Rj and Rj is independently hydrogen, (CrC₆)alkyl, aryl or heteroaryl.

-2cCA 2974477 2017-07-21

[0004B| Various aspects of the disclosure relate to a compound of formula Ila:

<img file="CA2974477C_D0003.tif" />

(Ha) or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H (hydrogen), or is selected from the group consisting of aryl and (C_rC₆)alkyl, each optionally substituted with one or more Rbî each Rh is independently selected from the group consisting of halo, cyano, nitro, and -OH;

A* isCR²;

R² is H (hydrogen), (Cj-Chalky I, aryl(Ci-Cô)alkyl, (Cj-Côjalkenyl, (C2-Cô)alkynyl, or aryl optionally substituted with one or more halo;

A and A are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is 0;

Z¹ is S (sulfur);

Z , and Z are each independently CR ;

each R⁵ is independently I I (hydrogen), or aryl(C|-C6)alkyl;

X is -C(=0)-, -C(=S)-, -S-, or -S(0)-;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0,1, and 2;

Y is -N(R⁴)₂ optionally substituted with one or more R^;

each R⁴ is independently selected from the group consisting of hydrogen, (C|-Cô)alkyl, (C2-Cé)alkenyl, (C2-C6)alkynyl, (Ci-Cé)alkanoyl, (C|-C6)alkoxycarbonyl, (C₃-C₈)cycloalkyl, -(CH₂)_n(C₃-C₈)cycloalkyl, heteroaryl, aryl, aryl(Ci-C₆)alkyl, heterocycle, heterocycle(C]-C6)alkyl, heterocycle(C|-C6)alkanoyl and NR_aRb; or two

-2dCA 2974477 2018-12-14

R⁴ groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NRc wherein each ring system is optionally substituted with one or more R&lt;i;

each R_a and R_b is independently hydrogen or (Ci-C₆)alkyl, or R_a and R_b are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-C _balkyl groups;

each R&lt; is independently selected from the group consisting of hydrogen, (Ci-Cé)alkyl, aryl, heteroaryl, (C|-C6)alkylsulfonyl, arylsulfonyl, (Ci-C6)alkylC(O)-, arylC(O)-, hydroxyl(Ci-C6)alkyl, alkoxy(Ci-C6)alkyl, heterocycle, (Ci-C6)alkylOC(O)-, (C i-Ce)alkylaminocarbonyl, and arylaminocarbonyl;

each Rd is independently halo, cyano, nitro, oxo, RfRgN(Ci-C6)alkyl, -(CH₂)_nNRfRg, -C(O)NR_fR_g, -NR«C(O)Rg, arylC(O)NR_fRg, -C(O)OH, (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-C₆)alkylC(O)-, (Ci-C₆)alkylOC(O)-, (C_rC6)alkylC(O)O-, heterocycle, aryl, heterocycle(C|-C₆)alkyl, aryl(Ci-C₆)alkyl, -NRcS(O)_z(Ci-C₆)alkyl, -NReS(O)_zaryl, -NR,C(O)NR_fRg, -NR_cC(O)OR_f, or -OC(0)NR_fRg;

each Rt is independently hydrogen, (C i -C₆)alkyl, aryl or heteroaryl;

each Rf and R_g is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl, or R_fand Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NR_C wherein each ring system is optionally substituted with one or more Rq;

each Rq is independently halo, cyano, nitro, oxo, RjRjN(C]-C6)aIkyl, -((2Η₂)_πΝΗίΚ_}, -C(O)NRjRj, -NR_kC(O)R_j5 arylC(O)NRiRj, -C(O)OH, (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, -(CH₂)_BOH, (C,-C₆)alkoxy, halo(C_rC₆)alkoxy, (Ci-C₆)alkylC(O)-, (Ci-C₆)alkylOC(O)-, (Ci-C₆)alkylC(O)O-, heterocycle, aryl, heterocycle(C|-C₆)alkyl,

- 2e CA 2974477 2017-07-21 aryl(C,-C₆)alkyl, -NReS(0)z(C|-C6)alkyl, -NR_kS(O)_zaryl, -NR_kC(O)NRjRj, -NRkC(O)ORi, or -OC(O)NRiRj;

each R_k is independently hydrogen, (Ci-CeJalkyl, aryl or heteroaryl; and each Rj and Rj is independently hydrogen, (Ci-C6)alkyl, aryl or heteroaryl;

with the proviso that the compound of formula Ha is not selected from the group consisting of:

<img file="CA2974477C_D0004.tif" />

<img file="CA2974477C_D0005.tif" />

[0004C] Various aspects of the disclosure are directed to a compound of formula Id:

<img file="CA2974477C_D0006.tif" />

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H (hydrogen), or is selected from the group consisting of aryl and (Ci-Cejalkyl, each optionally substituted with one or more R*;

each Rh is independently selected from the group consisting of halo, cyano, nitro, and -OH;

A’ is CR²;

R² is H (hydrogen), (Ci-C₆)alkyl, aryl(C,-C₆)alkyl, (C₂-C₆)alkenyl, (C2-Cé)alkynyl, or aryl optionally substituted with one or more halo;

2f

CA 2974477 2017-07-21

A² and A³ are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is 0;

Z¹ is S (sulfur);

Z², and Z³ are each independently CR^S;

each R⁵ is independently H (hydrogen), or aryl(C|-Cé)alkyl;

each R⁴ is independently selected from the group consisting of hydrogen, -OH, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C]-C₆)alkanoyl, (Ci-C₆)alkoxycarbonyl, (C3-Cg)cycloalkyl, -(CH₂)_O(C3-Cg)cycloalkyl, heteroaryl, aryl, aryl(C]-C₆)alkyl, heterocycle, hctcrocycle(C|-Chalky 1, heterocycle(C|-C6)alkanoyl and NR_aRb;

each R_a and Rb is independently hydrogen or (Ci-C^alkyl, or R_a and Rb are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more C,-C ₆alkyl groups;

each n is independently an integer selected from 0,1, and 2; and each R| and Rj is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl. [0004D] Various aspects of the claimed invention relate to a compound of the Formula le:

<img file="CA2974477C_D0007.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

R* is (C]-C(&gt;)alkyl substituted with one or more Rh;

each Rh is independently selected from the group consisting of fluoro, bromo, iodo, cyano, and nitro;

A* isCR²;

R² is H (hydrogen), (C]-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or aryl optionally substituted with one or more halo;

-2gCA 2974477 2017-07-21 each R_b is independently selected from the group consisting of fluoro, bromo, iodo, cyano, and nitro;

A* isCR²;

R² is H (hydrogen), (Ci-Côjalkyl, (C2-C_b)alkenyl, (Ci-Côjalkynyl, or aryl optionally substituted with one or more halo;

A and A are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is 0;

Z* is CR⁵;

Z²isCR^s;

Z³ is CR⁵;

Z⁴ is CR⁵;

R⁵ is H (hydrogen);

Xis-C(=O)-;

Y is R⁴, -N(R⁴)₂, -OR⁴, -SR⁴, or -C(R⁴)3, each optionally substituted with one or more Ra;

each R⁴ is independently selected from the group consisting of hydrogen, (Ci-Cô)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C^)alkanoyl, (Cj-Cgjalkoxycarbonyl, (Cj-Cgjcycloalkyl, -(CH2)n(C3-C8)cycloalkyl, heteroaryl, aryl, aryl(Ci-C6)alkyl, heterocycle, heterocycle(CrC6)alkyl, heterocycle(Ci-C6)alkanoyl and NRaRb; or when Y is -N(R⁴)2, then two R⁴ groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(0)z, and NR&lt;. wherein each ring system is optionally substituted with one or more R_d;

each R_a and R_b is independently hydrogen or (Ci-QJalkyl, or R_a and R_b are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-C 6alkyl groups;

-2hCA 2974477 2018-12-14 each Rc is independently selected from the group consisting of hydrogen, (C)-C₆)alkyl, aryl, heteroaryl, (C|-C₆)alkylsulfonyl, arylsulfonyl, (C|-C₆)alkylC(O)-, arylC(O)-, hydroxyl(C|-C₆)alkyl, alkoxy(C_rC₆)alkyl, heterocycle, (Ci-C6)alkylOC(O)-, (C)-C6)alkylaminocarbonyl, and arylaminocarbonyl;

each R&lt;) is independently halo, cyano, nitro, oxo, RfR_gN(Ci-C₆)alkyl, -(CH₂)_nNR_rRg, -C(O)NR_fRg, -NReC(O)Rg, arylC(O)NR_fRg, -C(O)OH, (C|-Cô)alkyl, (C3-C₈)cycloalkyl, -(CH2)_BOH, (Ci-C6)alkoxy, halo(C|-C₆)alkoxy, (Ci-C6)alkylC(O)-, (Ci-C6)alkylOC(O)~, (C|-C6)alkylC(O)O-, heterocycle, aryl, heterocycle(C|-C₆)alkyl, aryl(C_rC₆)alkyl, -NRtSiO^Ci-CôJalkyl, -NReS(O)_zaryl, -NR_tC(O)NR_fRg, -NR&lt;C(O)ORf, or -OC(O)NR_fRg;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0,1, and 2;

each Re is independently hydrogen, (C_f-C₆)alkyl, aryl or heteroaryl;

each R_f and Rg is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl, or R_fand R_g are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NRc wherein each ring system is optionally substituted with one or more Rq;

each Rq is independently halo, cyano, nitro, oxo, RjRjN(Ci-C₆)alkyl, -(CH₂)₀NRiRj, -C(O)NRiRj, -NR_kC(O)Rj, arylC(O)NRjRj, -C(O)OH, (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, -(CH₂)_nOH, (C|-C₆)alkoxy, halo(Ci-C6)alkoxy, (C]-C6)alkylC(O)-, (C|-C6)alkylOC(O)~, (C|-C6)alkylC(O)O, heterocycle, aryl, heterocycleiCi-Côjalkyl, aryl(CrC₆)alkyl, -NReS(O)_z(C_rC₆)alkyl, -NR_kS(O)_zaryl, -NR_kC(O)NRjRj, -NR_kC(0)ORj, or -OC(O)NRjRj;

each R_k is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl;

each Rj and Rj is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl; and wherein alkyl is a saturated or unsaturated, branched, straight, chain, or cyclic hydrocarbon group.

-2i CA 2974477 2018-12-14

[0004E] Various embodiments of the claimed invention relate to a compound of formula la:

R¹

<img file="CA2974477C_D0008.tif" />

da) or a pharmaceutically acceptable salt thereof, wherein:

R¹ is (C|-C₆)alkyl optionally substituted with one or more R_b;

each Rh is independently selected from the group consisting of halo, cyano, nitro, and -OH;

A¹ isCR²;

A² and A³ are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is 0;

R² is H (hydrogen), (Ci-C₆)alkyl, aryl(Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂Côjalkynyl, or aryl optionally substituted with one or more halo;

Xis-C(=0)-;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0,1, and 2;

Y is R⁴, -N(R⁴)2, -OR⁴, -SR⁴, or -C(R⁴)3, each optionally substituted with one or more R&lt;j;

each R⁴ is independently selected from the group consisting of hydrogen, (C i -Cé)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-Ce)alkanoyl, (C|-C6)alkoxycarbonyl, (Cj-Cgjcycloalkyl, -(CH2)n(C3-C8)cycloalkyl, heteroaryl, aryl, aryl(CrC6)alkyl, heterocycle, heterocycle(Ci-C6)alkyl, heterocycle(Ci-C6)aIkanoyl, and NR,Rb; or when Y is -N(R⁴)2, then two R⁴ groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom

-2jCA 2974477 2018-12-14 groups selected from 0 (oxygen), S(O)_Z, and NRc wherein each ring system is optionally substituted with one or more R^;

each R_a and R_b is independently hydrogen or (Ci-C₆)alkyl, or R_a and R_b are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-C _balkyl groups;

each Rc is independently selected from the group consisting of hydrogen, (Ci-Cejalkyl, aryl, heteroaryl, (Ci-Céjalkylsulfonyl, arylsulfonyl, (CrC6)alkylC(O)-, arylC(O)-, hydroxyl(C|-C6)alkyl, alkoxy(Ci-C6)alkyl, heterocycle, (C|-C6)alkylOC(O)-, (C|-C6)alkylaminocarbonyl, and arylaminocarbonyl;

each R&lt;j is independently halo, cyano, nitro, oxo, RfR_gN(C]-C6)alkyl, -(CH₂)_nNR_fRg, -C(O)NR_fRg, -NReC(O)Rg, arylC(O)NRfRg, -C(O)OH, (Ci-C₆)alkyl, (Cj-Cgjcycloalkyl, (Ci-Côjalkoxy, halo(C|-C6)alkoxy, (Cj-C6)alkylC(O)-, (Ci-Cé)alkylOC(O)-, (C|-C6)alkylC(0)O~, heterocycle, aryl, heterocycle(Ci-C6)alkyl, aryl(C_rC₆)alkyl, -NR^O^CrQalkyl, -NR_fS(O)_zaryl, -NReC(O)NR_fR_g, -NReC(O)OR_f, or -OC(O)NR_fRg;

each R« is independently hydrogen, (Ci-Cô)alkyl, aryl or heteroaryl;

Z¹ is S (sulfur);

Z², and Z³ are each independently CR⁵;

each R⁵ is independently H (hydrogen), or aryl(C ]-C₆)alkyl;

each Rf and Rg is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl, or R_fand Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NR_r wherein each ring system is optionally substituted with one or more R^;

each Rq is independently halo, cyano, nitro, oxo, RjRjN(C|-C6)alkyl, -(CH₂)_nNRjRj, -C(O)NRjRj, -NR_kC(O)Rj, arylC(O)NRiRj, -C(O)OH, (Ci-C6)alkyl, (Cj-Cgjcycloalkyl, -(CH₂)_nOH, (Ci-C₆)alkoxy, halo(C|-C6)alkoxy, (Ci-C6)alkylC(O)-, (Ci-C6)alkylOC(O)-, (C|-C6)alky 10(0)0-, heterocycle, aryl,

-2kCA 2974477 2018-12-14 heterocycle(C_rC₆)alkyl, aryl(Ci-C₆)alkyl, -NR.SiOUCi-Céjalkyl, -NR_kS(O)_xaryl, -NR_kC(O)NRjRj, -NR_kC(O)ORj, or -OC(O)NRjRj;

each R_k is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl; and each Rj and Rj is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl.

[0004F] Various embodiments of the claimed invention are directed to individual compounds as disclosed herein.

[0004G] Various embodiments of the claimed invention are directed to pharmaceutical compositions comprising a claimed compound or a pharmaceutically acceptable salt or prodrug ester thereof and a pharmaceutically acceptable diluent or carrier. Also claimed is a method for preparing a pharmaceutically acceptable salt of such a compound comprising: a) deprotecting a corresponding compound that comprises one or more protecting groups to provide the compound; and b) forming a pharmaceutically acceptable salt from the compound.

[0004HJ Various embodiments of this invention are directed to use of a claimed compound or pharmaceutically acceptable salt or prodrug ester thereof or a claimed composition to inhibit a monoamine oxidase (MAO) enzyme. Such a compound, salt, prodrug ester, or composition may be usefill for inhibiting such an enzyme in an animal and may be useful therapeutically, as described herein.

Embodiments, Aspects and Variations of the Invention

[0005] The present disclosure provides the following embodiments, aspects and variations: One embodiment provides a compound of formula I:

-21CA 2974477 2018-12-14

<img file="CA2974477C_D0009.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

R¹ is H (hydrogen), or is selected from the group consisting of aryl and (Ci C₆)alkyi, each optionally substituted with one or more R^;

each R_b is independently selected from the group consisting of halo, cyano, nitro, —C(O)OH, (Cj-C^alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_nOH, (Ci-C₆)alkoxy, haloiCrC₆)alkoxy, (C_rC₆)alkylC(O)—, (Ci -C₆)alkylOC(O}-, and (C_rCé)alkylC(0)0—;

A¹ is N (nitrogen), or CR²;

R²is H (hydrogen), (C^alkyl, aryi(Ci-Cs)alkyl, (C₂-C«)alkenyl, (C₂Cé)alkynyl, or aryl optionally substituted with one or more halo;

A² and A³ are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A¹ is 0, A³ is N and when A² is N, A³ is O;

B is aryl or heieroaryl, each optionally substituted with one or more R ;

X is €(-0)-, —C(-S&gt;—, —QR⁴)?—, or S(0)_z—;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0,1, and 2;

Y is R⁴, —N(R⁴)2, —OR⁴, —SR⁴ or —CfR⁴^, each optionally substituted with one or more Rj;

each R⁴is independently selected from the group consisting of hydrogen, —OH, (Ci -C'ejalkyl, (C₂-C6)alkenyl, (C₂-Cô)alkynyl, (Ci -C₆)alkanoyl, (Cr C₆)alkoxycarbonyl, (Cj-Cgjcycloalkyl, —(CH₂)_n(Cj-C8)cycloalkyl, heteroaryl, aryl, aryl(C]-C₆)alkyl, heterocycle, heterocycle(Ci-C₆)alkyl, heterocycle(Ci-C₆)alkanoyl and NR_aR_b; or when Y is —N(R⁴h, then two R⁴ groups are optionally

-3CA 2574477 2017-07-21 taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), 5(0)^ and NRç wherein each ring system is optionally substituted with one or more R&lt;i;

each R, and Rj&gt; is independently hydrogen or (Ci-Cô)alkyl, or R_a and Rb are optionally taken togeticr with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-Cgalkyl groups;

each Reis independently selected from the group consisting of hydrogen, (C)-Cô)alkyl, aryl, heteroaryl, (Ci-Csjalkylsulfonyl, arylsulfonyl, (C_rC6)alkylC(0)—, aryiC(O)—, hydroxy(Ci-C6)alkyl, alkoxy(C]-C₆)alkyl, heterocycle, (Ci-C6)alkylOC(O)—, (C|-Cé)alkylaminocarbonyl, and arylaminocarbonyl;

each Rd is independently halo, cyano, nitro, oxo, RfRgN(Ci-C₆)alkyl, —(CH₂)_nNRfRj, —QOjNRfRg, —NR_CQO)R_&lt;, arylC(O)NR^, —C(O)OH, (C_rC₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)nOH, (C_rC₆)alkoxy, haIo(C_rC₆)alkoxy, (CjCe)alkylC(O)—, (Ci-Cé)alkylOC(O)—, (Ci-C$)alkylC(O)O—, heterocycle, aryl, heterocycle(Cj-Ci)alkyl, aryl (Chalky!, -NKS^Cj-Cijalkyl, —NR_tS(O)_zaryl, —NReCiOJNRfRg, —NR^CiOjORj, or —0C(0)NR_fRg;

each R« is independently hydrogen, (Ci-Cb)alkyl, aryl or heteroaryl;

each Rf and Rg is independently hydrogen, (Ci-Céjalkyl, aryl or heteroaryl, or Rf and Rg are optionally taken together with die nitrogen to which they are studied to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(0)_z, and NR,, wherein each ring system is optionally substituted with one or more R,;

each R, is independently halo, cyano, nitro, oxo, RjRjN(Ci-C₆)aIkyl, —(CH₂)nNRiRj, —C(O)NRiRj, -NR_kC(O)Rj, aiylC(O)NRjRj, —C(O)OH, (C,C₆)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_nOH, (C_rC₆)alkoxy, halo(C_rC₆)alkoxy, (C|-4CA 2974477 2017-07-21

Cé)alkylC(O)—, (C|-C₆)alkylOC(O)~, (Ci-C&lt;,)alkylC(O)O—, heterocycle, aryl, heterocycle/Cj-C^alkyl, aryl(C|-C«)alkyl, —NR^SfO^Ci-C^alkyl, -NR_kS(O)_zaryl, —NR^CRNRiRj, -NR_kC(O)ORj, or—OCiOjNRjRj;

each R_k is independently hydrogen, (C_l-C₆)alkyl, aryl or heteroaryl;

each Rj and Rj is independently hydrogen, (Cj-C«)alkyl, aryl or heteroaryl; each R³ is (Cj-C^alkyl, —NRjRj, —C(O)NR|Rj, or aryl(Ci-C6)alkyl; and the dashed line represents an optional double bond wherein the ring comprising A , A , and A is heteroaromatic;

with the proviso that the compound of formula I is not selected from the group consisting of:

<img file="CA2974477C_D0010.tif" />

<img file="CA2974477C_D0011.tif" />

<img file="CA2974477C_D0012.tif" />

<img file="CA2974477C_D0013.tif" />

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<img file="CA2974477C_D0014.tif" />

<img file="CA2974477C_D0015.tif" />

O-N

<img file="CA2974477C_D0016.tif" />

<img file="CA2974477C_D0017.tif" />

O-N

<img file="CA2974477C_D0018.tif" />

<img file="CA2974477C_D0019.tif" />

<img file="CA2974477C_D0020.tif" />

<img file="CA2974477C_D0021.tif" />

<img file="CA2974477C_D0022.tif" />

<img file="CA2974477C_D0023.tif" />

<img file="CA2974477C_D0024.tif" />

CA 2974477 2017-07-21

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PCT/US2008/074353 )0006] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0025.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula 1. Another embodiment includes the compound of formula I, wherein each R³ can be independently (C|-C₆)alkyl, or aryl(C|-Cô)alkyl. Another embodiment includes the compound of formula 1, wherein each R_h can be halo, cyano, nitro, -OH, or (C|-C₆)alkyl. In some embodiments R_h can be fluoro.

)0007] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0026.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula I.

|0008] Another embodiment includes the compound of formula I with the proviso that when B is a 5-membered ring and Y is -N(R⁴)2, then R⁴ is not a 7azabicyclo[2.2.l]heptane or l-azabicyclo[2.2.2Joctane, each optionally substituted with (C|-C₆)alkyl. Another embodiment includes the compound of formula I with the proviso that when B is a 5-membered ring, then R³ is not -C(O)NR|Rj.

)0009] Another embodiment includes the compound of formula 1 with the proviso that when B is thiophene and not substituted with R³, X is -C(=O)-, Y is N(R⁴)₂, and one R⁴ is H, then the other R⁴ is not -OH; and when B is thiophene and not substituted with R³, and X is -C(=O)-, then

Y is not -OH, or-0(C|-C6)alkyl.

-7CA 2974477 2017-07-21

[0010] Another embodiment includes the compound of formula I having formula

R¹

<img file="CA2974477C_D0027.tif" />

(la) or a pharmaceutically acceptable salt or prodrug ester thereof wherein:

Z , Z, and Z are each independently 0 (oxygen), N (nitrogen), S (sulfur), or CR⁵ 0 (oxygen), N (nitrogen), S (sulfur), or CR⁵ with the proviso that at least one ofZ¹, Z², and Z³isnotCR⁵;

each R^s is independently H (hydrogen), (Cj -C₆)alkyl, —NRjR,, —C(O)NRfRg, or aryl(Ci -Q)alkyl;

each Rf and Rg is independently hydrogen, (Ci-C₆)alkyl, aryl or heteroaryl, or Rf and Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NRç wherein each ring system is optionally substituted with one or more R^;

each Rq is independently halo, hydroxy, cyano, nitro, oxo, COOH, —NRjRj, RjRjN(CrC(,)alkyl, —(CH₂)_DNRtRj,—C(O)NRjRj, —NR_kC(O)Rj, arylC(O)NRjRj, —C(0)0H, (CrQalkyl, (C₃-C₈)cycloalkyl, -&lt;CH₂)_nOH, (CiC₆)alkoxy, halo(Ci-C₆)alkoxy, (Cj-C₆)alkylC(O)—, (C|-C₆)alkyiOC(O)—, (C_rC₆)alkylC(O)O—, heterocycle, aryl, heterocycle(C|-C₆)alkyl, aryl(Ci-C₆)alkyl, —NR_€S(O)_Z(C|-C₆)alkyl, —NR_kS(O)_zaryl, —NR^QOjNRjRj, —NR_kC(O)OR_h or -OC(O)NR₁R_j;

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PCT/US2008/074353 each Rc is independently selected from the group consisting of hydrogen, (C|-C₆)alkyl, aryl, heteroaryl, (C|-C₆)alkylsulfonyl, arylsulfonyl, (C_rCé)alkylC(O)-, arylC(O)-, hydroxyfCi-Côjalkyl, aIkoxyfCi-Céjalkyl, heterocycle, (C|-C6)alkylOC(O)-, (C|-C₆)alkylaminocarbonyl, and arylaminocarbonyl;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0, 1, and 2;

each R_k is independently hydrogen, (CTC₆)alkyl, aryl or heteroaryl;

each Rj and Rj is independently hydrogen, (C)-Cô)alkyl, aryl or heteroaryl;

R¹, A¹, A², A³, X and Y are defined according to the definitions for the compound of formula 1; and the dashed line represents an optional double bond wherein the ring comprising Z¹, Z²,and Z³ is heteroaromatic.

In some embodiments Z* can be O (oxygen), N (nitrogen) or S (sulfur). In some embodiments Z² can be O (oxygen). N (nitrogen) S (sulfur), or CR⁵. In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵.

|0011] Another embodiment includes a compound of formula la with the proviso that when Z¹ is O (oxygen), N (nitrogen) or S (sulfur) and Y is -N(R⁴)₂, then R⁴is not a 7-azabicyclo[2.2.1]heptane or l-azabicyclo[2.2.2)octane, each optionally substituted with (CpCejalkyl. Another embodiment includes a compound of formula la with the proviso that when Z¹ is S (sulfur), then Z³ is not CR⁵ where R^s is - C(O)NR|Rj.

(0012] Another embodiment includes a compound of formula la, wherein Z¹is S (sulfur). Another embodiment includes a compound of formula la, wherein X is C(=O). Another embodiment includes the compound of formula la, wherein each R_k can be halo, cyano, nitro, -OH, or (Ci-C^alkyl. In some embodiments Rh can be fluoro.

(0013] Another embodiment includes the compound of formula la with the proviso that when Z¹ is S (sulfur) and Z² and Z³ are both CR⁵ where each R⁵ is H (hydrogen), X is -C(=O)-, Y is -N(R⁴)2, and one R⁴ is H, then the other R⁴ is not -OH; and when Z¹ is S (sulfur) and Z² and Z³ are both CR⁵ where each R⁵ is H, and X is

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C(=0)-, then Y is not -OH, or -0(C|-C6)alkyl. Another embodiment includes the compound of formula la with the proviso that when l) is S (sulfur) and ΊΪ is CR^S where R⁵ is H (hydrogen), X is -C(=O)-, Y is -N(R⁴)2, and one R⁴ is H, then the other R⁴ is not -OH; and when Z¹ is S (sulfur) and Z² is CR⁵ where R^s is H, and X is -C(=O)~, then Y is not -OH, or -0(C|-C6)alkyl. Another embodiment includes the compound of formula la with the proviso that when Z¹ is S (sulfur) and Z³ is CR⁵ where R⁵ is H (hydrogen), X is -0(=-0) , Y is -N(R⁴)₂, and one R⁴ is H, then the other R⁴ is not -OH; and when Z’ is S (sulfur) and Z³ is CR⁵ where R⁵ is H, and X is -0(=0)-, then Y is not OH, or-OfCpC^alkyl.

(0014] Another embodiment includes the compound of formula la, wherein Y is -N(R⁴)2. In some embodiments, -N(R⁴)2 is piperidinyl optionally substituted with one or more R&lt;j (0015] Another embodiment includes a compound having the formula:

R'

<img file="CA2974477C_D0028.tif" />

|0016] or a pharmaceutically acceptable salt or prodrug ester thereof, |0017] wherein the variables are defined according to the definitions for the compound of formula la.

|0018| Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0029.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula la.

-]0CA 2974477 2017-07-21

[0019] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0030.tif" />

X—Y or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula la.

[0020] Another embodiment includes the compound of formula I having the formula Ila

<img file="CA2974477C_D0031.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

R is H (hydrogen), or is selected from the group consisting of aryl and (Cj· Cé)alkyl, each optionally substituted with one of more R_k;

each R_k is independently selected from the group consisting of halo, cyano, nitro, —C(O)OH, (C^ejalkyl, (C₃-C_g)cycloalkyl, _(CH₂)_nOH, (Cj-C₆)alkoxy, halofCi-Qalkoxy, (Ci-C«)alkylC(O)—, (Ci-QalkylOCfO)—, and (C|C₆)alkyiC(O)O—;

. . 2

A is N (nitrogen), or CR ;

R² is H (hydrogen), (Cj -C₆)alkyl, aryl(C_rC6)alkyl, (C₂-C₆)alkenyl, (C₂Ce)alkynyl, or aryl optionally substituted with one or more halo;

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A² and A³ are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is O, A³ is N and when A² is N, A³ is O;

Z¹, Z², and Z³ are each independently O (oxygen), N (nitrogen), S (sulfur), or CR⁵ with the proviso that at least one of Z¹, Z², and Z³ is not CR^S;

each R⁵ is independently H (hydrogen), (C|-Ce)alkyl, ~NRRj, -C(O)NRjRj, or aryl(C|-C₆)alkyl;

X is -C(=O&gt;-, -C(-S)-, C(R⁴)₂ , or -S(O)_Z-;

each n is independently an integer selected from 0, 1, and 2;

each z is independently an integer selected from 0,1, and 2;

Y is -N(R⁴)₂ optionally substituted with one or more R&lt;i;

each R⁴ is independently selected from the group consisting of hydrogen, -OH, (Ci-Cô)alkyl, (C₂-C6)alkenyl, (C₂-C(&gt;)alkynyl, (C|-C6)alkanoyl, (C|Côjalkoxycarbonyl, (C₃-C_g)cycloalkyl, -(CH₂)_n(Cj-Cg)cycloalkyl, heteroaryl, aryl, aryl(C|-C₆)aIkyl, heterocycle, heterocycle(C|-C₆)alkyl, heterocycle(CiCôjalkanoyl and NR,Rt&gt;; or two R⁴ groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from O (oxygen), $(0),, and NRc wherein each ring system is optionally substituted with one or more R^;

each R, and Rb is independently hydrogen or (Ci-QJalkyl, or R, and Rt&gt; are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more CpC ealkyl groups;

each R&lt; is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, aryl, heteroaryl, (C|-C₆)alkylsulfonyl, arylsulfonyl, (C_rCô)alkylC(O)-, arylC(O)-, hydroxy(Ci-C6)alkyl, alkoxy(C|-C₆)alkyl, heterocycle, (C|-Q)alkylOC(O)~, (CrCejalkylaminocarbonyl, and arylaminocarbonyl;

each R_d is independently halo, cyano, nitro, oxo, R_fRgN(Ci-C6)alkyl, -(CH₂)_BNR_fR_K, -C(O)NRfR_?, -NR_fC(O)R_g, arylC(O)NR_fR_g, -C(O)OH, (C_r

-12CA 2974477 2017-07-21

Cé)alkyl, (C3-Cg)cycloalkyl, —(€Ή₂)_ηΟΗ, (Cj-Cô)alkoxy, halo(C|-Cé)alkoxy, (CiCé)alkylC(O)—, (C|-C6)alkylOC(O)—, (C|-Cé)alkylC(O)O—, heterocycle, aryl, heterocycle(Ci-C6)alkyi, aryl(C]-C6)alkyl, —NReSfO^Cj-Cejalkyl, —NReS(O)zaryl, —NR/XOJNRfRg, —NR^C/OJORf, or —00(0)ΝΚ^;

each R« is independently hydrogen, (Ci -Cé)alkyl, aryl or heteroaryl;

each Rf and Rj is independently hydrogen, (Ci-C^alkyl, aryl or heteroaryl, or Rf and Rj are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)z, and NRç wherein each ring system is optionally substituted with one or more R,;

each Rq is independently halo, cyano, nitro, oxo, RjRjN(C_rC₆)aIkyl, -(CH₂)_nNR_iR_J, —C(O)NR|Rj, —NR_kC(O)Rj, arylC(O)NRiRj, -C(O)OH, (C_rCé)alkyl, (C₃-Cg)cycloalkyl, —(CH₂)_nOH, (Ci-Cjjalkoxy, halofCrCjjalkoxy, (CjC6)alkylC(0)—, (Ci -C$) alkyl 0C(0)—, (Ci-Cô)alkylC(O)O—, heterocycle, aryl, heterocycle(Ci-C₆)a]kyl, arylfCj-CiJalkyl, —NR^O^Ci-C^alkyl, —NR_kS(O)_zaryl, —NR_kC(O)NRjRj, —NR_kC(O)ORj, or —OC(O)NRjRj;

each R_k is independently hydrogen, (C&gt;-C₆)alkyl, aryl or heteroaryl; each Rj and Rj is independently hydrogen, (Ci-Qalkyl, aryl or heteroaryl; and the dashed line represents an optional double bond wherein the ring comprising A¹, A², and A³ is heteroaromatic and the ring comprising Z¹, Z², and Z³is heteroaromatic;

with the proviso that the compound of formula Ila is not selected from the group consisting of:

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<img file="CA2974477C_D0032.tif" />

<img file="CA2974477C_D0033.tif" />

|0021J In some embodiments Z¹ can be O (oxygen), N (nitrogen) or S (sulfur). In some embodiments Z² can be O (oxygen), N (nitrogen) S (sulfur), or CR^S. In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵. In a typical embodiment, Z¹ can be S (sulfur), Z² can be CR⁵ and Z³ can be CR⁵.

[0022J Another embodiment includes the compound of formula Ila with the proviso that when Z¹ is O (oxygen), N (nitrogen) or S (sulfur), then R⁴ is not a 7azabicyclo[2.2.1]heptane or l-azabicyclo[2.2.2]octane, each optionally substituted with (C|-C6)alkyl. Another embodiment includes the compound of formula Ila with the proviso that, Z³ is not CR⁵ where R⁵ is ~C(O)NR;Rj. Another embodiment includes the compound of formula Ila with the proviso that when Z* is S (sulfur) and Z² and Z³ are both CR^S where each R⁵ is H, X is -C(=O}~, Y is -N(R⁴)2&gt; and one R⁴ is H, then the other R⁴ is not -OH; and when Z¹ is S (sulfur) and Z² and Z³ are both CR^S where each R⁵ is H, and X is -C(-O)-, then Y is not -OH, or -O(C|-C$)alkyl. Another embodiment includes the compound of formula Ila wherein -N(R⁴)₂ is piperidinyl optionally substituted with one or more R&lt;j. Another embodiment includes the compound of formula Ha, wherein each R_h can be halo, cyano, nitro, -OH, or (Ci-Cb)alkyl. In some embodiments R_b can be fluoro.

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PCT/LS2008/074353 |0023]

Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0034.tif" />

10024] (0025] or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula Ila.

10026] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0035.tif" />

R⁵

R⁵

X—Y or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula Ila.

[0027] Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0036.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula Ila.

[0028] Another embodiment includes the compound of formula Ila selected from the group consisting of:

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<img file="CA2974477C_D0037.tif" />

CA 2974477 2017-07-21

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PCT/US2008/074353

<img file="CA2974477C_D0038.tif" />

F O-N ₀ , F οΝ ο

<img file="CA2974477C_D0039.tif" />

F Ο-Ν ο , F O-N Ο

<img file="CA2974477C_D0040.tif" />

<img file="CA2974477C_D0041.tif" />

<img file="CA2974477C_D0042.tif" />

<img file="CA2974477C_D0043.tif" />

<img file="CA2974477C_D0044.tif" />

<img file="CA2974477C_D0045.tif" />

<img file="CA2974477C_D0046.tif" />

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<img file="CA2974477C_D0047.tif" />

<img file="CA2974477C_D0048.tif" />

<img file="CA2974477C_D0049.tif" />

<img file="CA2974477C_D0050.tif" />

<img file="CA2974477C_D0051.tif" />

F O'N o F O-N O

<img file="CA2974477C_D0052.tif" />

<img file="CA2974477C_D0053.tif" />

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<img file="CA2974477C_D0054.tif" />

<img file="CA2974477C_D0055.tif" />

<img file="CA2974477C_D0056.tif" />

<img file="CA2974477C_D0057.tif" />

<img file="CA2974477C_D0058.tif" />

<img file="CA2974477C_D0059.tif" />

<img file="CA2974477C_D0060.tif" />

<img file="CA2974477C_D0061.tif" />

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<img file="CA2974477C_D0062.tif" />

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PCT7US2008/074353

<img file="CA2974477C_D0063.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof.

10029) Another embodiment includes the compound of formula I having the formula Id:

-21CA 2974477 2017-07-21

<img file="CA2974477C_D0064.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof wherein:

R¹ is H (hydrogen), or is selected from the group consisting of aryl and (Cp C₆)alkyl, each optionally substituted with one or more Rhi each Rb is independently selected from the group consisting of halo, cyano, nitro, --C(O)OH, (Ci-Ce)alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_r.OH, (Ci-C₆)alkoxy, halo(C_rC₆)alkoxy, (CpC₆)alkyiC(O)—, (C_rC₆)aIkylOC(O)—, and (C_rC6)alkylC(O)O—;

A¹ is N (nitrogen), or CR²;

R²is H (hydrogen), (Ci-C«)alkyl, aryl(CpC₆)alkyl, (C₂-C6)alkenyl, (C₂Cé)alkynyl, or aryl optionally substituted with one or more halo;

A² and A³ are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is O;

Z , Z, and Z are each independently is 0 (oxygen), N (nitrogen), S (sulfur), or CR⁵ with the proviso that at least one of Z¹, Z², and Z³ is not CR⁵;

Z² is 0, N (nitrogen), S (sulfur), or CR^S;

Z³ is Ο, N (nitrogen), S (sulfur), or CR⁵;

each R⁵ is independently H (hydrogen), (CpC₆)alkyl, —NRjRj, —C(O)NR|Rj, or aryl(Ci-C_é)alky!;

each R⁴ is independently selected from the group consisting of hydrogen, —OH, (CpC«)alkyl, (C₂-C₆)alkenyl, (CrC₆)alkynyl, (CpQjalkanoyl, (Cp C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl, —(CH₂)_n(C₃-C₈)cycloalkyl, heteroaryl, aryl,

-22CA 2974477 2017-07-21 aryl(C)-C6)alkyl, heterocycle, hetero cycle(Ci-C₆)alkyI, hctcrocyclefCj-Côjalkanoyl and NR_aRt&gt;; each optionally substituted with one or more R^;

each R_a and R_b is independently hydrogen or (Ci-C₆)alkyl, or R, and R&amp; are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Ci-Ce alkyl groups;

each R«j is independently halo, cyano, nitro, oxo, RfRgN(Ci-C₆)alkyl, —(CH₂)_nNR_fRg, -&lt;(O)NRfRj, —NR/XOJRg, arylCXOJNRfRg, —C(O)OH, (CjC*)alkyl, (Cj-Cgjcycloalkyl, —(CH₂)nOH, (C|-Ce)alkoxy, halo(C]-C6)alkoxy, (C|Cô)alkylC(O)—, (C|-C6)alkylOC(O)—, (Cj-C6)alkylC(O)O—, heterocycle, aryl, heterocycle(Ci-C6)alkyl, aryliCj-C^alkyl, —NReSCOj/Ci-CeJalkyl, -NReS(0)₂aryl, --NR_tC(O)NR_fR_g, -NReC(O)OR_f, or —OC(O)NR^;

each n is independently an integer selected from 0,1, and 2;

each z is independently an integer selected from 0,1, and 2;

each Re is independently hydrogen, (Ci-Qalkyl, aryl or heteroaryl;

each Rf and Rg is independently hydrogen, (Cj-Côjalkyl, aryl or heteroaryl, or R_f and Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), S(O)_Z, and NR&lt; wherein each ring system is optionally substituted with one or more R_q;

each Rq is independently halo, cyano, nitro, oxo, RiRjN(C]-C₆)aIkyl, —(CHj/nNRjRj, —C(O)NR(Rj, —NR_kC(O)Rj, arylC(O)NRjRj, —C(O)OH, (C_rC₆)alkyl, (C₃-C₈)cycloalkyl, -(CH₂)_nOH, (Ci-C₆)alkoxy, haIo(Ci-C₆)alkoxy, (0,Ce)alkylC(O) , (C]-C6)alkylOC(O)—, (C|-C6)alkylC(O)O—, heterocycle, aryl, heterocycle(Ci-C₆)alkyl, aryXCi-Qalkyl, —NR^OVCrC^alkyl, —NRkSiO^ryl, —NRkQOjNRjRj, —NR_kC(O)ORi, or -OC(O)NRiRj;

each R_k is independently hydrogen, (C|-C₆)alkyl, aryl or heteroaryl; each Rj and Rj is independently hydrogen, (C₍ -C₆)alkyl, aryl or heteroaryl; and

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PCT/US2008/074353 the dashed line represents an optional double bond wherein the ring comprising A¹, A², and A³ is heteroaromatic and the ring comprising Z¹, Z², and Z³ is hctcroaromatic.

(0030] in some embodiments Z¹ can be O (oxygen), N (nitrogen) or S (sulfur). In some embodiments Z² can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵. In some embodiments Z³ can be O (oxygen), N (nitrogen) S (sulfur), or CR⁵. In a typical embodiment, Z* can be S (sulfur), Z² can be CR⁵ and Z³ can be CR^S. Another embodiment includes the compound of formula Id, wherein each R_b can be halo, cyano, nitro, -OH, or (Ci-Côjaikyl. In some embodiments R_k can be fluoro.

(0031] Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0065.tif" />

(0032] or a pharmaceutically acceptable salt or prodrug ester thereof, |0033] wherein the variables are defined according to the definitions for the compound of formula la.

|0034] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0066.tif" />

O or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula Id.

-24CA 2974477 2017-07-21

[0035] Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0067.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula Id.

[0036] Another embodiment includes the compound of formula I having the formula le:

<img file="CA2974477C_D0068.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein:

R¹ is H (hydrogen), or is selected from the group consisting of (C|-C₆)alkyl and aryl, each optionally substituted with one or more R_b;

each Rfc is independently selected from the group consisting of halo, cyano, nitro, —C(O)OH, (Q-C^alkyl, (C₃-C₈)cycloalkyl, —(CH₂)_nOH, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-C₆)alkylC(O)—, (C| -C₆)alkylOC(O)—, and (CjC₆)alkylC(O)O—;

A¹ is N (nitrogen), or CR²;

R²is H (hydrogen), (CrQalkyl, aryl(C_rC₆)alkyl, (Cz-Qalkenyl, (C₂C₆)alkynyl, or aryl optionally substituted with one or more halo;

3

A and A are each independently 0 (oxygen) or N (nitrogen) with the proviso that when A² is 0, A³ is N and when A² is N, A³ is O;

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Z¹ is N (nitrogen), or CR⁵;

Z² is N (nitrogen), or CR⁵;

Z³ is N (nitrogen), or CR⁵;

Z⁴ is N (nitrogen), or CR⁵;

each R⁵ is independently H, (Ci-Cé)alkyl, -NR₍Rj, -C(O)NR,Rj, or aryl(C|-Cé)alkyl;

X is -C(=O)-, -C(=S)-, -C(R⁴)₂-, or -S(O)_X-;

each n is independently an integer selected from 0,1, and 2;

each i is independently an integer selected from 0,1, and 2;

Y is R⁴, -N(R⁴)2, -OR⁴, -SR⁴, or -C(R⁴)3, each optionally substituted with one or more R&lt;j;

each R⁴ is independently selected from the group consisting of hydrogen, -OH, (C|-Cg)alkyl, (C2-C6)alkenyl, (Q-C^alkynyl, (Ci-C^jalkanoyl, (C|Cf,)alkoxycarbonyl, (G-Csjcycioalkyl, -(CH2)n(C3-Cs)cycloalkyl, heteroaryl, aryl, aryl(C|-Cô)alkyl, heterocycle, heterocycle(C|-C6)alkyl, heterocycle(C]C(,)alkanoyl and NR,Rt,; or when Y is -N(R⁴)2, then two R⁴ groups arc optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from O (oxygen), S(O)_Z, and NR&lt; wherein each ring system is optionally substituted with one or more R^;

each R, and R_b is independently hydrogen or (C)-C_b)alkyl, or R, and R_bare optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more Cι-C «alkyl groups;

each Rc is independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, aryl, heteroaryl, (Ci-C₆)alkylsulfonyl, arylsulfonyl, (C_rC₆)alkylC(O)-, arylC(O)-, hydroxy(C|-C₆)alkyl, alkoxy(C|-C₆)alkyl, heterocycle, (C|-Cf,)alkylOC(O)-, (Ci-C^alkylaminocarbonyl, and arylaminocarbonyl;

-26CA 2974477 2017-07-21 each Rd is independently halo, cyano, nitro, oxo, RjRgN(C|-C(5)alkyl, —(CHo^NRfRg, —C(O)NRfRg, —NR,C(O)Rg, aryiC(O)NRfRg, —C(O)OH, (C_rC₆)alkyi, (C₃-Cg)cycloalkyl, —(CH₂)_nOH, (Cj-Qjalkoxy, halo(C|-Cô)alkoxy, (CiQjalkylQO)—, (Ci-C6)alkylOC(O)—, (Ci-C6)alkylC(O)O—, heterocycle, aryi, hetaocycle(Ci-C6)alkyl, aryKCi-C^alkyl, -WiOMQ-Cejalkyl, —NReS(O)_zaryl, —NR&lt;C(O)NRfRg, —NReC(O)ORf, or—OC(O)NRfRg;

each R« is independently hydrogen, (Cj-C₆)alkyl, aryl or heteroaiyl; each Rf and Rg is independently hydrogen, (C i-QJalkyl, aryl or heteroaryl, or Rf and Rg are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from 0 (oxygen), 8(0)^ and NR&lt; wherein each ring system is optionally substituted with one or more R^;

each Rq is independently halo, cyano, nitro, oxo, RjRjN(C|-C6)a!kyl, HCH₂)_nNR_iR_J, -C(O)NRjRj, —NRkC(O)Rj, aryiQOjNRfRj, -C(O)OH, (C_rCé)alkyl, (C₃-C$)cycloalkyl, —(CH₂)_nOH, (Cj-CéJalkoxy, halo(Ci-C6)alkoxy, (C_rC6)alkyiC(0)—, (Cj-Cé)alkylOC(O)—, (Cj-C6)alkylC(0)0—, heterocycle, aryl, beterocycle(Ci-C6)alkyl, aryl(C_rC₆)alkyl, —NR^OUCrQjalkyl, -NR_kS(O)_zaiyl, —NR_kC(O)NRjRj, -NR_kC(O)ORi, or-OC(0)NRjRj;

each R_k is independently hydrogen, (C]-C₆)alkyl, aryl or heteroaryl; each Rj and R, is independently hydrogen, (Cj-C₆)alkyl, aryl or hetcroaryl; and the dashed line represents an optional double bond wherein the ring

J comprising A , A, and A is heteroaromatic and the ring comprising Z¹, Z², Z³ and Z is aromatic or heteroaromatic with the proviso that the compound of Formula le is not selected from the group consisting of:

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<img file="CA2974477C_D0069.tif" />

<img file="CA2974477C_D0070.tif" />

O-N

<img file="CA2974477C_D0071.tif" />

N

<img file="CA2974477C_D0072.tif" />

O-N

<img file="CA2974477C_D0073.tif" />

O-N

<img file="CA2974477C_D0074.tif" />

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[0037] Another embodiment includes the compound of formula le wherein Z¹, Z², Z³ and Z⁴ can each be CR⁵. Another embodiment includes the compound of formula le wherein Y can be -N(R⁴h- Another embodiment includes the compound of formula le wherein Z¹, Z², Z³ and Z⁴ can each be CR⁵ and Y can be -N(R⁴)2- Another embodiment includes the compound of formula le, wherein each Rh can be halo, cyano, nitro, -OH, or (Ci-C6)alkyl. In some embodiments R_k can be fluoro.

[0038] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0075.tif" />

R⁵ or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula le.

[0039] Another embodiment includes the compound of formula le selected from the group consisting of

<img file="CA2974477C_D0076.tif" />

<img file="CA2974477C_D0077.tif" />

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PC17liS2008/(l74353

<img file="CA2974477C_D0078.tif" />

<img file="CA2974477C_D0079.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof {0040] Another embodiment includes a compound having the formula:

R¹

<img file="CA2974477C_D0080.tif" />

R⁵ or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula le. In some embodiments, Y can be -N(R⁴)₂ and X can be -C(=O)-. In some embodiments, R* can be CF3 and A¹ can be CR².

(00411 Another embodiment includes the compound of formula le, wherein Z¹, Z², Z³ and Z⁴ can each be CR⁵, Y can be -N(R⁴)2, and X can be -C(=O)-. Another embodiment includes the compound of formula le, wherein Y can be -C(R⁴)3 and X can be -C(=O)~. Another embodiment includes the compound of formula le wherein Y can be -C(R⁴)3, X can be -C(=O)- and Z¹, Z², Z³ and Z⁴ can each be CR⁵.

-30CA 2S74477 2017-07-21

[0042] Another embodiment includes a compound having the formula:

<img file="CA2974477C_D0081.tif" />

or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variables are defined according to the definitions for the compound of formula le.

[0043] One embodiment of the invention provides a pharmaceutical composition comprising:

a) the compound of any of the embodiments and examples disclosed herein; and

b) a pharmaceutically acceptable carrier.

10044] The present embodiments provide for a method of preparing a pharmaceutically acceptable salt of the compound of any of the embodiments and examples disclosed herein, comprising:

a) deprotecting a corresponding compound that comprises one or more protecting groups to provide the compound; and

b) forming a pharmaceutically acceptable salt from the compound.

[0045] The present embodiments provide for a method of inhibiting one or more monoamine oxidase (MAO) enzymes in an animal comprising administering to the animal an effective amount of a compound of any of the embodiments and examples disclosed herein. The present embodiments provide for a pharmaceutical composition comprising a compound of any of the embodiments and examples disclosed herein and a pharmaceutically acceptable earner for inhibiting one or more monoamine oxidase (MAO) enzymes in an animal.'ln some embodiments, the animal is a healthy animal. In some embodiments, the animal is an aged animal.

-31CA 2974477 2017-07-21

[0046] The present embodiments provide for a method for improving cognitive function in an animal in need of such treatment comprising administering to the animal an effective amount of a compound of any of the embodiments and examples disclosed herein. The present embodiments provide for a pharmaceutical composition comprising a compound of any of the embodiments and examples disclosed herein and a pharmaceutically acceptable carrier for improving cognitive function in an animal in need of such treatment. In some embodiments, the animal can be a healthy animal. In some embodiments, the animal can be an aged animal.

|0047J The present embodiments provide for a method for activating the CREB pathway in an animal in need of such treatment, comprising administering to the animal an effective amount of a compound of compound of any of the embodiments and examples disclosed herein.

(0048) The present embodiments provide for a method for treating ageassociated memory impairment, mild cognitive impairment, Alzheimer’s disease or Parkinson’s disease in an animal in need of such treatment comprising administering to the animal an effective amount of a compound of any of the embodiments and examples disclosed herein. The present embodiments provide for a pharmaceutical composition comprising a compound of any of the embodiments and examples disclosed herein and a pharmaceutically acceptable carrier for treating age-associated memory impairment, mild cognitive impairment, Alzheimer’s disease or Parkinson’s disease in an animal in need of such treatment. In some embodiments, the animal can have a psychiatric disorder. In some embodiments, the psychiatric disorder can be a psychotic disorder, a neurological disorder, or a neurotic disorder. In the some embodiments, the psychotic disorder can be schizophrenia. In some embodiments, the animal can have a disorder of the central nervous system. In some embodiments, the animal can have head trauma, brain trauma, or cerebrovascular disease. In some embodiments, the cerebrovascular disease can be vascular dementia. In some embodiments, the animal can have attention deficit disorder. In some embodiments, the animal has an affective disorder the cerebrovascular disease is vascular dementia the mild cognitive impairment is associated with depression.

-32CA 2574477 2017-07-21 (0049] The present embodiments provide for a method for treating a psychiatric disorder in an animal comprising administering to an animal in need thereof an effective amount of of a compound of any of the embodiments and examples disclosed herein. The present embodiments provide for a pharmaceutical composition comprising a compound of any of the embodiments and examples disclosed herein and a pharmaceutically acceptable carrier for treating a psychiatric disorder in an animal. In some embodiments, the psychiatric disorder can be a disorder of the central nervous system. In some embodiments, the disorder of the central nervous system can be age-associated memory impairment, mild cognitive impairment, Alzheimer’s disease or Parkinson’s disease. In some embodiments, the psychiatric disorder can be associated with head trauma, brain trauma or cerebrovascular disease. In some embodiments, the psychiatric disorder can be attention deficit disorder. In some embodiments, the psychiatric disorder can be an affective disorder. In some embodiments, the cerebrovascular disease can be vascular dementia. In some embodiments, the psychiatric disorder can be depression.

(0050J The present embodiments provide for a use of a compound of any of compound of any of the embodiments and examples disclosed herein, or a pharmaceutically acceptable salt or prodrug ester thereof for the manufacture of a medicament useful for improving cognitive function in an animal. The present embodiments provide for a use of an effective amount of a compound of any of the embodiments and examples disclosed herein, or a pharmaceutically acceptable salt or prodrug ester thereof, for improving cognitive function in an animal.

10051 ] The present embodiments provide for a use of a compound of any of the embodiments and examples disclosed herein, or a phannaceutically acceptable salt or prodnig ester thereof, for the manufacture of a medicament useful for inhibiting MAO receptors in an animal. The present embodiments provide for a use of an effective amount of a compound of any of th. embodiments and examples disclosed herein, or a pharmaceutically acceptable salt or prodrug ester thereof, for inhibiting MAO receptors in an animal.

100521 The present embodiments provide for a use of a compound of any of the embodiments and examples disclosed herein, or a phannaceutically acceptable salt or prodrug ester thereof, for the manufacture of a medicament useful for activating the CREB pathway in an animal.

-33CA 2974477 2017-07-21 (0053] The present embodiments provide for a use of a compound of any of the embodiments and examples disclosed herein, or a pharmaceutically acceptable salt or prodrug ester thereof, for the manufacture of a medicament useful for treating a psychiatric disorder in an animal. The present embodiments provide for a use of an effective amount of a compound of any of the embodiments and examples disclosed herein, or a pharmaceutically acceptable salt or prodrug ester thereof, for treating a psychiatric disorder in an animal.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

<td> [0054]</td><td colspan="2"> As used herein, common organic abbreviations are defined as follows:</td>

<td> [0055]</td><td> Ac</td><td> Acetyl</td>

<td> [0056]</td><td> aq.</td><td> Aqueous</td>

<td> 10057]</td><td> Bu</td><td> n-Butyl</td>

<td> (0058]</td><td> cat.</td><td> Catalytic</td>

<td> (0059]</td><td> CDI</td><td> 1, Γ-carbonyldiimidazole</td>

<td> [0060]</td><td> °C</td><td> Temperature in degrees Centigrade</td>

<td> [0061]</td><td> Dowtherm®</td><td> eutectic mixture of diphenyl ether and biphenyl</td>

<td> [0062]</td><td> DBN</td><td> 1,5-Diazabicyclo[4.3.0]non-5-ene</td>

<td> 10063]</td><td> DBU</td><td> 1,8-Diazabicyclo[5.4.0]undec-7-ene</td>

<td> [0064]</td><td> DIEA</td><td> Diisopropylethylamine</td>

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<td> [0065]</td><td> DMA</td><td> Dimethylacetamide</td>

<td> [0066]</td><td> DMF</td><td> N.N’-Dimethylfbrmamidc</td>

<td> [0067]</td><td> DMSO</td><td> Dimethylsulfoxide</td>

<td> |0068]</td><td> Et</td><td> Ethyl</td>

<td> [0069]</td><td> g</td><td> Gram(s)</td>

<td> [00701</td><td> h</td><td> Hour (hours)</td>

<td> |0071]</td><td> HPLC</td><td> High performance liquid chromatography</td>

<td> [0072]</td><td> iPr or isopr</td><td> Isopropyl</td>

<td> [00731</td><td> LCMS</td><td> Liquid chromatography-mass spectrometry</td>

<td> |0074|</td><td> Me</td><td> Methyl</td>

<td> [0075]</td><td> MeOH</td><td> Methanol</td>

<td> 10076]</td><td> mL</td><td> Milliliter(s)</td>

<td> [00771</td><td> Pd/C</td><td> Palladium on activated carbon</td>

<td> |0078]</td><td> ppt</td><td> Precipitate</td>

<td> [0079]</td><td> rt</td><td> Room temperature</td>

<td> [0080]</td><td> TEA</td><td> Tricthylamine</td>

<td> [0081)</td><td> Tert, t</td><td> tertiary</td>

<td> [0082]</td><td> THF</td><td> tetrahydrofùran</td>

<td> |0083|</td><td> pL</td><td> Microliterfs)</td>

<td> [0084)</td><td> The term “halo”</td><td> used herein refers to fluoro, chloro, bromo, or iodo.</td>

As used herein, the term “alkyl” refers to an aliphatic hydrocarbon group. The alkyl moiety may or may not be a saturated alkyl” group, i.e., one that does not contain any alkene or alkyne moieties. An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety may be branched, straight chain, or cyclic. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and the like. Examples of cycloalkyl groups

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PCTYUS2008/074353 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

|0085] The term “alkoxy” used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an -O-- linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.

|0086] The term “alkoxycarbonyl” used herein refers to an alkoxy radical covalently bonded to the parent molecule through a carbonyl linkage. Examples of alkoxycarbonyl groups include, but are not limited to, methylOC(O)-, ethylOC(O)-, propylOC(O)-, isopropylOC(O)-, butylOC(O)-, n-butylOC(O)-, sec-butylOC(O)-, tbutylOC(O)- and the like.

|00871 The term “alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1 -propenyl, 1butenyl, 2-butenyI, and the like.

|0088| The term “alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like.

(0089] The term “aryl” used herein refers to homocyclic aromatic radical whether one ring or multiple fused rings. Moreover, the term “aryl” includes fused ring systems wherein at least two aryl rings, or at least one aryl and an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic share at least one chemical bond. Examples of “aryl” rings include, but are not limited to, optionally substituted phenyl, biphenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

|0090] The term, “heterocycle” or “heterocycle group” used herein refers to an optionally substituted monocyclic, bicyclic, or tricyclic ring system comprising at least one heteroatom in the ring system backbone. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. The term, “heterocycle” includes multiple fused ring systems. Moreover, the term “heterocycle” includes fused ring systems that may have

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PCT/US2008/074353 any degree of saturation provided that at least one ring in the ring system is not aromatic. The monocyclic, bicyclic, or tricyclic ring system may be substituted or unsubstituted, and can be attached to other groups via any available valence, preferably any available carbon or nitrogen. Preferred monocyclic ring systems are of 3 to 8 members. Six membered monocyclic rings contain from up to three heteroatoms wherein each hctcroatom is individually selected from oxygen, sulfur, and nitrogen, and wherein when the ring is five membered, preferably it has one or two heteroatoms wherein each heteroatom is individually selected from oxygen, sulfur, and nitrogen. Preferred bicyclic cyclic ring systems are of 7 to 12 members and include spirocycles. An example of an optional substituent includes, but is not limited to, oxo (=0).

|0091| The term “hetcroaryl” used herein refers to an aromatic heterocyclic group, whether one ring or multiple fused rings. In fused ring systems, the one or more heteroatoms may be present in only one of the rings, or in two or more rings. Examples of heteroaryl groups include, but are not limited to, benzolhiazyl, benzoxazyl, quinazolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyridyl, pyrrolyl, oxazolyl, indolyl, thienyl, and the like. The term “heterocycle” encompasses heteroaryl fused to a nonaromatic ring system.

[0092] The term “heteroatom” used herein refers to, for example, O (oxygen), S (sulfur) and N (nitrogen).

|0093] The term “heteroatom group” used herein refers to a radical containing a “heteroatom” optionally substituted with a substituent. I he “heteroatom group” is covalently bonded to the parent molecule through the “heteroatom.” Examples of a “heteroatom group” includes, but is not limited to, O (oxygen), S (sulfur), S(O), S(O)2, ΝΉ and N (nitrogen) substituted with a group selected from, but arc not limited to, (Cr C₆)alkyl, aryl, heteroaryl, (C|-C₆)alkylsulfonyl, arylsulfonyl, (C_t-C6)alkylC(O)-, arylC(O)-, hydroxy(Ci-C6)alkyl, alkoxy(C|-C6)alkyl, heterocycle, (Ci-Cé)alkylOC(O)-, (Ci-Céjalkylaminocarbonyl, and arylaminocarbonyi. When the “heteroatom group” is incorporated as a part of a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each “hctcroatom” within the “hctcroatom group” is covalently bonded twice as part of the ring system. For example, when O (oxygen) is incorporated in a ring system,

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PCT/US2008/074353 the oxygen is covalently bonded twice to provide an ether type linkage, this type of ring system includes, but is not limited to, morpholinyl and the like. In another example, when N (nitrogen) substituted with (C|-C&amp;)alkyl is incorporated in a ring system, the nitrogen is covalently bonded twice to provide an amine type linkage, this type of ring system includes, but is not limited to, N-methylpiperazinyl, N-ethylpiperazinyl, Npropylpiperazinyl, N-2-propylpiperazinyl, N-butylpiperazinyl, N-2-butylpiperazinyl, Npentylpiperazinyl, N-hexylpiperazinyl, and the like. In some embodiments, a “heteroatom group” can be a “hetcroatom.” In other embodiments, a “heteroatom group” is a “heteroatom” with a substituent, for example the substituent can be another heteroatom or a group as disclosed herein.

(0094] The term “amino” used herein refers to a nitrogen radical substituted with hydrogen, alky), aryl, or combinations thereof. Examples of amino groups include, but are not limited to, -NHMethyl, -NH₂, -NMcthyh, -NPhenylMcthyl, -NHPhenyl, -NEthylMethyl, and the like. An “alkylamino” refers to a nitrogen radical substituted with at least one alkyl group. Examples of alkylamino groups include, but are not limited to, -NHMethyl, -NMethyh, -NPropylMethyl, -NHButyl, -NEthylMethyl, -NPhenylMethyl, and the like. An “arylamino” refers to a nitrogen radical substituted with at least one aryl group. Examples of alkylamino groups include, but are not limited to, -NPhenylMethyl, -NHPhenyl, and the like.

(0095] The term “alkylaminocarbonyl” used herein refers to an alkylamino radical covalently bonded to the parent molecule through the carbon of a “carbonyl” group. Examples of alkylaminocarbonyl groups include, but are not limited to, -C(O)NHMethyl, -C(O)NMethyl₂, -C(O)NPropyIMethyl, -C(O)NHButyl, -C(O)NEthylMethyl, -C(O)NPhenylMethyl, and the like.

(0096] The term “arylaminocarbonyl” used herein refers to an alkylamino radical covalently bonded to the parent molecule through the carbon of a “carbonyl” group. Examples of arylaminocarbonyl groups include, but are not limited to, -C(O)NPhenylMethyl, -C(O)NHPhenyl, and the like.

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[0097] The term “arylalkyl” used herein refers to one or more aryl groups appended to an alkyl radical. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, phenpropyl, phenbutyl, and the like.

10098] The term “heteroaryl alkyl” used herein refers to one or more heteroary) groups appended to an alkyl radical. Examples of heteroary)alkyl include, but are not limited to, pyridylmethyl, furanylmethyl, thiopheneylethyl, and the like.

(0099] The term “aryloxy” used herein refers to an aryl radical covalently bonded to the parent molecule through an -O- linkage.

[0100] The term “alkylthio” used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an --S-- linkage. Examples of alkylthio groups include, but are not limited to, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, cyclopropylsulfanyl, butylsulfanyl, nbutylsulfanyl, sec-butyl sulfanyl, t-butylsulfanyl, cyclobutyl sulfanyl and the like.

[0101] The term “alkylsulfonyl” used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an --S- linkage where the sulfur is substituted with two oxygen atoms. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, butylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl, cyclobutylsulfonyl and the like.

(0102] The term “arylsulfonyl” used herein refers to optionally substituted aryl radical covalently bonded to the parent molecule through an -S-- linkage where the sulfur is substituted with two oxygen atoms. Examples of optionally substituted arylsulfonyl groups include, but are not limited to, phenylsulfonyl, trifluoromethylphenylsulfonyl, methoxyphenylsulfonyl, methylphenylsulfonyl, cyanophenylsulfonyl, fluorophenylsulfonyl, chlorophenylsulfonyl, bromophenylsulfonyl, biphenylsulfonyl, naphthalenyl.su) fonyl, phenanthrenylsulfonyl, anthracenylsulfonyl, tetralinylsulfonyl, fluorenylsulfonyl, indenylsulfonyl, and indanylsulfonyl propyl, isopropylsulfonyl, cyclopropylsulfonyl, butylsulfonyl, n-buty)sulfonyl, sec-butylsulfonyl, t-butylsulfonyl, cyclobutylsulfonyl and the like.

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PCT/US2008/074353 |0103] The term “carbonyl’’ used herein refers to OO (i.e. carbon double bonded to oxygen).

10104] The term “oxo” used herein refers to =0 (i.e. double bond to oxygen). For example, cyclohexane substituted with “oxo” is cyclohexanone.

[0105] The term “alkanoyl” used herein refers to a “carbonyl” substituted with an “alkyl” group, the “alkanoyl” group is covalently bonded to the parent molecule through the carbon of the “carbonyl” group. Examples of alkanoyl groups include, but are not limited to, methanoyl, ethanoyl, propanoyl, and the like. Methanoyl is commonly known as acetyl.

[0106] The term, “heterocyclealkanoyl” used herein refers to a “alkanoyl” substituted with an “heterocycle” group, the “heterocycle” group is covalently bonded to the parent molecule through the carbonyl of the “alkanoyl” group. Examples of heterocyclealkanoyl groups include, but are not limited to, 2-(piperidin-1 -yl)acetyl, 2(morpholin-4-yl)acetyl, 2-(pipera2in-l-yl)acetyl, 2-(4-methylpiperazin-l-yl)acetyl, 3(piperidin-l-yl)propanoyl, 3-(morpholin-4-yl)propanoyl, 3-(piperazin-l-yl)propanoyl, 3(4-methylpiperazin-l -yl)propanoyl, 3-(2,6-dimethylpiperidin-l -yl)propanoyl, 3-(3,5dimethy)morpholm-4-yl)propaooyl, 3-(pyrrolidin-1 -yl)propanoyl, 2-(pyrrolidin-1 yl)acetyl, 2-(azetidin-l-yl)acetyl, 3-(azetidin-l-yl)propanoyl, ethanoyl, propanoyl, and the like.

[0107] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.” ,0108] As used herein, a substituted group is derived from the unsubstituted parent structure in which there has been an exchange of one or more hydrogen atoms for another atom or group.

[0109] Asymmetric carbon atoms may be present in the compounds described. All such isomers, including diastereomers and enantiomers, as well as the mixtures thereof arc intended to be included in the scope of the recited compound. In certain cases,

-39CA 2974477 2017-07-21 compounds can exist in tautomeric forms. All tautomeric forms are intended to be included in the scope. Likewise, when compounds contain an alkenyl or alkenylene group, there exists the possibility of cis- and trans- isomeric forms of the compounds. Both cis- and trans- isomers, as well as the mixtures of cis- and trans- isomers, are contemplated. Thus, reference herein to a compound includes all of the aforementioned isomeric forms unless the context clearly dictates otherwise.

[0110] Various forms are included in the embodiments, including polymorphs, solvates, hydrates, conformers, salts, and prodrug derivatives. A polymorph is a composition having the same chemical formula, but a different structure. A solvate is a composition formed by solvation (the combination of solvent molecules with molecules or ions of the solute). A hydrate is a compound formed by an incorporation of water. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond. Salts of compounds can be prepared by methods known to those skilled in the art. For example, salts of compounds can be prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compound.

[0111] The term “pro-drug ester” refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of pro-drug ester groups include, but are not limited to fatty acid esters, pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-Æ-2-oxo-l,3-dioxolen-4-yl)methyl group. Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and Bioreversible Carriers in Drug Design: Theory and Application, edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for compounds containing carboxyl groups).

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PCT/US2008/074353 |0112] Where a dashed line (—-) appears in a structure, the dashed line represents a bond that is optionally present (in accordance with the rules of valency), indicating, together with the single bond to which it is adjacent, either a single or double bond. A dashed line encircling the inside of a ring indicates that the ring is optionally aromatic or heteroaromatic.

|0113] The term “animal” as used herein includes birds, reptiles, and mammals (e.g. domesticated mammals and humans).

[0114] The terms “ individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.

(0115] The term ‘selectively inhibiting” as used herein means that a compound inhibits the activity of MAO-B to a greater extent than it inhibits the activity of MAO-A (in vitro or in vivo). In one embodiment of the invention, the compound of formula I inhibits the activity of MAO-B two times more than it inhibits the activity of MAO-A. In another embodiment of the invention, the compound of formula I inhibits the activity of MAO-B five times more than it inhibits the activity of MAO-A. In another embodiment of the invention, the compound of formula I inhibits the activity of MAO-B ten times more than it inhibits the activity of MAO-A. In another embodiment of the invention, the compound of formula I inhibits the activity of MAO-B one hundred times more than it inhibits the activity of MAO-A.

|0116] The term “psychiatric disorder” as used herein includes psychotic disorders, neurological disorders and neurotic disorders. The term includes schizophrenia, age-associated memory impairment (AAMI); mild cognitive impairment (MCI), delirium (acute confusional state); depression, dementia (sometimes further classified as Alzheimer’s or non-Alzheimer’s type dementia); Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (chorea); mental retardation; (e.g., RubensteinTaybi and Downs Syndrome), cerebrovascular disease (e.g., vascular dementia, postcardiac surgery); affective disorders; psychotic disorders; autism (Kanner’s Syndrome);

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PCT/US2V08/074353 neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal-pressure hydrocephalus; brain tumor; head trauma (postconcussional disorder) or brain trauma.

[0117] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, stereoisomeric, or regioisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine MAO-B inhibiting activity using the standard tests described herein, or using other similar tests which are well known in the art.

|0118| Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

|0119] For example, (Ci-C&amp;)alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, and the like; (CjC₆)alkenyl includes, but is not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, I,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2hexenyl, 3-hexenyl, 4-hcxeny], 5-hexenyl, and the like; (Cz-CeJalkynyl includes, but is not limited to, ethynyl, l-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5hexynyl, and the like; (Cj-Cf)cycloalkyl can be cyclopropyl, cyclobuty), cyclopentyl, cyclohexyl, and the like; (Cj-Cs)cycloaIkyl(CrC6)alkyl includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2cyclopropylethyl, 2-cycIobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, and the like; (C)-Ce)alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (Ci-Cé)alkyl optionally substituted with one or more cyano includes, but is not limited to, 2-cyanoethyl, 3

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PCT/US2008/074353 cyanopropyl, 2-cyanopropyl, 4-cyanobutyl, and the like; (C|-C6)alkylC(O)-includes, but is not limited to, acetyl, propanoyl butanoyl, and the like; (CrCô)alkyl optionally substituted with one or more halo includes, but is not limited to, iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like; (Ci-Cô)alkyl optionally substituted with one or more hydroxy includes, but is not limited to, hydroxymethyl, 2-hydroxycthyl, 2-hydroxypropyl, 2,4-hydroxybutyl, and the like; (C|-C6)alkylOC(O)-includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (Ci-C6)alkylC(O)O-includes, but is not limited to, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; (Ci-C6)alkoxy(CrCt)alkyl includes, but is not limited to, 2methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 3-ethoxypropyl, 4,4-dimethoxybutyl; (Ci-C6)alkylOC(OXC)-C6)alkyl includes, but is not limited to, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, or ethoxycarbonylethyl; aryl includes, but is not limited to, phenyl, indenyl, or naphthyl; and heteroaryl includes, but is not limited to, furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

10120] Processes for preparing compounds of formula I are provided as further embodiments of the invention and arc illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.

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[0121] Compounds of formula I can be prepared using the general synthetic schemes illustrated below.

Scheme 1

<img file="CA2974477C_D0082.tif" />

a. (COCI)j. Toluene. DMF «1

b. THF. TEA. R^R/IH

<img file="CA2974477C_D0083.tif" />

CFjCfOOEl NaOMe

Tobene, 3040 C

<img file="CA2974477C_D0084.tif" />

a Hydroxytenwte nyûroctuonde

HOAc. 80 90 C

6. TFA. reflux

<img file="CA2974477C_D0085.tif" />

HaH. DMF Rpt 60 C

<img file="CA2974477C_D0086.tif" />

HOAc. 80-90 C

Hydroxylamine hyùrocNonoe

<img file="CA2974477C_D0087.tif" />

|0122| The thienyl carboxylic acid can be converted to an intermediate acid chloride followed by coupling with an appropriate amine to provide the desired product. The thienyl carboxylic acid can be treated with an appropriate chlorinating agent, with or without solvent, to provide an intermediate acid chloride which can be isolated or treated directly to provide the desired product The thienyl carboxylic acid can be converted to an acid chloride using a chlorinating agent in the presence of solvent or neat. For example, the chlorinating agent can be selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosgene and phosgene equivalents, and the like. The solvent can be selected from methylene chloride, chloroform, benzene, toluene and the like. In a representative example, oxalyl chloride in the presence of catalytic DMF can convert the thienyl carboxylic acid to an acid chloride with toluene as the solvent.

[0123J The intermediate acid chloride can then be reacted with an amine in an appropriate solvent optionally in the presence of a base to provide the desired product. The solvent can be selected from methylene chloride, chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like. The base can be selected from triethylamine, diisopropylethyl amine, DBU, DBN, DMAP, pyridine, and the like and combinations

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PCT/US20Û8/074353 thereof. In a representative example, the acid chloride can react with the appropriate amine in the presence of THF and triethylamine as a base to provide the desired product.

[0124) The amide can be condensed with ethyl tri fluoroacetate in the presence of solvent and a base to provide a β-diketone. The solvent can be selected from methylene chloride, DMF, NMP, toluene and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide. potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like. In a representative example, the amide can react with ethyl tri fluoroacetate in the presence of toluene and sodium ethoxide to provide the desired β-diketone.

[0125) The β-diketone can be converted to the isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent, optionally, an additional step of refluxing with trifluoroacetic acid may be advantageous to complete the conversion. In a representative example, the β-diketone can react with hydroxylamine hydrochloride in the presence of acetic acid followed by reacting in the presence of tri fluoroacetic acid at reflux to provide the desired isoxazole. In some embodiments a mixture of regioisomcric isoxazoles may form.

[0126| Alternatively, the β-diketone can be substituted at the α-position by an alkylation then converted to the isoxazole. The β-diketone can be reacted with an alkylating agent in an appropriate solvent and base to provide an α-substituted βdiketone. The alkylating agent can be selected from an optionally substituted alkylhalide, an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like. In a representative example, the β-diketone can react with an alkylhalide in DMF with sodium hydride as the base.

[0127] The a-substituted β-diketone can be converted to the isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent. In a representative

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PCT/US2008/074353 example, the a-substituted β-diketone can react with hydroxylamine hydrochloride in the presence of acetic acid. In some embodiments a mixture of regioisomeric isoxazoles may form.

Scheme 2

<img file="CA2974477C_D0088.tif" />

<img file="CA2974477C_D0089.tif" />

CF_sC(O)O£t. NaOEt

Toluene, 30*40 C

<img file="CA2974477C_D0090.tif" />

NaH. DMF.Rpc.60C

EtOH, H,SO, (cone) reflux

<img file="CA2974477C_D0091.tif" />

HydroxytarTune hydrocNoode

HOAe, 80-90 C

<img file="CA2974477C_D0092.tif" />

R2

<img file="CA2974477C_D0093.tif" />

a (COO),. Toluene. DMF cal b R,R₄NH. TEA. THF

Of

EDC DMAP. R₄R₄NH, 01/¾

<img file="CA2974477C_D0094.tif" />

[0128] The thienyl carboxylic acid can be converted to an thienyl carboxylic ester by esterfication. For example the thienyl carboxylic acid can be converted to a thienyl carboxylic ester by treating the thienyl carboxylic acid with acid in the presence of an alcoholic solvent and heating. The acid can be hydrochloric acid, sulfuric acid and the like. The solvent can be methyl alcohol, ethyl alcohol, and the like. In a representative example, the thienyl carboxylic acid can react with ethyl alcohol at reflux in the presence of sulfuric acid to provide the thienyl carboxylic ester. The thienyl carboxylic ester can be condensed with ethyl tri fluoroacetate in the presence of solvent and a base to provide a β-diketone. The solvent can be selected from methylene chloride, DMF, NMP, toluene and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydnde, and the like. In a representative example, the ester can react with ethyl trifluoroacetate in the presence of toluene and sodium ethoxide to provide the desired β-diketone ester.

|0129] The β-diketone ester can be substituted at the α-position by an alkylation then converted to the isoxazole. The β-diketone ester can be reacted with an

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PCT/US2008/074353 alkylating agent in an appropriate solvent and base to provide an α-substituted βdiketone. The alkylating agent can be selected from an optionally substituted alkylhalide, an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like. In a representative example, the β-diketone ester can react with an alkylhalide in DMF with sodium hydride as the base at around 60 °C.

I0130J The a-subslituted β-diketone ester can be converted to the isoxazole by reacting with hydroxylaminc hydrochloride in an appropriate solvent. In a representative example, the a-substituted β-diketone ester can react with hydroxylaminc hydrochloride in the presence of acetic acid to provide the α-substituted isoxazole ester. The α-substituted isoxazole ester can be converted to the α-substituted isoxazole carboxylic acid by acid or base catalyzed hydrolysis. The base catalyzed hydrolysis can be accomplished treating the α-substituted isoxazole ester with a base in an appropriate solvent in the presence of water. The base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The solvent can be selected from, ethyl alcohol, methyl alcohol, THF, dioxane, DMF, NMP, and the like and combinations thereof. In a representative example, the ester in THF can be hydrolyzed by reacting with lithium hydroxide in the presence of water to provide an α-substituted isoxazole carboxylic acid.

|0131] The α-substituted isoxazole carboxylic acid can be converted to an intermediate acid chloride followed by coupling with an appropriate amine to provide the desired product. The α-subslituted isoxazole carboxylic acid can be treated with an appropriate chlorinating agent, with or without solvent, to provide an intermediate acid chloride which can be isolated or treated directly to provide the desired product. The asubstituted isoxazole carboxylic acid can be converted to an acid chloride using a chlorinating agent in the presence of solvent or neat. For example, the chlorinating agent can be selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus

-ΑΊ

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PCT/US2008/074353 oxychloride, phosgene and phosgene equivalents, and the like. The solvent can be selected from methylene chloride, chloroform, benzene, toluene and the like. In a representative example, oxalyl chloride in the presence of catalytic DMF can convert the α-substituted isoxazole carboxylic acid to an acid chloride with toluene as the solvent. The intermediate acid chloride can then be reacted with an amine in an appropriate solvent optionally in the presence of a base to provide the desired product. The solvent can be selected from methylene chloride, chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like. The base can be selected from triethylamine, diisopropylethyl amine, DBU, DBN, DMAP, pyridine, and the like and combinations thereof. In a representative example, the acid chloride can react with the appropriate amine in the presence of THF and triethylamine as a base to provide the desired product.

(0132] Alternatively, the α-substituted isoxazole carboxylic acid can be converted to the desired product using a coupling reaction. The α-substituted isoxazole carboxylic acid can be reacted with a coupling agent in the presence of a catalyst and the appropriate amine in the presence of a solvent to provide the desired product. The reaction can be optionally run in the presence of a base. The coupling agent can be selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), O-BenzotriazoleΝΛΛ ’Λ ’-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 0-(7-Azabenzotriazol-1 yl)-.V,A^'^''-ietramethyluroniurn hexafluorophosphate (HATU), O-(Bcnzotriazol-l-yl)ΝΛΛ'Λ'-tetramethyluroniurn tetrafluoroborate (TBTU), (Benzotriazol-1yloxy)tripynolidinophosphonium hexafluorophosphate (PyBOP), Bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP), and the like. The catalyst can be selected from DMAP, 1-hydroxy-benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt) and the like. The solvent can be selected from methylene chloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. The base can be selected from tricthylaminc, diisopropylethylaminc and the like. In a representative example, the α-substituted isoxazole carboxylic acid can react with the appropriate amine in the presence of methylene chloride using EDC as the coupling agent and DMAP as the catalyst.

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Scheme 3

<img file="CA2974477C_D0095.tif" />

CHF,C(0)OEI. N«OEt loluçne, 30-40 C

<img file="CA2974477C_D0096.tif" />

NeH. DMF

RpC.eOC

<img file="CA2974477C_D0097.tif" />

Hydroiytemine hyttochtonde

HOAc 80-90 C

<img file="CA2974477C_D0098.tif" />

<img file="CA2974477C_D0099.tif" />

<img file="CA2974477C_D0100.tif" />

a. (COCi).. Tobene. DMF cat.

b ÎHF. ItA. RANH

LOH. THF. H,0

<img file="CA2974477C_D0101.tif" />

|0133] The thienyl carboxylic ester can be condensed with ethyl difluoroacetate in the presence of solvent and a base to provide a β-diketone. The solvent can be selected from methylene chloride, DMF, NMP, toluene and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like. In a representative example, the ester can react with ethyl difluoroacetate in the presence of toluene and sodium ethoxide to provide the desired β-diketone ester.

(0134] The β-diketone ester can be substituted at the α-position by an alkylation then converted to the isoxazole. The β-diketone ester can be reacted with an alkylating agent in an appropriate solvent and base to provide an α-substituted βdiketone. The alkylating agent can be selected from an optionally substituted alkylhalide, an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium

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PCT/US2008/074353 hydride, and the like. In a representative example, the β-dikctonc ester can react with an alkyihalide in DMF with sodium hydride as the base at around 60 °C.

10135] The a-substituted β-diketone ester can be converted to the isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent. In a representative example, the a-substituted β-diketone ester can react with hydroxylamine hydrochloride in the presence of acetic acid to provide the α-substituted isoxazole ester. In some embodiments a mixture of regioisomeric isoxazoles may form. The regioisomeric isoxazoles may be separated and individually taken through the remaining steps or taken through the remaining steps as the mixture.

j0136] The α-substituted isoxazole ester can be converted to the a-substituted isoxazole carboxylic acid by acid or base catalyzed hydrolysis. The base catalyzed hydrolysis can be accomplished treating the α-substitutcd isoxazole ester with a base in an appropriate solvent in the presence of water. The base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The solvent can be selected from, ethyl alcohol, methyl alcohol, THF, dioxane, DMF, NMP, and the like and combinations thereof. In a representative example, the ester in THF can be hydrolyzed by reacting with lithium hydroxide in the presence of water to provide an a-substituted isoxazole carboxylic acid.

|0137| The α-substituted isoxazole carboxylic acid can be converted to an intermediate acid chloride followed by coupling with an appropriate amine to provide the desired product. The α-substituted isoxazole carboxylic acid can be treated with an appropriate chlorinating agent, with or without solvent, to provide an intermediate acid chloride which can be isolated or treated directly to provide the desired product. The asubstituted isoxazole carboxylic acid can be converted to an acid chloride using a chlorinating agent in the presence of solvent or neat. For example, the chlorinating agent can be selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosgene and phosgene equivalents, and the like. The solvent can be selected from methylene chloride, chloroform, benzene, toluene and the like. In a representative example, oxalyl chloride in the presence of catalytic DMF can convert the

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PCT/US2008/074353 α-substituted isoxazole carboxylic acid to an acid chloride with toluene as the solvent. The intermediate acid chloride can then be reacted with an amine in an appropriate solvent optionally in the presence of a base to provide the desired product. The solvent can be selected from methylene chloride, chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like. The base can be selected from triethylamine, diisopropylethyl amine, DBU, DBN, DMAP, pyridine, and the like and combinations thereof. In a representative example, the acid chloride can react with the appropriate amine in the presence of THF and triethylamine as a base to provide the desired product.

<img file="CA2974477C_D0102.tif" />

HOAc. 00*90 C

D TFA. reflux a Hydroxytomme hydrochloride

Scheme 4

<img file="CA2974477C_D0103.tif" />

R₄QO)Cf. Feci,

CHjCI,. reflux

<img file="CA2974477C_D0104.tif" />

<img file="CA2974477C_D0105.tif" />

NaH, OMF R.X.60C

<img file="CA2974477C_D0106.tif" />

Hydroxyiamine hyorocWonde

HOAc. 80-90 C

<img file="CA2974477C_D0107.tif" />

R₄qO)Cl. Fed,

CMjCij. relknr

<img file="CA2974477C_D0108.tif" />

[0138] The thienyl β-diketone can be converted to the thienyl isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent, optionally, an additional step of refluxing with tri fluoroacetic acid may be advantageous to complete the conversion. In a representative example, the β-diketone can react with hydroxylamine hydrochloride in the presence of acetic acid followed by reacting in the presence of trifluoroacetic acid at reflux to provide the desired thienyl isoxazole.

[0139| The thienyl isoxazole can undergo a Friedel-Crafts acylation reaction with an acid chloride and a Lewis acid in an appropriate solvent. The Lewis acid can selected from AICI3, TiCU, FeClj and the like. The solvent can be selected from methylene chloride, nitrobenzene carbon disulfide and the like. In a representative

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PCT/ÜS2008/Û74353 example, the thienyl isoxazole can react in methylene chloride with an acid chloride in the presence of FeClj under reflux to provide the desired product.

[0140] The thienyl β-diketone can be substituted at the α-position by an alkylation then converted to the isoxazole. The thienyl β-diketone can be reacted with an alkylating agent in an appropriate solvent and base to provide an α-substituted thienyl βdiketone. The alkylating agent can be selected from an optionally substituted alkylhalide, an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like. In a representative example, the thienyl β-diketone ester can react with an alkylhalide in DMF with sodium hydride as the base at about 60 °C.

(0141] The α-substituted thienyl β-diketone can be converted to the isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent. In a representative example, the «-substituted thienyl β-dikctonc can react with hydroxylamine hydrochloride in the presence of acetic acid to provide the «-substituted thienyl isoxazole.

(0142) The «-substituted thienyl isoxazole can undergo a Friedel-Crafts acylation reaction with an acid chloride and a Lewis acid in an appropriate solvent. The Lewis acid can selected from AICI3, T1CI4, FeCh and the like. The solvent can be selected from methylene chloride, nitrobenzene carbon disulfide and the like. In a representative example, the «-substituted thienyl isoxazole can react in methylene chloride with an acid chloride in the presence of FeClj under reflux to provide the desired «-substituted thienyl isoxazole ketone product.

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<img file="CA2974477C_D0109.tif" />

EtOH, HySO^. reflux

<img file="CA2974477C_D0110.tif" />

<img file="CA2974477C_D0111.tif" />

O

CFjC(O)OEl NaOEt

Toluene. 30'40 C

<img file="CA2974477C_D0112.tif" />

10143] 4-Acetylbenzoic acid can be converted to 4-acetylbenzoic ester by esterfication. For example the 4-acetylbenzoic acid can be converted to 4-acetylbenzoic ester by treating 4-acetylbenzoic acid with acid in the presence of an alcoholic solvent and heating. The acid can be hydrochloric acid, sulfuric acid and the like. The solvent can be methyl alcohol, ethyl alcohol, and the like. In a representative example, the 4acctylbcnzoic acid can react with ethyl alcohol at reflux in the presence of sulfuric acid to provide ethyl 4-acetylbenzoate.

[0144] The ethyl 4-acetylbenzoate can be condensed with a β-ketoester in the presence of solvent and a base to provide a β-diketone. The solvent can be selected from methylene chloride, DMF, NMP, toluene and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxidc, sodium hydride, potassium hydride, and the like. In a representative example, the amide can react with ethyl tri fluoroacetate in the presence of toluene and sodium ethoxide to provide the desired β-diketone ester.

|0145] The β-dikelone ester can be substituted at the α-position by an alkylation then converted to the isoxazole. The β-diketone ester can be reacted with an alkylating agent in an appropriate solvent and base to provide an α-substituted βdiketone. The alkylating agent can be selected from an optionally substituted alkylhalide,

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PCT/US2008/O74353 an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like.

[0146] If no substitution at the α-position is required, the β-diketone can be converted directly to the isoxazole by reacting with hydroxylamine hydrochloride in an appropriate solvent. Optionally, an additional step of refluxing with tri fluoroacetic acid may be advantageous to complete the conversion. In a representative example, the βdiketone can react with hydroxylamine hydrochloride in the presence of acetic acid followed by reacting in the presence of trifluoroacetic acid at reflux to provide the desired isoxazole benzoic ester. In some embodiments a mixture of regioisomeric isoxazole benzoic esters may form.

[0147] The isoxazole benzoic ester can be converted to the isoxazole benzoic acid by acid or base catalyzed hydrolysis. The base catalyzed hydrolysis can be accomplished treating the isoxazole benzoic ester with a base in an appropriate solvent in the presence of water. The base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The solvent can be selected from, ethyl alcohol, methyl alcohol, THF, dioxane, DMF, NMP, and (he like and combinations thereof. In a representative example, the isoxazole benzoic ester in THF can be hydrolyzed by reacting with lithium hydroxide in the presence of water to provide an isoxazole benzoic acid.

[0148) The isoxazole benzoic acid can be converted to an intermediate isoxazole benzoic Ν,Ο-dimethylamide (i.e. Wcinrcb amide) followed by an organometallic reaction to provide an isoxazole ketone.

[0149| The isoxazole benzoic acid can be can be converted to the isoxazole benzoic Ν,Ο-dimethylamide using a coupling reaction. The isoxazole benzoic acid can be reacted with a coupling agent in the presence of a catalyst and N,ODimethylhydroxylamine hydrochloride in the presence of a solvent to provide the desired product. The reaction can be optionally run in the presence of a base. The coupling agent

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PCT/DS2008/074353 can be selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethy)aminopropyl) carbodiimidc hydrochloride (EDC), O-BenzotnazoleΝ,Ν,Ν'Λ ’-tetramethyi-uronium-hexafluoro-phosphate (HBTU), 0-(7-Azabenzotriazol-1 yl)-N,N,N’,N'-tetramethyluronium hexafluorophosphate (HATU), O-(Benzotriazol-l-yl)Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTLI), (Benzotriazol-1yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), Bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP), and the like. The catalyst can be selected from DMAP, 1-hydroxy-benzotriazole (HOBt), I-hydroxy-7-azabenzotriazole (HOAt) and the like. The solvent can be selected from methylene chloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. The base can be selected from triethylainine, diisopropylethylamine and the like. In a representative example, the isoxazole benzoic acid can react with Ν,Ο-Dimcthylhydroxylaminc hydrochloride in the presence of methylene chloride using DCC as the coupling agent and DMAP as the catalyst to provide the isoxazole benzoic N,O-dimethylamide.

[0150| The isoxazole benzoic Ν,Ο-dimethylamide can react with an organometallic reagent in an appropriate solvent to provide a isoxazole phenylketone. The organometetallic reagent can be a Grignard reagent, alkyl zinc and the like. The solvent can be THF, dioxane, diethyl ether and the like. In a representative example, the isoxazole benzoic Ν,Ο-dimethylamide can react with a Grignard reagent in THF to provide an isoxazole phenylkelone.

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<img file="CA2974477C_D0113.tif" />

o

Scheme 6

NaH. DMF, Rp&lt;. «0 C

<img file="CA2974477C_D0114.tif" />

HyOroxylamne hydrocNonOe

HOAc. 80-9C C

<img file="CA2974477C_D0115.tif" />

LOH. THF. H,0

<img file="CA2974477C_D0116.tif" />

DCC. NH[Me)OMe

DMAP. CH_?CI₂

<img file="CA2974477C_D0117.tif" />

O-n

THF

R.MgX

<img file="CA2974477C_D0118.tif" />

[0151] T he β-diketone benzoic ester can be substituted at the α-position by an alkylation then converted to the isoxazole. The β-diketone benzoic ester can be reacted with an alkylating agent in an appropriate solvent and base to provide an α-substituted fldiketone benzoic ester. The alkylating agent can be selected from an optionally substituted alkylhalide, an optionally substituted alkylsulfonate and the like. The solvent can be selected from DMF, NMP, THF, dioxane, and the like and combinations thereof. The base can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like.

[0152] The a-substituted β-diketone benzoic ester can be converted to the asubstituted isoxazole benzoic ester by reacting with hydroxylamine hydrochloride in an appropriate solvent. In a representative example, the a-substituted β-diketone ester can react with hydroxylamine hydrochloride in the presence of acetic acid to provide the substituted isoxazole benzoic ester. In some embodiments a mixture of regioisomeric isoxazoles may form.

[0153) The substituted isoxazole benzoic ester can be converted to the substituted isoxazole benzoic acid by acid or base catalyzed hydrolysis. The base catalyzed hydrolysis can be accomplished treating the substituted isoxazole benzoic ester with a base in an appropriate solvent in the presence of water. The base can be selected

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PCT/US2008/074353 from sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The solvent can be selected from, ethyl alcohol, methyl alcohol, THF, dioxane, DMF, NMP, and the like and combinations thereof. In a representative example, the ester in THF can be hydrolyzed by reacting with lithium hydroxide in the presence of water to provide a substituted isoxazole benzoic acid.

(0154] The substituted isoxazole benzoic acid can be converted to an intermediate substituted isoxazole benzoic Ν,Ο-dimethylamide (i.e. Weinreb amide) followed by an organometallic reaction to provide a substituted isoxazole kelone.

(0155) The substituted isoxazole benzoic acid can be can be converted to the substituted isoxazole benzoic Ν,Ο-dimethylamide using a coupling reaction. The substituted isoxazole benzoic acid can be reacted with a coupling agent in the presence of a catalyst and Ν,Ο-dimethylhydroxylamine hydrochloride in the presence of a solvent to provide the desired product. The reaction can be optionally run in the presence of a base. The coupling agent can be selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide hydrochloride (EDC), phosphate (HBTU), (DIC), l-ethyl-3-(3-dimethylaininopropyl) carbodiiinide

O-Benzotnazolc-.'VA’A 'Λ ’-tctramethyl-uronium-hcxafluoro0-(7-Azabenzotriazol-1 -yl)-N,N,N',N’-tetramethyluronium hexafluorophosphate (H ATU), O-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), (Benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP), and the like. The catalyst can be selected from DMAP, 1-hydroxy-benzotriazole (HOBt), l-hydroxy-7-aza-benzotriazole (HOAt) and the like. The solvent can be selected from methylene chloride, chloroform, DMF, NMP, THF, EtOAc, pyridine and the like. The base can be selected from triethylamine, diisopropylethylamine and the like. In a representative example, the isoxazole benzoic acid can react with Ν,Ο-Dimethylhydroxylamine hydrochloride in the presence of methylene chloride using DCC as the coupling agent and DMAP as the catalyst to provide the substituted isoxazole benzoic Ν,Ο-dimethylamide.

|0156] The substituted isoxazole benzoic Ν,Ο-dimethylamide can react with an organometallic reagent in an appropriate solvent to provide a isoxazole phenylketone.

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The organometetallic reagent can be a Grignard reagent, dialkyl zinc and the like. The solvent can be THF, dioxane, diethyl ether and the like. In a representative example, the substituted isoxazole benzoic Ν,Ο-dimethylamide can react with a Grignard reagent in THF to provide an substituted isoxazole phenylketone.

Scheme 7

<img file="CA2974477C_D0119.tif" />

o a (COCI)*. Toluene, DMF cet

------------------ ohc-&lt;_s-~yⁿ'_Wb. TMF. TEA, R₄R,NH q a HyOroxyfanune hyftochtonde pyridine. EtOH. reflux

b.(AcO),0.145 C

<img file="CA2974477C_D0120.tif" />

I lydroxyUmine hydrochloride

NaOAc. waler. EtOH, reflux

<img file="CA2974477C_D0121.tif" />

(CF,CO),0

Ichxnt. 80-90 C

<img file="CA2974477C_D0122.tif" />

(0157] The thienyl carboxylic acid aldehyde can be converted to an intermediate thienyl acid chloride aldehyde followed by coupling with an appropriate amine to provide the desired product amide. The thienyl carboxylic acid can be treated with an appropriate chlorinating agent, with or without solvent, to provide an intermediate acid chloride which can be isolated or treated directly to provide the desired product. The thienyl carboxylic acid aldehyde can be converted to an acid chloride using a chlorinating agent in the presence of solvent or neat. For example, the chlorinating agent can be selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosgene and phosgene equivalents, and the like. The solvent can be selected from methylene chloride, chloroform, benzene, toluene and the like. In a representative example, oxalyl chloride in the presence of catalytic DMF can convert the thienyl carboxylic acid aldehyde to an thienyl carboxylic acid chloride aldehyde with toluene as the solvent.

[0158| The intermediate thienyl carboxylic acid chloride aldehyde can then be reacted with an amine in an appropriate solvent optionally in the presence of a base to provide the desired product amide. The solvent can be selected from methylene chloride, chloroform, benzene, toluene, THF, diethyl ether, dioxane, and the like. The base can be selected from tricthylaminc, d’isopropylethyl amine, DBU, DBN, DMAP, pyridine, and

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PCT/US2008/074353 the like and combinations thereof. In a representative example, the acid chloride can react with the appropriate amine in the presence of THF and triethylamine as a base to provide the desired product thienyl aldehyde amide.

(0159] The thienyl aldehyde amide can be converted to a thienyl nitrile amide in a two step process. The thienyl aldehyde amide can be reacted with hydroxylamine hydrochloride in an appropriate solvent in the presence of base followed by dehydration to provide a thienyl nitrile amide. In a representative example, the thienyl aldehyde amide can react with hydroxylamine hydrochloride in the presence of pyridine and ethyl alcohol under reflux to provide the intermediate thienyl hydroxyimine amide. The intermediate thienyl hydroxyimine amide can be dehydrated to provide the thienyl nitrile amide. The dehydrating reagent can be acetic anhydride and the like. In a representative example, the thienyl hydroxyimine amide can react with acetic anhydride at elevated temperature to provide the thienyl nitrile amide. The reaction temperature can be in the range of from about 80 °C to about 90 °C.

[0160] The thienyl nitrile amide can be converted to the thienyl hydroxyamidine amide by reacting the thienyl nitrile amide with hydroxylamine hydrochloride under the appropriate conditions. The thienyl nitrile amide can be reacted with hydroxylamine hydrochloride, base, water and solvent to provide thienyl hydroxyamidine amide. The base can be sodium acetate, potasium acetate and the like. The solvent can be methyl alcohol, ethyl alcohol and the like. In a representative example, the thienyl nitrile amide can be reacted with hydroxylamine hydrochloride in the presence of sodium acetate, water and ethyl alcohol under reflux to provide the thienyl hydroxyamidine amide.

[0161| The thienyl hydroxyainidine amide can be converted to the azaisoxazole amide by reacting with trifluoroacetic anhydride in an appropriate solvent. In a representative example, the thienyl hydroxyamidine amide can be reacted with trifluoroacetic anhydride in the presence of toluene at elevated temperature. The reaction temperature can be in the range of from about 80 °C to about 90 °C.

(0162] In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be

-59CA 2974477 2017-07-21 appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methancsulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, aketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including but not limited to hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

[0163] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

[0164] In certain aspects a prodrug form of the agent or compound may be administered to an individual in need thereof. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985).

[0165] The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

[0166] Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent

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PCT/US2008/074353 or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0167] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be phannaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0168| The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof

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PCT/US2008/074353 and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0169] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutano), phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0170] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously stenle-filtered solutions.

[0171J For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

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PCTÆS2008/074353 (0172) Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or watcr-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

(0173] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0174] Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

(0175] The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

(0176] In general, however, a suitable dose will often be in the range of from about 0.15 to about 100 mg/kg, e g., from about 1 to about 75 mg/kg of body weight per day, such as 0.75 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 1 to 90 mg/kg/day, most preferably in the range of 1 to 60 mg'kg/day.

10177] The compound is conveniently administered in unit dosage form; for example, containing 1 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 5 to 500 mg of active ingredient per unit dosage form.

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PCT/US2008/074353 (0178] Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 μΜ, preferably, about 1 to 50 μΜ. most preferably, about 2 to about 30 μΜ. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).

[0179] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

[0180] The compounds of the invention can be administered to an animal for treatment of age-associated memory impairment, mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease and related diseases. The compounds of the invention can be administered to a heathly animal or an aged animal to improve cognitative function in the animal. The compounds of the invention can be administered to an animal having a condition selected from schizophrenia, age-associated memory impairment (AAMI); mild cognitive impairment (MCI), delirium (acute confusional state); depression, dementia (sometimes further classified as Alzheimer’s or non-Alzheimer’s type dementia); Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (chorea); mental retardation; (e g., Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease (e.g., vascular dementia, post-cardiac surgery); affective disorders; psychotic disorders; autism (Kanner’s Syndrome); neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal-pressure hydrocephalus; brain tumor, head trauma (postconcussional disorder), brain trauma (see DSM-IV, APA 1994) and the like.

(0181] The compounds of the invention can also optionally be administered in combination with one or more other therapeutic agents that are effective to improve cognition and/or one or more therapeutic agents that are effective to treat schizophrenia, agc-associatcd memory impairment (AAMI); mild cognitive impairment (MCI), delirium

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PCT/US2008/074353 (acute confusional state), depression, dementia (sometimes further classified as Alzheimer’s or non-Alzheimer’s type dementia); Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (chorea); mental retardation; (e.g., Rubenslein-Taybi and Downs Syndrome); cerebrovascular disease (eg., vascular dementia, post-cardiac surgery); affective disorders; psychotic disorders; autism (Kanner’s Syndrome); neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal-pressure hydrocephalus; brain tumor; head trauma (postconcussional disorder) or brain trauma (see DSM-1V, APA 1994).

[0182] The ability of a compound of the invention to act as an inhibitor of MAO-B can be determined using pharmacological models which are well known to the art, or using the following assay.

MAO Inhibition Assay (0183| MAO enzymatic assay was performed according to the fluromctric method described by Matsumoto and colleagues (Matsumoto, el. al., Clin. Biochem., 1985 18, 126-129). with the following modifications. Human recombinant MAO-A and MAO-B expressed in insect cells were used. For both assays, test compound and/or vehicle was preincubated with purified enzyme in phosphate buffer pH 7.4 for 15 minutes at 37 °C. The reaction was initiated by addition of 50 μΜ kynuramine. Following a 60 minute incubation period, the reaction was terminated by the addition of 6 N NaOH. The amount of 4-hydroxyquinoline formed was determined spectrofluorimetrically at 325 run/465 nm. Results were converted to percent inhibition and ICso’s were determined using the XLfit program from 1DBS (ID Business Solutions Ltd., 2 Occam Court, Suney Research Park, Guildford, Surrey, GU2 7QB UK). Representative compounds of the invention were evaluated in this assay. Typically, the compounds of the invention showed MAO-B inhibitory properties at a concentration of 10 μΜ. Preferred compounds also demonstrated selectivity for MAO-B over MAO-A.

[0184) In many embodiments, a subject compound shows MAO-B inhibitory properties at a concentration of less than about 50 μΜ, e.g., a subject compound shows MAO-B inhibitory properties at a concentration of less than about 40 μΜ. less than about

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PCT/LS2008/0'4353 μΜ, less than about 10 μΜ, less than about 1 μΜ, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.

[01851 A majority of the following compounds showed MAO-B inhibitory properties at a concentration of 10 μΜ or less:

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fW&gt;vïⁿ^-^h F^-Yr^s\r^Nx^⁷N^H

F O'N o A_o F O'N ο Αθ

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Η

I

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PCT/IJS2008/074353 (0186] The ability of a compound to modulate cognitive behavior can be evaluated using the following assay to measure memory after contextual fear conditioning.

Contextual Memory Assay: Fear Conditioning

[0187] Contextual memory is a form of Pavlovian fear conditioning in which a naïve mouse is placed into a novel chamber (context) containing distinct visual, olfactory and tactile cues. After a couple of minutes of acclimation, the mouse receives a brief, mild electric shock to its feet. From this negative experience, the mouse will remember for months that that chamber is dangerous. When placed back into the same context at some later time after training, the mouse’s natural response to danger is to “freeze,” sitting stone still for many seconds. This is similar to what happens to humans when they experience fear. The percent of time during an observation period that the mouse spends frozen represents a quantitative measure (memory score) of its memory of the context.

[0188] Contextual conditioning has been extensively used to investigate the neural substrates mediating fear-motivated learning (Phillips, R. G., LcDoux, J. E., Behav Neurosci, 1992, 106, 274-285; Kim, J. J., et. al., Behav Neurosci. 1993,107, 1093-1098; Bourtchouladze, R., et. al., Learn Mem, 1998, 5, 365-374; and Bourtchouladze, R et .al., Cell, 1994, 79, 59-68). Contextual conditioning has been also used to study the impact of various mutations on hippocampus-dependent memory (Bourtchouladze, R., et al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et. al.. Cell, 1994, 79, 59-68.; Silva, A. J., et. al.,Curr Biol, 1996,6, 1509-1518; Kogan J. L. et al.,Curr Biol, 1997, 7, 1-11; Abel, T, et. al.. Cell, 1997, 88, 615-626; and Giese K.P, et al., Science, 1998, 279, 870-873); and strain and genetic background differences in mice (Logue, S. F., et. al., Behav Neurosci, 1997,111, 104-113; and Nguyen, P. V., et. al., Learn Mem, 2000, 7, 170-179). Because robust memory can be triggered with a few minutes training session, contextual conditioning has been especially useful to study biology of temporally distinct processes of short- and long-term memory (Kim, J.J., et. al., Behav Neurosci, 1993, 107, 10931098; Bourtchouladze, R., et. al., Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et.

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PCT/US2008/074353 al, Cell. 1994, 79, 59-68; and Abel, T., el. al., Cell, 1997, 88, 615-626). As such, contextual conditioning is an excellent model to evaluate the role of various novel drugcompounds in hippocampus-dependent memory.

[0189] Young-adult (10-12 weeks old) C57BI76 male mice and Sprague Dawley male rats of 250-300 g (Taconic, NY) were used. Mice were group-housed (5 mice) in standard laboratory cages while rats were housed in pairs and maintained on a 12:12 light-dark cycle. The experiments were always conducted during the light phase of the cycle. With the exception of testing times, the mice had ad lib access to food and water. The experiments were conducted according with the Animal Welfare assurance SA3280-01 and animals were maintained in accordance with the animal Welfare Act and Department of Health and Human Services guide.

[0190J To assess contextual memory, a modified contextual fear conditioning task originally developed for evaluation of memory in CREB knock-out mice was used (Bourtchouladze. R., et. al.. Cell, 1994, 79, 59-68). On the training day, the mouse was placed into the conditioning chamber (Med Associates, Inc., VA) for 2 minutes before the onset of unconditioned stimulus (US), 0.5 mA, of 2 sec foot shock. The US was repeated two times with a 1 min inter-trial interval between shocks. Training was performed by automated software package (Med Associates, Inc.,VA). After the last training trial, the mice were left in the conditioning chamber for another 30 sec and were then placed back in their home cages. 24 hours after training, the mouse was placed into the same training chamber and contextual memory was assessed by scoring freezing behavior (‘freezing’ serves as memory score). Freezing was defined as the complete lack of movement in intervals of 5 seconds (Kim, J. J., et. al., Behav Neurosci, 1993, 107, 1093-1098; Phillips, R. G., LeDoux, J. E.. Behav Neurosci, 1992, 106, 274-285; Bourtchouladze, R., et. al.. Learn Mem, 1998, 5, 365-374; Bourtchouladze, R., et. al.. Cell, 1994, 79, 59-68; and Abel, T., et. al.. Cell, 1997,88,615-626). Total testing time lasted 3 minutes. After each experimental subject, the experimental apparatus was thoroughly cleaned with 75% ethanol, water, dried, and ventilated for a few minutes.

[0191] All experiments were designed and performed in a balanced fashion, meaning that (i) for each experimental condition (e.g. a specific dose-effect) an equal

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PCT/US2008/074353 number of experimental and control mice was used; and (ii) each experimental condition was replicated 2-3 independent times, and replicate days were added to generate final number of subjects. The proceeding of each experiment was filmed. In each experiment, the experimenter was unaware (blind) to the treatment of the subjects during training and testing. Data were analyzed by Student’s unpaired l test using a software package (Statview 5.0.1; SAS Institute, Inc). All values in the text and figures are expressed as mean + SEM.

|0192] Compounds were dissolved in 1% DMSO/PBS and administered intraperitonially (l.P.) in a volume of 8 mL/kg 20 min before training. Control animals received vehicle alone (1% DMSO/PBS). For oral administration the compounds were dissolved in 30% DMSO/70% CMC. Consequently, control animals received 30% DMSO/70% CMC. For each training and drug-injecting procedure, an experimentally naïve group of animals were used.

(0193] The ability of a compound to modulate cognitive behavior can also be evaluated using the following Object Recognition Assay.

Object Recognition Assay

[0194] Object recognition is an ethologically relevant task for rodents, which does not result from negative reinforcement (foot shock). This task relies on the natural curiosity of rodents to explore novel objects in their environments more than familiar ones. Obviously, for an object to be “familiar,” the animal must have attended to it before and remembered that experience. Hence, animals with better memory will attend and explore a new object more than an object familiar to them. During testing, the animal is presented with the training object and a second, novel one. Memory of the training object renders it familiar to the animal, and it then spends more time exploring the new novel object rather than the familiar one (Bourtchouladze, R., et. al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Recent neuroimaging studies in humans demonstrated that memory in object recognition depends on prefrontal cortex (PFC) (Deibert, et. al.. Neurology, 1999, 52, 1413-1417). Consistent with these findings, rats with the PFC lesions show poor working memory when they are required to discriminate between

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PCT/US2008/074353 familiar and novel objects (Mitchell, J.B., Laiacona, J., Behav Brain Res, 1998, 97, 107113). Other studies on monkeys and rodents suggest that the hippocampus is important for novel object recognition (Teng, E., et. ai, J. Neurosci, 2000, 20, 3853-3863; and Mumby, I). G., Brain Res, 2001, /27, 159-181). Hence, object recognition provides an excellent behavioral model to evaluate drug-compound effects on cognitive task associated with function of hippocampus and cortex.

(0195| Prior to initiation of training, animals were handled for 3-5 minutes for 5 days. Training and testing were performed identically for mice and rats with an exception of training apparatus dimensions (for mice: a Plexiglas box of L=48 cm; W=38 cm and H=20 cm; for rats: a Plexiglas box of L=70 cm; W=60 cm and H=35 cm). The day before training, an individual animal was placed into a training apparatus located in a dimly lit room and allowed to habituate to the environment for 15 minutes (also see Pittenger, C., et. al.. Neuron, 2002, 34, 447-462; and Bourtchouladze, R.., et. al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Training was initiated 24h hours after habituation. An animal was placed back into the training box, which contained two identical objects (e.g. a small conus-shape object), and was allowed to explore these objects. The objects were placed into the central area of the box and the spatial position of objects (left-right sides) was counterbalanced between subjects. Animals were trained for 15 minutes. To test for memory retention, animals were observed for 10 minutes 24 hours after training. A rodent was presented with two objects, one of which was used during training, and thus was ‘familiar’ and the other of which was novel (e.g. a small pyramid-shape object). To insure that the discrimination targets do not differ in smell, after each experimental subject, the apparatus and the objects were thoroughly cleaned with 90% ethanol, dried and ventilated for a few minutes.

(0196] The experiments were videotaped via an overhead video camera system. Types were then reviewed by a blinded observer and the following behavioral parameters were determined: time of exploration of an each object; the total time of exploration of the objects; number of approaches to the objects; and time (latency) to first approach to an object. The discrimination index - memory score - was determined as described previously (Ennaceur, A., Aggieton, J.P., Behav Brain Res, 1997, 88, 181-193;

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PCT/US2008/074353 and Bourtchouladze, R., et. al., Proc Natl Acad Sei USA, 2003,100, 10518-10522). This Data was analyzed by Student s unpaired t test using a software package (Statview 5.0.1 ; SAS Institute, Inc).

[0197] The compounds evaluated in the MAO Inhibition Assay can be tested in the Object Recognition Assay to show improvement of cognitive function in the subject animal.

[0198] The following Examples illustrate methods that are generally useful for preparing compounds of the invention.

[0199] LC Protocol: Observed, 254 iim. Solvent system, acetonitrile (0.1 % formic acid) and water (0.1 % formic acid). Column, XTerra MS C-18 3.5 pM (2.1 x 50 mm), 30 °C oven temperature. Run time, 10 min. Flow rate 0.3 mL/min. Substrate is dissolved in acetonitrile and diluted to equal volume with water for injection.

[0200] Inlet Method:

<td rowspan="2"> Time (min) θ</td><td> % acetonitrile (0.1 % formic acid)</td><td> % water (0.1 % formic acid)</td>

<td> 10</td><td> 90</td>

<td> 5</td><td> 90</td><td> 10</td>

<td> 7</td><td> 90</td><td> 10</td>

<td> 7.5</td><td> 10</td><td> 90</td>

<td> 10</td><td> 10</td><td> 90</td>

Preparative Examples

Preparative Example 1

<img file="CA2974477C_D0140.tif" />

O O l-[5-(Piperidine-l-carbonyl)-thiophen-2-yl]-ethanone

[0201] A solution of 5-acetylthiophcne-2-carboxylic acid (34.0 g, 200 mmol) in toluene (800 mL) was treated with DMF (500 pL) followed by oxalyl chloride (22.3

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PCT/LS2008/074353 mL, 260 mmol) and allowed to stir 3 hr after which time the reaction was evaporated in vacuo to afford intermediate acid chloride. The intermediate acid chloride was then dissolved in THF (500 mL) and treated with a THF solution (100 mL) of triethylamine (30.7 mL, 220 mmol) and piperdine (20.7 mL, 210 mmol). The reaction was allowed to stir for 3 hr then evaporated to approximately % volume and partitioned between EtOAc (150 mL) and a IN HC1 solution (100 mL). The organic portion was then further washed with a saturated aqeuous solution of NaHCOj (100 mL) followed by a brine solution (100 mL), then dried over MgSO-i, filtered, and evaporated in vacuo to afford product as yellow colored solid which was triturated and filtered with the aid of hexanes to afford product as a solid (43.2 g, 91%). *H NMR (CDCI₃) 1.63-1.71 (m, 6 H), 2.57 (s, 3 H), 3.62 (br s, 4 H), 7.24 (d, J - 4.0, 1 H), 7.60 (d, J - 4.0,1 H). ^I3C NMR 24.7, 26.3 (br), 27.1, 44.5 (br), 48.0 (br), 128.8, 131.6, 144.7, 145.5, 162.7, 190.8. LC/MS 4.92 min, [M+l]⁺238.

Preparative Example 2

O

O

5-Acetyl-thiophene-2-carboxylic acid ethyl ester

[0202] A solution of 5-acetylthiophene-2-carboxylic acid (17.0 g, 100 mmol) in ethanol (500 mL) was treated with a concentrated H2SO4 solution (10 mL) and heated at reflux for 3 days after which time the reaction was evaporated to approximately % volume and partitioned between EtOAc (300 mL) and water (100 mL). The organic portion was then further washed with a saturated aqueous solution of NaHCCh (2 x 100 mL) followed by a brine solution (100 mL), then dried over MgSCh, filtered, and evaporated in vacuo to afford product as light brown colored solid (25.0 g, 84%). 'H NMR (CDClj) 1.39 (t, J = 7.0,3 H), 2.59 (s, 3 H), 4.38 (q, J = 7.3, 2 H), 7.64 (d, J = 4.0, 1 H), 7.76 (d, J = 4.0, 1 H). ^,3C NMR 14.3, 27.1, 61.9, 131.8, 133.3, 140.3, 148., 161.7, 190.9. LC/MS 5.47 min, [M+l]⁺ 199.

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Preparative Example 3

<img file="CA2974477C_D0141.tif" />

4,4,4-Trifluoro- i -[5-(piperidine-1 -carbonyl)-thiophen-2-yi]-butane-1,3-dione

[0203) A suspension of sodium methoxide (8.78, 162.5 mmol) in toluene (300 mL) was treated with ethyl trifluoroacetate and allowed to stir at 30 °C for 30 min after which time solid l-[5-(Piperidine-l-carbonyl)-thiophen-2-yl]-etbanone (Preparative Example 1, 11.87 g, 50 mmol) was added portionwise. The reaction was heated at 40 °C for 3 hr and allowed to stir at room temperature for a further 16 hr. The reaction was then cooled to 0-5 °C and filtered with the aid of cold toluene. The filtered solids were then partitioned between EtOAc (300 mL) and an aqueous 5% H2SO4 solution (100 mL) and the organic layer further washed with a brine solution (2 x 50 mL), then dried over MgSO₄, filtered, and evaporated in vacuo to afford product as light brown colored solid (15.26 g, 91%). An approx. 2.Ί isomer mixture was observed in the NMR spectra of product. 'H NMR (CDCI3) 1.65-1.71 (m, 6 H), 3.63 (br s, 4 H), 7.06 (s, 1 H), 5.38 (br s, minor enol, 1 H), 6.45 (s, major isomer, I H), 7.25 (d, minor isomer, J = 3.8, 1 H), 7.28 (d, major isomer, J = 4.1, 1 H), 7.71 (d, minor isomer, J = 4.1, 1 H), 7.74 (d, major isomer, J = 3.8, 1 H). ¹⁹F NMR -87.3 (minor isomer), -76.2 (major isomer). LC/MS 5.05 min, [M+l+HjO]’ 352.

Preparative Example 4

<img file="CA2974477C_D0142.tif" />

4,4,4-Trifluoro-2-methyl-l -[5-(piperidine-l -carbonyl)-thiophen-2-yl]-butane-1,3-dione

[0204J A suspension of 60% sodium hydride (440 mg, 11 mmol) in DMF (15 mL) at 0-5 °C was treated portionwise with 4,4,4-Trifluoro-1 -(5-(piperidine-l-carbonyl)

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PCT/US2008/074353 thiophen-2-yl]-butane-l,3-dione (Preparative Example 3, 3.34 g, 10 mmol) and allowed to stir until all hydrogen evolution had ceased. The reaction mixture was then treated with iodomethane (1.25 mL, 20 mmol) and heated at 60 °C for 16 hr. The reaction mixture was then cooled and partitioned between EtOAc (25 mL) and an aqueous 5% H₂SO« solution (50 mL) and the organic layer further washed with a brine solution (2 x 25 mL), then dried over MgSCh, filtered, and evaporated in vacuo to afford product as light brown oil. The residue was chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford product as an oil (2.70 g, 78%). An approximately 1:1 mixture of isomers was observed in the NMR spectra of product. ’H NMR (CDCI3) 1.40 (d, isomer, J = 7.0, 3 H), 1.58 (d, isomer, J = 7.0, 3 H), 1.65-1.71 (m, 6 H), 3.63 (br s, 4 H), 3.83 (q, isomer, J - 7.0, 1 H), 4.78 (q, isomer, J = 6.7, 1 H), 5.06 (s, isomer, 1 H), 5.67 (s, isomer, 1 H), 7.27 (d, isomer, J = 4.0, 1 H), 7.29 (d, isomer, J = 4.0, 1 H), 7.71 (d, isomer, J = 4.0, 1 H), 7.74 (d, isomer. J = 4.0, 1 H). ^,9F NMR -83.7 (isomer), -77.6 (isomer). LC/MS 5.05 min, [M+I + HjO]^ 366.

Preparative Example 5

<img file="CA2974477C_D0143.tif" />

5-(4,4,4-l'rifluoro-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester |0205] Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester as described in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. Product was not chromatographed, but obtained as a yellow solid (11.5 g, 78%). 'H NMR (CDClj) 1.41 (t, J = 7.0, 3 H), 4.41 (q, J = 7.0, 2 H), 6.48 (s, 1 H), 7.77 (d, J = 7.0, I H), 7.81 (d, J = 4.0, 1 H). ⁿC NMR 14.4, 62.3, 93.8, 117.5 (q, J = 281), 132.0, 133.7, 141.5, 143.7, 161.4, 174 0(q, J = 37), 181.4 ⁱ⁹FNMR -76.4. LC/MS 5.44 min, [M+l]⁺ 295, (M+l¹ U₂O]¹ 313.

Preparative Example 6

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<img file="CA2974477C_D0144.tif" />

5-(4.4,4-Trifluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester (0206] Prepared from 5-(4,4,4-Trifluoro-3-oxO'butyryl)-thiophene-2carboxylic acid ethyl ester as described in Preparative Example 4. Product was not chromatographed, but obtained as a brown oil (12.2 g, 113%) and used as such. LC/MS 5.81 min, [M+1+H₂O]⁺327.

Preparative Example 7

<img file="CA2974477C_D0145.tif" />

4-(4,4,4-Trifluoro-3-oxo-butyryl)-benzoic acid eihyl ester |0207) Prepared from 4-Acetyl-benzoic acid ethyl ester as desribed in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. Product was not chromatographed, but obtained as an off-white solid (10.4 g, 90%). ’H NMR (CDClj) 1.43 (t, J = 7.0, 3 H), 4.43 (q, J = 7.3, 2 H), 6.61 (s, 1 H), 8.00 (d, J = 8.8, 2 H), 8.40 (d, J = 8.4, 2 H). ^I9F NMR -77.1. LC/MS 5.51 min, [M+l]⁺ 289, (M+1 + H₂O]^l307.

Preparative Example 8

<img file="CA2974477C_D0146.tif" />

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4-(4,4,4-Trifluoro~2-methyl-3-oxo-butyryl)-benzoic acid ethyl ester (0208] Prepared from 4-(4,4,4-Trifluoro-3-oxo-butyiyl)-benzoic acid ethyl ester as described in Preparative Example 4. Sodium methoxide was substituted with sodium ethoxide. Product was chromatographed on silica gel with EtOAc/hexanes (15%) to afford a copper-colored oil (1.14 g, 38%). LC/MS 5.94 min, [M+l]⁺ 303, [M+1 + H₂O]⁺ 321.

Preparative Example 9

O

4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester

[0209] A solution of 4-(4.4.4-Trifluoro-3-oxo-butyryl)-benzoic acid ethyl ester (Preparative Example 7, 2.88 g, 10 mmol) in glacial acetic acid (2.5 mL) was treated with hydroxylamine hydrochloride (833 mg, 12 mmol) and heated at 80-90 °C for 16 hr, after which time the reaction was cooled and the resulting solids filtered with the aid of water to afford the 5-hydroxy-4,5,-dihydro-isoxazole intermediate (2.25 g. 74%). The intermediate (2.2 g, 7.25 mmol) was then dissolved in trifluoroacetic acid (10 mL) and heated at reflux for 3 days. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (20%) as eluant to afford product as a colorless solid (1.30 g, 63%). 'H NMR (CDC1_}) 1.41 (t, J - 7.5, 3 H), 4.41 (q, J - 7.0, 2 H), 7.06 (s, 1 H), 7.89 (d, J = 8.8, 2 H), 8.15 (d, J = 8.8, 2 H). ⁿC NMR 14.5, 61.7,

103.8, 118.0 (q, J = 270), 127.1, 130.6, 131.5, 132.8, -150 quartet not resolved from baseline noise, 162.0,166.0. ‘'FNMR -63.6. LC/MS 7.15 min, [Μ-Η]⁺ 286.

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Preparative Example 10

F F

Ο.

N

<img file="CA2974477C_D0147.tif" />

Ο

4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester (0210] A solution of 4-(4,4,4-Trifluoro-2-mcthyl-3-oxo-butyryl)-benzoic acid ethyl ester (0211] (927 mg, 3.07 mmol) in glacial acetic acid (10 mL) was treated with hydroxylamine hydrochloride (256 mg, 3.68 mmol) and heated at 80-90 °C for 48 hr, after which time the reaction was evaporated in vacuo. The crude material was then chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless oil (840 mg, 91%). ’H NMR (CDCIj) 1.43 (t, J = 7.0, 3 H), 2.29 (q, J = 3 H), 4.43 (q, J = 7.0, 2 H), 7.72 (d, J = 8.8, 2 H), 8.19 (d, J = 8.3, 2 H). ^I3C NMR 7.7, 14.5, 61.6, 115.0, 118.9 (q, J = 271), 128.5, 130.3, 132.1, 132.3, -150 quartet not resolved from baseline noise, 163.0, 166.0. 'V NMR -63.2. LC/MS 7.28 min, [MH]’ 300.

Preparative Example 11

OH

4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid

10212] A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester (Preparative Example 9, 2.25 g, 7.86 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (660 mg, 15.72 mmol) and allowed to stir for 16 hr. The reaction was then evaporated to a small volume and treated

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PCT/US2008/074353 with a 1 N aqueous hydrochloric acid solution (25 mL) and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (1.48 g, 73%). 'H NMR (DMSO-J6) 8.06 (s, 4 H), 8.13 (s, 1 H). ⁿCNMR 106.5, 118.0 (q, J = 270), 127.9,

130.8, 131.2, 132.4, -150 quartet not resolved from baseline noise, 133.8, 162.8, 167.3. ^,9F NMR -63.6. LC/MS 6.04 min, [M+l ]⁺ 258.

Preparative Example 12

<img file="CA2974477C_D0148.tif" />

4-(4-Methyl-5-trifluoromethyl-isoxa2ol-3-yl)-benzoic acid

[0213] Prepared from 4-(4-Methyl-5-trifluoromethyl-isoxazo)-3-yl)-benzoic acid ethyl ester as described in Preparative Example 11 to afford product as a colorless solid (3.7 g, 98%). 'H NMR (DMSO-r/6) 2.25 (s, 3 H), 7.81 (d. J = 7.9, 2 H), 8.10 (d, J =

8.2, 2 H), 13.26 (s, 1 H). ^I3CNMR 7.8, 116.9, 119.3 (q, J = 270), 129.3, 130.6, 131.6,

133.2, 153.6 (q, J = 39), 163.6,167.4. ^I9FNMR -62.3. LC/MS 6.14 min, [M+lf 272.

Preparative Example 13

<img file="CA2974477C_D0149.tif" />

F O-N o

5-(4-A/erAy/-5-fr'i/7worozMe//zv/-isoxaco/-3-y/)-rA&lt;qpAene-2-car6oxyhc acid ethyl ester

[0214] Prepared from crude 5-(4,4,4-Trifluoro-2-methyl-3-oxo-butyryl)thiophene-2-carboxylic acid ethyl ester as described in Preparative Example 10. Crude material was chromatographed on silica gel with EtOAc/hexanes (25%) as eluant to afford product as a colorless solid (7.4 g, 66%). 'H NMR (CDClj) 1.41 (t, J = 7.0, 3 H), 2.38 (s, 3 H), 4.43 (q, J = 7.5, 2 H), 7.51 (d, J = 4.0, I H), 7.83 (d, J = 4.0, 1 H). ^,3C

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NMR 7.9, 14.5, 61.9, 114.8, 118.7 (q, J = 271), 128.4, 133.6, 134.7, 136.6, 155.4 (q, J = 41),157.9,161.8. ^,9FNMR-63.2. LC7MS 7.26 min, (M+l]⁺306.

Preparative Example 14

<img file="CA2974477C_D0150.tif" />

F O-N o

5-(4-Methyl-5-lrifluoromethyl-isoxazol-3-yl)'thiophene-2-carboxylic acid |0215} Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yI)thiophene-2-carboxylic acid ethyl ester as described in Preparative Example 11 to afford product as a colorless solid (6.15 g, 94%). ‘H NMR (DMSO-J6) 2.33 (s, 3 H), 7.64-7.66 (m, 2 H). ^I3C NMR 8.0, 116.6, 119.1 (q, J = 271), 129.3, 130.7, 131.8, 132.4, 142.7, 153.8 (q, J = 40), 158.8, 163.6. ^I9F NMR -62.3. LC/MS 6.02 min, [M rlf 278.

Preparative Example 15

<img file="CA2974477C_D0151.tif" />

N-Melhoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-henzamide |0216J A solution of 4-(5-Trifluoromethyl-isoxazoI-3-yl)-benzoic acid (Preparative Example 11, 1.024 g, 4.0 mmol) in dichloromethane (14 mL) at 0-5 °C was treated with DMF (2 mL) followed by DMAP (50 mg), hydroxyiamine hydrochloride (468 mg, 4.8 mmol), triethylamine (458 μΐ., 4.8 mmol), and DCC (990 mg, 4.8 mmol). The reaction was allowed to warm to room temperature and stirred 16 hr then evaporated in vacuo. The crude material was then chromatogrphed on silica gel with EtOAc/hexanes (40%) as eluant to afford product as a colorless solid (890 mg, 74%). ’H NMR (CDCIj) 3.40 (s, 3 H), 3.57 (s, 3 H). 7.06 (s, 3 ), 7.82 (d, J = 8.3, 2 H), 7.88 (d, J = 8.8, 2 H). ⁿC

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NMR 33.7, 61.4, 103.7, 118.0 (q, J = 460), 127.1, 129.3, 129.4, 136.6, 159.7 (q, J = 42),

162.2, 169.0. ^,9FNMR -64.6. LC/MS6.01 minJM-lf 301.

Preparative Example 16

<img file="CA2974477C_D0152.tif" />

O

N-Methoxy-N-meihyl-4-(4-methyl-5-triJluoromethyl-isoxazol-3-yl)-benzamide |0217] Prepared from 4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-benzoic acid as described in Preparative Example 15. Crude material was chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (1.41 g, 75%). 'H NMR (CDCI₃) 2.26 (s, 3 H), 3.36 (s, 3 H), 3.55 (s, 3 H), 7.65 (d, J = 7.9, 2 11). 7.80 (d, J = 7.9,2 H). ^I3C NMR 7.7, 33.7, 61.4,117.1, 117.9 (q, J = 428),

128.2, 129.0, 130.0, 136.1, 155 (obs q), 163.1, 169.1. ^,9F NMR-63.2. LC/MS 6.27 min, [M+lf 315.

Preparative Example 17

<img file="CA2974477C_D0153.tif" />

O 0

5-(Piperidine-l-carbonyl)-thiophene-2-carbaldehyde (0218] A solution of 5-formylthiophenecarboxylic acid (9.0 g, 57.6 mmol) in toluene (100 mL) was treated with DMF (100 pL) followed by oxalyl chloride (9.9 mL, 115 mmol) and stirred at room temperature for 3 hr then evaporated in vacuo. The crude acid chloride was then dissolved in THF (100 mL), cooled in an ice bath, and treated with a THF solution (50 mL) containing triethylamine (10 mL, 72 mmol) and piperdine (6.3 mL, 63.4 mmol). The reaction was placed in a 5 °C refrigerator for 16 hr and then treated

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PCT/US2008/074353 with a IN HC1 solution (200 mL) and EtOAc (200 mL). The organic portion was further washed with a saturated aqueous solution of NaHCOj (100 mL) followed by a brine solution (100 mL), then dried over MgSO4, filtered, and evaporated in vacuo to afford product as an oil (12.87 g, 100%). *H NMR (CDCI₃) 1.64-1.71 (m, 6 H), 3.62 (br s, 4 H), 7.31 (d, J = 4.0, 1 H), 7.71 (d, J = 3.5,1 H), 9.94 (s, 1 H). ^,3C NMR 24.6,26.3 (br), 44.2 (br), 49.0 (br), 128.8, 135.4,144 8, 146.1,162.5,183.3. LC/MS 4.78 min, [M+lf 224.

Preparative Example 18

5-(Piperidine-l-carbonyl)-thiophene-2-carbonitrile

[0219] A solution of 5-(Piperidine-l-carbonyl)-thiophene-2-carbaldehyde (Preparative Example 17, 2.23 g, 10 mmol) in EtOH (50 mL) was treated with pyridine (971 pL, 12 mmol, 1.2 eq) followed by hydroxylamine hydrochloride (833 mg, 12 mmol, 1.2 eq) and heated at reflux for 2 hr then evaporated in vacuo. The crude intermediate oxime was then dissolved in acetic anhydride and heated at 145 °C for 16 hr then evaporated in vacuo to a small volume which was partitioned between EtOAc (50 mL) and water (200 mL). The organic layer was further washed with a brine solution (50 mL), dried over MgSO«, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (30 then 50%) as eluant to afford product as a yellowtinted oil (1.43 g, 65%). ‘H NMR (CDCh) 1.65-1.76 (m, 6 H), 3.64 (br s, 4 H), 7.23 (d, J = 4.0, 1 H), 7.56 (d, J = 4.0, 1 H). ^I3C NMR 24.5, 26.2, 44.3 (br), 48.5 (br), 111.9, 113.7, 128.0, 137.0, 144.7, 161.3. LC/MS 5.09 min, [M-tif 221.

Preparative Example 19

O O

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4,4,4-Trifluoro-2-methyl-l-thiophen-2-yl-butane- 1,3-dione

[0220| Prepared from 2-Thenoyltrifluoroacetone as described in Preparative Example 4. Product was not chromatographed, but obtained as a brown oil (13.6 g, 115%) and used as such. LC/MS 4.99 min, [M+l + H₂O]⁺ 255.

Preparative Example 20

F O'N

3-Thiophen-2-yl-5-trifluoromethyl-isoxazole

[0221] Prepared from 2-Thenoyltrifluoroacetone as described in Preparative Example 9. Product was chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless solid (2.57 g, 59%). Intermediate: LC/MS 5.23 min, [M+1 + H₂Of 255. Product: 'H NMR (CDCI₃) 6.93 (s, 1 H), 7.14 (dd, J = 3.5 and

4.8, I H), 7.47-7.52 (m, 2 H). ^I3C NMR 103.7, 118.0 (q, J = 271), 128.2, 128.9, 129.1, 158.0, 159.3 (q, J = 43). A NMR -64.7. LC/MS 6.62 min, [M+lf 220.

Preparative Example 21

<img file="CA2974477C_D0154.tif" />

F O'N

4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole

[0222] Prepared from crude 4,4,4-Trifluoro-2-methyl-l-thiophen-2-yl-butane1,3-dione as described in Preparative Example 10. Product was not chromatographed, but obtained as a colorless solid after filtration with aid of water (3.05 g, 65%). 'H NMR (CDClj) 2.35 (s, 3 H), 7.16-7.19 (m, 1 H), 7.49-7.52 (m, 2 H). ^,3C NMR 7.9, 114.6, 118.9 (q, J = 271), 128.1, 128.6, 128.7, 154.9 (q, J = 40), 158.5. ^I9F NMR -63.2. LC/MS 6.79 min, [M+l]⁺ 234.

Preparative Example 22

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<img file="CA2974477C_D0155.tif" />

5-(4,4-Difluoro-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester

[0223] Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester and ethyl di fluoroacetate by the method described in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. The product was obtained as a crude oil (5.4 g, 85 %). An approx. 5:1 isomer mixture was observed in the NMR spectra of product. 'H NMR (CDC1₃) 1.41 (t, J = 7.0, 3 H), 3.63 (q, J = 7.0, 2 H), 5.98 (t, minor isomer, J - 53.2, 1 H), 6.05 (t, major isomer, J = 54.0,1 H), 6.45 (s, 1 H), 7.74 (d, J = 4.0, 1 H), 7.80 (d, J = 4.0, 1 H). ^I9F NMR -127.8 (minor isomer, J - 53.5), -127.1 (major isomer, J = 55.5). LC/MS 5.18 min, [M+l f 277.

Preparative Example 23

<img file="CA2974477C_D0156.tif" />

5-(4,4-Difluoro-2-methyl-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester

[0224J Prepared from 5-(4,4-Difluoro-3-oxo-butyryl)-thiophene-2-carboxylic acid ethyl ester by the method described in Preparative Example 4 to afford product as a crude oil (5.5 g, 108 %). LC/MS 5.37 min, [M+1J⁺ 291.

Preparative Example 24 and 25

<img file="CA2974477C_D0157.tif" />

5-(3-Difluoromethyl-4-melhyl-isoxazol-5-yI)-thiophene-2-carboxylic acid ethyl ester and 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid ethyl ester

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[0225] Prepared from 5-(4,4-Difluoro-2-methyl-3-oxo-butyryl)-thiophcne-2carboxylic acid ethyl ester by the method described in Preparative Example 10. The crude material was chromatographed on silica gel with EtOAc/hexanes (10%) as eluant and the pure fractions isolated to afford products as colorless solids. High Rf material (Rf = 0.40, 440 mg, 9 %), low Rf material (Rf = 0.24, 1.1 g, 22 %), as well as an approximately 1:1 mixture of isomers (1.5 g, 30 %).

(0226) Higher Rf Product: 5-(3-Difluoromethy)-4-methyl-isoxazol-5-yl)thiophene-2-carboxylic acid ethyl ester: 'H NMR (CDCh) 1.41 (t, J = 7.0, 3 H), 2.38 (s, 3 H), 4.38 (q, J = 7.0, 2 H), 6.80 (t, J = 53.2, 1 H), 7.51 (d, J = 4.4, 1 H), 7.82 (d, J = 4.4, 1 H). ^BC NMR 7.7, 14.5, 61.9, 109.5, 110.3 (t, J = 236), 127.5, 133.7, 134.1, 136.3, 158.7 (t, J - 29), 161.9. ^!9F NMR -118.2 (J = 53.5). LC/MS 6.60 min, [MH]' 288.

|0227] Lower Rf Product: 5-(5-Difluoromethyl-4-mcthyl-isoxazol-3-yl)thiophcne-2-carboxylic acid ethyl ester. 'H NMR (CDCI3) 1.41 (t, J = 7.0, 3 H), 2.37 (s, 3 H), 4.39 (q, J = 7.0, 2 H). 6.81 (t, J = 52.7, 1 H), 7.50 (d, J = 4.0, 1 H), 7.82 (d, J = 4.0, 1 H). ”C NMR 7.7, 14.5, 61.8, 108.1 (t, J = 238), 113.5, 128.4, 133.6, 135.4, 136.2, 157.7, 159.8 (t, J = 29), 161.9. ^I9F NMR -118.2 (J = 53.5). LC/MS 6.85 min, (M+l]' 288.

Preparative Example 26

<img file="CA2974477C_D0158.tif" />

5-(5d)ifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid

[0228] A solution of 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene2-carboxylic acid ethyl ester (Preparative Example 25,1.0 g, 3.48 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (292 mg, 6.96 mmol) and allowed to stir for 20 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution to a pH of - 2 and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (900 mg, 99%). 'H NMR (DMSO-Jd) 2.29 (s, 3 H), 7.44 (t, J = 51.9, 1 H), 7.66 (d,

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J = 2.6,1 H), 7.78 (d, J = 2.6,1 H). ^I3CNMR7.7,108.1 (t. J = 236), 115.0, 130.3,134.3, 134.5, 137.4, 157.8, 159.6 (t, J = 26), 163.1. ^I9F NMR -118.8 (J - 51.5). LC/MS 5.41 min, [M+l ]⁺ 260.

Preparative Example 27

Ή

5-(3-Difluoromethyl-4-methyl-isoxazoI-5-yl)-ihiophene-2-carboxylic acid

[0229] Prepared from 5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)thiophcne-2-carboxylic acid ethyl ester by the method described in Preparative Example 26 to afford product as a colorless solid (355 mg, 99%). 'H NMR (DMSO-r/6) 2.27 (s, 3 H), 7.33 (t, J = 51.9,1 H), 7.67 (d. J = 4.0,1 H), 7.80 (d, J = 4.0, 1 H). ^I9F NMR -118.8 (J = 51.5). LC/MS 5.90 min, [M+l ]⁺ 260.

Preparative Example 28

N

Dimethyl-(R)-l-piperidin-3-ylmethyl-amine, dihydrochloride

[0230] A solution of (S)-l-Boc-3-(aminomethyl)piperdine (429 mg, 2.0 mmol, CAS [140645-24-5], CHN Technologies, Wobum MA, USA) in dichloromethane (10 mL) was treated with a 37% aqueous formaldehyde solution (551 pL, 20.0 mmol) followed by sodium triacetoxyborohydnde (4.23 g, 20.0 mmol). The mixture was stirred for 4 h then quenched with dichloromethane (10 mL) and saturated aqueous solution of NaHCOj (50 mL). The organic portion was further washed with a brine solution (10 mL), then dried over MgSOi, filtered, and evaporated in vacuo to afford product as an oil. LC/MS 1.10 min, [M+l]* 243. The methylated intermediate was dissolved in 1,4dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (5

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PCT/IJS2008/074353 mL) and stirred for 2 hr, after which time product had precipitated out of solution. 1'he reaction mixture was evaporated in vacuo and filtered with the aid of ethyl ether. The resulting solids were air dried to afford product as a colorless solid (290 mg, 67% overall). LC/MS 0.60 min, [M— 1 ]⁺ 143.

Preparative Example 29

<img file="CA2974477C_D0159.tif" />

Dimethyl-(S)-l-piperidin-3-ylmethyl-amine. dihydrochloride (0231] Prepared from (R)-l-Boc-3-(aminomethyl)piperdine (429 mg, 2.0 mmol, CAS [140645-23-4], CHN Technologies, Wobum MA, USA) in the same manner as the R isomer described in Preparative Example 28. Colorless solid (306 mg, 71% overall). LC/MS 0.60min, [M+ if 143.

Preparative Example 30

<img file="CA2974477C_D0160.tif" />

Methyl-piperidin-3-ylmethyl-carbamic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (0232] A solution of 9-fluorenylmethoxycarbony) chloride (259 mg, 1.0 mmol) in THF (3 mL), at 0-5 °C, was treated with a THF solution (2 mL) containing 1Boc-3-methylaminopiperdine (214 mg, 1.0 mmol, CAS [392331-89-4], CHN Technologies, Wobum MA, LISA) and diisopropylethylamine (174 pL, 1.0 mmol). The reaction mixture was allowed Io stir for 1 h then placed in a 0-5 °C refrigerator for 16h. After this time the reaction mixture was evaporated in vacuo, partitioned between EtOAc (10 mL) and a IN aqueous HC1 solution (10 mL), and the organic portion further washed with a saturated aqueous solution of NaHCOj (10 mL) followed by a brine solution (10

-91CA 2974477 2017-07-21 mL). The organic portion was then dried over MgSO₄, filtered, and evaporated in vacuo to afford crude oil. The oil was chromatographed on silica gel with EtOAc/hexane (40%) to afford the Fmoc/Boc-protected intermediate as a colorless foam (409 mg, 94%). The intermediate was then dissolved dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (5 mL), stirred for 2 hr, then evaporated in vacuo to afford product as a colorless solid. LC/MS 4.42 min, [M+l]⁺ 337.

Preparative Example 31

<img file="CA2974477C_D0161.tif" />

O (3R)-N-methylpiperidine-3-carboxamide

A solution of D-Cbz-Nipecotic acid ((R)-Piperdine-l,3,-dicarboxylic acid 1-benzyl ester) (1.32 g, 5.0 mmol) in toluene (25 mL) was treated with DMF ( 20 pL) followed by oxalyl chloride (646 μ I ., 7.5 mmol). The reaction mixture was stirred for 3 hr and evaporated to an oil. The crude acid chloride was then dissolved in THF (20 mL), cooled to 0-5 °C, and treated with a 2 M THF solution of methylamine (7.5 mL, 15 mmol). The reaction mixture was stirred for 2 hr, allowed to warm to room temperature and evaporated in vacuo to afford solids which were filtered with the aid of water to afford Cbz-protected intermediate as a colorless solid (1.2 5 g, 91%). LC/MS 5.05 min, [M+l]⁺ 277. The CbZ-protected intermediate (1.0 g, 3.62 mmol) was dissolved in EtOH ( 50 mL), treated with a 10% palladium on carbon (50% water content) catalyst (750 mg) and hydrogenated at 60-70 psi hydrogen for 5 hr. The crude reaction mixture was then filtered through Celite™, evaporated in vacuo, and redisolved in EtOH (10 mL) which was filtered through a nylon syringe filter to remove residual catalyst. Evaporation of the solution afforded crude product as a tacky solid (581 mg, 113%). LC/MS 0.68 min, [M+l]⁺143.

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Preparative Example 32

O H

I

<img file="CA2974477C_D0162.tif" />

(3S)-N-methylpiperidine-3-carboxamide

Prepared from L-Cbz-Nipecotic acid in the same manner as the D/(R) isomer described in Preparative Example 31. CBz-protected intermediate as a colorless solid (1.22 g, 88%). LC/MS 4.96 min, [M+l]⁺ 277. Evaporation of the mixture afforded crude product as a tacky solid (571 mg, 111%). LC/MS 0.64 min. [Μτ1]⁺ 143.

Preparative Example 33

<img file="CA2974477C_D0163.tif" />

tert-butyl methylf(3R)-piperidin-3-ylmethyl)carbamate

A solution of (3R)-N-methyIpiperidine-3-carboxamide (Preparative Example 31,430 mg, 3.0 mmol) in acetonitrile (3 mL) was treated with triethylamine (836 pL, 6.0 mmol) followed by benzylbromide (449 pL, 3.75 mmol). The reaction mixture was allowed to stir for 24 hr then partitioned between EtOAc (20 mL) and a saturated aqueous solution of NaHCOj (20 mL). The organic portion was washed with an additional portion of NaHCOj solution followed by a brine solution (10 mL), then dried over MgSOa, filtered, and evaporated in vacuo to afford N-benzylated intermediate as a waxy solid (459 mg, 66%). The intermediate (450 mg, 1.94 mmol) was then dissolved in THF (20 mL) and treated with a IM THF solution of lithium aluminum hydride (2.9 mL, 2.91 mmol) followed by heating at 60 °C for 8 hr. After this time the reaction mixture was cooled in an icc bath and quenched sequentially with water (0.5 mL), a 1 M NaOH solution (1 mL), and solid MgSCh. The reaction mixture was allowed to stir for 30 min followed by filtration with the aid of THF. Evaporation of the filtrate in vacuo afforded the N

-93CA 2974477 2017-07-21 benzylated amine intermediate as a clear liquid (403 mg, 95%). LC/MS 0.66 min, [M+l ]⁺ 219. The amine intermediate (400 mg, 1.83 mmol) was then dissolved in THF (10 mL) amd treated with triethylamine (510 pL, 3.66 mmol) followed by di-/er/-butyl dicarbonate (600 mg, 1.83 mmol) and allowed to stir for 16 hr. After this time the reaction mixture was partitioned between EtOAc (20 mL) and a saturated aqueous solution of NaHCOj (20 mL). The organic portion was washed with an additional portion of NaHCOj solution followed by a brine solution (10 mL), then dried over MgSÛ4, filtered, and evaporated in vacuo to afford and oil that was chromatographed on silica gel with EtOAc/hexanes (30%) then MeOH/EtOAc (10%) as eluant to afford N-benzylated-N-BOC-protected product as colorless oil (442 mg, 76%). LC/MS 4.42 min, [M+l]⁺ 319. The differentially protected intermediate (440 mg, 1.38 mmol) was dissolved in EtOH (50 mL), treated with palladium hydroxide on carbon (Pearlman’s catalyst, 500 mg) and hydrogenated at 60-70 psi hydrogen for 8 hr. The crude reaction mixture was then filtered through Celite™, evaporated in vacuo, and redisolved in EtOH (10 mL) which was filtered through a nylon syringe filter to remove residual catalyst. Evaporation of the mixture afforded crude product a clear colorless oil (298 mg, 94%, 45% overall). LC/MS 3.71 min, [M+l]⁺229.

Preparative Example 34

<img file="CA2974477C_D0164.tif" />

tert-butyl methylf(3S)-piperidin-3-ylmethylJcarbamate

Prepared from (3S)-N-methylpiperidine-3-carboxamide (Preparative Example 32) in the same manner as the (3R) isomer described in Preparative Example 33. Product obtained as a colorless oil (340 mg, 51% overall). LC/MS 1.76 min, [M+l ]⁺ 229

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Preparative Example 35

<img file="CA2974477C_D0165.tif" />

(tert-butyl methyl[(3 R)-piperidin-3-yl] carbamate

A solution of (R)-3-(tert-butoxycarbonylamino)piperdinc (2.0 g, 10.0 mmol) in THF (25 mL), at 0-5 °C, was treated with triethylamine (1.67 mL, 12.0 mmol) followed by benzyl chloroformate (1.55 mL, 11.0 mmol) and allowed to stir at that temperature for 24 hr. The reaction mixture was then evaporated in vacuo to ~ Ά volume and partitioned between EtOAc (20 mL) and a 1 M HC1 solution (20 mL). The organic portion was then sequentially washed with another portion of 1 M HC1 (10 mL), a saturated aqueous solution of NaHCOj (10 mL), and a brine solution (10 mL). The organic portion was then dried over MgSO&lt;, filtered, and evaporated in vacuo to afford the N-Cbz protected intermediate as a colorless solid (3.2 g, 96%). LC/MS 6.58 min, [M+lf 335. The differentially protected intermediate (1.67g, 5.0 mmol) was then dissolved in DMF (20 mL) at 0-5 °C and treated with a 60% suspension of sodium hydride (240 mg, 6.0 mmol). The reaction mixture was allowed to warm to room temperature for 10 min then recooled and iodomethane (374 pL, 6.0 mmol) added. After 2 hr, and warming to room temperture, an additional amount (40 pL, 1.0 mmol) of iodomethane was added and the reaction mixture allowed to stir 16 hr. After this time the reaction mixture was evaporated in vacuo to ~ % volume and partitioned between EtOAc (50 mL) and a water (50 mL). The organic portion was then washed with a brine solution (50 mL), dried over MgSÛ4, filtered, and evaporated in vacuo to afford a residue which was chromatographed on silica gel with EtOAc/hexanes (20% then 30%) to afford the N-methylated intermediate as a colorless oil (1.59 g, 93%). LC/MS 6.92 min, [M+lf 349. The N-methylated intermediate (1.56 g, 4.48 mmol) was dissolved in EtOH (50 mL), treated with 10% palladium on carbon (250 mg) and hydrogenated at 60-70 psi hydrogen for 6 hr. The crude reaction mixture was then filtered through Celite™, evaporated in vacuo, and redisolved in EtOH (5 mL) which was filtered through a nylon syringe filter to remove

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Preparative Example 36

<img file="CA2974477C_D0166.tif" />

tert-butyl methylf(3S)-piperidin-3-yl] carbamate

Prepared from (S)-3-(tert-butoxycarbonylamino)piperdine in the same scale and manner as the (3R) isomer described in Preparative Example 35. Yields were 96% and 93% for the first two steps. Product yield was treated as quantitative for last step and used as reagent in a further reaction (Example 94). LC/MS 1.30 min, [M+l ]⁺ 215.

Compound Preparations

Example 1

<img file="CA2974477C_D0167.tif" />

Piperidin-l-yl-[5-(5-lri.fluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

[0233J A solution of 4,4,4-Trifluoro-l-[5-(piperidine-l-carbonyl)-thiophen-2yl]-butane-1,3-dione (Preparative Example 3, 333 mg, 1 mmol) in glacial acetic acid (2.5 mL) was treated with hydroxylamine hydrochloride ( 73 mg, 1.05 mol) and heated at 8090 °C for 24 hr, after which time the reaction was evaporated and filtered with the aid of 30% EtOAc/hexanes to afford the 5-hydroxy-4,5,-dihydro-isoxazole intermediate (225 mg). The intermediate was then dissolved in trifluoroacetic acid (2.5 mL) and heated at reflux for 3 days. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (30 then 50%) as eluant to afford product as a colorless

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PCT7US2008/074353 solid (105 mg, 32%). 'H NMR (CDClj) 1.65-1.73 (m, 6 H), 3.66-3.69 (m, 4 H), 6.95 (s, 1 H), 7.28 (d, J = 4.0, 1 H), 7.44 (d, J = 4.0, 1 H). ^I3C NMR 24.7, 26.4, 47.0 (br), 103.7, 110.0, 114.3 (q, J = 267), 128.0, 129.0, 131.0, 140.9, 155.1 (q, J = 40), 157.5, 162.5. ^,9F NMR -64.6. LC/MS 6.63 min, fM+lf 331.

Example 2

<img file="CA2974477C_D0168.tif" />

[5-(4-Meihyl-5-trifluorornethyl-isoxazol-3-yl)-thiophen-2-ylJ-piperidin-l-yl-methanone Method A

[0234] Prepared from 4,4,4-Trifluoro-2-rnethyl-l-(5-(piperidine-l-carbonyl)thiophen-2-yl]-butane- 1,3-dione as described in Example 1. Chromatographed on silica gel with EtOAc/hexanes (40%) as eluant to afford product as a colorless solid (90 mg, 26%). 'H NMR (CDClj) 1.62-1.68 (m, 6 H), 2.33 (d, J = 1.3, 3 H), 3.64-3.67 (m, 4 H), 7.28 (d, J = 4.0, 1 H), 7.41 (d, J = 3.5, I H). ^I3C NMR 7.9, 24.7, 26.3, 46.0 (br), 114.7, 118.8 (q, J = 271), 128.0, )29.0, 131.0, 140.3, 155.1 (q,J = 40), 158.0, 162.3. ”F NMR -63.2. LC/MS 7.92 min, [M+if 344.

Method B

[0235] A solution of S-(4-Methyl-5-trifluoromcthyI-isoxazol-3-yl)-thiophene2-carboxylic acid (Preparative Example 14, 139 mg, 0.5 mmol) in toluene (5 mL) was treated with DMF (~ 5 pL) followed by oxalyl chloride (85 pL, 1.0 mmol). The reaction was allowed to stir for 2 hr at room temperature and 1 hr at 40 °C. The reaction was then concentrated in vacuo to afford crude acid chloride which was dissolved in THF (5 mL) and treated with a THF solution (2 mL) of triethylamine (84 pL, 0.6 mmol) and piperdine (54 pL, 0.55 mmol). The reaction was allowed to stir for 2 hr and concentrated to approximately % volume and partitioned between EtOAc (10 mL) and an aqueous IN hydrochloric acid solution (10 mL). The organic portion was then washed with a second

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PCT/US20WM074353 portion of IN hydrochloric acid solution followed by a saturated aqueous solution of NaHCO₃ (10 mL) and brine (10 mL). The organic solution was then dried over MgSO₄, filtered, and concentrated in vacuo to afford product which required no further purification.

Example 3

Cyclohexyl-[5‘(4-methyl-5-lrifluoromethyl-isoxazol-3-yl)-thiophen-2-yl] -methanone

[0236] A solution of 4-Methyl-3-thiophen-2-yl-5-trifluoroinethyl-isoxazole (Preparative Example 21, 468 mg, 2.0 mmol) in dichloromethane (20 mL) was treated with FeClj (324 mg, 2.0 mmol) followed by cyclohexylcarbonyl chloride (268 pL, 05. mmol). The reaction was heated at reflux for 20 hours followed by evaporation and partitioning between EtOAc (25 mL) and an aqueous IN hydrochloric acid solution (25 mL). The organic portion was then washed with a second portion of 1N hydrochloric acid solution and brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford crude product. The crude product was then chromatographed on silica gel with EtOAc/hexancs (3%) as eluant to afford product as a colorless solid (240 mg, 35%). *Η NMR (CDC1₃)

1.24-1.76 (m, 6 H), 1.84-1.94 (m, 4 H), 2.37 (d, J = 1.3, 3 H), 3.05-3.15 (m, I H), 7.54 (d, J = 4.0, 1 H), 7.74 (d, J = 4.0, 1 H). ^I3C NMR 7.9, 25.9, 26.0,29.7,47.8, 114.8, 118.7 (q, J = 271), 129.1, 131.6, 135.5, 146.0, 155.4 (q, J = 41), 158.0, 196.8. ”F NMR -63.1. LC/MS 7.92 min, [M+l]* 344.

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<img file="CA2974477C_D0169.tif" />

Piperidin-I-yl-[4-(5-trifluoromethyI-isoxazol-3-yl)-phenyl]-methanone

[0237] A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid (Preparative Example 11, 256 mg, 1.0 mmol) in toluene (10 mL) was treated with DMF (~ 5 pL) followed by oxalyl chloride (112 pL, 1.3 mmol). The reaction was allowed to stir for 3 hr then concentrated in vacuo to afford crude acid chloride which was dissolved in THF (5 mL) and treated with a THF solution (2 mL) of triethylamine (174 pL, 1.25 mmol) and piperdine (109 pL, 1.1 mmol). The reaction was allowed to stir for 3 hr and concentrated in vacuo to afford crude product which was filtered with the aid of water and solids air dried to afford product as a colorless solid (295 mg. 91%). ’H NMR (CDClj) 1.55-1.70 (m, 6 H), 3.35 (br s, 2 H), 3.73 (br s, 2 H), 7.04 (s, 1 H), 7.52 (d, J 8.3, 2 H), 7.86 (d, J = 7.9, 2 H). ^,3C NMR 24.7,25.8, 26.8, 43.4,49.0, 103.7, 118.0 (q, J = 270), 127.3, 127.9, 128.4, 139.2, 162.2, 169.4. ^,9F NMR -64.6. LC/MS 6.49 min, [M+l]* 325.

Example 5

<img file="CA2974477C_D0170.tif" />

O

Cyclohexyl-[4-(5-trifluoromethyl-isoxazol-3 -yl)-phenyl]-methanone

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[0238| A solution of N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3yl)-benzamide (Preparative Example 15, 300 mg, 1.0 mmol) in THF (10 mL) was treated with a 1 N THF solution of cyclohexylmagnesium bromide (4 mL, 4 mmol) and stirred for 2 hr then quenched with a saturated ammonium chloride solution (2 mL) and diluted with EtOAc (10 mL). The organic layer was then washed with brine (2x10 mL), dried over MgSO₄, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (81 mg, 25%). 'H NMR (CDCI₃) 1.26-1.58 (m, 5 H), 1.74-1.94 (m, 5 H), 3.23-3.32 (m, I H), 7.09 (s, 1 H), 7.79 (d, J = 8.3,2 H), 7.87 (d, J - 8.3, 2 H). ^I9F NMR -64.6. LC/MS 7.79 min, [M+1 ]⁺ 324.

Example 6

O

2,2-Oimethvl-l-[4-(5-trifluoromethyl-isoxazol-3-yl)-phenyl] -propan- 1-one |0239J Prepared from N-Methoxy-N-meibyl-4-(5-trifluoromethy]-isoxazol-3yl)-benzamide and a 1.7 N THF solution of tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (21 mg, 7%). 'H NMR (CDCI3) 1.37 (s, 9 H), 7.05 (s, 1 H), 7.79 (d, J = 8.4, 2 H), 7.87 (d, J = 7.9, 2 H). ^,9F NMR -64.6. LC/MS 7.28 min, [M+lf 298.

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<img file="CA2974477C_D0171.tif" />

[4-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-phenyl]-piperidin-l-yl-methanone )0240] Prepared from 4-(4-Methyl-5-trifluoromethyI-isoxazol-3-yl)-benzoic acid as described in Example 4. Chromatographed on silica gel with EtOAc/hexanes (20 then 25%) as eluant to afford product as a colorless solid (136 mg, 80%). *H NMR (CDCIj) 1.49-1.64 (m, 6 H), 2.21 (d, J = 1.8, 3 H), 3.31 (br s, 2 H), 3.67 (br s, 2 H), 7.47 (d, J = 7.9, 2 H), 7.60 (d, J = 7.9, 2 H). ^I3C NMR 7.6, 24.7, 25.8, 26.7,43.3,48.9, 115.0, 118.9 (q, J = 271), 127.6, 128.7, 128.8, 138.6, 154.8 (q, J = 40), 163.2, 169.4. ^,9F NMR -63.3. LC/MS 6.65 min, [M+if 339.

Example 8

<img file="CA2974477C_D0172.tif" />

o

Cyclohexyl-[4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-phenyl]-methanone

[0241] Prepared from N-Methoxy-N-methyl-4-(4-methy)-5-trifluoromethylisoxazol-3-yl)-benzamide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless solid (130 mg, 19%). ‘H NMR (CDCh) 1.23-1.56 (m, 5 H), 1.71-1.91 (m, 5 H), 2.27 (d, J = 0.9, 3 H), 3.223.30 (m, 1 H), 7.71 (d, J = 7.9,2 H), 8.04 (d, J = 8.3, 2 H). ^|9F NMR -63.3. LC/MS 7.88 min, [M+l]⁺ 338.

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Example 9

F F

<img file="CA2974477C_D0173.tif" />

Ο

2,2-Dimethyl-l-[4-(4-methyl-5-trifluoromethyl-isoxazol-3-yI)-phenylJ-propan-l-one |0242] Prepared from N-Methoxy-N-methyl-4-(4-rnethyl-5-trifluoromethylisoxazol-3-yl)-benzamide and tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless solid (53 mg, 9%). 'H NMR (CDCI3) 1.37 (s, 9 H), 2.29 (d, J = 1.3, 3 H), 7.68 (d, J = 7.9,2 H), 7.81 (d, J = 8.3,2 H). ^I9F NMR -63.2. LC/MS 7.42 min, [M+lf 312.

Example 10

Piperidin-l-yl-[5-(5-trifluororr.elhyl-[!,2.4Joxadiazol-3-y!)-thiophen-2-yl]-methanone |0243] A solution of 5-(Piperidine-1 -carbonyl)-thiophene-2-carbonitrile (Preparative Example 18, 1.27 g, 5.77 mmol) in EtOH/water (20 mL/4 mL) was treated with sodium acetate (638 mg, 6.92 mmol) followed by hydroxylamine hydrochloride (481 mg, 6.92 mmol) and the resulting mixture heated at reflux for 2 hr then evaporated in vacuo. The resulting solids were filtered with the aid of water and air dried for 1.25 g (86%) of intermediate amidoxime. The intermediate amidoxime (1.15 g, 4.54 mmol) was dissolved in toluene (30 mL), treated with trifluoroacetic anhydride (1.89 mL, 13.62 mmol), and heated at reflux for 3 hr. The reaction was allowed to cool to room temperature and stir 16 hr then evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (20 then 40%) as eluant to afford product as a colorless

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PCT/US2008/074353 solid (953 mg, 63%). 'll NMR (CDClj) 1.66-1.73 (m, 6 H), 3.66-3.70 (m, 4 H), 7.32 (d, J = 4.0, 1 H), 7.80 (d, J = 4.0,1 H). ^I3C NMR 24.6, 26.3, 45.5 (br), 48.3 (br), 116.0 (q, J - 274), 128.2, 129.2, 130.7, 142.5, 162.4, 165.0, 166.1 (q, J = 45). ^I9F NMR -65.8. LC/MS 6.50 min, [M+l]⁺332.

Example 11

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid dimethylamide

J0244J Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and dimethylamine hydrochloride by the method described in Example 2 Method B utilizing an additional equivalent of triethylamine. The reaction mixture was evaporated to a solid then triturated and filtered with the aid of water to afford product as a colorless solid (110 mg, 72%). 'H NMR (CDClj) 2.37 (s, 3 H), 3.22 (br s, 6 H), 7.41 (d, J = 4.0, 1 H), 7.47 (d, J = 4.0, 1 H). ^I3C NMR 7.9, 37.0 (br), 39.8 (br), 114.7, 118.8 (q, J = 271), 128.0,129.7, 131.6, 140.9, 155.7 (q, J = 41), 158.0, 163.7. ^I9FN.MR -63.2. LC/MS 6.03 min, [M+l]’ 305.

Example 12

5~(4'Melhyl-5-trifluoromethyl-isoxazol-3~yl)-thiophene-2-carboxylic acid (2-chlorophenyl)-amide

[0245] Prepared from 5-(4-MethyL5-trifluoromethyl-isoxazoI-3-yl)thiophene-2-carboxylic acid and 2-chloroaniline by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by

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PCT/US2008/074353 water. The crude solid was then chromatographed on silica gel with EtOAc/hexanes (10 then 15%) as eluant to afford product as a colorless solid (42 mg, 43%). *H NMR (CDClj) 2.39 (d, J = 1.3,3 H), 7.10 (id, J - 7.9,1.3,1 H), 7.33 (td, J = 7.9,1.3, I H), 7.42 (dd, J = 8.3,1.8,1 H), 7.56 (d, J = 4.0, 1 H), 7.69 (d, J - 4.0,1 H), 8.34 (s, 1 H), 8.46 (dd, J = 1.3, 1 H).ⁱ³CNMR 8.0, 114.8, 118.7 (q, J = 271), 123.2, 125.4, 128.2, 129.0, 129.3, 134.0, 134.3, 141.7, 155.5 (q, J = 40), 157.8, 159.0. ⁱ⁹FNMR -63.1. LC/MS 7.19 min.

[M+lf 387.

Example 13

F

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid cyclopropylmelhyl-amide |0246) Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-.3-yl)thiophene-2-carboxylic acid and cyclopropylmethylamine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then triturated with a 25% EtOAc/hexanes solution (3 x 1 mL) and air dried to afford product as a colorless solid (H0mg,67%). 'HNMR(CDCh) 0.27-0.32 (m, 2 H), 0.55-0.61 (m, 2 H), 1.03-1.12 (m, 1 H), 2.37 (d, J = 0.9, 3 H), 3.31 (d, J = 5.7, I H), 3.33 (d, J = 5.7, 1 H), 6.23 (br s, 1 H). 7.50 (d, J = 4.0, 1 H), 7.56 (d, J = 4.0, I H). ^I9F NMR -63.1. LC/MS 6.5 min, [M+l f 331.

Example 14

7~Ç »

F O-N

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[5-(5-Difluoromethyl-4-methyi-isoxazol-3-yl)-lhiophen-2-yl]-piperidin-!-yl-methanone [0247] Prepared from 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid (Preparative Example 26) and piperdine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (54 mg, 66%). *H NMR (CDC1₃) 1.65-1.72 (6, 3 H), 2.34 (s, 3 H), 3.67-3.70 (m, 4 H), 6.80 (t, J = 53.2,1 H), 7.30 (d, J = 4.0, 1 H), 7.43 (d, J = 3.5,1 H). ⁿC NMR 7.7, 24.7, 26.3, -46 (br), 39.8 (br), 108.1 (t, J = 238), 113.5, 127.6, 128.9, 131.6, 140.1, 157.8, 159.5 (q, J = 29), 162.7. ^I9F NMR -118.2 (J = 53.5). LC/MS 6.18 min, [M+l]⁺ 327.

Example 15

[5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-ihiophen-2-yl]-piperidin-I-yl-methanone |0248] Prepared from 5-(3-DifluoromethyI-4-methyl-isoxazol-5-yl)thiophene-2-carboxylic acid (Preparative Example 27) and piperdine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica ge! with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid ( 110 mg, 72%). 'H NMR (CDC1₃) 1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J = 53.2, 1 H), 7.31 (d, J = 4.0, I H), 7.45 (d, J = 4.0, 1 H). ”C NMR 7.7, 24.7, 26.3, ~46 (br), 39.8 (br), 108.7, 110.3 (t, J = 236), 126.8, 128.8, 130.6, 140.6, 158.6 (q, J - 30), 162.1, 162.5. ^I9F NMR -117.4 (J = 53.5). LC/MS 6.36 min, [M+l]’ 327.

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Example 16

<img file="CA2974477C_D0174.tif" />

[5-(5-Methyl-[/, 2,4]oxadiazol-3-yl)-thiophen-2-yl] -piperidin-1 -yl-meihanone

[0249] Prepared from 5-(5-Methyl-[l,2,4]oxadiazol-3-yl)-thiophene-2carboxylic acid (CAS [133380-64-0]) as described in Example 4. Product was obtained as a colorless solid (80 mg, 77%). 'H NMR 1.60 (br m, 6 H), 2.59 (s, 3 H), 3.61 (br m, 4 H), 7.22 (d, J = 4.0, 1 H), 7.61 (d, J = 3.5, 1 H). ^I3C NMR 12.5, 24.7, 26.3, 46.5 (br), 128.7,129.1,130.6,141.0, 162.7,164.2,177.0. LC/MS 5.51 min, [M+lf 278.

Example 17

<img file="CA2974477C_D0175.tif" />

F O-N o (4-Hvdroxy-piperidin-]-yI)-[5-(4-methyl-5-lrifhtoromethyl-isoxazol-3-yl)-thiophen-2-yl}methanone

[0250] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-hydroxypiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (141 mg, 78%). *H NMR (CDCh) 1.58-1.69 (m, 2 H), 1.93-2.00 (m, 2 H), 2.26 (br s, 1 H), 2.37 (s, 3 H), 3.44-3.52 (m, 2 H), 4.00-4.12 (m, 3 H), 7.33 (d, J = 4.0, 1 H), 7.46 (d, J = 3.5, 1 H). ^I3C NMR 7.9,34.4, 42 (br), 66.9, 114.8,118.7 (q, J = 271), 128.0, 129.2, 131.2, 140.1, 155.2 (q, J = 40), 158.1, 162.8. ^I9FNMR -63.1. LC/MS 5.71 min, [M+lf 361.

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Example 18

<img file="CA2974477C_D0176.tif" />

(4-Melhoxy-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yljmethanone

[0251] Prepared from 5-(4Methyl-5-trifluoromethyI-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-methoxypiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (151 mg, 81%). '11 NMR (CDCIj) 1.64-1.72 (m, 2 H), 1.86-1.93 (m, 2 H), 2.33 (d, J = 1.3, 3 H), 3.36 (s, 3 H), 3.47-3.58 (m, 3 H), 3.87-3.95 (m, 2 H), 7.29 (d, J = 3.5, I H), 7.42 (d, J = 4.0, 1 H). '³C NMR 7.9, 30.9,42 (br), 56.1, 75.2,114.7,118.7 (q, J = 271 ), 128.0,129.1, 131.1, 140.3, 155.2 (q, J - 40), 158.0,162.7. ^I9FNMR -63.2. LC/MS6.31 min, [M+lf 375.

Example 19

<img file="CA2974477C_D0177.tif" />

F ON o (1.1 -Dioxo-i lambda-6—ihiomorpholin-4-yl)-(5-(4-methyl-5-trifluoromethyl-isoxazol-3yl)-thiophen-2-yl] -methanone (0252] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and thiomopholine 1,1-dioxide by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a I N aqueous hydrochloric acid solution

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Example 20

<img file="CA2974477C_D0178.tif" />

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-lhiophen-2-yl] -piperazin-1 -yl-methanone, hydrochloride |0253| Prepared from 5-(4-MethyI-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and N-Boc-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford intermediate N-Boc protected product as a colorless solid (165 mg, 74%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately Ά volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (131 mg, 69% overall). *H NMR (D₂O) 2.16 (s, 3 H), 3.22 (m. 4 H), 3.87 (m, 4 H), 7.34 (d, J = 4.0, 1 H), 7.42 (d, J = 4.0, 1 H). ^,9F NMR -63.6. LC/MS 4.34 min, [M+l]⁺ 346.

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Example 21

O-H

<img file="CA2974477C_D0179.tif" />

(4-Hydroxy-4-trifluoromethyl-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3yl)-thiophen-2-yl} -methanone

[0254] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-hydroxy-4-trifluoromethyl-piperdinc by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylainine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford product as a colorless solid (53 mg, 49%). 1H NMR (£)MSO-d6) 1.701.72 (m, 4 H), 2.34 (d, J = 1.8,3 H), 3.24 (br, 2 H), 4.19 (br, 2 H), 6.17 (s, 1 H), 7.56 (d, J = 4.0, 1 H), 7.65 (d, J = 4.0, 1 H). 19F NMR - 83.5, -63.1. LC/MS 6.40 min, [M+l]+ 429.

Example 22

F

<img file="CA2974477C_D0180.tif" />

(3,3-Difluoro-azelidin-]-yl)-[5-(4-methyl-5-triJluoromethyl-isoxazol-3-yl)-thiophen-2-ylJmethanone (02551 Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 3,3-difluoroazetidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid

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Example 23

<img file="CA2974477C_D0181.tif" />

[5-(4-Methyl-5-trifluoromethyi-isoxazol-3-yl)-lhiophen-2-ylJ-((S)-2-pynolidinUylmethyl-pyrrolidin-l-yl)-methanone |0256| Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and (S)-(+)-l-(2-pyrrolidinylmethyl)-pyrrolidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCOj solution followed by water to afford product as a pale yellow solid (88 mg, 85%). 'H NMR (CDCI₃) 1.76 (m, 4 H), 1.96-2.10 (m, 4 H), 2.37 (d, J = 1.3, 3 H), 2.56-2.64 (m, 6 H), 3.80 (m, 2 H), 4.48 (m, I H), 7.50 (d, ) = 4.0,1 H), 7.57 (br, I H). ^I9F NMR-63.2. LC/MS 4.66 min, [M+if 414.

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Example 24

<img file="CA2974477C_D0182.tif" />

((R)-3-Hydroxy-piperidin-l-yl)-[5-(4-meihyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2yl]-methanone

J0257J Prepared from 5-(4-Methyl-5-tnfluoromethyl-isoxazol-3-yl)thiophcne-2-carboxylic acid and (R)-(+)-3-hydroxypiperidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq. to neutralize the piperdinyl hydrochloride salt) and piperdine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2x5 mL), dried over MgSO₄₎filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (50 then 75 then 100%) as eluant to afford product as a colorless solid (41 mg, 45%). 'HNMRiCDCh) 1.56-1.62 (m, 1 H), 1.62-1.80(m, 1 H). 1.83-2.10 (m, 2 H), 2.36 (d, J = 1.3, 3 11), 2.86 (br, 1 H), 3.50-3.76 (m. 4 H), 3.82-3.98 (m, 2 H), 7.39 (br d, J = 4.0, 1 H), 7.44 (d, J = 4.0, 1 H). ^I3C NMR 7.9, 22.6, 32.5, -48 (br), ~52 (br), 66.2, 114.7, 118.7 (q, J = 271), 128.0, 129.6, 131.3, 140.1, 155.2 (q, J = 40), 157.9, 163.5. ^I9F NMR-63.2. LC/MS 5.65 min, [M+l]⁺361.

Example 25

<img file="CA2974477C_D0183.tif" />

((S)-3-Hydroxy-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyi-isoxazol'3-yl)-lhiophen-2ylj-methanone

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[0258] Prepared in the same manner as the R isomer. Colorless solid (27 mg, 30%). LC/MS 5.68 min, [M+1 ]⁺ 361.

Example 26 ((S)-3-Amino-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2yl]-methanone, hydrochloride

[0259) Prepared from 5-(4-Methyl-5-trifluoromcthyl-isoxa2ol-3-yl)thiophene-2-carboxylic acid and N-Boc-3-(S)-aminopiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a I N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50 then 75%) as eluant to afford intermediate N-Boc protected product as a colorless solid (87 mg, 76%). The Boc-protected intermediate was dissolved in 1,4dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately 'A volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (70 mg, 71% overall). ‘H NMR (D₂O) 1.36 (m, 1 H), 1.58 (m, 2 H), 1.90 (s, 3 H), 1.96 (m, 1 H), 3.08 (m, 3 H), 3.21 (m, 1 H), 3.65 (m, 1 H), 4.18 (br d, J = 11.4, 1 H), 7.06 (br d, 1 H), 7.09 (br d, 1 H). ^,9F NMR -64.6. LC/MS 4.40 min, [M+1]⁺ 360.

Example 27

<img file="CA2974477C_D0184.tif" />

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PCT/US2008/074353 ((R)-3-Amino-piperidin-]-yl)-[5-(4-methyl-5-trifluoromcthyl-isoxazol-3-yl)-thiophen-2yl]-methanone, hydrochloride

[0260J Prepared in the same manner as the S isomer. Colorless solid (15 mg,

20% overall). LC/MS 4.49 min, [M+l]* 360.

Example 28 ((R)-3-Dimethylamino-piperidin-l-yl)-(5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophen-2-y I]-methanone

10261] A suspension of ((R)-3-Amino-piperidin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26,40 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with a 37% aqueous formaldehyde solution (14 pL, 0.5 mmol) followed by sodium triacetoxyborohydride (128 mg, 0.6 mmol) and allowed to stir 24 hr. The reaction was then quenched by pouring onto a mixture of dichloromethane (5 mL) and a saturated aqueous NaHCO₃ solution (5 mL). The organic layer was separated, dried over MgSO&lt;t, filtered, and evaporated to afford product as a colorless oil which solidified on standing (34 mg, 87%). ’H NMR (CDC1₃) 1.46-1.60 (m, 2 H), 1.83-1.90(m, 1 H), 2.02-2.12 (m, 1 H), 2.31 (s, 3 H), 2.34 (d, J = 1.3, 3 H), 2.80-3.00 (m, 2 H), 4.28 (br s, 1 II), 4.50 (br s, 1 H), 7.31 (d, J = 4.0,1 H), 7.43 (d, J = 4.0,1 H). ^I3CNMR 7.9, 24.9,42.4,-48 (br), 61.5, 115.0, 118.8 (q, J = 271 ), 128.0, 129.0, 131.2, 140.4 (q, J = 41 ), 158.0, 162.8. '’FNMR -63.1. LC/MS 4.51 min, [M+l]⁴388.

Example 29

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PCT/US2008/074353 ((S)-3-Dimethylamino-pipendin-l-yl)-(5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone

[0262] Prepared in the same manner as the R isomer. Colorless solid (32 mg,

83%). LC/MS 4.34 min, [M+lf 388.

Example 30 (3,5-Dimethyl-piperazin-l-yl)-[5-(4-melhyl-5-trifuoromethyl-isoxazol-3-yl)-thiophen-2yl]-methanone

[0263] Prepared from 5-(4-MethyI-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 2,6-cis-dimethylpiperazine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperazine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2x5 mL), dried over MgSO₄, filtered, and evaporated to a colorless solid (79 mg, 85%). *H NMR (CDCI3) 1.03 (d, J = 4.8, 6 H), 1.72-2.20 (m, 1 H), 2.29 (s, 3 H), 2.58 (br, 1 H), 2.78-2.90 (m, 2 H), 4.25 (br, 2 H), 7.24-7.26 (m, 1 H), 7.37-7.39 (m, 1 H). ^BC NMR 7.9, 19.4, -50 (br obsc), 51.3, 114.7, 118.7 (q, J = 271), 128.0, 129.3, 131.2, 140.2, 155.1 (q, J = 40), 157.9, 162.4. ^,9F NMR -63.2. LC/MS 4.43 min, [M+lf 374.

Example 31

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5-(4-Meihyl-5-tnfluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid (3-chloropyridin-4-yl)-amide (0264] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and pyridine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO] solution followed by water to afford product as a colorless solid (80 mg, 83%). *H NMR (CDC1₃) 2.40 (s, 3 H), 7.59 (d, J = 4.0, I H), 7.73 (d, J = 4.0, 1 H), 8.46 (s, 3 H), 8.59 (s, 1 H). ^,3C NMR 7.9, 114.5, 114.7, 118.6 (q, J - 271), 129.0, 129.7, 135.2, 140.4, 141.0, 149.4, 149.6, 155.6 (q, J = 40), 157.6, 159.3. ^,9FNMR -63.1. LC/MS 6.68 min. [M+if 388.

Example 32

<img file="CA2974477C_D0185.tif" />

5-(4-Melhyl-5-lrifluoromethyI-isoxazol-3-yl)-lhiophene-2-carboxylic acid (4-chloropyridin-3-yl)-amide |0265] A solution of 3-amino-4-chloropyridinc (129 mg, 1.0 mmol) in THF (2 mL) was treated with solid 5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2carbonyl chloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) and allowed to stir for 1 hr. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (70%) as eluant to afford product as a colorless sohd (31 mg, 16%). ’H NMR (CDC1₃) 2.39 (d, J = 1.5, 3 H), 7.39 (d, J = 5.3, 1 H), 7.56 (d, J = 7.56, 4.1, I H). 7.72 (d, J = 4.1, 1 H), 8.22 (s, I H), 8.33 (d, J = 4.7, I H), 9.61 (s, 1 H). ^I3C NMR 8.0, 114.8, 118.7 (q. J = 271), 129.0, 129, 7,132.9, 134.6, 140.5, 143.8, 146.1, 157.7.159.0, ^l9FNMR-63.1. LC/MS6.34 min, [M+if 388.

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Example 33

<img file="CA2974477C_D0186.tif" />

N-{(R)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl}-thiophene-2-carbonylJ-piperidin3-yl}-acetamide

[0266] A suspension of ((R)-3-Amino-piperidin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)4hiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with tricthylamine (70 pL, 0.5 mmol) followed by acetyl chloride (22 pL, 0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporated and chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) as eluant to afford product as a colorless solid (66 mg, 83%). *H NMR (CDClj) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H), 2.33 (d, J = 1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J = 11.0,1 H), 6 10 (br d, J = 6.6, 1 H), 7.43 (d, J - 4.0, I H), 7.49 (br s, 1 H). ^I3C NMR 7.9, 23.5, 30.1,46.5, 51.0 (br), 114.8, 118.7 (q, J = 271), 128.3, 129.7, 131.7, 140.1, 155.2 (J = 40), 157.9, 163.3, 170.3 ^!9F NMR -63.1. LC/MS 5.72 min, [M+lf 402.

Example 34

<img file="CA2974477C_D0187.tif" />

N-{(S)-I-f5-(4-Methyt-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin3-yl}-acetamide |0267] Prepared in the same manner as the R isomer. Colorless solid (66 mg, 83%). LC/MS 5.60 min, [M+l ]⁺ 402.

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Example 35

<img file="CA2974477C_D0188.tif" />

F O'N o O=S=O

I

N-{(R)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2carbonyl]-piperidin3-yl}-melhanesulfonamide (0268] A suspension of ((R)-3-Amino-piperidin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 ml.) was treated with triethylamine (63 pL, 0.45 mmol) followed by methanesulfonyl chloride (19 pL, 0.24 mmol). The reaction mixture was allowed to stir 48 h, evaporated, and chromatographed on silica gel with EtOAc as eluant to afford product as a colorless foam (61 mg, 70%). *H NMR (CDClj) 1.68 (m, 2 H), 1.88 (m, 2 H), 2.02 (m, 1 H), 2.33 (d, J - 1.8, 3 H), 2.98 (s, 3 H), 3.46 (m, 2 H), 3.57 (m, 1 H), 3.84 (m, 1 H), 4.05 (d, J = 12.7, 1 H), 5.45 (d, J = 7.5, 1 H), 7.39 (d, J = 4.0, 1 H), 7.43 (d, J = 3.5, 1 H). ⁿCNMR 7.9, 2.3.4, 31.6,41.9,47 (br), 52 (br), 49.9, 114.8, 118.7 (q, J =271), 128.2, 129.8, 131.8, 139.6, 155.2 (q, 40), 157.9, 163.5. ^I9F NMR -63.1. LC/MS 5.82 mm, (M+l]⁺ 438.

<img file="CA2974477C_D0189.tif" />

N-{(S)-]-[5-(4-Melhyl-5-trifIuoromethyl-isoxazol-3-yl)-lhiophene-2-carbonyl]-piperidin3-yl}-melhanesulfonamide |0269| Prepared in the same manner as the R isomer. Colorless foam (57 mg, 65%). LC/MS 5.82 min, [M+l Γ 438.

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Example 37

<img file="CA2974477C_D0190.tif" />

((R)-2-Methyl-piperazin-]-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2ylj-methanone, hydrochloride (0270] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2 Method B. Tire reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a I N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford intermediate N-Boc protected product as a colorless solid (106 mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4,-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately Ά volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 86% overall). *H NMR (D₂O) 1.27 (d, J = 7.5, 3 H), 2.02 (s, 3 H), 3.04 (dt, J = 12.7, 3.1, 1 H), 3.12-3.18 (m, 2 H), 3.303.50m (m, 2 H), 4.21 (d, J = 14.5, 1 H), 7.23 (s, 2 H). ^I9F NMR -64.1. LC/MS 4.50 min, [M+l]* 360.

Example 38

<img file="CA2974477C_D0191.tif" />

((S)-2-Methyl-piperazin-J-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yI)-thiophen-2ylj-methanone, hydrochloride

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[02711 Prepared in the same manner as the R isomer. Colorless solid (81 mg, 79%). LC/MS 4.37 min, [M+lf 360.

<img file="CA2974477C_D0192.tif" />

Example 39

<img file="CA2974477C_D0193.tif" />

((R)-2-}iydroxymelhyl-piperazin-l-yl)-[5-(4-methyl-3-lrifhioromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone, hydrochloride

[02721 Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxa2ol-3-yl)thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-hydroxymethyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried afford intermediate N-Boc protected product as a colorless solid (102 mg, 86%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4,-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately '4 volume and diluted with ethyl ether (4 mL). 'The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 83% overall). 'H NMR (D₂O) 2.17 (s, 3 H), 3.26-3.46 (m, 3 H), 3.60-3.80 (m, 3 H), 4.00-4.04 (m, 1 H), 4.48 (dd, J = 12.7, 5.3, 1 H), 4.60 (obs dd, J = 13.2, 3.5, 1 H), 7.46 (d, J = 4.3, 1 H), 7.82 (d, J = 4.0, 1 H). ¹⁹FNMR -63.5. LC/MS 3.89min, [M+lf 376.

Example 40

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PCT/US2008/074353 (S)-Hexahydro-pyrrolo[l,2-a]pyrazin-2-yl-[5-(4-methyl-5-lrifluoromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone

[0273] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (S)-l,4-diazabicyclo[4.3.0]nonanc. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCOj solution followed by water to afford product as a yellow colored solid (82 mg. 85%). ’H NMR (CDCI3) 1.34-1.48 (τη, 1 H), 1.70-1.90 (m, 3 H), 1.92-2.20 (m, 1 H), 2.10-2.26 (m, 2 H), 2.32 (d, J = 1.3, 3 H), 2.80 (br s, 1 H), 3.03-3.11 (m, 2 H), 3.20 (obs br s, 1 H), 4.40 (br s , 2 H), 7.29 (d, J = 4.0, 1 II), 7.41 (d, J = 3.5, 1 H). ^I3C NMR 7.9, 21.3, 27.5, 30.0, -48 (br), 51.8, 53.5, 62.8, 114.7, 118.7 (q, J = 271), 128.0,129.3,131.2,140.2, 155.2 (q, J = 40), 157.9, 162.9. ^,9FNMR-

63.1. LC/MS 4.34 min, [M+lf 386.

Example 41

<img file="CA2974477C_D0194.tif" />

(4-Methyl-piperazin-l-yl)-[5-(4-methyl-5-trifluoromethyI-isoxazol-3-yl)-thiophen-2-yl]~ methanone |0274| A suspension of 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid acid (90 mg, 0.33 mmol) in dichloromethane (2 mL) was treated with 4-dimethylaminopyridine (100 mg, 0.82 mmol), l-(3-dimethylaminopropyl)3-cthylcarbodiimide hydrochloride (157 mg, 0.82 mmol), and N-mcthylpipcrazinc (0.1 mL, 0.90 mmol). A further portion of dichloromethane (2 mL) and DMF (5 drops) was added and the reaction stirred at room temperature for 20 hr. The reaction mixture was partitioned between dichloromethane (20 mL) and a 1 N aqueous hydrochloric acid solution (20 mL). The organic layer was further washed with a a 1 N aqueous

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PCT/I.S2008/074353 hydrochloric acid solution (20 mL), then a 5% aqueous sodium hydroxide solution (2 x 20 mL) followed by brine (20 mL). The organic layer was dried over Na?SO₄, filtered, and concentrated in vacuo to afford a yellow colored oil (66.5 mg). Gradient column chromatography on silica with MeOH/EtOAc (10 to 50%) as eluant to afford product as a colorless solid (26 mg, 22%). ‘H NMR (CD₃OD) 2.40 (s, 3 H), 2.42 (d , J = 1.4, 3 H), 2.59 (t, J = 5.0,4 H), 3.84 (t, J = 5.0, 4 H), 7.52 (d, J = 3.8, 1 H), 7.64 (d, J = 3.8,1 H). ”F NMR -64.8. LC/MS 4.48 min, [M+l ]’ 360.

Example 42

<img file="CA2974477C_D0195.tif" />

(4-Methyl-[l ,4] diazepan-1 -yl)-[5-(4-methyl-5-trifluoromelhyl-isoxazol-3-yl)-thiophen-2yl]-methanone (0275] Prepared from 5-(4-Mcthyl-5-trifluoromcthyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 1 -methyl-[ 1,4]diazepane by the method described in Example 41. Yellow colored solid (49 mg, 37%). ’h NMR (CDC1₃) 1.97-2.05 (m, 2 H),

2.36 (d, J — 1.4, 3 H), 2.40 (s, 3 H), 2.62 (br s , 2 H), 2.74 (br s , 2 H), 3.80 (br s , 2 H),

7.37 (br s, 1 H), 7.45 (d, J = 3.8,1 H). ^I9F NMR -63.1. LC/MS 4.43 min, [M+1 ]⁺ 374.

Example 43

H

I

<img file="CA2974477C_D0196.tif" />

i4-Amino-piperidin-l-yl)-l5-(4-methyl-5-trifluoromethyi-isoxazol-3-yl)-thiophen-2-yl}methanone

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PCT/DS2008/074353 (0276] Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carboxylic acid and piperidin-4-yl-carbamic acid tert-butyl ester by the method described in Example 41. N-Boc intermediate. The crude product was chromatographed on silica with EtOAc/hexanes (25 then 50%) as eluant to afford intermediate as a colorless solid (110 mg, 68%):LC/MS 6.70 min, [M+1 ]⁺ 460. The NBoc intermediate (84.8 mg, 0.18 mmol) in EtOAc (4 mL) was treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 22 hr. The resulting precipitate was filtered and washed with EtOAc (2 x 10 mL). The solids were then partitioned between a 2.5% aqueous sodium hydroxide solution (40 mL) and dichlromethane (20 mL). The aqueous phase was further extracted with dichlromethane (2 x 20 mL) and the combined organics dried over Na₂SO4, filtered, and concentrated in vacuo to afford product as a colorless solid (56 mg, 57% overall). *Η NMR (CDjOD) 1.36-1.50(m, 2 H), 1.98 (d, J = 11.8, 2 H), 2.43 (s, 3 H), 3.02 (m, 1 H), 3.18 (brs , 2 H), 4.40 (br s , 2 H), 7.49 (d, J = 3.6, 1 H), 7.64 (d, J = 3.8, 1 H). ^,9F NMR -64.8. LC/MS 4.51 min, [M+l]⁺ 360.

Example 44

[5-(4-Melhyl-5-trifluoromethyl-isox£izol-3-yl)-thiophen-2-yl]-phenyl-methanone

[0277J Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and benzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (118 mg, 70%). 'H NMR (CDC1₃) 2.33 (d, J = 1.3, 3 H), 7.437.59 (m, 4 H), 7.62 (d, J = 4.0, 1 H), 7.80-7.83 (m, 2 H). ¹³C NMR 7.9, 118.7 (q, J = 271), 128.8, 128.9, 129.4, 133.0, 134.8, 136.3, 137.7, 145.8, 155.5 (q, J = 40), 157.9, 188.0. ¹⁹F NMR-63.1. LC/MS 7.29min, [Mt if 338.

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Example 45

<img file="CA2974477C_D0197.tif" />

F

F O-N

N

4-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonylJ-benzonitrile (0278J Prepared from 4-Methyi-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 4-cyanobenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (130 mg, 36%). 'H NMR (CDCI₃) 2.42 (d, J = 1.3, 3 H), 7.62 (d, J = 4.0, 1 H), 7.67 (d, J = 4.0, 1 H), 7.85 (d, J = 8.3, 1 H), 7.98 (d, J = 7.9,1 H). ^,3C NMR 8.0, 114.9, 116.3, 118.7 (q, J = 271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6,

141.1, 144.6, -155 (q, obscured due to baseline noise), 157.7, 186.4. ^,MF NMR -63.1. LC/MS 7.08 min, [M+l]⁺ 363.

Example 46 (3-Hydroxymethyl-piperidin-1 -yl)-{5-(4-methyl-5-trifliioromeihyl-isoxazol-3-yl)-thiophen2-yl] -methanone

[0279] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 3-piperdinemethanol by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to an oil then partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2x5 mL), dried over MgSO₄, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with

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EtOAc/hexanes (75%) as eluant to (190 mg, 75%). ’H NMR (CDC1₃) 1.28-1.35 (m, 1 H), 1.44-1.56 (m, 1 H), 1.67-1.82 (m, 3 H), 2.28 (d, J = 0.9, 3 H), 2.99 (dd, J = 13.2, 9.7, 1 H), 3.32 (br s, 1 H), 3.41-3.52 (m, 2 H), 4.10 (br s, 1 H), 4.21 (d, J = 114,1 H), 7.29 (d, J = 4.0,1 H), 7.37 (d, J = 4.0,1 H). ^I3C NMR 7.8,24.9, 27.2, 39.1,-49 (br), 64.5,114.8, 118.7 (q, J = 271), 128.1, 129.3, 131.2, 140.3, 155.0 (q, J = 40), 157.9, 162.9. ^,9F NMR -63.2. LC/MS 5.91 min, [M+lf 375.

Example 47

[5-(4-Melhyl-5-trifluoromethyl4soxazol-3-yl)-thiophen-2-ylJ-morpholin-4-yl-methanone |0280] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and morpholine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative, fhe reaction mixture was evaporated to a solid, triturated and filtered with the aid of waler, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (66 mg, 95%). 'H NMR (CDCI3) 2.34 (d, J = 1.3, 3 H), 3.713.77 (m, 8 H), 7.32 (d, J = 4.0,1 H), 7.43 (d, J = 4.0, 1 H). ^,3C NMR 7.9, -48 (br), 67.0, 114.7, 118.7 (q, J = 271), 128.0, 129.5, 131.7, 139.5, 157.9, 162.8. ^I9F NMR -63.2. LC/MS 5.93 min, [M+l f 347.

Example 48

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PCT/LÎS200R/074353 l-(5-(4-Methyl-5-trifluoromelhyl-isoxazol-3-yl)-lhiophene-2-carbonyl]-piperidine-4carbonitrile |0281| Prepared from 5-(5-Trifluoromethyi-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-cyanopiperdine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on a short column of silica gel with EtOAc as eluant to afford product as a colorless solid (91 mg, 61%). *H NMR (CDCh) 1.91-2.06 (m, 4 H), 2.37 (d, J — 1.3, 3 H), 2.97-3.03 (m, 1 H), 3.71-3.79 (m, 2 II), 3.90-3.98 (m, 2 H), 7.34 (d, J = 4.0, 1 11), 7.47 (d, J = 4.0, 1 H). ^,3C NMR 7.9, 26.5, 28.9, 43.6, 114.8, 118.7 (q, J = 271), 120.8,

128.1, 129.5, 131.7, 139.4, 155.2 (q, J = 40), 157.8, 162.9. ^,9FNMR -63.2. LC/MS 6.18 min, [M+l]⁺ 370.

Example 49

<img file="CA2974477C_D0198.tif" />

l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonylJ-piperidine-3carboxylic acid amide

[0282] Prepared from 5-(5-Trifluoromethyl-4-methyI-isoxazoI-3-y))thtophene-2-carboxylic acid and 3-piperidinecarboxamide by the method described in Example 2 Method B reversing the order of addition such that solid acid chlonde was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (120 mg, 97%). 'H NMR (DMSO-r/6) 1.36-1.49 (m, 1 H), 1.55-1.75 (m, 2 H), 1.89-1.93 (m, 1 H), 2.35 (d, J = 1.8, 3 H), 3.03 (brs, 2 H), 4.10

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Example 50

[5-(4-Methyl-5-lrifluoromethyi-isoxazol-3-yl)-thiophen-2-yl]-(3-morpholin-4-ylpiperidin-l-yl)-methanone, hydrochloride

[0283] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 4-piperidin-3-yl-morpholine, di-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. An additional 2 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCOi solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO&lt;, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (61 mg, 65%). LC/MS 4.66 min, [M+lf 430.

Example 51

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[3-(4-Methyl-piperazin-l-yl)-pîperidin-]-ylJ-[5-(4-methyl-5-trifluoromethyl-isoxazol-3yl)-thiophen-2-yl]-methanone, hydrochloride

[0284] Prepared from 5-(5-Trifluoromethyl-4-mcthyl-isoxazol-3-yl)thiophene-2-carboxylic acid and l-Methyl-4-piperidin-3-yl-piperazine, tri-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. An additional 3 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCOj solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO₄, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (47 mg, 53%). LC/MS 4.62 min, [M+l]* 443.

Example 52 (3-Dimethylaminomethyl-piperidin-l-yl)-[5-(4-methyl-5-lrifluoromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone, hydrochloride |0285] A solution of (3-HydroxymethyI-piperidin-l-yl)-(5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone (Example 46, 170 mg, 0.454 mmol) and triethylamine (111 pL, 0.795 mmol) in CHjCL (4 mL) at -10 to -5 °C, was treated with methanesulfonyl chloride (53 pL, 0.681 mmol) and allowed to stir for 1 hr. The reaction mixture was then quenched with CHjCh (4 mL) and water (4 mL), and the organic portion further washed with a 1 N aqueous hydrochloric acid solution (2x3 mL) followed by a saturated aqueous NaHCOi solution (2x3 mL) and brine (3 mL). The

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PCT.^/US2(IO8/O74353 organic layer was then dried over MgSO₄, filtered, and evaporated to the Methanesulfonic acid l-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yI)-thiophene-2-carbonyl]-piperidin-3ylmethyl ester intermediate as an oil (180 mg, 88%). A solution of the intermediate sulfonate (60 mg, 0.1326 mmol) in acetonitrile (2 mL) was treated with a 2 N THF solution of dimethylamine (265 pL, 0.5304 mmol) and heated at 45 °C in a sealed tube for 2 weeks. The reaction was then evaporated and the resulting oil triturated with water (3x2 mL) then dissolved in EtOAc (2 mL), dried over MgSO₄, filtered, and evaporated. The crude oil product was then dissolved in diethyl ether (2 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (30 mg, 52%). 'H NMR (CDC1₃) 1.12-1.29 (m, 1 H), 1.44-1.58 (m, 1 H), 1.67-1.79 (m, 2 H), 1.80-1.90 (m, 1 H), 2.05-2.15 (m, 8 H), 2.29 (d, J = 1.3,3 H), 2.70 (br s, 1 H), 3.00 (br s, J H), 4.10-1.40 (br m, 2 H), 7.28 (d, J = 3.5, 1 H), 7.38 (d, J = 3.5, 1 H). ^I3C NMR 7.9, 25.2, 29.7, 34.9, 46.1, 63.3, 114.7, 118.8 (q, J = 271), 128.0, 129.1, 131.0, 140.8, 155.1 (q, 3 = 40), 158.0, 162.8. ^|9FNMR -63.1 LC/MS 4.52 min, [M+lf 402.

Example 53

<img file="CA2974477C_D0199.tif" />

[5-(4-Meihyl-5-trifluoromethyi-isoxazo!-3-yl)-thiophen-2-yl]-(3-morpholin-4-ylmethylpiperidin-1 -yl)-methanone

[0286] Prepared from Methanesulfonic acid l-[5-(4-methyl-5-trifluoromethylisoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl (60 mg, 0.1326 mmol) and morpholine (46 pL, 0.530 mmol) by the method described in Example 52. The reaction mixture was heated at 65 °C for 10 days and isolated as the free-base oil (5) mg, 86%).

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PCT/US2008/07-I353 'H NMR (CDClj) 1.12-1.29 (m, 1 H), 1.44-1.58 (m, 1 H), 1.68-1.90 (m, 3 H), 2.12-2.16 (m, 2 H), 2.20-2.32 (m, 5 H), 2.34-2.42 (m, 2 H), 2.76 (br s, 1 H), 3.04 (br t, J = 11.4, 1 H), 3.57 (s, 4 H), 4.18 (br s, 1 H), 4.32 (br s, 1 H), 7.29 (d, J = 4.0, 1 H), 7.37 (d, J = 3.5, 1H). ¹⁹FNMR -63.1. LC/MS 4.62 min, [Mtif 444.

Example 54 ]3-(4-Methyl-piperazin-I-ylmethyl)-piperidin-I-yl}-[5-(4-methyl-5-trifluoromethylisoxazol-3-yl)-thiophen-2-yl]-methanone

[0287} Prepared from Methanesulfonic acid l-[5-(4-methyl-5-trifluoromethylisoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl (60 mg, 0.1326 mmol) and NMethylpiperazine (58 pL, 0.530 mmol) by the method described in Example 52. The reaction mixture was heated at 65 °C for 10 days and isolated as the free-base oil (44 mg, 73%). ‘H NMR (CDC1₃) 1.14-1.30 (m, I H), 1.42-1.58 (m, 1 H), 1.66-1.90 (m, 3 H). 2.10-2.45 (m, 16 H), 2.34-2.42 (m, 2 H), 2.76 (br s, 1 H), 3.02 (br t, J = 10.5, 1 H), 4.18 (br s, 1 H), 4.28 (br s, 1 H), 7.31 (br d, J = 3.5,1 H), 7.38 (d, J = 4.0,1 H). ¹⁹F NMR -

63.1. LC/MS 4.64 min, [M+ if 457.

Example 55

O Q'

2-DimethyIamino-N-{(S)-l-[5-(4-methyI-5-irifluoromethyl-isoxazol-3-yl)-thiophene-2carbonyl]-piperidin-3-yl]-acetamide

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[0288] A solution of ((S)-3-Amino-piperidin-I-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophcn-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) in THF (3 mL) was treated with dimethylaminoacetyl chloride hydrochloride (40 mg, 0.24 mmol) followed by tnethylamine (62 pL, 0.44 mmol). The resulting mixture was stirred for 16 hr, evaporated to an oil, and dissolved in water (3 mL). The solution was then basified with a saturated aqueous K2CO3 solution and the precipitated product filtered, washed with water, and air dried to afford product as a colorless solid (69 mg, 78%). 'H NMR (CDCI3) 1.62-1.72 (m, 2 H), 1.78-1.84 (m, 1 H),

1.94- 2.04 (m, 1 H), 2.25 (s, 6 H), 2.32 (d, J = 1.3,3 H), 2.49 (s, 2 H), 3.24-3.40 (m, 2 H),

3.94- 4.04 (m, 2 H), 4.12 (br d, J - 13.2, 1 H), 7.23 (br d, J = 7.5, 1 H), 7.44 (d, J - 4.0, 1 H), 7.47 (br s, 1 H). ^I3C NMR 7.9, 23.5, 30.4, 45.6,46.2, -51 (br), 63.2, 114.8,118.8 (q, J = 271), 128.3, 129.5, 131.6, 140.2, 155.1 (q, J = 40), 157.9, 163.1, 170.7. ^,9F NMR -

63.1. LC/MS 4.59 min, [M+l]⁴ 445.

Example 56

<img file="CA2974477C_D0200.tif" />

N-{(S)-l-[5-(4-Melhyl-54rifluoromeihyl4soxazol-3-yl)-thiophene-2-carbonylJ-piperidin3-yl]-2-morpholin-4 -yl-acetamide |0289| A solution of ((S)-3-Ammo-piperidin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) and tnethylamine (69 pL, 0.42 mmol) in THF (3 mL) was treated with chloroacetyl chloride (18 pL, 0.22 mmol), stirred for 1 hr and evaporated to a solid. The solid was triturated and filtered with the aid of water, then air dried to provide the 2Chloro-N-{(S)-l-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yi)-thiophene-2-carbonyl]piperidin-3-yl}-acetamide intermediate as a colorless solid (75 mg, 86%). LC/MS 6.13 min, [M+l]⁴ 436. The chloroacetyl intermediate (35 mg, 0.08 mmol) was dissolved in

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PCT/US2008/074353 acetonitrile (3 mL) containing anhydrous K2COJ, treated with morpholine (14 pL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide an oil which was then triturated with water (3x2 mL), dissolved in EtOAc (4 mL), dried over MgSO₄, filtered, and evaporated to afford product as an oil (34 mg, 87%). 'H NMR (CDC1₃) 1.62-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.29 (d, J = 1.3, 3 H), 2.45-2.48 (m, 4 H), 2.93 (s, 2 H), 3.52 (br s, 1 H), 3.63-3.67 (m, 4 H), 3.72-3.92 (m, 2 H), 3.98-4.08 (m, 1 H), 7.32 (br s, 1 H), 7.41 (s, 2 H). ^I9F NMR -63.1. LC/MS 4.68 min, [M+l ]⁺ 487.

Example 57

<img file="CA2974477C_D0201.tif" />

2-(4-Methyl-piperazin-l-yl)-N-{(S)-l-/5-(4-meihyl-5-lrifluoromethyI-isoxazol-3-yl)lhiophene-2-carbonyl]-piperidin-3-yl}-aceiamide

[0290] 2-Chloro-N-{(S)-l-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carbonyl]-piperidin-3-yl)-acetamide (35 mg, 0.08 mmol, as prepared in Example 56) was dissolved in acetonitrile (3 mL) containing anhydrous K.2CO3, treated with N-methylpiperazine (18 pL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide a homogeneous solution which was extracted with EtOAc (2x4 mL), dried over MgSO₄, filtered, and evaporated to afford product as an foam (34 mg, 85%). 'H NMR (CDCI₃) 1.60-1.76 (m, 3 H), 1.881.98 (m, 1 H), 2.22 (s, 3 H), 2.29 (d, J = 1.3, 3 H), 2.32-2.52 (m, 8 H), 2.92 (s, 2 H), 3.52 (br s, 1 H), 3.48 (br s, 2 H), 3.72-4.46 (m. 3 H), 7.32-7.44 (br m, 3 H). ^,9F NMR -63.1. LC/MS 4.59 min, [M+l Γ 500.

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Example 58

<img file="CA2974477C_D0202.tif" />

(3-Hydroxy-azetidin-J-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yljmethanone

[0291] Prepared from 5-(5-Trifluoromelhyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 3-hydroxyazetidine hydrochloride by the method described in Example 41. Colorless solid (78 mg, 73%). *H NMR (DMSO-&lt;/6) 2.38 (s, 3H), 3.77 - 3.90 (m, IH), 4.19-4.38 (m, 2H), 4.52 - 4.63 (m, IH), 4.65 - 4.78 (m, 1H), 5.88 (d, J - 5.9, IH), 7.62 (d, J = 4.0, IH), 7.73 (d, J = 4.0, IH). ^I3C NMR 7.4, 58.9, 60.6,62.5, 116.0 (q, J = 2), 118.5 (q, J = 271), 130.3, 130.5, 131.0, 140.2, 153.2 (q, J = 40), 157.9,160.8. ^,9F NMR -62.3. LC/MS 5.42 min, (M+l]⁺ 333.

Example 59

<img file="CA2974477C_D0203.tif" />

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid 1-methylpiperidin-4-yl ester

[0292J Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 1 -methyi-piperidin-4-ol by the method described in Example 41. Colorless solid (51 mg, 75%). 'H NMR (CD₃OD) 1.85 - 1.98 (m, 2H), 2.03 - 2.15 (m, 2H), 2.38 (s, 3H), 2.43 (br q, J = 1.3, 3H), 2.40 - 2.56 (m, 2H), 2.73 2.86 (m, 2H), 5.02 - 5.14 (m, IH), 7.69 (d, J = 4.0, IH), 7.90 (d, J = 4.0, IH). ^I3C NMR 7.9, 31.4, 46.2, 53.5 (br), 71.9 (br), 116.8 (br), 120.3 (q, J = 270), 130.7, 135.1, 136.0, 137.5,159.4,162.3. ^I9F NMR -64.8. LC/MS 4.75 min, [M+l]* 375.

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5'(4-Methyl-5-irifluoromelhyl-isoxazcd-3-yl)-lhiophene-2-carboxylicacid prop-2ynylamide |0293] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophenc-2-carboxylic acid and propragylamine by the method described in Example 2 Method B. Pale yellow solid (122 mg, 97%). *H NMR (DMSO-^) 2.41 (d, J ~ 1.3, 3H), 3.25 (t, J = 2.6, 1H), 4.13 (dd, J = 5.7, 2.6, 2H), 7.79 (d, J = 4.0, IH), 7.97 (d, J = 4.0, IH), 9.29 (t, ) = 5.7, IH). ^,9F NMR-62.30. LC/MS 6.07 min, [M+lf 315.

Example 61

<img file="CA2974477C_D0204.tif" />

5-(4-Methyl-5-trifluorome:hyl-isoxazol-3-yl)-thiophene-2-carboxylic acid methyi-prop-2ynyl-amidc (0294) Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and N- methyl propragylamine by the method described in Example 2 method B. Colorless solid (128 mg, 98%). *H NMR (CDClj) 2.37 (d, J = 1.8, 3H), 3.28 (br s, 3H), 4.34 (br s, 2H), 7.48 (d, J = 3.5, IH), 7.51 (br d, IH). ¹⁹F NMR 63.13. LC/MS 6.36 min, [M+l]⁺329.

Example 62

<img file="CA2974477C_D0205.tif" />

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PCT/US2008/074353 (3-Methylaminomelhyl-piperidin-l-yl)-[5-(4-methyl-5-trifluorome!hyl-isoxazol-3-yl)thiophen-2-yl]-methanone, hydrochloride

[0295] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and 3-(tert-butoxycarbonylamino)piperdine (CAS [17260305-3], CHN Technologies, Woburn MA, USA) by the method described in Example 2 method B. The intermediate Boc-protected adduct was chromatographed on silica gel with EtOAc to afford product as a colorless solid (54 mg, 44%). LC/MS 7.26 min, [M+l]* 488. The Boc-protected intermediate was dissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (4 mL) and stirred for 4 lu-, after which time the reaction mixture was evaporated to approximately Vi volume and diluted with ethyl ether ( 10 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (47 mg, 100%, 44% overall). LC/MS 4.58 min, [M+l]* 388.

Example 63

H ((R)-3-Amino-pyrrolidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2yl] -methanone, hydrochloride

[0296] Prepared from 5-(5-Trifluoromethyl-4-mcthyl-isoxazol-3-yl)thiophcnc-2-carboxyhc acid and (R)-(+)-3-(Boc-amino)pyrrolidine (CAS [122536-77-0], CHN Technologies, Wobum MA, USA) by the method described in Example 2 Method B. The intermediate Boc-protected adduct was chromatographed on silica gel with EtOAc to afford product as a colorless solid (66 mg, 30%). LC/MS 6.54 min, [M+I]* 446. The Boc-protected intermediate was dissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (4 mL) and stirred for 24 hr, after which time the reaction mixture was evaporated to approximately ‘Λ volume and

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PCT/l)S20(i8/074353 diluted with ethyl ether (10 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (45 mg, 80%, 24% overall). LC/MS 4.29 min, [M+1 ] 346.

Example 64

H ('(S)-3-Amino-pyrrolidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2ylj-methanone

[0297J Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and (S)-(-)-3-(Boc-amino)pyno)idine (CAS [122536-76-9], CHN Technologies, Woburn MA, USA) by the method described in Example 2 Method B. The intermediate Boc-protected adduct was chromatographed on silica gel with EtOAc to afford product as a colorless solid (145 mg, 65%). LC/MS 6.54 min, [M+l]⁺446. The Boc-protected intermediate was dissolved in 1,4-dioxane (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (4 mL) and stirred for 24 hr, after which time the reaction mixture was evaporated to approximately 'Λ volume and diluted with ethyl ether (10 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (90 mg, 72%, 47% overall). LC/MS 4.29 min, [M+1 ]⁺ 346.

Example 65

O (S)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonylJ-piperidine-3carboxylic acid ethyl ester

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PCT/US2008/074353 |0298] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and (S)-(+)-nipecotic acid, ethyl ester (TCI America, Portland OR, USA) by the method described in Example 2 Method B. Colorless solid (415 mg, 91%). 'H NMR (CDCI₃) 1.19 (t, J = 7.0,3H), 1.50-1.60 (m, 1H), 1.66-1.82 (m, 2H), 2.02-2.12 (m, 1H), 2.29 (d, J = 1.4, 3H), 2.46-2.56 (m, 1H), 3.13 (t, J = 11.0, 1H), 3.28 (br s, 1H), 4.08 (q, J 7.0, 3H), 4.10 (obs m, 1H), 4.34 (br s, 1H), 7.28 (d, J = 4.0, 1H), 7.39 (d, J = 3.5,1H). ^I9FNMR-63.12. LC/MS 6.74 min, [M+lf 417.

Example 66 .0 (R)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3carboxylic acid ethyl ester

[0299) Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and (R)-(-)-nipecotic acid, ethyl ester (TCI America, Portland OR, USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%). LC/MS 6.76 min, [M+lf 417.

Example 67 ((S)-3-DimethyIamino-pyrrolidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone

[0300) A solution of ((S)-3-amino-pyrrolidin-l-yl)-[5-(4-methyl-5lrifluoiOmethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 64, 80

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PCTUS2008/074353 mg, 0.21 mmol) in dichloromethane (10 mL) was treated with a 37% aqueous formaldehyde solution (58 pL, 2.10 mmol) followed by sodium triacetoxyborohydride (445 mg, 2.10 mmol). The mixture was stired for 24 h then quenched with saturated aqueous solution of NaHCOj (10 mL) and stirred for 30 min. The organic portion was further washed with an additional portion of NaHCOj solution (10 mL) followed by a brine solution (10 mL), then dried over MgSO₄, filtered, and evaporated in vacuo to afford product as a colorless solid. *Η NMR (CDClj) 1.70-2.00 (m, 1H), 2.06-2.20 (m, 1 H), 2.23 (s, 6 H), 2.29 (s, 3H), 2.62-2.80 (m, 1 H), 3.32-4.00 (m, 4H), 7.42 (d, J = 4.0, 1H), 7.47 (brd, 1H). LC/MS 4.25 min, [M+lf 374.

Example 68 ((R)-3-Dimethylamino-pyrroiidin-l-yl)-[5-(4-methyl-5-trifluorome.thyl-isoxazol-3-yl)thiophen-2-yl)-methanone

[0301] Prepared from ((R)-3-amino-pyrrolidm-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-lhiophen-2-yl]-methanone, hydrochloride (Example 63, 40 mg, 0.105) in the same manner as the S isomer. LC/MS 4.27 min, [M+lf 374.

Example 69

<img file="CA2974477C_D0206.tif" />

((S)-3-Hydroxymethyl-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophen-2-ylJ-methanone

[0302] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B)

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PCT/LS2008/074353 and (S)Tpipendin-3-yl-metli£nol, hydrochloride (76 mg, 0.5 mmol) by the method used in Example 46 for the achiral isomer. Gummy solid (70 mg, 74%). LC/MS 5.85 min, [M+lf 375.

Example 70

<img file="CA2974477C_D0207.tif" />

((R)-3-Hydroxymethyl-piperidin-1 -yl)-f5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)ihiophen-2-yl]-methanone (0303] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-l-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) in the same manner as the S isomer (Example 69). Gummy solid (56 mg, 60%). LC/MS 5.86 min. [M+l ]* 375.

Example 71

<img file="CA2974477C_D0208.tif" />

((R)-3-Dimethylaminomethyl-piperidin-]-yl)-[5-(4-methyI-5-trifhioromethyl-isoxazol-3y!)-thiophen-2-ylJ -methanone (0304] A solution of dimethyl-(S)-l-piperidin-3*ylmethyl-amine, dihydrochloride (Preparative Example 29, 108 mg, 0.5 mmol) in THF/DMF (3 mL/500 pL) was treated with triethylamine (95 pL, 1.0 mmol) followed by 5-(5-Trifluoromethyl4-mcthyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg. 0.25 mmol, as prepared in Example 2 Method B). The reaction mixture was vigorously stirred or 16h then

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PCT/ÜS2(l08/074353 evaporated and diluted with water (5 ml.). The crude reaction mixture was extracted with EtOAc (2x3 mL) which was then washed with a 1 N NaOH solution (2x3 mL), dried over MgSO«, filtered, and evaporated in vacuo to afford product as a colorless solid. The solid was dissolved in a EtOAc/hcxancs (1:1) mixture (1 mL), filtered through a PTFE syringe filter, and again evaporated in vacuo to afford product as a colorless solid (31 mg, 31%). LC/MS 5.13 min, [M+lf 402.

Example 72 ((S)-3-Dimethylaminomeihyl-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3yI)-thiophen-2-yl] -methanone

[0305] Prepared from dimethyl-(R)-l-pipcndin-3-ylmethyl-amine, dihydrochloride (Preparative Example 28, 108 mg, 0.5 mmol) and 5-(5-Trifluoromethyl4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) as described for the R isomer (Example 70). Colorless solid (41 mg, 41%). LC/MS 5.28 min, [M+lf 402.

Example 73 .0

<img file="CA2974477C_D0209.tif" />

(S)-J -[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyI} -piperidine-3carboxylic acid amide

[0306) A solution of (S)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophene-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (Example 65, 88 mg, 0.20

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PCT/US2008/074353 inmol) in 7N methanolic ammonia (5 mL) was heated at 60 °C in a sealed vial for 48 hr. After this time the reaction mixture was evaporated and triturated and filtered with the aid of water. The filtered solids were air dried to aflbid product as a colorless solid (67 mg, 86%). LC/MS 5.52 min, [M+lf 388.

Example 74

<img file="CA2974477C_D0210.tif" />

(R)-l-f5-(4-Methyl-5-trifluoromeihyl-isoxazol-3-yl)-thiophene-2-carbonylJ -piperidine-3carboxylic acid amide

[0307] Prepared from (R)-l-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)thiophcnc-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (Example 66, 88 mg, 0.20 mmol) in the same manner as the S isomer (Example 72). Colorless solid (68 mg, 88%). LC/MS 5.52 min, [M+lf 388.

Example 75

<img file="CA2974477C_D0211.tif" />

(3-Methylamino-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2· yl]-methanone

[03081 A solution of 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene2-carbonyl chloride (74 mg. 0.25 mmol, as prepared in Example 2 Method B) in THF (2 mL) was treated with a THF solution (2 mL) of methyl-piperidin-3-ylmethyl-carbamic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (112 mg, 0.30 mmol, Preparative Example 30) and diisopropylcthylamine (52 pL, 0.30 mmol). 'ITie reaction mixture was

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PCT,US2008/074353 allowed to stir for 2 hr then evaporated to ~1 mL volume and diluted with EtOAc (10 mL). The resulting solution was then washed with a IN aqueous HC1 solution (10 mL), then a saturated aqueous solution of NaHCOj (10 mL) followed by a brine solution (10 mL). The organic portion was then dried over MgSCU, filtered, and evaporated in vacuo to afford crude oil. The oil was chromatographed on silica gel with EtOAc/hexane (75%) to afford the Fmoc-protected intermediate as a colorless oil (103 mg, 69%). LC/MS 7.63 min, [M+l)⁺ 596. The intermediate was then dissolved in DMF (2.5 mL), treated with morpholine (200 pL), and stirred for 4 h resulting in precipitated colorless solids. The reaction mixture was cooled to 0 °C and filtered through a glass wool plug tv remove solids, then evaporated in vacuo to afford crude product which was chromatographed on a small silica gel column with EtOAc then MeOH/EtOAc (10%) containing 2% triethylaminc to afford product as a copper colored oil (59 mg, 89%, 61% overall). 'H NMR (CDCh) 1.54-1.64 (m, 2H), 1.84-1.92 (m, 1 H), 2.05-2.14 (m, 1H), 2.37 (d, J = 1.8, 3H), 2.51 (br s, 3 H), 2.70-2.80 (m, 1 H), 3.13 (dd, J = 13.2, 9.2, 1H), 3.22-3.30 (m, 1H), 4.10 (br, 1H), 4.34 (br d, J = 11.0, 1H), 5.05 (br s, 1H), 7.37 (d, J = 4.0, 1H), 7.46 (d, J-4.0,1H). ^,9F NMR-63.11. LC/MS 4.46 min, [M+l]⁺ 374.

Example 76

5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-ihiophene-2-carboxylic acid cyclohexylamide |0309[ Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and cyclohexylamine by the method described in Example 2 Method B reversing the order of addition such that intermediate solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. Colorless solid (80 mg, 89%). 'H NMR (CDClj) 1.18-1.36 (m, 1H), 1.36-1.50 (m, 1H), 1.60-1.82 (m, 4H),

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1.98-2.10 (m, 2H), 2.37 (d, J = 0.9, 3H), 3.90-4.04 (m, I H), 5.88 (br d, J = 7.0, IH), 7.49 (d, J --= 4.0, IH), 7.51 (d, J = 3.5, IH). ^I9F NMR -63.36. LC/MS 7.18 min, [M+lf 359.

Example 77 (S)-5-(4-Meihyl-5-lrifluoromethyl-isoxazol-3-yl)-lhiophene-2-carboxylic acid (1 -azabicyclo[2.2.2]oct-3-yl)-amide |0310] A suspension of (S)-(-)-aminoquinuclidine dihydrochloride (55 mg, 0.275 mmol) in dichloromethane (1 mL) as treated with triethylamine (53 pL, 0.55 mmol) followed by 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol) and the reaction mixture allowed to stir for 20hr. After this time, the reaction mixture was evaporated and the residue partitioned between EtOAc (5 mL) and a 1 N HC1 solution ( 10 mL). The aqueous portion was then basified to pH ~ 10-12 with a IN NaOH solution. The aqueous portion was then extracted with EtOAc (10 mL) which was then washed with a brine solution (10 mL), dried over MgSOi, filtered, and evaporated in vacuo to afford product as a colorless solid (38 mg, 40%). 'H NMR (CDC1₃) 1.50-1.62 (m, IH), 1.70-1.88 (m, 3H), 2.08-2.12 (m, 2H), 2.37 (d, J = 1.3, 3H), 2.72-3.10 (m, 5H), 3.44 (ddd. J = 14.0, 9.7, 2.2, IH), 4.14-4.22 (m, IH), 6.56 (br d, J = 7.0, IH), 7.49 (d, J = 4.0, IH), 7.56 (d, J = 4.0, IH). ^I9F NMR -63.13. LC/MS 4.63 min, [M+l]*386.

Example 78

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PCT/US2008/()74353 (R)-5-(4-Methyl-5-trifluoromethyI-isoxazol-3-yl)-thiophene-2-carboxylic acid (1-azabicyclo[2.2.2]oct-3-yl)· amide

[0311] Prepared from (R)-(+)-aminoquinuclidine dihydrochloride in the same manner as the R isomer (Example 77). Colorless solid (40 mg, 42%). LC/MS 4.58 min, [M+lf 386.

Example 79 (4-Fluoro-piperidin-l-yl)-[5-(4-methyl-5-lrifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]methanone

[0312] Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yI)thiophene-2-carboxylic acid and 4-fluoromethylpiperidine hydrochloride by the method described in Example 41. Colorless solid (116 mg, 89%). *H NMR (CDCl?) 1.85 - 2.03 (m, 4H), 2.37 (s, 3H), 3.63 - 3.76 (m, br, 2H), 3.89 - 4.03 (m, br, 2H), 4.95 (dm, J_H-f 48, 1H). 7.34 (d, J = 3.6, 1H), 7.46 (d, J = 3.6, 1H). ^BC NMR 7.7, 31.3 (J = 20), 41.2 (br), 87.2 (d, J = 171), 114.5 (q, J = 2), 118.3 (q, J = 271), 127.8, 129.0, 131.1, 139.6, 155.0 (q, J = 40), 157.7, 162.6. ^|9F NMR-63.1. LC/MS 6.42 min, [M~if 363.

Example 80

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yi)-thiophen-2-yl]-(3-irifluoromethylpiperidin-1 -yl)-methanone

[0313J Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)thiophene-2-carboxylic acid and (±)-3-trifluoromethylpiperidine hydrochloride by the

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PCT/LS2(HI8/(I74353 method described in Example 41. Colorless solid (123 mg, 82%). *H NMR (CDCIj) 1.53 - 1.76 (m, br, 2H), 1.84 - 1.95 (ni, br, 1H), 2.10 - 2.22 (m, br, 1H), 2.31 - 2.43 (m, br, 4H), 2.92 - 3.16 (m, br, 2H), 4.28 - 4.45 (m, br, 111), 4.54 -4.72 (m, br, 1H), 7.34 (d, J = 4.0, 1H), 7.47 (d, J = 4.0, 1H). ^I3C NMR 7.7, 23.5, 24.2, 40.5 (q, J = 27), 44.0 (br), 46.3 (br), 114.5 (q, J = 2), 118.5 (q, J = 271), 126.1 (q, J = 283), 127.8, 129.1, 131.4,

139.3, 155.0 (q, J = 41 ), 157.6, 162.8. ^,9F NMR-72.8,-63.2. LC/MS 6.99 min, [M+lf 413.

Example 81

O-N (4-Meihyl-5-trifluoromethyl-isoxazol-3-yl)-lhiophen-2-ylJ-(4-trifluoromethyl-piperidin-/yl)-methanone |0314] Prepared from 5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene2-carboxylic acid and 4-trifluoromethylpiperidine hydrochloride by the method described in Example 41. Colorless solid (135 mg, 90%). ’H NMR (CDCh) 1.54 - 1.73 (m, br. 2H), 2.00 (d, br, J = 12.7, 2H), 2.31 - 2.42 (m, br, 4H), 2.89 - 3.12 (m, br, 2H), 4.43 4.68 (m, br, 2H), 7.33 - 7.37 (m, br, 1H), 7.44 - 7.50 (m, br, 1H). ^,3C NMR 7.7, 24.7,

40.5 (q, J = 28), 44.4 (br), 114.5 118.5 (q, .1 = 271), 126.8 (q, J = 278), 127.8, 129.1,

131.3, 139.4, 155.0 (q, J = 41), 157.6, 162.6. ^I9F NMR -74.2, -63.2. LC/MS 7.01 min, (M+lf 413.

Example 82 o

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6-Dihydro-2H-pyridin-J-yl)-[5-(4-methyl-5-irifluoromelhyl-isoxazoI-3-yl)-thiophen-2-ylJmethanone

[0315] Prepared from 5-(5-tnfluoromcthyl-4-mcthyl-isoxazol-3-yl)-thiophene2-carboxylic acid and 1,2,3,6-tetrahydropyridine hydrochloride by the method described in Example 41. Colorless solid (59 mg, 89%). 'H NMR (CDClj) 2.26 - 2.34 (m, br, 2H), 2.36 (s, 3H), 3.81 (t, br, J = 5.9, 2H), 4.20 - 4.25 (m, br, 2H), 5.67 - 5.77 (m, 1H), 5.88 5.97 (m, 1H), 7.37 (d, J = 3.9,1H), 7.47 (d, J = 3.9, 1H). ^,3C NMR 7.7, 25.5 (br), 29.7,

44.5 (br), 114.5 (q, J = 2), 118.5 (q, J = 271), 123.8, 125.7, 127.8, 128.9, 131.1, 140.3, 155.0(q, J-41), 157.7, 162.7. ^,9FNMR-63.1. LC/MS 6.61 min, [M+lf 343.

Example 83

OH (3-Hydroxy-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yI]methanone

[0316] Prepared from 5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene2-carboxylic acid and (±)-3-hydroxypiperidine hydrochloride by the method described in Example 41. Colorless solid (101 mg, 85%). 'H NMR (CD₃OD) 1.51 - 1.71 (m, 2H), 1.84 - 2.05 (m, 2H). 2.39 (q, J_H-f = L5, 3H), 3.34 - 3.65 (m. 2H), 3.68 - 3.85 (m, 2H), 3.86 - 4.14 (m, 1H), 7.49 (d, br, J = 3.9, IH), 7.60 (d, br, J = 3.9, 1H). ^I3C NMR 8.0,

23.6 (br), 33.5,45.1 (br), 55.1 (br), 67.0,116.7 (q, J = 2), 120.3 (q, J = 270), 129.8,130.9,

132.4, 141.1, 155.8 (q, J =40), 159.4, 165.0. ⁱ⁹FNMR -64.8. LC/MS 6.00 min, [M+lf 361.

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Example 84

OH

<img file="CA2974477C_D0212.tif" />

ο-n o (i)((cis)-3.4-Dihydroxy-piperidin-l-yl)-[5-(4-methyl-5-trifluoromethy!-isoxazol-3-yl)thiophen-2-yl] -methanone

[0317] A solution of (3,6-Dihydro-2H-pyridin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone (31 mg, 0.09 mmol) in acetone (2 mL) and water (1 mL) was treated with N-methylmorpholine-N-oxide (17 mg, 0.14 mmol) followed by Κ.₂θ5θ₄.2Η₂Ο (catalytic). The resulting mixture was stirred at room temperature for 16 hr, at which time LC/MS analysis showed full conversion of starting material (6.91 min, MH⁺ = 343) to product (5.57 min, MH⁺ = 377).

|0318J A saturated aqueous Na₂SO₃ solution (10 mL) was then added and the reaction stirred vigorously for 10 minutes. The mixture was then partitioned between CH2CI2 (10 mL) and water (10 mL) and the aqueous portion further extracted with CH2CI2 (3 x 20 mL). The combined organic extract was dried over Na₂SO₄, filtered, and concentrated in vacuo to crude product (32 mg).

[0319] Gradient column chromatography on silica eluting with 75% EtOAc/hexanes, 100% EtOAc, 5% then 10% MeOH/EtOAc gave the title compound as a colorless solid (29 mg, 0.77 mmol, 85%). 'HNMR(CDjOD) 1.69-1.81 (m, 1H), 1.851.99 (m, 1H), 2.39 (s, 3H), 3.37 - 3.72 (m, br, 2H), 3.75- 3.84 (m, 1H), 3.84 - 4.16 (m, br, 3H), 7.53 (s, br, 1H), 7.60 (d. br, J = 3.8,1H). ^,3C NMR 8.0, 30.9 (br), 41.6 (br), 52.1 (br), 69.5, 70.0, 116.7 (q, J = 2), 120.3 (q, J = 270), 129.8, 131.1, 132.4, 141.1, 155.8 (q, J = 40), 159.4,165.3. ^I9F NMR-64.8. LC/MS 5.57 min, [M+lf 377.

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Example 85

<img file="CA2974477C_D0213.tif" />

[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-lhiophen-2-yl]-(7-oxa-3-azabicyclo[4.1.0]hept-3-yl)-methanone

[0320] A solution of (3,6-Dihydro-2W-pyndin-l-yl)-[5-(4-methyl-5trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone (177 mg, 0.52 mmol) in CH2CI2 (5 mL) was treated with MCPBA (presumed 50% purity, 356 mg, 1.03 mmol). The reaction was stirred at room temperature for 16 hr at which time LC/MS analysis showed full conversion of starting material (6.93 min, MH⁴ = 343) to product (6.29 min, MH⁺ 359).

|0321] The reaction mixture was then treated with a 5% NaOH solution (10 mL) with vigorous mixing. The mixture was partitioned between CH2CI2 (10 mL) and water (10 mL) and the aqueous portion further extracted with CH2CI2 (3 x 20 mL). The combined organic extract was dried over Na₂SO4, filtered, and concentrated in vacuo to afford crude product ( 192 mg).

(0322] Gradient column chromatography on silica eluting with 75% EtOAc/hexanes, 100% EtOAc then 10% MeOH/EtOAc gave the title compound as a colorless solid (177 mg. 0.49 mmol, 95%). *H NMR (CDCI3) 1.98 - 2.26 (m, br, 2H), 2.34 (s, br, 3H), 3.18 - 3.73 (m, br, 4H), 3.82 -- 4.30 (m, br, 2H), 7.33 (s, br, 1H), 7.43 (s, br, 1H). ^,3C NMR 7.6, 24.6 (br), 37.1 - 47.2 (br), 50.1, 50.5, 114.5 (br), 118.4 (q, J = 271), 127.8, 129.2, 131.2, 139.5, 154.9 (q, J = 40), 157.6, 162.9. ^,9F NMR -63.2. LC/MS 6.29 min, (M+l ]⁺ 359.

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<img file="CA2974477C_D0214.tif" />

(±)((trans)-3,4-Dihydroxy-piperidin-I-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)thiophen-2-yl]-methanone

[0323] A solution of [5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen2-yl]-(7-oxa-3-aza-bicyclo[4.1.0]hept-3-yl)-methanone (93 mg, 0.26 mmol) in CHjCN (4 mL) and H₂O (2 mL) was treated with cerium (IV) ammonium nitrate (cat.). The resulting solution was stirred at room temperature for 40 hr, at which time LC/MS analysis confirmed full conversion of starting material (6.29 min, MH⁺ = 359) to product (5.53 mins, M1T = 377).

[0324] The mixture was then partitioned between CH?CL (10 mL) and water (10 mL) and aqueous portion further extracted with CH₂C1₂ (3 x 20 ml.), dried over Na₂SO4. filtered, and concentrated in vacuo to afford crude product.

[0325] Gradient column chromatography on silica eluting with 100% EtOAc, then 5% MeOH/EtOAc gave the title compound as a colorless solid (72 mg, 0.19 mmol, 73%). ‘H NMR (CDiOD) 1.48 - 1.63 (m, br, IH), 1.99 - 2.14 (m, br, 1H), 2.39 (s, br, 3H), 3.32 - 3.72 (m, br, 4H), 3.87 - 4.19 (m, br, 2H), 7.50 (s, br, IH), 7.59 (s, br, IH). ^I3C NMR 8.0, 30.3 - 33.0 (br), 40.5 - 43.8 (br), 71.7, 72.1 (br), 116.6 (br), 120.2 (q, J = 270), 129.8, 131.0, 132.5, 140.8, 155.8 (q, J = 41), 159.3, 164.9. ”F NMR -64.7. LC/MS 5.53 min, [M+lf 377.

Example 87

<img file="CA2974477C_D0215.tif" />

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PCT7L'S2008/074353 (3R,4S)-l-({5-[4-me.thyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}carbonyl)piperidine3,4-diol

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3R,4S)-3,4-Piperidinediol (CAS [135501-61-0]) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF/DMF (4 mL/Ι mL) solution of triethylamine and (3R,4S)-3,4Piperidinediol (2 mmol). After 30 min the reaction mixture was quenched with the addition of water. The resulting solids were then filtered and washed with a 1 N aqueous HCI solution followed by water. The material was air dried to afford product as a colorless solid (304 mg, 81%). 'H NMR (DMSO-Ai) 1.53-1.60 (m, 1 H), 1.65-1.71 (m, 1 H), 2.34 (d, J = 1.3, 3 H), 3.10-4.00 (br m, 6 H), 4.70 (d, J = 4.4, 1 H),4.81 (d, J = 4.0, 1 H), 7.54 (br s, I H), 7.65 (d, J = 4.0, 1 H). ^I9F NMR -62.2. LC/MS 5.44 min, [M+l f 377.

Example 88

F O-N (3S,4R)-i-({5-[4-methyI-5-(trifluoromethyl)isoxazol-3-yl}lhien-2-yl}carbonyl)piperidine3,4-diol

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic add and (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner as the (3R, 4S) isomer (Example 87) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.43 min, [M+1J* 377.

Example 89

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PCT/LÎS2008/074353 (3R)-N-methyl-l-({5-[4-methyl-5-(trifluoromeihyl)isoxa2ol-3-yl]thien-2yl}carbonyl)piperidine-3-carboxamide

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3R)-N-methylpiperidine-3-carboxamide (Preparative Example 31) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (3R)-N-methylpiperidine-3carboxamide. After 3 hr the reaction mixture was evaporated in vacuo and filtered with the aid of water. The resulting solids were then washed with a 1 N aqueous HC1 solution followed by water. The material was air dried to afford product as a colorless solid (157 mg, 86%). LC/MS 6.00 min, [M+l f 402.

Example 90 (3S)-N-methyl-J-U5-[4-methyl-5-(trifluoromcihyl)isoxazol-3-ylJthien-2yl}carbonyl)piperidine-3-carboxamide

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-y))-thiophene-2-carboxylic acid and (3S)-N-methylpiperidine-3-carboxamide (Preparative Example 32) in the same manner as the 3R isomer (Example 89) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.88 min, [M+l ]* 402.

Example 91

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N-methyl-N-{[(3S)-l-({5-[4-methyl-5-(trifîuoromethyl)isoxazol-3-yl]lhien-2yl}carbonyl)piperidin-3-yl] methyl}amine, hydrochloride

Prepared from 5-(5-Trifluoromethy)-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate (Preparative Example 33, 298 mg, 1.30 mmol) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride (0.90 eq) was added to a THF solution of tnethylamine and and tert-butyl methyl|(3R)-piperidin-3-ylmethyl]carbamate. The reaction was allowed to stir 4 hr then partitioned between EtOAc (10 mL) and a I N aqueous HC1 solution (10 mL). The organic portion was washed with a further portion of IN HC1 solution (10 mL) followed by a saturated aqueous NaHCOj solution (10 mL) and brine (10 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to a residue that was chromatographed on silica gel with EtOAc/hexane (40% then 60%) as eluant to afford Boc-protected intermediate as a yellow-tinted oil (423 mg, 67%). LC/MS 7.44 min, [M+lf 487. The intermediate was then treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stined for 24 hr, after which time the reaction mixture was evaporated in vacuo to afford a free-flowing colorless powder (320 mg, 88%). LC/MS 4.9) min, [M+1 f 388.

Example 92

N-methyI-N-{[(3R)-l-({5-[4-methyl-5-(irifluoromethyl)isoxazol-3-yl] thien-2yl}carbonyl)piperidin-3-yl}methyl}amine, hydrochloride

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3S)-piperidin-3-ylmethyl]carbamate (Preparative Example 34, 340 mg, 1.48 mmol) in the same manner as the 3S isomer (Example 91) to afford Bocprotected intermediate as a colorless oil (547 mg, 76%). LC/MS 7.36 min, [M+lf 487.

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The product was obtained as a colorless free-flowing powder (440 mg, 93%). LC/MS 4.82 min, [M+l]⁺388.

Example 93 (3R)-N-methyl-l-({5-[4-methyl-5-(trifuoromethyl)isoxazol-3-yl]thien-2yl}carbonyl)piperidin-3-amine, hydrochloride

Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (tert-butyl methyl[(3R)-piperidin-3-yl]carbamate (Preparative Example 35, presumed quantitative yield, 4.48 mmol) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride (0.90 eq) was added to a THF solution of triethylamine and and and (tert-butyl methyl[(3R)-piperidin-3-yl]carbamate (presumed quantitative yield, 4.48 mmol). The reaction was allowed to stir 4 hr, evaporated in vacuo, and the solids filtered with the aid of water. The air-dried solids were then chromatographed on a short silica gel column with EtOAc/hexane (75%) to afford Boc-protecled intermediate as a colorless solid (1.61 g, 76%). LC/MS 7.33 min, [M+l]* 474. The intermediate was then treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane (20 mL) and stirred for 24 hr, after which time the reaction mixture was evaporated in vacuo to afford a free-flowing colorless powder (1.14 g, 82%, some loss of material had occurred on rotary evaporation). LC/MS 4.57 min, [M+l]* 374.

Example 94

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PCT/US2(IO8/()74353 (3S)-N-methyl-l-({5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl/thien-2yl]carbonyl)piperidin-3-amine, hydrochloride

Prepared from 5-(5-Trifluoromelhyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3S)-piperidin-3-ylmcthyl]carbamate (Preparative Example 36, presumed quantitative yield, 4.48 mmol) in the same manner as the 3R isomer (Example 93) to afford Boc-protected intermediate as a colorless oil (1.51 g, 71%). LC/MS 7.32 min, [M+l ]⁺ 474. The product was obtained as a colorless free-flowing powder (1.06 g, 81%, some loss of material had occurred on rotary evaporation). LC/MS 4.55 min, [M+lf 374.

Example 95

F O'N (2-methoxyphenyl){5-[4-methy!-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yi! methanone Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2mcthoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a yellow-tinted oil (100 mg, 54%). ‘H NMR (CDCh) 2.39 (d, J = 1.3, 3 H), 3.82 (s, 3 H), 7.01-7.08 (m, 2 H), 7.27-7.54 (m, 4 H). ⁿC NMR 8.0, 55.9, 111.9, 115.9 (q, J = 151), 120.7, 128.2, 129.0. 129.6, 132.7, 135.0, 136.3, 147.1, 155.4 (q, J = 41), 157.3, 158.0,188.2. ^,9FNMR-63.1. LC/MS 7.50min, [M+lf 368.

Example 96 )-{5-/4-methyl-5-(trifluoromethyl)isoxazol-3-ylJthien-2-yl}ethanone

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Prepared from 4-Methyt-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2acetoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a tan colored solid (80 mg, 58%). *H NMR (CDC1₃) 2.39 (d, J = 1.3, 3 H), 3.62 (s, 3 H), 7.57 (d, J = 4.0,1 H), 7.74 (d, J = 4.0, 1 H). ¹⁹F NMR -63.1. LC/MS 7.82 min, [M+lf 276.

<img file="CA2974477C_D0216.tif" />

(2-hydroxyphenyl){5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]lhien-2-yl}me!hanone (0326) A solution of (2-methoxyphenyl){5-[4-methyl-5(tnfIuoromethyl)isoxazol-3-yl]thien-2-yl]methanone (Example 95, 37 mg, 0.1 mmol) in dichloromethane ( 2 mL) at -78 °C was treated with boron tribromidc (100 pL of a 1 M dichloromethane solution, 0.1 mol) and allowed to warm to 0 °C and stir at that temperature for 16 h. After that time the reaction was quenched with water (3 mL) and partitioned between water (10 mL) and EtOAc (10 mL). The organic extract was washed with a brine solution ( 10 mL) then dried over NajSOi, filtered, and concentrated in vacuo to afford crude product. The crude product was chromatographed on silica gel with EtOAc/hexanes (20%) as eluant to afford product as a yellow colored solid (29 mg, 82%). 'H NMR (CDCI3) 2.92 (d, J = 1.8, 3 H), 7.46-7.76 (m, 2 H), 8.03-8.08 (m, 1 H), 8.12 (d, J = 4.0, 1 H), 8.28 (d, J = 4.0, 1 H), 8.46 (dd, J = 8.4, 1.8,1 H), 11.50 (s, 1 H). ^,9F NMR 63.1.