Inhibitors of beta-secretase

This application is the U.S. National Stage of PCT International Application Number PCT/US2009/004686, filed Aug. 14, 2009, which claims the benefit of U.S. Provisional Application No. 61/189,464, filed on Aug. 19, 2008, and U.S. Provisional Application No. 61/211,750 filed on Apr. 2, 2009. The entire teachings of the above applications are incorporated herein by reference.

β-Amyloid deposits and neurofibrillary tangles are two major pathologic characterizations associated with Alzheimer's disease (AD). Clinically, AD is characterized by the loss of memory, cognition, reasoning, judgment, and orientation.

Also affected, as the disease progresses, are motor, sensory and linguistic abilities until global impairment of multiple cognitive functions occurs. These cognitive losses take place gradually, but typically lead to severe impairment and eventual death in 4-12 years.

β-Amyloid deposits are predominantly an aggregate of Aβ peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, Aβ peptide results from the cleavage of APP at the C-terminals by one or more γ-secretases, and at the N-terminus by β-secretase enzyme (BACE), also known as aspartyl protease, as part of the β-amyloidogenic pathway.

BACE activity is correlated directly to the generation of Aβ peptide from APP, and studies increasingly indicate that the inhibition of BACE inhibits the production of Aβ peptide.

Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders.

Recently, Amyloid-β (Aβ) has been reported to be implicated in the development of RGC apotosis in glaucoma, with evidence of caspase-3-mediated abnormal amyloid precursor protein processing, increased expression of Aβ in RGCs in experimental glaucoma and decreased vitreous Aβ levels (consistent with retinal Aβ deposition) in patients with glaucoma.

The present invention provides compounds that are BACE inhibitors and are useful as therapeutic agents in the treatment, prevention and amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.

The present invention relates to compounds represented by the following Structural Formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl;

each R 2 is independently selected from a) —H, -halogen, —CN, —NO 2 , —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , and —C(═O)R 5 ; and b) (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl;

R 3 and R 4 are each independently —H, -halogen, —CN, —NO 2 , —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —C(═O)R 5 , (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, an aryl group, and a heteroaryl group; or

X is —O—, —S—, —SO—, —SO 2 —, —CH 2 —O—, or —O—CH 2 —;

each Y is independently —C(R 8 R 9 )—;

W is —N(R 14 )—, —S—, —O—;

Z is —C(═O)—, —C(═S)—, —C(═NR 15 )—, —O—, —C(═O)C(R 16 R 17 )—, —C(═S)CR 16 R 17 —, —C(═NR 15 )C(R 16 R 17 )—, —N(R 18 )—, —N(CR 16 R 17 ) m — or —O—(CR 16 R 17 )—;

R 5 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;

each R 6 and R 7 are independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;

each R 8 and R 9 are independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl; or

R 8 and R 9 , together with the carbon to which they are attached, form ring A, which is a 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring, wherein ring A is optionally substituted with 1 to 4 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl;

R 11 is —H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;

R 12 and R 13 are each independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl;

or R 12 and R 13 , together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl; wherein the 3-8 membered ring optionally contains 1 to 3 additional heteroatoms, which are independently selected from O, N, and S, wherein when the additional heteroatom is nitrogen, the nitrogen is optionally substituted with (C 1 -C 3 )alkyl or halo(C 1 -C 3 )alkyl, and when the additional heteroatom is sulfur, the sulfur is optionally mono or di-oxygenated;

R 14 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy;

R 15 is —H or (C 1 -C 6 )alkyl;

R 16 and R 17 are each independently —H or (C 1 -C 3 )alkyl;

R 18 is —H or (C 1 -C 3 )alkyl;

i is 0, 1 or 2;

p is 1, 2, 3 or 4;

m is 1 or 2; and

n is 1 or 2.

In another embodiment, compounds of the invention is represented by Structural Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is R 1 is —H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 )alkyl;

R 2 is a) —H, —F, —Cl, —Br, or —CN or b) (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl;

R 3 and R 4 are each independently —H, —F, —Br, —Cl or (C 1 -C 6 )alkyl;

X is —O—, —S—, —SO—, —SO 2 —, —CH 2 O— or —OCH 2 —;

Y is —C(R 8 R 9 )—;

W is —N(R 14 )—, —S—, —O—;

Z is —C(═O)—, —C(═S)—, —C(═NR 15 )—, —O—, —C(═O)C(R 16 R 17 )—, —C(═S)C(R 16 R 17 )—, —C(═NR 15 )C(R 16 R 17 )—, —N(R 18 )—, or —(CR 16 R 17 ) m —;

R 5 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;

R 6 and R 7 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Br, —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;

R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy; or

R 8 and R 9 , together with the carbon to which they are attached, form a 3-8 membered ring (ring A) optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, wherein ring A contains 0 to 3 heteroatoms, which are independently selected from O, N and S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl, and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated;

R 11 is —H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;

R 12 and R 13 are each independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl;

or R 12 and R 13 , together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, wherein ring A contains 0 to 3 heteroatoms, which are independently selected from O, N and S, wherein when the heteroatom is nitrogen, the nitrogens is substituted with —H, (C 1 -C 3 )alkyl or halo(C 1 -C 3 )alkyl, and when the heteroatom is sulfur, the sulfurs is optionally mono or di-oxygenated;

R 14 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy;

R 15 is —H or (C 1 -C 6 )alkyl;

R 16 and R 17 are each independently —H or (C 1 -C 3 )alkyl;

R 18 is —H or (C 1 -C 3 )alkyl;

i is 0, 1 or 2;

p is 1 or 2;

m is 1 or 2; and

n is 1 or 2.

One embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof).

Another embodiment of the invention is a method of inhibiting BACE activity in a subject in need of such treatment. The method comprises administering to the subject an effective amount of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof).

Another embodiment of the invention is a method of treating a BACE mediated disorder in a subject. The method comprises administering to the subject an effective amount of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof).

Another embodiment of the invention is a method of treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject in need of such treatment comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′) or a pharmaceutically acceptable salt thereof).

Another embodiment of the invention is the use of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for inhibiting BACE activity in a subject.

Another embodiment of the invention is the use of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating a BACE mediated disorder in a subject.

Another embodiment of the invention is the use of a compound disclosed herein (e.g., a compound represented by Structural Formula (I) or (I′), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject.

The present invention is directed to compounds represented by the Structural Formula (I) or a pharmaceutically acceptable salt thereof. Values and particular values for the variables in Structural Formula I or an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e., R 1 , R 2 , R 3 , etc.) defined herein. For Structural Formula (I):

or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof:

R 1 is —H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl. In one embodiment R 1 is —H, (C 1 -C 6 )alkyl or benzyl. In another embodiment, R 1 is —H.

each R 2 is independently selected from a) —H, —F, —Cl, —Br, and —CN and b) (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl.

In one embodiment, R 2 is —H, —Br, —F, —Cl, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl.

In another particular embodiment, R 2 is —H, —Cl, —Br or —F.

In another particular embodiment, R 2 is (C 1 -C 6 )alkyl. More particularly, R 2 is (C 1 -C 3 )alkyl.

In another particular embodiment, R 2 is a (C 2 -C 6 ) alkynyl optionally substituted with —F, —Cl, —Br, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl or heteroaryl. More particularly, R 2 is a a (C 2 -C 6 ) alkynyl optionally substituted with (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl.

In another particular embodiment, R 2 is phenyl optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. More specifically, the substituents are independently selected from the group consisting of —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.

In another particular embodiment, R 2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl, cyclohexyl, or thiazolyl, each optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. More particularly, the substituents are independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 3 )alkyl, a 5-6 membered aryl or heteroaryl. Even more specifically, the substituents are independently selected from the group —F, —Cl, —Br, —CN, (C 1 -C 3 )alkyl, pyrrolyl and imidazolyl.

In another particular embodiment, R 2 is phenoxy or benzyloxy, each optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. More particularly, R 2 is unsubstituted phenoxy or benzyloxy.

R 3 and R 4 are each independently —H, —F, —Br, —Cl or (C 1 -C 6 )alkyl optionally substituted with an aryl group or a heteraryl group. In a particular embodiment, R 3 and R 4 are both —H. In another particular embodiment, R 3 and R 4 are independently —H, —F or methyl. In another particular embodiment, one of R 3 and R 4 are —H, the other is a (C 1 -C 6 )alkyl optionally substituted with a phenyl group, where the phenyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl.

R 5 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl, or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl. In a particular embodiment, R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloheteroalkyl or benzyl. In a more particular embodiment, R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, pyrrolidinyl or benzyl. More particular, R 5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl.

each R 6 and R 7 are independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl. In a particular embodiment, R 6 and R 7 are each independently —H or (C 1 -C 6 )alkyl. In another particular embodiment, R 6 and R 7 are both —H.

In one embodiment, each R 8 and R 9 are independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.

In a particular embodiment, R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteraryl, each of which optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloheteroalkyl, phenyloxy and benzyloxy.

In another particular embodiment, R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More particularly, R 8 and R 9 are both —H, methyl or hydroxymethyl.

In another embodiment, one of R 8 and R 9 is —H, the other one is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Even more particularly, one of R 8 and R 9 is —H, the other one is a (C 1 -C 3 )alkyl optionally substituted (C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran or tetrahydropyran).

In another embodiment, one of R 8 and R 9 is —H, the other one is a (C 2 -C 6 )alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.

In another particular embodiment, one of R 8 and R 9 is —H and the other is unsubstituted phenyl. In another particular embodiment, one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. More particularly, the substituents independently selected from —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy.

In another particular embodiment, one of R 8 and R 9 is —H and the other is (C 3 -C 14 )cyloalkyl (preferrably monocyclic (C 3 -C 8 )cycloalkyl such as cyclopentyl and cyclohexyl, or bicyclic fused (C 9 -C 14 )cycloalkyl, such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), (C 3 -C 13 )cycloheteroalkyl (preferrably monocyclic (C 3 -C 7 )cycloheteroalkyl such as tetrahydrofuran, tetrahydropyran and piperidine, or bicyclic fused or bridged (C 8 -C 13 )cycloheteroalkyl such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. More particularly, one of R 8 and R 9 is —H and the other is unsubstituted (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl). In another more particular embodiment, one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each of which is optionally substituted with (C 1 -C 6 )alkyl, preferably methyl.

In another embodiment, R 8 and R 9 , together with the carbon to which they are attached, form ring A, which is a 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. In a particular embodiment, ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. In a particular embodiment, ring A is a 5-7 membered monocyclic ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbonyl. In another particular embodiment, ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbonyl. In another particular embodiment, ring A is selected from tetrahydropyran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbonyl.

R 11 is —H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl. In a particular embodiment, R 11 is —H.

Each R 12 and R 13 are independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl. In a particular embodiment, R 12 and R 13 are independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl. More particularly, R 12 and R 13 are independently —H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl.

R 14 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy. In a particular embodiment, R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. In another particular embodiment, R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another particular embodiment, R 14 is methyl.

R 15 is —H or (C 1 -C 6 )alkyl. In a particular embodiment, R 15 is —H.

R 16 and R 17 are each independently —H or (C 1 -C 3 )alkyl. In a particular embodiment, R 16 and R 17 are both —H.

R 18 is —H or (C 1 -C 3 )alkyl. In a particular embodiment, R 18 is —H.

X is —O—, —S—, —SO—, —SO 2 —, —CH 2 O—, or —OCH 2 —. In a particular embodiment, X is —O—. In another particular embodiment, X is —S—. In another particular embodiment, X is —SO—. In another particular embodiment, X is —SO 2 —.

Y is —C(R 8 R 9 )—.

W is —N(R 14 )—, —S—, or —O—. In a particular embodiment, W is —N(R 14 )—.

Z is —C(═O)—, —C(═S)—, —C(═NR 15 )—, —O—, —C(═O)C(R 16 R 17 )—, —C(═S)C(R 16 R 17 )—, —C(═NR 15 )C(R 16 R 17 )—, —N(R 18 )—, or —(CR 16 R 17 ) m —. In a particular embodiment, Z is —O—. In another particular embodiment, Z is —C(═O)—.

i is 0, 1 or 2;

p is 1 or 2. In a particular embodiment, p is 1.

m is 1 or 2.

n is 1 or 2. In a particular embodiment, n is 1.

One embodiment of the present invention is directed to compounds represented by the Structural Formula (I′) or a pharmaceutically acceptable salt thereof. Values and particular values for the variables in Structural Formula (I′) or an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e., R 1 , R 2 , R 3 , etc.) defined herein. For Structural Formula (I′):

or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof:

R 1 is —H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl. In one embodiment R 1 is —H, (C 1 -C 6 )alkyl or benzyl. In another embodiment, R 1 is —H.

R 2 is a) —H, —F, —Cl, —Br, or —CN or b) (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl and aryl.

In one embodiment, R 2 is —H, —Br, —F, —Cl, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —COOR 5 , —CONR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —COR 5 , (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl.

In another particular embodiment, R 2 is —H, —Cl, —Br or —F.

In another particular embodiment, R 2 is (C 1 -C 6 )alkyl. More particularly, R 2 is (C 1 -C 3 )alkyl.

In another particular embodiment, R 2 is phenyl optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 ; (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl.

In another particular embodiment, R 2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl or cyclohexyl, each optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl and aryl. More particularly, the substituents are independently selected from the group consisting of —F, —Cl, —Br, —CN and (C 1 -C 3 )alkyl.

In another particular embodiment, R 2 is phenoxy or benzyloxy, each optionally substituted with 1-3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, or (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl. More particularly, R 2 is unsubstituted phenoxy or benzyloxy.

R 3 and R 4 are each independently —H, —F, —Br, —Cl or (C 1 -C 6 )alkyl. In a particular embodiment, R 3 and R 4 are both —H. In another particular embodiment, R 3 and R 4 are independently —H, —F or methyl.

R 5 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl, or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl. In a particular embodiment, R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloheteroalkyl or benzyl. In a more particular embodiment, R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, pyrrolidinyl or benzyl. More particular, R 5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl.

R 6 and R 7 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl. In a particular embodiment, R 6 and R 7 are each independently —H or (C 1 -C 6 )alkyl. In another particular embodiment, R 6 and R 7 are both —H.

In one embodiment, R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. In a particular embodiment, R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. In another particular embodiment, R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More particularly, R 8 and R 9 are both —H, methyl or hydroxymethyl. In another particular embodiment, one of R 8 and R 9 is —H and the other is unsubstituted phenyl. In another particular embodiment, one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. More particularly, the substituents independently selected from —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy. In another particular embodiment, one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. More particularly, one of R 8 and R 9 is —H and the other is unsubstituted (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl). In another more particular embodiment, one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each of which is optionally substituted with (C 1 -C 6 )alkyl, preferably methyl.

In another embodiment, R 8 and R 9 , together with the carbon to which they are attached, form a substituted 3-8 membered ring (ring A) optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl; wherein ring A contains 0 to 3 heteroatoms, which are selected from O, N, S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl, and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated. In a particular embodiment, ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. In a particular embodiment, ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, or piperidine, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkylcarbonyl.

R 11 is —H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl. In a particular embodiment, R 11 is —H.

R 12 and R 13 are each independently (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl. In a particular embodiment, R 12 and R 13 are independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl. More particularly, R 12 and R 13 are independently —H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl.

R 14 is —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy. In a particular embodiment, R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. In another particular embodiment, R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another particular embodiment, R 14 is methyl.

R 15 is —H or (C 1 -C 6 )alkyl. In a particular embodiment, R 15 is —H.

R 16 and R 17 are each independently —H or (C 1 -C 3 )alkyl. In a particular embodiment, R 16 and R 17 are both —H.

R 18 is —H or (C 1 -C 3 )alkyl. In a particular embodiment, R 18 is —H.

X is —O—, —S—, —SO—, —SO 2 —, —CH 2 O—, or —OCH 2 —. In a particular embodiment, X is —O—. In another particular embodiment, X is —S—. In another particular embodiment, X is —SO—. In another particular embodiment, X is —SO 2 —.

Y is —C(R 8 R 9 )—.

W is —N(R 14 )—, —S—, or —O—. In a particular embodiment, W is —N(R 14 )—.

Z is —C(═O)—, —C(═S)—, —C(═NR 15 )—, —O—, —C(═O)C(R 16 R 17 )—, —C(═S)C(R 16 R 17 )—, —C(═NR 15 )C(R 16 R 17 )—, —N(R 18 )—, or —(CR 16 R 17 ) m —. In a particular embodiment, Z is —O—. In another particular embodiment, Z is —C(═O)—.

i is 0, 1 or 2;

p is 1 or 2. In a particular embodiment, p is 1.

m is 1 or 2.

n is 1 or 2. In a particular embodiment, n is 1.

In a 1 st specific embodiment, the compound of the present invention is represented by Structural Formula (II):

Ring A is an optionally substituted 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring. Values and particular values for the remainder of the variables in Structural Formula (II) are as described above for Structural Formula (I). Ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy.

Alternatively, Ring A is an optionally substituted 3-8 membered ring containing 0 to 3 heteroatoms, which are independently selected from O, N and S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl, and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated. Values and particular values for the remainder of the variables in Structural Formula (II) are as described above for Structural Formula (I′). Ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.

In a 2 nd specific embodiment, the compound of the present invention is represented by the following Structural Formulas:

Values and particular values for Structural Formulas (III), (IV), (V), (VI), (VII) and (XIV) are as described above for Structural Formula (II) in the 1 st specific embodiment. More specifically, R 2 is independently —H, —F, —Cl or —Br and p is 2.

In a 3 rd specific embodiment, the compound of the present invention is represented by the following Structural Formulas:

Values and particular values for Structural Formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and (XIVa) are as described above for Structural Formula (II).

In a more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —O—, and the values and specific values of the remainder of the variable are as described in the 3 rd specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), X is —S—, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO—, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO 2 —, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.

In a 4 th specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), R 2 is —H, —Cl, —Br, —F or (C 1 -C 6 )alkyl, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.

In a more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), R 2 is —H, —Cl, —Br, —F or (C 1 -C 6 )alkyl and X is —O—. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), R 2 is —H, —Cl, —Br, —F or (C 1 -C 6 )alkyl and X is —S—. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), R 2 is —H, —Br, —F or (C 1 -C 6 )alkyl and X is —SO—. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), R 2 is —H, —Cl, —Br, —F or (C 1 -C 6 )alkyl and X is —SO 2 —. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIa)-(VIa) and (XIVa) are as described above in the 4 th specific embodiment. In a even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIa)-(VIa) are as described above in the 4th specific embodiment. In a even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIa)-(VIa) are as described above in the 4 th specific embodiment. In a even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa), and (XIVa), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa), and (XIVa), are as described above in the 4 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another even more specific embodiment, X is —O—; and R 14 is methyl.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), are as described above in the 4 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; and ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, or piperidine. In another even more specific embodiment, X is —O—; R 14 is methyl; and ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane.

In a 5 th specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), R 2 is (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloheteroalkyl, heteroaryl, phenoxy or benzyloxy, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. Values and specific values of the remainder of the variable are as described in the 3 rd specific embodiment. More specifically, R 2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl. Even more specifically, the substituents are independently selected from —F, —Cl, —Br, —CN, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, phenyl and 5-6 membered heteroaryl (preferrably pyridine or pyrimidine).

In a more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —O—, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —S—, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO—, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO 2 —, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIa)-(VIa) and (XIVa) are as described above in the 5 th specific embodiment. In a even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more embodiment, for compounds of Structural Formulas (IIa)-(VIa) and (XIVa), ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIa)-(VIa) are as described above in the 5 th specific embodiment. In a even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIa)-(VIIa) are as described above in the 5 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa) and (XIVa); R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa) and (VIa) are as described above in the 5 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbonyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa) and (XIVa) are as described above in the 5 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane; R 3 and R 4 are —H; and R 1 is —H.

In a 6 th specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa), R 2 is aryl and values and specific values for the remainder of the variables are as described above in the 3 rd specific embodiment. More specifically, R 2 is phenyl.

In a more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —O—, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —S—, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO—, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), X is —SO 2 —, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IIIa)-(VIIa) and (XIVa), ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIa)-(VIIa) and (XIVa) are as described above in the 6 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), are as described above in the 6 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), are as described above in the 6 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane; R 3 and R 4 are —H; and R 1 is —H.

In a 7 th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:

R 10 is —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl or heteroaryl. s is 0, 1, 2 or 3. Values and specific values for the remainder of the variables in Structural Formulas (IIIb)-(VIIb) and (XIVb) are as described above for Structural Formula (II).

In a more specific embodiment, for compounds of Structural Formulas (IIb)-(VIb) and (XIVb), ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIb)-(VIb) and (XIVb) are as described above in the 7 th specific embodiment. In a even more specific embodiment, R 3 and R 4 are —H; and R 1 is —H.

In another more embodiment, for compounds of Structural Formulas (IIb)-(VIb) and (XIVb),), ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIb)-(VIb) and (XIVb) are as described above in the 7 th specific embodiment. In a even more specific embodiment, R 3 and R 4 are —H; and R 1 is —H.

In another more specific embodiment, for compounds of Structural Formulas (IIIb)-(VIIb) and (XIVb), ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIb)-(VIIb) and (XIVb) are as described above in the 7 th specific embodiment. Even more specifically, R 3 and R 4 are —H.

In a more specific embodiment, for compounds of Structural Formulas (IIIb), (IVb), (VIb) and (XIVb), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIb), (IVb), (VIb) and (XIVb), are as described above in the 7 th specific embodiment. Even more specifically, R 14 is methyl.

In another more specific embodiment, for compounds of Structural Formulas (IIIb), (IVb), (VIb) and (XIVb), R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl; 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IIIb), (IVb), (VIb) and (XIVb) are as described above in the 7 th specific embodiment. Even more specifically, R 14 is methyl, R 1 is —H, and ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane.

In an 8 th specific embodiment, for compounds of Structural Formulas (IIIb)-(VIIb) and (XIVb), the values for the variables are defined as the following:

R 10 is —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 ; (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl;

s is 0, 1 or 2;

ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy;

R 1 is —H;

R 3 and R 4 are —H;

R 5 is (C 1 -C 6 )alkyl or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl;

R 6 and R 7 are —H;

R 11 is —H;

R 12 and R 13 are independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl;

R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and i is 0, 1, or 2.

In a more specific embodiment, for compounds of Structural Formulas (IIIb)-(VIIb) and (XIVb), R 10 is —Cl, —CN, —CF 3 , or —OR 5 ; and R 14 is methyl. Values and specific values for the remainder of the variables are as described above in the 8 th specific embodiment.

In a 9 th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:

wherein R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values for the remainder of the variables are as described above for Structural Formula (I).

Alternatively, for compounds represented by Structural Formula (VIII), R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. Values and specific values for the remainder of the variables are as described above for Structural Formula (I′).

In a 10 th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:

Values and specific values for variables for Structural Formulas (IX)-(XIII) and (XV) are as described above for Structural Formula (VIII) in the 9 th specific embodiment. In a more specific embodiment, X is —O—. In another more specific embodiment, X is —O—, R 2 is independently —H, —F, —Cl or —Br and p is 2.

In an 11 th specific embodiment, compounds of the present invention are represented by the following Structural Formulas:

Values and specific values for variables for Structural Formulas (IXa)-(XIIIa) and (XVa) are as described above for Structural Formula (VIII) in the 9 th specific embodiment

In a more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —O— and the values and specific values of the remainder of the variables are as described above in the 11 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —S—, and the values and specific values of the remainder of the variables are as described above in the 11 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO—, and the values and specific values of the remainder of the variables are as described in the 11 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO 2 —, and the values and specific values of the remainder of the variables are as described in the 11 th specific embodiment.

In a 12 th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 2 is —H, —Cl, —Br, —F or (C 1 -C 6 )alkyl, and the values and specific values of the remainder of the variable are as described above in the 11 th specific embodiment.

In a more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —O—, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —S—, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO—, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO 2 —, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—, and R 8 and R 9 are —H, methyl or hydroxymethyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. More particularly, X is —O—. Even more particularly, one of R 8 and R 9 is —H, the other one is a (C 1 -C 3 )alkyl optionally substituted (C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 2 -C 6 )alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. More particularly, X is —O—. Even more particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting independently selected from —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.

In another particular embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. In another even more specific embodiment, X is —O—; one of R 8 and R 9 is —H and the other is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxyl.

In another particular embodiment, for compounds of Structural Formula (IXa)-(XIIIa), one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 (C 1 -C 6 )alkyl.

In a 13 th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 2 is (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloheteroalkyl, heteroaryl, phenoxy or benzyloxy, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —NR 11 C(═O) i R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl and heteroaryl. Values and specific values of the remainder of the variable are as described in the 11 th specific embodiment. Even more specifically, R 2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl. Even more specifically, the substituents are independently selected from —F, —Cl, —Br, —CN, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, phenyl and 5-6 membered heteroaryl.

In a more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —O—, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —S—, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO—, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO 2 —, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. Even more specifically, X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa), R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and R 8 and R 9 are —H, methyl or hydroxymethyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. More particularly, X is —O—. Even more particularly, one of R 8 and R 9 is —H, the other one is a (C 1 -C 3 )alkyl optionally substituted (C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 2 -C 6 )alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. More particularly, X is —O—. Even more particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. Even more specifically, X is —O—.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydropyran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. In another even more specific embodiment, X is —O—; one of R 8 and R 9 is —H and the other is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxyl.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa), one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 (C 1 -C 6 )alkyl.

In a 14 th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 2 is aryl and the values and specific values of the remainder of the variable are as described in the 11 th specific embodiment. More specifically, R 2 is phenyl. In another more specific embodiment, R 2 is indolinyl or benzoimidazole (connected through the benzene ring).

In a more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —O—, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —S—, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO—, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.

In a more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is —SO 2 —, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. Even more specifically, X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and R 8 and R 9 are —H, methyl or hydroxymethyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. More particularly, X is —O—. Even more particularly, one of R 8 and R 9 is —H, the other one is a (C 1 -C 3 )alkyl optionally substituted (C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is —O—.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H, the other one is a (C 2 -C 6 )alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. More particularly, X is —O—. Even more particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.

In another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa)) and (XVa), one of R 8 and R 9 is —H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. Even more specifically, X is —O—.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. In another even more specific embodiment, X is —O—; one of R 8 and R 9 is —H and the other is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxyl.

In another specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa), one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. In an even more specific embodiment, X is —O—. In another even more specific embodiment, X is —O—; and one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 (C 1 -C 6 )alkyl.

In a 15 th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:

wherein R 10 is —F, —Cl, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —C(═O)OR 5 , —C(═O)NR 12 R 13 , —C(═O)R 5 , —C(═S)NR 12 R 13 , —C(═O)R 5 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, aryl or heteroaryl; and s is 0, 1, 2 or 3. Values and specific values for the remainder of the variables for Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), are as described above in the 11 th specific embodiment

In a more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), R 8 and R 9 are each independently —H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 ) cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting, of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 14 ) cycloalkyl and (C 3 -C 13 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), R 8 and R 9 are both —H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More specifically, R 8 and R 9 are —H, methyl or hydroxymethyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H, the other one is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment. Even more particularly, one of R 8 and R 9 is —H, the other one is a (C 1 -C 3 )alkyl optionally substituted (C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran).

In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H, the other one is a (C 2 -C 6 )alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment. Even more particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.

In another more specific embodiment, for compounds of Structural Formula (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.

In another specific embodiment, for compounds of Structural Formulas (IXb(IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. More specifically, the substituents are independently selected from —F, —Cl, —Br, —CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.

In another specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H and the other is monocyclic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocyclic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxy. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment. In another even more specific embodiment, one of R 8 and R 9 is —H and the other is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxyl. Values and specific values for the remainder of the variables are as described above in the 15 th specific embodiment.

In another specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (IXc)-(XIIIc), (IXd)-(XIIId) and (IXe)-(XIIIe), one of R 8 and R 9 is —H and the other is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. More specifically, the substitutents (C 1 -C 6 )alkyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.

In a 16 th specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), the variables are as defined below:

R 10 is —F, —Br, —CN, —OR 5 , —NR 6 R 7 , —S(O) i R 5 , —NR 11 S(═O) i R 5 , —COOR 5 , —CONR 12 R 13 , —NR 11 C(═O)R 5 , —C(═S)NR 12 R 13 , —COR 5 ; (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, or (C 1 -C 3 )alkylsulfonylaminoalkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylcarbonylamino(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl;

s is 0, 1 or 2;

one of R 8 and R 9 is —H, the other is selected from the group consisting of phenyl, tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of —F, —Cl, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with —F, —Br, —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C 3 )alkoxyl;

R 1 is —H;

R 3 and R 4 are independently selected from the group consisting of —H, —F, —Cl, —Br and (C 1 -C 3 )alkyl;

R 5 is (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl or pyrrolidinyl;

R 6 and R 7 are —H;

R 11 is —H;

R 12 and R 13 are independently —H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl;

R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and i is 0, 1, or 2.

In a more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), R 10 is —CN, —F, —Cl, or —Br; and the remainder of the variables are as described above in the 16 th specific embodiment.

In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), one of R 8 and R 9 is —H, the other is phenyl, tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each of which is unsubstituted; and the remainder of the variables are as described above in the 16 th specific embodiment

In another embodiment of the present invention, the compounds are listed in the following table:

Also included in the present invention are all possible stereoisomers of compounds 1-531 depicted above.

When any variable (e.g., aryl, heterocyclyl, R 1 , R 2 , etc.) occurs more than once in a compound, its definition on each occurrence is independent of any other occurrence.

“Alkyl” means a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms. Thus, “(C 1 -C 6 )alkyl” means a radical having from 1-6 carbon atoms in a linear or branched arrangement. “(C 1 -C 6 )alkyl” includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. Also included within the definition of “alkyl” are those alkyl groups that are optionally substituted. Suitable substitutions include, but are not limited to, -halogen, —OH, —CN, alkoxy, amino, cycloalkyl, aryl, heteroaryl, or aryloxy.

“Alkenyl” means branched or straight-chain monovalent hydrocarbon radical containing at least one double bond and having specified number of carbon atoms. Alkenyl may be mono or polyunsaturated, and may exist in the E or Z onfiguration. Thus, “(C 2 -C 6 )alkenyl” means a radical having from 2-6 carbon atoms in a linear or branched arrangement.

“Alkynyl” means branched or straight-chain monovalent hydrocarbon radical containing at least one triple bond and having specified number of carbon atoms. Thus, “(C 2 -C 6 )alkynyl” means a radical having from 2-6 carbon atoms in a linear or branched arrangement.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. It can be monocyclic, bicyclic, polycyclic (e.g., tricyclic), fused, bridged, or spiro. For example, monocyclic (C 3 -C 8 )cycloalkyl means a radical having from 3-8 carbon atoms arranged in a ring. Monocyclic (C 3 -C 8 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctane.

Monocyclic ring systems have a single ring structure. They include saturated or unsaturated aliphatic cyclic hydrocarbon rings or aromatic hydrocarbon ring having the specified number of carbon atoms. The monocyclic ring system can optionally contain 1 to 3 heteroatoms in the ring structure and each heteroatom is independently selected from the group consisting O, N and S. When the heteroatom is N, it can be substituted with —H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc. When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. —S(O)— or —S(O) 2 —). Examples of monocyclic ring system include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctane, azetidine, pyrrolidine, piperidine, piperazine, hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine, tetrahydro-2H-1,2-thiazine 1,1-dioxide, and isothiazolidine 1,1-dioxide, tetrahydrothiophene 1-oxide, tetrahydrothiophene 1,1-dioxide, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, and isothiazolidine 1,1-dioxide, pyrrolidin-2-one, piperidin-2-one, piperazin-2-one, and morpholin-2-one.

Bicyclic ring systems have two rings that have at least one ring atom in common. Bicyclic ring systems include fused, bridged and Spiro ring systems. The two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof. The bicyclic ring systems can optionally contain 1 to 3 heteroatoms in the ring structure and each heteroatom is independently selected from the group consisting O, N and S. When the heteroatom is N, it can be substituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc. When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. —S(O)— or —S(O) 2 —).

A fused bicyclic ring system has two rings which have two adjacent ring atoms in common. The two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof. For example, the first ring can be monocyclic cycloalkyl or monocyclic cycloheteroalkyl, and the second ring can a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl. For example, the second ring can be a (C 3 -C 6 )cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, the second ring can be an aryl ring, e.g., phenyl. Examples of fused bicyclic ring systems include, but not limited to, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, octahydro-1H-indene, tetrahydronaphthalene, decahythonaphthalene, indoline, isoindoline, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole, octahydro-1H-benzo[d]imidazole, octahydrobenzo[d]thiazole, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroisoquinoline and 2,3,4,5-tetrahydrobenzo[b]oxepine.

A spiro bicyclic ring system has two rings which have only one ring atom in common. The two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof. For example, the first ring can be a monocyclic cycloalkyl or a monocyclic cycloheteroalkyl and the second ring can be a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl. Examples of sprial bicyclic ring system include, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane, spiro[2.5]octane, azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.

A bridged bicyclic ring system has two rings which have three or more adjacent ring atoms in common. The two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof. For example, the first ring can be a monocyclic cycloalkyl or a monocyclic cycloheteroalkyl and the other ring is a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl. Examples of bridged bicyclic ring system include, but are not limited to, bicyclo[1.1.0]butane, bicyclo[1.2.0]pentane, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.2.0]octane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[3.3.2]decane bicyclo[3.3.3]undecane, azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane, azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.2]octane and 2-oxabicyclo[2.2.2]octane.

Polycyclic ring systems have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common. Polycyclic ring systems include fused, bridged and Spiro ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common. Examples of polycyclic ring system include, but not limited to, tricyclo[3.3.1.0 3,7 ]nonane (noradamantane) and tricyclo[3.3.1.1 3,7 ]decane (adamantane) and 2,3-dihydro-1H-phenalene.

“Cycloheteroalkyl” means a saturated 4-12 membered ring containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one or more double bonds. It can be monocyclic, bicyclic, polycyclic (e.g. tricyclic), fused, bridged, or spiro.

When the heteroatom is N, it can be substituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc. When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. —S(O)— or —S(O) 2 —).

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, and bromine.

“Heteroaryl” means a monovalent heteroaromatic monocyclic or polycyclic ring radical. Heteroaryl rings are 5- and 6-membered aromatic heterocyclic rings containing 1 to 4 heteroatoms independently selected from N, O, and S, and include, but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole 1,1-dioxide, 1,3,4-thiadiazole, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,3,5-triazine, and tetrazole. Bicyclic heteroaryl rings are bicyclo[4.4.0] and bicyclo[4,3.0] fused ring systems containing 1 to 4 heteroatoms independently selected from N, O, and S, and include indolizine, indole, isoindole, benzo[b]furan, benzo[b]thiophene, indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom. “(C 1 -C 4 )-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

“Aromatic” means an unsaturated cycloalkyl ring system.

“Aryl” means an aromatic monocyclic, or polycyclic carbocyclic ring system. Aryl systems include, but limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.

“Hetero” refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. A hetero ring may have 1, 2, 3, or 4 carbon atom members replaced by a heteroatom.

“Halogen” used herein refers to fluorine, chlorine, bromine, or iodine.

“Carbocycle” means 3-14 membered saturated or unsaturated aliphatic cyclic hydrocarbon ring.

“Cycloalkene” a unsaturated and non-aromatic aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. It can be monocyclic, bicyclic, tricyclic, fused, bridged, or spiro. Thus, (C 3 -C 8 )cycloalkene means a radical having from 3-8 carbon atoms arranged in a ring. (C 3 -C 8 )cycloalkene includes cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

Ring A is a 3-14 membered monocyclic ring system, 9-14 membered bicyclic ring system or 9-14 membered polycyclic ring system. The rings of the bicyclic and polycyclic ring systems can be fused, bridged or spiral. Ring A can be aromatic (e.g., aryl or heteroaryl) or aliphatic (saturated or unsaturated), provided that when Ring A is a monocyclic ring, it can only be aliphatic. For example, ring A can be a carbocycle such as a cycloalkene (e.g., cyclopentene, cyclohexene, cycloheptene or cyclooctene), a cycloalkane ring or a cycloheteroalkane ring as defined above. Ring A can optionally contain 1 to 3 heteroatoms each independently selected from O, S and N. When the heteroatom is N, it can be substituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc. When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. —S(O)— or —S(O) 2 —).

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.

It may be necessary and/or desirable during synthesis to protect sensitive or reactive groups on any of the molecules concerned. Representative conventional protecting groups are described in T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999. Protecting groups may be added and removed using methods well known in the art.

The invention also includes various isomers and mixtures thereof. “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).

Certain of the compounds of the present invention may exist in various stereoisomeric or tautomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. The invention encompasses all such forms, including compounds in the form of essentially pure entiomers, racemic mixtures and tautomers, which includes forms not depicted structurally. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, tautomers, geometric isomers or a combination thereof.

Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present.

“Racemate” or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.

Atoms (other than H) attached to a carbocyclic ring may be in a cis or trans configuration. In the “cis” configuration, the substituents are on the same side in relationship to the plane of the ring; in the “trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring. A mixture of “cis” and “trans” species is designated “cis/trans”.

The point at which a group or moiety is attached to the remainder of the compound or another group or moiety can be indicated by “ ” which represents “ ”, “ ” or “ ”.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).

The compounds of the invention are BACE inhibitors for treating, preventing or ameliorating disorders or diseases characterized by elevated β-amyloid deposits or β-amyloid levels in a subject. Such diseases or disorders include, but not limited to, Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-typle (HCHWA-D), other neurodegenerative disorders and glaucoma. Accordingly, the present invention provides methods for modulating BACE and treating, preventing or ameliorating Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-typle (HCHWA-D) and other neurodegenerative disorders. Such methods comprises administering to a patient suffering from, suspected of suffering from or being susceptible to the disease or disorder an effective amount of the compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for the treatment of a disorder related to or associated with excessive BACE activity in a patient in need thereof which comprises administering to said patient an effective amount of the compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof. Representative disorders include Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma. Certain of these diseases are characterized by production of β-amyloid deposits or neurofibrillary tangles.

The present invention also provides methods for inhibiting the activity of BACE, comprising administering to a subject and/or contacting a receptor thereof with an effective amount of at least one compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of ameliorating β-amyloid deposits in a subject, comprising administering to said subject an effective amount of at least one compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the disorder is Alzheimer's disease. In another embodiment, the disorder is glaucoma.

A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I or any formula of the invention described herein, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.

The compositions of the invention are BACE inhibitors. Said compositions can contain compounds having a mean inhibition constant (IC 50 ) against BACE of between about 50 μM to about 0.01 nM; between about 10 μM to about 0.01 nM; between about 5 μM to about 0.01 nM; between about 1 μM to about 0.01 nM; between about 500 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; between about 50 nM to about 0.01 nM; or between about 5 nM to about 0.01 nM.

The invention includes a therapeutic method for treating or ameliorating an BACE mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I or any other formulas of the invention described herein, or the enantiomers, diastereomers, or salts thereof or composition thereof.

Administration methods include administering an effective amount (i.e., an effective amount) of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form. The methods of the invention include all known therapeutic treatment regimens.

As used herein, the term “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

As used herein, the term “treating” or “treatment” refers to obtaining desired pharmacological and/or physiological effect. The effect can be prophylactic or therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome; or partially or totally delaying, inhibiting or reducing the likelihood of the onset or development of disease, disorder or syndrome.

“Prodrug” means a pharmaceutically acceptable form of an effective derivative of a compound (or a salt thereof) of the invention, wherein the prodrug may be: 1) a relatively active precursor which converts in vivo to a compound of the invention; 2) a relatively inactive precursor which converts in vivo to a compound of the invention; or 3) a relatively less active component of the compound that contributes to therapeutic activity after becoming available in vivo (i.e., as a metabolite). See “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

“Metabolite” means a pharmaceutically acceptable form of a metabolic derivative of a compound (or a salt thereof) of the invention, wherein the derivative is an active compound that contributes to therapeutic activity after becoming available in vivo.

“Effective amount” means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a compound of the invention in such a therapeutic method is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50 mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.

“Pharmaceutically acceptable carrier” means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.

“BACE mediated disorder or disease” includes disorders or diseases associated with the elevated expression or overexpression of BACE and conditions that accompany such diseases.

An embodiment of the invention includes administering β-secretase inhibiting compound of Formula I or any formula of the invention described herein or a composition thereof in a combination therapy with one or more additional agents for the treatment of Alzheimer's disease. Additional agents include, but are not limited to: cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine; memantine; tacrine; antidepressants, such as citalopram, fluoxetine, paroxetine, sertraline and trazodone; anxiolytics, such as lorazepam and oxazepam; antiphychotics, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.

Combination therapy includes co-administration of the compound of the invention and said other agent, sequential administration of the compound and the other agent, administration of a composition containing the compound and the other agent, or simultaneous administration of separate compositions containing of the compound and the other agent.

The invention further includes the process for making the composition comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.

The compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), and injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally). The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.

Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for ocular administration include sterile solutions or ocular delivery devices. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

The compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration. For example, an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect. The composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration. The composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.

For oral administration, the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation.

The oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention. Preferably, the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth). Disintegrating agents include starch, methyl cellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or filmcoated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect. The dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component. The two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release. A variety of enteric and non-enteric layer or coating materials (such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well known in the art. Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound(s) therein. The particles are preferably nanoparticles (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter). In a process for preparing a slow release composition, a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.

The compound of Formula I may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.

The compounds may be administered parenterally via injection. A parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil may be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using a suitable intranasal vehicle.

Compounds of the invention may also be administered topically using a suitable topical transdermal vehicle or a transdermal patch.

For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette. Preferably, the compositions are sterile and aqueous based, using purified water. In addition to the compound of the invention, an ophthalmic composition may contain one or more of: a) a surfactant such as a polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fe), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservative, and/or pH-controlling agent. The pH of the ophthalmic composition is desirably within the range of 4 to 8.

Methods of Preparation

In cases where the synthetic intermediates and final products of Formula I described below contain potentially reactive functional groups, for example amino, hydroxy, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not usually described explicitly. Generally, reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05-5 equivalents).

Compounds of the invention can be prepared employing conventional methods that utilize readily available reagents and starting materials. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. Representative compounds of the present invention can be prepared using the following synthetic schemes.

General Synthetic Schemes

when R 8 and/or R 9 is not aryl

when R 8 and/or R 9 is aryl

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

3-(2′-amino-1′-methyl-5′-oxo-2-(tetrahydro-2H-pyran-3-yl)-1′,5′-dihydrospiro[chro man-4,4′-imidazole]-6-yl)benzonitrile (compound 1)

Experimental Data

140 g of water, 186 g of CH 2 Cl 2 , H 3 PO 4 (34 g) was added to the acrylaldehyde (62 g, 1.1 mol) and the mixture was stirred at 80° C. overnight. The organic layer was separated and the upper aqueous layer was extracted with 100 mL of CH 2 Cl 2 . Distillation of the organic phase gave 5,6-dihydro-2H-pyran-3-carbaldehyde (25 g, 40%). 1 H-NMR (CDCl 3 ): 2.41 (d, 2H), 2.69 (t, 1H), 3.74 (t, 4H), 3.90 (t, 1H), 4.31 (s, 2H), 6.81 (m, 1H), 9.46 (s, 1H).

5,6-Dihydro-2H-pyran-3-carbaldehyde (20 g, 178.6 mmol) was dissolved in MeOH (150 mL). Pd/C (1 g, 5%) was added and the mixture was reacted at room temperature under H 2 at 50 Psi. The mixture was concentrated in vacuo to give tetrahydro-2H-pyran-3-carbaldehyde (20 g, 100%). 1 H-NMR (CDCl 3 ): 2.40 (t, 2H), 3.74 (t, 2H), 4.27 (m, 2H), 6.89 (m, 1H), 9.36 (t, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (19.45 g, 90.9 mmol), tetrahydro-2H-pyran-3-carbaldehyde (10 g, 90.9 mmol) and borax (34.6 g, 90.9 mmol) in ethanol (120 mL) and H 2 O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (4 g, 15%). 1 H-NMR (CDCl 3 ): 1.30 (m, 2H), 1.48 (m, 5H), 1.64 (m, 4H), 1.94 (d, 2H), 6.86 (d, 1H), 7.51 (dd, 1H), 7.92 (d, 1H).

A glass pressure tube was charged with a mixture 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (4 g, 13.03 mmol), KCN (1.7 g, 26.06 mmol), and (NH 4 ) 2 CO 3 (9.4 g, 97.7 mmol). Formamide (30 mL) was added to fill the tube nearly completely. The mixture was heated at 80° C. for 2 days. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then redissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.5 g, 30%). 1 H-NMR (MeOD): 1.20 (s, 1H), 1.42 (s, 1H), 1.65 (m, 2H), 1.89 (m, 2H), 2.01 (m, 1H), 2.19 (m, 1H), 3.40 (m, 2H), 3.85 (m, 2H), 4.10 (m, 1H), 6.79 (d, 1H), 7.23 (s, 1H), 7.33 (t, 1H).

A suspension of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.79 mmol) and Lawesson's Reagent (319 mg, 0.79 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 minutes in microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (120 mg, 40%).

Step 6. 6-bromo-1′-methyl-2′-(methylthio)-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2′-thioxospiro[chroman-4,4′-imidazo-lidin]-5′-one (120 mg, 0.3 mmol) in MeOH (16 mL) was added a solution of NaOH (0.6 N, 1.2 mL) and MeI (0.3 mL). The reaction mixture was heated at 60° C. for 10 minutes in microwave. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-1′-methyl-2′-(methylthio)-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 100%).

Step 7. 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one

A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH 4 I (54.5 mg, 0.37 mmol) in a solution of NH 3 /EtOH (2 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 100%).

Step 8. 3-(2′-amino-1′-methyl-5′-oxo-2-(tetrahydro-2H-pyran-3-yl)-1′,5′-dihydrospiro[chro man-4,4′-imidazole]-6-yl)benzonitrile (compound 1)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-(tetrahydro-2H-pyran-3-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.51 mg, 10%). 1 H-NMR (MeOD): 1.69 (t, 2H), 1.91 (m, 2H), 2.18 (t, 1H), 2.41 (d, 1H), 3.08 (t, 2H), 3.24 (s, 3H), 3.49 (m, 2H), 3.88 (dd, 2H), 4.40 (m, 1H), 7.05 (d, 1H), 7.50 (m, 1H), 7.61 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (50 g, 0.23 mol), cyclohexanecarbaldehyde (26 g, 0.23 mol) and borax (89 g, 0.23 mol) in ethanol (300 mL) and H 2 O (500 mL) was refluxed overnight. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give the crude product, which was purified by column chromatography to give 6-bromo-2-cyclohexylchroman-4-one (60 g, 83%). 1 H-NMR (CDCl 3 ): 1.05-1.33 (m, 5H), 1.67-1.81 (m, 5H), 1.95 (d, 1H), 2.64 (m, 2H), 4.15 (m, 1H), 6.86 (d, 1H), 7.51 (m, 1H), 7.94 (s, 1H).

A mixture of 6-bromo-2-cyclohexylchroman-4-one (1.5 g, 5 mmol), KCN (0.63 g, 10 mmol), (NH 4 ) 2 CO 3 (3.6 g, 37.5 mmol) in HCONH 2 (30 mL) were added to fill a 40 mL CEM microwave test tube nearly completely. The mixture was heated at 70° C. for 4 hrs. The reaction mixture was then cooled and poured over ice water. Acidification with concentrated HCl was performed to give a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column chromatography to give 6-bromo-2-cyclohexylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (0.75 g, 42%). 1 H-NMR (CDCl 3 ): 1.11-1.30 (m, 5H), 1.74 (m, 2H), 1.83 (m, 2H) 1.97 (m, 2H), 2.04 (d, 1H), 2.25 (d, 1H), 4.59 (m, 1H), 5.56 (s, 1H), 6.78 (d, 1H), 7.30 (m, 2H), 7.82 (s, 1H).

A suspension of 6-bromo-2-cyclohexylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (400 mg, 1.06 mmol) and Lawesson's Reagent (427 mg, 1.06 mmol) in dry 1,4-dioxane (6 mL) was heated at 120° C. in a 10 mL CEM microwave test tube for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-cyclohexyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (280 mg, 67%). 1 H-NMR (CDCl 3 ): 0.78-0.92 (m, 2H), 1.13 (m, 1H), 1.17-1.31 (m, 3H), 1.71 (m, 2H), 1.78 (m, 2H), 1.94 (d, 1H), 2.05 (t, 1H), 2.61 (d, 1H), 4.91 (m, 1H), 6.78 (d, 1H), 7.04 (s, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 9.33 (s, 1H).

A mixture of 6-bromo-2-cyclohexyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (57×5 mg, 0.75 mmol), NaOH solution (0.6 N, 0.7×5 mL), CH 3 I (0.2×5 mL) in methanol (4×5 mL) was heated at 60° C. in a 10 mL CEM test tube for 10 minutes. The reaction mixture was concentrated to give the residue, which was purified by column chromatography to give 6-bromo-2-cyclohexyl-1′-methyl-2′-(methylthio) spiro[chroman-4,4′-imidazol]-5′(1′H)-one (170 mg, 56%).

A solution of 6-bromo-2-cyclohexyl-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (170 mg, 0.40 mmol), NH 4 I (117 mg, 0.80 mmol) in a solution of NH 3 /EtOH (10 mL, 1.5 N) was heated at 120° C. in a 40 mL test tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-cyclohexy-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (90 mg, 57%).

Step 6. 3-(2′-amino-2-cyclohexy-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

A mixture of 2′-amino-6-bromo-2-cyclohexy-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.08 mmol), 3-cyanophenylboronic acid (23 mg, 0.15 mmol), Pd(PPh 3 ) 2 Cl 2 (20 mg), aqueous cesium carbonate solution (2 M, 0.5 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave for 35 minutes. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC and preparative HPLC to give 3-(2′-amino-2-cyclohexy-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (18.2 mg, 56%). 1 H-NMR (MeOD): 1.22-1.39 (m, 4H), 1.69-1.86 (m, 4H), 2.01 (s, 1H), 2.13-2.24 (m, 1H), 2.28-2.46 (m, 1H), 3.12 (s, 1H), 3.27-3.36 (m, 3H), 4.63 (m, 1H), 7.06 (m, 1H), 7.49 (s, 1H), 7.57-7.76 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), thiophene-2-carbaldehyde (10.46 g, 0.093 mol) and borax (35.4 g, 0.093 mol) in ethanol (120 mL) and H 2 O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-thiophen-2-yl-chroman-4-one (16 g, 50%). 1 H-NMR (CDCl 3 ): 3.01 (m, 1H), 3.10 (m, 1H), 5.75 (dd, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.54 (dd, 1H), 8.00 (d, 1H).

A glass pressure tube was charged with a mixture of 6-bromo-2-thiophen-2-yl-chroman-4-one (1.5 g, 48.7 mmol), KCN (0.63 g, 97.4 mmol), and (NH 4 ) 2 CO 3 (3.27 g, 34.1 mmol). Formamide (30 mL) and DMF (10 mL) were added to fill the tube nearly completely. The mixture was heated at 70° C. for 2 h with microwave. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (150 mg, 8%).

A suspension of 6-bromo-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (135 mg, 0.357 mmol) and Lawesson's Reagent (144.3 mg, 0.357 mmol) in anhydrous 1,4-dioxane (4 mL) was heated under reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(thiophen-2-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 80%). 1 H-NMR (CDCl 3 ): 2.41 (m, 1H), 2.55 (dd, 1H), 6.04 (dd, 1H), 6.80 (d, 1H), 6.94 (t, 1H), 7.12 (d, 1H), 7.33 (m, 3H).

To a solution of 6-bromo-2-(thiophen-2-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 0.254 mmol) in MeOH (6 mL) was added a solution of NaOH (20.32 mg, 0.508 mmol) in H 2 O (1 mL). After stirring for 10 minutes, MeI (544.4 mg, 3.81 mmol) was added. The reaction mixture was heated under reflux for 2 h. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-1′-methyl-2′-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 20%). 1 H-NMR (CDCl 3 ): 2.22 (d, 1H), 2.41 (t, 1H), 2.74 (s, 3H), 3.02 (s, 3H), 6.12 (d, 1H), 6.80 (d, 1H), 6.94 (m, 2H), 7.31 (m, 1H), 7.33 (m, 2H).

A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH 4 I (13.7 mg, 0.094 mmol) in a solution of NH 3 /EtOH (2 mL, 2 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 20%). 1 H-NMR (CDCl 3 ): 2.52 (m, 2H), 3.14 (s, 3H), 6.12 (d, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.14 (d, 1H), 7.43 (t, 3H).

Step 6. 3-(2S,4S)-2′-amino-1′-methyl-5′-oxo-2-(thiophen-2-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (20 mg) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 0.117 mmol) in 1,4-dioxane (5 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 4-cyanophenylboronic acid (34.5 mg, 0.23 mmol). The mixture was refluxed under Ar for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-((2S,4S)-2′-amino-1′-methyl-5′-oxo-2-(thiophen-2-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 8a, 1.35 mg, 1%), 1 H-NMR (CDCl 3 ): 442-069-3B: 2.30 (d, 1H), 2.49 (d, 1H), 3.01 (d, 3H), 5.81 (dd, 1H), 6.95 (t, 1H), 7.00 (m, 2H), 7.05 (s, 1H), 7.30 (d, 1H), 7.40 (d, 1H), 7.49 (d, 1H), 7.51 (t, 1H) 7.61 (t, 2H), and 3-((2R,4S)-2′-Amino-1′-methyl-5′-oxo-2-(thiophen-2-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-benzonitrile (Compound 8b, 1.10 mg, 1%). 1 H-NMR (CDCl 3 ): 2.40 (d, 1H), 2.63 (t, 1H), 3.31 (s, 3H), 6.12 (d, 1H), 6.95 (t, 1H), 7.00 (d, 1H), 7.05 (m, 2H), 7.30 (d, 1H), 7.48 (m, 2H), 7.54 (d, 1H), 7.68 (t, 2H).

3-(2′-amino-2-(2-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 9)

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 70.1 mmol), 2-fluorobenzaldehyde (8.7 g, 70.1 mmol), and borax (26.7 g, 70.1 mmol) in ethanol (90 mL) and H 2 O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O, and extracted with ether. The ether was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman-4-one (15 g, 50%). 1 HNMR (CDCl 3 ): 2.8 (d, 1H), 3.0 (t, 1H), 5.7 (d, 1H), 6.7 (d, 1H), 6.9 (t, 1H), 7.2 (m, 2H), 7.3 (m, 2H), 7.5 (m, 2H), 7.9 (t, 1H), 8.1 (d, 1H).

A steel bomb was charged with a mixture of 6-bromo-2-(2-fluorophenyl)chroman-4-one (2 g, 6.25 mmol), KCN (0.82 g, 12.5 mmol), and (NH 4 ) 2 CO 3 (4.5 g, 46.87 mmol). Formamide (25 mL) is added to fill the steel bomb nearly completely. The mixture was heated at 70° C. for 48 h then at 110° C. for another 8 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column to give 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 10%). 1 H-NMR (CDCl 3 ): 2.3 (t, 1H), 2.5 (d, 1H), 5.6 (s, 1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.1 (t, 1H), 7.2 (t, 1H), 7.4 (m, 3H), 7.6 (t, 1H), 7.9 (s, 1H).

A suspension of 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (259 mg, 0.64 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (180 mg, 67%).

To a solution of 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (180 mg, 0.443 mmol) in MeOH (10 mL) was added a solution of NaOH (35.46 mg, 0.887 mmol) in H 2 O (2 mL). After stirring for 10 min, MeI (951 mg, 6.65 mmol) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give a residue, which as purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 41%).

A solution of 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.183 mmol) and NH 4 I (53.21 mg, 0.367 mmol) in a solution of NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (52 mg, 70%). 1 H-NMR (MeOD): 2.15 (d, 1H), 2.25 (d, 1H), 3.20 (s, 3H), 6.15 (d, 1H), 6.78 (d, 1H), 6.99 (t, 1H), 7.05 (s, 1H), 7.15 (t, 1H), 7.25 (d, 2H), 7.50 (t, 1H).

Pd(PPh 3 ) 4 (3.84 mg, 0.1 mmol) was added to the solution of 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.1 mmol) and 3-cyanophenylboronic acid (18.3 mg, 0.12 mmol) in dimethyl-benzene (6.6 mL) and an aqueous solution of Na 2 CO 3 (2 M, 0.23 mL). The mixture was heated at 90° C. in an oil bath overnight. The mixture was concentrated to give the crude product which was purified by prepared HPLC to give the desired product 3-(2′-amino-2-(2-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.2 mg, 0.5%). 1 H-NMR (MeOD): 2.5 (d, 1H), 3.30 (t, 1H), 3.5 (s, 3H), 6.35 (d, 1H), 7.2 (t, 2H), 7.3 (d, 2H), 7.65 (t, 3H), 7.75 (s, 2H), 7.85 (d, 2H).

2′-amino-6-(3-cyclopropylphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 11)

Experimental Data

1-Bromo-3-vinylbenzene (1 g, 5.5 mmol), bis(pinacolaco) (1.5 g, 6 mmol), K 2 CO 3 (2.3 g, 16.5 mol) and Pd(PPh 3 ) 2 Cl 2 (0.3 g 0.33 mol) were dissolved in dioxane (5 ml). The mixture was flushed with argon for 30 minutes, and then refluxed for 12 hour. The mixture was cooled to room temperature, extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give 4,4,5,5-tetramethyl-2-(3-vinylphenyl)-1,3,2-dioxaborolane (500 mg, 16%).

To a solution of Zn(C 2 H 5 ) 2 (1 M, 6 mL) in DCM (1 mL) was added trifluoro-acetic acid (0.46 ml, 6 mmol) in DCM (1 mL) very slowly under N 2 in ice bath. The mixture was stirred for 20 minutes. CH 2 I 2 (1.61 g, 6 mmol) in DCM (1 mL) was added to the mixture. After stirring for 20 minutes, 4,4,5,5-tetramethyl-2-(3-vinylphenyl)-1,3,2-dioxaborolane (690 mg, 3 mmol) in DCM (1 mL) was added. The mixture was stirred at room temperature for 2 hour. the mixture was quenched by NH 4 Cl solution, extracted with DCM 3 times, washed with brine, filtered and concentrated to give the residue, which was purified preparative TLC and HPLC to give 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 10%).

Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (110 mg, 0.29 mmol) in 1,4-dioxane (5.0 mL), Cs 2 CO 3 (2 N, 1 mL) and 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.29 mmol) The mixture was refluxed for 2 hour. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 2′-amino-6-(3-cyclopropylphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.6 mg, 3%). 1 H-NMR (MeOD): 0.71 (m, 1H), 0.98 (m, 1H), 1.97 (m, 1H), 2.31 (m, 1H), 2.65 (m, 0.8H), 2.75 (m, 0.2H), 3.32 (m, 3H), 5.24 (m, 0.2H), 5.86 (m, 0.8H), 6.99 (m, 1H), 7.12 (m, 2H), 7.23 (m, 2H), 7.28 (m, 2H), 7.46 (m, 6H).

3-(2′-amino-1′-ethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 12)

To a mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.64 mmol) and K 2 CO 3 (356 mg, 2.6 mmol) in CH 3 CN (8 mL) was added EtI (402 mg, 2.6 mmol). The reaction mixture refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 69%).

A solution of 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 0.44 mmol) and NH 4 I (128 mg, 0.88 mmol) in a solution of NH 3 /EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 24%). 1 H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, 1H), 3.16 (m, 1H), 3.54 (m, 2H), 5.75 (m, 1H), 6.77 (m, 1H), 6.95 (m, 1H), 7.23 (m, 2H), 7.33 (m, 4H).

Pd(PPh 3 ) 4 (40 mg, 0.10 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.10 mmol) in toluene (5 mL), Na 2 CO 3 (2 N, 2 mL), and 4-cyanophenylboronic acid (31 mg, 0.21 mmol). The mixture refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-ethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.76 mg, 3%). 1 H-NMR (MeOD): 1.31 (m, 3H), 2.55 (m, 2H), 3.84 (m, 2H), 5.26 (m, 1H), 5.86 (m, 1H), 7.14 (m, 1H), 7.47 (m, 6H), 7.59 (m, 1H), 7.28 (m, 2H), 7.90 (m, 2H).

2′-amino-6-(3-methoxyphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 13)

Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-methoxyphenylboronic acid (16 mg, 0.104 mmol). The mixture was heated under 120° C. under Ar using microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 2′-amino-6-(3-methoxyphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1H)-one (1.69 mg, 8%). 1 H-NMR (MeOD): 2.05 (m, 1H), 2.21 (m, 1H), 3.06 (m, 3H), 3.72 (s, 3H), 5.19 (m, 0.3H), 5.81 (m, 0.7H), 6.76 (m, 1H), 6.91 (m, 2H), 6.97 (m, 1H), 7.08 (m, 1H), 7.21 (m, 1H), 7.26 (m, 1H), 7.33 (m, 2H), 7.39 (m, 2H), 7.57 (m, 1H).

3-(2′-amino-2-(2,3-difluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 14)

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (22.6 g, 0.11 mol), 2,3-difluoro-benzaldehyde (15 g, 0.11 mol) and borax (40.2 g, 0.11 mol) in ethanol (140 mL) and H 2 O (234 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (5.3 g, 15%). 1 H-NMR (CDCl 3 ): 2.95 (d, 1H), 3.05 (t, 3H), 5.75 (d, 1H), 6.97 (d, 1H), 7.20 (m, 2H), 7.35 (m, 1H), 7.60 (d, 1H), 8.05 (s, 1H).

A mixture of 6-bromo-2-(2,3-difluorophenyl)chroman-4-one (1.49 g, 4.4 mmol), KCN (0.57 g, 8.8 mmol), (NH 4 ) 2 CO 3 (2.96 g, 30.8 mmol) in HCONH 2 (30 mL) and DMF (5 mL) was added to fill a 40 mL CEM microwave test tube nearly completely. The mixture was heated at 70° C. for 2 hrs. The reaction mixture was then cooled and poured over ice water. Acidification with concentrated HCl was performed to give a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column chromatography to give 6-bromo-2-(2,3-difluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (235 mg, 13%). 1 H-NMR (CDCl 3 ): 2.34 (t, 1H), 2.54 (d, 1H), 5.50 (s, 1H), 6.18 (d, 1H), 6.91 (m, 1H), 7.16 (m, 3H), 7.28 (m, 1H), 7.39 (m, 2H), 7.70 (s, 1H).

A suspension of 6-bromo-2-(2,3-difluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (212 mg, 0.52 mmol) and Lawesson's Reagent (201 mg, 0.52 mmol) in dry m-xylene (4.5 mL) was heated at 150° C. in a 10 mL CEM microwave test tube for 25 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2,3-difluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (163 mg, 74%). 1 H-NMR (CDCl 3 ): 2.33 (t, 3H), 2.54 (d, 1H), 5.36 (s, 1H), 6.17 (d, 1H), 6.91 (d, 1H), 7.17 (m, 3H), 7.30 (m, 2H), 7.46 (s, 1H).

Step 4. 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-(2,3-difluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (173 mg, 0.41 mmol) in MeOH (5 mL) was added a solution of NaOH (41 mg, 1.02 mmol) in H 2 O (1 mL) After stirring for 10 minutes, MeI (0.87 g, 6.12 mmol) was added. The reaction mixture was heated under reflux for 2 h. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (63 mg, 16%). 1 H-NMR (CDCl 3 ): 2.06 (d, 1H), 2.47 (t, 1H), 2.58 (s, 3H), 3.12 (s, 3H), 6.23 (d, 1H), 6.86 (m, 2H), 7.14 (m, 2H), 7.31 (m, 2H).

A solution of 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio) spiro[chroman-4,4′-imidazol]-5′(1′H)-one (63 mg, 0.14 mmol), NH 4 I (60.6 mg, 0.42 mmol) in a solution of NH 3 /EtOH (3 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 60%). 1 H-NMR (CDCl 3 ): 2.31 (d, 1H), 2.45 (t, 1H), 3.27 (s, 3H), 6.12 (d, 1H), 6.87 (m, 1H), 7.09 (m, 3H), 7.34 (m, 2H), 7.45 (m, 1H).

Step 6. 3-(2′-amino-2-(2,3-difluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

A mixture of 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (25 mg, 0.05 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.104 mmol), Pd(PPh 3 ) 2 Cl 2 (10 mg, 50%), aqueous cesium carbonate solution (2 M, 0.3 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave reactor for 30 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-(2,3-difluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (7.02 mg, 27%). 1 H-NMR (CDCl 3 ): 2.20 (m, 2H), 3.12 (s, 3H), 6.25 (d, 1H), 6.77 (d, 1H), 7.13 (m, 3H), 7.29 (m, 1H), 7.34 (d, 1H), 7.43 (m, 1H), 7.48 (m, 2H), 7.51 (m, 1H), 7.61 (d, 1H), 7.68 (s, 1H), 7.78 (d, 1H).

A solution of 6-bromo-1′-(cyclohexylmethyl)-2′-(cyclohexylmethylthio)-2-phenylspiro chroman-4,4′-imidazol]-5′(1′H)-one (70 mg, 0.293 mmol), NH 4 I (85 mg, 0.586 mmol) in a solution of NH 3 /EtOH (3 mL, 1.5 N) was heated at 120° C. in a tube under microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-(cyclohexylmethyl)-1-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 54%).

Step 3. 3-(2′-amino-1′-(cyclohexylmethyl)-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 3-cyanophenylboronic acid (19 mg, 0.128 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-(cyclohexylmethyl)-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (9.74 mg, 31%). 1 H-NMR (MeOD): 1.02 (m, 5H), 1.62 (m, 6H), 2.03 (m, 1H), 2.24 (m, 1H), 3.30 (m, 1H), 3.44 (m, 1H), 5.91 (m, 1H), 6.97 (m, 1H), 7.16 (m, 1H), 7.25 (m, 1H), 7.35 (m, 3H), 7.46 (m, 2H), 7.56 (m, 1H), 7.71 (m, 2H)

3-(2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 19 and 19a)

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (30 g, 0.14 mol), 4-fluorobenzaldehyde (19.3 g, 0.14 mol) and borax (53.34 g, 0.14 mol) in ethanol (180 mL) and H 2 O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(4-fluoro-phenyl)-chroman-4-one (10 g, 20%). 1 H-NMR (CDCl 3 ): 2.81 (dd, 1H), 2.99 (t, 1H), 5.49 (dd, 1H), 6.87 (d, 1H), 7.04 (t, 2H), 7.38 (t, 2H), 7.51 (dd, 1H), 7.94 (d, 1H).

A glass pressure tube was charged with a mixture of 6-bromo-2-(4-fluoro-phenyl)-chroman-4-one (1.5 g, 4.7 mmol), KCN (0.6 g, 9.4 mmol), and (NH 4 ) 2 CO 3 (3.16 g, 32.9 mmol). Formamide (40 mL) was added to fill the tube nearly completely. The mixture was heated at 70° C. for 2 h with microwave. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then redissolved in ethyl acetate, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-(4-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 20%). 1 H-NMR (MeOD): 2.19 (m, 1H), 2.23 (m, 1H), 5.76 (dd, 1H), 6.78 (d, 1H), 7.00 (t, 2H), 726 (t, 2H), 7.37 (m, 2H).

A suspension of 6-bromo-2-(4-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's Reagent (310 mg, 0.77 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 min with microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (160 mg, 50%).

Step 4. 6-bromo-2-(4-fluorophenyl)-1′-methyl-2′-(methylthio)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-(4-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (160 mg, 0.39 mmol) in MeOH (16 mL) was added a solution of NaOH (0.6 N, 1.6 mL) and MeI (0.3 mL). The reaction mixture was heated at 60° C. for 10 min with microwave. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-2-(4-fluorophenyl)-1′-methyl-2′-(methylthio)-spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 50%).

A solution of 6-bromo-2-(4-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroma-4,4′-imizol]-5′(1′H)-one (80 mg, 0.184 mmol), NH 4 I (214 mg, 1.47 mmol) in a solution of NH 3 /EtOH (2 mL, 8 N) was heated at 120° C. in a tube under microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuum to give 2′-amino-6-bromo-1-(4-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 50%).

Step 6. 3-((2S,4S)-2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro [chroman-4,4′-imidazole]-6-yl)benzonitrile (6 mg, 10%) and 3-(2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (19)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with 2′-amino-6-bromo-2-(4-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 0.099 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-((2S,4S)-2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (19a) (6 mg, 10%), 1 H-NMR (MeOD): 2.41 (t, 1H), 2.60 (t, 1H), 3.10 (s, 3H), 5.83 (d, 1H), 7.16 (m, 3H), 7.52 (m, 2H), 7.60 (m, 2H), 7.69 (m, 2H), 7.90 (m, 1H), 7.99 (d, 1H), and 3-(2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (19) (4 mg, 8%), 1 H-NMR (MeOD): 2.42 (t, 1H), 2.60 (t, 1H), 3.20 (s, 3H), 5.87 (d, 1H), 7.19 (m, 3H), 7.45 (m, 2H), 7.51 (m, 1H), 7.54 (m, 1H), 7.64 (m, 2H), 7.90 (t, 1H), 7.99 (d, 1H).

3-(2′-amino-2-(3-chlorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 20)

In a bottle 1-(5-bromo-2-hydroxyphenyl)ethanone (25 g, 0.02 mol), 3-chlorobenzaldehyde (16.35 g, 0.12 mol), EtOH (96%, 144 mL), and NaOH (42.1 g, 1.06 mol) were combined. The mixture was stirred vigorously for 0.5 h. 2-Methoxy-2-methylpropane was added and the mixture was filtered. The filtrate was poured into HCl (1 N, 800 mL) and filtered. The combined solid was dried to give 1-(5-bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-1-one (23.47 g, 60%). 1 H-NMR (CDCl 3 ): 6.88 (d, 1H), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, 1H), 7.80 (m, 1H), 7.93 (m, 1H), 12.56 (s, 1H).

1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23 g, 68 mmol) was dissolved in H 2 O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered. The solid was dissolved in EtOAc and washed with H 2 O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1 H-NMR (CDCl 3 ): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).

In a steel bomb, a mixture of 6-bromo-2-(3-chlorophenyl)chroman-4-one (7 g, 21 mmol), KCN (2.71 g, 42 mmol), and (NH 4 ) 2 CO 3 (15 g, 156 mmol) in formamide (60 mL) was heated and stirred at 70° C. for 24 h and then heated at 110° C. for 2 days. The mixture was poured into ice/water. Concentrated HCl was added till pH=1. The mixture is filtered to afford a solid, and the filtrate was extracted with CH 2 Cl 2 . The organic layer was concentrated to give a residue, which was combined with the solid above. The combined solid was purified through column chromatography to give 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 5%). 1 H-NMR (CDCl 3 ): 2.20 (m, 1H), 2.28 (m, 1H), 5.76 (m, 1H), 6.82 (m, 1H), 7.27 (m, 5H), 7.39 (m, 1H).

A mixture of 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 1.16 mmol) and Lawesson's Reagent (468 mg, 1.16 mmol) in 1,4-dioxane (16 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (350 mg, 71%).

To a mixture of 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.6 mmol) and K 2 CO 3 (327 mg, 2.4 mmol) in CH 3 CN (6 mL) was added MeI (339 mg, 2.4 mmol). The reaction mixture was heated under reflux for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-1′-methyl-2′-(methylthio)spiro chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 37%). 1 H-NMR (CDCl 3 ): 1.92 (m, 1H), 2.41 (m, 1H), 2.56 (s, 3H), 3.07 (s, 3H), 5.80 (m, 1H), 6.80 (m, 2H), 7.26 (m, 4H), 7.39 (m, 1H).

A solution of 6-bromo-2-(3-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 0.22 mmol) and NH 4 I (64 mg, 0.44 mmol) in a solution of NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 46%).

1 H-NMR (MeOD): 2.12 (m, 2H), 3.06 (s, 3H), 5.80 (m, 1H), 6.83 (m, 1H), 7.03 (m, 1H), 7.27 (m, 4H), 7.40 (m, 1H).

Pd(PPh 3 ) 4 (27 mg, 0.072 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.072 mmol) in toluene (5 mL), Na 2 CO 3 (2 N, 2 mL), and 4-cyanophenylboronic acid (12.9 mg, 0.088 mmol). The mixture was refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-chlorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.03 mg, 3%). 1 H-NMR (MeOD): 2.63 (m, 2H), 3.22 (s, 3H), 5.34 (m, 1H), 7.18 (m, 1H), 7.41 (m, 3H), 7.54 (m, 2H), 7.10 (m, 1H), 7.17 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (18 g, 84.1 mmol), 3-methoxy-benzaldehyde (11.4 g, 84.1 mmol) and borax (32 g, 84.1 mmol) in ethanol (112 mL) and H 2 O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ether. The ether was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(3-methoxyphenyl)chroman-4-one (10 g, 36%). 1 H-NMR (CDCl 3 ): 2.71 (d, 1H), 2.99 (t, 1H), 3.75 (s, 3H), 5.38 (d, 1H), 6.90 (m, 4H), 7.27 (t, 1H), 7.51 (d, 1H), 7.95 (s, 1H).

A steel bomb was charged with a mixture of 6-bromo-2-(3-methoxyphenyl) chroman-4-one (3.3 g, 9.94 mmol), KCN (1.29 g, 20 mmol), and (NH 4 ) 2 CO 3 (7.15 g, 75 mmol). Formamide (25 mL) was added to fill the steel bomb nearly completely. The mixture was heated at 70° C. for 48 h then at 110° C. for another 4 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.3 g, 32%). 1 H-NMR (CDCl 3 ): 2.21 (t, 1H), 2.40 (d, 1H), 3.41 (s, 3H), 5.74 (d, 1H), 6.81 (d, 2H), 6.90 (t, 2H), 7.25 (m, 3H), 7.89 (s, 1H).

A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (250 mg, 0.62 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 45%).

Step 4. 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 0.24 mmol) in MeOH (5 mL) was added a solution of NaOH (19.14 mg, 0.48 mmol) in H 2 O (1 mL). After stirring for 10 min, MeI (515 mg, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (65 mg, 60%).

A solution of 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (65 mg, 0.146 mmol), NH 4 I (42.26 mg, 0.3 mmol) in a solution of NH 3 /EtOH (2 mL, 8 N) was heated at 120° C. in a tube under microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuum to give 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 80%).

Step 6. 3-(2′-amino-2-(3-methoxyphenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 0.11 mmol) in 1,4-dioxane (5 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 4-cyanophenylboronic acid (32.6 mg, 0.22 mmol). The mixture was refluxed under Ar for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-methoxyphenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 20%). 1 H-NMR (CDCl 3 ): 2.26 (m, 1H), 2.48 (m, 1H), 3.72 (s, 3H), 5.62 (m, 1H), 6.79 (m, 3H), 6.94 (d, 1H), 7.12 (d, 1H), 7.20 (s, 1H), 7.29 (m, 1H), 7.36 (m, 1H), 7.41 (t, 1H), 7.61 (d, 2H).

2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 24)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-fluoro-3-(trifluoromethoxy)phenylboronic acid (20 mg, 0.106 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.32 mg, 14%). 1 H-NMR (MeOD): 2.23 (m, 2H), 3.10 (s, 3H), 5.80 (d, 1H), 6.98 (m, 1H), 7.13 (m, 1H), 7.26 (m, 2H), 7.34 (m, 3H), 7.38 (m, 3H), 7.46 (m, 2H).

3-((2S,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 25a) and 3-((2R,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 25b)

To a solution of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (440 mg, 1.18 mmol) in 1,4-dioxane (3.6 mL) in a 10 mL CEM microwave test tube was added Lawesson's reagent (477 mg, 1.18 mmol). The resulting mixture was heated in a CEM microwave reactor at 110° C. for 40 min and then cooled to room temperature. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (238 mg, 52%). MS m/z 389 (M+H + ).

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (110 mg, 0.28 mmol) in MeOH (5 mL) in a 10 mL CEM microwave test tube was added a 0.6 N NaOH aqueous solution (1.0 mL). After stirring at room temperature for 10 min, MeI (158 mg, 1.08 mmol) was added, and the reaction was stirred at room temperature for 2 hrs. Upon removing the solvent in vacuo, the residue was purified by flash chromatography to give 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(PH)-one (63.3 mg, 39%). MS m/z 569 (M+H + ).

To a solution of 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1:1, 2 mL) in a 10 mL CEM microwave test tube was added NH 4 I (50 mg, 0.34 mmol) and NH 3 /MeOH (7 N, 2 mL). The resulting mixture was heated in a CEM microwave reactor at 120° C. for 60 min. The cooled mixture was concentrated in vacuo and the residue was purified by reversed phase. HPLC to give 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H + ).

To a solution of 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 0.04 mmol) in 1,4-dioxane (1.5 mL) was added Cs 2 CO 3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl 2 dppf. After degassing, the resulting mixture was heated in a CEM microwave reactor at 130° C. for 30 min. Solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give 3-((2R,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (6.0 mg, 33%) as a TFA salt (25b) and 3-((2S,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (0.86 mg, 4.8%) as a TFA salt. (25a). 1 H NMR (400 MHz, CD 3 OD): 7.84-7.60 (m, 4 H), 7.74-7.24 (m, 12 H), 7.12 (d, 1 H), 5.92 (d, 1 H), 4.62 (s, 2 H), 2.60 (d, 1 H), 2.42 (d, 1 H); MS m/z 485 (M+H + ) (25b). 1 H NMR (400 MHz, CD 3 OD): 7.74-7.36 (m, 16 H), 7.16 (d, 1 H), 5.24 (d, 1 H), 5.08, 5.00 (two d, 2 H), 2.64 (d, 1 H), 2.56 (d, 1 H); MS m/z 485 (M+H + ) (25a).

A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (64.2 g, 0.3 mol), 1-phenyl-ethanone (46.8 g, 0.39 mol) and pyrrolidine (6 g, 0.084 mol) in toluene (125 mL) was stirred vigorously at room temperature overnight. Then the mixture was refluxed for 6 h. After cooling, the mixture was treated with water (100 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-chroman-4-one (23.7 g, 25%). 1 H-NMR (CDCl 3 ): 1.74 (s, 3H), 3.06 (d, 1H), 3.31 (d, 1H), 6.95 (d, 1H), 7.20-7.37 (m, 5H), 7.52 (d, 1H), 7.84 (s, 1H).

A steel pressure tube was charged with a mixture of 6-bromo-2-methyl-2-phenyl-chroman-4-one (6.2 g, 19.6 mmol), KCN (2.55 g, 39.2 mmol), and (NH 4 ) 2 CO 3 (14.1 g, 147 mmol). Formamide (70 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70° C. for 48 h then at 110° C. for another 24 h. The reaction mixture was then cooled and poured over ice. After acidification with concentrated HCl, the mixture was extracted with ethyl acetate (150 mL*3). The combined organic layers were dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (3 g, 40%). 1 H-NMR (CDCl 3 ): 1.76 (s, 3H), 2.77 (m, 1H), 2.85 (m, 1H), 4.48 (s, 1H), 7.05 (m, 2H), 7.21-7.54 (m, 6H), 8.55 (s, 1H).

A suspension of 6-bromo-2-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.16 g, 3 mmol) and Lawesson's Reagent (1.21 g, 3 mmol) in dry 1,4-dioxane (24 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (748 mg, 61%). 1 H-NMR (CDCl 3 ): 1.75 (s, 3H), 3.78 (m, 2H), 5.79 (s, 1H), 6.94 (m, 1H), 7.14 (m, 1H), 7.22 (m, 1H), 7.26-7.53 (m, 5H), 8.39 (s, 1H).

Step 4. (2R,4S)-6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one & (2S,4S)-6-Bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro [chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (748 mg, 1.86 mmol) in MeOH (22 mL) was added a solution of NaOH (149 mg, 3.72 mmol) in H 2 O (4.5 mL) After stirring for 10 minutes, MeI (2.11 g, 149 mmol) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give (2R,4S)-6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (29 mg, total yield 36%) and (2S,4S)-6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (263 mg, total yield 36%).

(2R,4S)-6-Bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one: 1 H-NMR: 1.75 (s, 3H), 1.99 (m, 1H), 2.47 (d, 1H), 2.53 (s, 3H), 3.07 (s, 3H), 6.70 (d, 1H), 6.84 (d, 1H), 7.18-7.33 (m, 4H), 7.49 (d, 2H).

(2S,4S)-6-Bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one: 1 H-NMR: 1.61 (s, 3H), 2.10 (s, 3H), 2.82-2.95 (m, 2H), 3.28 (s, 3H), 6.82-6.98 (m, 2H), 7.12-7.46 (m, 5H), 7.72 (m, 1H).

A solution of 6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (292 mg, 0.667 mmol), NH 4 I (245.7 mg, 1.668 mmol) in a solution of NH 3 /EtOH (30 mL, 5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 4 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro [chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1 H-NMR (MeOD): 1.63 (s, 3H), 1.77 (s, 3H), 2.74 (d, 2H), 6.75 (d, 1H), 7.06 (d, 1H), 7.22 (m, 1H), 7.31 (m, 3H), 7.45 (m, 2H).

Step 6. 3-(2′-amino-1′,2-dimethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (14 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 0.113 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.45 mL) and 4-cyanophenylboronic acid (33 mg, 0.226 mmol). The mixture was refluxed under Ar in a microwave reactor for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2′-amino-1′,2-dimethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (17 mg, 36%). 1 H-NMR (CDCl 3 ): 1.78 (s, 3H), 1.97 (s, 3H), 2.60 (d, 1H), 2.85 (d, 1H), 6.84&6.93 (s, 1H), 7.23 (m, 2H), 7.31 (m, 4H), 7.48 (m, 2H), 7.52 (m, 2H), 7.62 (m, 1H), 7.67 (m, 1H), 11.51 (brs, 1H).

2′-amino-6-(3-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 33)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(hydroxymethyl)phenylboronic acid (15 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-6-(3-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.3 mg, 5%). 1 H-NMR (MeOD): 2.05 (t, 1H), 2.21 (t, 1H), 3.07 (s, 3H), 4.50 (s, 1H), 5.81 (d, 1H), 6.94 (d, 1H), 7.11 (s, 1H), 7.19 (d, 1H), 7.30 (m, 4H), 7.41 (m, 4H).

2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 34)

In a bottle, 1-(5-bromo-2-hydroxyphenyl)ethanone (25 g, 0.02 mol), 3-chlorobenzaldehyde (16.35 g, 0.12 mol), EtOH (96%, 144 mL) and NaOH (42.1 g, 1.06 mol) were combined. The mixture was stirred vigorously for 0.5 h. 2-Methoxy-2-methylpropane (300 mL) was added and the mixture was filtered. The filtrate was poured into HCl (1 N, 800 mL) and filtered to give 1-(5-bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-1-one (23.47 g, 60%). 1 H-NMR (CDCl 3 ): 6.88 (d, 1H), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, 1H), 7.80 (m, 1H), 7.93 (m, 1H), 12.56 (s, 1H).

1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-1-one (23 g, 68 mmol) was dissolved in H 2 O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered to give a solid cake. The cake was dissolved in EtOAc and washed with H 2 O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1 H-NMR (CDCl 3 ): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).

In a steel bomb, a mixture of 6-bromo-2-(3-chlorophenyl)chroman-4-one (7 g, 21 mmol), KCN (2.71 g, 42 mmol) and (NH 4 ) 2 CO 3 (15 g, 156 mmol) in formamide (60 mL) was heated and stirred at 70° C. for 24 h and then at 110° C. for 2 days. The mixture was poured into ice/water. Concentrated HCl was added till pH=1. The mixture was filtered to yield a solid cake. The filtrate was extracted with CH 2 Cl 2 . The organic layer was concentrated to give a residue, which was combined with the cake above. The solid was purified by column chromatography to give 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 5%). 1 H-NMR (CDCl 3 ): 2.20 (m, 1H), 2.28 (m, 1H), 5.76 (m, 1H), 6.82 (m, 1H), 7.27 (m, 5H), 7.39 (m, 1H).

A mixture of 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 1.16 mmol) and Lawesson's Reagent (468 mg, 1.16 mmol) in 1,4-dioxane (16 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (350 mg, 71%).

To a mixture of 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.6 mmol) and K 2 CO 3 (327 mg, 2.4 mmol) in CH 3 CN (6 mL) was added MeI (339 mg, 2.4 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue which was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-1′-methyl-2′-(methylthio)spiro chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 37%).

1 H-NMR (CDCl 3 ): 1.92 (m, 1H), 2.41 (m, 1H), 2.56 (s, 3H), 3.07 (s, 3H), 5.80 (m, 1H0, 6.80 (m, 2H), 7.26 (m, 4H), 7.39 (m, 1H).

A solution of 6-bromo-2-(3-chlorophenyl)-1′-methyl-2′-(methylthio)spiro chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 0.22 mmol), NH 4 I (64 mg, 0.44 mmol) in a solution of NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 46%). 1 H-NMR (MeOD): 2.12 (m, 2H), 3.06 (s, 3H), 5.80 (m, 1H), 6.83 (m, 1H0, 7.03 (m, 1H), 7.27 (m, 4H), 7.40 (m, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 0.07 mol), 3-fluorobenzaldehyde (8.7 g, 0.07 mol) and borax (26.7 g, 0.07 mol) in ethanol (90 mL) and H 2 O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (8.3 g, 3.7%). 1 H-NMR (CDCl 3 ): 2.93 (d, 1H), 3.03 (m, 1H), 5.47 (d, 1H), 7.06 (d, 1H), 7.11 (m, 1H), 7.22 (m, 2H), 7.40 (m, 1H), 7.57 (d, 1H), 8.04 (s, 1H).

A steel bomb was charged with a mixture of 6-bromo-2-(3-fluorophenyl)chroman-4-one (3.2 g, 0.01 mol), potassium cyanide (1.95 g, 0.03 mmol), and (NH 4 ) 2 CO 3 (7.2 g, 0.075 mmol). Formamide (20 mL) was added to fill the steel bomb nearly completely. The mixture was heated at 70° C. for 48 h then at 110° C. for another 8 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl was performed to give a precipitate which is filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-2-(3-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (0.31 g, 8%). 1 H-NMR (CDCl 3 ): 2.27 (t, 1H), 2.48 (d, 1H), 5.53 (s, 1H), 5.88 (d, 1H), 6.89 (d, 1H), 7.08 (m, 1H), 7.18 (m, 2H), 7.38 (m, 3H), 7.78 (s, 1H).

A suspension of 6-bromo-2-(3-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's reagent (312 mg, 0.77 mmol) in dry 1,4-dioxane (10 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (35 mg, 17%).

To a solution of 6-bromo-2-(3-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (264 mg, 0.65 mmol) in MeOH (10 mL) was added a solution of NaOH (65 mg, 1.63 mmol) in H 2 O (2 mL). After stirring for 10 minutes, MeI (1.4 g, 9.75 mmol) was added. The reaction mixture was heated under reflux for 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-2-(3-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 28%).

A solution of 6-bromo-2-(3-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.18 mmol) and NH 4 I (52 mg, 0.36 mmol) in NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC and then by preparative HPLC to afford 2′-amino-6-bromo-2-(3-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (36 mg, 50%). 1 H-NMR (MeOD): 2.16 (m, 2H), 3.12 (s, 3H), 5.87 (d, 1H), 6.90 (d, 1H), 7.08 (m, 2H), 7.25 (m, 2H), 7.33 (d, 1H), 7.41 (m, 1H).

Anhydrous aluminum chloride (84 g, 0.486 mol) was suspended in methylene chloride (1200 mL), and then acetyl chloride (49.2 g, 0.629 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-bromophenol (98 g, 0.57 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then ice water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 4-bromophenyl acetate (104 g, 85%). 1 H-NMR (CDCl 3 ): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).

A mixture of 4-bromophenyl acetate (104 g, 0.484 mol) and anhydrous aluminum chloride (130.5 g, 0.968 mol) was stirred at 120-140° C. for 20 minutes. The reaction mixture was cooled to 60-80° C. Ice water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 1-(5-bromo-2-hydroxy-phenyl)-ethanone (101 g, 98%). 1 H-NMR (CDCl 3 ): 2.60 (s, 3H), 6.87 (d, 1H), 7.53 (dd, 1H), 7.81 (s, 1H), 12.12 (s, 1H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (29 g, 0.135 mol), benzaldehyde (14.3 g, 0.135 mol) and borax (51.5 g, 0.135 mol) in ethanol (180 mL) and H 2 O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-phenyl-chroman-4-one (8.5 g, 21%). 1 H-NMR (CDCl 3 ): 2.89 (dd, 1H), 3.06 (dd, 1H), 5.46 (dd, 1H), 6.95 (d, 1H), 7.37-7.46 (m, 5H), 7.58 (d, 1H), 8.02 (d, 1H).

A glass pressure tube was charged with a mixture of 6-bromo-2-phenyl-chroman-4-one (7.6 g, 25 mmol), KCN (3.25 g, 50 mmol), and (NH 4 ) 2 CO 3 (18 g, 187.5 mmol). Formamide (80 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70° C. for 24 h then at 110° C. for another 48 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column to give 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (466 mg, 5%). 1 H-NMR (MeOD): 2.28 (t, 1H), 2.43 (dd, 1H), 5.83 (d, 1H), 6.90 (d, 1H), 7.33-7.45 (m, 7H).

A suspension of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (186 mg, 0.5 mmol) and Lawesson's Reagent (202 mg, 0.5 mmol) in dry 1,4-dioxane (8 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (115 mg, 62%). 1 H-NMR (CDCl 3 ): 2.35 (t, 1H), 2.49 (dd, 1H), 5.83 (d, 1H), 6.90 (d, 1H), 7.36-7.45 (m, 7H).

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (115 mg, 0.298 mmol) in MeOH (5 mL) was added a solution of NaOH (24 mg, 0.608 mmol) in H 2 O (1 mL). After stirring for 10 minutes, MeI (176 mg, 1.236 mmol) was added. The reaction mixture was refluxed for 2 h. And then MeI (500 mg, 3.52 mmol) was added and the reaction mixture was refluxed for another 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (59 mg, 48%).

A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (59 mg, 0.142 mmol), NH 4 I (41.5 mg, 0.286 mmol) in a solution of NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (21 mg, 38%). 1 H-NMR (MeOD): 2.04 (d, 1H), 2.15 (dd, 1H), 4.51 (m, 1H), 5.75 (d, 1H), 6.78 (m, 1H), 6.99 (d, 1H), 7.20-7.26 (m, 2H), 7.26-7.35 (m, 4H).

Cis-2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 44b) and

Trans-2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 44a)

A mixture of 4-bromophenyl acetate (64.2 g, 0.3 mol), benzaldehyde (31.8 g, 0.3 mol), 96% EtOH (370 mL), and NaOH (108 g) was stirred vigorously for 0.5-1 h, during which time, the reaction solidified. After standing for 3 h, the reaction mixture was triturated with MTBA (400 mL), and the solid was filtered and then dissolved in 600 mL of ethyl acetate. The organic layers was separated, dried over Na 2 SO 4 , filtered, and concentrated to give 1-(5-bromo-2-hydroxy-phenyl)-3-phenyl-propenone (55 g, 61%. 1 H-NMR (CDCl 3 ): 6.86 (m, 1H), 7.38 (m, 3H), 7.49 (m, 2H), 7.61 (m, 2H), 7.93 (t, 2H), 12.66 (s, 1H).

To a solution of 1-(5-bromo-2-hydroxy-phenyl)-3-phenyl-propenone (55 g, 0.182 mol) in water (1365 mL) and EtOH (455 mL) was added NaOH (7.3 g, 0.182 mol). The resulting orange slurry was stirred for 5 h at room temperature and then filtered. The solid was washed with water and then dissolved in ethyl acetate (400 mL). The water was removed and the product was dried over Na 2 SO 4 , filtered, and concentrated to give 6-bromo-2-phenyl-chroman-4-one (49.5 g, 90%). 1 H-NMR (CDCl 3 ): 2.82 (dd, 1H), 3.03 (dd, 1H), 5.42 (dd, 1H), 6.90 (d, 1H), 7.31-7.41 (m, 5H), 7.52 (dd, 1H), 7.97 (d, 1H).

A glass pressure tube was charged with a mixture of 6-bromo-2-phenyl-chroman-4-one (15.1 g, 50 mmol), KCN (6.5 g, 100 mmol), and (NH 4 ) 2 CO 3 (36 g, 375 mmol). Formamide (80 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70° C. for 24 h then at 110° C. for another 48 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column to give 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (2.4 g, 13%). 1 H-NMR (CDCl 3 ): 2.28 (t, 1H), 2.43 (dd, 1H), 5.66 (m, 1H), 5.82 (d, 1H), 6.86 (d, 1H), 7.33-7.41 (m, 7H), 8.03 (m, 1H).

A suspension of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.12 g, 3 mmol) and Lawesson's Reagent (1.21 g, 3 mmol) in dry 1,4-dioxane (25 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (780 mg, 67%). 1 H-NMR (CDCl 3 ): 2.26 (dd, 1H), 2.43 (dd, 1H), 5.76 (dd, 1H), 6.84 (m, 2H), 7.32-7.36 (m, 6H), 8.22 (m, 1H).

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (580.5 mg, 1.5 mmol) in MeOH (10 mL) was added a solution of NaOH (120 mg, 3 mmol) in H 2 O (2 mL). After stirring for 10 min, MeI (3.2 g, 225 mmol) was added. The reaction mixture was refluxed for 2 h. Then MeI (3.2 mg, 225 mmol) was added and the reaction was refluxed for another 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (380 mg, 61%).

A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (380 mg, 0.913 mmol), and NH 4 I (265 mg, 1.83 mmol) in a solution of NH 3 /EtOH (8 mL, 1.5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one with two isomers: cis isomer (21 mg, 38%) and trans isomer (25 mg, 45%).

(cis): 1 H-NMR (MeOD): 2.05 (t, 1H), 2.25 (t, 1H), 3.13 (s, 3H), 5.86 (d, 1H), 6.87 (d, 1H), 7.09 (m, 1H), 7.31-7.35 (m, 2H), 7.36-7.48 (m, 4H).

(trans): 1 H-NMR (MeOD): 2.12 (m, 1H), 2.25 (t, 1H), 3.14&3.20 (s, 3H), 5.87 (d, 1H), 6.88 (d, 1H), 7.11 (m, 1H), 7.32-7.36 (m, 2H), 7.38-7.48 (m, 4H).

3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (Compound 45)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(N,N-dimethylsulfamoyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (1.7 mg, 7%). 1 H-NMR (MeOD): 2.47 (m, 1H), 2.62 (m, 1H), 2.71 (s, 6H), 3.29 (s, 3H), 5.28 (d, 0.3H), 5.89 (d, 0.7H), 7.19 (m, 1H), 7.47 (m, 6H), 7.69 (m, 2H), 7.75 (m, 1H), 7.93 (m, 2H).

2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 46)

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (18 g, 84.1 mmol), 3-methoxy-benzaldehyde (11.4 g, 84.1 mol), and borax (51.5 g, 0.135 mol) in ethanol (112 mL) and H 2 O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O, and extracted with ether. The ether was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(3-methoxy-phenyl)-chroman-4-one (5 g, 18%). 1 H-NMR (CDCl 3 ): 2.89 (d, 1H), 3.04 (t, 1H), 3.81 (s, 3H), 5.43 (d, 2H), 6.96 (m, 3H), 7.32 (m, 1H), 7.58 (m, 1H), 8.01 (s, 1H)

A steel bomb was charged with a mixture of 6-bromo-2-(3-methoxyphenyl)chroman-4-one (2 g, 6 mmol), KCN (770 mg, 12 mmol), and (NH 4 ) 2 CO 3 (4 g, 42 mmol). Formamide (20 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70° C. for 72 h then at 110° C. for another 5 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which is purified by column to give 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (534 mg, 22%). 1 H-NMR (MeOD): 2.26 (d, 1H), 2.37 (t, 1H), 3.79 (s, 3H), 5.80 (d, 1H), 6.88 (m, 2H), 7.00 (m, 2H), 7.44 (m, 2H).

A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (273 mg, 0.679 mmol) and Lawesson's Reagent (274 mg, 0.629 mmol) in dry 1,4-dioxane (10 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (200 mg, 71%).

1 H-NMR (CDCl 3 ): 2.24 (m, 1H), 2.41 (m, 1H), 3.76 (s, 3H), 5.72 (m, 1H), 6.88 (m, 4H), 7.31 (m, 1H), 8.24 (m, 1H).

To a solution of 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (50 mg, 0.12 mmol) in MeOH (5 mL) was added a solution of NaOH (9.5 mg) in H 2 O (1 mL). After stirring for 10 minutes, MeI (171 mg) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (13 mg, 21%).

A solution of 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (13 mg) and NH 4 I (10 mg) in a solution of NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.17 mg, 22%).

1 H-NMR (MeOD): 2.00 (d, 1H), 2.13 (m, 1H), 3.03 (s, 3H), 3.70 (s, 3H), 5.70 (m, 1H), 6.77 (m, 2H), 6.89 (m, 2H), 7.00 (m, 1H), 7.21 (m, 2H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 4-chlorobenzaldehyde (3.92 g, 28 mmol), and borax (10H 2 O, 10.67 g, 28 mmol) in H 2 O (60 mL) and EtOH (36 mL) was stirred at 110° C. overnight. The mixture was filtered to give a solid cake. The cake was dissolved in EtOAc and filtered. The filtrate was dried, filtered, and concentrated to give 6-bromo-2-(4-chloro-phenyl)-chroman-4-one (8.43 g, 89%). 1 H-NMR (CDCl 3 ): 2.88 (m, 1H), 3.04 (m, 1H), 5.44 (m, 1H), 6.94 (m, 1H), 7.39 (m, 4H), 7.57 (m, 1H), 8.02 (m, 1H).

In a steel bomb, a mixture of 6-bromo-2-(4-chlorophenyl)chroman-4-one (4 g, 12 mmol), KCN (1.54 g, 24 mmol), and (NH 4 ) 2 CO 3 (8.6 g, 90 mmol) in formamide (40 mL) was heated and stirred at 70° C. for 24 h and then at 110° C. for 2 days. The mixture was poured into ice/water. Concentrated HCl was added until pH=1. The mixture was filtered to give a solid cake and the filtrate was extracted with CH 2 Cl 2 . The organic layer was concentrated to give a residue, which was combined with the cake above. The solid was purified by column chromatography to give 6-bromo-2-(4-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 12%).

A mixture of 6-bromo-2-(4-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 1.48 mmol) and Lawesson's Reagent (596 mg, 1.48 mmol) in 1,4-dioxane (25 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (450 mg, 69%). 1 H-NMR (MeOD): 2.24 (m, 1H), 2.45 (m, 1H), 6.82 (m, 1H), 6.91 (m, 1H), 7.20 (m, 1H), 7.44 (m, 5H).

To a mixture of 6-bromo-2-(4-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (450 mg, 1.07 mmol) and K 2 CO 3 (588 mg, 4.27 mmol) in CH 3 CN (10 mL) was added MeI (610 mg, 4.27 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-2-(4-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′H-one (325 mg, 37%). 1 H-NMR (CDCl 3 ): 1.89 (m, 1H), 2.41 (m, 1H), 2.56 (t, 3H), 3.17 (m, 3H), 5.81 (m, 1H), 6.79 (m, 2H), 7.23 (m, 1H), 7.43 (m, 4H).

A solution of 6-bromo-2-(4-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (300 mg, 0.67 mmol) and NH 4 I (194 mg, 1.33 mmol) in NH 3 /EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(4-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 12%). 1 H-NMR (MeOD): 2.19 (m, 1H), 2.41 (m, 1H), 3.11 (m, 3H), 5.15 (m, 0.5H), 5.38 (m, 0.5H), 6.78 (m, 1H), 6.82 (m, 0.5H), 7.02 (m, 0.5H), 7.23 (m, 1H), 7.31 (m, 3H), 7.44 (m, 1H).

To a mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (300 mg, 0.77 mmol) and K 2 CO 3 (427 mg, 3.1 mmol) in CH 3 CN (6 mL) was added PrBr (380 mg, 3.1 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (285 mg, 90%). 1 H-NMR (CDCl 3 ): 0.87 (m, 3H), 1.00 (m, 3H), 1.64 (m, 2H), 1.73 (m, 2H), 1.89 (m, 1H), 2.48 (m, 1H), 3.16 (m, 2H), 3.44 (m, 2H), 5.82 (m, 1H), 6.81 (m, 2H), 7.22 (m, 1H), 7.30 (m, 3H), 7.48 (m, 2H).

A solution of 6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (280 mg, 0.6 mmol) and NH 4 I (172 mg, 1.2 mmol) in NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-phenyl-1′-propylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1 H-NMR (MeOD): 0.93 (m, 3H), 1.66 (m, 2H), 2.04 (m, 1H), 2.25 (m, 1H), 3.56 (m, 2H), 5.83 (m, 1H), 6.87 (m, 1H), 7.06 (m, 1H), 7.31 (m, 2H), 7.40 (m, 4H).

(2R,4S)-2′-amino-6-bromo-2-phenyl-1′-propylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 57a)

To a mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (131 mg, 0.34 mmol) and K 2 CO 3 (186 mg, 1.35 mmol) in CH 3 CN (5 mL) was added PrBr (166 mg, 1.35 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give (2R,4S)-6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (75 mg, 47%).

A solution of (2R,4S)-6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (75 mg, 0.16 mmol), and NH 4 I (46 mg, 0.32 mmol) in NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford (2R,4S)-2′-amino-6-bromo-2-phenyl-1′-propylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (15 mg, 23%). 1 H-NMR (MeOD): 1.00 (m, 3H), 1.45 (m, 2H), 2.23 (m, 1H), 2.48 (m, 1H), 3.75 (m, 2H), 5.85 (m, 1H), 6.90 (m, 1H), 7.14 (m, 1H), 7.40 (m, 6H).

2′-amino-1′-methyl-2-phenyl-6-(pyridin-4-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 58)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and pyridin-4-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(pyridin-4-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.51 mg, 10%). 1 H-NMR (MeOD): 2.50 (t, 1H), 2.64 (dd, 1H), 3.37 (s, 3H), 5.91 (d, 1H), 7.26 (d, 1H), 7.45 (m, 5H), 7.82 (d, 1H), 7.94 (t, 1H), 8.16 (s, 2H), 8.71 (s, 2H).

2′-amino-6-bromo-1′-(2-cyclopropylethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 59)

A mixture of 2-cyclopropylethanol (2 g, 0.023 mol) and pyridine (0.51 g, 0.006 mol) was added dropwise with magnetic stirring over 2 hours to PBr 3 (2.5 g, 0.009 mol) at 0° C. Then ether was added and the mixture was washed with an aqueous NaHCO 3 solution and brine. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give (2-bromoethyl)cyclopropane (1.3 g, 38%). 1 H-NMR (CDCl 3 ): 0.01 (m, 2H), 0.40 (m, 2H), 0.69 (m, 1H), 1.51 (m, 2H), 4.08 (m, 2H).

A mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.644 mmol), excess (2-bromoethyl)cyclopropane (381 mg, 2.58 mmol), and solid K 2 CO 3 (356 mg, 2.58 mmol) in CH 3 CN (10 mL) was stirred for 4 hours at 60° C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC to give 6-bromo-1′-(2-cyclopropylethyl)-2′-(2-cyclopropylethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 11%).

A solution of 6-bromo-1′-(2-cyclopropylethyl)-2′-(2-cyclopropylethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 0.076 mmol), and NH 4 I (22 mg, 0.153 mmol) in a solution of NH 3 /EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-(2-cyclopropylethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (8 mg, 24%). 1 H-NMR (MeOD): 0.01 (m, 2H), 0.34 (m, 2H), 0.61 (m, 1H), 1.48 (m, 2H), 2.10 (m, 1H), 2.37 (m, 1H), 3.67 (m, 2H), 5.12 (d, 0.3H), 5.74 (d, 0.7H), 6.70 (m, 1H), 7.00 (m, 1H), 7.31 (m, 6H).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 70.1 mmol), 2-fluorobenzaldehyde (8.7 g, 70.1 mmol), and borax (26.7 g, 70.1 mmol) in ethanol (90 mL) and H 2 O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O, and extracted with ether. The ether was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman-4-one (15 g, 50%).

A steel bomb was charged with a mixture of 6-bromo-2-(2-fluorophenyl)chroman-4-one (2 g, 6.25 mmol), KCN (0.82 g, 12.5 mmol), and (NH 4 ) 2 CO 3 (4.5 g, 46.87 mmol). Formamide (25 mL) was added to fill the steel bomb nearly completely. The mixture was heated at 70° C. for 48 h then at 110° C. for another 12 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column to give 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 10%).

A suspension of 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (259 mg, 0.64 mmol) in anhydrous 1,4-dioxane (20 mL) was heated under reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro-[chroman-4,4′-imidazolidin]-5′-one (180 mg, 67%).

To a solution of 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (180 mg, 0.443 mmol) in MeOH (10 mL) was added a solution of NaOH (35.46 mg, 0.887 mmol) in H 2 O (2 mL). After stirring for 10 minutes, MeI (951 mg, 6.65 mmol) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 41%).

A solution of 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.183 mmol) and NH 4 I (53.21 mg, 0.367 mmol) in NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (52 mg, 70%). 1 H-NMR (MeOD): 2.15 (d, 1H), 2.25 (d, 1H), 3.20 (s, 3H), 6.15 (d, 1H), 6.78 (d, 1H), 6.99 (t, 1H), 7.05 (s, 1H), 7.15 (t, 1H), 7.25 (d, 2H), 7.50 (t, 1H).

2′-amino-1′,6-dimethyl-2-phenylspiro[chroman-4,4′-imidizol]-5′(1′H)-one (Compound 64)

Anhydrous aluminum chloride (88 g, 0.66 mol) was suspended in methylene chloride (1500 mL), and then acetyl chloride (51.5 g, 0.66 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-methylphenol (50 g, 0.46 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then poured into ice water slowly to quench the reaction. After extraction with ethyl acetate, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield acetic acid 4-methylphenyl ester (52.6 g, 76%). 1 H-NMR (CDCl 3 ): 2.25 (s, 3H), 2.36 (s, 3H), 6.96 (d, 2H), 7.18 (d, 2H).

A mixture of 4-methylphenyl acetate (52.6 g, 0.35 mol) and anhydrous aluminum chloride (94 g, 0.70 mol) was stirred at 120-140° C. for 20 minutes. The reaction mixture was cooled to 60-80° C. and ice water was slowly added. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 2′-hydroxy-5′-methyl-acetophenone (32 g, 61%). 1 H-NMR (CDCl 3 ): 2.28 (s, 3H), 2.57 (s, 3H), 6.83 (d, 1H), 7.25 (d, 1H), 7.46 (s, 1H), 12.01 (s, 1H).

A mixture of 1-(2-hydroxy-5-methyl-phenyl)-ethanone (15 g, 0.10 mol), benzaldehyde (10.6 g, 0.10 mol) and borax (38 g, 0.10 mol) in ethanol (90 mL) and H 2 O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ether. The ether was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-methyl-2-phenyl-chroman-4-one (8.1 g, 34%). 1 H-NMR (CDCl 3 ): 2.32 (s, 3H), 2.86 (d, 1H), 3.06 (t, 1H), 5.44 (d, 1H), 6.96 (d, 1H), 7.38 (d, 1H), 7.44 (m, 5H), 7.71 (s, 1H).

A steel bomb was charged with a mixture of 6-methyl-2-phenyl-chroman-4-one (1 g, 4.2 mmol), potassium cyanide (0.82 g, 12.6 mmol), and (NH 4 ) 2 CO 3 (3.03 g, 31.5 mmol). Formamide (20 mL) was added to fill the steel bomb nearly completely. The mixture was heated at 70° C. for 24 h and then at 110° C. for another 48 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl was performed to give a precipitate which was filtered, washed twice with water. The precipitate was dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 6-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (0.42 g, 32%).

A suspension of 6-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (200 mg, 0.65 mmol) and Lawesson's Reagent (263 mg, 0.65 mmol) in anhydrous 1,4-dioxane (8 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (35 mg, 17%). 1 H-NMR (CDCl 3 ): 2.28 (s, 3H), 2.47 (d, 1H), 2.51 (d, 1H), 5.30 (s, 1H), 6.92 (s, 1H), 6.70 (d, 2H), 7.10 (m, 1H), 7.41 (m, 1H), 8.18 (s, 1H).

To a solution of 6-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (55 mg, 0.17 mmol) in MeOH (5 mL) was added a solution of NaOH (13 mg, 0.34 mmol) in H 2 O (1 mL). After stirring for 10 min, MeI (363 mg, 2.55 mmol) was added. The reaction mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to give 1′,6-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′-(1′H)-one (40 mg, 67%).

A solution of 1′,6-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′-(1′H)-one (40 mg, 0.12 mmol), and NH 4 I (35 mg, 0.24 mmol) in NH 3 /EtOH (4 mL, 1.5N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC and preparative HPLC to afford 2′-amino-1′,6-dimethyl-2-phenylspiro[chroman-4,4′-imidizol]-5′(1′H)-one (2.03 mg, 6%). 1 H-NMR (MeOD): 2.28 (s, 3H), 2.40 (d, 1H), 2.55 (d, 1H), 3.28 (s, 3H), 5.74 (d, 1H), 6.92 (d, 1H), 7.13 (s, 1H), 7.35 (d, 1H), 7.40-7.50 (m, 6H).

To the suspension of anhydrous aluminum chloride (84.0 g, 0.49 mol) in methylene chloride (1200 mL) was add acetyl chloride (49.2 g, 0.63 mol) while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice followed by addition of 4-bromophenol (98 g, 0.57 mol). The reaction mixture was stirred at room temperature for 1 h and then ice water was added. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 4-bromophenyl acetate (104.0 g, 85%). 1 H-NMR (CDCl 3 ): 2.28 (s, 3 H), 6.98 (d, 2 H), 7.48 (d, 2 H).

A mixture of 4-bromophenyl acetate (104.0 g, 0.48 mol) and anhydrous aluminum chloride (130.5 g, 0.968 mol) was stirred at 120-140° C. for 20 minutes. The reaction mixture was cooled to 60-80° C. and ice water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 1-(5-bromo-2-hydroxyphenyl)-ethanone (101.0 g, 98%). 1 H-NMR (CDCl 3 ): 2.60 (s, 3 H), 6.87 (d, 1 H), 7.53 (dd, 1 H), 7.81 (s, 1 H), 12.12 (s, 1 H).

A solution of 1-(5-bromo-2-hydroxyphenyl)-ethanone (21.4 g, 0.1 mol), acetone (365 mL) and pyrrolidine (8.4 mL) in toluene (220 mL) was refluxed for 4 h. To the reaction mixture was added acetone (36.5 mL). The mixture was refluxed for 15 h. Then 1 N HCl (220 mL) was added, and the resulting mixture was extracted with ethyl acetate (200 mL, 3×). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18.0 g, 71%). 1 H-NMR (CDCl 3 ): 1.45 (s, 6 H), 2.71 (s, 2 H), 6.82 (d, 1 H), 7.52 (dd, 1 H), 7.96 (d, 1 H).

A glass pressure tube was charged with a mixture of 6-bromo-2,2-dimethyl-chroman-4-one (6.4 g, 25 mmol), KCN (3.25 g, 50 mmol), and (NH 4 ) 2 CO 3 (18 g, 187.5 mmol). Formamide (80 mL) was added to fill the pressure tube nearly completely. The resulting mixture was heated at 70° C. for 24 h then at 110° C. for another 48 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then redissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column to give 6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (8.2 g, 100%). 1 H-NMR (DMSO): 1.24 (s, 3 H), 1.40 (s, 3 H), 2.16 (d, 1 H), 2.30 (d, 1 H), 6.80 (d, 1 H), 7.10 (m, 1 H), 7.39 (d, 1 H), 8.69 (s, 1 H), 11.08 (brs, 1 H).

6-Bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (4.0 g, 12.3 mmol) and 1 M Et 3 O.BF 4 (4.7 g, 24.7 mmol) were dissolved in dry CH 2 Cl 2 (100 mL). Then the mixture was refluxed for 24 h. The solvent was removed in vacuo to give a residue, which was purified by column to give 6-bromo-2′-ethoxy-2,2-dimethylspiro-[chroman-4,4′-imidazol]-5′(3′H)-one (1.0 g, 25%).

To a solution of 6-bromo-2′-ethoxy-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (500 mg, 1.42 mmol) in EtOH (30 mL) was added NH 3 .H 2 O (30 mL). The mixture was refluxed for 18 h. The solvent was removed in vacuo to give a residue, which was purified by preparative TLC to give 2′-amino-6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (120 mg, 30%).

To a solution of 2′-amino-6-bromo-2,2-dimethyl-spiro[chroman-4,4′-imidazol]-5′(3′H)-one (45 mg, 0.131 mmol) in THF (3 mL) at 0° C. under N 2 was added NaH (5.3 mg, 0.131 mmol). The resulting mixture was stirred for 1 h at room temperature. Then MeI (18.6 mg, 0.131 mmol) was added. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo. The residue was purified by preparative TLC to give 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 80%) and 6-bromo-1′,2,2-trimethyl-2′-(methylamino)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 10%).

1 H-NMR (MeOD): 1.3 (s, 3 H), 1.40 (s, 3 H), 1.85 (d, 1 H), 2.25 (d, 1 H), 3.1 (s, 3 H), 6.65 (d, 1 H), 6.8 (s, 1 H), 7.20 (s, 1 H) (67).

1 H-NMR (MeOD): 1.3 (s, 3 H), 1.40 (s, 3 H), 1.85 (d, 1 H), 2.25 (d, 1 H), 2.8 (s, 3 H), 3.0 (s, 3 H), 6.65 (d, 1 H), 6.8 (s, 1 H), 7.20 (s, 1 H).

4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (Compound 68)

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(dimethylcarbamoyl)phenylboronic acid (20.1 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (7.97 mg, 34%). 1 H-NMR (MeOD): 2.07 (m, 1H), 2.24 (m, 1H), 3.00 (m, 6H), 3.11 (m, 3H), 5.22 (d, 0.3H), 5.86 (d, 0.7H), 6.97 (m, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.34 (m, 2H), 7.39 (m, 4H), 7.46 (m, 1H), 7.54 (m, 2H).

2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 69)

To a mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.64 mmol) and K 2 CO 3 (356 mg, 2.6 mmol) in CH 3 CN (8 mL) was added EtI (402 mg, 2.6 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 69%).

A solution of 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 0.44 mmol), NH 4 I (128 mg, 0.88 mmol) in NH 3 /EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 24%). 1 H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, 1H), 3.16 (m, 1H), 3.54 (m, 2H), 5.75 (m, 1H), 6.77 (m, 1H), 6.95 (m, 1H), 7.23 (m, 2H), 7.33 (m, 4H).

To the solution of 3,4-dihydro-2H-pyran (126 g, 1.5 mol) in dry THF (1100 mL) was added a solution of B 2 H 6 in Me 2 S (10 M, 75 mL, 0.75 mol) under nitrogen atmosphere at 0° C. The mixture was stirred at this temperature for 3 h, and then 25° C. for another 2 h. The mixture was warmed to 40° C.˜45° C., and aq. NaOH (3 N, 300 mL) and H 2 O 2 (30%, 170 mL) were added. After stirring for 2 h, the reaction was quenched by saturated brine. The reaction mixture was filtered, and the filtrate was extracted with EtOAc (3×300 mL). The organic phase was washed with aq. Na 2 S 2 O 3 (3×100 mL), dried over Na 2 SO 4 , and concentrated in vacuum to give the crude product, which was purified by distillation to give the product (43 g, 33%). 1 H-NMR (CDCl 3 ): 1.1.51-1.61 (m, 2H), 1.78-1.91 (m, 4H), 3.40 (m, 1H), 3.54-3.65 (m, 2H), 3.69-3.76 (m, 2H).

To a solution of tetrahydro-pyran-3-ol (30 g, 0.29 mol) in dry CH 2 Cl 2 (900 mL) was added 3 Å molecule sieves (30 g) and PCC (94.9 g, 0.44 mol). The mixture was stirred at room temperature overnight. When the reaction was completed, the mixture was filtered through celite, dried over Na 2 SO 4 , and concentrated in vacuum to give the crude product, which was distilled in vacuo to give dihydro-pyran-3-one (10.5 g, 36%). 1 H-NMR (CDCl 3 ): 2.06-2.13 (m, 2H), 2.53 (m, 2H), 3.85 (m, 2H), 4.02 (s, 2H).

A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (17.3 g, 0.081 mol), dihydro-pyran-3-one (10.5 g, 0.105 mol) and pyrrolidine (7.5 g, 0.105 mol) in toluene (200 mL) was stirred vigorously at room temperature overnight. Then the mixture was refluxed overnight. After cooling, the mixture was treated with water (100 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were concentrated and the residue was purified by column to give the product 72i (12 g, 50%). 1 H-NMR (CDCl 3 ): 1.49 (m, 1H), 1.65 (m, 1H), 1.86 (m, 1H), 2.04 (m, 1H), 2.63 (t, 2H), 3.48 (m, 2H), 3.79 (m, 2H), 6.88 (d, 1H), 7.50 (dd, 1H), 7.89 (m, 1H).

A pressure tube was charged with a mixture of the compound 72i (12 g, 0.04 mol), KCN (5.27 g, 0.08 mol), and (NH 4 ) 2 CO 3 (28.8 g, 0.3 mol). Formamide (65 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70° C. for 72 h then at 110° C. for another 3 h. The reaction mixture was then cooled and poured over ice. After acidification with concentrated HCl, the mixture was extracted with ethyl acetate (150 mL*3). The combined organic layers were dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give the compound 72ii (7.8 g, 53%). 1 H-NMR (CDCl 3 ): 1.74-2.12 (m, 4H), 2.36 (m, 1H), 2.47 (m, 1H), 3.51-3.55 (m, 4H), 6.85 (m, 1H), 7.18 (m, 1H), 7.32 (m, 1H), 8.18 (d, 1H), 8.93 (s, 1H).

A suspension of 72ii (600 mg, 1.638 mmol) and Lawesson's Reagent (662 mg, 1.638 mmol) in dry 1,4-dioxane (6 mL) was heated at 110° C. for 0.5 h in a CEM microwave reactor. The mixture was concentrated in vacuo and the residue was purified by column to give the compound 72iii (385 mg, 61%). 1 H-NMR (CDCl 3 ): 1.52-1.74 (m, 2H), 1.95 (m, 2H), 2.15 (m, 1H), 2.49 (m, 1H), 3.56 (m, 2H), 3.84 (m, 2H), 7.12 (m, 1H), 7.35 (m, 1H), 7.14 (s, 1H), 9.14 (s, 1H).

To a solution of 72iii (192 mg, 0.5 mmol) in MeOH (20 mL) was added a solution of NaOH (1.9 mL, 0.6 N). After stirring for 5 min, MeI (0.4 mL) was added. The reaction mixture was heated at 60° C. for 10 minutes in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 72iv (93 mg, yield 45%).

A solution of 72iv (93 mg, 0.227 mmol), NH 4 I (82 mg, 0.567 mmol) in NH 3 /EtOH (7 mL, 5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford the amine 72v (45 mg, 53%).

Pd(PPh 3 ) 2 Cl 2 (20 mg, 0.029 mmol) in a 10 mL flask under Ar was treated sequentially with the amine 72v (45 mg, 0.12 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.6 mL) and 3-cyanophenylboronic acid (35.3 mg, 0.24 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure final product 72 (22.6 mg, 46%). 1 H-NMR (MeOD): 1.68 (m, 1H), 1.89 (m, 2H), 2.03 (m, 1H), 2.12 (m, 1H), 2.25 (t, 1H), 3.16 (s, 3H), 3.58 (m, 2H), 3.84 & 4.05 (m, 2H), 7.04 (m, 2H), 7.49-7.58 (m, 2H), 7.62 (m, 1H), 7.86 (m, 1H), 7.84 (m, 1H).

Compound 72a and Compound 72b

Experimental Data

To a solution of 3,4-dihydro-2H-pyran (126 g, 1.5 mol) in dry THF (1100 mL) was added a solution of B 2 H 6 in Me 2 S (10 M, 75 mL, 0.75 mol) under nitrogen atmosphere at 0° C. The mixture was stirred at this temperature for 3 h, and then 25° C. for another 2 h. The mixture was warmed to 40˜45° C., and aqueous NaOH (3 N, 300 mL) and H 2 O 2 (30%, 170 mL) were added. After stirring for 2 h, the reaction was quenched by saturated brine. The reaction mixture was filtered, and the filtrate was extracted with EtOAc (3×300 mL). The organic phase was washed with aq. Na 2 S 2 O 3 (3×100 mL), dried over Na 2 SO 4 , and concentrated in vacuum to give the crude product, which was purified by distillation to give tetrahydro-pyran-3-ol (86 g, 33%). 1 H-NMR (CDCl 3 ): 1.51-1.61 (m, 2H), 1.78-1.91 (m, 4H), 3.40 (m, 1H), 3.54-3.65 (m, 2H, 3.69-3.76 (m, 2H).

To a solution of tetrahydro-pyran-3-ol (30 g, 0.29 mol) in dry CH 2 Cl 2 (900 mL) was added 3 Å molecule sieves (30 g) and PCC (94.9 g, 0.44 mol). The mixture was stirred at room temperature overnight. When the reaction was completed, the mixture was filtered through celite, dried over Na 2 SO 4 , and concentrated in vacuum to give the crude product, which was distilled in vacuo to give dihydro-pyran-3-one (10.5 g, 36%). 1 H-NMR (CDCl 3 ): 2.06-2.13 (m, 2H), 2.53 (m, 2H), 3.85 (m, 2H), 4.02 (s, 2H).

A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (17.3 g, 0.081 mol), dihydro-pyran-3-one (10.5 g, 0.105 mol) and pyrrolidine (7.5 g, 0.105 mol) in toluene (200 mL) was stirred vigorously at room temperature overnight. Then the mixture was refluxed overnight. After cooling, the mixture was treated with water (100 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were concentrated and the residue was purified by column to give the product 72i (12 g, 50%). 1 H-NMR (CDCl 3 ): 1.49 (m, 1H), 1.65 (m, 1H), 1.86 (m, 1H), 2.04 (m, 1H), 2.63 (t, 2H), 3.48 (m, 2H), 3.79 (m, 2H), 6.88 (d, 1H), 7.50 (dd, 1H), 7.89 (m, 1H).

A pressure tube was charged with a mixture of the compound 72i (12 g, 0.04 mol), KCN (5.27 g, 0.08 mol), and (NH 4 ) 2 CO 3 (28.8 g, 0.3 mol). Formamide (65 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 65° C. for 72 h. The reaction mixture was then cooled and poured over ice. After acidification with concentrated HCl, the mixture was extracted with ethyl acetate (200 mL*3). The combined organic layers were dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give the compound 2 (7.8 g, 53%). 1 H-NMR (CDCl 3 ): 1.74-2.12 (m, 4H), 2.36 (m, 1H), 2.47 (m, 1H), 3.51-3.55 (m, 4H), 6.85 (m, 1H), 7.18 (m, 1H), 7.32 (m, 1H), 8.18 (d, 1H), 8.93 (s, 1H).

A suspension of 72ii (600 mg, 1.638 mmol) and Lawesson's Reagent (662 mg, 1.638 mmol) in dry 1,4-dioxane (6 mL) was heated under 110° C. for 0.5 h in a CEM microwave reactor. The mixture was concentrated in vacuo and the residue was purified by column to give the compound 3 (385 mg, 61%). 1 H-NMR (CDCl 3 ): 1.52-1.74 (m, 2H), 1.95 (m, 2H), 2.15 (m, 1H), 2.49 (m, 1H), 3.56 (m, 2H), 3.84 (m, 2H), 7.12 (m, 1H), 7.35 (m, 1H), 7.14 (s, 1H), 9.14 (s, 1H).

To a solution of 72iii (385 mg, 1.007 mmol) in MeOH (20 mL) was added a solution of NaOH (3.85 mL, 0.6 N). After stirring for 5 min, MeI (0.8 mL) was added. The reaction mixture was heated at 60° C. for 10 minutes in microwave. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 72iv (123 mg, yield 30%).

A solution of 72iv (123 mg, 0.3 mmol), NH 4 I (109 mg, 0.75 mmol) in NH 3 /EtOH (12 mL, 5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford the amine 72v (48 mg, 42%).

Step 8: Compound 72a Pd(PPh 3 ) 2 Cl 2 (20 mg) in a 10 mL of microwave tube under Ar 2 was treated sequentially with the amine 72v (45 mg, 0.12 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (35.3 mg, 0.24 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure final products 72 (3.71 mg), compound 72a (6.83 mg) and compound 72b (3.7 mg, total yield 30%).

Compound 72: 1 H-NMR (MeOD): 1.53-1.69 (m, 1H), 1.88 (m, 1H), 2.06 (m, 2H), 2.32-2.46 (s, 2H), 3.30 (s, 3H), 3.59 (m, 2H), 3.76-3.94 (m, 2H), 7.10 (m, 1H), 7.41 (m, 1H), 7.54 (t, 1H), 7.63 (m, 2H), 7.84 (m, 1H), 7.92 (m, 1H).

Compound 72a: 1 H-NMR (MeOD): 1.48 (m, 1H), 1.81 (m, 1H), 1.92 (m, 1H), 2.04 (m, 1H), 2.38 (m, 2H), 3.30 (s, 3H), 3.58 (m, 2H), 3.85 (m, 2H), 7.09 (d, 1H), 7.31 (m, 1H), 7.58 (m, 3H), 7.79 (m, 1H), 7.85 (m, 1H).

Compound 72b: 1 H-NMR (MeOD): 1.65 (m, 1H), 1.92 (m, 1H), 2.02 (m, 1H), 2.10 (m, 1H), 2.45 (s, 2H), 3.31 (s, 3H), 3.63 (m, 2H), 3.77 (m, 2H), 7.09 (m, 1H), 7.40 (m, 1H), 7.55 (t, 1H), 7.64 (m, 2H), 7.83 (m, 1H), 7.92 (m, 1H).

Compound 73

Experimental Data

A suspension of the compound 73i (300 mg, 0.79 mmol) and Lawesson's Reagent (320 mg, 0.79 mmol) in dry 1,4-dioxane (4 mL) was heated at 110° C. for 45 minutes in a microwave reactor. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (PE:EtOAc=3:1) to give the compound 73ii (229 mg, 73%).

To a solution of the compound 73ii (187 mg, 0.47 mmol) in 1,4-dioxane (19 mL) was added a solution of NaOH (0.6 N, 1.87 mL) and MeI (0.152 mL). The reaction mixture was heated at 60° C. for 20 minutes in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC (PE:EtOAc 6:1) to give the compound 73iii (150 mg, 75%). 1 H NMR (CDCl 3 /400M): δ 7.25-7.19 (m, 1H), 6.74-6.69 (m, 2H), 3.13 (s, 3H), 2.58-2.50 (m, 4H), 2.31-2.19 (m, 1H), 2.18-2.05 (m, 1H), 2.03-1.95 (m, 1H), 1.90-1.60 (m, 3H) 1.51-1.40 (m, 1H), 1.39-1.15 (m, 3H), 0.95-0.80 (m, 3H).

A solution of the compound 73iii (127 mg, 0.3 mmol), NH 4 I (87 mg, 0.6 mmol) in NH 3 /EtOH (12.7 mL, 1.5 N) was heated at 120° C. in a tube in a microwave reactor for 3 hours. After cooling, the mixture was concentrated in vacuo to give the residue, which was diluted in CH 2 Cl 2 and filtered to separate off NH 4 I. The solution was concentrated in vacuo and purified by preparative TLC (CH 2 Cl 2 : CH 3 OH 11:1) to afford the compound 73iv (85 mg, 72%).

Pd(PPh 3 ) 2 Cl 2 (18 mg) in a 10 mL tube under Ar was treated sequentially with the compound 73iv (55 mg, 0.14 mmol) in 1,4-dioxane (5.2 mL), Cs 2 CO 3 (2 N, 0.78 mL) and 3-cyanophenylboronic acid (41.25 mg, 0.28 mmol). The mixture was heated in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC (CH 2 Cl 2 : CH 3 OH 13:1) and then by preparative HPLC to give the Compound 73 (32 mg, 43%). 1 H NMR (MeOD/400M): δ 7.91 (s, 1H), 7.84 (d, 1H, 9.2 Hz), 7.66-7.40 (m, 3H), 7.39 (s, 1H), 7.02-6.98 (m, 1H), 3.30 (s, 3H), 2.64-2.59 (m, 1H), 2.37-2.32 (m, 1H), 2.30-2.09 (m, 2H), 2.08-1.92 (m, 2H), 1.91-1.66 (m, 1H), 1.65-1.51 (m, 1H), 1.50-1.21 (m, 3H), 0.98-0.88 (m, 3H).

Compound 75

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), 4-methylcyclohexanone (21.31 g, 0.187 mol) and pyrrolidine (12.63 g, 0.178 mol) in methanol (400 mL) was refluxed for overnight. The reaction mixture was concentrated in vacuo, diluted with an equal volume of H 2 O and then added HCl until pH=1. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-4′-methylspiro(chroman-2,1′-cyclohexan)-4-one (45 g, 100%).

A glass pressure tube was charged with a mixture of 6-bromo-4′-methylspiro(chroman-2,1′-cyclohexan)-4-one (2 g, 6.47 mmol), KCN (0.84 g, 12.94 mmol), and (NH 4 ) 2 CO 3 (4.66 g, 48.525 mmol). Formamide (10.352 mL) was added to fill the tube nearly completely. The mixture was heated at 110° C. for 1.5 h with microwave. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-4′-methylspiro(chroman-4,4′-imidazolidine)-2′,5′-dione (270 mg, 11%).

A suspension of 6-bromo-4′-methylspiro(chroman-4,4′-imidazolidine)-2′,5′-dione (270 mg, 0.712 mmol) and Lawesson's Reagent (287.81 mg, 0.712 mmol) in dry 1,4-dioxane (10.8 mL) was heated at 120° C. for 30 minutes in a microwave reactor. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-4′-methylspiro-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (160 mg, 57%).

To a solution of 6-bromo-4′-methylspiro-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (40 mg, 0.1 mmol) in MeOH (4 mL) was added a solution of NaOH (8 mg, 0.2 mmol) and MeI (57.2 mg, 0.4 mol). The reaction mixture was heated at 60° C. for 10 minutes in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 6-bromo-4′-methylspiro-1′-methyl-2′-(methylthio)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one (22.5 mg, 53%).

A solution of 6-bromo-4′-methylspiro-1′-methyl-2′-(methylthio)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one (90 mg, 0.212 mmol), NH 4 I (246 mg, 1.696 mmol) in NH 3 /EtOH (2.5 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuo to give 2′-amino-6-bromo-4′-methylspiro-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 100%).

Pd(PPh 3 ) 2 Cl 2 (8 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-4′-methylspiro-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.0775 mmol) in 1,4-dioxane (3 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (24.03 mg, 0.13175 mmol). The mixture was heated in a microwave reactor at 60° C. for 10 minutes. The reaction mixture was concentrated in vacuo give the residue, which was purified by preparative TLC and then by preparative HPLC to give Compound 75 (6.5 mg, 8%). 1 H-NMR (MeOD): 0.98 (d, 3H), 1.21 (m, 2H), 1.58 (t, 2H), 1.65 (m, 2H), 2.0 (d, 2H), 2.4 (s, 2H), 2.68 (s, 3H), 3.31 (s, 3H), 7.0 (d, 1H), 7.40 (s, 1H), 7.59 (m, 3H), 7.86 (d, 2H), 7.11 (s, 1H).

Compound 76

In a 50 mL round bottom flask was added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by cyclohexanone (0.96 mL, 9.3 mmol). MeOH (20 mL) was added to give a clear solution followed by pyrrolidine (1 mL). A condenser was attached to the flask, and the resulting solution was heated at 60° C. overnight. MeOH was removed and the residue was redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL) and 1 N HCl (10 mL), and then dried over Na 2 SO 4 . Solvent was removed in vacuo to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (2.25 g, 82%), which is used for the next step without purification.

A 10 mL CEM microwave test tube was filled with a mixture of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (0.32 g, 1.08 mmol), KCN (0.15 g, 2.2 mmol), and (NH 4 ) 2 CO 3 (0.8 g, 7.7 mmol). A 2:1 mixture of formamide and DMF (6.5 to 7 mL) was added to fill the test tube nearly completely. The resulting mixture as heated in a CEM microwave reactor at 65° C. for 5 hrs. Another 3 tubes (total 1.28 g) were irradiated under the same conditions, and the resulting mixtures were combined, acidified with concentrated HCl, diluted with EtOAc (20 mL), and washed with H 2 O (10 mL×3). The organic layer was dried over Na 2 SO 4 , and solvent was removed in vacuo to give a crude product, which was purified by flash chromatography (0 to 60% EtOAc/hexane) to give cyclohexyl-spiro-hydanton (0.61 g, 55% corrected for recovered starting material 0.38 g). MS m/z 365 (M+H + ).

To a solution of the above hydantoin (0.61 g, 1.66 mmol) in 1,4-dioxane (5 mL) in a 10 mL CEM microwave test tube was added Lawesson's reagent (0.67 g, 1.66 mmol). The resulting mixture was heated in a CEM microwave reactor at 110° C. for 30 min and cooled to room temperature. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the thiol-cyclohexyl-spiro-hydantoin (0.39 g, 62%). MS m/z 381 (M+H + ).

To a solution of the above thiol-cyclohexyl-spiro-hydantoin (105.2 mg, 0.27 mmol) in MeOH (5 mL) in a 10 mL CEM microwave test tube was added a 0.6 N NaOH aqueous solution (1.0 mL). After stirring at room temperature for 10 min, MeI (158 mg, 1.08 mmol) was added, and the reaction mixture was heated in a CEM microwave reactor at 60° C. for 10 min. Another 3 tubes (95 mg, 0.25 mmol) were irradiated under the same conditions, and the resulting mixture were combined and concentrated in vacuo to give the crude product, which was purified by flash chromatography to give the dimethylated thiol-cyclohexyl-spiro-hydantoin (318.8 mg, 77%). MS m/z 409 (M+H + ).

To a solution of the above dimethylated thiol-cyclohexyl-spiro-hydantoin (150 mg, 0.37 mmol) in MeOH (1 mL) in a 10 mL CEM microwave test tube was added NH 4 I (100 mg, 0.69 mmol) and NH 3 /MeOH (7 N, 2 mL). The resulting mixture was heated in a CEM microwave reactor at 120° C. for 30 min. Another tube (100 mg, 0.24 mmol) was also irradiated under the same conditions. The combined mixtures were concentrated in vacuo and the residue was redissolved in EtOAc (10 mL), washed with water (5 mL×3), and dried over Na 2 SO 4 . The solvent was then removed in vacuo to give the cyclohexyl-acyl-guanidine (181 mg, 78%) as a white solid, which is used for the next step without purification. MS m/z 378 (M+H + ).

To a solution of the above cyclohexyl-acyl-guanidine (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added Cs 2 CO 3 (142 mg, 0.43 mmol), 3-cyanophenylboronic acid (29.1 mg, 0.20 mmol), and a catalytical amount of PdCl 2 dppf. After degassing, the resulting mixture was heated in a CEM microwave reactor at 120° C. for 40 min. Solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give the final product 76 (21.3 mg, 40%) as a TFA salt. 1 H NMR (400 MHz, CD 3 COCD 3 ): 8.44 (br, 1 H), 7.98 (s, 1 H), 7.94 (d, 1 H), 7.76 (m, 2 H), 7.68 (m, 2 H), 7.18 (d, 1 H), 3.42 (s, 3 H), 2.62, 2.46 (two d, 2 H), 2.06-1.84 (m, 3 H), 1.80-1.42 (m, 7 H); MS m/z 401 (M+H + ).

Compound 77

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), dihydro-2H-pyran-4(3H)-one (9.35 g, 93.45 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H 2 O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (15 g, 100%). 1 HNMR (CDCl 3 ): 1.74 (m, 2H), (m, 2H), 1.94 (t, 2H), 2.71 (s, 2H), 3.76 (m, 4H), 6.91 (d, 1H), 7.54 (d, 1H), 7.96 (s, 1H).

A mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (10 g, 33.78 mmol), KCN (4.4 g, 67.57 mmol), (NH 4 ) 2 CO 3 (22.7 g, 236.46 mmol) and formamide (60 mL) in a 100 mL steel bomb was heated at 70° C. for 72 hrs. The reaction mixture was cooled and poured into ice water. Acidification with concentrated HCl was performed to give a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column chromatography to give the compound 77ii (9 g, 73%). 1 H-NMR (MeOD): 1.83 (m, 4H), 2.22 (d, 1H), 2.46 (d, 1H), 3.68 (m, 2H), 3.82 (m, 1H), 3.93 (t, 1H), 6.89 (d, 1H), 7.18 (s, 1H), 7.38 (d, 1H), 8.04 (s, 1H).

A mixture of compound 77ii (300 mg, 0.82 mmol) and Lawesson's Reagent (331 mg, 0.82 mmol) in 1,4-dioxane (4.5 mL) was heated at 150° C. in a 10 mL CEM microwave test tube for 50 minutes. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC to give the compound 77iii (40 mg, 13%).

A mixture of compound 77iii (60 mg, 0.16 mmol), NaOH solution (0.6 N, 06 mL) and CH 3 I (0.2 mL) in methanol (2 mL) was heated at 60° C. for 5 minutes in a CEM microwave reactor. The reaction mixture was concentrated and the residue was purified by preparative TLC to give the compound 77iv (28 mg, 44%).

A solution of compound 77iv (28 mg, 0.07 mmol), NH 4 I (20 mg, 0.14 mmol) in NH 3 /EtOH (3 mL, 1.5 N) was heated at 120° C. in a 10 mL CEM test tube in a microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was used for the next step without further purification (24 mg, 93%).

A mixture of compound 77v (24 mg, 0.06 mmol), 3-cyanophenylboronic acid (18.6 mg, 0.13 mmol), Pd(PPh 3 ) 2 Cl 2 (15 mg, 50%), and aqueous cesium carbonate solution (2 N, 0.3 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. in a microwave reactor for 35 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give pure final product Compound 77 (1.97 mg, 8%). 1 H-NMR (MeOD): 1.84 (m, 3H), 2.05 (s, 1H), 2.34 (d, 1H), 2.51 (d, 1H), 3.29 (s, 3H), 3.73 (m, 3H), 3.93 (m, 1H), 7.13 (d, 1H), 7.42 (s, 1H), 7.63 (m, 3H), 7.84 (m, 1H), 7.92 (s, 1H).

Compound 78

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), cycloheptanone (11 mL, 93.5 mmol) and pyrrolidine (7.7 mL, 93.5 mmol) in MeOH (190 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cycloheptan]-4-one (18.3 g, 100%). 1 H-NMR (CDCl 3 ): 1.34 (m, 1H), 1.49 (m, 1H), 1.62 (m, 10H), 1.71 (m, 1H), 2.02 (m, 1H), 6.78 (m, 1H), 7.47 (m, 1H), 7.86 (m, 1H).

In a steel bomb, a mixture of 6-bromospiro[chroman-2,1′-cycloheptan]-4-one (1.5 g, 4.87 mmol), KCN (0.633 g, 9.74 mmol) and (NH 4 ) 2 CO 3 (3.5 g, 36.52 mmol) in formamide (30 mL) was heated to 70-75° C. for 3 days. The mixture was poured into ice/water. Concentrated HCl was added until pH=1. The mixture was filtered, and the filtrate was extracted with CH 2 Cl 2 . The organic layer was concentrated to give compound 78i (370 mg, 20%). 1 H-NMR (DMSO): 1.79 (m, 4H), 1.96 (m, 6H), 2.13 (m, 1H), 2.22 (m, 2H), 2.36 (m, 1H), 7.19 (m, 1H), 7.50 (m, 1H), 7.72 (m, 1H).

A mixture of compound 78i (75 mg, 0.20 mmol) and Lawesson's Reagent (80 mg, 0.20 mmol) in 1,4-dioxane (1.2 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give compound 78ii 13%).

To a mixture of compound 78ii (35 mg, 0.089 mmol) and NaOH (0.2 mL, 0.6 N) in MeOH (3 mL) was added MeI (52 mg, 0.356 mmol). The reaction mixture was stirred in a microwave reactor at 60° C. for 15 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give compound 78iii (20 mg, 53%).

A solution of compound 78iii (20 mg, 0.047 mmol) and NH 4 I (14 mg, 0.094 mmol) in NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford compound 78iv (10 mg, 50%).

Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.005 mmol) in a 10 mL flask under Ar was treated sequentially with compound 78iv (10 mg, 0.025 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.15 mL) and 3-cyanophenylboronic acid (8 mg, 0.05 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC twice to give pure Compound 78 (2.25 mg, 20%). 1 H-NMR (MeOD): 1.41 (m, 2H), 1.60 (m, 4H), 1.80 (m, 3H), 2.01 (m, 3H), 2.16 (m, 1H), 2.22 (m, 1H), 2.82-3.05 (m, 3H), 6.85 (m, 1H), 6.91 (m, 1H), 7.37 (m, 1H), 7.48 (m, 1H), 7.54 (m, 1H), 7.68 (m, 1H), 7.71 (m, 1H).

Compound 79

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15.8 g, 73.8 mmol), cyclopentanone (12.35 g, 147 mmol) and pyrrolidine (12 mL, 140 mmol) in MeOH (300 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cyclopentan]-4-one (23 g, 100%). 1 H-NMR (CDCl 3 ): 1.64 (m, 4H), 1.72 (m, 2H), 2.03 (m, 2H), 2.78 (s, 2H), 6.78 (m, 1H), 7.48 (m, 1H), 7.91 (m, 1H).

In a steel bomb, a mixture of 6-bromospiro[chroman-2,1′-cyclopentan]-4-one (1.5 g, 5.36 mmol), KCN (0.7 g, 10.72 mmol) and (NH 4 ) 2 CO 3 (3.86 g, 40.22 mmol) in formamide (30 mL) was heated to 80° C. for 3 days. The mixture was poured into ice/water. Concentrated HCl was added until pH=1. The mixture was filtered, and the filtrate was extracted with CH 2 Cl 2 . The organic layer was concentrated to give compound 79i (1.75 g, 93%). 1 H-NMR (CDCl 3 ): 1.42 (m, 1H), 1.61 (m, 5H), 1.76 (m, 1H), 1.92 (m, 2H), 2.57 (m, 1H), 6.57 (m, 1H), 7.00 (s, 1H), 7.13 (m, 1H), 7.91 (m, 1H).

A mixture of compound 79i (375 mg, 1.07 mmol) and Lawesson's Reagent (430 mg, 1.07 mmol) in 1,4-dioxane (3.2 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give compound 79ii (60 mg, 15%). 1 H-NMR (CDCl 3 ): 1.51 (m, 1H), 1.69 (m, 3H), 1.79 (m, 2H), 1.98 (m, 2H), 2.17 (m, 1H), 2.64 (m, 1H), 6.68 (m, 1H), 7.02 (m, 1H), 7.25 (m, 1H).

A mixture of compound 79ii (20 mg, 0.055 mmol) and NaOH (0.2 mL, 0.6 N) in 1,4-dioxan (2 mL) was added MeI (40 mg, 0.275 mmol). The reaction mixture was stirred in a microwave reactor at 60° C. for 10 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give compound 79iii (20 mg, 85%).

A solution of compound 79iii (20 mg, 0.051 mmol), NH 4 I (15 mg, 0.102 mmol) in NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford compound 79iv (10 mg, 54%).

Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.005 mmol) in a 10 mL flask under Ar was treated sequentially with compound 79iv (10 mg, 0.027 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.15 mL) and 3-cyanophenylboronic acid (8 mg, 0.055 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC twice to give pure Compound 79 (2.25 mg, 21%). 1 H-NMR (MeOD): 1.69 (m, 4H), 1.86 (m, 3H), 2.04 (m, 1H), 2.22 (m, 1H), 2.49 (m, 1H), 3.07 (s, 3H), 6.82 (m, 1H), 6.96 (m, 1H), 7.11 (m, 2H), 7.39 (m, 1H), 7.52 (m, 1H), 7.70 (m, 1H).

Compound 84

To a solution of the cyclohexyl-acyl-guanidine (57 mg, 0.15 mmol) in 1,4-dioxane (1.5 mL) was added Cs 2 CO 3 (161 mg, 0.45 mmol), pyridin-4-ylboronic acid (28 mg, 0.22 mmol), and PdCl 2 dppf (6 mg, 5 mol %). After degassing, the resulting mixture was heated in a CEM microwave reactor at 120° C. for 30 min. Solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give the final product (9.5 mg, 16.8%) as a TFA salt. 1 H NMR (400 MHz, CD 3 OD): 8.76 (d, 2 H), 8.24 (d, 2 H), 7.96 (dd, 1 H), 7.78 (d, 1 H), 7.18 (d, 1 H), 3.30 (s, 3 H), 2.44 (s, 2 H), 2.00-1.80 (m, 3 H), 1.76-1.48 (m, 6 H), 1.42 (m, 1 H); MS m/z 377 (M+H + ).

Compound 81

Experimental Data

A suspension of the compound 81i (300 mg, 0.69 mmol) and Lawesson's Reagent (280 mg, 0.69 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 minutes under microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give the compound 81ii (160 mg, 50%).

To a solution of the compound 81ii (160 mg, 0.36 mmol) in MeOH (12 mL) was added a solution of NaOH (0.6 N. 1.2 mL) and MeI (0.8 mL). The reaction mixture was heated at 60° C. for 10 min in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 81iii (80 mg, 50%).

A solution of the compound 81iii (80 mg, 0.168 mmol) and NH 4 I (195 mg, 1.34 mmol) in NH 3 /EtOH (2.5 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give compound 81iv (100 mg, 90%).

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with the compound 81 (30 mg, 0.067 mmol) in 1,4-dioxane (1.5 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (19.8 mg, 0.135 mmol). The mixture was heated in a microwave reactor at 120° C. for 35 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give the compound 81v (4.0 mg, 10%). 1 H-NMR (MeOD): 1.36 (t, 1H), 1.52 (t, 2H), 1.70 (d, 1H), 1.87 (m, 1H), 2.00 (d, 1H), 2.15 (dd, 1H), 2.24 (t, 1H), 2.34 (d, 1H), 2.51 (m, 2H), 3.28 (s, 3H) 7.11 (d, 1H), 7.41 (t, 1H), 7.56 (t, 1H), 7.63 (m, 2H), 7.84 (d, 1H), 7.93 (s, 1H).

Compound 82

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), 3-methylcyclohexanone (10.5 g, 93.4 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and then H 2 O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclohexan]-4-one (18 g, 100%). 1 HNMR (CDCl 3 ): 0.86 (m, 3H), 0.91 (m, 2H), 1.02 (m, 2H), 1.30 (m, 2H), 1.52 (m, 2H), 1.65 (m, 4H), 1.80 (m, 7H), 2.01 (m, 4H), 2.22 (m, 1H), 2.48 (m, 1H), 2.60 (s, 2H), 2.72 (t, 3H), 6.81 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H).

A pressure tube was charged with a mixture of 6-bromo-3′-methylspiro[chroman-2,1′-cyclohexan]-4-one (8 g, 19.48 mmol), KCN (3.37 g, 39 mmol), and (NH 4 ) 2 CO 3 (17.5 g, 136.36 mmol). Formamide (80 mL) was added to fill the tube nearly completely. The mixture was heated at 80° C. for 78 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate. The ethyl acetate solution was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give the product 82i (8 g, 90%). 1 HNMR (MeOD): 0.81 (d, 1H), 0.92 (m, 3H), 1.49 (m, 2H), 1.71 (d, 2H), 2.03 (d, 1H), 2.13 (s, 2H), 2.41 (dd, 1H), 6.78 (dd, 1H), 7.12 (d, 1H), 7.30 (m, 1H).

A suspension of the compound 82i (375 mg, 1 mmol) and Lawesson's Reagent (400 mg, 1 mmol) in dry 1,4-dioxane (3.5 mL) was heated at 110° C. for 30 min in a microwave reactor. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give the compound 82ii (100 mg, 30%).

To a solution of the compound 82ii (200 mg, 0.51 mmol) in MeOH (10 mL) was added a solution of NaOH (0.6 N, 2 mL) and MeI (0.6 mL). The reaction mixture was heated at 60° C. for 14 min in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 82iii (90 mg, 45%).

A solution of the compound 82iii (90 mg, 0.21 mmol) and NH 4 I (246 mg, 1.7 mmol) in NH 3 /EtOH (2.5 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuo to give the compound 82iv (90 mg, 90%).

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with the compound 82iv (30 mg, 0.076 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (22.56 mg, 0.15 mmol). The mixture was heated in a microwave reactor at 120° C. for 35 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give Compound 82 (2.58 mg, 10%). 1 H-NMR (MeOD): 0.90 (dd, 3H), 0.95 (d, 1H), 1.25 (m, 2H), 1.60 (m, 2H), 1.90 (m, 4H), 2.30 (dd, 1H), 3.34 (s, 3H), 7.05 (dd, 1H), 7.38 (s, 1H), 7.61 (m, 3H), 7.84 (d, 1H), 7.92 (s, 1H).

Compound 83

Experimental Data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 3,5-dimethylcyclohexanone (7.12 g, 56 mmol) and pyrrolidine (3.8 g, 53.3 mmol) in methanol (120 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and H 2 O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 6-bromo-3′,5′-dimethylspiro[chroman-2,1′-cyclohexan]-4-one (10 g, 100%). 1 HNMR (CDCl 3 ): 0.51 (m, 1H), 0.71 (m, 4H), 0.72 (m, 3H), 0.91 (m, 3H), 1.11 (d, 1H), 1.19 (t, 1H), 1.50 (s, 1H), 1.64 (t, 1H), 1.79 (m, 3H), 1.90 (m, 2H), 2.0 (m, 3H), 2.24 (t, 1H), 2.53 (s, 1H), 2.79 (s, 1H), 6.75 (t, 1H), 7.49 (t, 1H), 7.89 (d, 1H).

A tube was charged with a mixture of 6-bromo-3′,5′-dimethylspiro[chroman-2,1′-cyclohexan]-4-one (1.5 g, 4.64 mmol), KCN (0.6 g, 39.3 mmol), and (NH 4 ) 2 CO 3 (3.12 g, 32.48 mmol). Formamide (350 mL) was added to fill the tube nearly completely. The mixture was heated at 110° C. for 4 h in a microwave reactor. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give the compound 83i (700 mg, 40%).

A suspension of the compound 83i (375 mg, 0.96 mmol) and Lawesson's Reagent (386 mg, 0.957 mmol) in dry 1,4-dioxane (3.5 mL) was heated at 110° C. for 30 min in a microwave reactor. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give the compound 83ii (200 mg, 60%).

To a solution of the compound 83ii (200 mg, 0.50 mmol) in MeOH (10 mL) was added a solution of NaOH (0.6 N, 2 mL) and MeI (0.6 mL). The reaction mixture was heated at 60° C. for 14 min in a microwave reactor. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 83iii (15 mg, 10%).

A solution of the compound 83iii (15 mg, 0.034 mmol) and NH 4 I (39.7 mg, 0.27 mmol) in NH 3 /EtOH (2.5 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuo to give the compound 83iv (20 mg, 100%).

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with the compound 83iv (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (14.7 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 35 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give Compound 83 (2.7 mg, 10%). 1 H-NMR (MeOD): 0.55 (dd, 1H), 0.87 (m, 6H), 1.20 (m, 2H), 1.70 (m, 5H), 2.35 (m, 1H), 2.51 (m, 1H), 6.99 (t, 1H), 7.34 (s, 1H), 7.54 (m, 3H) 7.81 (d, 1H), 7.89 (s, 1H).

3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (Compound 85)

Experimental Data

A mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (39 g, 181.8 mmol), tetrahydro-2H-pyran-3-carbaldehyde (20 g, 181.8 mmol) and borax (69.3 g, 181.8 mmol) in ethanol (240 mL) and H 2 O (400 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (10 g, 20%).

To a solution of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (300 mg, 0.98 mmol) in anhydrous DCM (8 mL) was added TiCl 4 (1 M solution in DCM, 1.96 mL, 1.96 mmol) dropwise within 15 min at room temperature. It was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (400.7 mg, 2.15 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide (300 mg, 100%), which was used in next step without further purification.

Step 3: 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxa diazol]-3′-amine

To a solution of methylhydroxylamine HCl salt (75 mg, 0.9 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25 w % in MeOH, 0.13 mL), followed by (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide (300 mg, 0.9 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL). The mixture was filter, and the solvent was removed in vacuo. The resulting residue was purified by preparative TLC to give 20 mg of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 10%).

Step 4: 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (31 mg, 0.2 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (5 mg, 10%). 1 H-NMR (MeOD): 1.69 (m, 2.5H), 2.01 (m, 3H), 2.51 (m, 1H), 2.72 (m, 1H), 3.42 (d, 2H), 3.52 (m, 3H), 3.90 (m, 2H), 4.15 (m, 1.5H), 7.02 (d, 1H), 7.59 (t, 1H), 7.68 (m, 2H), 7.94 (m, 3H).

3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]-oxadiazole]-6-yl)benzonitrile (Compound 88)

Experimental Data

To a solution of tetrahydro-2H-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfonic acid hydrate (72.5 g, 385 mmol). The mixture was refluxed for 2 hr. The solvent was removed in vacuo. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (8.3 g, 75%) which was used in next step without purification.

To a stirred solution of methyl tetrahydro-2H-pyran-4-carboxylate (1 g, 6.95 mmol) in dried THF was added DIBAL-H (7.6 mL, 7 mmol) at −78° C. The mixture was stirred at the same temperature until the reaction was complete. The mixture was quenched with saturated NH 4 Cl. The mixture was filtrated and the filtrate was extracted with ethyl ether for 3 times. The combined organic layers were dried over Na 2 SO 4 . Filtration followed by concentration in vacuo gave tetrahydro-2H-pyran-4-carbaldehyde (450 mg, 50%), which was used in next step without purification.

To a stirred solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (943.9 mg, 4.39 mmol) in EtOH (5.6 mL) and H 2 O (9.4 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 4.39 mmol) and borax (1.67 g, 4.39 mmol). The mixture was refluxed overnight. Then the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in CR 2 Cl 2 and filtrated. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography to give 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (270 mg, 20%). 1 H-NMR (CDCl 3 , 400 MHz): 1.54 (m, 2H), 1.78 (m, 1H), 1.95 (m, 1H), 2.75 (m, 2H), 3.44 (m, 3H), 4.09 (m, 2H), 4.15 (m, 1H), 6.89 (m, 1H), 7.56 (m, 1H), 8.01 (m, 1H).

To a solution of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (310 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl 4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. The reaction mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL) The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (240 mg, 78%), which was used in next step without further purification.

Step 5 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxa-diazol]-3′-amine

To a solution of methylhydroxylamine HCl salt (25.08 mg, 0.3 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25% in MeOH (Wt. %), 0.06 mL, 0.27 mmol), followed by (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (100 mg, 0.3 mmol). After stirring 10 min, the solvent was removed in vacuo. The resulting residue was redissolved in DCM (10 mL), The mixture was filtered and the solvent was removed to give the residue, which was purified by column chromatography to give compound 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 40%).

Step 6 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]-oxadiazole]-6-yl)benzonitrile

A mixture of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.131 mmol), 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs 2 CO 3 (2 M, 0.5 mL) and Pd(PPh 3 ) 2 C 12 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1 H-NMR (CDCl 3 ): 1.54 (m, 2H), 1.62 (m, 1H), 1.88 (m, 1H), 2.10 (m, 1H), 2.48 (m, 1H), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).

A mixture of 6-bromo-2-(pyridine-3-yl)chroman-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (294 mg, 2 mmol), Cs 2 CO 3 (2 M, 5 mL) and Pd(PPh 3 ) 2 Cl 2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile (110 mg, 34%). 1 H-NMR (MeOD): 2.97-3.02 (d, 1H), 3.25-3.33 (m, 1H), 5.74-5.78 (d, 1H), 7.23 (d, 1H), 7.52 (m, 1H), 7.60-7.64 (m, 2H), 7.70 (d, 1H), 7.90-7.95 (m, 2H), 7.99 (s, 1H), 8.07 (d, 1H), 8.15 (s, 1H), 8.57 (d, 1H), 8.75 (s, 1H).

To a solution of 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile (70 mg, 0.22 mmol) in anhydrous DCM (3 mL) was added TiCl 4 (1 M solution in DCM, 293 mg, 1.54 mmol) dropwise within 15 minutes at room temperature in the absence of light. The resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (164 mg, 0.88 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (E)-N-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (70 mg, 93%), which was used in next step without further purification.

Step 3. 3-(3′-amino-2′-methyl-2-(pyridine-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

To a solution of methylhydroxylamine HCl salt (17 mg, 0.2 mmol) in anhydrous MeOH (2 mL) was added NaOMe (25% in MeOH (Wt. %), 0.10 mL, 0.2 mmol), followed by (E)-N-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (70 mg, 0.2 mmol). After stirring for 10 mins, the solvent was removed in vacuo. The resulting residue was redissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by preparative TLC and preparartive HPLC to give 3-(3′-amino-2′-methyl-2-(pyridine-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.5 mg, 3%). 1 H-NMR (MeOD): 2.40-2.47 (t, 1H), 2.92-3.16 (m, 1H), 3.46 (s, 3H), 5.61-5.69 (m, 1H), 7.21 (m, 1H), 7.64-7.67 (m, 1H), 7.75 (d, 1H), 7.81-7.88 (m, 2H), 7.96-8.00 (t, 1H), 8.04-8.10 (t, 2H), 8.40 (m, 1H), 8.43 (m, 1H), 8.75 (s, 1H).

Compound 97

Experimental Data

To a solution of aqueous NaOH (0.5 M, 0.2 mol) was slowly added 4-bromophenol (34.4 g, 0.2 mol) at room temperature. After heating to boiling, 3-bromopropanoic acid (30.60 g 0.2 mol) in aqueous NaOH (0.5M, 0.2 mol) was added dropwise to the mixture above. The resulting mixture was then refluxed for 2 h. The mixture was cooled to 0° C. and the pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The resulting mixture was filtered to give a solid cake, which was washed with water and n-pentane and dried to give 3-(4-bromophenoxy)propanoic acid (30 g, 60%). 1 H-NMR (CDCl 3 ): 2.72 (m, 2H), 4.90 (s, 1H), 5.01 (d, 1H), 5.50 (s, 1H), 6.73 (m, 1H), 7.21-7.43 (m, 6H), 7.61 (m, 1H).

3-(4-Bromophenoxy)propanoic acid (4.98 g, 20 mmol) was dissolved in PPA (51.1 g, 360 mmol) and the resulting mixture was heated at 110° C. for 4 hour. The mixture was poured into ice-water and extracted with CH 2 Cl 2 (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product (4 g, 88%).

To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (289.3 mg, 1.28 mmol) in DCM (10 mL) was added TiCl 4 (2.6 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.63 mL, 2.82 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer was dried and concentrated to give crude N-(6-bromochroman-4-ylidene)cyanamide (300 mg, 94%).

To a solution of N-methyl-hydroxylamine hydrochloride (101 mg, 1.2 mmol) in MeOH (4 mL) was added MeONa (0.24 mL, 25% (Wt.) in MeOH), followed by N-(6-bromochroman-4-ylidene)cyanamide (300 mg, 1.2 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The resulting residue was purified by preparative TLC to give 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (315 mg, 88%).

Pd(PPh 3 ) 2 Cl 2 (7 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (59.4 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL), Cs 2 CO 3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (6.7 mg, 10%). 1 H-NMR (MeOD): 2.31 (m, 1H), 2.62 (m, 1H), 3.39 (m, 3H), 4.32 (m, 1H), 4.46 (m, 1H), 7.00 (d, 1H), 7.58-7.71 (m, 3H), 7.95 (m, 3H).

6-(3-isopropylphenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 101)

Pd(PPh 3 ) 2 Cl 2 (5 mg) in a 10 mL flask under Ar was treated sequentially with the 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.105 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.2 mL) and 3-isopropylphenylboronic acid (25.8 mg, 144 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give 6-(3-isopropylphenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (7.5 mg, 18%). 1 H NMR (MeOD): 1.31 (d, 6H), 1.68 (m, 2H), 1.92-2.07 (m, 3H), 2.43-2.72 (m, 1H), 2.96 (m, 1H), 3.34 (s, 3H), 3.45-3.58 (m, 2H), 3.83-4.01 (m, 2H), 4.12-4.23 (m, 2H), 6.98 (m, 1H), 7.21 (m, 1H), 7.38 (m, 3H), 7.63 (m, 1H), 7.79 (m, 1H).

5-(3′-amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazole)-6-yl)-2-fluorobenzonitrile (Compound 103)

Experimental Data

To a solution of 6-bromo-2-phenylchroman-4-one (387 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl 4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (525 mg, 2.82 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (Z)—N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (400 mg, 96%) which was used in next step without further purification.

To a solution of methylhydroxylamine HCl salt (26 mg, 0.307 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25 wt. % in MeOH, 0.07 mL, 0.276 mmol), followed by (Z)—N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (100 mg, 0.307 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was dissolved in DCM (20 mL). The mixture was filtered, and the solvent was removed in vacuo to give 6-bromo-2′methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-3′-amine (100 mg, 87%), which was used in the next step without further purification.

Step 3: 5-(3′-amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazole)-6-yl)-2-fluorobenzonitrile

To a solution of 6-bromo-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4) oxadiazol)-3′-amine (50 mg, 0.134 mmol), 3-cyano-5-fluorinphenylboronic acid (38 mg, 0.228 mmol) and Cs 2 CO 3 (109 mg, 0.338 mmol) in 1,4-dioxane (6.7 mL) and H 2 O (0.5 mL) was added PdCl 2 (PPh 3 ) 2 (13.4 mg). After degassing, the mixture was refluxed for 3 h (black precipitate came out at this point of time). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 5-(3′-amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazole)-6-yl)-2-fluorobenzonitrile (0.65 mg, 1.2%) as a TFA salt. 1 H-NMR (MeOD): 2.26 (m, 0.3H), 2.57 (m, 0.7H), 2.72 (m, 1H), 3.31 (m, 3H), 5.26 (m, 1H), 7.00 (m, 1H), 7.34 (m, 4H), 7.45 (m, 2H), 7.61 (s, 1H), 7.94 (d, 3H).

7-fluoro-6-(2-fluoropyridin-3-yl)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 104)

Experimental Data

A mixture of 6-bromo-7-fluoro-2-phenylchroman-4-one (318 mg, 0.994 mmol), 2-fluoropyridin-3-ylboronic acid (210 mg, 1.5 mmol), Na 2 CO 3 (318 mg, 2.98 mmol), PPh 3 (34 mg) and Pd(PPh 3 ) 2 Cl 2 (59 mg, 0.1 mmol) in toluene/EtOH (v/v=1/1, 10.5 mL) was degassed and stirred at 110° C. for 20 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one (78 mg, 23%).

To a solution of 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one (78 mg, 0.23 mmol) in CH 2 Cl 2 (5 mL) under N 2 was added TiCl 4 (1 M solution in DCM, 1.15 mL, 1.15 mmol) dropwise within 15 minutes at room temperature under dark. After addition, the reaction mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (94.3 mg, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenylchroman-4-ylidene-cyanamide (100 mg, 100%).

Step 3. 7-fluoro-6-(2-fluoropyridin-3-yl)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine

To a solution of methylhydroxylamine HCl salt (27 mg, 0.277 mmol) in anhydrous MeOH (3 mL) was added NaOMe (25% in MeOH (Wt. %), 0.10 mL), followed by 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenyl-chroman-4-ylidene-cyanamide (100 mg, 0.277 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was redissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by preparative TLC to give 7-fluoro-6-(2-fluoropyridin-3-yl)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (4.65 mg, 4%). 1 H-NMR (MeOD): 2.21 (m, 1H), 2.34 (m, 1H), 3.03 (s, 3H), 5.46 (m, 1H), 6.73 (m, 1H), 7.32 (m, 4H), 7.49 (m, 3H), 7.91 (m, 1H), 8.28 (m, 1H).

3-(3′-amino-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (Compound 105)

Experimental Data

To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (50 g, 0.23 mol) in EtOH (285 mL) and H 2 O (15 mL) was added isonicotinaldehyde (25 g, 0.23 mol) and NaOH (84 g, 0.23 mol). The reaction mixture was stirred overnight. EtOH was added to the mixture and filtered to give a solid residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (30 g, 40%).

To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (20 g, 63.3 mmol) in EtOH (160 mL) and H 2 O (480 mL) was added NaOH (2.53 g, 63.3 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na 2 SO 4 and concentrated in vacuo to give 6-bromo-2-(pyridin-4-yl)chroman-4-one (10 g, 50%). 1 H-NMR (CDCl 3 ): 3.00 (t, 2H), 5.51 (dd, 1H), 7.02 (d, 1H), 7.39 (d, 2H), 7.63 (t, 1H), 8.04 (s, 1H), 8.72 (d, 2H).

To a solution of 6-bromo-2-(pyridin-4-yl)chroman-4-one (1 g, 3.3 mmol) in anhydrous DCM (25 mL) was added TiCl 4 (1 M solution in DCM, 6.6 mL, 6.6 mmol) dropwise within 15 min at room temperature. After the addition, the reaction mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (1.35 g, 7.26 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-bromo-2-(pyridin-4-yl)chroman-4-ylidene)cyanamide (1 g, 100%), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (76.9 mg, 0.92 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25 w % in MeOH, 0.19 mL, 0.828 mmol), followed by (E)-N-(6-bromo-2-(pyridin-4-yl)chroman-4-ylidene)cyanamide (300 mg, 0.92 mmol), After stirring for 10 min, the solvent was removed in vacuo. The residue was dissolved in DCM (20 mL). The mixture was filtered, and the solvent was removed in vacuo to give a reside, which was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (80 mg, 30%).

Step 5: 3-(3′-amino-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (20 mg, 0.053 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (14.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (3 mg, 10%). 1 H-NMR (MeOD): 2.24 (m, 1H), 3.01 (m, 1H), 3.39 (t, 3H), 5.54 (d, 1H), 7.19 (m, 1H), 7.60 (m, 1H), 7.62 (t, 1H), 7.69 (m, 1H), 7.89 (m, 3H), 8.02 (, 2H), 8.70 (s, 2H).

3-(3′-amino-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (Compound 106)

Experimental Data

Pd(PPh 3 ) 2 Cl 2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2-(pyridin-2-yl)chroman-4-one (300 mg, 1 mmol) in [1,4]dioxane (40 mL), Cs 2 CO 3 (2 N, 5 mL) and 3-cyanophenylboronic acid (250 mg, 1 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (110 mg, 60%). 1 H-NMR (CDCl 3 ): 3.13 (m, 2H), 5.61 (m, 1H), 7.13 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.79 (m, 3H), 8.09 (d, 1H), 8.58 (d, 1H).

To a solution of 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (50 mg, 0.15 mmol) in DCM (2 mL) was added TiCl 4 (1 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.07 mL, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer was dried and concentrated to give crude (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (100 mg, crude).

Step 3. 3-(3′-amino-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

To a solution of N-methyl-hydroxylamine hydrochloride (14 mg, 0.14 mmol) in MeOH (4 mL) was added MeONa (0.03 mL, 25% (Wt.) in MeOH), followed (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (50 mg, crude). After stirring for 10 minutes, the solvent was removed in vacuo to give a residue. The residue was purified by preparative TLC to give 3-(3′-amino-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (4.3 mg, 8%). 1 H-NMR (MeOD): 2.11 (m, 1H), 2.51 (m, 1H), 3.02 (s, 2H), 3.28 (s, 1H), 4.12 (m, 1H), 5.32 (m, 1H), 6.97 (m, 1H), 7.32 (m, 1H), 7.55 (m, 5H), 7.82 (m, 3H), 8.46 (m, 1H).

3-(3′-amino-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (Compound 107)

Experimental Data

To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.4 mmol) in EtOH (114 mL) and H 2 O (6 mL) was added 4-(trifluoromethoxy)benzaldehyde (17.75 g, 93.4 mmol) and NaOH (33.6 g, 840.6 mmol). The reaction mixture was stirred overnight. Ethoxyethane was added to the mixture and filtered to give a residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (30 g, 80%). 1 H-NMR (CDCl 3 ): 6.87 (d, 1H), 7.21 (d, 2H), 7.49 (m, 1H), 7.52 (m, 1H), 7.59 (d, 2H), 7.84 (t, 1H), 7.92 (s, 1H).

To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (8 g, 20 mmol) in EtOH (144 mL) and H 2 O (432 mL) was added NaOH (800 mg, 20 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na 2 SO 4 and then concentrated in vacuo to give 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (6 g, 80%). 1 H-NMR (CDCl 3 ): 2.91 (d, 1H), 3.04 (m, 1H), 5.49 (dd, 1H), 6.94 (m, 1H), 7.31 (d, 2H), 7.50 (d, 2H), 7.59 (m, 1H), 8.03 (s, 1H).

To a solution of 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (530 mg, 1.37 mmol) in anhydrous DCM (15 mL) was added TiCl 4 (1 M solution in DCM, 2.74 mL, 2.74 mmol) dropwise within 15 min at room temperature. After the addition, the reaction mixture was stirred for 1 h. To this mixture was added Bis-trimethylsilylcarbodiimide (561.6 mg, 3 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (80 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide (540 mg, 90%), which was used in the next step without further purification.

Step 4: 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]-oxadiazol]-3′-amine

To a solution of methylhydroxylamine HCl salt (110 mg, 1.317 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25 w % in MeOH, 0.23 mL, 1.02 mmol), followed by (E)-N-(6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide (540 mg, 1.32 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL). The mixture was filtered and the solvent was removed in vacuo, which was purified by preparative TLC to give 50 mg crude product of 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (100 mg, 20%).

Step 5: 3-(3′-amino-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.11 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (32.4 mg, 0.22 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (1.39 mg, 5%). 1 H-NMR (MeOD): 2.34 (t, 1H), 2.89 (d, 1H), 5.41 (t, 1H), 7.13 (d, 1H), 7.37 (t, 2H), 7.64 (m, 3H), 7.70 (d, 1H), 7.78 (t, 1H), 7.94 (t, 1H), 8.04 (m, 2H).

2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 108)

Experimental Data

A solution of 4-phenoxy-phenol (169 g, 0.9 mol) in pyridine (500 mL) was treated with acetic anhydride (90 mL). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and 10% HCl solution, and the resulting mixture was stirred for 1 h. The organic phase was washed with 10% HCl and water until pH=7. The organic layer was dried and the solvent was evaporated to afford acetic acid 4-phenoxy-phenyl ester (200 g, 97%). 1 H-NMR (CDCl 3 ): 2.21 (s, 3H), 6.94 (m, 6H), 7.04 (m, 1H), 7.28 (m, 2H).

A mixture of acetic acid 4-phenoxy-phenyl ester (114 g, 0.5 mol) and AlCl 3 (133.5 g, 1 mol) was stirred at 120-140° C. for 20-30 minutes. The mixture was cooled to 60-80° C. and ice water was added. The resulting mixture was extracted with EtOAc. The organic layers were washed with brine and dried over Na 2 SO 4 . After concentration, the residue was purified by column (25.8 g, 23%). 1 H-NMR (CDCl 3 ): 2.57 (s, 3H), 6.96 (m, 3H), 7.07 (m, 1H), 7.21 (m, 1H), 7.31 (m, 2H), 7.40 (m, 1H), 12.05 (s, 1H).

In a bottle 1-(2-hydroxy-5-phenoxy-phenyl)-ethanone (5 g, 21.93 mmol), benzaldehyde (2.33 g, 21.93 mmol), EtOH (96%, 26.3 mL) and NaOH (7.02 g, 175.44 mmol) were combined. The mixture was stirred vigorously for 0.5 h and then filtered. The filtrate was poured into HCl (1 N, 200 mL) and filtered to give a solid. The solid was dried to give 3-(3-chloro-phenyl)-1-(2-hydroxy-5-phenoxy-phenyl)-propenone (5.87 g, 85%). 1 H-NMR (CDCl 3 ): 6.95 (m, 2H), 7.07 (m, 2H), 7.23 (m, 1H), 7.34 (m, 2H), 7.42 (m, 3H), 7.53 (m, 1H), 7.64 (m, 3H), 7.95 (m, 1H), 12.62 (s, 1H).

3-(3-Chloro-phenyl)-1-(2-hydroxy-5-phenoxy-phenyl)-propenone (5.85 g, 0.018 mol) was dissolved in H 2 O (140 mL) and EtOH (46.2 mL) and NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered to give a solid cake. The cake was dissolved in EtOAc and washed with H 2 O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-phenoxy-2-phenyl-chroman-4-one (5.86 g, 100%). 1 H-NMR (CDCl 3 ): 2.87 (m, 1H), 3.06 (m, 1H), 5.46 (m, 1H), 6.96 (m, 2H), 7.08 (m, 2H), 7.25 (m, 1H), 7.33 (m, 2H), 7.39 (m, 1H), 7.42 (m, 2H), 7.48 (m, 2H), 7.51 (m, 1H).

To a solution of 6-phenoxy-2-phenylchroman-4-one (316 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl 4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 90%), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (83.6 mg, 1 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25% in MeOH (Wt. %), 0.2 mL, 0.9 mmol), followed by (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 1 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (30 mL) The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give 2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1, 2, 4]oxadiazol]-3′-amine (200 mg, 52%). 1 H-NMR (CDCl 3 ): 2.41-2.66 (m, 1H), 2.65 (m, 1H), 2.75 (m, 1H), 3.32 (m, 3H), 5.35 (m, 1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H).

Compound 109

Experimental Data

To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (2 g, 6.8 mmol) in MeOH Selectfluor™ (2.5 g, 7.1 mmol) was added. The suspension was refluxed overnight. Then the solvent was removed in vacuo. CH 2 Cl 2 was added to the resulting residue and insoluble material filtered off. The filtrate was washed with H 2 O, dried and concentrate in vacuo. The crude product was purified by column chromatography to give 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 10%). 1 H-NMR (CDCl 3 ): 1.72-2.21 (m, 4H), 3.44 (m, 1H), 3.63 (m, 1H), 3.73 (m, 1H), 3.92 (m, 1H), 4.91 (m, 1H), 6.94 (m, 1H), 7.56 (m, 1H), 7.90 (m, 1H).

To a solution of 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 0.65 mmol) in anhydrous DCM was added TiCl 4 (1 M in DCM, 1.4 mL) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (264 mg, 1.42 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to give crude product, which was used in the next step without further purification.

To a solution MeNHOH.HCl (25 mg, 0.3 mmol) in anhydrous MeOH was added NaOMe (14 mg, 25 w % in MeOH), followed by (Z)—N-(6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (100 mg, 0.3 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was dissolved in DCM and the resulting solution was filtered. The filtrate was collected and the solvent was removed to give the crude product, which was purified by column chromatography to give product 109i (50 mg, 44%).

Pd(PPh 3 ) 2 Cl 2 (14 mg) in a 10 mL flask under Ar was treated sequentially with compound 109i (50 mg, 0.13 mmol) in 1,4-dioxane (3 mL), Cs 2 CO 3 (2 N, 0.162 mL) and 3-cyanophenylboronic acid (32.6 mg, 0.22 mmol). The mixture was heated at 120° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure Compound 109 (10.2 mg, 19%). 1 H-NMR (MeOD): 1.51-2.10 (m, 2H), 2.16 (m, 2H), 3.41 (d, 3H), 3.48-3.90 (m, 3H), 3.96 (m, 1H), 5.24 (m, 1H), 7.13 (m, 1H), 7.64 (m, 1H), 7.71 (m, 1H), 7.82 (m, 1H), 7.97 (m, 1H), 8.09 (m, 2H).

Compound 110

Pd(PPh 3 ) 2 O 2 (6 mg) under Ar was treated sequentially with the amine 110i (20 mg, 0.062 mmol) in 1,4-dioxane (1.5 mL), Cs 2 CO 3 (2 N, 0.25 mL) and 3-chlorophenylboronic acid (16 mg, 0.11 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give Compound 110 (2.05 mg, 8%). 1 H-NMR (MeOD): 1.45-1.94 (m, 3H), 2.04 (m, 2H), 2.89 (m, 1H), 3.37 (m, 3H), 3.61 (m, 2H), 3.82 (m, 2H), 7.02 (m, 1H), 7.34 (m, 2H), 7.51 (m, 1H), 7.18 (m, 2H), 7.88 (m, 1H).

Compound 111

Experimental Data

4-Bromophenol (28.4 g, 0.165 mol) and DMAP (0.17 g, 1.4 mmol) were dissolved in dichloromethane (110 mL). The solution was cooled in an ice-bath and triethylamine (24 mL) was added portionwise. Propionyl chloride (16 g, 0.17 mmol) was then added dropwise and the resulting mixture was stirred at room temperature for 2 hrs. The mixture was washed with water, followed by brine, dried and concentrated to give 4-bromophenyl propionate, which was used in the next step without further purification (34 g, 92%). 1 H NMR (MeOD, 400 MHz): 1.12-1.24 (m, 3H), 2.57-2.63 (m, 2H), 7.02-7.06 (m, 2H), 7.51-7.55 (m, 2H).

4-Bromophenyl propionate (34 g, 0.15 mmol) and aluminum chloride (44 g, 0.3 mmol) were heated together at 100° C. for 30 mins. The solution became dark and hydrogen chloride gas was evolved. After cooling, the reaction mixture was carefully poured into ice water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the residue, which was purified by column chromatography to give 1-(5-bromo-2-hydroxyphenyl)propan-1-one. (20 g, 59%) 1 H NMR (CDCl 3 , 400 MHz): 1.24 (t, 3H), 2.98-3.04 (m, 2H), 6.88 (d, 1H), 7.52 (t, 1H), 7.76 (s, 1H).

A mixture of 1-(5-bromo-2-hydroxyphenyl)propan-1-one (5.7 g, 25 mol), dihydro-2H-pyran-3(4H)-one (5 g, 50 mmol) and pyrrolidine (3.4 g, 48 mmol) in methanol (80 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H 2 O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.2 g, 16%). 1 HNMR (CDCl 3 ): 1.16-1.27 (m, 3H), 1.51-1.57 (m, 1H), 1.66-1.73 (m, 1H), 1.91-2.08 (m, 2H), 2.59-2.69 (m, 1H), 3.46-3.56 (m, 2H), 3.88-3.98 (m, 2H), 6.97 (m, 1H), 7.58 (m, 1H), 7.95 (s, 1H).

A solution of 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 0.65 mmol) and TiCl 4 (864 mg, 4.55 mmol) in anhydrous DCM (8 mL) was heated at 50° C. under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (360 mg, 1.95 mmol) was added and the mixture was heated at 65° C. for another 1 hr. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give (E)-N-(6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (300 mg, crude), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (84 mg, 1 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25% in MeOH (Wt. %), 0.3 mL, 1 mmol), followed by (E)-N-(6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (346 mg, 1 mmol). After stirring for 10 mins, the solvent was removed in vacuo. The residue was redissolved in DCM (10 mL). The mixture was filtered and concentrated to give the residue, which was purified by preparative TLC to give Compound 111i (100 mg, 25%). 1 H-NMR (CDCl 3 ): 1.02-1.11 (m, 3H), 1.89-2.17 (m, 2H), 1.17-2.24 (m, 2H), 3.05 (s, 3H), 3.63-3.68 (m, 1H), 3.95-4.33 (m, 2H), 4.25-4.40 (s, 2H), 6.79-6.87 (m, 1H), 7.30-7.39 (m, 1H), 7.47 (s, 1H).

A mixture of Compound 111i (69 mg, 0.18 mmol), 3-cyanophenylboronic acid (53 mg, 0.36 mmol), Cs 2 CO 3 (2 M, 1 mL) and Pd(PPh 3 ) 2 Cl 2 (30 mg) in 1,4-dioxane (5 mL) under Ar was stirred under microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give Compound 111 (10 mg, 14%). 1 H-NMR (MeOD): 0.99-1.30 (m, 3H), 1.45-2.00 (m, 2H), 2.00-2.70 (m, 2H), 3.38 (m, 3H), 3.40-3.60 (m, 1H), 3.61-3.65 (m, 2H), 3.80-4.10 (m, 2H), 7.07-7.17 (m, 1H), 7.59-7.79 (m, 3H), 7.90-8.01 (m, 3H).

Compound 113a and 113b

Experimental Data

To a solution of tetrahydrofuran-3-ol (29.7 g, 0.337 mol) in dry DCM (1 L) was added 3 Å molecule sieves (35 g) and PCC (110.2 g, 0.515 mol). The mixture was stirred at room temperature overnight. When the reaction was completed, the mixture was filtered through celite and the filtrate was dried over Na 2 SO 4 and concentrated in vacuo to give the crude product, which was distilled in vacuo to give product (7.07 g, 29%). 1 H-NMR (MeOD): 2.45 (m, 2H), 3.8 (m, 2H), 4.2 (m, 2H).

A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (4.97 g, 23.23 mmol), dihydrofuran-3(2H)-one (3 g, 34.87 mmol) and pyrrolidine (2.48 g, 34.87 mmol) in toluene (60 mL) was refluxed overnight. After cooling, the mixture was treated with water and acidified with concentrated HCl to pH around 1. The resulting solution was extracted with ethyl acetate and washed with brine. The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (1.7 g, 30%). 1 H-NMR (CDCl 3 ): 1.9 (m, 1H), 2.3 (m, 1H), 2.8 (m, 2H), 3.65 (m, 1H), 3.9 (m, 1H), 4.0 (m, 2H), 6.8 (m, 1H), 7.5 (m, 1H), 7.9 (m, 1H).

To a solution of 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (206 mg, 0.731 mmol) in anhydrous DCM (6 mL) was added TiCl 4 (281 mg, 1.48 mmol) dropwise within 15 minutes at room temperature and resulting mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (300 mg, 1.61 mmol). The resulting mixture was stirred for another 18 hours after addition. The reaction mixture was poured into water-ice and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give crude product (225 mg, 100%), which was used in the next step without further purification.

To a solution of N-methylhydroxylamine hydrochloride (62 mg, 0.735 mmol) in anhydrous MeOH (8.6 mL) was added NaOMe (25%, 0.143 mL), followed by (E)-N-(6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-ylidene)cyanamide (225 mg, 0.735 mmol). After stirring for 10 min, the solvent was removed in vacuo and the residue was dissolved in DCM. The resulting solution was filtered, and solvent was removed in vacuo to give compound 113i (52 mg, 20%). 1 H-NMR (CDCl 3 ): 2.0 (m, 2H), 2.25 (m, 2H), 3.0 (d, 3H), 3.65 (m, 1H), 3.8 (m, 1H), 3.9 (m, 2H), 6.65 (d, 1H), 7.25 (d, 2H), 7.45 (d, 1H).

Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.005 mmol) in a 10 mL flask under Ar was treated sequentially with compound 113i (30 mg, 0.085 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (30.94 mg, 0.17 mmol). The mixture was heated at 120° C. under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure isomer 113a (5.52 mg, 17%) and 113b (2.81 mg, 9%). 1 H-NMR (MeOD): 2.15 (m, 1H), 2.35 (m, 1H), 2.55 (m, 1H), 2.8 (m, 1H), 3.35 (m, 3H), 3.8 (m1H), 3.95 (m, 2H), 4.1 (m, 1H), 7.0 (m, 1H), 7.55 (m, 1H), 7.7 (m, 2H), 7.9 (m, 1H), 8.0 (m, 2H) (113a). 1 H-NMR (MeOD): 2.15 (m, 2H), 2.4 (m, 1H), 2.8 (m, 1H), 3.35 (m, 3H), 3.8 (m, 1H), 3.95 (m, 2H), 4.05 (m, 1H), 7.0 (m, 1H), 7.6 (m, 1H), 7.7 (m, 2H), 7.9 (m, 1H), 8.0 (m, 2H) (113b).

Compound 114

Experimental Data

An oil slurry of NaH (68 g of a 60% suspension) was rinsed with petroleum ether and added to THF (1600 mL). The prop-2-en-1-ol (1.6 mol, 108.92 mL) was then added and the resulting solution was stirred for 2 hours. Chloromethyl-oxirane (639.12 mL) was added and the solution was stirred for 16 hours at room temperature followed by refluxation for 4 h. After the excess base was nentralized with 30% methanolic H 2 SO 4 , the solution was filtered, concentrated under reduced pressure and distilled wider vacuo to give (Z)-2,3,4,5-tetrahydrooxepin-3-ol as colorless oil.

1.3 M sBuLi in hexane (1.3 M, 38.5 mL) was added dropwise to a solution of allyl glycidyl ether 114i (0.05 mol, 5.93 mL) and HMPT (26 mL) in anhydrous THF (260 mL) at −78° C. under argon. After stirring for 30 minutes at the same temperature, the reaction was quenched with phosphate buffer (pH=7.0, 30 mL). The reaction mixture was saturated with solid NaCl and extracted with ethyl acetate (6×30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure below 25° C. The resulting mixture was separated by flash chromatography on silica gel (PE:EA=7:1-5:1) to give (Z)-2,3,4,5-tetrahydrooxepin-3-ol (925 mg, yield 16%). 1 H-NMR (CDCl 3 /400M): δ 6.32-6.30 (m, 1H), 4.82-4.78 (m, 1H), 4.04-3.94 (m, 2H), 3.93-3.88 (m, 1H), 2.28-2.15 (m, 1H), 2.14-2.05 (m, 1H), 2.04-1.95 (m, 1H), 1.89 (br, 1H, OH), 1.76-1.68 (m, 1H).

To a solution of (Z)-2,3,4,5-tetrahydrooxepin-3-ol (1141i) (6.9 mmol, 786 mg) in MeOH (7.86 mL), was added Pd(OH) 2 (78.6 mg) at room temperature under protection of H 2 . The reaction mixture was stirred at room temperature for 4 hours. TLC showed that the reaction was completed. The reaction mixture was filtered through celite and the filtrate was concentrated to give oxepan-3-ol (730 mg, yield 91%). 1 H-NMR (CDCl 3 /400M): δ 3.89-3.85 (m, 1H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 3H), 1.85-1.75 (m, 3H), 1.74-1.62 (m, 2H), 1.60-1.52 (m, 1H).

PCC (9.4 mmol, 2.02 g) was added to a solution of oxepan-3-ol (114iii) (6.27 mmol, 727 mg) in 18.8 mL CH 2 Cl 2 . The resulting mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was filtered through silca and the filtrate was concentrated to give oxepan-3-one (290 mg, yield 41%). 1 H-NMR (CDCl 3 /400M): δ 4.07 (s, 2H), 3.80-3.78 (m, 2H), 3.70-3.67 (m, 2H), 1.90-1.85 (m, 2H), 1.77-1.72 (m, 2H).

A mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (0.698 mmol, 150 mg) and oxepan-3-one (1.395 mmol, 159.1 mg) was added pyrrolidine (1.33 mmol, 0.1143 mL) in MeOH (2.85 mL). The reaction mixture was refluxed overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The resulting mixture was extracted with EtOAc and the organic layer was concentrated to give the crude product, which was purified by preparative TLC (PE:EA=3:1) to give compound 114v (63 mg, yield 29%). 1 H-NMR (CDCl 3 /400M): δ 7.94 (d, 1H, J=2.8 Hz), 7.56-7.53 (m, 1H), 6.90 (d, 1H, J=8.8 Hz), 4.00 (d, 1H, J=16 Hz), 3.91-3.82 (m, 1H), 3.75-3.67 (m, 1H), 3.64 (d, 1H, J=14 Hz), 2.79-2.65 (m, 2H), 2.09-2.00 (m, 1H), 1.92-1.68 (m, 4H), 1.55-1.42 (m, 1H).

To a solution of compound 114v (223 mg, 0.72 mmol) in anhydrous DCM (5.6 mL) was added TiCl 4 (1 M solution in DCM, 2.87 mL, 2.87 mmol) dropwise within 15 minutes at room temperature and the resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (400 mg, 0.48 mL, 2.15 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give compound 114vi as light brown solid (168 mg), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (42 mg, 0.50 mmol) in anhydrous MeOH (5.9 mL) was added NaOMe (25 w % in MeOH, 98.5 uL, 0.45 mmol), followed by cyanamide 114vi (168 mg, 0.50 mmol), After stirring for 1 hour, the solvent was removed in vacuo. The resulting residue was redissolved in DCM (15 mL). The mixture was filtered, and the solvent was removed in vacuo to give the crude product, which was purified by preparative TLC (CH 2 Cl 2 : MeOH 12:1) to give the pure product 114vii (114 mg, 59%).

Pd(PPh 3 ) 2 Cl 2 (18.4 mg) in a 10 mL tube under Ar was treated sequentially with the compound 114vii (50 mg, 0.131 mmol) in 1,4-dioxane (5.0 mL), Cs 2 CO 3 (2 N, 0.73 mL) and 3-cyanophenylboronic acid (38.5 mg, 0.262 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC (CH 2 Cl 2 : MeOH 10:1) and preprative HPLC to give the target compound Compound 114. 1 H-NMR (MeOD/400M): δ 7.99-7.97 (m, 1H), 7.95-7.87 (m, 2H), 7.72-7.68 (m, 1H), 7.67-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7.15-6.98 (m, 1H), 3.92-3.85 (m, 2H), 3.82-3.65 (m, 2H), 3.41-3.35 (m, 3H), 3.05-2.88 (m, 1H), 2.15-2.05 (m, 1H), 2.04-2.01 (m, 1H), 2.00-1.95 (m, 1H), 1.92-1.71 (m, 3H), 1.68-1.48 (m, 1H).

Compound 115

Experimental Data

A mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (298 mg, 2 mmol), Cs 2 CO 3 (2 M, 4 mL) and Pd(PPh 3 ) 2 Cl 2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred under microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified bypreparative TLC to give 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (140 mg, 43%). 1 H-NMR (CDCl 3 ): 1.81-1.85 (m, 2H), 2.00-2.04 (d, 2H), 2.80 (s, 2H), 3.78-3.87 (m, 4H), 7.14 (d, 1H), 7.52-7.56 (t, 1H), 7.61-7.64 (d, 1H), 7.71-7.74 (d, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 8.07 (s, 1H).

A solution of 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (170 mg, 0.53 mmol) and TiCl 4 (403 mg, 2.12 mmol) in anhydrous DCM (5 mL) was heated at 50° C. under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (198 mg, 1.06 mmol) was added and the mixture was heated at 60° C. for another 30 mins. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give (Z)—N-(6-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-ylidene)cyanamide (147 mg, crude), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (36 mg, 0.43 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25% in MeOH (Wt. %), 0.10 mL, 0.39 mmol), followed by (Z)—N-(6-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-ylidene)cyanamide (147 mg, 0.43 mmol). After stirred for 10 mins, the solvent was removed in vacuo. The residue was redissolved in DCM (5 mL). The mixture was filtered and concentrated to give the residue, which was purified by preparative TLC to give Compound 115 (39.7 mg, 24%). 1 H-NMR (CDCl 3 ): 1.79-1.90 (m, 3H), 2.03-2.07 (d, 1H), 2.24 (d, 1H), 2.33 (d, 1H), 3.09 (s, 3H) 3.73-3.82 (m, 3H), 3.91-3.97 (m, 1H), 6.97 (d, 1H), 7.41-7.43 (d, 1H), 7.47-7.51 (t, 1H), 7.56-7.58 (m, 2H), 7.74-7.81 (m, 2H).

Compound 116

Experimental Data

To a solution of tetrahydro-pyran-4-one (15 g, 0.15 mol) in Et 2 O (90 mL) was added dropwise a solution of CH 2 N 2 (1 M in Et 2 O, 300 mL) at 0° C. After addition, MeOH (75 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir for 2 hours. The remaining diazomethane was destroyed with a few drops of acetic acid. The solvent was removed under reduced pressure to give oxepan-4-one, which was used in the next step directly without purification. 1 H-NMR (CDCl 3 ): 1.79 (m, 2H), 2.61 (m, 4H), 3.81 (m, 4H).

A mixture of oxepan-4-one (10 g, 87.7 mmol), 1-(5-bromo-2-hydroxy-phenyl)-ethanone (13 g, 58.5 mmol) and pyrrolidine (6.2 g, 87.7 mmol) in MeOH (150 mL) was refluxed overnight. The solvent was removed in vacuo. The residue was diluted with water, acidified with con. HCl to pH=1. The solution was extracted with EtOAc, washed with brine, and concentrated. The residue was purified by preparative HPLC to give compound 116i (220 mg, 1%). 1 H-NMR (CDCl 3 ): 1.52 (m, 1H), 1.84 (m, 2H), 1.98 (m, 1H), 2.13 (m, 2H), 2.70 (m, 2H), 3.65 (m, 1H), 3.74 (m, 3H), 6.81 (d, 1H), 7.49 (m, 1H), 7.90 (m, 1H).

To a solution of compound 116i (200 mg, 0.645 mmol) in anhydrous DCM (7 mL) was added TiCl 4 (1 M solution in DCM, 1.29 mL, 1.29 mmol) dropwise within 15 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (264 mg, 1.42 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give compound 116ii, which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (38 mg, 0.45 mmol) in anhydrous MeOH (6 mL) was added NaOMe (25 w % in MeOH, 0.09 mL, 0.42 mmol), followed by compound 116ii (155 mg, 0.45 mmol). After stirring 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM. The mixture was filtered, and the solvent was removed in vacuo to give crude product of compound 116iii, which was purified by preparative TLC (60 mg, 34%).

Pd(PPh 3 ) 2 C12 (8 mg) in a 10 mL of tube under Ar 2 was treated sequentially with compound 116iii (30 mg, 0.0787 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (23 mg, 0.157 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure Compound 116 (3 mg, 10%). 1 H-NMR (MeOD): 1.71 (m, 1H), 2.05 (m, 4H), 2.20 (m, 3H), 3.01 (m, 1H), 3.38 (m, 3H), 3.71 (m, 2H), 3.81 (m, 2H), 7.06 (m, 0.7H), 7.20 (m, 0.3H), 7.64 (m, 1H), 7.72 (m, 1H), 7.97 (m, 3H), 8.30 (m, 0.3H).

Compound 117

Experimental Data

To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (379 mg, 1.28. mmol) in anhydrous DCM (10 mL) was added TiCl 4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylide-ne)cyanamide (350 mg, 90%), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (62.7 mg, 0.75 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25% in MeOH (Wt. %), 0.15 mL, 0.675 mmol), followed by (E)-N-(6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (240 mg, 0.75 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (10 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by column chromatography to give compound 117i (140 mg, 50%).

A mixture of compound 117i (50 mg, 0.157 mmol), 3-cyanophenylboronic acid (40 mg, 0.266 mmol), Cs 2 CO 3 (2 M, 0.5 mL) and Pd(PPh 3 ) 2 Cl 2 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give compound 2 (15 mg, 20%). 1 H-NMR (MeOD): 1.61 (m, 1H), 1.78 (m, 2H), 2.11 (m, 2H), 2.93 (m, 1H), 3.37 (m, 3H), 3.64 (m, 2H), 3.75 (m, 2H), 7.09 (m, 1H), 7.67 (m, 1H), 7.75 (m, 2H), 7.97 (m, 3H).

3-(3″-Imino-2″-methylspiro[spiro(chroman-2,1″-cyclohexane)-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 118)

To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (379 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl 4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 min at rt. The mixture was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)cyanamide as a light brown solid (410 mg), which was used in the next step without further purification. MS ESI +ve m/z 319 (M+H) + .

To a solution of methylhydroxylamine HCl salt (107 mg, 1.28 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25 w % in MeOH, 0.25 mL, 1.15 mmol), followed by N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)cyanamide (410 mg, 1.28 mmol). After stirring for 10 min, the solvent was removed in vacuo. The resultign residue was redissolved in DCM (20 mL). The mixture was filter, and the solvent was removed in vacuo to give 515 mg crude product of 6-bromo-2″-methylspiro[spiro(chroman-2,1′-cyclohexane)-4,5″-[1,2,4]oxadiazolidin]-3″-imine, which is used for next step without further purification. MS ESI +ve m/z 366 (M+H) + .

To a solution of 6-bromo-2″-methylspiro[spiro(chroman-2,1′-cyclohexane)-4,5″-[1,2,4]oxadiazolidin]-3″-imine (77 mg, 0.2 mmol), 3-cyanophenylboronic acid (62 mg, 0.34 mmol), and Cs 2 CO 3 (163 mg, 0.5 mmol) in 1,4-dioxane (10 mL) and H 2 O (0.5 mL) in a 25 mL round-bottom flask equipped with a condenser was added PdCl 2 (PPh 3 ) 2 (20 mg). After degassing by vacuum and purge with N 2 , the mixture was refluxed for 3 h (a black precipitate comes out at this time). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 3-(3″-imino-2″-methylspiro[spiro(chroman-2,1′-cyclohexane)-4,5″-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (18 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H) + . 1 H NMR (400 MHz, CD 3 OD): 8.29-7.02 (m, 12H), 3.38 and 3.34 (s and s, 3H), 2.86 (m, 1H), 2.12-1.40 (m, 11H).

Compound 119

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with compound 117i (50 mg, 0.136 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-fluorophenylboronic acid (38.4 mg, 0.272 mmol). The mixture was heated under microwave at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure Compound 119 (13 mg, 25%). 1 H-NMR (MeOD): 1.61 (m, 1H), 1.92 (m, 2H), 2.13 (m, 2H), 2.69 (t, 1H), 3.32 (d, 3H), 3.61 (m, 2H), 3.84 (m, 2H), 7.02 (m, 2H), 7.33 (d, 1H), 7.42 (m, 2H), 7.62 (d, 1H), 7.79 (d, 1H).

Compound 120

Experimental Data

To a solution of 6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentan]-4-one (226 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl 4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (60 mg, 0.72 mmol) in anhydrous MeOH (8.5 mL) was added NaOMe (25 w % in MeOH, 0.14 mL, 0.65 mmol), followed by (E)-N-(6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (225 mg, 0.72 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (15 mL). The mixture was filter, and the solvent was removed in vacuo to give the crude product, which was purified by preparative TLC (CH 2 Cl 2 : MeOH 12:1) to give the pure product 120i (174 mg, 63%). 1 H NMR (CDCl 3 ): 7.50 (s, 1H), 7.27 (d, 1H), 6.67 (d, 1H), 3.10 (s, s, 3H), 2.42-2.23 (m, 2H), 2.22-2.05 (m, 2H), 2.04-1.92 (m, 2H), 1.90-1.65 (m, 2H), 1.49-1.39 (m, 1H), 1.35-1.22 (m, 2H), 0.92-0.79 (m, 3H).

Pd(PPh 3 ) 2 Cl 2 (18.5 mg) in a 10 mL tube under Ar was treated sequentially with the compound 120i (50 mg, 0.13 mmol) in 1,4-dioxane (4.9 mL), Cs 2 CO 3 (2 N, 0.74 mL) and 3-cyanophenylboronic acid (39 mg, 0.26 mmol). The mixture was heated under microwave at 120° C. for 45 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC (PE:EA 1:1.5) and then by preparative HPLC to give Compound 120 (2.44 mg, 5%). 1 H NMR (MeOD/400M): δ 7.99 (s, 1H), 7.95-7.92 (m, 2H), 7.71-7.64 (m, 2H), 7.62-7.60 (m, 1H), 7.00-6.96 (m, 1H), 3.39 (s, s, 3H), 2.78-2.67 (m, 1H), 2.45-2.33 (m, 1H), 2.31-2.19 (m, 1H), 2.18-2.02 (m, 3H), 2.01-1.87 (m, 2H), 1.48-1.31 (m, 3H), 1.01-0.89 (m, 3H).

Compound 121

Experimental Data

To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr—SMe 2 (188 mg, 0.91 mmol), chlorotrimethylsilane (4.59 mL, 36.54 mmol) amd HMPA (6.55 g, 36.54 mmol) in THF (30 mL) was added isopropylmagnesium bromide (36.54 mL, 1 M in THF) at −70° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et 2 O. The organic layer was washed with aqueous NaHCO 3 and brine. After dried over Na 2 SO 4 , the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).

A mixture of 3-isopropylcyclopentanone (0.5 g, 3.962 mmol), 1-(5-bromo-2-hydroxyphenyl)ethanone (0.424 g, 1.98 mmol) and pyrrolidine (0.143 g, 1.98 mmol) in MeOH (25 mL) was refluxed overnight. The solvent was removed in vacuo to give crude 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (500 mg, 79%). 1 H-NMR (CDCl 3 ): 0.78 (m, 3H), 0.82 (m, 3H), 1.34 (m, 1H), 1.58 (m, 3H), 1.75 (m, 1H), 1.91 (m, 2H), 2.08 (m, 1H0, 2.73 (s, 2H), 6.74 (m, 1H), 7.44 (m, 1H), 7.89 (d, 1H).

To a solution of 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (250 mg, 0.776 mmol) in DCM (10 mL) was added TiCl 4 (1.55 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.38 mL, 1.707 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH 2 Cl 2 , which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (250 mg, 93%). 1 H-NMR (CDCl 3 ): 0.82 (m, 6H), 1.36 (m, 2H), 1.69 (m, 3H), 1.96 (m, 3H), 3.10 (d, 2H), 6.75 (m, 1H), 7.52 (m, 1H), 8.04 (d, 1H).

To a solution of N-methyl-hydroxylamine hydrochloride (72 mg, 0.723 mmol) in MeOH (15 mL) was added MeONa (0.154 mL, 25% (Wt.) in MeOH), followed by N-(6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (250 mg, 0.723 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give compound 121i (148 mg, 52%). 1 H-NMR (CDCl 3 ): 0.82 (m, 6H), 1.26 (m, 3H), 1.93 (m, 5H), 2.27 (m, 2H), 3.04 (m, 3H), 6.62 (m, 1H), 7.22 (m, 1H), 7.42 (m, 1H).

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL flask under Ar was treated sequentially with compound 121i (50 mg, 0.127 mmol) in 1,4-dioxane (3 mL), Cs 2 CO 3 (2 N, 0.16 mL) and 3-cyanophenylboronic acid (33 mg, 0.216 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give Compound 121 (25.43 mg, 48%). 1 H-NMR (MeOD): 0.91 (m, 6H), 1.42 (m, 2H), 1.53-1.98 (m, 3H), 1.99-2.27 (m, 3H), 2.38 (m, 1H), 2.71 (m, 0.8H), 3.01 (m, 0.3H) 3.38 (m, 3H), 7.02 (m, 1H), 7.67 (m, 3H), 7.96 (m, 2.8H), 8.30 (m, 0.2H).

Compound 122

Experimental Data

Pd(PPh 3 ) 2 Cl 2 (60 mg) in a 40 mL tube under Ar was treated sequentially with 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (600 mg, 2.01 mmol) in THF (20 mL*3), CuI (600 mg) and cyclohexylzinc(II) bromide (8.1 mL, 4.02 mmol). The mixture was heated under microwave at 160° C. for 10 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 30%). 1 H-NMR (CDCl 3 ): 1.31 (t, 4H), 1.48 (m, 1H), 1.62 (m, 5H), 1.76 (d, 4H), 1.89 (m, 1H), 2.06 (d, 1H), 2.49 (s, 1H), 2.61 (m, 2H), 3.49 (m, 2H), 3.79 (m, 2H), 6.88 (d, 1H), 7.29 (d, 2H), 7.61 (s, 1H).

To a solution of 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (240 mg, 0.804 mmol) in anhydrous DCM (10 mL) was added TiCl 4 (1 M solution in DCM, 608.6 mg, 3.2 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (380.6 mg, 3.12 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (20 mg, 10%), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (5.16 mg, 0.06 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25 w % in MeOH, 0.08 mL), followed by (E)-N-(6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (20 mg, 0.06 mmol), After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL), the mixture was filtered and the solvent was removed in vacuo, which was purified by preparative TLC to give Compound 122 (5.24 mg, 30%). 1 H-NMR (MeOD): 1.24 (m, 2H), 1.37 (m, 4H), 1.52 (m, 1H), 1.72 (d, 1.5H), 1.79 (d, 5H), 1.88 (t, 1H), 2.04 (m, 1H), 2.42 (m, 1H), 3.01 (d, 3H), 3.50 (m, 2H), 3.69 (d, 0.5H), 3.74 (m, 1H), 3.90 (d, 0.5H), 6.71 (d, 1H), 7.04 (d, 1H), 7.19 (d, 1H).

Compound 124

Pd(PPh 3 ) 2 Cl 2 (15 mg) in a 10 mL of flask under Ar 2 was treated sequentially with the amine 117i (40 mg, 0.13 mmol) in 1,4-dioxane (2.3 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 3-ethoxy-benzonitrile (31 mg, 0.19 mmol). The mixture was heated at 120° C. under Ar under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give Compound 124 (2.2 mg, 4%). 1 H-NMR (MeOD): 1.26 (m, 3H), 1.51 (m, 1H), 1.75-2.06 (m, 3H), 2.66-2.92 (m, 1H), 3.22 (m, 3H), 3.32 (m, 1H), 3.52 (m, 2H), 3.69 (m, 2H), 3.98 (m, 2H), 6.77 (m, 1H), 6.91 (m, 1H), 7.02 (m, 2H), 7.22 (m, 1H), 7.38-7.54 (m, 1H), 7.69-8.11 (m, 1H).

Compound 125

Experimental data

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.193 g, 10.2 mmol), 3-methylcyclopentanone (2 g, 20.4 mmol) and pyrrolidine (1.67 mL, 19.43 mmol) in MeOH (42 mL) was stirred at room temperature overnight, followed by reflux for 2 days. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one, which was purified by chromatography (PE:EA 300:1-200:1) (2.3 g, 76%). 1 H NMR (CDCl 3 ): 7.94 (d, 1H), 7.52-7.49 (m, 1H), 6.83-6.79 (m, 1H), 2.79 (m, 2H), 2.39-2.22 (m, 0.5H), 2.21-1.95 (m, 3H), 1.91-1.75 (m, 1H), 1.67-1.57 (m, 1H), 1.51-1.41 (m, 0.5H), 1.31-1.15 (m, 1H), 1.08-0.98 (m, 3H).

To a solution of 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one (216 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl 4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred forl h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na 2 S O 4 , filtered, and concentrated to give (E)-N-(6-bromo-3′-methylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.

To a solution of methylhydroxylamine HCl salt (59 mg, 0.71 mmol) in anhydrous MeOH (8.3 mL) was added NaOMe (25 w % in MeOH, 0.14 mL, 0.63 mmol), followed by (E)-N-(6-bromo-3′-methylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (225 mg, 0.71 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (15 mL). The mixture was filtered, and the solvent was removed in vacuo to give the crude product, which was purified by preparative TLC (CH 2 Cl 2 : MeOH 12:1) to give the pure product 125i (197 mg, 76%).

Pd(PPh 3 ) 2 Cl 2 (19.2 mg) in a 10 mL tube under Ar was treated sequentially with the compound 125i (50 mg, 0.14 mmol) in 1,4-dioxane (5.1 mL), Cs 2 CO 3 (2 N, 0.76 mL) and 3-cyanophenylboronic acid (40 mg, 0.27 mmol). The mixture was heated under microwave at 120° C. for 45 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC (PE:EA 1:1.5) to give Compound 125 (2.26 mg, 4%). 1 H-NMR (MeOD): 7.92 (s, 1H), 7.89-7.87 (m, 1H), 7.75 (s, 1H), 7.66-7.64 (m, 1H), 7.61-7.55 (m, 2H), 7.32-7.24 (m, 1.5H), 6.97-6.88 (m, 1.5H), 3.20 (s, 3H), 2.41-2.31 (m, 2H), 2.12-2.08 (m, 2H), 1.90-1.65 (m, 2H), 1.60-1.40 (m, 2H), 1.14-1.11 (m, 1H), 1.09-1.01 (m, 3H).

Compound 126

Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with the compound 117i (40 mg, 0.088 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.2 mL) and 3-propoxyphenylboronic acid (32 mg, 0.176 mmol). The mixture was heated at 120° C. under Ar under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give Compound 126 (5 mg, 15%). 1 H-NMR (MeOD): 1.06 (m, 3H), 1.53-1.68 (m, 1H), 1.74-1.91 (m, 3H), 1.93-2.13 (m, 2H), 2.79-2.98 (m, 1H), 3.56-3.68 (m, 2H), 3.72-3.89 (m, 2H), 3.97 (t, 2H), 6.88 (d, 1H), 7.01-7.17 (m, 3H), 7.33 (t, 1H), 7.63 (d, 1H), 7.81 (m, 1H).

Compound 127a and 127b

Experimental Data

4-tert-butylcyclohexanol (10 g, 64.1 mmol) was dissolved in trifluoroacetic acid and then NaNO 2 (17.09 g, 256.4 mmol) was added to the solution at 0° C. under an air. After the resulting solution was stirred at room temperature for 5 hours, the solvent was removed in vacuo at room temperature and the residue was added into an aqueous 5% NaHCO 3 . After the solution was treated with methylene chloride, the aqueous solution was acidified with 10% HCl solution followed by extraction with ethyl acetate to give 3-tert-butyl-6-hydroxyhexanoic acid (5.26 g, 41%).

A suspension of the 3-tert-butyl-6-hydroxyhexanoic acid (1 g, 4.95 mmol), anhydrous NaOAc (0.321 g, 3.91 mmol) and acetic anhydride was refluxed for 5 hours during which time the solution mixture turned black. After the reaction mixture was cooled to room temperature, the formed acetic acid and remaining acetic anhydride were removed on a rotary evaporator and then under high vacuum. The residue was then dissolved in ethyl acetate, filtered through a plug of celite to remove the precipitate NaOAc, and concentrated in vacuo to give the crude product of 3-tert-butylcyclopentanone (0.557 g, 58%).

A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3-tert-butylcyclopentanone (750 g, 5.36 mol) and pyrrolidine (362 mg, 5.092 mol) in methanol was refluxed overnight. The reaction mixture was removed in vacuo. The residue was diluted with an equal volume of H 2 O and then added HCl until pH=1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (0.8 g, 89%). 1 H NMR (CDCl 3 ): 0.77 (s, 9H), 1.34 (m, 1H), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, 1H), 7.47 (d, 1H), 7.89 (s, 1H).

To a solution of 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (200 mg, 0.60 mmol) in dried CH 2 Cl 2 (10 mL) was added TiCl 4 (1 M solution in DCM, 1.20 mmol) dropwise within 15 minutes. The mixture was stirred for 1 h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (244 mg, 1.31 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (30 g) and extracted with CH 2 Cl 2 . The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (E)-N-(6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (200 mg, crude), which was used for the next step without further purification.

To a solution of MeNHOH.HCl (46.3 mg, 0.55 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 0.11 mL, 0.50 mmol), followed by (E)-N-(6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (200 mg, 0.55 mmol). After stirring for 30 minutes, the solvent was removed in vacuo. The residue was redissolved in CH 2 Cl 2 and filtered. The filtrate was concentrated to give the residue, which was purified by preparative TLC to afford compound 127i (86 mg, 38%). 1 H NMR (CDCl 3 ): 1.48-1.61 (m, 1H), 1.73-2.28 (m, 4H), 2.98 (d, 3H), 3.47-3.63 (m, 2H), 3.27 (m, 2H), 3.98 (m, 1H), 6.81-6.93 (m, 4H), 7.02 (m, 2H), 7.24 (m, 2H).

Pd(PPh 3 ) 2 Cl 2 (5 mg) in a 10 mL flask under Ar was treated sequentially with the compound 127i (42 mg, 0.103 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.2 mL) and 3-cyanophenylboronic acid (28.1 mg, 0.154 mmol). The mixture was heated at 120° C. under Ar under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give Compound 127a (7 mg, 16%) and Compound 127b (11 mg, 25%). 1 H NMR (MeOD): 0.84-0.96 (m, 9H), 1.52-1.64 (m, 1H), 1.77 (m, 1H), 1.96 (m, 2H), 2.03-2.14 (m, 2H), 2.38 (t, 1H), 2.76 (d, 1H), 3.39 (s, 3H), 6.98 (m, 1H), 7.58-7.73 (m, 3H), 7.99 (m, 3H) (127a). 1 H NMR (MeOD): 0.88-0.97 (m, 9H), 1.36 (m, 1H), 1.56-2.07 (m, 6H), 2.43 (m, 1H), 2.73 (m, 1H), 3.41 (s, 3H), 7.01 (m, 1H), 7.59-7.74 (m, 3H), 7.93-8.31 (m, 3H) (127b).

Compound 128

Experimental Data

3-Methoxypropan-1-ol (23.85 g, 0.294 mmol) was dissolved in pyridine (20.6 mL) and cooled to 5° C. SOCl 2 (28.4 mL) was added dropwise under stirring. After the addition was completed, the reaction mixture was refluxed for 3 h and poured onto crashed ice in concentrated HCl (20 mL). The organic layer was separated and dried over K 2 CO 3 and filtered. The filtrate was concentrated to give the residue, which was purified by fractional distillation to give 1-chloro-3-methoxypropane (13 g, 41%). 1 H-NMR (CDCl 3 ): 1.99 (m, 2H), 3.33 (s, 3H), 3.49 (t, 2H), 3.62 (t, 2H).

A mixture of 3-bromophenol (5 g, 29 mmol), 1-chloro-3-methoxypropane (4.33 g, 40 mmol) and K 2 CO 3 (8 g, 57.8 mmol) in DMF (90 mL) was stirred at 100° C. for 2 h. the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was taken up in t-BuME, and the organic layer was washed with aqueous NaOH (1N), water (50 mL) and brine. The organic layer was dried and concentrated to give 1-bromo-3-(3-methoxypropoxy)benzene (7 g, 99%). 1 H-NMR (CDCl 3 ): 2.02 (m, 2H), 3.33 (s, 3H), 3.54 (m, 2H), 4.02 (m, 2H), 6.82 (m, 1H), 7.11 (m, 3H).

1-Bromo-3-(3-methoxypropoxy)benzene (1 g, 4.61 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.27 g, 5.07 mmol), K 2 C O 3 (2.55 g, 18.44 mmol) and Pd(PPh 3 ) 2 Cl 2 (250 mg, 0.277 mmol) in 1,4-dioxane (40 mL) was refluxed under Ar for 12 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried and concentrated to give the residue, which was purified by preparative TLC to give 2-(3-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65 mg, 6%).

Pd(PPh 3 ) 2 Cl 2 (12 mg) in a 10 mL of flask under Ar was treated sequentially with the amine 117i (40 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL), Cs 2 CO 3 (2 M, 0.5 mL) and 2-(3-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.19 mmol). The mixture was heated under Ar at 120° C. under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give Compound 128 (1.47 mg, 3%). 1 H-NMR (MeOD): 1.52 (m, 1H), 1.75 (m, 2H), 1.98 (m, 5H), 2.71-2.98 (m, 2H), 3.37 (m, 6H), 3.55 (m, 4H), 3.76 (m, 2H), 4.01 (m, 2H), 6.81 (m, 1H), 6.92 (m, 1H), 7.02 (m, 2H), 7.24 (m, 1H), 7.58 (m, 1H), 7.76 (m, 1H).

Compound 129

Experimental Data

A mixture of 3-bromophenol (5 g, 28.9 mmol), 1-chloro-2-methoxyethane (3.77 g, 40 mmol) and K 2 CO 3 (12.63 g, 0.178 mol) in DMF (90 mL) was stirred at 100° C. for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether, and the organic phase was washed once each with 50 ml of 1 N NaOH, 50 ml of water and 50 ml of brine. The organic layer was dried with sodium sulphate, filtered and concentrated to give 1-bromo-3-(2-methoxyethoxy)benzene (5.28 g, 79%).

1-Bromo-3-(2-methoxyethoxy)benzene (2 g, 12.6 mmol), K 2 CO 3 (6.96 g, 50 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.687 g, 0.756 mmol) were dissolved in 1,4-dioxane (90 ml). The mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative TLC to give 2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 26%).

Pd(PPh 3 ) 2 Cl 2 (8 mg) in a 10 mL tube under Ar was treated sequentially with compound 117i (50 mg, 0.139 mmol) in 1,4-dioxane (2.5 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66 mg, 0.236 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure product of Compound 129 (4.43 mg, 7%). 1 H-NMR (MeOD): 1.60 (s, 1H), 1.91 (m, 2H), 2.12 (m, 2H), 2.85 (m, 1H), 3.0 (m, 0.5H), 3.07 (m, 3H), 3.35 (OH), 3.45 (s, 3H), 3.65 (m, 2H), 3.8 (m, 4H), 4.2 (s, 2H), 6.95 (s, 1H), 7.05 (t, 1H), 7.2 (m, 2H), 7.35 (m, 1H), 7.65 (d, 1H), 7.8-7.9 (m, 1H), 8.25 (s, 0.2H)

Compound 130

Experimental Data

To a solution of 1-(2-hydroxy-5-phenoxyphenyl)ethanone (2.0 g, 8.77 mmol) in toluene (30 mL) was added dihydro-2H-pyran-3(4H)-one (1.14 g, 11.40 mmol) and pyrrolidine (0.81 g, 11.40 mmol), and the reaction mixture was refluxed overnight. After cooling, the mixture was concentrated. The residue was washed with 1 N HCl, brine, dried and concentrated to give the crude product, which was purified by chromatography to afford 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.40 g, 52%). 1 H-NMR (CDCl 3 ): 0.79 (m, 1H), 1.52 (m, 2H), 1.67 (m, 1H), 1.92 (m, 1H), 2.08 (m, 1H), 2.57-2.61 (q, 2H), 3.51 (m, 2H), 3.88 (m, 2H), 6.89 (d, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.26 (t, 2H), 7.39 (m, 1H).

To a solution of 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (500 mg, 1.27 mmol) and triethylamine (227 mg, 0.73 mmol) in dried CH 2 Cl 2 (10 mL) was added TiCl 4 (1 M solution in DCM, 1.47 mmol) dropwise within 15 minutes. The mixture was stirred forl h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 1.16 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (50 g) and extracted with CH 2 Cl 2 . The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (E)-N-(6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyan amide (100 mg, crude), which was used for the next step without further purification.

To a solution of MeNHOH.HCl (25 mg, 0.30 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25 w % in MeOH, 0.06 mL, 0.27 mmol), followed by (E)-N-(6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (100 mg, 0.30 mmol). After stirring for 30 minutes, the solvent was removed in vacuo. The residue was redissolved in CH 2 Cl 2 and filtered. The filtrate was concentrated to give the residue, which was purified by preparative TLC to afford Compound 130 (29 mg, 25%). 1 H NMR (CDCl 3 ): 1.48-1.61 (m, 1H), 1.73-2.28 (m, 4H), 2.98 (d, 3H), 3.47-3.63 (m, 2H), 3.27 (m, 2H), 3.98 (m, 1H), 6.81-6.93 (m, 4H), 7.02 (m, 2H), 7.24 (m, 2H).

3-(3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (Compound 96)

To a solution of 6-bromo-2-phenylchroman-4-one (1.016 g, 3.35 mmol) in anhydrous DCM under N 2 atmosphere was added 1 M TiCl 4 (in DCM, 6.7 mL, 6.7 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.374 g, 7.37 mmol) dropwise. The resulting mixture was stirred for another 24 h after the addition. The reaction mixture was poured into ice-water (100 g), stirred for a while and filtered through a pad of Celite. The filtrate was extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (E)-N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide as light brown solid (899 mg), which was used in the next step without further purification. MS ESI +ve m/z 327 (M+H) + .

To a solution of methylhydroxylamine HCl salt (280 mg, 3.35 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25 w % in MeOH, 0.67 mL, 3.02 mmol), followed by (E)-N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (899 mg, 2.75 mmol) solution in MeOH (20 mL), After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL), filtered, and the solvent was removed in vacuo to give 825 mg crude product of 6-bromo-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine as a yellow solid. 270 mg of the crude product was purified on preparative HPLC to give pure title compound as a TFA salt. MS ESI +ve m/z 374 (M+H) + .

Step 3: Preparation of 3-(3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile

To a solution of 6-bromo-2′-methyl-2-phenylspiro[chroman-4,5′-[1,2,4]oxadiazolidin]-3′-imine TFA salt (45 mg, 0.092 mmol), 3-cyanophenylboronic acid (20 mg, 0.14 mmol) and Cs 2 CO 3 (60 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and H 2 O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl 2 (PPh 3 ) 2 (10 mg). After degassing by purging with N 2 , the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 3-(3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (10 mg) as a TFA salt. MS ESI +ve m/z 397 (M+H) + . 1 H-NMR (400 MHz, DMSO-d 6 ): 8.14-8.12 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.84-7,79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.54-7.40 (m, 5H), 7.09 (d, J=8.8 Hz, 1H), 5.29 (d, 11.6 Hz, 1H), 3.34 (s, 3H), 2.75 (d, 14.0 Hz, 1H), 2.37 (dd, J=14.4, 13.2 Hz, 1H).

2′-methyl-2-phenyl-6-(pyridin-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 102)

To a solution of 6-bromo-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine TFA salt (65 mg, 0.13 mmol), 3-pyridineboronic acid (64 mg, 0.52 mmol) and Cs 2 CO 3 (127 mg, 0.39 mmol) in 1,4-dioxane (3 mL) and H 2 O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl 2 (PPh 3 ) 2 (10 mg). After degassing by purging with N 2 , the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 2′-methyl-2-phenyl-6-(pyridin-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (17 mg) as a TFA salt. MS ESI +ve m/z 393 (M+H) + . 1 H-NMR (400 MHz, CD 3 OD): 9.19 (br s, 1H), 8.87 (d, J=7.6 Hz, 1H), 8.78 (br s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11 (t, J=6.4 Hz, 1H), 7.91 (dd, J=8.8, 2.4 Hz, 1H), 7.54-7.38 (m, 5H), 7.21 (d, J=8.8 Hz, 1H), 5.37 (d, 12.8 Hz, 1H), 3.43 (s, 3H), 2.88 (dd, J=14.4, 2.0 Hz, 1H), 2.42 (dd, J=14.4, 12.8 Hz, 1H).

3-(2,2-bis(hydroxymethyl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 100) and 3-(3″-imino-2″-methylspiro[spiro(chroman-2,1′-(4,4-dimethyl-3,5-dioxane))-4,5″-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 123)

A solution of 2,2-dimethyl-1,3-dioxan-5-one (2.290 g, 17.62 mmol), 5′-bromo-2-hydroxy-acetophone (3.576 g, 17.62 mmol) in MeOH containing pyrrolidine (1 mL) was refluxed for 2 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 M NaOH, 1 M HCl, H 2 O and brine successively, dried, and filtered. The filtrate was concentrated to dryness. The crude product was further purified by flash chromatography on silica gel (40 g, eluted with ethyl acetate in hexane 0-25%) give 6-bromo-2′,2′-dimethylspiro[chroman-2,5′-[1,3]dioxan]-4-one as a brownish solid (2.06 g).

To a solution of 6-bromo-2′,2′-dimethylspiro[chroman-2,5′-[1,3]dioxan]-4-one (498 mg, 1.5 mmol), 3-cyanophenylboronic acid (440 mg, 3.0 mmol) and Cs 2 CO 3 (1.460 mg, 4.5 mmol) in 1,4-dioxane (4 mL) and H 2 O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl 2 (PPh 3 ) 2 (75 mg). After degassed by purging with N 2 , the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (12 g, eluted with ethyl acetate in hexane 0-30%) give 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile as a yellowish solid (298 mg). MS ESI +ve m/z 350 (M+H) + .

To a solution of 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile (155 mg, 0.44 mmol) in anhydrous DCM (10 mL) under N 2 atmosphere was added 1 M TiCl 4 (in DCM, 0.88 mL, 0.88 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (181 mg, 217 μL 0.97 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (25 g), stirred for 30 min and filtered through a pad of Celite. The separated aqueous phase of the filtrate was extracted with DCM once. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2,2-bis(hydroxymethyl)chroman-4-ylidene)cyanamide (160 mg), which was used in the next step without further purification. MS ESI +ve m/z 374 (M+H) + .

Step 4: Preparation of 3-(2,2-bis(hydroxymethyl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 100)

To a solution of methylhydroxylamine HCl salt (36.7 mg, 0.44 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25 w % in MeOH, 90 μL, 0.39 mmol), followed by a solution of (E)-N-(6-(3-cyanophenyl)-2,2-bis(hydroxymethyl)chroman-4-ylidene)cyanamide (147 mg, 0.44 mmol) solution in MeOH (2 mL) after 5 min. After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL), filtered, and the solvent was removed in vacuo to give crude product, which was purified by preparative HPLC to afford 43 mg of 3-(2,2-bis(hydroxymethyl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile TFA salt as a white solid. MS ESI +ve m/z 381 (M+H) + . 1 H NMR (400 MHz, CD 3 OD): 7.98-7.90 (m, 3H), 7.72-7.58 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 3.86-3.70 (m, 4H), 3.67 (s, 3H), 2.84 (d, J=14.8 Hz, 1H), 2.43 (d, J=14.8 Hz, 1H).

Step 5: Preparation of 3-(3″-imino-2″-methylspiro[spiro(chroman-2,1′-(4,4-dimethyl-3,5-dioxane))-4,5″-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 123)

To a solution of 3-(2,2-bis(hydroxymethyl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile TFA salt (16 mg, 0.03 mmol) in 2,2-dimethoxypropane (2.5 mL) and acetone (0.5 mL) was added catalytic amount of anhydrous p-TSA. The reaction was monitored by HPLC, very low conversion was found at 2 h. Excess of p-TSA (>1 eq.) was added and stirred for another 20 min. The reaction mixture turned cloudy. HPLC showed only a little starting material left. TEA (0.5 mL) was added and the reaction mixture was stirred for another 5 min and concentrated to dryness. The residue was purified by preparative HPLC to afford 3-(3″-imino-2″-methylspiro[spiro(chroman-2,1′-(4,4-dimethyl-3,5-dioxane))-4,5″-[1,2,4]oxadiazolidine]-6-yl)benzonitrile TFA salt (8 mg). MS ESI +ve m/z 421 (M+H) + . 1 H NMR (400 MHz, CD 3 OD): 7.90 (d, J=1.2 Hz, 1H), 7.87 (m, 1H), 7.66 (m, 2H), 7.61-7.56 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 4.12-3.85 (m, 4H), 3.09 (s, 3H), 2.42 (d, J=14.4 Hz, 1H), 2.01-1.43 (m, 1H), 1.47 (s, 3H), 1.43 (s, 3H).

3-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 132)

Anhydrous aluminum chloride (84 g, 0.486 mol) is suspended in methylene chloride (1200 mL), and then acetyl chloride (49.2 g, 0.629 mol) is added while stirring and cooling on ice. The mixture is stirred for 20 minutes while cooling on ice and 4-bromophenol (98 g, 0.57 mol) is added. The reaction mixture is stirred at room temperature for 1 h, and then ice water is added and extraction is performed with ethyl acetate. The organic layer is washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by silica gel column chromatography to yield acetic acid 4-bromo-phenyl ester (104 g, 85%).

1 H-NMR (CDCl 3 ): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).

A mixture of 4-bromophenyl acetate (104 g, 0.484 mol) and anhydrous aluminum chloride (130.5 g, 0.968 mol) is stirred at 120-140° C. for 20 minutes. The reaction mixture is cooled to 60-80° C., ice water is added and extraction is performed with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by silica gel column chromatography to yield thel-(5-bromo-2-hydroxy-phenyl)-ethanone (101 g, 98%).

1 H-NMR (CDCl 3 ): 2.60 (s, 3H), 6.87 (d, 1H), 7.53 (dd, 1H), 7.81 (s, 1H), 12.12 (s, 1H).

A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (21.4 g, 0.1 mol), acetone (365 mL) and pyrrolidine (8.4 mL) in toluene (220 mL) is refluxed for 4 h. To the reaction mixture is added acetone (36.5 mL), the mixture is refluxed for 15 h. Then 1 N HCl (220 mL) is added, extracted with ethyl acetate (200 mL 3×). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18 g, 71%).

1 H-NMR (CDCl 3 ): 1.45 (s, 6H), 2.71 (s, 2H), 6.82 (d, 1H), 7.52 (dd, 1H), 7.96 (d, 1H).

A glass pressure tube is charged with a mixture of 6-bromo-2,2-dimethyl-chroman-4-one (6.4 g, 25 mmol), KCN (3.25 g, 50 mmol), and (NH 4 ) 2 CO 3 (18 g, 187.5 mmol). Formamide (80 mL) is added to fill the pressure tube nearly completely. The mixture is heated at 70° C. for 24 h then at 110° C. for another 48 h. The reaction mixture is then cooled and poured over ice. Acidification with concentrated HCl yields a precipitate which is filtered, washed twice with water, and then resolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate is concentrated in vacuo to give a residue, which is purified by column to give 6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (8.2 g, 100%).

1 H-NMR (DMSO): 1.24 (s, 3H), 1.40 (s, 3H), 2.16 (d, 1H), 2.30 (d, 1H), 6.80 (d, 1H), 7.10 (m, 1H), 7.39 (d, 1H), 8.69 (s, 1H), 11.08 (brs, 1H).

6-Bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (4 g, 12.3 mmol) and 1 M Et 3 O.BF 4 (4.7 g, 24.7 mmol) is dissolved in dry CH 2 Cl 2 (100 mL). Then the mixture is heated to reflux for 24 h. The solvent is removed in vacuo to give a residue, which is purified by column to give 6-bromo-2′-ethoxy-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (1 g, 25%).

6-Bromo-2′-ethoxy-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (500 mg, 1.42 mmol) is dissolved in 30 mL of EtOH, and NH 3 .H 2 O (30 mL) is added. The mixture is heated to reflux for 18 h. The mixture is removed in vacuo to give a residue, which is purified by preparative TLC to give 2′-amino-6-bromo-2,2-dimethylspiro-[chroman-4,4′-imidazol]-5′(3′H)-one (120 mg, 30%).

NaH (5.3 mg, 0.131 mmol) is added to a solution of 2′-amino-6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (45 mg, 0.131 mmol) in THF (3 mL) at 0° C. under N 2 . The mixture is stirred for 1 h at room temperature. Then MeI (18.6 mg, 0.131 mmol) is added. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is concentrated in vacuo. The residue is purified by preparative TLC to give 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 80%).

1 H-NMR (MeOD): 1.3 (s, 3H), 1.40 (s, 3H), 1.85 (d, 1H), 2.25 (d, 1H), 3.1 (s, 3H), 6.65 (d, 1H), 6.8 (s, 1H), 7.20 (s, 1H).

Pd(PPh 3 ) 4 (15.13 mg, 0.013 mmol) is added to the solution of 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (44.15 mg, 0.13 mmol) and 3-cyanophenylboronic acid (19.25 mg, 0.13 mmol) in dimethyl-benzene (5 mL) and an aqueous solution of Na 2 CO 3 (2 M, 0.24 mL). The mixture is heated at 90° C. in an oil bath overnight. The mixture is concentrated to give the crude product, which is purified by preparative TLC to give the desired product 3-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 15%).

1 H-NMR (MeOD): 2.1 (s, 6H), 3.30 (s, 3H), 4.0 (s, 2H), 7.7 (t, 2H), 7.9 (d, 2H), 8.1 (d, 2H), 8.3 (s, 1H).

2′-amino-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Comp. 133)

A mixture of 1-(2-hydroxyphenyl)ethanone (30 g, 220 mmol), benzaldehyde (23.3 g, 220 mmol) and borax (84 g, 220 mmol) in ethanol (180 mL) and H 2 O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H 2 O, and extracted with ether. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and evaporated. The residue was purified by column to give 2-phenylchroman-4-one (20 g, 40%).

A glass pressure tube is charged with a mixture of 2-phenylchroman-4-one (8 g, 35.7 mmol), KCN (4.64 g, 71.4 mmol), and (NH 4 ) 2 CO 3 (25.7 g, 267.7 mmol). Formamide (100 mL) is added to fill the pressure tube nearly completely. The mixture is heated at 70° C. for 24 h then at 110° C. for another 48 h. The reaction mixture is then cooled and poured over ice. Acidification with concentrated HCl gives a precipitate which is filtered, washed twice with water, and then resolved in ethyl acetate, dried over Na 2 SO 4 , and filtered. The filtrate is concentrated in vacuo to give a residue, which is purified by column to give 2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (2 g, 20%).

A suspension of 2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 2.04 mmol) and Lawesson's Reagent (825 mg, 2.04 mmol) in dry 1,4-dioxane (28 mL) is heated under reflux for 24 h. The mixture is concentrated in vacuo and the residue is purified by column to give 2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (300 mg, 50%).

To a solution of 2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (200 mg, 0.645 mmol) in MeOH (10 mL) is added a solution of NaOH (51.6 mg, 1.29 mmol) in H 2 O (2 mL). After stirring for 10 minutes, MeI (922 mg, 6.45 mmol) is added. The reaction mixture is heated under reflux for 2 h. The mixture is concentrated in vacuo to give a residue, which is purified by preparative TLC to give 1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 30%).

A solution of 1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 0.148 mmol) and NH 4 I (42.9 mg, 0.296 mmol) in NH 3 /EtOH (4 mL, 1.5 N) is heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture is concentrated in vacuo to give a residue, which is purified by preparative TLC to afford 2′-amino-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 10%).

1 H-NMR (MeOD): 2.0 (d, 1H), 2.35 (t, 1H), 3.0 (s, 3H), 5.2 (d, 0.376H), 5.75 (d, 1H), 6.78 (m, 2H), 6.99 (d, 1H), 7.16 (t, 1H), 7.2 (m, 3H), 7.4 (m, 2H).

Compound 134

To a 50 mL round bottom flask is added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by 4-tert-butylcyclohexanone (1.43 g, 9.3 mmol). MeOH (20 mL) is added to give a clear solution, followed by pyrrolidine (1 mL). A condenser is attached to the RB flask, and the resulting solution is heated at 60° C. for two hours. MeOH is removed and the residue is redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL), and 1 N HCl (10 mL), and dried over Na 2 SO 4 . Solvent is removed in vacuo to give 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.41 g, 74%), which is used for the next step without purification.

A 10 mL CEM microwave test tube is filled with a mixture of 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (0.4 g, 1.1 mmol), KCN (0.15 g, 2.2 mmol), and (NH 4 ) 2 CO 3 (0.8 g, 7.7 mmol). A 2:1 mixture of formamide and DMF (6.5 to 7 mL) is added to fill the test tube nearly completely. The resulting mixture is heated in a CEM microwave reactor at 65° C. for 5 hrs. Another 4 tubes (total 1.87 g) are irradiated under the same conditions, and the resulting mixture is combined, acidified with concentrated HCl, diluted with EtOAc (20 mL), and washed with H 2 O (10 mL×3). The organic layer is dried over Na 2 SO 4 , and solvent is removed in vacuo to give a crude product, which is purified by flash chromatography column (0 to 60% EtOAc/hexane) to give the hydantoin 134ii (42 g, 26% corrected for recovered starting material 0.52 g). MS m/z 421 (M+H + ).

To a solution of the above hydantoin (0.42 g, 1.0 mmol) in 1,4-dioxane (5 mL) in a 10 mL CEM microwave test tube, there is added Lawesson's reagent (0.40 g, 1.0 mmol). The resulting mixture is heated in a CEM microwave reactor at 110° C. for 30 min and cooled to rt. The solvent is removed in vacuo, and the residue is purified by flash chromatography column to give the thiol-hydantoin 134iii (0.35 g, 81%). MS m/z 437 (M+H + ).

To a solution of the above thio-hydantoin (100 mg, 0.23 mmol) in MeOH (2 mL) in a 10 mL CEM microwave test tube, there is added a 0.6 N NaOH aqueous solution (0.5 mL). After stirring at rt for 10 min, MeI (0.5 mL, excess) is added and the reaction mixture is heated in a CEM microwave reactor at 60° C. for 10 min. The resulting mixture is concentrated in vacuo to give the crude product, which is purified by flash chromatography column to give the dimethy thiol-hydrantoin 134iv (25.5 mg, 24%). MS m/z 465 (M+H + ).

To a solution of the above dimethylated thiol-hydantoin (25.5 mg, 0.05 mmol) in NH 3 /MeOH (7 N, 1 mL) in a CEM microwave test tube, there is added NH 4 I (24 mg, 0.15 mmol). The resulting mixture is heated in a CEM microwave reactor at 110° C. for 3 hrs. After the reaction is done, the mixture is concentrated in vacuo to give the crude product, which is purified by reversed phase HPLC to give the acyl-guanidine 134v (23 mg, 84%) as a TFA salt. MS m/z 434 (M+H + ).

To a solution of the above acyl-guanidine (23 mg, 0.04 mmol) in 1,4-dioxane (1 mL) there is added excess amount of Cs 2 CO 3 , 3-cyanophenylboronic acid, and catalytical amount of 1,1′-Bis(diphenylphosphino)ferrocene palladium dichloride. After degassing, the resulting mixture is heated in a CEM microwave reactor at 120° C. for 30 min. Solvent is removed in vacuo and the residue is purified by reversed phase HPLC to give the final product compound 134 (2.5 mg, 11%) as a TFA salt.

1 H NMR (400 MHz, CD 3 OD): 8.16-7.84 (m, 2 H), 7.78-7.64 (m, 3 H), 7.52 (s, 1 H), 7.14 (m, 1 H), 3.38 (s, 3 H), 3.20, 3.14 (two s, 2 H), 2.80-2.10 (m, 3 H), 1.98-1.10 (m, 6 H), 0.98 (s, 9 H); MS m/z 457 (M+H + ).

3-(2′-Amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Cmpds. 135a and 135b)

To a solution of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (440 mg, 1.18 mmol) in 1,4-dioxane (3.6 mL) in a 10 mL CEM microwave test tube, there is added Lawesson's reagent (477 mg, 1.18 mmol). The resulting mixture is heated in a CEM microwave reactor at 110° C. for 40 min and cooled to rt. The solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (238 mg, 52%). MS m/z 389 (M+H + ).

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (110 mg, 0.28 mmol) in MeOH (5 mL) in a 10 mL CEM microwave test tube is added a 0.6 N NaOH aqueous solution (1.0 mL). After stirring at rt for 10 min, MeI (158 mg, 1.08 mmol) is added, and the reaction is continued with stirring at rt for 2 hrs. Upon removing the solvent in vacuo, the residue is purified by flash chromatography column to give 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (63.3 mg, 39%). MS m/z 569 (M+H + ).

To a solution of 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1:1, 2 mL) in a 10 mL CEM microwave test tube is added NH 4 I (50 mg, 0.34 mmol) and NH 3 /MeOH (7 N, 2 mL). The resulting mixture is heated in a CEM microwave reactor at 120° C. for 60 min. The cooled mixture is concentrated in vacuo and the residue is purified by a reversed HPLC to give 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H + ).

To a solution of 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 0.04 mmol) in 1,4-dioxane (1.5 mL) there is added Cs 2 CO 3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl 2 dppf. After degassing, the resulting mixture is heated in a CEM microwave reactor at 130° C. for 30 min. Solvent is removed in vacuo and the residue is purified by reversed phase HPLC to give 3-((2R,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (6.0 mg, 33%) as a TFA salt (135a) and 3-((2S,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (0.86 mg, 4.8%) as a TFA salt. (135b).

1 H NMR (400 MHz, CD 3 OD): 7.84-7.60 (m, 4 H), 7.74-7.24 (m, 12 H), 7.12 (d, 1 H), 5.92 (d, 1 H), 4.62 (s, 2 H), 2.60 (d, 1 H), 2.42 (d, 1 H); MS m/z 485 (M+H + ) (135a).

1 H NMR (400 MHz, CD 3 OD): 7.74-7.36 (m, 16 H), 7.16 (d, 1 H), 5.24 (d, 1 H), 5.08, 5.00 (two d, 2 H), 2.64 (d, 1 H), 2.56 (d, 1 H); MS m/z 485 (M+H + ) (135b).

Compound 136

To a solution of the 4-N-Boc-piperidinyl-spiro-hydantoin (167.3 mg, 0.36 mmol) in 1,4-dioxane (4.5 mL) in a 10 mL CEM microwave test tube, there is added Lawesson's reagent (144.0 mg, 0.36 mmol). The resulting mixture is heated in a CEM microwave reactor at 150° C. for 40 min and cooled to rt. The solvent is removed in vacuo to give a crude thiol-4-piperidinyl-spiro-hydantoin, which is used for the next step without purification. MS m/z 382 (M+H + ).

To a solution of the above crude product in MeCN/H 2 O (3:1, 1 mL) there is added K 2 CO 3 (excess) followed by acetyl chloride (excess). The resulting solution is stirred at rt for 10 min, and solvent is removed in vacuo. The residue is purified by reversed phase HPLC to give the thio-4-N-acyl-piperidinyl-spiro-hydantoin (80 mg, 52% two steps). MS m/z 424 (M+H + ).

To a solution of the thio-4-N-acyl-piperidinyl-spiro-hydantoin (80 mg, 0.19 mmol) in MeOH (6 mL) in a 10 mL CEM microwave test tube, there is added a 0.6 N NaOH aqueous solution (1.0 mL). After stirring at rt for 10 min, MeI (100 μL, excess) is added, the reaction mixture is stirred at rt for 30 min, and then heated in a CEM microwave reactor at 60° C. for 20 min. The resulting mixture is concentrated in vacuo to give crude dimethylated thiol-4-N-acyl-piperidinyl-spiro-hydantoin, which is used for the next step without purification. MS m/z 452 (M+H + ).

To a solution of the dimethylated thiol-4-N-acyl-piperidinyl-spiro-hydantoin (0.19 mmol) in MeOH (1 mL) in a 10 mL CEM microwave test tube, there is added NH 4 I (excess) and NH 3 /MeOH (7 N, 1.5 mL). The resulting mixture is heated in a CEM microwave reactor at 120° C. for 30 min. Upon cooling, solvent is removed in vacuo and the residue is purified by a reversed phase HPLC to give 4-N-acyl-piperidinyl-spiro-acyl-guanidine (20 mg, 25%) as a TFA salt. MS m/z 421 (M+H + ).

To a solution of 4-N-acyl-piperidinyl-spiro-acyl-guanidine (20 mg, 0.05 mmol) in 1,4-dioxane (1.5 mL) there is added Cs 2 CO 3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl 2 dppf. After degassing, the resulting mixture is heated in a CEM microwave reactor at 120° C. for 30 min. Solvent is removed in vacuo and the residue is purified by a reversed phase HPLC to give the 4-N-acyl-piperidinyl-spiro-acyl-guanidine final product compound 136 (7.0 mg, 32%) as a TFA salt.

1 H NMR (400 MHz, CD 3 OD): 7.94 (m, 1 H), 7.86 (m, 1 H), 7.66 (m, 2 H), 7.60 (m, 1 H), 7.48 and 7.40 (two d, 1 H), 7.16 (m, 1 H), 3.34 (m, 1 H), 3.86-3.40 (m, 3 H), 3.22 (m, 1 H), 3.10, 3.06 (two s, 3 H), 2.56, 2.40 (two m, 2 H), 2.20-1.96 (m, 5 H), 1.90-1.62 (m, 2 H); MS m/z 444 (M+H + ).

4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (Compound 137)

Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar 2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(2-(dimethylamino) ethylcarbamoyl)phenylboronic acid (25 mg, 0.104 mmol). The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (4.68 mg, 18%). 1 H-NMR (MeOD): 2.47 (m, 1H), 2.63 (m, 1H), 3.01 (s, 6H), 3.30 (s, 3H), 3.42 (m, 2H), 3.79 (m, 2H), 5.88 (m, 1H), 7.17 (m, 1H), 7.39 (m, 1H), 7.46 (m, 2H), 7.52 (m, 2H), 7.58 (m, 1H), 7.71 (m, 1H), 7.76 (m, 2H), 7.96 (m, 2H).

3-(2′-amino-5′-oxo-2-phenyl-1′-(2,2,2-trifluoroethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 138)

Experimental Data

Combine 2,2,2-trifluoro-ethanol (6.2 mL), pyridine (6.8 mL) and CH 2 Cl 2 (20 mL) cooled in an ice bath. Add Tf 2 O (25 g) over about 45 minutes. After 15 minutes, add water, separate the layers and extract with water. The organic layer was dried over Na 2 SO 4 and concentrated through a short path distillation apparatus (8 g, 54%).

Step 2: 6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)-2′-(2,2,2-trifluoroethylthio)spiro [chroman-4,4′-imidazol]-5′(1′H)-one

To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (113 mg, 0.29 mmol) in DMF (7 mL) was added Cs 2 CO 3 (190 mg, 0.58 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (204 mg, 0.87 mmol). After stirring for 2 days, the mixture was extracted from water with EtOAc. The combined organic layers were washed with water and brine, dried and then concentrated to give the residue, which was purified by preparative TLC to give 6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)-2′-(2,2,2-trifluoroethylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 36%).

A solution of 6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)-2′-(2,2,2-trifluoroethylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg), NH 4 I (10 mg) in a solution of NH 3 /EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 61%).

Step 4: 3-(2′-amino-5′-oxo-2-phenyl-1′-(2,2,2-trifluoroethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with 2′-amino-6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.044 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 M, 0.3 mL) and 3-cyanophenylboronic acid (13 mg, 0.088 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3-(2′-amino-5′-oxo-2-phenyl-1′-(2,2,2-trifluoroethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (3.7 mg, 12%). 1 H-NMR (MeOD): 2.27 (m, 1H), 2.35 (m, 1H), 3.87 (m, 2H), 5.83 (m, 1H), 7.01 (d, 1H), 7.26(m, 1H), 7.32 (m, 5H), 7.59 (m, 3H), 7.76 (m, 1H), 7.81 (m, 1H).

2′-amino-6-(4-(benzyloxy)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (Compound 139)

Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar 2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(benzyloxy)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 2′-amino-6-(4-(benzyloxy)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.75 mg, 7%). 1 H-NMR (MeOD): 2.46 (m, 1H), 2.59 (m, 1H), 3.29 (s, 3H), 5.12 (s, 2H), 5.83 (m, 1H), 7.04 (m, 2H), 7.09 (m, 1H), 7.31 (m, 1H), 7.38 (m, 4H), 7.45 (m, 4H), 7.50 (m, 4H), 7.56 (m, 1H).

2′-methyl-3′-(phenoxyamino)-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (Compound 140)

Experimental Data

To a solution of 6-(benzylox)-2-phenylchroman-4-one (211.2 mg, 0.64 mmol) in anhydrous DCM (5 mL) was added TiCl 4 (1 M solution in DCM, 1.3 mL, 1.3 mmol) dropwise with in 15 minutes at room temperature. It was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (262 mg, 0.32 mL, 1.408 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (25 g), extracted with DCM (3×15 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and then concentrated to give (E)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (140 mg, 83%), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (28 mg, 0.326 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25 wt. % in MeOH, 15.83 mg, 0.294 mmol), followed by (E)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (86 mg, 0.326 mmol). After stirred 10 minutes, the solvent was removed in vacuum. The residue was dissolved in DCM (15 mL) and filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC to give 3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (20 mg, 20%). 1 HNMR(CDCl 3 ): 7.30-7.51 (m, 5H), 6.95 (s, 1H), 6.69 (m, 2H), 5.15 (t, 3H), 2.98 (s, 3H), 2.28 (d, 2H), 1.17 (s, 1H).

Step 3: 6-(benzyloxy)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine and 2′-Methyl-3′-(phenoxyamino)-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol

A mixture of 3′ amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-6-ol (30 mg, 0.096 mmol), (bromomethyl)benzene (21.45 mg, 0.125 mmol) and K 2 CO 3 (16 mg, 0.115 mmol) was dissolved in acetone, then the mixture was stirred at room temperature for 24 hours. The mixture was filtrated and concentrated. The residue was purified by preparative HPLC to give 6-(benzyloxy)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]3′-amine (140) (0.95 mg, 3%). 1 H-NMR (MeOD): 7.32-7.56 (m, 10H), 6.91-7.23 (m, 3H), 5.12 (d, 2H), 5.23 (t, 2H), 3.31 (s, 3H) 2.73 (m, 1H), 2.32 (m, 1H);

2′-methyl-3′-(phenoxyamino)-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (1.05 mg, 3%). 1 H-NMR (MeOD): 7.32 (s, 6H), 7.20 (s, 2H), 7.06 (s, 2H), 6.83 (d, 1H), 6.74 (t, 2H), 4.91 (d, 1H), 4.25 (d, 1H), 3.36 (s, 3H), 2.37 (d, 2H), 1.86 (t, 3H)

6-bromo-2′-methyl-2-(gyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 142)

Experimental Data

In a bottle were combined 1-(5-bromo-2-hydroxy-phenyl)-ethanone (12 g, 56 mmol), pyridine-2-carbaldehyde (5.4 mL, 56 mmol), EtOH (96%, 67 mL) and NaOH (19.75 g, 494 mmol). The mixture was stirred vigorously for 0.5 h and then filtered. The mixture was poured into HCl (1 N, 500 mL) and filtered. The solid was dried to give 1-(5-bromo-2-hydroxy-phenyl)-3-pyridin-2-yl-propenone (10 g, 59%).

1-(5-Bromo-2-hydroxy-phenyl)-3-pyridin-2-yl-propenone (13 g, 43 mmol) was dissolved in H 2 O (321 mL) and EtOH (107 mL). Then NaOH (1.72 g, 43 mmol) was added. The mixture was stirred overnight and filtered. The cake was dissolved in EtOAc and washed with H 2 O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-pyridin-2-yl-chroman-4-one (2.22 g, 17%). 1 H-NMR (CDCl 3 ): 3.14 (m, 2H), 5.57 (m, 1H), 6.98 (m, 1H), 7.29 (m, 1H), 7.57 (m, 1H), 7.76 (m, 1H), 8.00 (m, 1H), 8.61 (m, 1H).

To a solution of 6-bromo-2-pyridin-2-yl-chroman-4-one (303 mg, 1 mmol) in DCM (10 mL) was added TiCl 4 (4 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.5 mL, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CHCl 2 , which was combined with the organic layer. The organic layer was dried and concentrated to give crude 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (300 mg, 92%).

To a solution of N-methyl-hydroxylamine hydrochloride (31 mg, 0.31 mmol) in MeOH (4 mL) was added MeONa (0.06 mL, 25% (Wt.) in MeOH), followed by 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (100 mg, 0.31 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (45 mg, 40%). 1 H-NMR (MeOD): 2.13 (m, 1H), 2.48 (m, 1H), 3.08 (m, 3H), 5.32 (m, 1H), 6.86 (m, 1H), 7.36 (m, 2H), 7.51 (m, 1H), 7.68 (m, 1H), 7.90 (m, 1H), 8.52 (m, 1H.).

6-bromo-2′-methyl-2-(pyridine-3-yl)-2′H-spiro-[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 143)

Experimental Data

To a solution of 6-bromo-2-(pyridine-3-yl)chroman-4-one (1.0 g, 3.3 mmol) in anhydrous DCM (20 mL) was added TiCl 4 (1 M solution in DCM, 2.5 g, 13.2 mmol) dropwise within 15 minutes at room temperature in absence of light. It was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.35 g, 7.26 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 64%), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (176 mg, 2.1 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25% in MeOH (Wt. %), 0.47 mL, 1.89 mmol), followed by (E)-N-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 2.1 mmol). After stirred for 10 mins, the solvent was removed in vacuo. The residue was redissolved in DCM (15 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridine-3-yl)-2′H-spiro-[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (190 mg, 24%). 1 H-NMR (MeOD): 2.18-2.25 (m, 1H), 2.39 (m, 1H), 3.09 (s, 3H), 5.34-5.38 (m, 1H), 6.81-6.86 (t, 1H), 7.37-7.40 (m, 1H), 7.45-7.55 (m, 1H), 7.62 (s, 1H), 7.97-7.99 (m, 1H), 8.52-8.54 (m, 1H), 8.66 (d, 1H).

8-chloro-2′-methyl-2′H,11H-spiro[dibenzo[b,f]oxepine-10,5′-[1,2,4]oxadiazol]-3′-amine (Compound 144)

Experimental Data

To a solution of 2-(2-bromophenyl)acetic acid (2 g, 9.3 mmol) in anhydrous methanol (20 mL) was added 4-methylbenzenesulfonic acid hydrate (1.767 g, 9.3 mmol). The mixture was heated to reflux for 3 hr. The solvent was removed in vacuum. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated to give methyl 2-(2-bromophenyl)acetate (2 g, 80%), which was used for next step without purification.

2-(2-Bromophenyl)acetate (10 g, 43.7 mmol) and 4-chlorophenol (5.61 g, 43.7 mmol) were dissolved in dioxane (150 mL) whiling warming to 50° C. To the resulting solution were added, under stirring in an inert nitrogen atmosphere, cesium carbonate (28.35 g, 87.4 mmol) and copper (I) chloride (1.73 g, 17.48 mmol). Finally N,N-dimethylglycine (0.9 g, 8.74 mmol) was added to the green suspension. The mixture was heated at 110° C. for 2 days while stirring. The mixture was filtrated over dicalite, which was washed with dioxane (20 mL). The dioxane was removed in vacuum to leave brownish oil. EtOAc was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCl. The organic phase was washed with saturated brine, dried over Na 2 SO 4 and concentrated under vacuum to yield the crude product, which was purified by column chromatography to give 2-(2-(4-chlorophenoxy)phenyl)acetic acid (8 g, 70%).

The solution of 2-(2-(4-chlorophenoxy)phenyl)acetic acid (2.1 g, 8 mmol) and PPA (21 g, 148 mmol) was heated to reflux overnight. Then the mixture was and the filtrate was removed in vacuo, dissolved in CH 2 Cl 2 , filtrated. The solvents were evaporated to give the crude product, which was purified by column chromatography to give 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (1.7 g, 80%).

To a solution of 8-chlorodibenzo[b,f]oxepin-10(11H)-one (732 mg, 3.84. mmol) in anhydrous DCM (30 mL) was added TiCl 4 (1 M solution in DCM, 7.8 mL, 7.8 mmol) dropwise within 15 minutes at room temperature. It was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.48 g, 1.89 mL, 8.46 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g), extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated to give (E)-N-(8-chlorodibenzo[b,f]oxepin-10(11H)-ylidene)cyanamide (500 mg, 68%), which was used for next step without further purification.

To a solution of methylhydroxylamine HCl salt (50.16 mg, 0.6 mmol) in anhydrous MeOH (6 mL) was added NaOMe (25% in MeOH (Wt. %), 0.12 mL, 0.54 mmol), followed by (E)-N-(8-chlorodibenzo[b,f]oxepin-10(11H)-ylidene)cyanamide (160 mg, 0.6 mmol). After stirred 10 min, the solvent was removed in vacuum. The residue was redissolved in DCM (10 mL) The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give compound 144 (100 mg, 80%). 1 H-NMR (CDCl 3 ): 3.20 (m, 2H), 3.48 (m, 2H), 1.95 (m, 1H), 3.51 (m, 1H), 7.12 (m, 1H), 7.18 (m, 3H), 7.22 (m, 2H), 7.32 (m, 1H), 7.48 (m, 1H).

6-bromo-7-fluoro-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (Compound 146)

Experimental Data

A mixture of 4-bromo-3-fluorophenyl acetate (30 g, 0.13 mol) and AlCl 3 (34.32 g, 0.26 mol) was stirred at 120-140° C. for 2 h. The reaction mixture was cooled to 60-80° C. and ice-water was added and extraction was performed with EtOAc. The organic layer was washed with brine, dried and concentrated to give the residue, which was purified by column chromatography to give 1-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (20 g, 67%). 1 H-NMR (CDCl 3 ): 2.61 (s, 3H), 6.76 (d, 1H), 7.92 (d, 1H), 12.41 (s, 1H).

In a bottle were combined 1-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (8.63 g, 37.15 mmol), benzaldehyde (3.94 g, 37.15 mmol), EtOH (96%, 45 mL) and NaOH (13.08 g, 327 mmol). The mixture was stirred vigorously for 0.5 h. and then filtered. The mixture was poured into HCl (1 N, 50 mL) and filtered. The solid was dried to give 1-(5-bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 91%).

1-(5-Bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 33.75 mmol) was dissolved in H 2 O (252 mL) and EtOH (84 mL). Then NaOH (1.35 g, 33.75 mmol) was added. The mixture was stirred overnight and filtered. The cake was dissolved in EtOAc and washed with H 2 O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-7-fluoro-2-phenylchroman-4-one (5.8 g, 54%). 1 H-NMR (CDCl 3 ): 2.85 (m, 1H), 3.04 (m, 1H), 5.43 (m, 1H), 6.78 (m, 1H), 7.37 (m, 5H), 8.07 (m, 1H).

To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (400 mg, 1.25 mmol) in DCM (10 mL) was added TiCl 4 (2.5 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N-methanediylidenebis(1,1,1-trimethylsilanamine) (0.62 mL, 2.75 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CH 2 Cl 2 , which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide (327 mg, 78%). 1 H-NMR (CDCl 3 ): 3.19 (m, 1H), 3.49 (m, 1H), 5.34 (m, 1H), 6.81 (d, 1H), 7.41 (m, 5H), 8.27 (d, 1H).

To a solution of N-methyl-hydroxylamine hydrochloride (35 mg, 0.355 mmol) in MeOH (5 mL) was added MeONa (0.07 mL, 25% (Wt.) in MeOH), followed by N-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide (122 mg, 0.355 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-7-fluoro-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (30 mg, 30%). 1 H-NHR (MeOD): 2.18 (m, 1H), 2.33 (m, 1H), 3.08 (d, 3H), 5.28 (m, 1H), 6.75 (m, 1H), 7.38 (m, 5H), 7.61 (m, 1H).

Compound 148

Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar 2 was treated sequentially with the amine 117i (52 mg, 0.14 mmol) in [1,4]dioxane (2 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 3-butoxyphenylboronic acid (51 mg, 0.28 mmol). The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give pure final product (6.50 mg, 10%). 1 H-NMR (MeOD): 1.01 (m, 3H), 1.32 (m, 1H), 1.53 (m, 2H), 1.79 (m, 2H), 1.87-2.05 (m, 4H), 2.95 (m, 1H), 3.35 (m, 3H), 3.63 (m, 2H), 3.76-3.87 (m, 2H), 4.04 (m, 2H), 6.87 (m, 1H), 7.12 (m, 3H), 7.35 (m, 1H) 7.50 (m, 0.5H), 7.68 (m, 0.5H.), 7.82 (m, 1H).

3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile (Compound 153)

Experimental Data

4-Bromo-phenol (172 g, 1 mol), 4-bromo-butyric acid ethyl ester (212 g, 1.1 mol) and K 2 CO 3 (250 g, 1.8 mol) was dissolved in DMF (1000 mL), the mixture was stirred at room temperature overnight. the solvent was removed and water was added to the residue, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over Na 2 SO 4 the solvent was removed, to the residue was added NaOH (3M, 1000 mol) and CH 3 OH (600 mL), the mixture was stirred at 70° C. for 30 minutes and concentrated, the residue was dissolved in H 2 O and the mixture was washed with diethylether, the aqueous layer was acidified with HCl, and the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 concentrated to give crude 4-(4-bromophenoxy)butanoic acid (239 g, 98%).

4-(4-Bromophenoxy)butanoic acid (39 g, 25.6 mmol) was dissolved in SOCl 2 (100 ml) mixture was heated to refluxed overnight. the mixture was concentrated in vacuo to give 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 67%).

A solution of 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 100 mmol) in DCM (200 mL) was added dropwise to a solution of AlCl 3 (50 g, 0.38 mol) in DCM (100 mL) at 0° C. within 40 minutes, the mixture was stirred at 0° C. for 1.5 hours, and then stirred at room temperature overnight. the mixture was added to a stirred mixture of concentrated hydrochloric (500 mL) and ice, and then stirred for 1.5 hours. The mixture was extracted with DCM, washed with NaHCO 3 , dried over Na 2 SO 4 and concentrated to give crude 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (25 g, 96%).

To a 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (3 g, 12.6 mmol) and triethylamine (10 mL, 18.9 mmol) in DCM (100 mL) was added tert-butyldimethyl(trifluoromethylsulfonyl) silane (3.06 g, 12.4 mmol) dropwise under argon at room temperature, the mixture was stirred for 1 hour at room temperature. The mixture was washed with NaHCO 3 , dried over Na 2 SO 4 , concentrated to give crude (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dim ethylsilane (3.40 g, 81%).

2,4,6-Collidine (5.6 ml), DDQ (9.0 g, 40 mmol) and (7-bromo-2,3-dihydrobenzo [b]oxepin-5-yloxy)(tert-butyl)dimethylsilane was dissolved in toluene, the mixture was stirred for 5.5 hours at room temperature. the mixture was concentrated in vacuo and then purified by column chromatography to give 7-bromobenzo[b]oxepin-5(2H)-one (4.5 g, 94%). 1 H-NMR (MeOD): 4.71 (m, 2H), 6.38 (m, 1H), 6.76 (m, 1H), 6.99 (m, 1H), 7.54 (m, 1H), 8.06 (m, 1H).

To a solution of 7-bromobenzo[b]oxepin-5(2H)-one (1.33 g, 5.6 mmol), CuBr—SMe 2 (60 mg, 0.3 mmol) and HMPA (2.058 g, 11.5 mmol) in THF (30 mL) was added phenylmagnesium bromide (3.0 M, 3.7 mL) at −78° C., the mixture was stirred at −78° C. for 1 hour. The mixture was quenched by HCl (10%, 5 mL), extracted with ethoxyethane, and then washed with NaHCO 3 , brine, dried over Na 2 SO 4 , concentrated and purified by column chromatography to give 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (300 mg, 17%). 1 H-NMR(CH 2 D 2 ): 3.11 (m, 2H), 3.49 (m, 1H), 4.28 (m, 2H), 6.93 (m, 1H), 7.17 (m, 1H), 7.23 (m, 4H), 7.45 (m, 1H), 7.83 (m, 1H)

To a solution of 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (158 mg, 0.5 mmol) in DCM (5 mL) was added TiCl 4 (1 mL, 1 M in CH 2 Cl 2 ) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.25 mL, 1.11 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH 2 Cl 2 , which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (160 mg, 94%).

Step 8. 7-bromo-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazol]-3′-amine

To a solution of N-methyl-hydroxylamine hydrochloride (42 mg, 0.5 mmol) in MeOH (10 mL) was added MeONa (0.1 mL, 25% (Wt.) in MeOH), followed by N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (170 mg, 0.5 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (140 mg, 72%).

Step 9. 3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile

Pd(PPh 3 ) 2 Cl 2 (3 mg, 0.003 mmol) in a 10 mL of flask under Ar 2 was treated sequentially with 7-bromo-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazol]-3′-amine (77.4 mg, 0.2 mmol) in [1,4]dioxane (2.0 mL), Cs 2 CO 3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol) The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile (20 mg, 24%). 1 H-NMR (MeOD): 2.67 (m, 2H), 3.48 (m, 3H), 3.65 (m, 1H), 3.88 (m, 0.3H), 4.19 (m, 0.7H), 4.50 (d, 1H), 7.23 (m, 6H), 7.66 (m, 3H), 7.81 (m, 1H), 8.02 (m, 3H).

Compound 154

Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with 1 (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (29 mg, 0.2 mmol). The mixture was heated under microwave at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give the target molecule compound 154 (11 mg, 10%). 1 H-NMR (MeOD): 1.80 (m, 1H), 2.01 (s, 3H), 2.23 (m, 2H), 2.74 (m, 1H), 3.05 (m, 1H), 3.39 (m, 3H), 3.61 (s, 2H), 3.92 (m, 1H), 4.34 (m, 1H), 7.02 (m, 1H), 7.64 (m, 2H), 7.92 (m, 2H).

3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 155)

A solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (1.858 g, 13.08 mmol), 5′-bromo-2-hydroxy-acetophone (2.813 g, 13.08 mmol) in MeOH (30 mL) containing pyrrolidine (1 mL) was heated to reflux for 2 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 M NaOH, 1 M HCl, H 2 O and brine successively, and dried, and filtered. The filtrate was concentrated to dryness. The crude product was further purified by flash chromatography on silica gel (40 g, eluted with ethyl acetate in hexane 0-30%) give 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one as a brownish solid (2.32 g). MS ESI +ve m/z 339 (M+H) + .

To a solution of crude 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one (460 mg, 1.36 mmol), 3-cyanophenylboronic acid (299 mg, 2.0 mmol) and Cs 2 CO 3 (866 mg, 2.72 mmol) in 1,4-dioxane (5 mL) and H 2 O (1 mL) charged in a 10 mL CEM microwave test tube was added PdCl 2 (PPh 3 ) 2 (50 mg), then the system was degassed by sweeping N 2 and capped. Then the mixture was heated to 100° C. for 10 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica eel give (3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg). MS ESI +ve m/z 362 (M+H) + .

Step 3: Preparation of (E)-N-(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide

To a solution of 3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg, 0.69 mmol) in anhydrous DCM (15 mL) under N 2 atmosphere was added 1 M TiCl 4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 5 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (283 mg, 340 μL 1.52 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (20 g), It was transferred to a separating funnel after stirred for 30. The separated aqueous phase was extracted with DCM (2×20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , and filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (276 mg), which was used for next step without further purification. MS ESI +ve m/z 386 (M+H) + .

Step 4: Preparation of 3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile

To a solution of methylhydroxylamine HCl salt (58 mg, 0.69 mmol) in anhydrous MeOH (3 mL) was added NaOMe (25 w % in MeOH, 140 μL, 0.62 mmol), 10 min later, followed by a solution of crude (E)-N-(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yOchroman-4-ylidene)cyanamide obtained in step 3 (276 mg, 0.69 mmol) solution in MeOH (5 mL), After stirred 10 min, the solvent was removed in vacuum. The residue was redissolved in DCM (20 mL) and filtered, and the solvent was removed in vacuum to give crude product, which was purified by preparative HPLC to afford 130 mg of 3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3′-imino-2′-methylspiro[chroman-4,5′-[1,2,4]oxadiazolidine]-6-yl)benzonitrile TFA salt as a white solid. MS ESI +ve m/z 433 (M+H) + . 1 H NMR (400 MHz, CD 3 OD): 8.00-7.92 (m, 3H), 7.74-7.68 (m, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 4.07 (dd, J=12.4, 5.6 Hz, 1H), 3.78 (m, 2H), 3.38, 3.44, 3.43 (s, 3H, several isomers), 2.20 (m, 1H), 2.01 (m, 1H), 1.88 (m, 1H), 1.66 (m, 1H), 1.49-1.32 (m, 2H), 1.29 (s, 3H), 1.26 (m, 3H).

3-(2-Amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (Cmpd. 156)

To a 10 mL CEM microwave test tube charged with 6-bromo-2-phenylthiochroman-4-one (344 mg, 1.08 mmol), KCN (150 mg, 2.2 mmol), and (NH 4 ) 2 CO 3 (800 mg, 7.7 mmol) is added formamide (6.5 mL). The resulting mixture is heated in a CEM microwave reactor at 60° C. for 1.5 hrs, 65° C. for 1.5 hrs, then 70° C. for 2 hrs. The resulting mixture is diluted with EtOAc (20 mL) and washed with H 2 O (3×10 mL). The organic layer is dried over Na 2 SO 4 , and solvent is removed in vacuo to give a crude product, which is purified by flash chromatography column (0 to 60% EtOAc/hexane) to give the 6′-bromo-2′-phenylspiro[imidazolidine-4,4′-thiochroman]-2,5-dione (237 mg). MS ESI +ve m/z 389 (M+H) + .

A solution of 6′-bromo-2′-phenylspiro[imidazolidine-4,4′-thiochroman]-2,5-dione (237 mg, 0.61 mmol) and Lawesson's reagent (246 mg, 0.61 mmol) in 1,4-dioxane (3 mL) in a 10 mL CEM microwave test tube is heated in a CEM microwave reactor at 110° C. for 30 min. After cooled to rt, the solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6′-bromo-2′-phenyl-2-thioxospiro[imidazolidine-4,4′-thiochroman]-5-one (200 mg, 81%). MS ESI +ve m/z 405 (M+H) + .

To a solution of 6′-bromo-2′-phenyl-2-thioxospiro[imidazolidinel-4,4′-thiochroman]-5-one (100 mg, 0.25 mmol) in MeOH (2 mL) charged in a 10 mL CEM microwave test tube is added a 0.6 N NaOH aqueous solution (0.5 mL). After stirring at rt for 10 min, MeI (0.5 mL, excess) is added, and the reaction mixture is heated in a CEM microwave reactor at 60° C. for 10 min. In another 10 mL CEM microwave test tube, the same reaction is repeated with the same amounts of starting material, reagents, and solvent. The resulting mixtures are combined, and diluted with ethyl acetate, and washed with H 2 O and brine successively, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product, which is purified by preparative HPLC to give 6′-bromo-1-methyl-2-(methylthio)-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one (56 mg) MS ESI +ve m/z 433 (M+H) + .

A suspension of 6′-bromo-1-methyl-2-(methylthio)-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one (56 mg, 0.13 mmol) and NH 4 I (100 mg, excess) in 7 M NH 3 /MeOH (4 mL) and 1,4-dioxane (1 mL) charged in a 10 mL CEM microwave test tube is heated to 110° C. for 1 h. The solvent is removed in vacuo and the residue is purified by preparative HPLC to give 2-amino-6′-bromo-1-methyl-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one as TFA salt. MS ESI +ve m/z 402 (M+H) + .

To a solution of 2-amino-6′-bromo-1-methyl-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one TFA salt (70 mg, 0.14 mmol), 3-cyanophenylboronic acid (51 mg, 0.34 mmol), and Cs 2 CO 3 (250 mg) in 1,4-dioxane (4 mL) and H 2 O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl 2 (PPh 3 ) 2 (20 mg). Then the system is degassed by sweeping with N 2 . The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro-[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (30 mg) as a TFA salt. MS ESI +ve m/z 425 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): less polar isomer: 8.00-7.87 (m, 2H), 7.72-7.59 (m, 3H), 7.52-7.33 (m, 7H), 5.26 and 4.65 (dd and dd, 1H), 3.34 and 3.25 (s and s, 3H), 2.84-2.60 (m, 2H); more polar isomer: 7.99-7.87 (m, 2H), 7.72-7.57 (m, 3H), 7.51-7.33 (m, 7H), 5.30 (dd, 1H), 3.34 and 3.08 (s and s, 3H), 2.82-2.63 (m, 2H).

3-(2-Amino-1-methyl-1′,5-dioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (Cmpd 157)

To a solution of 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile TFA salt (27 mg, 0.05 mmol) in MeOH (5 mL) and H 2 O (0.1 mL) is added NaIO 4 (21.4 mg, 0.10 mmol). The resulting mixture is stirred overnight at rt, then purified by preparative HPLC to give 3-(2-amino-1-methyl-1′,5-dioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile TFA salt (16 mg) with 5 mg of recovered starting material. MS ESI +ve m/z 441 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): 8.10-7.41 (m, 12H), 5.20 (dd, 1H), 3.61 (m, 1H), 3.26, 3.25 and 3.11 (s, s and s, 3H), 2.70 (m, 1H).

3-(2-Amino-1-methyl-1′,1′,5-trioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (Cmpd. 158)

A crude product of 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (60 mg, 0.14 mmol) from Suzuki coupling is dissolved in THF (10 mL). To this solution is added TEA (1 mL, excess) and Boc 2 O (250 mg). The resulting mixture is stirred for 12 h at rt and concentrated. The residue is dissolved in ethyl acetate (15 mL), washed with 1 M HCl and brine successively, and dried over Na 2 SO 4 . The solvent is removed in vacuo to give a crude product, which is purified by preparative HPLC to give 3-(N-Boc-2-amino-1-methyl-1′,5-dioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile. MS ESI +ve m/z 525 (M+H) + .

To a solution of 3-(N-Boc-2-amino-1-methyl-1′,5-dioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (5 mg) in DCM (3 mL) at 0° C. is added mCPBA (40 mg, excess). The mixture is stirred for 10 min at 0° C., then it is allowed to warm to rt for 1.5 h. NaHCO 3 (40 mg) is added and evaporated to dryness. The residue is dissolved in MeOH, filtered, and purified by preparative HPLC to give 3-(2-amino-1-methyl-1′,1′,5-trioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile TFA salt (6 mg). MS ESI +ve m/z 457 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): 8.12-7.42 (m, 12H), 5.20 (dd, 1H), 3.59 (m, 1H), 3.32 and 3.21 (s and s, 3H), 2.83 (m, 1H).

Compound 163

Experimental Data

To a solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (60 g, 280 mmol) and pyrrolidine (37.8 g, 532 mmol) in methanol (1200 mL) was added cyclohexanone (55 g, 560 mmol), and the mixture was reflux overnight. The solvent was removed in vacuo, and then added H 2 O and HCl to make the mixture to PH=1, extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (90 g, 100%). 1 H NMR (CDCl 3 ): 1.49 (d, 4H), 1.64 (d, 4H), 1.83 (s, 1H), 1.98 (d, 2H), 2.11 (t, 1H), 2.31 (s, 1H), 2.68 (s, 1H), 6.87 (d, 1H), 7.50 (d, 1H), 7.92 (s, 1H).

The compound of 2-methylpropane-2-sulfinamide (29.54 g, 244.2 mmol) was added the solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (78.97 g, 268.6 mmol) in dry THF (900 mL), and then tetraisopropoxytitanium (193.1 g, 488.3 mmol) was added, The reaction mixture was reflux overnight. The mixture was removed in vacuo, and then quenched by brine, extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfinamide (50 g, 40%). 1 H NMR (CDCl 3 ): 1.30 (s, 10H), 1.51 (m, 5H), 1.62 (m, 4H), 1.83 (d, 2H), 3.07(d, 1H), 3.43 (d, 1H), 5.29 (s, 2H), 6.79 (d, 1H), 7.41 (dd, 1H), 7.96 (d, 1H).

Step 3. methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate

To a solution of methyl acetate (1.86 g, 0.025 mol) in THF (18 mL) was added LDA (2 M in THF) was added dropwise via a syring at −78° C. After stirring at −78° C. for 30 minutes, a solution of (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfonamide (5.0 g, 0.0126 mol) in THF (7.4 mL) was added dropwise via a syring. The mixture was stirring at −78° C. for 3 h. The reaction was quenched with aqueous NH 4 Cl solution and allowed to warming to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the product, which was purified by chromatography to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (1.4 g, 33%). 1 H NMR (CDCl 3 ): 1.23 (s, 9H), 1.36-1.52 (m, 4H), 1.57 (m, 1H), 1.66 (m, 3H), 1.86 (d, 2H), 2.24 (d, 1H), 2.67 (d, 1H), 2.93 (s, 3H), 3.71 (s, 3H), 5.34 (s, 1H), 6.79 (d, 1H), 7.26 (s, 1H), 7.39 (s, 1H).

To a solution of methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro [chroman-2,1′-cyclohexane]-4-yl)acetate (200 mg, 0.42 mmol) in MeOH (2 mL) was added 4 NHCl/1,4-dioxane (2 mL). After stirring for 30 minutes, the mixture was concentrated. The residue was dissolved in MeOH (1 mL) stirring for 5 minutes and evaporated again to afford methyl 2-(4-amino-6-bromospiro[chroman-2,1′-cyclohexane]-4-yDacetate (140 mg, 90%). 1 H NMR (CDCl 3 ): 1.22-1.38 (m, 1H), 1.39-1.52 (m, 6H), 1.72-1.88 (m, 3H), 1.93-2.02 (d, 2H), 2.13-2.24 (t, 1H), 2.59 (d, 1H), 2.86 (d, 1H), 3.65 (s, 3H), 6.74 (d, 1H), 7.24 (s, 1H), 7.52 (s, 1H).

To a solution of methyl 2-(4-amino-6-bromospiro[chroman-2,1′-cyclohexane]-4-yl)acetate (400 mg, 1.09 mmol), EDCI (226 mg, 1.14 mmol) and DIEA (703 mg, 5.45 mmol) in DMF (4 mL) was added the compound 163ii (207 mg, 1.09 mmol), and the resulting mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2 SO 4 , and concentrated to give the crude product, which was purified by preparative TLC to afford the compound 163i (80 mg, 165%). 1 H NMR (CDCl 3 ): 1.38 (s, 2H), 1.42 (s, 9H), 1.53 (m, 5H), 1.76 (m, 3H), 1.91 (d, 1H), 2.13 (d, 1H), 2.68 (d, 1H), 3.03 (d, 1H), 3.31 (s, 3H), 6.73 (d, 1H), 7.29 (d, 1H), 7.43 (s, 1H).

Pd(PPh 3 ) 2 Cl 2 (8 mg) in a 10 mL of flask under Ar 2 was treated sequentially with the compound 1 (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (44 mg, 0.24 mmol). The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and preparative HPLC to give compound 163 (20 mg, 30%). 1 H NMR (MeOD): 1.32-1.71 (m, 7H), 1.78-1.91 (m, 2H), 1.98 (m, 1H), 2.12 (d, 1H), 2.44 (d, 1H), 2.93 (d, 1H), 3.38 (s, 3H), 3.68 (d, 1H), 7.09 (d, 1H), 7.62-7.72 (m, 3H), 7.89-8.03 (m, 3H).

Compound 164

Experimental Data:

A solution of n-BuLi (2.5 M, 3.80 mL) was added to a mixture of PPh 3 •MeI. (4.092 g, 10.13 mmol) in THF at −10° C. The mixture was stirred for 1 h at the same temperature, and then 6-bromo-2-phenylchroman-4-one (2 g, 6.62 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was concentrated and purified by column chromatography to give 6-bromo-4-methylene-2-phenylchroman (400 mg, 20%). 1 H-NMR (CDCl 3 ): 2.76 (m, 2H), 4.90 (d, 1H), 5.01 (m, 1H), 5.48 (d, 1H), 6.76 (d, 1H), 7.31 (m, 6H), 7.62 (d, 1H).

Pd(PPh 3 ) 2 Cl 2 (40 mg) in a 100 mL of flask under Ar 2 was treated sequentially with 6-bromo-4-methylene-2-phenylchroman (200 mg, 0.67 mmol) in [1,4]dioxane (20 mL), Cs 2 CO 3 (2 N, 3.33 mL) and 3-cyanophenylboronic acid (167 mg, 1.13 mmol). The mixture was heated under 120° C. at Ar 2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (110 mg, 51%). 1 H-NMR (CDCl 3 ): 2.81 (m, 2H), 4.96 (d, 1H), 5.10 (m, 1H), 5.61 (d, 1H), 7.98 (d, 1H), 7.29 (m, 1H), 7.35 (m, 3H), 7.41 (m, 2H), 7.46 (m, 1H), 7.52 (m, 1H), 7.72 (m, 2H), 7.79 (d, 1H).

To a solution of 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (50 mg, 0.156 mmol) in CHCl 3 (5 mL) was added I 2 (93 mg, 0.367 mmol), KSCN (76 mg, 0.78 mmol) and catalyst amount t-BtNBr. The mixture was stirred overnight and used directly.

t-BuNH 2 (55 mg, 0.75 mmol) was added to 3-(4-iodomethyl-4-isothiocyanato-2-phenyl-chroman-6-yl)-benzonitrile (190.5 mg, 0.375 mmol) in CHCl 3 above and the mixture was stirred for 20 minutes. The solvent was removed in vacuo to give the residue, which was purified by preparative TLC to give 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (35 mg, 21%).

A mixture of 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (30 mg, 0.066 mmol) in concentrated HCl (5 mL) was stirred at 100° C. for 2 h. Aqueous NaOH (6 N) was added until pH=8. The mixture was extracted with EtOAc and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 73%).

To a solution of 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 0.048 mmol) and DIEA (21 mg, 0.096 mmol) in CH 2 Cl 2 was added TFAA (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (1.53 mg, 8%). 1 H-NMR (MeOD): 2.27 (m, 2H), 3.36 (m, 1H), 3.84 (m, 1H), 5.24 (m, 1H), 6.92 (m, 1H), 7.31 (m, 4H), 7.48 (m, 4H), 7.81 (m, 3H).

3-(2′-Amino-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-6-yl)benzonitrile (Cmpd. 165)

To a solution of 6-bromo-2-phenylchroman-4-one (2.021 g, 6.67 mmol) in anhydrous

THF (35 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 10 mL, 10 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH 4 Cl and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H 2 O, brine, and dried over Na 2 SO 4 , and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-2-phenyl-4-vinylchroman-4-ol as an oil (1.961 g. 89%). MS ESI +ve m/z 313 (M+H—H 2 O) + .

The mixture of 6-bromo-2-phenyl-4-vinylchroman-4-ol (345 mg, 1.04 mmol) and thiourea (97 mg, 1.56 mmol) in HOAc (3 mL) and 1 M HCl (1.2 mL) is heated to 40° C. for 12 h. The solvent is removed under reduced pressure to give a white solid as a mixture of 2-(6-bromo-2-phenylchroman-4-ylidene)ethyl carbamimidothioate HCl salt and thiourea. It is used for next step without purification. MS ESI +ve m/z 313 (M+H-thiourea) + 389 (weak) (M+H) + .

The above mixture of 2-(6-bromo-2-phenylchroman-4-ylidene)ethyl carbamimidothioate HCl salt and thiourea is dissolved in TFA (4 mL) containing MeSO 3 H (0.4 mL) and stirred at rt for 1 h. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with sat NaHCO 3 . The separated aqueous phase is extracted with ethyl acetate once and the combined organic phases are washed with brine, and dried over Na 2 SO 4 , and filtered. The filtrate is concentrated to give crude 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine, which is used for next step without further purification.

MS ESI +ve m/z 389 (M+H) +

1 H NMR (400 MHz, CD 3 OD): less polar isomer: 7.17 (s, 1H), 7.50-6.65 (m 7H), 5.36 and 5.13 (d, 1H), 3.53-1.28 (m, 6H); more polar isomer: 7.41-6.71 (m, 8H), 4.66 and 4.39 (m, 1H), 3.35-2.00 (m, 6H).

The above crude product of 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine is dissolved in THF (5 mL). To this solution is added TEA (1 mL) and Boc 2 O (227 mg, 1.04 mmol). The solution is concentrated after being stirred 2 h at rt. The crude product is purified through flash chromatography on silica gel to afford t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate 415 mg (81% for 3 steps). MS ESI +ve m/z 489 (M+H) + .

A solution of t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate (41 mg, 0.084 mmol), 3-cyanophenylboronic acid (23.5 mg, 0.16 mmol), Cs 2 CO 3 (78 mg, 0.24 mmol), and a catalytic amount of Pd(dppf)Cl 2 in 1,4-dioxane (4 mL) and H 2 O (0.4 mL) is heated at 110° C. in microwave oven for 10 min. Then, 4 mL of 4 M HCl in 1,4-dioxane is added and stirred another 2 h at rt. Water (10 mL) is added and extracted with EA. The separated organic phase is washed with brine, and dried over Na 2 SO 4 , and filtered. The filtrate is concentrated to give a crude product which is purified through preparative HPLC to give 3-(2′-amino-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-6-yl)benzonitrile. MS ESI +ve m/z 412 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): less polar isomer: 8.03 (s, 1H), 7.96 (m 1H), 7.88 (s, 1H), 7.70-7.60 (m, 3H), 7.53-7.52 (m, 2H), 7.46-7.38 (m, 3H), 7.16 (d, 1H), 5.19 (d, 1H), 3.54 (td, 1H), 3.32 (m, 1H), 2.81 (td, 1H), 2.58 (d, 1H), 2.36-2.27 (m, 2H); more polar isomer: 7.41-6.78 (m, 12H), 4.69 (m, 1H), 3.37-3.24, 3.04-2.88, 3.63, 3.42, 2.29-2.15, 1.28 (m, 6H).

2-Phenyl-6-(pyridin-3-yl)-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine (Cmpd. 166)

To a solution of t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate (39 mg, 0.08 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.16 mmol), and Cs 2 CO 3 (120 mg) in 1,4-dioxane (4 mL) and H 2 O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl 2 (PPh 3 ) 2 (20 mg). The system is degassed by sweeping with N 2 . The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 2-phenyl-6-(pyridin-3-yl)-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine (1.7 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): 8.59 (D, 1H), 8.00-7.15 (m, 11H), 5.22 (d, 1H), 3.56 (m, 1H), 3.26 (m, 1H), 2.82 (td, 1H), 2.60 (dd, 1H), 2.38 (m, 1H), 2.32 (m, 1H).

3-(2″-Amino-5″,6″-dihydrospiro[spiro(chroman-2,1′-(4-t-butylcyclohexan))-4,4″-[1,3]thiazine]-6-yl)benzonitrile (Cmpd. 167)

To a solution of 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.155 g, 6.13 mmol) in anhydrous THF (20 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 9.2 mL, 9.2 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH 4 Cl, and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H 2 O and brine, then dried over Na 2 SO 4 , and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-4′-tert-butyl-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil (1.907 g, 82%). MS ESI +ve m/z 361 (M+H—H 2 O) + .

The mixture of 6-bromo-2-phenyl-4-vinylchroman-4-ol (1.114 g, 2.94 mmol) and thiourea (345 mg, 4.41 mmol) in HOAc (9 mL) and 1 M HCl (3.6 mL) is heated to 40° C. for 12 h. The solvent is removed under reduced pressure to give a white solid as a mixture of 2-(6-bromo-4′-t-butylspiro-[chroman-2,1′-cyclohexane]-4-ylidene)ethyl carbamimidothioate HCl salt and excess thiourea. It is used in the next step without purification. MS ESI +ve m/z 361 (M+H-thiourea) + 437 (weak) (M+H) + .

The above crude product is dissolved in TFA (8 mL) containing MeSO 3 H (0.8 mL) and stirred at rt for 1 h. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with sat NaHCO 3 . The separated aqueous phase is extracted with ethyl acetate once, and the combined organic phases are washed with brine, and dried over Na 2 SO 4 , and filtered. The filtrate is concentrated to give crude product. Pure 6-bromo-5″,6″-dihydrospiro[spiro(chroman-2,1′-(4-t-butylcyclohexan))-4,4″-[1,3]thiazin]-2″-amine is obtained by preparative HPLC. MS ESI +ve m/z 4.37 (M+H) + .

To a solution of 6-bromo-5″,6″-dihydrospiro[spiro(chroman-2,1″-(4-t-butylcyclohexane))-4,4′-[1,3]thiazin]-2″-amine TFA salt (47 mg, 0.07 mmol) and 3-cyanophenylboronic acid (21 mg, 0.14 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs 2 CO 3 (146 mg, 0.45 mmol) and H 2 O (0.5 mL), followed by a catalytic amount of PdCl 2 dppf. The system is degassed by sweeping with N 2 . Then it is capped and heated 10 min at 130° C. in microwave. The separated organic phase is concentrated and then purified through preparative HPLC to afford cis- and trans-3-(2″-amino-5″,6″-dihydrospiro[spiro(chroman-2,1″-(4-t-butylcyclohexane))-4,4′-[1,3]thiazine]-6-yl)benzonitrile respectively. MS ESI +ve m/z 460 (M+H) + .

1 H NMR (400 MHz, CD 3 OD): less polar isomer: 8.00 (s, 1H), 7.93 (d, 1H), 7.72 (s, 1H), 7.68-7.58 (m, 3H), 7.06 (d, 1H), 3.53 (td, 1H), 3.28 (m, 1H), 0.91 (s, 9H); more polar isomer: 8.00 (s, 1H), 7.93 (d, 1H), 7.71-7.59 (m, 4H), 7.02 (d, 1H), 3.58 (td, 1H), 3.34 (m, 1H), 0.91 (s, 9H).

3-(2″-Amino-5″,6″-dihydrospiro[spiro(chroman-2,1′-cyclohexane)-4,4″-[1,3]thiazine]-6-yl)benzonitrile (Cmpd 168)

To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (383 mg, 1.30 mmol) in anhydrous THF (10 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 1.95 mL, 1.95 mmol) dropwise within 10 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH 4 Cl, and extracted with ethyl acetate (2×30 mL). The combined organic phases are washed with H2O, brine, dried over Na 2 SO 4 , and filtered. The filtrate is concentrated to give crude 6-bromo-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil, which is used for the next step without further purification. MS ESI +ve m/z 305 (M+H—H 2 O) + .

The mixture of above crude product and thiourea (242 mg, 3.9 mmol) in HOAc (20 mL) and 1 M HCl (4 mL) is heated to 40° C. for 24 h. The solvent is removed under reduced pressure to give a white solid as a mixture of 2-(6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexane]-4-ylidene)ethyl carbamimidothioate HCl salt and excess thiourea. It is used for the next step without purification. MS ESI +ve m/z 381 (M+H) + .

The above crude product is dissolved in TFA (5 mL) contain MeSO 3 H (0.5 mL) and stirred at rt overnight. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with sat NaHCO 3 . The separated aqueous phase is extracted with ethyl acetate once, and the combined organic phases are washed with brine, and dried over Na 2 SO 4 , and filtered. The filtrate is concentrated to give crude 6-bromo-5″,6″-dihydrospiro[spiro(chroman-2,1′-cyclohexan)-4,4″-[1,3]thiazin]-2″-amine. Pure product is obtained by preparative HPLC. MS ESI +ve m/z 437 (M+H) + .

To a solution of 6-bromo-5″,6″-dihydrospiro[spiro(chroman-2,1″-(4-t-butylcyclohexane))-4,4′-[1,3]thiazin]-2″-amine TFA salt (70 mg, 0.14 mmol) and 3-cyanophenylboronic acid (41 mg, 0.28 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs 2 CO 3 (200 mg, 0.61 mmol) and H 2 O (0.5 mL), followed by a catalytic amount of PdCl 2 (PPh 3 ) 2 . The system is degassed by sweeping with N 2 . Then it is capped and heated for 30 min at 110° C. in microwave. The separated organic phase is concentrated and the purified through preparative HPLC to afford 3-(2″-amino-5″,6″-dihydrospiro[spiro(chroman-2,1′-cyclohexane)-4,4″-[1,3]thiazine]-6-yl)benzonitrile representatively. MS ESI +ve m/z 460 (M+H) + . 1 H NMR (400 MHz, CD 3 OD): 8.00 (s, 1H), 7.92 (d, 1H), 7.71 (s, 1H), 7.68-7.59 (m, 3H), 7.07 (d, 1H), 3.53 (td, 1H), 3.28 (m, 1H), 2.56 (td, 1H), 2.37-2.29 (m, 2H), 2.18 (d, 1H), 1.90-1.82 (m, 3H), 1.67-1.61 (m, 4H), 1.55-1.37 (m, 3H).

3-(2′-Imino-1′-methyl-6′-oxo-2-phenyl-2′,3′,5′,6′-tetrahydro-1′H-spiro[chroman-4,4′-pyrimidine]-6-yl)benzonitrile (Cmpd. 169)

To a solution of 6-bromo-2-phenylchroman-4-one (2.010 g, 6.63 mmol) and 2-methyl-2-propane sulfonamide (804 mg, 6.63 mmol) in anhydrous THF (22 mL) is added Ti(OEt) 4 (3.025 g, 2.80 mL, 13.22 mmol). The resulting mixture is heated to reflux for 20 h. Brine (10 mL) is added after the mixture is cooled to rt, and stirred vigorously for 10 min. The mixture is filtered through a pad of Celite, and washed with ethyl acetate (50 mL). The filtrate is washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue is purified through chromatography on silica gel to afford N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide 1.05 g, 39%) as a light yellow solid. MS ESI +ve m/z 406 (M+H) +

To a solution of methyl acetate (383 mg, 0.41 mL, 5.17 mmol) in anhydrous THF (10 mL) at −78° C. under N 2 atmosphere is added 2 M LDA solution in THF (3.4 mL, 6.8 mmol) dropwise, and the solution is stirred another 30 min at the same temperature after the addition. To this mixture is added TiCl(OiPr) 3 (1.681 g, 6.45 mmol) dropwise. The mixture is then stirred another 30 min at −78° C. To this mixture is added a solution of N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide (1.050 g, 2.58 mmol) in anhydrous THF (10 mL) dropwise within 30 min. The reaction mixture is stirred another 3 h at −78° C. then quenched with sat. aq. NH 4 Cl. The mixture is stirred 10 min after being warmed to rt and filtered through a pad of Celite®, and washed with EA (80 mL). The filtrate is transferred to separating funnel and the separated organic phase is washed with brine, and dried over anhydrous Na 2 SO 4 , filtered and concentrated, and the residue is purified through chromatography on silica gel to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)-2-phenylchroman-4-yl) acetate 427 mg as an oil. MS ESI +ve m/z 480 (M+H) +

A solution of methyl 2-(6-bromo-4-(1,1-dimethylethylsulfmamido)-2-phenylchroman-4-yl)acetate (427 mg, 0.89 mmol) in MeOH (7 mL) and 4 M HCl solution in 1,4-dioxane (14 mL) is stirred at rt for 30 min. The solvent is removed under reduced pressure to give 418 mg methyl 2-(4-amino-6-bromo-2-phenylchroman-4-yl)acetate HCl salt as a white foam, which is used for next step without further purification. MS ESI +ve m/z 376 (M+H) + .

The above crude product is added to a solution of NaHCO 3 (714 mg, 8.5 mmol) in H 2 O (10 mL), which is chilled at 0° C. To this stirred mixture was added thiophosgene (71 μL, 107 mg, 0.93 mmol) and the mixture stirred for 1 h at 0° C. The reaction is diluted with DCM and the separated organic phase is washed with semi-saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to produce methyl 2-(6-bromo-4-isothiocyanato-2-phenylchroman-4-yl) acetate as an oil (384 mg). MS ESI +ve m/z 359 (M-NCS) + .

To a solution of 2-(6-bromo-4-isothiocyanato-2-phenylchroman-4-yl)acetate (192 mg, 0.46 mmol) in DCM (5 mL) is added a solution of 2 M MeNH 2 in THF (1.3 mL), and stirred for 1 h. The solvent is removed under reduced pressure and the residue is dissolved in DCM (2 mL) and hexane (2 mL) and evaporated to afford 6-bromo-1′-methyl-2-phenyl-2′-thioxo-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one as a white foam (209 mg), which is used for the next step without further purification. MS ESI +ve m/z 417 (M+H) + .

To a solutio