WO2010021680A2 - Inhibitors of beta-secretase - Google Patents

Inhibitors of beta-secretase Download PDF

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WO2010021680A2
WO2010021680A2 PCT/US2009/004686 US2009004686W WO2010021680A2 WO 2010021680 A2 WO2010021680 A2 WO 2010021680A2 US 2009004686 W US2009004686 W US 2009004686W WO 2010021680 A2 WO2010021680 A2 WO 2010021680A2
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alkyl
alkoxy
halo
compound
hydroxy
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WO2010021680A3 (en
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Lawrence W. Dillard
Jing Yuan
Lanqi Jia
Yajun Zheng
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Vitae Pharmaceuticals, Inc.
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Priority to EP09789150.1A priority Critical patent/EP2324032B1/en
Priority to US13/059,879 priority patent/US8450308B2/en
Publication of WO2010021680A2 publication Critical patent/WO2010021680A2/en
Publication of WO2010021680A3 publication Critical patent/WO2010021680A3/en
Priority to US13/867,590 priority patent/US8921359B2/en

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Abstract

The present invention is directed to a compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof. Pharmaceutical composition comprising a compound represented by Strucutral Formula (I) and method of use of these compound for inhibiting BACE activity in a subject in need of such treatment are also described.

Description

INHIBITORS OF BETA-SECRET ASE
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/189,464, filed on August 19, 2008, and U.S. Provisional Application No. 61/211,750 filed on April 2, 2009. The entire teachings of the above applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION 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 ablities 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 (AB) 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.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by the following Structural Formula:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri is -H, (Ci-C6)alkyl, aryl(Ci-C6)alkyl or heteroaryl(CrC6)alkyl; each R2 is independently selected from a) -H, -halogen. -CN, -NO2. -OR5, -NR6R7, -S(O)1R5, -C(O)OR5, -C(O)NRi2R13, and -C(O)R5; and b) (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)jR5, -NRnS(=O)iR5, -C(O)OR5, -C(K))NRi2Ri3, -NR11C(O)R5, -C(^S)NR12R13, -C(O)R5, (C1-C6)^k7L (C3-C8)cycloalkyl, (C2- C6)alkenyl, halo(C)-C6)alkyL (C1-C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(Ci-C6)alkyl, (d-C3)alkoxy, halo(d- C3)alkoxy ,(Ci-C6)alkoxy(C]-C3)alkyl, aryl and heteroaryl:
R3 and R4 are each idependently -H, -halogen, -CN, -NO2, -OR5, -NR6R7, -S(O)jR5, -C(O)OR5, -C(O)NR12Ri3, -C(O)R5, (C,-C6)alkyL (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C8)cycloalkyl. aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5. -NR6R7, -S(O)jR5, -NR1 ,S(O)1R5, -C(O)OR5, -C(O)NR12R13, -NRnC(O)R5, -C(=S)NR12Ri3, -C(=O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, halo(Ci-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(C]-C6)alkyl, (Cj- C3)alkylcarbonylamino(Ci-C6)alkyl, (C]-C3)alkoxy, 1IaIo(C1 -C3)alkoxy, (Cr C6)alkoxy(C!-C3)alkyl, an aryl group, and a heteroaryl group ; or X is -O-, -S-, -SO-, -SO2-, -CH2-O-, or -0-CH2-; each Y is independently -C(R8R9)-; W is -N(R14)-, -S-, -O-;
Z is -C(O)-, -C(=S)-,
Figure imgf000004_0001
-CC=NRi5)C(R16Ri7)-, -N(Ri8)-, -(CR16R17)m- or -O-(CR,6R17)-; R5 is -H, (CrC6)alkyL halo(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-
C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (C3-C7) 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, (Ci-C6)alkyl, halo(C,-C6)alkyl, and (CrC3)alkoxy(Ci-C6)alkyl; each R6 and R7 are independently -H, (Ci-C6)alkyl, hydroxy(C]-C6)alkyl, 1IaIo(C1-
C6)alkyl, (C3-C8) cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, each optionally substituted with -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl or (Ci-C3)alkoxy(Ci-C6)alkyl.; each R8 and R9 are independently -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, 1IaIo(C1 - C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Ci4) cycloalkyl, (C3-C i3)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)jR5, -NR, iS(=O)iR5, -C(O)OR5, -C(O)NR12Ri3, -NRnC(O)R5, -Q=S)NRi2R13, -C(O)R5, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C,-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (C1- C3)alkylcarbonylamino(Ci-C6)alkyl, (C,-C3)alkoxy, halo(Ci-C3)alkoxy, (Ci-C6)alkoxy(Cr C3)alkyl, aryl, heteroaryl, (C3-C8) cycloalkyl and (C3-Cg)cycloheteroalkyl; or
R8 and R9, 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, -OR5, -NR6R7,
-S(O)1R55 -NRnS(O)JR55 -C(O)OR5, -C(O)NR12Rn, -NRnC(O)R5, -Q=S)NR12R13, -C(O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(Ci-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy, (C1- C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl;
Rn is -H, (Ci-C6)alkyl or halo(C]-C6)alkyl;
R12 and Ri3 are each independently -H, (Ci-C6)alkyl, (C]-C3)alkoxy(Ci-C6)alkyl, hydroxy(C i -C6)alkyL cyano(C i -C6)alkyl, amino(C x -C6)alkyl, (C i -C3)alkylamino(C i - C6)alkyl, or di(C1-C3)alkylamino(Ci-C6)alkyl; or Ri2 and R13, 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, -OR5, -NR6R7, -S(O)1R5, -NR, , S(O)1R5, -C(O)OR5, -C(O)NRi2Ri3, -NRnC(O)R5, -C(=S)NR12Ri3, -C(O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(C,-C6)alkyl, cyano(Ci-C6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (C]-C3)alkoxy, halo(Ci- C3)alkoxy. and (Ci-C6)alkoxy(Ci-C3)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 (Ci-C3)alkyl or halo(C]-C3)alkyl, and when the additional heteroatom is sulfur, the sulfur is optionally mono or di-oxygenated;
Ri4 is -H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (C3-C8)cycloalkyl, cycloheteroalkyl(Cr C3)alkyl, (C3-C8)cycloalkyl(d-C3)alkyL aryl(CrC6)alkyl, heteroaryl(C,-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl and (Ci-C3)alkoxy:
Ri5 is -H or (Ci-C6)alkyl;
Rj6 and R]7 are each independently -H or (Ci-C3)alkyl;
Ri8 is -H or (Ci-C3)alkyl; i is O. 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 (F):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein:
R] is Ri is -H, (C,-C6)alkyl, aryl(CrC6)alkyl, or heteroaryl(d-C6)alkyl; R2 is a) -H, -F, -Cl, -Br, or -CN or b) (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)iR5,
Figure imgf000006_0002
Figure imgf000006_0003
-CC=O)R5, CC,-C6)alkyl, CC2-C6)alkenyl, haloCC,-C6)alkyl, (C,- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(C!-C6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy and (Ci- C6)alkoxy(Ci-C3)alkyl;
R3 and R4 are each independently -H, -F, -Br, -Cl or (C]-C6)alkyl.; X is -O-, -S-, -SO-, -SO2-, -CH2O- or -OCH2-; Y is -C(R8R9)-; W is -N(R14)-, -S-, -O-;
Z is -C(O)-, -C(=S)-, -C(=NR15)-, -0-, -CC=O)CCR16Rn)-, -CC=S)C(R16R17)-,
Figure imgf000006_0004
-N(R18)-, or -(CRi6R,7)m-;
R5 is -H, (d-C6)alkyl, halo(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C7) 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, (Ci-C6)alkyl, halo(C,-C6)alkyl, and (Ci-C3)alkoxy(CrC6)alkyl;
R6 and R7 are each independently -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci- C6)alkyl, (C3-C8) cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C)-C6)alkyl, halo(Ci-C6)alkyl and (C,-C3)alkoxy(Ci-C6)alkyl;
R8 and R9 are each independently -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, ImIo(C1 - C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci-C6)alkyl, halo(C!-C6)alkyl, hydroxy(C]-C6)alkyl, (Ci-C3)alkoxy and halo(C!-C3)alkoxy; or
R8 and R9, 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, -OR5, -NR6R7, -S(O)1R5,
Figure imgf000007_0001
-C(O)R5, (d-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (Q- C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl. cyano(Ci-C6)alkyl, (C1- C3)alkylcarbonylamino(Ci-C6)alkyl, (CrC3)alkoxy, halo(d-C3)alkoxy and (C1- C6)alkoxy(C]-C3)alkyl, wherein ring A contains O to 3 heteroatoms, which are independently selected from O, N and S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with -H. (d-C6)alkyl, halo(Ci-C6)alkyl or (Ci-C3)alkylcarbonyl. and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated; R1 , is -H, (C,-C6)alkyl or halo(CrC6)alkyl;
R12 and R13 are each independently -H, (d-C6)alkyl, (Ci-C3)alkoxy(C]-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(C1-C6)alkyl, amino(Ci-C6)alkyl, (C]-C3)alkylamino(Ci- C6)alkyl, or di(C1-C3)alkylamino(C1-C6)alkyl; or R12 and R13, 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, -OR5, -NR6R7, -S(O)jR5, -NRnS(O)iR5, -C(O)OR5, -C(O)NR12Ri3, -NR11C(O)R5, -C(=S)NR12Ri3, -C(O)R5, (CrC6)alkyL (C2-C6)alkenyl, halo(Ci-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(CrC6)alkyl, cyano(C]-C6)alkyl, (Ci-C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(Cj- C3)alkoxy and (Ci-C6)alkoxy(C!-C3)alkyl, wherein ring A contains O to 3 heteroatoms, which are independently selected from O, N and S, wherein when the heteroatom is nitrogen, the nitrogens is substituted with -H, (Ci-d)alkyl or halo(C1-C3)alkyl, and when the heteroatom is sulfur, the sulfurs is optionally mono or di-oxygenated;
RH is -H, (CrC6)alkyL halo(C1-C6)alkyl, (C3-C8)cycloalkyl, cycloheteroalkyl(Cr C3)alkyl, (C3-C8)cycloalkyl(Ci-C3)alkyl, aryl(d-C6)alkyl, heteroaryl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F; -CL -Br: -CN, (Ci-C6)alkyL halo(C1-C6)alkyl and (Ci-C3)alkoxy; Ri 5 is -H or (Ci-C6)alkyl: Ri6 and Rj7 are each independently -H or (Ci-C3)alkyl; Ri8 is -H or (Ci-C3)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 (F), 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 (F), 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 (F), or a pharmaceutically acceptable salt thereof). Another embodiment of the invention is a method of 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 (F) 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 (F). 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 (F). 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 (F), 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.
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds represented by the Structural
Formula (I) or a phamaceutically 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., Ri, R2, R3, etc.) defined herein. For Structural Formula (I):
Figure imgf000009_0001
or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof:
Ri is -H, (C,-C6)alkyL aryl(CrC6)alkyl or heteroaryl(Ci-C6)alkyl. In one embodiment R] is -H, (C]-C6)alkyl or benzyl. In another embodiment, Ri is -H. each R2 is independently selected from a) -H, -F, -Cl, -Br, and -CN and b) (C)-
C6)alkyl, (C2-C6)alkenyl. (C2-C6)alkynyl, (C3-C8)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, -OR5, -NR6R?, -S(O);R5, -NRπS(=O)iR5, -C(O)OR5, -C(O)NRi2Rn, -NRnC(O)R5, -C(=S)NRi2Ri3, -C(O)R5, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C2-C6)alkenyl, halo(C,-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(C|-C6)alkyl, cyano(CrC6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (C1- C3)alkoxy, halo(C]-C3)alkoxy ,(Ci-C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl. . In one embodiment R2 is -H, -Br, -F, -Cl, (Ci-C6)alkyl, (C3-C8)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, -OR5, -NR6R7, -S(O)1R5, -NR11SC=O)1R5, -C(=O)OR5, -CC=O)NR12R13, -NR11CC=O)R5, -CC=S)NR12R13, -CC=O)R5, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C2-C6)alkenyl, halo(C,-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, CCi-C3)alkoxy, halo(Ci-C3)alkoxy ,(C1- C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl.
In another particular embodiment, R2 is -H, -Cl, -Br or -F. In another particular embodiment, R2 is (Ci-C6)alkyl. More particularly, R2 is (Ci-
C3)alkyl.
In another particular embodiment, R2 is a (C2-C6) alkynyl optionally substituted with -F5 -Cl, -Br, -CN, -OR5, -SR5, -NR6R7, -S(O)1R5, -NRπS(=O)IR5, -C(=O)OR5, -C(=O)NR,2R13, -NRnC(O)R5, -C(=S)NR12R13, -C(=O)R5, (C,-C6)alkyl, (C3- C8)cycloalkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(CrC6)alkyl, cyano(CrC6)alkyl, (Ci-C3)alkylcarbonylamino(CrC6)alkyl, (C r C3)alkoxy, halo(C!-C3)alkoxy ,(Ci-C6)alkoxy(C]-C3)alkyl, aryl or heteroaryl. More particularly, R2 is a a (C2-C6) alkynyl optionally subsituted with (Ci-C6)alkyl or (C3- C8)cycloalkyl. In another particular embodiment, R2 is phenyl optionally substituted with 1 -3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR11S(O)1R5, -C(O)OR5, -C(O)NR12R13, -NR11C(O)R5, -C(=S)NR12R13, -C(O)R5, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C2-C6)alkenyl, halo(Cr C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(d-C6)alkyl, cyano(CrC6)alkyl, (C1- C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(d-C3)alkoxy, (C1-
C6)alkoxy(C]-C3)alkyl, aryl and heteroaryl. More specifically, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, , hydroxy(C]-C6)alkyl, (d-C3)alkoxy, halo(CrC3)alkoxy, (C1- C3)alkylthio, (Ci-C3)alkylcarbonyl and (C!-C3)alkoxycarbonyl. In another particular embodiment, R2 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. -OR5, -NR6R7, -S(O)1R51 -NR11S(O)1R55 -C(O)OR5, -C(O)NRi2R13, -NRnC(O)R5, -Q=S)NR12R13, -C(=O)R5, (C1-C6)EIlCyI, (C3-C8)cycloalkyl, (C2-C6)alkenyl, HaIo(C1-C6)OIlCyI, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, (Cj- C6)alkoxy(C]-C3)alkyl, aryl and heteroaryl. More particularly, the substituents are independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci-C3)alkyl, a 5-6 membered aryl or heteroaryl. Even more specifically, the substituents are independently selected from the group -F, -Cl, -Br, -CN, (Ci-C3)alkyl, pyrrolyl and imidazolyl.
In another particular embodiment, R2 is phenoxy or benzyloxy, each optionally substituted with 1 -3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)jR5, -NRn S(O)1R5, -C(O)OR5, -C(=O)NR12R13, -NRπC(=0)R5, -C(^S)NR12R13, -C(=O)R5, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C2- C6)alkenyL halo(Ci-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(C,-C6)alkyl, cyano(C]-C6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (C)-C3)alkoxy, halo(Cj- C3)alkoxy, (Ci-C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl. More particularly, R2 is unsubstituted phenoxy or benzyloxy.
R3 and R4 are each idependently -H, -F, -Br, -Cl or (Cj-C6)alkyl optionally substituted with an aryl group or a heteraryl group. In a particular embodiment, R3 and R4 are both -H. In another particular embodiment, R3 and R4 are independently -H, -F or methyl. In another particular embodiment, one of R3 and R4 are -H, the other is a (Cr C6)alkyl optionally susbstituted 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]-C3)alkoxy, halo(C1-C3)alkoxy, (Ci-C6)alkyl and halo(Ci-C6)alkyl. R5 is -H, (C,-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C,- C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (C3-C7) 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, (Ci-C6)alkyl, halo(CrC6)alkyl, (CrC3)alkoxy, halo(CrC3)alkoxy and (Ci-C3)alkoxy(Ci- Cό)alkyl. In a particular embodiment, R5 is (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C3)alkoxy(C]-C6)alkyl, (C3-C7)cycloheteroalkyl or benzyl. In a more particular embodiment, R5 is (CrC6)alkyl, halo(C,-C6)alk>'l, (C,-C3)alkoxy(CrC3)alkyl, pyrrolidinyl or benzyl. More particlular, R5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl. each R6 and R7 are independently -H5 (Ci-C6)alkyl. hydroxy(Ci-C6)alkyl, halo(Ci- C6)alkyl, (C3-C8) cycloalkyl, (C3-Cg)cycloalkyl(Ci-C6)alkyL each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CL -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl and (CrC3)alkoxy(Ci-C6)alkyl. In a particular embodiment, R6 and R7 are each independently -H or (Ci-C6)alkyl. In another particular embodiment, R6 and R7 are both -H.
In one embodiment, each R8 and R9 are independently -H, (CrC6)alkyl, hydroxy(C,-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Ci4) cycloalkyl, (C3-C i3)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl. -Br, -CN5 (C,-C6)alkyl, halo(d-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy, (C3-C8) cycloalkyl and (C3-C7)cycloheteroalkyl.
In a particular embodiment, R8 and R9 are each independently -H, (Ci-C6)alkyl. hydroxy(Ci-C6)alkyl, (C3-Ci4) cycloalkyl, (C3-C13)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, (CrC6)alkyl, halo(d-C6)alkyL hydroxy(Cr C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl, (C3-C8)cycloheteroalkyl, phenyloxy and benzyloxy.
In another particular embodiment, R8 and R9 are both -H, (Ci-C3)alkyl or hydroxy(Ci-C3)alkyl. More particluarly, Rg and R9 are both -H, methyl or hydroxymethyl.
In another embodiment, one of R8 and R9 is -H, the other one is a (Ci-C6)alkyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(d-C6)alkyL hydroxy(Ci-C6)alkyl, (C,- C3)alkoxy, halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C]-C6)alkyl and (C3- Cg)cycloheteroalkyl. Even more particularly, one of Rg and R9 is -H, the other one is a (C]-C3)alkyl optionally substituted(C3-C8)cycloheteroalkyl (preferrably a tetrahydrofuran or tetrahydropyran).
In another embodiment, one of R8 and R9 is -H, the other one is a (C2-Ce)alkenyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -CL -Br, -CN, (Ci-C6)alkyL halo(Ci-C6)alkyL hydroxy(Ci-C6)alkyl, (C r C3)alkoxy, halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl and (C3-Cg)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (Ci-C3)alkyl and hydroxy(Ci-C3)alkyl.
In another particular embodiment, one of R8 and R9 is -H and the other is unsubstituted phenyl. In another particular embodiment, one OfR8 and R9 is -H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (CrC6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C r C3)alkoxy, halo(Ci-C3)alkoxy, (Ci-C3)alkylcarbonyl and (Ci-C3)alkoxycarbonyl. More particularly, the substituents independently selected from -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy. In another particular embodiment, one OfR8 and R9 is -H and the other is (C3-
Ci4)cyloalkyl (preferrably monocyclic (C3-C8)cycloalkyl such as cyclopentyl and cyclohexyl, or bicyclic fused (C9-C14)cycloalkyl, such as 6,7,8,9-tetrahydro-5H- benzo[7]annulene, 2.3-dihydro-lH-indene, tetrahydronaphthalene, decahydronaphthalene), (C3-C i3)cycloheteroalkyl (preferrably monocyclic (C3- C7)cycloheteroalkyl such as tetrahydrofuran, tetrahydropyran and piperidine, or bicyclic fused or bridged (C8-C i3)cycloheteroalkyl such as 5.6,7, 8-tetrahydroquinoline. 5.6,7.8- tetrahydroisoquinoline, and 2-oxabicycIo[2.2.2]octane ) or heteroaryl (preferrably 5-6 membered heteroaryl such as pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C1- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)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,-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(d- C3)alkoxy . More particularly, one of R8 and R9 is -H and the other is unsubstituted (C3- C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl
(preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl). In another more particular embodiment, one Of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each of which is optionally substituted with (C1-C6)alkyl, preferably methyl.
In another embodiment, R8 and R9, 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, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR11SC=O)1R5, -C(=O)OR5, -Q=O)NR12R13, -NRnCC=O)R5, -CC=S)NR12R13, -C(O)R5, (Cj-C6)alkyl, (C2-C6)alkenyl, halo(C,- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(CrC6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, (C,-C3)alkoxy, halo(C]-C3)alkoxy, (Ci- C6)alkoxy(Ci-C3)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, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci- C3)alkoxy, halo(Ci-C3)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, (CrC6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)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 (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Q- C6)alkoxy and (C]-C3)alkylcarbonyl. In another particular embodiment, ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring optionally subsituted with 1 to 3 substituents independently selected from the group consisting of (C]-C6)alkyl. halo(C|- C6)alkyl, (Ci-C6)alkoxy and (Cj-C3)alkylcarbonyl. In another particular embodiment, 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-lH-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 (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and (C]-C3)alkylcarbonyl. Rn is -H, (Ci-C6)alkyl or halo(C]-C6)alkyl. In a particular embodiment. Rn is -H.
Each Rn and Rj3 are independently -H, (Ci-C6)alkyl. (Ci-C3)alkoxy(Ci-C6)alkyl, hydroxy(C]-C6)alkyl, cyano(Ci-C6)alkyl, amino(C1-C6)alkyl, (Ci-C3)alkylamino(Cr C6)alkyl, or di(C]-C3)alkylamino(CrC6)alkyl. In a particular embodiment, Ri2 and Rj3 are independently -H, (CrC6)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, hydroxy(Ci-C3)alkyl, cyano(Ci-C3)alkyl, or di(Ci-C3)alkylamino(Cj-C3)alkyl. More particularly, Ri2 and Ri3 are independently -H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl . Ri4 is -H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (C3-C8)cycloalkyl, cycloheteroalkyl(Cr C3)alkyl, (C3-C8)cycloalkyl(Ci-C3)alkyl, aryl(Cj-C6)alkyl, heteroaryl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl and (C,-C3)alkoxy. In a particular embodiment, Ri4 is (Ci-C6)alkyl, halo(Ci-C3)alkyl, (C3-C8)cycloalkyl(Ci- C3)alkyl or benzyl. In another particular embodiment, Ri4 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another particular embodiment, Ri4 is methyl.
R15 is -H or (Ci-C6)alkyl. In a particular embodiment, Ri5 is -H. Ri6 and R)7 are each independently -H or (Ci-C3)alkyl. In a particular embodiment, Ri6 and Ri7 are both -H.
Ri8 is -H or (Ci-C3)alkyl. In a particular embodiment, R18 is -H.
X is -O-, -S-, -SO-, -SO2-, -CH2O-, or -OCH2-. 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 -SO2-.
Y is -C(R8R9)-.
W is -N(Ri4)-, -S-, or -O-. In a particular embodiment, W is -N(R]4)-.
Z is -C(O)-, -C(=S)-, -C(=NR15)-, -0-,
Figure imgf000015_0001
-C(=NR15)C(Ri6R] 7)-, -N(Ri8)-, or -(CR]6Ri7)m-. In a particular embodiment, Z is -0-. In another particular embodiment. Z is -C(=0)-. i is O, 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 (F) or a phamaceutically acceptable salt thereof. Values and particular values for the variables in Structural Formula CI') 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.. R1, R2, R3, etc.) defined herein. For Structural Formula (F):
Figure imgf000016_0001
or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof:
Ri is -H, (C,-C6)alkyl, aryl(Ci-C6)alkyl or heteroaryl(CrC6)alkyl. In one embodiment Rj is -H, (Ci-C6)alkyl or benzyl. In another embodiment, Ri is -H. R2 is a) -H, -F, -Cl, -Br, or -CN or b) (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C8)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, -OR5, -NR6R7, -S(O)1R5, -NR11S(O)JR5, -C(=0)0R5, -C(O)NR12R13, -NRnC(O)R5,
Figure imgf000016_0002
-C(O)R5, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C,- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (C1- C3)alkylcarbonylamino(Ci-C6)alkyl, (d-C3)alkoxy, halo(C1-C3)alkoxy, (C1- C6)alkoxy(C]-C3)alkyl and aryl.
In one embodiment, R2 is -H, -Br, -F, -Cl, (d-C6)alkyl, (C3-Cs)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, -OR5, -NR6R7, -S(O)1R55 -NR11S(O)JR55 -COOR5, -CONR12R13, -NR11C(O)R5, -C(=S)NR12R13, -COR5, (CrC3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(Cr C6)alkyl, cyano(C!-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, or (Cj- C6)alkoxy(Ci-C3)alkyl. In another particular embodiment, R2 is -H, -Cl, -Br or -F.
In another particular embodiment, R2 is (Ci-C6)alkyl. More particularly, R2 is (Ci- C3)alkyl.
In another particular embodiment, R2 is phenyl optionally substituted with 1-3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R75 -S(O)1R51 -NRI I S(O)JR55 -C(O)OR5, -C(O)NRI2R13, -NR11C(O)R5, -Q=S)NR12R13, -C(O)R5: (C,-C6)alkyl5 (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci -C6)alkyl. cyano(C1-C6)alkyl. (C1- C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(C]-C3)alkoxy and (Ci- C6)alkoxy(Ci-C3)alkyl.
In another particular embodiment, R2 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, -OR5, -NR6R7,
-S(O)1R5, -NRnSC=O)1R5, -C(K))OR5, -CC=O)NR12Ri3, -NR1 1CC=O)R5, -CC=S)NR12R13, -CC=O)R5, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(d-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(C!-C6)alkyl, cyano(C!-C6)alkyl, (Ci- C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(C]-C3)alkoxy, (C1- C6)alkoxy(Ci-C3)alkyl and aryl. More particularly, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -CN and (C]-C3)alkyl.
In another particular embodiment, R2 is phenoxy or benzyloxy, each optionally substituted with 1-3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR, , SC=O)1R5, -CC=O)OR5, -CC=O)NR12R13, -NRnCC=O)R5, -CC=S)NR12R13, -CC=O)R5, CC1-C6)alkyl, (C2-C6)alkenyl, halo(Cr
C6)alkyl, or (Cj-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(C!-C6)alkyl, (Ci-C3)alkylcarbonylamino(C1-C6)alkyl, (d-C3)alkoxy, halo(Ci-C3)alkoxy, and (Ci- C6)alkoxy(C]-C3)alkyl. More particularly, R2 is unsubstituted phenoxy or benzyloxy. R3 and R4 are each idependently -H, -F, -Br, -Cl or (Ci-C6)alkyl. In a particular embodiment, R3 and R4 are both -H. In another particular embodiment, R3 and R4 are independently -H, -F or methyl.
R5 is -H, (Ci-C6)alkyl, halo(d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C7) 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, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (CrC3)alkoxy, halo(CrC3)alkoxy and (d-C3)alkoxy(Ci- C6)alkyl. In a particular embodiment, R5 is (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C3)alkoxy(Ci-C6)alkyl, (C3-C7)cycloheteroalkyl or benzyl. In a more particular embodiment, R5 is (Cj-C6)alkyl, halo(C]-C6)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, pyrrolidinyl or benzyl. More particlular, R5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl.
R6 and R7 are each independently -H. (Ci-C6)alkyl. hydroxy(Ci-C6)alkyl, halo(Ci- C6)alkyl. (C3-C8) cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl. each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci-C6)alkyl, halo(C,-C6)alkyl and (Ci-C3)alkoxy(C,-C6)alkyl. In a particular embodiment, R6 and R7 are each independently -H or (Cj-C6)alkyl. In another particular embodiment, R6 and R7 are both -H. In one embodiment, R8 and R9 are each independently -H, (Ci-C6)alkyl. hydroxy(C,-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(CrC6)alkyl5 (CrC3)alkoxy and halo(Cr C3)alkoxy. In a particular embodiment, R8 and R9 are each independently -H, (Cj-
C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (CrC6)alkyl, ImIo(C1 -C6)alkyl, hydroxy(Cr C6)alkyl, (Cj-C3)alkoxy and halo(Ci-C3)alkoxy. In another particular embodiment, R8 and R9 are both -H, (Ci-C3)alkyl or hydroxy(Ci-C3)alkyl. More particluarly, R8 and R9 are both -H, methyl or hydroxymethyl. In another particular embodiment, one OfR8 and R9 is -H and the other is unsubstituted phenyl. In another particular embodiment, one of R8 and R9 is -H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(C]-C6)alkyl. hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy and halo(Ci-C3)alkoxy. More particularly, the substituents independently selected from -F. -Cl, -Br, -CN, trifluoromethyl, methoxy. trifluoromethoxy. In another particular embodiment, one of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl. halo(CrC6)alkyl, hydroxy(C]-C6)alkyl, (Ci-C3)alkoxy and halo(C]-C3)alkoxy. More particularly, one Of R8 and R9 is -H and the other is unsubstituted (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl). In another more particular embodiment, one OfR8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each of which is optionally substituted with (Ci-C6)alkyl, preferably methyl.
In another embodiment, R8 and R9, together witli 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, -OR5, -NR6R7, -S(O)1R5, -NRHS(=O)iR5, -C(K))OR5, -C(=O)NR12R13, -NR11Q=O)R5, -C(=S)NR12R13, -C(O)R5, (CrC6)alkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Cj-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(Ci-C6)alkyl, (Cj-C3)alkoxy, halo(Ci-C3)alkoxy and (Ci- C6)alkoxy(Ci-C3)alkyl; wherein ring A contains O to 3 heteroatoms, which are selected from O. N, S: wherein when the heteroatom is nitrogen, the nitrogen is substituted with -H, (C]-C6)alkyL halo(Ci-C6)alkyl or (Ci-C3)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 -C6)alkyL halo(C 1 -C6)alkyl, hydroxy(C 1 -C6)alkyl, (C 1 - C3)alkoxy and halo(C]-C3)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 (C1-C6)BIkVl. halo(Cj -C6JaIkVl and (Ci-C3)alkylcarbonyl. Rn is -H, (Ci-C6)alkyl or halo(C]-C6)alkyl. In a particular embodiment, Rn is -H.
Ri2 and Rn are each independently -FL (Ci-C6)alkyl, (Ci-C3)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, amino(Ci-C6)alkyl, (Ci-C3)alkylamino(Ci- C6)alkyl, or di(Ci-C3)alkylamino(C]-C6)alkyl. In a particular embodiment, R]2 and R13 are independently -H, (CrC6)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyL hydroxy(Ci-C3)alkyl, cyano(C)-C3)alkyl, or di(Ci-C3)alkylamino(Ci-C3)alkyl. More particularly. Rj2 and Ri3 are independently -H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl.
Ri4 is -H, (Ci-C6)alkyl, halo(C)-C6)alkyl, (C3-C8)cycloalkyl, cycloheteroalkyl(Cr C3)alkyl, (C3-C8)cycloalkyl(Ci-C3)alkyl, aryl(Ci-C6)alkvL heteroaryl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F; -Cl, -Br, -CN. (Ci-C6)alkyl, halo(CrC6)alkyl and (Ci-C3)alkoxy. In a particular embodiment, Rj4 is (Ci-C6)alkyl, halo(Ci-C3)alkyl, (C3-C8)cycloalkyl(Ci- C3)alkyl or benzyl. In another particular embodiment, R!4 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another particular embodiment, RH is methyl.
Ri5 is -H or (Ci-C6)alkyl. In a particular embodiment, Rj5 is -H.
R16 and Ri7 are each independently -H or (Cj-C3)alkyl. In a particular embodiment, Rj6 and Ri7 are both -H.
Ri 8 is -H or (Ci-C3)alkyl. In a particular embodiment, Ri8 is -H.
X is -O-, -S-. -SO-, -SO2-, -CH2O-, or -OCH2-. 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 -SO2-.
Figure imgf000020_0001
W is -N(Ri4)-. -S-, or -O-. In a particular embodiment, W is -N(Ri4)-.
Z is -C(=O>, -C(=S)-, -C(=NRis)-, -O-, -C(=O)C(R16R,7)-, -C(=S)C(R16R17)-, -C(^NRi5)C(Ri6Ri7)-, -N(Ri8)-, or -(CRi6R17)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 1st specific embodiment, the compound of the present invention is represented by Structural Formula (II):
Figure imgf000020_0002
Ring A is an optionally subsituted 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, (CrC6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (CrC3)alkoxy, halo(C]-C3)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. (Ci-C6)alkyl. halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(Ci-C3)alkoxy.
Alternatively, Ring A is an optionally subsituted 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)-C6)alkyl. halo(Ci-C6)alkyl or (Ci-C3)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 (F). Ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, ImIo(C1 -C6)alkyL hydroxy(CrC6)alkyl, (Ci- C3)alkoxy and halo(Ci-C3)alkoxy.
In a 2nd specific embodiment, the compound of the present invention is represented by the following Structural Formulas:
Figure imgf000021_0001
Figure imgf000022_0001
Values and particular values for Structural Formulas (III), (IV), (V)5 (VI), (VII) and (XIV) are as described above for Structural Formula (II) in the 1 st specific embodiment. More specifically, R2 is independently -H, -F, -Cl or -Br and p is 2.
In a 3rd specific embodiment, the compound of the present invention is represented by the following Structural Formulas:
Figure imgf000022_0002
Values and particular values for Structural Formulas (Ilia), (IVa), (Va), (Via), (Vila) and (XIVa) are as described above for Structural Formula (II).
In a more specific embodiment, for compounds of Structural Formulas (HIa)- (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 (Ha)- (VIa) and (XIVa), X is -S-, and the values and specific values of the remainder of the variable are as described above in the 3rd specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (HIa)-(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 (HIa)-(VIIa) and (XIVa), X is -SO2-. and the values and specific values of the remainder of the variable are as described above in the 3rd specific embodiment. In a 4th specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), R2 is -H, -Cl, -Br. -F or (Ci-C6)alkyl, and the values and specific values of the remainder of the variable are as described above in the 3rd specific embodiment.
In a more specific embodiment, for compounds of Structural Formulas (HIa)- (VIIa) and (XIVa), R2 is -H, -Cl, -Br, -F or (CrC6)alkyl and X is -O-. Values and specific values of the remainder of the variable are as described above in the 4th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (IHa)-(VIIa) and (XIVa), R2 is -H, -Cl, -Br, -F or (d-C6)alkyl and X is -S-. Values and specific values of the remainder of the variable are as described above in the 4th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (IHa)-(VIIa) and (XIVa), R2 is -H, -Cl, -Br, -F or (C,-C6)alkyl and X is -SO-. Values and specific values of the remainder of the variable are as described above in the 4th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas (Ha)-
(VIa) and (XIVa)5 R2 is -H, -Cl, -Br; -F or (d-C6)alkyl and X is -SO2-. Values and specific values of the remainder of the variable are as described above in the 4th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas (Ha)- (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 (Ci-C6)alkyl, halo(Ci- C6)alkyl, (Ci-C6)alkoxy, (C]-C3)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, (Ci-C6)alkyl, halo(Ci- C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ha)-(VIa) and (XIVa) are as described above in the 4l specific embodiment. In a even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; R3 and R4 are -H; and Rj is -H.
In another more embodiment, for compounds of Structural Formulas (Ha)-(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 subsituted with 1 to 3 substituents independently selected from the group consisting of (C]-C6)alkyl5 halo(Cj -C6JaIkYl, (Cj-C6)alkoxy, (Ci-C3)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, (Ci- C6)alkyl, halo(C i -C6)alkyl, hydroxy(C i -C6)alkyl, (C i -C3)alkoxy or halo(C , -C3)alkoxy . Values and specific values for the remainder of the variables in Structural Formulas (Ha)- (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-; R3 and R4 are -H; and Ri is -H. In another more specific embodiment, for compounds of Structural Formulas (Ha)-
(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-lH-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 (Ci-C6)alkyl, halo(Ci-C6)alkyl. (C]-C6)alkoxy. (d- C3)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, (CrC6)alkyl, ImIo(C1 -C6)alkyl, hydroxy(CrC6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ha)-(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-; R3 and R4 are -H; and R1 is -H.
In another more specific embodiment, for compounds of Structural Formulas (Ilia), (IVa), (Via), and (XIVa), R14 is (C,-C6)alkyl, halo(d-C3)alkyl, (C3- C8)cycloalkyl(Ci-C3)alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa), (Via), and (XIVa), are as described above in the 4th specific embodiment. In an even more specific embodiment, X is -O- . In another even more specific embodiment, X is -O-: and Rj4 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another even more specific embodiment, X is -O-; and R14 is methyl.
In another more specific embodiment, for compounds of Structural Formulas (Ilia), (IVa), (Via) and (XIVa), Ri4 is (d-C6)alkyl, halo(C1-C3)alkyl, (C3-
C8)cycloalkyl(Ci-C3)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-lH-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 subsituents independently selected from the group consisting of (Ci-C6)alkyl, halo(Ci- C6)alkyl, (C]-C6)alkoxy, (Ci-C3)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]-C6)alkyl, halo(Ci- C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa), (Via) and (XIVa). are as described above in the 4th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; Ri4 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-; RH 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-lH-indene, tetrahydronaphthalene, decahydronaphthalene, 5.6.7.8-tetrahydroquinoline, 5,6.7,8-tetrahydroisoquinoline. or 2-oxabicyclo[2.2.2]octane. In a 5th specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), R2 is (C3-C8)cycloalkyl, (C3-Cg)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, -OR5, -SR5, -NR6R7, -S(O))R5, -NRn S(=O)iR5, -C(=O)OR5, -CC=O)NR12Ri3, -NR11C(O)R5, -C(=S)NR,2R13, -C(=0)R5, (d-C6)alkyl, (C3-C8)cycloalkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(C]-C6)alkyl, (C1- C3)alkylcarbonylamino(C1-C6)alkyl, (d-C3)alkoxy, ImIo(C1 -C3)alkoxy ,(Cr
C6)alkoxy(C!-C3)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, R2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl. Even more specifically, the substituents are independently selected from -F, -Cl, -Br, -CN, hydroxy(CrC6)alkyl, cyano(d-C6)alkyl, (C1-C3)alkoxy, ImIo(C1 -C3)alkoxy ,(C1-
C6)alkoxy(Ci-C3)alkyl, phenyl and 5-6 membered heteroaryl (preferrably pyridine or pyrimidine).
In a more specific embodiment, for compounds of Structural Formulas (HIa)- (VIIa) and (XIVa), X is -0-, and the values and specific values of the remainder of the variable are as described in the 5th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), X is -S-, and the values and specific values of the remainder of the variable are as described in the 5th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), X is -SO-, and the values and specific values of the remainder of the variable are as described in the 5th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), X is -SO2-. and the values and specific values of the remainder of the variable are as described in the 5th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas (Ha)-
(VIa) and (XFVa), ring A a 5-7 membered monocyclic ring containing O 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]-C6)alkyl. halo(Ci- C6)alkyl. (Ci-C6)alkoxy, (Q-Cs^lkylcarbonyL 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, (Ci-C6)alkyl, halo(Cr C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(C]-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ha)-(VIa) and (XIVa) are as described above in the 5l specific embodiment. In a even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; R3 and R4 are -H; and Ri is -H.
In another more embodiment, for compounds of Structural Formulas (Ha)-(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 subsituted with 1 to 3 substituents independently selected from the group consisting of (C]-C6)alkyl, halo(Ci-C6)alkyl, (C]-C6)alkoxy, (Ci-C3)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. (Ci- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(d-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ha)- (VIa) are as described above in the 5th specific embodiment. In a even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-: R3 and R4 are -H; and Ri is -H.
In another more specific embodiment, for compounds of Structural Formulas (IHa)-(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- 1 H-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 subsituents independently- selected from the group consisting of (Ci-C6)alkyl, halo(Ci-C6)alk)4, (d-C6)alkoxy. (Ci- C3)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,-C6)alkyl, 1IaIo(C1 -C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-Cs)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IHa)-(VIIa) are as described above in the 5th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; R3 and R4 are -H; and Ri is -H.
In another more specific embodiment, for compounds of Structural Formulas (Ilia), (IVa), (Via) and (XIVa), R14 is (C,-C6)alkyl, halo(CrC3)alkyl, (C3- Cg)cycloalkyl(Ci-C3)alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa) and (Via) are as described above in the 5th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and Ri4 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; R3 and R4 are -H; and Ri is -H. In another more specific embodiment, , for compounds of Structural Formulas
(Ilia), (IVa), (Via) and (XIVa), R14 is (Ci-C6)alkyl, halo(CrC3)alkyl, (C3- C8)cycloalkyl(Ci-C3)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- 1 H-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 (Ci-C6)alkyl, halo(Cj -C6MkYl, (Ci-C6)alkoxy and (Ci-C3)alkylcarbonyl. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa), (Via) and (XIVa) are as described above in the 5th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; Ri4 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-lH-indene. tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5.6,7.8- tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane: R3 and R4 are -H: and Ri is -H.
In a 6th specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa), R2 is aryl and values and specific values for the remainder of the variables are as described above in the 3rd specific embodiment. More specifically, R2 is phenyl. In a more specific embodiment for compounds of Structural Formulas (HIa)-
(VIIa) and (XTVa), X is -O-, and values and specific values for the remainder of the variables are as described above in the 6th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas (IHa)-(VIIa) and (XIVa), X is -S-, and values and specific values for the remainder of the variables are as described above in the 6th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (IHa)-(VIIa) and (XIVa), X is -SO-, and values and specific values for the remainder of the variables are as described above in the 6th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (HIa)-(VIIa) and (XIVa), X is -SO2-, and values and specific values for the remainder of the variables are as described above in the 6th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas
(HIa)-(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-lH-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 subsituents independently selected from the group consisting of (Cj-C6)alkyl, halo(CrC6)alkyL (CrC6)alkoxy, (Ci-C3)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, (CrC6)alkyl, halo(CrC6)alkyl, hydroxy(CrC6)alkyl, (C,-C3)alkoxy or ImIo(C1- C3)alkoxy. Values and specific values for the remainder of the variables in Structural
Formulas (HIa)-(VIIa) and (XIVa) are as described above in the 6th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-: R3 and R4 are -H; and Ri is -H..
In another more specific embodiment, for compounds of Structural Formulas (Ilia), (IVa), (Via) and (XIVa), R]4 is (C,-C6)alkyl, halo(CrC3)alkyl, (C3-
Cg)cycloalkyl(C]-C3)alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa), (Via) and (XIVa), are as described above in the 6th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-: and Rj4 is methyl, ethyl, propyl, cyclohexylmethyl. cyclopropylethyl, trifluoroethyl, or benzyl; R3 and R4 are -H: and Ri is -H.
In another more specific embodiment, for compounds of Structural Formulas (Ilia), (IVa), (Via) and (XTVa), R14 is (d-C^alkyl, halo(Ci-C3)alkyl, (C3- C8)cycloalkyl(Ci-C3)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-l H-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 subsituents independently selected from the group consisting of (Ci-C6)alkyl. halo(C]-C6)alkyl, (Cj-C6)alkoxy. (Ci- C3)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, (CrC6)alkyl, halo(CrC6)alkyl, hydroxy(d-C6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Ilia), (IVa), (Via) and (XIVa), are as described above in the 6th specific embodiment. In an even more specific embodiment, X is -O- . In another even more specific embodiment, X is -O-; R14 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-l H-indene, tetrahydronaphthalene. decahydronaphthalene, 5,6,7.8-tetrahydroquinoline, 5,6,7,8- tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane: R3 and R4 are -H: and Rj is -H. In a 7th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:
Figure imgf000030_0001
Figure imgf000031_0001
R10 is -F5 -Cl, -Br, -CN5 -OR5, -NR6R7, -S(COJR5, -NRnS(=O)iR5, -C(O)OR5, -C(O)NR12R13, -NR11C(O)R5, -Q=S)NR12R13= -C(O)R5, (C,-C6)alkyl, (C2- C6)alkenyl, halo(Ci-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl: cyano(C i -C6)alkyl, (C i -C3)alkylcarbonylamino(C i -C6)alkyl, (C , -C6)alkoxy(C j -C3)alky 1, aryl or heteroaryl. s is O, 1. 2 or 3. Values and specific values for the remainder of the variables in Structural Formulas (IHb)-(VIIb) and (XIVb) are as described above for Structural Formula (II).
In a more specific embodiment, for compounds of Structural Formulas (Hb)-(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 (Ci-C6)alkyl, halo(Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-Csjalkylcarbonyl. 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, (Ci-C6)alkyl, halo(Cj- C6)alkyl, hydroxy(Ci-C6)alkyl, (C]-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Hb)-(VIb) and (XIVb) are as described above in the 7th specific embodiment. In a even more specific embodiment, R3 and R4 are -H; and Ri is -H.
In another more embodiment, for compounds of Structural Formulas (Hb)-(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 subsituted with 1 to 3 substituents independently selected from the group consisting of (C]-C6)alkyl. halo(CrC6)alkyl, (Ci-C6)alkoxy. (Ci-Cs^lkylcarbonyl. 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, (Ci-C6)alkyl, halo(C,-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(Cr C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (Hb)-(VIb) and (XIVb) are as described above in the 7th specific embodiment. In a even more specific embodiment, R3 and R4 are -H; and Ri is -H. In another more specific embodiment, for compounds of Structural Formulas
(IHb)-(VIIb) and (XWb), ring A is tetrahydrofuran. tetrahydropyran. cyclopentane, cyclohexane. cycloheptane, oxepane, L3-dioxane: piperidine,. 6.7.8,9-tetrahydro-5H- benzo[7]annulene. 2,3-dihydro-lH-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 subsituents independently selected from the group consisting of (C,-C6)alkyl; halo(CrC6)alkyl, (Ci-C6)alkoxy, (C,-C3)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, -CN5 (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (CrC3)alkoxy or halo(Cr C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IHb)-(VIIb) and (XIVb) are as described above in the 7th specific embodiment. Even more specifically, R3 and R4 are -H. In a more specific embodiment, for compounds of Structural Formulas (HIb),
(IVb), (VIb) and (XIVb), R14 is (C]-C6)alkyl, halo(C,-C3)alkyl, (C3-C8)cycloalkyl(Ci- C3)alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IHb), (IVb), (VIb) and (XIVb), are as described above in the 7th specific embodiment. Even more specifically, Ri4 is methyl. In another more specific embodiment, for compounds of Structural Formulas
(HIb), (IVb), (VIb) and (XIVb), R14 is (d-C6)alkyl, halo(C,-C3)alkyl, (C3- C8)cycloalkyl(C]-C3)alkyl or benzyl: and ring A is tetrahydrofuran. tetrahydropyran. cyclopentane, cyclohexane, cycloheptane. oxepane, L3-dioxane, piperidine, 6,7,8,9- tetrahydro-5H-benzo[7]annulene. 2,3-dihydro- 1 H-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 subsituents independently selected from the group consisting of (C]-C6)alkyl, halo(Ci-C6)alkyl. (Ci-C6)alkoxy. (Ci- C3)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, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(C,-C6)alkyl, (Ci-C3)alkoxy or halo(C]-C3)alkoxy. Values and specific values for the remainder of the variables in Structural Formulas (IHb), (IVb), (VIb) and (XIVb) are as described above in the 7th specific embodiment. Even more specifically, R]4 is methyl, Ri 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- lH-indene, tetrahydronaphthalene. decahydronaphthalene, 5,6,7.8-tetrahydroquinoline, 5.6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane.
In an 8th specific embodimetn, for compouds of Structural Formulas (HIb)-(VIIb) and (XIVb), the values for the variables are defined as the following: R10 is -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRj , S(=O)iR5, -C(O)OR5,
-C(O)NRi2R13, -NRπC(=0)R5, -C(=S)NR,2Ri3, -C(K))R5: (C,-C6)alkyl, (C2- C6)alkenyl, halo(CrC6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(CrC6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, or (Ci-C6)alkoxy(Ci- C3)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-lH-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 subsituents independently selected from the group consisting of (CrC6)alkyl, halo(C]-C6)alkyl, (CrC6)alkoxy, (Ci-C3)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]-C6)alkyl, halo(CrC6)alkyl, hydroxy(CrC6)alkyl, (CrC3)alkoxy or halo(Cr C3)alkoxy;
R, is -H; R3 and R4 are -H;
R5 is (Ci-C6)alkyl or (Ci-C3)alkoxy(Ci-C3)alkyl;
R6 and R7 are -H:
Rn is -H;
Ri2 and R[3 are independently -H, (Ci-C6)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, hydroxy(Ci-C3)alkyl, cyano(d-C3)alkyl, or di(Ci-C3)alkylamino(Ci-C3)alkyl:
Ri4 is (C,-C6)alkyl, halo(Ci-C3)alkyl, (C3-C8)CyClOaIkVl(C1 -C3)alkyl or benzyl; and i is 0, 1, or 2.
In a more specific embodiment, for compouds of Structural Formulas (IHb)-(VIIb) and (XIVb), R10 is -F, -Cl, -Br, -CN, -CF3, or -OR5: and Ri4 is methyl. Values and specific values for the remainder of the variables are as described above in the 8th specific embodiment.
In a 9th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:
Figure imgf000035_0001
wherein R8 and R9 are each independently -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C]4) cycloalkyl, (C3-C13)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C1- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C1-C6)alkyl, (C]-C3)alkoxy, ImIo(C1 -C3)alkoxy, aryl, heteroaryl, (C3-C8) cycloalkyl and (C3-C7)cycloheteroalkyl. Values and specific values for the remainder of the variables are as described above for Strucutral Formula (I).
Alternatively, for compounds represented by Structural Formula (VIII), Rg and R9 are each independently -H, (C]-C6)alkyl, hydroxy(C1-Co)alkyl, halo(C]-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(d-C6)alkyl, hydroxy(Cr Ce)alkyl, (Ci-C3)alkoxy and halo(Ci-C3)alkoxy. Values and specific values for the remainder of the variables are as described above for Strucutral Formula (F).
In a 10th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:
Figure imgf000035_0002
(Xi)
Figure imgf000036_0001
Values and specific values for varibles for Strucutral Formulas (IX)-(XIII) and (XV) are as described above for Structural Formula (VIII) in the 9th specific embodiment. In a more specific embodiment, X is -O-. In another more specific embodiment, X is -O-, R2 is independently -H, -F, -Cl or -Br and p is 2.
In an 1 1th specific embodiment, compounds of the present invention are represented by the following Structural Formulas:
Figure imgf000036_0002
(LXa) (Xa) (XIa)
Figure imgf000037_0001
or
(XIIa) (XIIIa)
Values and specific values for varibles for Strucutral Formulas (IXa)-(XIIIa) and (XVa) are as described above for Structural Formula (VIII) in the 9th 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 11th specific embodiment.
In another more specific embodiment, for compounds of Structural Formula (FXa)- (XIIIa) and (XVa), X is -S-, and the values and specific values of the remainder of the variables are as described above in the 11th 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 11th specific embodiment.
In another more specific embodiment, for compounds of Structural Formula (FXa)- (XIIIa) and (XVa), X is -SO2-, and the values and specific values of the remainder of the variables are as described in the 11th specific embodiment.
In a 12th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa). R2 is -H, -Cl5 -Br, -F or (Ci-C6)alkyl, and the values and specific values of the remainder of the variable are as described above in the 11th 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 12th 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 12th 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 12th specific embodiment. In another more specific embodiment, for compounds of Structural Formula (IXa)-
(XIIIa) and (XVa), X is -SO2-, and the values and specific values of the remainder of the variable are as described above in the 12th specific embodiment.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), R8 and R9 are each independently -H, (CrC6)alkyl, (C2-C6)alkenyl, hydroxy(Ci-C6)alkyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CL -Br, -CN, (C1-C6)alkyL ImIo(C1 -C6)alkyl, hydroxy(C1-C6)alkyl, (C1- C3)alkoxy, 1IaIo(C1 -C3)alkoxy, aryl, heteroaryl, (C3-C8) cycloalkyl and (C3-C7)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment, hi an even more specific embodiment, X is -O-. hi another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), R8 and R9 are both -H, (d-C3)alkyl or hydroxy(C1-C3)alkyl. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment. X is -O-. and R8 and R9 are -H, methyl or hydroxymethyl.
In another more specific embodiment, for compounds of Structural Formula (LXa)- (XIIIa) and (XVa). one of R8 and R9 is -H, the other one is a (Ci-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CL -Br, -CN, (C1-C6)alkyl, halo(CrC6)alkyL hydroxy(CrC6)alkyl, (CrC3)alkoxy, halo(Ci-C3)alkoxy. (C3-CS) cycloalkyl and (C3-C8)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (Ci-C6)alkyl and (C3- C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. More particularly, X is -O-. Even more particularly, one of R8 and R9 is -H, the other one is a (Ci-C3)alkyl optionally substituted(C3-C8)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 R8 and R9 is -H, the other one is a (C2-C6)alkenyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (CrC6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci- C3)alkoxy, halo(C]-C3)alkoxy, (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. More particularly, X is -O- . Even more particularly, substituents are selected from the group consisting of (Q-C^alkyl and hydroxy^ -C3)alkyl.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa). one of Rg and R9 is -H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 12th 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 R8 and R9 is -H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C1- C6)alkyl, halo(d-C6)alkyl, hydroxy(d-C6)alkyl, (CrC3)alkoxy, halo(C1-C3)alkoxy, (C1- C3)alkylcarbonyl and (Ci-C3)alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. In an even more specfici embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one OfR8 and R9 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 R8 and R9 is -H and the other is monocylic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9-C i4)cycloalkyl (such as 6,7,8,9- tetrahydro-5H-benzo[7]annulene. 2,3-dihydro-lH-indene. tetrahydronaphthalene. decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicycic bridged (C8- C]3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN. (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C]-C6)alkyl, (C]-C3)alkoxy, halo(Ci-C3)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]- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (d-C3)alkoxy or halo(C,-C3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-: and one Of R8 and R9 is -H and the other is monocylic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9- Ci4)cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-lH-indene. tetrahydronaphthalene. decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C8- C]3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (CrC3)alkoxy, halo(CrC3)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. (Ci- C6)alkyL halo(CrC6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(CrC3)alkoxy. In another even more specific embodiment, X is -O-: one Of R8 and R9 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-lH-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, (Ci- C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C6)alkyl: (CrC3)alkoxy, halo(Ci-C3)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, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C6)aIkyl, (C,-C3)alkoxy or halo(Cr C3)alkoxyl.
In another particular embodiment, for compounds of Structural Formula (IXa)- (XIIIa), one of Rg and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (Ci-C3)alkoxy and halo(C1-C3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 12th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3- C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (Cj-C6)alkyl. In a 13th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R2 is (C3-C8)cycloalkyl, (C3-C8)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, -OR5, -SR5, -NR6R7, -S(O)jR5, -NR, ]S(=O)iR5, -C(K))OR5, -C(O)NR12R13, -NR11Q=O)R5, -Q=S)NR12R13, -C(K))R5, (CrC6)alkyl, (C3-C8)cycloalkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (Cr C3)alkylsulfonylaminoalkyl, hydroxy(Cj-C6)alkyl, cyano(C]-C6)alkyl, (C1- C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(d-C3)alkoxy ,(C1- C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl. Values and specific values of the remainder of the variable are as described in the 11th specific embodiment. Even more specifically, R2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl. Even more specifically, the substituents are independently selected from -F. -Cl. -Br, -CN. hydroxy(Ci-C6)alkyl, cyano(CrC6)alkyl, (C!-C3)alkoxy, halo(Ci-C3)alkoxy ,(Ci - C6)alkoxy(Ci-C3)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 13th 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 13th specific embodiment.
In another more specific embodiment, , for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), X is -SO2-, and the values and specific values of the remainder of the variable are as described above in the 13th specific embodiment. In another more specific embodiment, for compounds of Structural Formula (IXa)-
(XIIIa) and (XVa), R8 and R9 are each independently -H, (Ci-C6)alkyl, (C2-C6)alkenyl, hydroxy(Ci-C6)alkyl, (C3-C)4) cycloalkyl, (C3-C i3)cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(C1-C6)alkyl, hydroxy(CrC6)alkyl, (Q- C3)alkoxy, halo(Ci-C3)alkoxy, aryl, heteroaryl, (C3-C8) cycloalkyl and
(C3-C7)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment. Even more specifically. X is -O-.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa), R8 and R9 are both -H, (C]-C3)alkyl or hydroxy(Ci-C3)alkyl. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-: and R8 and R9 are -H, methyl or hydroxymethyl.
In another more specific embodiment, for compounds of Structural Formula (EXa)- (XIIIa) and (XVa), one of R8 and R9 is -H, the other one is a (Cj-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy, halo(Ci-C3)alkoxy. (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (Ci-Cό)alkyl and (C3- Cg)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment. More particularly. X is -O-. Even more particularly, one Of R8 and R9 is -H, the other one is a (Ci-C3)alkyl optionally substituted(C3-C8)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 R8 and R9 is -H, the other one is a (C2-C6)alkenyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C,-C6)alkyl, halo(C]-C6)alkyl, hydroxy(d-C6)alkyl, (Ci- C3)alkoxy, halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13l specific embodiment. More particularly, X is -O-. Even more particularly, substituents are selected from the group consisting of (Cj-C3)alkyl and hydroxy(Ci-C3)alkyl.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), one OfR8 and R9 is -H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment. Even more specifically, X is -O-.
In another specific embodiment, for compounds of Structural Formula (EXa)- (XIIIa) and (XVa), one Of R8 and R9 is -H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C1- C6)alkyl, halo(CrC6)alkyl, hydroxy(CrC6)alkyl, (CrC3)alkoxy, halo(Ci-C3)alkoxy, (C1- C3)alkylcarbonyl and (Ci-C3)alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one OfR8 and R9 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 Rg and R9 is -H and the other is monocytic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9-C i4)cycloalkyl (such as 6,7.8.9- tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-l H-indene, tetrahydronaphthalene. decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C8- Ci3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (CrC6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy, halo(d-C3)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, (Cj- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(Ci-C3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 13th specific embodiment, hi an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one of R8 and R9 is -H and the other is monocylic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9- C]4)cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2.3-dihydro-lH-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C8- Ci3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(C)-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, ImIo(C1 -C3)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)- C6)alkyl, halo(C,-C6)alkyl, hydroxy(Ci-C6)alkyl, (C,-C3)alkoxy or halo(d-C3)alkoxy. In another even more specific embodiment, X is -O-; one of R8 and R9 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-lH-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, (C1- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (CrC3)alkoxy, halo(CrC3)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, (Ci-C6)alkyl, halo(d-C6)alkyl, hydroxy(Ci-C6)alkyl, (CrC3)alkoxy or halo(Cr C3)alkoxyl. In another specific embodiment, for compounds of Structural Formula (IXa)-
(XIIIa), one Of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl5 -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl: hydroxy(CrC6)alkyl, (Ci-C3)alkoxy and halo(Ci-C3)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 R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3- C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (Cj-C6)alkyl. In a 14th specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), R2 is aryl and the values and specific values of the remainder of the variable are as described in the 11th specific embodiment. More specifically, R2 is phenyl. In another more specfic embodiment, R2 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 14th 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 14th specific embodiment. In another more specific embodiment, for compounds of Structural Formula (EXa)-
(XIIIa) and (XVa), X is -SO-, and the values and specific values of the remainder of the variable are as described above in the 14th specific embodiment.
In a more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), X is -SO2-, and the values and specific values of the remainder of the variable are as described above in the 14th specific embodiment.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), R8 and R9 are each independently -H, (CrC6)alkyl, (C2-C6)alkenyl, hydroxy(Ci-C6)alkyl, (C3-Ci4) cycloalkyl, (C3-Ci3)cycloheteroalkyl, phenyl or heteraryl. each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN5 (Ci-C6)alkyl5 halo(Ci-C6)alkyl5 hydroxy(CrC6)alkyl5 (Cj- C3)alkoxy, halo(Ci-C3)alkoxy, aryl. heteroaryl. (C3-C8) cycloalkyl and (C3-C7)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14 specific embodiment. Even more specifically. X is -O-. In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), R8 and R9 are both -H, (C,-C3)alkyl or hydroxy(d-C3)alkyl. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. In an even more specific embodiment, X is -O- . In another even more specific embodiment, X is -O-; and R8 and R9 are -H, methyl or hydroxymethyl.
In another more specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa), one Of R8 and R9 is -H. the other one is a (C]-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F. -Cl, -Br, -CN, (C,-C6)alkyl, halo(C,-C6)alkyl, hydroxy(C]-C6)alkyl, (C,-C3)alkoxy5 halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (Q-C^alkyl and (C3- C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. More particularly, X is -O-. Even more particularly, one of R8 and R9 is -H, the other one is a (C]-C3)alkyl optionally substituted(C3-C8)cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is -O-. hi another more specific embodiment, for compounds of Structural Formula (IXa)-(XIIIa) and (XVa), one of R8 and R9 is -H, the other one is a (C2-C6)alkenyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -Cl, -Br5 -CN, (C,-C6)alkyl, halo(CrC6)alkyL hydroxy(CrC6)alkyL (Ci- C3)alkoxy, halo(Ci-C3)alkoxy, (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. More particularly, X is -O-. Even more particularly, substituents are selected from the group consisting of (Ci-C3)alkyl and hydroxy(Ci-C3)alkyl. In another more specific embodiment, for compounds of Structural Formula (IXa)-
(XIIIa) ) and (XVa), one OfR8 and R9 is -H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. Even more specifically, X is -O-.
In another specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa) and (XVa). one Of R8 and R9 is -H and the other is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, (C1- C3)alkylcarbonyl and (Ci-C3)alkoxycarbonyl. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one OfR8 and R9 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 R8 and R9 is -H and the other is monocylic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9-C i4)cycloalkyl (such as 6,7,8,9- tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-l H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bridged (C8-C i3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C)-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C]-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)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, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (Ci-C3)alkoxy or halo(CrC3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. In an even more specific embodiment, X is -O- . In another even more specific embodiment, X is -O-: and one OfR8 and R9 is -H and the other is monocylic (C3- Cg)cyloalkyl (such as cyclopentyl and cyclohexyl). bicyclic fused (C9-C j4)cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-l H-indene. tetrahydronaphthalene, decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C8- C]3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl. halo(C)-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy. halo(Ci-C3)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 |- C6)alkyl, halo(d-C6)alkyL hydroxy(C,-C6)alkyl, (CrC3)alkoxy or halo(Ci-C3)alkoxy. In another even more specific embodiment, X is -O- ; one of R8 and R9 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-lH-indene, tetrahydronaphthalene; decahydronaphthalene, 5,6.7,8-tetrahydroquinόline, 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, (Ci- C6)alkyl, halo(d-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)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, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(Cr C3)alkoxyl.
In another specific embodiment, for compounds of Structural Formula (IXa)- (XIIIa), one of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(C,-C6)alkyl, hydroxy(d-C6)alkyl, (CrC3)alkoxy and halo(Ci-C3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 14th specific embodiment. In an even more specific embodiment, X is -O-. In another even more specific embodiment, X is -O-; and one of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3- C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (Ci-C6)alkyl. In a 15th specific embodiment, the compounds of the present invention are represented by the following Structural Formulas:
Figure imgf000048_0001
Figure imgf000049_0001
(Xb)
Figure imgf000049_0002
(Xib)
Figure imgf000049_0003
(XIIb)
Figure imgf000049_0004
(XVb)
Figure imgf000050_0001
(IXc)
Figure imgf000050_0002
(Xc)
Figure imgf000050_0003
(XlIc)
Figure imgf000051_0001
(XVc)
Figure imgf000051_0002
(Xd)
Figure imgf000052_0001
(XIId)
Figure imgf000052_0002
(xπid)
Figure imgf000052_0003
(XVd)
Figure imgf000053_0001
(IXe)
Figure imgf000053_0002
(Xe)
Figure imgf000053_0003
(XIe)
Figure imgf000053_0004
(XlIe)
Figure imgf000054_0001
(XVe)
wherein R10 is -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRnS(O)1R5, -C(O)OR5, -C(O)NR12R13, -NR11C(O)R5, -C(=S)NR12R13, -C(O)R5, (CrC6)alkyl, (C2- C6)alkenyl, halo(d-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyL hydroxy(C1-C6)alkyl, cyano(CrC6)alkyl, (C1-C3)alkylcarbonylamino(Ci-C6)alkyL (Ci-C6)alkoxy(Ci-C3)alkyl, aryl or heteroaryl: and s is O, 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 11th specific embodiment
In a more specific embodiment, for compounds of Structural Formulas (EXb)- (XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe), R8 and R9 are each independently -H, (CrC^alkyl, (C2-C6)alkenyl, hydroxy(CrC6)alkyl, (C3-C14) cycloalkyl, (C3-C 13)cycloheteroalkyl, phenyl or heteraryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F5 -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(C1-C6)alkyl, (CrC3)alkoxy, halo(Ci-C3)alkoxy, aryl, heteroaryl, (C3-C]4) cycloalkyl and (C3-C i3)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment. In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb)5 (IXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd)5 (IXe)-(XIIIe) and (XVe)5 R8 and R9 are both -H, (Ci-C3)alkyl or hydroxy(C]-C3)alkyl. More specifically, R8 and R9 are -H5 methyl or hydroxymethyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment.
In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb)5 (IXc)-(XIIIc)5 (XVc)5 (IXd)-(XIIId)5 (XVd)5 (IXe)-(XIIIe) and (XVe)5 one of R8 and R9 is -H5 the other one is a (C]-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl5 hydroxy(CrC6)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy5 (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C)-C6)alkyl and (C3-C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment. Even more particularly, one of R8 and R9 is -H, the other one is a (Ci-C3)alkyl optionally substituted(C3-C8)cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran).
In another more specific embodiment, for compounds of Structural Formulas (IXb)-(XIIIb), (XVb), (IXc)-(XIIIc), (XVc), (IXd)-(XIIId)5 (XVd)5 (IXe)-(XIIIe) and (XVe)5 one Of R8 and R9 is -H, the other one is a (C2-C6)alkenyl optionally substituted withl to 3 substituents independently selected from the group consisting of -F, -Cl. -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy5 halo(Cr C3)alkoxy. (C3-C8) cycloalkyl and (C3-C8)cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment. Even more particularly, substituents are selected from the group consisting of (Ci-C3)alkyl and hydroxy(d-C3)alkyl.
In another more specific embodiment, for compounds of Structural Formula (IXb)- (XIIIb)5 (XVb), (IXc)-(XIIIc)5 (XVc), (IXd)-(XIIId), (XVd), (IXe)-(XIIIe) and (XVe)5 one of Rg and R9 is -H and the other is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment. In another specific embodiment, for compounds of Structural Formulas (IXb(EXb)-
(XIIIb)5 (XVb)5 (EXc)-(XIIIc), (XVc), (IXd)-(XIIId), (XVd), (EXe)-(XIIIe) and (XVe), one of Rg and R9 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]-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, (Ci- C3)alkylcarbonyl and (Ci-C3)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 15th 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 R8 and R9 is -H and the other is monocylic (C3-C8)cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C9-C j4)cycloalkyl (such as 6,7,8,9-tetrahydro-5H- benzo[7]annulene, 2.3-dihydro- 1 H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C3-C7)cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C8- Ci3)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 subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br. -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl. (C)-C3)alkoxy, halo(C]-C3)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, (C1- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (CrC3)alkoxy or halo(CrC3)alkoxy. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment. In another even more specific embodiment, one of R8 and R9 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-l H-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, (Ci-C6)alkyl, halo(d-C6)alkyl, hydroxy(CrC6)alkyl, (Ci- C3)alkoxy, halo(Ci-C3)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, (C1-C6)alkyl, halo(CrC6)alkyl, hydroxy(C]-C6)alkyl, (Ci-Cs)alkoxy or 1IaIo(C1 -C3)alkoxyl. Values and specific values for the remainder of the variables are as described above in the 15th specific embodiment. In another specific embodiment, for compounds of Structural Formulas (IXb)- (XIIIb), (IXc)-(XIIIc), (IXd)-(XIIId) and (IXe)-(XIIIe), one Of R8 and R9 is -H and the other is (C3-C8)cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C3-
C7)cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C,-C3)alkoxy and halo(CrC3)alkoxy. More specifically, the substitutents (Cj-C6)alkyl. Values and specific values of the remainder of the variables are as described above in the 15th specific embodiment.
In a 16th 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: RJ0 is -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRuS(=0)iR5, -COOR5,
-CONR12Ri3, -NRnC(=0)R5, -C(^S)NRi2R13, -COR5; (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, or (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci- C6)alkyl, (Cj-C3)alkylcarbonylamino(Ci-C6)alkyl, or (C1-C6)alkoxy(Ci-C3)alkyl; s is O, 1 or 2; one of R8 and R9 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-lH-indene, tetrahydronaphihalene, 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, (d- C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C,-C6)alkyl, (Ci-C3)alkoxy, halo(d-C3)alkoxy, (C1- C3)alkylcarbonyl and (Ci-C3)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, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci- C6)alkyl, hydroxy(CrC6)alkyl, (CrC3)alkoxy or halo(Ci-C3)alkoxyl.; R, is -H:
R3 and R4 are indpendently selected from the group consisting of -H. -F, -Cl, -Br and (Ci-C3)alkyl: R5 is (Ci-C6)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl or pyrrolidinyl;
R6 and R7 are -H;
R11 Is -H;
Ri2 and Ri3 are independently -H, (Ci-C6)alkyl, (Ci-C3)alkoxy(CrC3)alkyl, hydroxy(C)-C3)alkyl, cyano(CrC3)alkyl, or di(Ci-C3)alkylamino(Ci-C3)alkyl;
Ri4 is (Ci-C6)alkyl, halo(C]-C3)alkyl, (C3-C8)cycloalkyl(CrC3)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), Ri0 is -CN, -F, -Cl, or -Br; and the remainder of the variables are as described above in the 16th 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 R8 and R9 is -H, the other is phenyl, tetrahydrofuran, tetrahydropyran, cyclopentane. cyclohexane, cycloheplane, oxepane. 1,3-dioxane. piperidine, 6,7,8,9- tetrahydro-5H-benzo[7]annulene, 23-dihydro-l H-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 16th specific embodiment In another embodiment of the present invention, the compounds are listed in the following table:
Compound STRUCTURE
No.
1
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
- Ill -
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000131_0002
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Also included in the present invention are all possible stereoisomers of compounds 1-531 depicted above.
When any variable (e.g.. aryl. heterocyclyl, R1, R2, 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, "(Ci-C6)alkyl" means a radical having from 1-6 carbon atoms in a linear or branched arrangement. "(Ci- C6)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 subsitutions 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, "(C2-C6)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, "(C2-C6)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 (C3-C8)cycloalkyl means a radical having from 3-8 carbon atoms arranged in a ring. Monocyclic (C3-C8)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 subsituted with -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (Ci-C6)alkyl, halo(C]-C6)alkyl or (Ci-C3)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-l,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 sytems 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 subsituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (Ci-C6)alkyl, halo(CrC6)alkyl or (Ci-C3)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 moncyclic 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 (C3-C6)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-lH-indene, octahydro- lH-indene, tetrahydronaphthalene, decahydronaphthalene, indoline, isoindoline, 2.3- dihydro-lH-benzo[d] imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3- dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole, octahydro- 1 H-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[3.3.1.03'7]nonane (noradamantane) and tricyclo[3.3.1.13'7]decane (adamantane) and 2,3-dihydro-lH-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 subsituted with H, alkyl, cycloalkyl, cycloalkylalkyl. aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (Ci-C6)alkyl, halo(Ci-C6)alkyl or (Ci-C3)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 polycylic 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. "(Ci- C4)-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, (C3-C8)cycloalkene means a radical having from 3-8 carbon atoms arranged in a ring. (C3-C8)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 subsituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (Ci-C6)alkyl, 1IaIo(C1 -C6)alkyl or (Ci-C3)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 "S1" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "/?*" and "iS*" 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 " ^w^ " which represents
Figure imgf000172_0001
"R," "S5" "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 neurofibrillar)' 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 Structrual 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 (IC50) against BACE of between about 50 μM to about 0.01 nM; between about lOμM 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).
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0002
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 Scheme 1
Figure imgf000183_0001
(A4)
(A5) (A6)
Scheme 2
Figure imgf000184_0001
R2 is aryl or heteroaryl
Figure imgf000184_0002
Figure imgf000184_0003
(A7) (A8) when R8 and/or R9 is not aryl
Figure imgf000184_0004
(A7) (A8) when R« and/or R9 is aryl
Figure imgf000184_0005
(A7) (A8) Scheme 3 MeNHOH
Figure imgf000185_0001
Figure imgf000185_0002
Suzuki R2B(OH)2 R2 is aryl or heteroaryl
Figure imgf000185_0003
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.
EXEMPLIFICATION
Example 1 3-(2'-amino-r-methyl-5'-oxo-2-(tetrahydro-2H-pyran-3-yl)-l ',5'-dihydrospiro[chro man-
4,4'-imidazole]-6-yl)benzonitrile (compound 1)
Figure imgf000185_0004
Experimental data:
Figure imgf000186_0001
Step 1. 556-dihydro-2H-pyran-3-carbaldehyde
140 g of water, 186 g Of CH2Cl2, H3PO4 (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 CH2Cl2. Distillation of the organic phase gave 5,6-dihydro-2H-pyran-3-carbaldehyde (25 g. 40%). 1H-NMR (CDCl3): 2.41 (d, 2H), 2.69 (t, IH), 3.74 (t, 4H), 3.90 (t, IH), 4.31 (s, 2H), 6.81 (m, IH), 9.46 (s, IH).
Figure imgf000186_0002
Step 2. tetrahydro-2H-pyran-3-carbaldehyde
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 H2 at 50Psi. The mixture was concentrated in vacuo to give tetrahydro- 2H-pyran-3-carbaldehyde (20 g, 100%). 1H-NMR (CDCl3): 2.40 (t, 2H), 3.74 (t, 2H), 4.27 (m, 2H)5 6.89 (m, IH), 9.36 (t, IH).
Figure imgf000186_0003
Step 3. 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (19.45 g, 90.9 mmol), tetrahydro-2//-pyran-3-carbaldehyde (10 g, 90.9 mmol) and borax (34.6 g, 90.9 mmol) in ethanol (120 mL) and H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2- (tetrahydro-2H-pyran-3-yl)chroman-4-one (4 g, 15%). 1H-NMR (CDCl3): 1.30 (m, 2H), 1.48 (m, 5H), 1.64 (m, 4H), 1.94 (d, 2H), 6.86 (d, IH), 7.51 (dd, IH), 7.92 (d, IH).
Figure imgf000187_0001
Step 4. 6-bromo-2-(tetrahydro-2//-pyran-3-yl)spiro[chroman-4,4'-imidazolidine]-2',5'- dione
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 (MLt)2CO3 (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 Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column to give 6-bromo-2-(tetrahydro-2//-pyran-3-yl)spiro[chroman-4,4'- imidazolidine]-2',5'-dione (1.5 g, 30%). 1H-NMR (MeOD): 1.20 (s, 1Η), 1.42 (s, 1Η), 1.65 (m, 2Η), 1.89 (m, 2H), 2.01 (m, IH), 2.19 (m, IH), 3.40 (m, 2H), 3.85 (m, 2H), 4.10 (m, IH), 6.79 (d, IH), 7.23 (s, IH), 7.33 (t, IH).
Lawesson's reagent 1,4-dιoxane
Figure imgf000187_0003
Figure imgf000187_0002
Step 5. 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2'-thioxospiro[chroman-4,4'-imidazolidin]- 5'-one
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 0C 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%).
Figure imgf000188_0001
Step 6. 6-bromo-l'-methyl-2'-(methylthio)-2-(tetrahydro-2//- pyran-3-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one
To a solution of 6-bromo-2-(tetrahydro-2/f-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-l'-methyl-2'-(methylthio)- 2- (tetrahydro-2H- pyran-3-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 100%).
Figure imgf000188_0002
Step 7. 2'-amino-6-bromo-l '-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one
A solution of 6-bromo- 1 '-methyl-2'-(methylthio)-2-(tetrahydro-2//-pyran-3- yl)spiro[c- hroman- 4:4'-imidazol]-5'(l'H)-one (20 mg5 0.047 mmol), NH4I (54.5 mg, 0.37 mmol) in a solution of NH3/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-r-methyl-2-(tetrahydro-2//-pyran-3-yl)spiro[chroman-4.4'-imidazol]- 5'(l'H)-one (20 mg, 100%).
Figure imgf000189_0001
Step 8. 3-(2'-amino-r-methyl-5'-oxo-2-(tetrahydro-2H-pyran-3-yl)-r,5'- dihydrospiro[chro man-4,4'-imidazole]-6-yl)benzonitrile (compound 1)
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4.4'-imidazol]- 5'(l'H)-one (20 mg, mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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 ΗPLC to give pure 3-(2'-amino- 1 '-methyl-5'-oxo-2-(tetrahydro-2H-pyran-3-yl)-r,5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (2.51 mg, 10%). 1H-NMR (MeOD): 1.69 (t, 2H), 1.91 (m, 2H), 2.18 (t, IH), 2.41 (d, IH), 3.08 (t, 2H), 3.24 (s, 3H), 3.49 (m, 2H), 3.88 (dd, 2H), 4.40 (m, IH), 7.05 (d, IH), 7.50 (m, IH), 7.61 (m, 3H), 7.86 (t, IH), 7.94 (d, IH).
Example 2.
3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (Compound 2)
Figure imgf000189_0002
Pd(PPh3)4 (28 mg, 0.073 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]-5'(7 'H)-one (28 mg, 0.073 mmol) in toluene (4.4 mL), Na2CO3 (2 N, 2.2 mL) and 4-cyanophenylboronic acid (12.9 mg, 0.088 mmol). The mixture was refluxed under Ar for 3-5 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-r-methyl-5'-oxo-2-phenyl- l'J'-dihydrospirotchroman^^'-imidazoleJ-ό-yObenzonitrile (2.58 mg, 9%). 1H-NMR (CDCl3): 0.92 (m, IH), 1.07 (m, IH), 1.75 (s, 3H), 4.32 (d, IH), 5.62 (d, IH), 5.82-5.98 (m, 5H)5 6.06 (m, 2H), 6.15 (m, 2H), 6.47 (d, IH), 6.46 (s, IH).
Example 2a. Synthesis of Compound 2a
Figure imgf000190_0001
Pd(PPh3 )4 (60 mg, 0.052 mmol) in a 100 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]-5'(lΗ)-one (100 mg, 0.26 mmol) in toluene (15.6 mL), Na2CO3 (2 N, 7.8 mL), and 4-cyanophenylboronic acid (76.5 mg. 0.52 mmol). The mixture was refluxed under Ar for 3-5 h. 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-r-methyl-5'-oxo-2-phenyl- r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (31 mg, 29%) as a racemic product. 1H-NMR (CDCl3): 2.18 (m, IH), 2.29 (t, IH), 3.13 (s, 3H), 5.90 (d, IH), 7.05 (d, IH), 7.25 (m, IH), 7.34 (m, IH), 7.38 (m, 2H), 7.45 (m, 2H), 7.50-7.64 (m, 3H), 7.82-7.87 (m, 2H).
Example 3
3-(2;-amino-2-cyclohexy-l '-methyl-5:-oxo-l :.5'- dihydrospiro[chroman-4,4:- imidazole]-
6-yl)benzonitrile (Compound 3)
Figure imgf000191_0001
Experimental data:
Figure imgf000191_0002
Step 1. 6-bromo-2-cyclohexylchroman-4-one
A mixture of l-(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 H2O (500 mL) was refluxed overnight. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. 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%). 1H-NMR (CDCl3): 1.05-1.33 (m, 5H), 1.67-1.81 (m, 5H), 1.95 (d, IH), 2.64 (m, 2H), 4.15 (m, IH), 6.86 (d, IH), 7.51 (m, IH), 7.94 (s, IH).
Figure imgf000191_0003
Step 2. 6-bromo-2-cyclohexylspiro[chroman-4,45-imidazolidine]-2;,5'-dione A mixture of 6-bromo-2-cyclohexylchroman-4-one (1.5 g, 5 mmol), KCN (0.63 g, 10 mmol), (NH4)2CO3 (3.6 g, 37.5 mmol) in HCONH2 (3OmL) 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 Na2SO4, 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%). 1H-NMR (CDCl3): 1.11-1.30 (m, 5H), 1.74 (m, 2H), 1.83 (m, 2H) 1.97 (m, 2H), 2.04 (d, IH), 2.25 (d, IH), 4.59 (m, IH), 5.56 (s, IH), 6.78 (d, IH), 7.30 (m, 2H), 7.82 (s, IH).
Figure imgf000192_0001
Step 3. 6-bromo-2-cyclohexyl-2 ' -thioxospiro [chroman-4,4 ' -imidazolidin] -5 ' -one
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%). 1H-NMR (CDCl3): 0.78-0.92 (m, 2H), 1.13 (m, IH), 1.17-1.31 (m, 3H), 1.71 (m, 2H), 1.78 (m, 2H), 1.94 (d, IH), 2.05 (t, IH), 2.61 (d, IH), 4.91 (m, IH), 6.78 (d, IH), 7.04 (s, IH), 7.13 (s, IH), 7.32 (d, IH), 9.33 (s, IH).
Figure imgf000192_0002
Step 4. 6-bromo-2-cyclohexyl-r -methyl -2'- (methylthio)spiro[chroman-4,4'- imidazol]- 5'(l'H)-one
A mixture of 6-bromo-2-cyclohexyl-2'-thioxospiro[chroman-4,4'-imidazolidin]- 5'-one (57x5 mg, 0.75 mmol), NaOH solution (0.6.N, 0.7x5 mL), CH3I (0.2x5 mL) in methanol (4x5 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-r-methyl-2'-(methylthio) spiro[chroman- 4,4'-imidazol]-5'(l'H)-one (170 mg, 56%).
Figure imgf000193_0001
Step 5. 2'-amino-6-bromo-2-cyclohexy-l '- methylspiro[chroman- 4.4'-imidazol]- 5'(1 'H)- one
A solution of 6-bromo-2-cyclohexyl-r-methyl-2'-(methylthio)spiro[chroman-4,4'- imidazol]- 5'(I 'H)-one (170 mg, 0.40 mmol), NH4I (1 17 mg, 0.80 mmol) in a solution of NH3/EtOH (10 mL, 1.5 N) was heated at 120 0C 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-l '- methylspiro[chroman- 4,4'-imidazol]-5'(l 'H)-one (90 mg, 57%).
Figure imgf000193_0002
Step 6. 3-(2'-amino-2-cyclohexy-l '-methyl-5'-oxo-l ',5'-dihydrospiro[chroman- 4.4'- imidazole] -6-yl)benzonitrile
A mixture of 2"-amino-6-bromo-2-cyclohexy-r- methylspiro[chroman- 4.4'- imidazol]- 5'(l 'H)-one (30 mg. 0.08 mmol), 3-cyanophenylboronic acid (23 mg, 0.15 mmol), Pd(PPh3)2Cl2 (20 mg). aqueous cesium carbonate solution (2 M, 0.5mL) 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-r-methyl-5'-oxo-r,5'- dihydrospiro[chroman-4,4'- imidazole] -6-yl)benzonitrile (18.2 mg, 56%). 1H-NMR (MeOD): 1.22-1.39 (m, 4H), 1.69-1.86 (m, 4H), 2.01 (s, IH), 2.13-2.24 (m, IH), 2.28-2.46 (m, IH), 3.12 (s, IH), 3.27-3.36 (m, 3H), 4.63 (m, IH), 7.06 (m, IH), 7.49 (s, IH), 7.57- 7.76 (m, 3H), 7.86 (t, IH), 7.94 (d, IH).
Example 4.
5-(2 '-amino- 1 '-methyl-5 '-oxo-2-phenyl- 1'.5 '- dihydrospiro [chroman-4,4'-imidazole] -6-yl)- 2- fluorobenzonitrile (Compound 4)
Figure imgf000194_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- cyano-4-fluorophenylboronic acid (17 mg, 0.104 mmol). The mixture was heated under Ar at 120 °C under microwave for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 5- (2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)-2- fluorobenzonitrile (7 mg, 32%). 1H-NMR (MeOD): 2.15 (m, IH), 2.29 (t, IH), 3.12 & 3.18 (s, 3H), 5.30 & 5.89 (m, IH), 7.03 (m, IH), 7.21 (m, IH), 7.31-7.50 (m, 6H); 7.85 (m, 2H).
Example 5.
5-(2'-amino- l'-methyl-5'-oxo-2-phenyl- 1 '.5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)nicotinonitrile (Compound 5)
Figure imgf000195_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-nicotinonitrile (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 to give pure 5-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)nicotinonitrile (6.27 mg, 30%). 1H-NMR (MeOD): 2.04 (d, IH), 2.20 (m, IH), 3.06 (m, 3H), 5.24 (d, 0.3H), 5.82 (d, 0.7H), 7.01 (m, IH), 7.36 (m, 6H), 7.50 (m, IH), 8.29 (m, IH), 8.70 (m, IH), 8.89 (m, IH).
Example 6. Synthesis of Compound 8a and 8b
Figure imgf000195_0002
Experimental data:
Figure imgf000196_0001
Step 1. 6-bromo-2-thiophen-2-yl-chroman-4-one
A mixture of l-(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 H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-thiophen-2- yl-chroman-4-one (16 g, 50%). 1H-NMR (CDCl3): 3.01 (m, IH), 3.10 (m, IH), 5.75 (dd, IH), 6.94 (d, IH), 7.02 (t, IH), 7.05 (d, IH), 7.32 (d, IH), 7.54 (dd, IH), 8.00 (d, IH).
Figure imgf000196_0002
Step 2. 6-bromo-2-(thiophen-2-yl)spiro[chroman-4,4'-imidazolidine]-2'.5'-dione 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 (NH4^CO3 (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 0C 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 Na2SO4, 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%).
Lawsson's Reagent
Figure imgf000196_0004
Figure imgf000196_0003
Step 3. 6-bromo-2-(thiophen-2-yl)-2'- thioxospiro[chroman- 4,4'-imidazolidin]-5'-one 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%). 1H- NMR (CDCl3): 2.41 (m, IH), 2.55 (dd, IH), 6.04 (dd, IH), 6.80 (d, 1H): 6.94 (t, IH), 7.12 (d, IH), 7.33 (m, 3H).
Figure imgf000197_0001
Step 4. 6-bromo-l '-methyl-2'-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4,4'- imidazol]- 5'(l'H)-one
To a solution of 6-bromo-2-(thiophen-2-yl)-2'-thioxospiro[chroman-4,4'-imidazo- lidin]-5'-one (100 mg, 0.254 mmol) in MeOH (6 mL) was added a solution of NaOH (20.32 mg, 0.508 mmol) in H2O (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-r-methyl-2'-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4.4'- imidazol]-5'(l'H)-one (20 mg, 20%). 1H-NMR (CDCl3): 2.22 (d, IH), 2.41 (t, IH), 2.74 (s, 3H), 3.02 (s, 3H), 6.12 (d; IH), 6.80 (d, IH), 6.94 (m, 2H), 7.31 (m, IH), 7.33 (m, 2H).
Figure imgf000197_0002
Step 5. 2'-amino-6-bromo-r-methyl-2-(thiophen-2-yl)spiro[chroman-4,4'-imidazol]- 5'(1'H) -one
A solution of 6-bromo- 1 '-methyl-2'-(methylthio)-2-(thiophen-2-yl)spiro[chroman- 4,4'- imidazol]-5'(l'H)-one (20 mg, 0.047 mmol), NH4I (13.7 mg, 0.094 mmol) in a solution of NH3/EtOH (2 mL, 2 N) was heated at 110 0C 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-l'-methyl-2- (thiophen-2- yl)spiro[chroman-4,4'-imidazol]-5'(l'H)- one (5 mg, 20%). 1H-NMR (CDCl3): 2.52 (m, 2H), 3.14 (s, 3H), 6.12 (d, IH), 6.94 (d, IH), 7.02 (t, IH), 7.14 (d, IH), 7.43 (t, 3H).
Figure imgf000198_0001
Step 6. 3-((25')45)-2I-amino-r-methyl-5'-oxo-2-(thiophen-2-yl)-r,5'-dihydrospiro[chrom- an-4,4'-imidazole]-6-yl)benzonitrile
Pd(PPh3 )2C12 (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'(rH)-one (46 mg, 0.117 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (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)-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (Compound 8a, 1.35 mg, 1%), 1H-NMR (CDCl3): 442-069-3B: 2.30 (d, IH), 2.49 (d, IH), 3.01 (d, 3H), 5.81 (dd, IH), 6.95 (t, IH), 7.00(m, 2H), 7.05 (s, IH), 7.30 (d, IH), 7.40 (d, IH), 7.49 (d, IH), 7.51 (t, IH) , 7.61 (t, 2H), and
3-((2R, 4S)-T- 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%). 1H-NMR (CDCl3): 2.40 (d, IH), 2.63 (t, IH), 3.31 (s, 3H), 6.12 (d, IH), 6.95 (t, IH), 7.00(d, IH), 7.05 (m, 2H), 7.30 (d, IH), 7.48 (m, 2H), 7.54 (d, IH), 7.68 (t, 2H).
Example 7
3 -(2'-amino-2 -(2-fluorophenyl)- 1 '-methyl-5 '- oxo- 1 ',5 '-dihydrospiro [chroman-4,41- imidazole]-6-yl)benzonitrile (Compound 9) Lawsεon's Reagent
Figure imgf000199_0002
Figure imgf000199_0001
Figure imgf000199_0003
A mixture of l-(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 H2O (150 mL) was reflux ed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman- 4-one (15 g, 50%). 1HNMR (CDCl3): 2.8 (d, IH), 3.0 (t, IH), 5.7(d, IH)5 6.7 (d, IH), 6.9 (t, IH), 7.2 (m, 2H), 7.3 (m, 2H), 7.5 (m, 2H), 7.9 (t IH), 8.1 (d, IH).
Figure imgf000199_0004
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 (NH4^CO3 (4.5 g, 46.87 mmol). Formamide (25 mL) is added to fill the steel bomb nearly completely. The mixture was heated at 700C for 48 h then at 1100C for another 8 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCI yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na2SO4, 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%). 1H-NMR (CDCl3): 2.3 (t, IH), 2.5 (d, IH), 5.6 (s, IH), 6.2 (d, IH), 6.9 (t, IH), 7.1 (t, IH), 7.2 (t, IH), 7.4 (m, 3H), 7.6 (t, IH), 7.9 (s, IH).
Step 3:
Lawsson's Reagent
Figure imgf000200_0001
Figure imgf000200_0002
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%). Step 4:
Figure imgf000200_0003
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 H2O (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'(7 'H)- one (80 mg, 41%). Step 5:
Figure imgf000201_0001
A solution of 6-bromo-2-(2-fluorophenyl)- 1 '-methyl-2'-(methylthio)spiro[chroman- 4,4'-imidazol]-5'(7 'H)-one (80 mg, 0.183 mmol) and NH4I (53.21 mg, 0.367 mmol) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at HO0C 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'(i Η)-one (52 mg, 70%). 1H-NMR (MeOD): 2.15 (d, IH), 2.25 (d, IH), 3.20 (s, 3H), 6.15 (d, IH), 6.78 (d, IH), 6.99 (t, IH), 7.05 (s, IH), 7.15 (t, IH), 7.25 (d, 2H), 7.50 (t, IH).
Step 6:
Figure imgf000201_0002
Pd(PPh3)4 (3.84 mg, 0.1 mmol) was added to the solution of 2'-amino-6-bromo-2-(2- fiuorophenyl)-^-methylspiro[chroman-4,4'-imidazol]-5Xi 'H)-one (42 mg, 0.1 mmol) and 3-cyanophenylboronic acid (18.3 mg, 0.12 mmol) in dimethy-benzene (6.6 mL) and an aqueous solution OfNa2CO3 (2 M, 0.23 mL). The mixture was heated at 9O0C 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-fiuorophenyl)-r- methyl-5'- oxo-r.5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (2.2 mg. 0.5%). 1H-NMR (MeOD): 2.5 (d, IH), 3.30 (t, IH), 3.5 (s, 3H), 6.35 (d, IH), 7.2 (t, 2H), 7.3 (d, 2H), 7.65 (t, 3H), 7.75(s, 2H), 7.85 (d, 2H).
Example 8.
2'-amino-6-(3-cyclopropylphenyl)-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]-
5'(VH)-OnC (Compound 11)
Figure imgf000202_0001
Experimental data:
Figure imgf000202_0002
Step 1. 4,4,5.5-tetramethyl-2-(3-vinylphenyl)-l,3.2-dioxaborolane l-Bromo-3-vinylbenzene (1 g, 5.5 mmol), bis(pinacolaco) (1.5 g, 6 mmol), K2CO3 (2.3 g, 16.5 mol) and Pd(PPh3)2Cl2 (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 Na2SO4 and concentrated in vacuo to give 4,4,5, 5-tetramethyl-2-(3- vinylphenyl)-l,3,2-dioxaborolane (500 mg, 16%).
Figure imgf000202_0003
Step 2. 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane
To a solution OfZn(C2H5)? (I M, 6mL) in DCM (1 mL) was added trifluoro-acetic acid (0.46 ml. 6 mmol) in DCM (1 mL) very slowly under N2 in ice bath. The mixture was stirred for 20 minutes. CH2I2 (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 NH4Cl 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-l,3,2-dioxaborolane (70 mg, 10%).
Figure imgf000203_0001
Step 3. 2'-amino-6-(3-cyclopropylphenyl)- 1 '-methyl-2-phenylspiro[chroman-4.4'- imidazol]-5'(l'H)-one
Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2'-amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(1'/0-(HIe (HO mg, 0.29 mmol) in 1,4-dioxane (5.0 mL), Cs2CO3 (2 N, 1 mL) and 2-(3- cyclopropylphenyl)- 4,4,5, 5-tetramethyl-l,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)-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one (3.6 mg, 3%). 1H-NMR (MeOD): 0.71 (m, IH), 0.98 (m, IH), 1.97 (m, IH), 2.31 (m, IH), 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, IH), 7.12 (m, 2H);7.23 (m, 2H), 7.28 (m, 2H), 7.46 (m, 6H).
Example 9 3-(2'-amino-r-ethyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (Compound 12)
Figure imgf000204_0001
Step 1 :
Figure imgf000204_0002
To a mixture of 6-bromo-2-phenyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (250 mg, 0.64 mmol) and K2CO3 (356 mg, 2.6 mmol) in CH3CN (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-r-ethyl-2'-(ethylthio)-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (195 mg, 69%).
Step 2:
Figure imgf000204_0003
A solution of 6-bromo-r-ethyl-2'-(ethylthio)-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (195 mg, 0.44 mmol) and NH4I (128 mg, 0.88 mmol) in a solution of NH3/EtOH (5 mL, 1.5 N) was heated at HO0C 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-r-ethyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (42 mg; 24%). 1H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, IH), 3.16 (m, IH), 3.54 (m, 2H), 5.75 (m, IH)5 6.77 (m, IH), 6.95 (m, IH)5 7.23 (m, 2H)5 7.33 (m, 4H).
Step 3:
Figure imgf000205_0001
Pd(PPh3 )4 (40 mg, 0.10 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r-ethyl-2-phenylspiro[chroman-4.4'-imidazol]-5'(rH)-one (42 mg, 0.10 mmol) in toluene (5 mL), Na2CO3 (2 N5 2 mL)5 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-r-ethyl-5'-oxo-2-phenyl-r,5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (1.76 mg, 3%). 1H-NMR (MeOD): 1.31 (m, 3H), 2.55 (m, 2H), 3.84 (m, 2H), 5.26 (m, IH)5 5.86 (m, IH), 7.14 (m, IH)5 7.47 (m, 6H)5 7.59 (m, IH)5 7.28 (m, 2H)5 7.90 (m, 2H).
Example 10
2'-amino-6-(3-methoxyphenyl)-r-methyl- 2-phenylspiro[chroman-4,4'- imidazol]-5'(l 'H)- one (Compound 13)
Figure imgf000205_0002
Pd(PPh3 )2C12 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2- phenylspiro[chroman-4,4'- imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- methoxyphenylboronic acid (16 mg, 0.104 mmol). The mixture was heated under 120 0C 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 T- amino-6-(3-methoxyphenyl)-l '-methyl- 2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (1.69 mg, 8%). 1H-NMR (MeOD): 2.05 (m, IH), 2.21 (m, IH), 3.06 (m, 3H), 3.72 (s, 3H), 5.19 (m, 0.3H), 5.81 (m, 0.7H), 6.76 (m, IH), 6.91 (m, 2H), 6.97 (m, IH), 7.08 (m, IH), 7.21 (m, IH), 7.26 (m, IH), 7.33 (m, 2H), 7.39 (m, 2H), 7.57 (m, IH).
Example 1 1
3-(2 ' -amino-2-(2,3 -difluorophenyl)- 1 ' -methyl-5 ' -oxo- 1 ' ,5 ' -dihydrospiro [chroman-4,4 ' imidazole]- 6-yl)benzonitrile (Compound 14)
Figure imgf000206_0001
Experimental data:
Figure imgf000206_0002
Step 1. 6-bromo-2-(3-flurophenyl)chroman-4-one
A mixture of l-(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 H2O (234 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3- flurophenyl)chroman-4-one (5.3 g, 15%). 1H-NMR (CDCl3): 2.95 (d, IH), 3.05 (t, 3H), 5.75 (d, IH), 6.97 (d, IH), 7.20 (m, 2H), 7.35 (m, IH), 7.60 (d, IH), 8.05 (s, IH).
Figure imgf000207_0001
Step 2. 6-bromo-2-(2,3-difluorophenyl)spiro[chroman- 4,4'-imidazolidine]- 2',5'-dione
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-O2CO3 (2.96 g, 30.8 mmol) in HCONH2 (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 Na2SO4, 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%). 1H-NMR (CDCl3): 2.34 (t, IH), 2.54 (d, IH), 5.50 (s, IH), 6.18 (d, IH), 6.91 (m, IH), 7.16 (m, 3H), 7.28 (m, IH), 7.39 (m, 2H), 7.70 (s, IH).
Figure imgf000207_0002
Step 3. 6-bromo-2-(2,3-difluorophenyl)-2'- thioxospiro [chroman-4,4'-imidazolidine]-5'- one
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 0C 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-4,41- imidazolidine]-5'-one (163 mg, 74%). 1H-NMR (CDCl3): 2.33 (t, 3H), 2.54 (d, IH), 5.36 (s, IH), 6.17 (d, IH), 6.91 (d, IH), 7.17 (m, 3H), 7.30 (m, 2H), 7.46 (s, IH).
Figure imgf000208_0001
Step 4. 6-bromo-2- (2,3-diflurophenyl) -r-methyl-2'-(methylthio)spiro[chroman-4,4'- imidazol]- 5'(l '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 H2O (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-diflurophenyl) -r-methyl-2;-(methylthio)spiro[chroman-4.4'- imidazol]- 5'(l 'H)-one (63 mg, 16%). 1H-NMR (CDCl3): 2.06 (d, IH), 2.47 (t, IH), 2.58 (s, 3H), 3.12 (s, 3H), 6.23 (d, IH), 6.86 (m, 2H), 7.14 (m, 2H), 7.31 (m, 2H).
Figure imgf000208_0002
Step 5. 2'-amino-6-bromo-2- (2,3-difluorophenyl)-r-methylspiro [chroman-4,4'- imidazol]- 5'(1 'H)- one
A solution of 6-bromo-2- (2,3-diflurophenyl) -r-methyl-2'-(methylthio) spiro[chroman- 4,4'-imidazol]-5'(rH)-one (63 mg, 0.14 mmol), NH4I (60.6 mg, 0.42 mmol) in a solution of NH3/EtOH (3 mL. 1.5 N) was heated at 1 10 °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)-r-methylspiro [chrornan-4,4:-imidazol]- 5'(1 'H)- one (35 mg, 60%). 1H- NMR (CDCl3): 2.31 (d, IH), 2.45 (t, IH), 3.27 (s, 3H), 6.12 (d, IH), 6.87 (rn. IH), 7.09 (m, 3H), 7.34 (m, 2H), 7.45 (m, IH).
Figure imgf000209_0001
Step 6. 3-(2'-amino-2-(253-difluorophenyl)-l '- methyl-5'-oxo-l ',5'- dihydrospiro[chroman- 4,4'- imidazole]- 6-yl)benzonitrile
A mixture of 2'-amino-6-bromo-2- (2,3-difluorophenyl)-r-methylspiro [chroman- 4,4'-imidazol]-5'(r/f)-one (25 mg, 0.05 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.104 mmol), Pd(PPh3)2Cl2 (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)-r-methyl-5'-oxo-r,5'- dihydrospiro[chroman-4,4'- imidazole]- 6-yl)benzonitrile (7.02 mg, 27%). 1H-NMR (CDCl3): 2.20 (m, 2H), 3.12 (s, 3H), 6.25 (d, IH), 6.77 (d, IH), 7.13 (m, 3H), 7.29 (m, IH), 7.34 (d, IH), 7.43 (m, 1H),7.48 (m, 2H), 7.51 (m JH), 7.61 (d, IH), 7.68 (s, IH), 7.78 (d, IH).
Example 12
2'-amino-r-methyl-2-phenyl-6-(pyridin-3-yl)spiro[chroman-4,4'-imidazol]- 5'(lΗ)-one
(Compound 15)
Figure imgf000209_0002
Pd(PPh3 )2C12 (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'(l 7/)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and pyridin-3-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated under microwave at 120 0C 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-l'-methyl-2-phenyl-6-(pyridin-3-yl)spiro[chroinan- 4,4'-imidazol]- 5'(l'H)-one (18 mg, 80%). 1H-NMR (MeOD): 2.39 (t, IH), 2.52 (dd, IH), 3.28 (s, 3H), 5.80 (d, IH), 7.10 (d, IH), 7.31(m, 2H), 7.35 (m, 2H), 7.39 (m, 3H), 7.51 (s, IH), 7.61 (m, 2H), 8.19 (d, IH).
Example 13
3-amino-5-(2'-amino- 1 '-methyl-5'-oxo-2-phenyl- 1 ',5'-dihydrospiro[chroman-4,4'-im idazole]-6-yl)benzonitrile (Compound 17)
Figure imgf000210_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-l '-(cyclohexylmethyl)-2-phenylspiro[chroman-4.4'-imidazol]-5'(rH)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-amino-5- cyanophenylboronic acid hydrochloride (21 mg, 0.104 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 ΗPLC to give pure 3-amino-5-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro [chroman-4,4'-imidazole]-6-yl)benzonitrile (3.53 mg, 16%). 1H-NMR (MeOD): 2.44 (m, IH), 2.60 (m, 1H); 5.24 (d, 0.3H), 5.85 (d; 0.7H), 6.91 (m, IH), 7.14 (m, 3H), 7.48 (m, 6H), 7.60 (m, IH).
Example 14
3 -(2 '-amino- 1 '-(cyclohexylmethyl)-5'-oxo-2 -phenyl - 1 '.5 '-dihydrospiro [chroman-4,41- imidazole]-6-yl)benzonitrile (Compound 18)
Figure imgf000211_0001
Figure imgf000211_0002
Experimental data:
Figure imgf000211_0003
Step 1. 6-bromo-l '-(cyclohexylmethyl)-2'-(cyclohexylmethylthio)-2-phenylspirochroman- 4,4'-imidazol]-5'(l'H)-one
A mixture of 6-bromo-2-phenyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (180 mg, 0.464 mmol). excess bromomethyl-cyclohexane (327 mg, 1.856 mmol) and solid K2CO3 (256 mg, 1.856 mmol) in CH3CN (10 mL) was stirred for 4 hours at 60 0C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (71 mg. 26%).
Figure imgf000211_0004
Step 2. 2'-amino-6-bromo- 1 '-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]- 5'(11H)- one
A solution of 6-bromo-l '-(cyclohexylmethyl)-2'-(cyclohexylmethylthio)-2- phenylspiro chroman-4,4'-imidazol]-5'(rH)-one (70 mg, 0.293 mmol), NH4I (85 mg, 0.586 mmol) in a solution of NH3/EtOH (3 mL, 1.5 N) was heated at 120 0C 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-l'- (cyclohexylmethyl)- -phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (30 mg, 54%).
Figure imgf000212_0001
Step 3. 3-(2'-amino-r-(cyclohexylmethyl)-5'-oxo-2-phenyl-l ',5'-dihydrospiro[chroman- 4,4' -imidazole] -6-yl)benzonitrile
Pd(PPh3)2Cl2 (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'(l'H)-one (30 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (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 ΗPLC to give pure 3-(2'-amino-l'-(cyclohexylmethyl)-5'-oxo-2-phenyl-r,5'- dihydrospiro[chroman-4,4'- imidazole] -6-yl)benzonitrile (9.74 mg, 31%). 1H-NMR (MeOD): 1.02 (m, 5H), 1.62 (m, 6H), 2.03 (m, IH), 2.24 (m, IH), 3.30 (m, IH), 3.44 (m, IH), 5.91 (m, IH), 6.97 (m, IH), 7.16 (m, IH), 7.25 (m, IH), 7.35 (m, 3H), 7.46 (m, 2H), 7.56 (m, IH), 7.71 (m, 2H)
Example 15
3-(2'-amino-2-(4-fluorophenyl)-r-methyl-5'-oxo-r.5'-dihydrospiro[chrom- an-4,4'- imidazole]-6-yl)benzonitrile (Compound 19 and 19a)
Figure imgf000213_0001
Experimental data:
Figure imgf000213_0002
Step 1. 6-Bromo-2-(4-fluoro-phenyl)-chroman-4-one
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (30 g, 0.14 mol), 4-fluoro- benzaldehy- de (19.3 g. 0.14 mol) and borax (53.34 g, 0.14 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume OfH2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(4-fIuoro-phenyl)- chroman- 4-one (10 g, 20%). 1H-NMR (CDCl3): 2.81 (dd, IH), 2.99 (t, IH), 5.49 (dd, IH), 6.87 (d, IH), 7.04 (t, 2H), 7.38 (t, 2H), 7.51 (dd, IH) , 7.94 (d, IH).
Figure imgf000213_0003
Step 2. 6-bromo-2-(4-fluorophenyl)spiro[chrornan-4,4'- imidazolidine]-2',5'-dione
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 (NH4)2CO3 (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 Na2SO4 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%). 1H-NMR (MeOD): 2.19 (m, IH), 2.23 (m, IH), 5.76 (dd, IH), 6.78 (d, IH), 7.00 (t, 2H), 726 (t, 2H), 7.37 (m, 2H).
Lawsson's reagent
Figure imgf000214_0001
Figure imgf000214_0002
Step 3. 6-bromo-2-(4-fluorophenyl)-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one 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%).
Figure imgf000214_0003
Step 4. 6-bromo-2-(4-fluorophenyl)-r-methyl-2'-(methylthio)spiro-[chroman-4.4'- imidazol]-5'(rH)-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 N5 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)-r-methyl-2'- (methylthio)-spiro[chroman-4,4'-imidazol]-5'(rH)-one (80 mg, 50%).
Figure imgf000215_0001
Step 5. 2'-amino-6-bromo-(4-fluorophenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(l-
Η)-one
A solution of 6-bromo-2-(4-fluorophenyl)-r-methyl-2'-(methylthio)spiro[chroma -
4;4'-imi- zol]-5'(l'H)-one (80 mg, 0.184 mmol), NH4I (214 mg, 1.47 mmol) in a solution of NH3/EtOH (2 mL, 8 N) was heated at 120 °C in a tube under microwave reactor for 3h. After cooling, the mixture was concentrated in vacuum to give 2'-amino-6-bromo- -(4- fluorophenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(lΗ)-one (40 mg, 50%).
Figure imgf000215_0002
Step 6. 3-((25,45)-2'-amino-2-(4-fluorophenyl)-r-methyl-5'-oxo-r,5'-dihydrospiro [chroman-4,4'-imidazole]-6-yl)benzonitrile(6 mg, 10%) and 3-(2'-amino-2-(4- fluorophenyl)- r-methyl-5'-oxo-r,5'-dihydrospiro[chrom- an-4.4'-imidazole]-6- yl)benzonitrile (19).
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with
2'-amino-6- bromo-2-(4-fluorophenyl)- 1 '-methylspiro[chroman-4,4'-imidazol]-5'(l Η)-one (40 mg, 0.099 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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,45)-2'-amino-2-(4- fluorophenyl)- r-methyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile (19a) (6 mg, 10%), 1H-NMR (MeOD): 2.41 (t, IH), 2.60 (t, IH), 3.10 (s, 3H), 5.83 (d, IH), 7.16 (m, 3H), 7.52 (m, 2H), 7.60 (m, 2H), 7.69 (m, 2H), 7.90 (m, IH), 7.99 (d, IH), and 3-(2'-amino-2-(4-fluorophenyl)-l'-methyl-5'-oxo-l',5'- dihydrospiro[chrom- an-4,4'-imidazole]-6-yl)benzonitrile (19) (4 mg, 8%), 1H-NMR (MeOD): 2.42 (t, IH), 2.60 (t, IH), 3.20 (s, 3H), 5.87 (d, IH), 7.19 (m, 3H), 7.45 (m, 2H), 7.51 (m, IH), 7.54 (m, IH), 7.64 (m, 2H), 7.90 (t, IH), 7.99 (d, IH).
Example 16
3-(2'-amino-2-(3-chlorophenyl)-r-methyl-5'-oxo-r,5'-dihydrosρiro[chroman-4,4'- imidazole]-6-yl)benzonitrile (Compound 20)
Figure imgf000216_0001
Lawsson's Reagent
Figure imgf000216_0003
Figure imgf000216_0004
Figure imgf000216_0002
Figure imgf000216_0005
In a bottle l-(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 l-(5-bromo-2- hydroxyphenyl)-3-(3- chlorophenyl) prop-2-en-l-one (23.47 g, 60%). 1H-NMR (CDCl3): 6.88 (d, IH), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, IH), 7.80 (m, IH), 7.93 (m, IH), 12.56 (s, IH).
Step 2:
Figure imgf000217_0001
l-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-l-one (23 g, 68 mmol) was dissolved in H2O (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 H2O 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%). 1H- NMR (CDCl3): 2.87 (m, IH), 3.02 (m, IH), 5.44 (m, IH), 6.96 (d, IH), 7.31 (m, IH), 7.37 (m, 2H), 7.48 (s, IH), 7.58 (m, IH), 8.02 (d, IH).
Step 3:
Figure imgf000217_0002
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 (NHt)2CO3 (15 g, 156 mmol) in formamide (60 mL) was heated and stirred at 70 0C 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=l . The mixture is filtered to afford a solid, and the filtrate was extracted with CH2Cl2. The organic layer was concentrated to give a residue, which was combined with the solid above. The combinded solid was purified through column chromatography to give 6-bromo-2-(3- chlorophenyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione (470 mg, 5%). 1H-NMR (CDCl3): 2.20 (m, IH), 2.28 (m, IH), 5.76 (m, IH), 6.82 (m, IH), 7.27 (m, 5H), 7.39 (m, IH).
Step 4: Lawsson's Reagent
Figure imgf000218_0002
Figure imgf000218_0001
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 HO0C 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%). Step 5:
Figure imgf000218_0003
To a mixture of 6-bromo-2-(3-chlorophenyl)-2'-thioxospiro[chroman-4,4'- imidazolidin]-5'-one (250 mg, 0.6 mmol) and K2CO3 (327 mg, 2.4 mmol) in CH3CN (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)-l'-methyl-2'- (methylthio)spiro chroman-4,4'-imidazol]-5'(lΗ)-one (100 mg, 37%). 1H-NMR (CDCl3): 1.92 (m, IH), 2.41 (m, IH), 2.56 (s, 3H), 3.07 (s, 3H), 5.80 (m, IH), 6.80 (m, 2H), 7.26 (m, 4H), 7.39 (m, IH).
Step 6:
Figure imgf000218_0004
A solution of 6-bromo-2-(3-chlorophenyl)- 1 '-methyl-2'-(methylthio)spiro[chroman- 4;41-imidazol]-5'(l'H)-one (100 mg, 0.22 mmol) and NH4I (64 mg, 0.44mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at HO0C 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)-r methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (42 mg, 46%).
1H-NMR (MeOD): 2.12 (m, 2H), 3.06 (ss 3H), 5.80 (m, IH), 6.83 (m, IH), 7.03 (m, IH), 7.27 (m, 4H), 7.40 (m, IH).
Figure imgf000219_0001
Pd(PPh3 )4 (27 mg, 0.072 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-2-(3-chlorophenyl)-r-methylspiro[chroman-4,4'-imidazol]- 5'(I Η)-one (30 mg, 0.072 mmol) in toluene (5 mL), Na2CO3 (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[chrornan-4,4'-imidazole]-6- yl)benzonitrile (1.03 mg, 3%). 1H-NMR (MeOD): 2.63 (m, 2H), 3.22 (s, 3H), 5.34 (m, IH), 7.18 (m, IH), 7.41 (m, 3H), 7.54 (m, 2H), 7.10 (m, IH), 7.17 (m; 2H), 7.89 (m, IH), 7.98 (m, IH).
Example 17 3-(2'-amino-r-methyl-5'-oxo-2- phenyl- r,5'-dihydrospiro[chroman-4,4'-imidazole]- 6-yl)- 4-chlorobenzonitrile (Compound 21)
Figure imgf000219_0002
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2l-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]- 5'(11H)-OiIe (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2- chloro-5-cyanophenylboronic acid (18.9 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar under microwave for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2'- amino-r-methyl-5'-oxo-2- phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-4- chlorobenzonitrile (4.2 mg, 18%). 1H-NMR (MeOD): 2.38 (m, IH), 2.52 (m, IH), 3.15 (s, 3H), 5.18 & 5.76 (m, IH), 7.03 & 7.18 (m, IH), 7.26-7.64 (m, 10H).
Example 18
2'-amino-r-methyl-2-phenyl-6-(3-vinylphenyl)spiro[chroman-4, 4'-imidazol]-5'(rH) — one (Compound 22)
Figure imgf000220_0001
Pd(PPh3 )2C12 (15 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-l '-memyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.6 mL) and 3-vinylphenylboronic acid (29 mg, 0.19 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-l'-methyl-2-phenyl-6-(3- vinylphenyl)spiro[chroman-4, 4'-imidazol]-5'(rH)-one (3 mg, 6%). 1H-NMR (MeOD):
1.40 (s, 9H), 2.44 (m, IH), 2.61 (m, IH), 3.25 (s, 3H), 5.85 (d, IH), 6.14 (m, IH), 6.23 (m,
IH), 7.05 (m, IH), 7.16 (m, IH), 7.32 (m, 2H), 7.49 (m, 5H).
Example 19 3-(2'-amino-2-(3-methoxyphenyl)-r-methyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'- imidazole] -6-yl)benzonitrile (Compound 23)
Figure imgf000221_0001
Lawsson's Reagent NH4I
Figure imgf000221_0002
Figure imgf000221_0003
Experimental data:
Figure imgf000221_0004
Step 1. 6-bromo-2-(3-methoxyphenyl)chroman-4-one
A mixture of l-(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 H2O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume OfH2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3- methoxyphenyl)chroman-4-one (10 g, 36%). 1H-NMR (CDCl3): 2.71 (d, IH), 2.99 (t IH)5 3.75 (s; 3H), 5.38 (ds IH), 6.90 (m, 4H), 7.27 (t, IH), 7.51 (d, IH), 7.95 (s, IH).
Figure imgf000221_0005
Step 2. 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione
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 (NHU)2CO3 (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 Na2SO4, 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%). 1H-NMR (CDCl3): 2.21 (t, IH), 2.40 (d, IH), 3.41 (s, 3H); 5.74 (d, IH), 6.81 (d, 2H), 6.90 (t, 2H), 7.25 (m, 3H), 7.89 (s, IH).
Lawsson's Reagent
Figure imgf000222_0001
Figure imgf000222_0002
Step 3. 6-bromo-2-(3-methoxyphenyl)-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4t-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%).
Figure imgf000222_0003
Step 4. 6-bromo-2- (3-methoxyphenyl)-r-methyl-2'-(methylthio)spiro[chroman-4.4'- imidazol]-5'(l '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 H2O (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)-r-methyl-2'-(methylthio)spiro[chroman-4,4'-imidazol]- 5'(1T-O-OiIe (65 mg, 60%).
Figure imgf000223_0001
Step 5. 2'-amino-6-bromo-2-(3-methoxyphenyl)-l '-methylspiro[chroman-4,4'-imidazol]- 5'(lΗ)-one
A solution of 6-bromo-2-(3-methoxyphenyl)-r-methyl-2'-
(methylthio)spiro[chroman- 4,4'-imidazol]-5'(rH)-one (65 mg, 0.146 mmol), NH4I (42.26 mg, 0.3 mmol) in a solution of NH3/EtOH (2 mL, 8 N) was heated at 120 °C in a tube under microwave reactor for 2h. After cooling, the mixture was concentrated in vacuum to give 2'-amino-6-bromo-2-(3-methoxyphenyl)-r-methylspiro[chroman-4,4'-imidazol]- 5'(1T-O-OiIe (46 mg, 80%).
Figure imgf000223_0002
Step 6. 3-(2'-amino-2-(3-methoxyphenyl)-r-methyl-5'-oxo-r,5'-dihydrospiro[chroman- 4.4'- imidazole] -6-yl)benzonitrile
Pd(PPh3)2Cl2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 2'- amino-6-bromo-2-(3-methoxyphenyl)-r-methylspiro[chroman-4.4'-imidazol]-5'(rH)-one (46 mg, 0.11 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (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- r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (10 mg, 20%). 1H-NMR (CDCl3): 2.26 (m, IH), 2.48 (m, IH), 3.72 (s, 3H), 5.62 (m, IH), 6.79 (m, 3H), 6.94(d, IH), 7.12 (d, IH), 7.20 (s, IH), 7.29 (m, IH), 7.36 (m, IH)5 7.41 (t, IH) , 7.61 (d, 2H).
Example 20
2'-amino-r-methyl-2-phenyl- 6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4,4'' imidazol]-5'(l'//)-one (Compound 24)
Figure imgf000224_0001
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-fluoro-3- (trifluoromethoxy) phenylboronic acid (20 mg, 0.106 mmol). The mixture was heated at 120 °G 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- r-methyl-2-phenyl- 6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4.4'-imidazol]-5'(r/f)- one (3.32 mg, 14%). 1H-NMR (MeOD): 2.23 (m, 2H), 3.10 (s, 3H), 5.80 (d, IH), 6.98 (m, IH), 7.13 (m; IH), 7.26 (m. 2H), 7.34 (m, 3H), 7.38 (m, 3H); 7.46 (m, 2H).
Example 21
3-((2S,4R)-2'-amino-r-benzyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile (Compound 25a) and 3-((2R,4R)-2'-amino-r-benzyl-5'-oxo-
2-phenyl-l '.S'-dihydrospirotchroman^^'-imidazoleJ-ό-yObenzonitrile (Compound 25b)
Figure imgf000225_0001
Step 1 :
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 1 10 °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+). Step 2:
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 r-benzyl-2'-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (63.3 mg; 39%). MS m/z 569 (M+H4). Step 3: To a solution of r-benzyl-2'-(benzylthio)-6-bromo-2-phenylspiro[chroinan-4,4'- imidazol]-5'(l'H)-one (60 mg, 0.10 mmol) in MeOHTEtOH (1 :1, 2 mL) in a 10 mL CEM microwave test tube was added NH4I (50 mg, 0.34 mmol) and NH3/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-r-benzyl-6-bromo-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)- one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H+). Step 4.
To a solution of 2'-amino-r-benzyl-6-bromo-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (17.3 mg, 0.04 mmol) in 1,4-dioxane (1.5 mL) was added Cs2CO3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCbdppf. 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-r-benzyl-5'-oxo-2-phenyl-r,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). 1H NMR (400MHz, CD3OD): 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). 1H NMR (400MHz, CD3OD): 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).
Example 22
: 2'-amino-6-(4-(hydroxymethyl)phenyl)- 1 '- methyl-2-phenylspiro[chroman-4,4'-imi dazol]-5'(l'H)-one (Compound 26)
Figure imgf000226_0001
Pd(PPh3)2Cl2 (5 mg, 0.007mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl-2-phenylspiro[chroman-4.4'-imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4- (hydroxymethyl)phenylboronic acid (17 mg, 0.104 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 2'-amino-6-(4-(hydroxymethyl)phenyl)-r-methyl-2-phenylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one (1.16 mg, 5%). 1H-NMR (MeOD): 2.42 (m, IH)5 2.57 (m, IH), 3.31 (m, 3H), 4.15 (s, 2H), 5.83 (m, IH), 7.09 (m, IH), 7.28 (m, IH), 7.38 (m, 4H), 7.47 (m, 3H), 7.56 (m, IH), 7.61 (m, IH).
Example 23
2'-amino-r-methyl-2,6-diphenylspiro- [chroman-4,4'-imidazol]-5'(l 'H)-one (Compound
27)
Figure imgf000227_0001
Pd(PPh3 )2C12 (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'(l 'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and phenylboronic acid (16 mg, 0.1 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 2'-amino-l'-methyl-2,6- diphenylspiro- [chroman-4,4'-imidazol]-5'(l 'H)-one (1.55 mg, 5%). 1H-NMR (MeOD): 2.42 (m, IH), 2.61 (m, IH), 3.27 (s: 3H), 5.83 (d, IH), 7.10 (d, IH), 7.29 (m, IH)5 7.40 (m, 5H), 7.59 (m, 5H).
Example 24 2'-amino-r-methyl-6-(3-(methylsulfonyl) phenyl)-2-phenylspiro[chroman-4, 4'-imidazol]-
5'(11H)-OnC (Compound 28)
Figure imgf000228_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (methylsulfonyl)phenylboronic acid (20.8 mg, 0.104 mmol). The mixture was heated atl20 °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 2'-amino-r-methyl-6-(3-(methylsulfonyl) phenyl)-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (16.89 mg, 70%). 1H-NMR (MeOD): 2.01 (m, IH), 2.31 (m, IH), 3.14 (m, 3H), 3.21 (m, 3H), 5.22 (m, 0.2H), 5.83 (m, 0.7H), 6.89 (m, IH), 7.18 (m, IH), 7.23 (m, IH), 7.32 (m, 2H), 7.39 (m, 2H), 7.45 (m, IH), 7.57 (m, IH), 7.76 (m, 2H), 7.96 (m, IH).
Example 25 2-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imi dazole]-6- yl)phenyl)acetonitrile (Compound 29)
Figure imgf000228_0002
Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-(cyclohexyhnethyl)-2-phenylspiro[chroman-4,4'- imidazol]-5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(cyanomethyl)phenylboronic acid (16.7 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 2-(3-(2'-amino- 1 '-methyl-5'-oxo-2-phenyl- 1 ',5'-dihydrospiro[chroman- 4,4'- imidazole]-6-yl)phenyl)acetonitrile (5.25 mg, 24%). 1H-NMR (MeOD): 2.04 (m, IH), 2.21 (m, IH), 3.08 (d, 3H), 3.85 (s, 2H), 5.21 (d, 0.2H), 5.81 (d, 0.8H), 6.94 (d, IH), 7.11 (m, IH), 7.24 (m, 2H), 7.35 (m, 3H), 7.39 (m, 5H).
Example 26
2 ' -amino- 1 ' -methyl-2- phenyl-6-(3 -(trifluoromethyl)phenyl)spiro [chroman-4.4 ' imidazol]- 5'(l'H)-one (Compound 30)
Figure imgf000229_0001
Pd(PPh3)2Cl2 ( 10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg. 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(trifluoromethyl) phenylboronic acid (19.7 mg, 0.1 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 preparative ΗPLC to give pure 2'- amino-1 '-methyl-2- phenyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4.4'-imidazol]- 5'(l 'H)-one (4.31 mg, 18%). 1H-NMR (CDCl3): 1.95 (d, 1Η), 2.66 (t, 1Η), 3.16 (d, 3Η), 5.97 (d, IH), 6.96 (s, IH), 7.06 (m, 2H), 7.20 (s, IH), 7.38 (m, 3H), 7.44 (m, 3H), 7.53 (m, IH), 7.62 (m, IH), 7.70 (s, IH).
Example 27
3-(2'-amino-r,2- dimethyl-5'-oxo-2-phenyl-r.5'- dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (Compound 32)
Figure imgf000230_0001
Experimental data:
Figure imgf000230_0002
Step 1. 6-bromo-2-methyl-2-phenyl-chroman-4-one
A solution of l-(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%). 1H-NMR (CDCl3): 1.74 (s, 3H), 3.06 (d, IH), 3.31 (d, IH), 6.95 (d, IH), 7.20-7.37 (m, 5H), 7.52 (d, IH), 7.84 (s, IH).
Figure imgf000230_0003
Step 2. 6-bromo-2-methyl-2-phenylspiro[chroman-4,4'-imidazolidine]-2'.5'-dione
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 (NH4)2CO3 (14.1 g, 147 mmol). Formamide (70 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70 0C 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 Na2SO4 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%). 1H-NMR (CDCl3): 1.76 (s, 3H), 2.77 (m, IH), 2.85 (m, IH), 4.48 (s, IH)5 7.05 (m, 2H), 7.21-7.54 (m, 6H), 8.55 (s, IH).
Lawssson's Reagent
Figure imgf000231_0002
Figure imgf000231_0001
Step 3. 6-bromo-2-methyl-2-phenyl-2'-thioxospiro[chroman-4,4'- imidazolidin]-5'-one 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%). 1H-NMR (CDCl3): 1.75 (s, 3H), 3.78 (m, 2H), 5.79 (s, IH), 6.94 (m, IH), 7.14 (m, IH), 7.22 (m, IH), 7.26-7.53 (m, 5H), 8.39 (s, IH).
Figure imgf000231_0003
Step 4. (2i?,45)-6-bromo- 1 ',2-dimethyl-2I-(methylthio)-2-phenylspiro[chroman-4,41- imidazol]-5'(l 'H)-one & (25,4^-6-BrOmO-I ';2-dimethyl-2'-(methylthio)-2-phenylspiro [chroman-4,4'-imidazol]-5'(l '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 H2O (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 (2i?,45)-6-bromo-l',2- dimethyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'-imidazol]-5'(r/f)-one (29 mg, total yield 36%) and (2S,4S>6-bromo-l',2-dimethyl-2'-(methylthio)- 2-phenylspiro[chroman- 4,4'-imidazol]-5'(17f)-one (263 mg, total yield 36%).
(2i?,45)-6-Bromo-r,2-dimethyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one: 1H-NMR: 1.75 (s, 3H), 1.99 (m, IH), 2.47 (d, IH), 2.53 (s, 3H), 3.07 (s, 3H), 6.70 (d, IH), 6.84 (d, IH), 7.18-7.33 (m, 4H), 7.49 (d, 2H).
(25',45)-6-Bromo-r,2-dimethyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one: 1H-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; IH).
Figure imgf000232_0001
Step 5. 2'-amino-6-bromo-r.2-dimethyl-2-phenylspiro [chrornan-4,4'-imidazol]-5'(rH)- one
A solution of 6-bromo- 1 ',2-dimethyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'- imidazol]- 5'(l'H)-one (292 mg, 0.667 mmol), NH4I (245.7 mg, 1.668 mmol) in a solution of NH3ZEtOH (30 mL, 5 N) was heated at 110 0C 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-r,2-dimethyl-2-phenylspiro [chroman-4,4'-imidazol]-5'(l'H)-one (45 mg, 18%). 1H-NMR (MeOD): 1.63 (s: 3H), 1.77 (s, 3H), 2.74 (d, 2H), 6.75 (d, IH), 7.06 (d, IH), 7.22 (m, IH), 7.31 (m, 3H); 7.45 (m, 2H).
Figure imgf000233_0001
Step 6. 3-(2'-amino-r.2-dimethyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4.4'- imidazole] -6-yl)benzonitrile
Pd(PPh3)2Cl2 (14 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r,2-dimethyl-2-phenylspiro [chroman-4,4'-imidazol]- 5'(lΗ)-one (45 mg, 0.113 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (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-l',2- dimethyl-5'-oxo-2-phenyl-l',5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (17 mg, 36%). 1H-NMR (CDCl3): 1.78 (s, 3H), 1.97 (s, 3H), 2.60 (d, IH), 2.85 (d, IH), 6.84&6.93 (s, IH), 7.23 (m, 2H), 7.31 (m, 4H), 7.48 (m, 2H), 7.52 (m, 2H), 7.62 (m, IH), 7.67 (m, IH), 11.51 (brs, IH).
Example 28
2'-amino-6-(3-(hydroxymethyl)phenyl)-r-methyl-2-phenylspiro[chroman-4,4'- imidazol]-
5'(lΗ)-one (Compound 33)
Figure imgf000233_0002
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(r//)-one (20 mg, 0.05 mmol) in 1.4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-
(hydroxyrnethyl)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 - 2J3 -
to give the residue, which was purified by preparative TLC to give pure 2'-amino-6-(3- (hydroxyrnethyl)phenyl)-r-rnethyl-2-phenylspi- ro[chroman-4,4'-imidazol]-5'(rH)-one (1.3 mg, 5%). 1H-NMR (MeOD): 2.05 (t, IH), 2.21 (t, IH), 3.07 (s, 3H), 4.50 (s, IH), 5.81 (d, IH), 6.94 (d, IH), 7.11 (s, IH), 7.19 (d, IH), 7.30 (m, 4H), 7.41 (m, 4H).
Example 29
2'-amino-6-bromo-2 -(3 -chlorophenyl)- 1 '-methylspiro [chroman-4,4'-imidazol] -
5'(l'H)-one (Compound 34)
Figure imgf000234_0001
Lawesson's Reagent
Figure imgf000234_0002
Figure imgf000234_0003
Figure imgf000234_0004
Figure imgf000234_0005
In a bottle, l-(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 l-(5-bromo-2-hydroxyphenyl)-3-(3- chlorophenyl) prop-2-en- 1 -one (23.47 g, 60%). 1H-NMR (CDCl3): 6.88 (d, IH), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, IH), 7.80 (m; IH), 7.93 (rn. IH), 12.56 (s, IH).
Figure imgf000235_0001
l-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-l-one (23 g, 68 mmol) was dissolved in H2O (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 H2O 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%). 1H-NMR (CDCl3): 2.87 (m, IH), 3.02 (m, IH), 5.44 (m, IH), 6.96 (d, IH), 7.31 (m, IH), 7.37 (m, 2H), 7.48 (s, IH), 7.58 (m, IH), 8.02 (d, IH).
Figure imgf000235_0002
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 (NfLt)2CO3 (15 g, 156 mmol) in formamide (60 mL) was heated and stirred at 70 0C for 24 h and then at 1 10 0C for 2 days. The mixture was poured into ice/water. Concentrated HCl was added till pH=l. The mixture was filtered to yield a solid cake. The filtrate was extracted with CH2Cl2. 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%). 1H-NMR (CDCl3): 2.20 (m, IH), 2.28 (m, IH), 5.76 (m; IH), 6.82 (m, IH), 7.27 (m, 5H), 7.39 (m, IH).
Step 3:
Lawesson's Reagent
Figure imgf000235_0004
Figure imgf000235_0003
A mixture of 6-bromo-2-(3-chlorophenyl)spiro[cliroman-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 0C 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%). Step 4:
Figure imgf000236_0001
To a mixture of 6-bromo-2-(3-chlorophenyl)-2'-thioxospiro[chroman-4.4'- imidazolidin]-5'-one (250 mg, 0.6 mmol) and K2CO3 (327 mg, 2.4 mmol) in CH3CN (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)-r-methyl-2'-(methylthio)spiro chroman-4,4'-imidazol]-5'(rH)-one (100 mg, 37%).
1H-NMR (CDCl3): 1.92 (m, 1Η), 2.41 (m; 1Η), 2.56 (s, 3Η), 3.07 (s, 3H), 5.80 (m, IHO, 6.80 (m, 2H), 7.26 (m, 4H), 7.39 (m, IH).
Step 5:
Figure imgf000236_0002
A solution of 6-bromo-2-(3-chlorophenyl)- 1 '-methyl-2'-(methylthio)spiro chroman-4,4'- imidazol]-5'(rH)-one (100 mg, 0.22 mmol), NH4I (64 mg, 0.44mmol) in a solution OfNH3ZEtOH (4 mL, 1.5 N) was heated at 110 0C 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)-l'- me%lspiro[cruOman-4,4'-imidazol]-5'(l'H)-one (42 mg; 46%). 1H-NMR (MeOD): 2.12 (m, 2H), 3.06 (s, 3H), 5.80 (m, IH), 6.83 (m, IHO, 7.03 (m, IH), 7.27 (m, 4H), 7.40 (m, IH). Example 30
2-(2'-amino-l '-methyl-5'-oxo-2-phenyl-l ',5'-dihydrospiro[chroman-454'-irnidazole] -6- yl)benzonitrile (Compound 35)
Figure imgf000237_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2- cyanophenylboronic acid (15.3 mg, 0.104 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 HPLC twice to give pure 2- (2'-amino-r-methyl-5'-oxo-2-phenyl-r.5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl) benzonitrile (2.83 mg, 13%). 1H-NMR (MeOD): 2.48-2.60 (m, 2H), 3.33 (s, 3H), 5.26 & 5.88 (m, IH), 7.17 (m, IH), 7.37-7.60 (m, 9H), 7.70 (m, IH), 7.81 (m, IH).
Example 31
2'-amino-l '-methyl-2-phenyl-6-(thiophen-2-yl)spiro[chroman-4,4'-imidazol]-5'(l 'H)- one
(Compound 36)
Figure imgf000237_0002
A mixture of 2'-amino-6-bromo-r-methyl-2- phenylspiro[chroman-4.4'- imidazol]- 5'(1'H)- one (21 mg. 0.05 mmol), thiophen-2-ylboronic acid (14 mg, 0.1 mmol), Cs2CO3 solution (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (10 mg) in 1.4-dioxane (1 mL) was stirred in a microwave test tube under Ar at 120 0C for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2'-amino-l '-methyl-2- phenyl-6- (thiophen-2-yl)spiro[chroman-4,4'-irnidazol]-5'-(l 'H)- one (0.87 mg, 4%). 1H-NMR (MeOD): 2.45-2.54 (M5 1Η), 2.60-2.63 (m, 1Η), 3.32 (s, 3Η), 5.88 (d, IH), 7.06-7.14 (m, 2H), 7.33-7.39 (m, 2H), 7.41-7.50 (m, 3H), 7.51-7.64 (m, 4H).
Example 32
5-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'- dihydrospiro[chroman-4,4'-imidazole]- 6-yl)-
2-fluorobenzonitrile (Compound 37)
Figure imgf000238_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l 'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(2- methoxyethylcarbarnoyl)phenylboronic acid (23.2 mg, 0.104 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 ΗPLC twice to give pure 5-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'- dihydrospiro[chroman-4,4!- imidazole]-6-yl)-2- fluorobenzonitrile (9.38 mg, 37%). 1H-NMR (MeOD): 2.38 (m, IH), 2.55 (m, IH), 3.24 (s, 3H), 3.39 (s, 3H), 3.50 (s, 4H), 5.15 & 5.76 (m, IH), 7.04 (m, IH), 7.32 (m, 3H), 7.40 (m, 4H), 7.55-7.67 (m, 3H), 7.94 (m, IH).
Example 33
2'-amino-6-bromo-2- (3-flurophenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one
(Compound 38)
Figure imgf000239_0001
Figure imgf000239_0002
A mixture of l-(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 H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume Of H2O. and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-flurophenyl)chroman-4- one (8.3 g, 37%). 1H-NMR (CDCl3): 2.93 (d, IH), 3.03 (m, IH), 5.47 (d, IH), 7.06 (d, IH), 7.1 1 (m, IH), 7.22 (m, 2H), 7.40 (m, IH), 7.57 (d, IH), 8.04 (s, IH).
Step 2:
Figure imgf000239_0003
A steel bomb was charged with a mixture of 6-bromo-2-(3-flurophenyl)chroman-4-one
(3.2 g, 0.01 mol), potassuim cyanide (1.95 g, 0.03 mmol), and (NHO2CO3 (7.2 g, 0.075 mmol). Formamide (2OmL) was added to fill the steel bomb nearly completely. The mixture was heated at 70 0C for 48 h then at 1 10 0C 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 Na2SO4, 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-4,4l-imidazolidine]-2',5'-dione ( 0.31 g, 8%). 1H-NMR (CDCl3): 2.27 (t, IH), 2.48 (d, IH), 5.53 (s, IH), 5.88(d, IH), 6.89 (d, IH), 7.08 (m, IH), 7.18 (m, 2H), 7.38 (m, 3H), 7.78(s ,1H).
Lawsson's Reagent
Figure imgf000240_0001
Figure imgf000240_0002
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%). Step 4:
Figure imgf000240_0003
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 H2O (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 -flurophenyl)- 1 ' -methyl-2 ' -(methylthio)spiro [chroman-4.4 ' -imidazol] - 5'(l '/Q-one (80 mg. 28%). Step 5:
Figure imgf000241_0001
A solution of 6-bromo-2-(3-flurophenyl)-r-methyl-2'-(methylthio)spiro[chroman- 4,4'-imidazol]-5'(l 'H)-one (80 mg, 0.18 mmol) and NH4I (52 mg, 0.36 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110 0C in a tube in a microwave reactor for 2-2.5h. 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- flurophenyl)-l '-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (36 mg, 50%). 1H- NMR (MeOD): 2.16 (m, 2H), 3.12 (s, 3H), 5.87 (d, IH), 6.90 (d, IH), 7.08 (m, 2H), 7.25 (m ,2H), 7.33 (d, IH), 7.41 (m, IH).
Example 34
3-(2'-amino-r-methyl-5'-oxo-2- phenyl- r,5'-dihydrospiro[chroman-4,4'-imidazole]- 6-yl)-
ΛyV-dimethylbenzamide (Compound 39)
Figure imgf000241_0002
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl -2 -phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in L4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (dimethylcarbamoyl) phenylboronic acid (20 mg, 0.104 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-(2'-amino-l '-methyl-5'-oxo-2- phenyl- 1 '.5 '-dihydrospiro [chroman-4,4'-imidazole] -6-yl)- MN-dimethylbenzamide (1.44 mg, 6%). 1H-NMR (MeOD): 2.44 (m; 1Η), 2.62 (m, 1Η), 3.14 (s, 3Η), 3.13 (s, IH), 5.24 (m, 0.3H), 5.88 (m; 0.7H), 7.15 (m, IH), 7.41 (m, 3H), 7.45 (m, IH), 7.53 (m, 4H), 7.18 (m, 3H). Example 35
5-(2'-amino- r-methyl-5'-oxo-2-phenyl- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)- 2-fluoro-N-(2-hydroxyethyl)benzamide (Compound 40)
Figure imgf000242_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with T- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(r/f)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 Ν, 0.3 mL) and 4-fluoro-3-(2- hydroxyethylcarbamoytyphenylboronic acid (23 mg, 0.106 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 5-(2'- amino-r-methyl-5'-oxo-2-phenyl-r.5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-2- fluoro-iV-(2-hydroxyethyl)benzamide (3.1 mg, 12%). 1H-NMR (MeOD): 2.48 (m, IH), 2.61 (m, IH), 3.34 (s, 3H), 3.57 (m, 2H), 3.72 (m, 2H), 5.27 (d, 0.3H), 5.89 (d, 0.8H), 7.18 (m, IH), 7.30 (m, IH), 7.45 (m, IH), 7.52 (m, 4H), 7.67 (m, IH), 7.79 (m, IH), 8.01 (m, IH), 8.32 (m, IH).
Example 36 N-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imida zole]-6- yl)phenyl)acetamide (Compound 41)
Figure imgf000242_0002
Pd(PPhS)2Cb (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]-5'(l Η)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-acetamidophenylboronic acid (17.9 mg, 0.1 mmol). The mixture was heated at 120 °C in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'- dihydrospir- o[chroman-4,4'-imidazole]-6-yl)phenyl)acetamide (5.8 mg, 20%). 1H-NMR (MeOD): 2.03 (s, 3H), 2.21 (t, IH), 2.41 (t, IH), 3.07 (s, 3H), 5.81 (d, IH), 6.92 (d, IH), 7.12 (t, IH), 7.21 (t 2H), 7.33 (t, 2H), 7.49 (m, 4H), 7.59 (d, IH).
Example 37
N-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole] -6- yl)benzyl)acetamide (Compound 43)
Figure imgf000243_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (acetamidomethyl)phenylboronic acid (19.3 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2'- amino-l'-methyl-S'- oxo-2-phenyl-l",5;- dihydrospiro- [chroman-4,4'-imidazole]-6- yl)benzyl)acetamide (2.5 mg, 1 1%). 1H-NMR (MeOD): 2.01 (s, 3H), 2.16 (d, IH), 2.32 (t, IH), 3.17 (S5 3H), 4.40 (s, 2H), 5.92 (d, IH), 7.03 (d, IH), 7.23 (d, 2H), 7.36 (m, 2H), 7.41 (t, 4H), 7.48 (m, 3H).
Example 38 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(lΗ)-one (Compound 44)
Figure imgf000244_0001
NH4I, NH3ZEtOH
Figure imgf000244_0002
Figure imgf000244_0003
Figure imgf000244_0004
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%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H). Step 2:
Figure imgf000244_0005
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 l-(5-bromo-2-hydroxy-phenyl)-ethanone (101 g, 98%). 1H-NMR (CDCl3): 2.60 (s, 3H), 6.87 (d, IH), 7.53 (dd, IH), 7.81 (s, IH), 12.12 (s, IH). Step 3:
Figure imgf000245_0001
A mixture of l-(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 H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-phenyl-chroman-4-one (8.5 g, 21%). 1H-NMR (CDCl3): 2.89 (dd, IH), 3.06 (dd, IH), 5.46 (dd, IH), 6.95 (d, IH), 7.37-7.46 (m, 5H), 7.58 (d, IH), 8.02(d, IH). Step 4:
Figure imgf000245_0002
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 (NILO2CO3 (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 Na2SO4, 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%). 1H-NMR (MeOD): 2.28 (t, IH), 2.43 (dd, IH), 5.83 (d, IH), 6.90 (d, IH), 7.33-7.45 (m, 7H). Step 5:
Lawesson's Reagent
Figure imgf000246_0001
Figure imgf000246_0002
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%). 1H-NMR (CDCl3): 2.35 (t, IH), 2.49 (dd, IH), 5.83 (d, IH), 6.90 (d, IH), 7.36-7.45 (m, 7H).
Step 6:
Figure imgf000246_0003
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 H2O (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-l'-methyl-2'-(methylthio)-2- phenylspiro[chroman-4.4'-imidazol]-5'(lΗ)-one (59 mg, 48%). Step 7:
Figure imgf000246_0004
A solution of 6-bromo- 1 '-methyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'- imidazol]- 5'(l'H)-one (59 mg; 0.142 mmol), NH4I (41.5 mg, 0.286 mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at 110°C in a tube in a microwave reactor for 2-2.5h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (21 mg, 38%). 1H-NMR (MeOD): 2.04 (d, IH), 2.15 (dd, IH), 4.51 (m, IH), 5.75 (d, IH), 6.78 (m, IH), 6.99 (d, IH), 7.20-7.26 (m, 2H), 7.26-7.35 (m, 4H).
Example 38a Cw-2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
(Compound 44b) and 7>αra-2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(lΗ)-one
(Compound 44a)
Figure imgf000247_0001
Lawesson's Reagent MeI, NaOH
Figure imgf000247_0004
Figure imgf000247_0002
NH4I, NH3ZEtOH
Figure imgf000247_0005
Figure imgf000247_0003
Figure imgf000247_0006
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 Na2SO4, filtered, and concentrated to give l-(5-bromo-2-hydroxy-phenyl)-3-phenyl-propenone (55 g, 61%. 1H-NMR (CDCl3): 6.86 (m, IH), 7.38 (m, 3H), 7.49 (m, 2H), 7.61 (m, 2H), 7.93 (t, 2H), 12.66 (s, IH).
Step 2:
Figure imgf000248_0001
To a solution of l-(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 Na2SO4, filtered, and concentrated to give 6- bromo-2-phenyl-chroman-4-one (49.5 g, 90%). 1H-NMR (CDCl3): 2.82 (dd, IH), 3.03 (dd, IH), 5.42 (dd, IH), 6.90 (d, IH), 7.31-7.41 (m, 5H), 7.52 (dd, IH), 7.97(d, IH).
Step 3:
Figure imgf000248_0002
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 (NH4)2CO3 (36 g, 375 mmol). Formamide (80 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70 0C for 24 h then at 110 0C 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 Na2SO4, 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%). 1H-NMR (CDCl3): 2.28 (t, IH), 2.43 (dd, IH), 5.66 (m, IH), 5.82 (d, IH), 6.86 (d, IH), 7.33-7.41 (m, 7H), 8.03 (m, IH). Step 4: Lawesson's Reagent
Figure imgf000249_0001
Figure imgf000249_0002
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%). 1H-NMR (CDCl3): 2.26 (dd, IH), 2.43 (dd, IH), 5.76 (dd, IH), 6.84 (m, 2H), 7.32-7.36 (m, 6H), 8.22 (m, IH).
Figure imgf000249_0003
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 H2O (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-l'-methyl-2'- (methylthio)-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (380 mg, 61%). Step 6:
NH4I, NH3ZEtOH
Figure imgf000249_0005
Figure imgf000249_0004
A solution of 6-bromo- 1 '-methyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'- imidazol]- 5'(l'H)-one (380 mg; 0.913 mmol), and NH4I (265 mg, 1.83 mmol) in a solution of NH3/EtOH (8 mL, 1.5 N) was heated at 110 0C 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-r-methyl-2- phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one with two isomers: cis isomer (21 mg, 38%) and trans isomer (25 mg, 45%).
(cis): 1H-NMR (MeOD): 2.05 (t, IH), 2.25 (t, IH), 3.13 (s, 3H), 5.86 (d, IH), 6.87 (d, IH), 7.09 (m, IH), 7.31-7.35 (m, 2H), 7.36-7.48 (m, 4H). (trans): 1H-NMR (MeOD): 2.12 (m, IH), 2.25 (t, IH), 3.14&3.20 (s, 3H), 5.87 (d, IH), 6.88 (d, IH), 7.11 (m, IH), 7.32-7.36 (m, 2H), 7.38-7.48 (m, 4H).
Example 39
3-(2'-amino-l'-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6 -yl)- N,N-dimethylbenzenesulfonamide (Compound 45)
Figure imgf000250_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with T- amino-6-bromo-r-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 Ν, 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-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4l- imidazole]-6-yl)-A^-dimethylbenzenesulfonamide (1.7 mg, 7%). 1H-NMR (MeOD): 2.47 (m, IH), 2.62 (m, IH), 2.71 (s, 6H), 3.29 (s, 3H), 5.28 (d, 0.3H), 5.89 (d, 0.7H), 7.19 (m, IH), 7.47 (m, 6H), 7.69 (m, 2H), 7.75 (m, IH), 7.93 (m, 2H).
Example 40
2'-amino-6-bromo-2-(3-methoxyphenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(7 'H)- one (Compound 46)
Figure imgf000251_0001
Lawsson's Reagent NH4I
Figure imgf000251_0002
Figure imgf000251_0003
Figure imgf000251_0004
A mixture of l-(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 H2O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O. and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-methoxy-phenyl)-chroman-4-one (5 g, 18%). 1H-NMR (CDCl3): 2.89 (d, IH), 3.04 (t, IH), 3.81 (s, 3H), 5.43 (d, 2H), 6.96 (m, 3H), 7.32 (m, IH), 7.58 (m, IH), 8.01 (s, IH)
Figure imgf000251_0005
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 (NH4^CO3 (4 g, 42 mmol). Formamide (20 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70 0C 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 Na2SO4, 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%). 1H-NMR (MeOD): 2.26 (d, IH), 2.37 (t, IH), 3.79 (s, 3H), 5.80 (d, IH), 6.88 (m, 2H), 7.00 (m, 2H), 7.44 (m, 2H).
Lawsson's Reagent
Figure imgf000252_0001
Figure imgf000252_0002
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%).
1H-NMR (CDCl3): 2.24 (m, IH), 2.41 (m; IH), 3.76 (s, 3H), 5.72 (m, IH), 6.88 (m, 4H), 7.31 (m, IH), 8.24 (m, IH).
Figure imgf000252_0003
To a solution of 6-bromo-2-(3-methoxyphenyl)-2'-thioxospiro[chrornan-4.4'- imidazolidin]-5'-one (50 mg, 0.12 mmol) in MeOH (5 mL) was added a solution of NaOH (9.5 mg) in H2O (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)-l'- methyl-2'- (methylthio)spiro[chroman-4.4'-imidazol]-5'(7 'H)-one (13 mg, 21%).
Figure imgf000253_0001
A solution of 6-bromo-2-(3-methoxyphenyl)- 1 '-methyl-2'-(methylthio)spiro[chroman- 4,4'-imidazol]-5'(7 'H)-one (13 mg) and NH4I (10 mg) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at 110 0C 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)-r-methylspiro[chroman-4,4'- imidazol]-5'(7 Η)-one (2.17 mg, 22%).
1H-NMR (MeOD): 2.00 (d, IH), 2.13 (m, IH)5 3.03 (s, 3H), 3.70 (s, 3H), 5.70 (m, IH), 6.77 (m, 2H)5 6.89 (m, 2H), 7.00 (m, IH), 7.21 (m, 2H).
Example 41
3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole] -6- yl)-N-(2-cyanoethyl)benzamide (Compound 47)
Figure imgf000253_0002
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4l-imidazol]-5'(rH)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(2-cyanoethyl- carbamoyl)phenylboronic acid (22 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3 -(2 ' -amino- 1 '- methyl- 5'- oxo-2-phenyl-l '.5:-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-N-(2- cyanoethyl)benzamide ( 1.96 mg, 8%). 1H-NMR (MeOD): 2.52 (m, 1 H), 2.64 (m, IH)5 2.83 (t, 2H), 3.35 (s, 3H), 3.68 (t, 2H), 5.86 (d, IH), 7.18 (d, IH), 7.43 (m, 3H), 7.55 (m, 3H), 7.57 (d, IH), 7.71 (d, IH), 7.79 (m, 2H), 8.05 (s, IH).
Example 42
3-(2'-amino-r-methyl-5'-oxo- 2-phenyl-l', 5'-dihydrospiro [chroman-4, 4'-imidazole] -6- yl)-N-methylbenzenesulfonamide (Compound 48)
Figure imgf000254_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(N- methylsulfamoyl) phenylboronic acid (23 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in 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-(2'-amino-r-methyl-5'-oxo-2-phenyl-r, 5'-dihydrospiro [chroman-4, 4'-imidazole]-6- yl)- N-methylbenzenesulfonamide (5.88 mg, 24%). 1H-NMR (MeOD): 2.16 (m, IH), 2.22 (m, IH), 2.41 (m, 3H), 3.15 (m, 3H), 5.21 (m, 0.2H), 5.83 (m, 0.8H), 6.98 (m, IH), 7.16 (m, IH), 7.25 (m, IH), 7.32 (m, 2H), 7.38 (m, 2H), 7.42 (m, IH), 7.51 (m, IH), 7.66 (m, 2H), 7.86 (m, IH).
Example 43
2'-amino-r-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenylspir-o[chroman-4,4'- imidazol]-
5'(17/)-one (Compound 49)
Figure imgf000254_0002
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(l Η)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4- (methylsulfonyl)phenylboronic acid (20.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 0C 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-l'- methyl-6-(4-(methylsulfonyl)phenyl)-2-phenylspir- o[chroman-4,4'-imidazol]-5'(rH)-one (18 mg, 80%). 1H-NMR (CDCl3+MeOD): 2.07 (dd, IH), 2.41 (t, IH), 3.01 (s, 3H), 3.12 (s, 3H), 5.25 (d, 0.5H)5 5.89 (d, IH), 6.90 (d, IH), 7.31(s, 2H), 7.32 (t, 2H), 7.39 (d, 3H), 7.60 (t, 2H), 7.87 (d, 2H).
Example 44
3-(2'-amino-r-methyl-5'-oxo-2-phenyl-l ',5'-dihydrospiro[chroman-4,4'-imidazole]- 6- yl)- ΛLmethylbenzamide (Compound 50)
Figure imgf000255_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL CEM test tube, under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (methylcarbamoyl)phenylboronic acid (18.6 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120 0C 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 pure 3-(2!-amino-r-methyl-5'-oxo-2-phenyl-r.5'-dihydrospiro[chroman-4.4'- imidazole]- 6-yl)- N- methylbenzamide (0.96 mg, 4%). 1H-NMR (CDCl3): 2.36 (d, IH), 2.57 (t, IH), 2.73 (s, 3H), 2.97 (s, 3H), 5.87 (d, IH), 7.1 1 (m, 2H), 7.45 (m; 8H), 7.51 (m, IH), 7.60 (s, IH), 7.78 (s, lH).
Example 45 iV-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r.5'-dihydrospiro[chronian-4,4'- imidazole]-6- yl)phenyl)methanesulfonamide (Compound 52)
Figure imgf000256_0001
Pd(PPh3)2Cl2 (10 mg, 0.0.1 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(1'H)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (methylsulfonamido) phenylboronic acid (22 mg, 0.104 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 N-(3-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6 -yl)phenyl)methanesulfonamide (0.91 mg, 4%). 1H-NMR (MeOD): 2.46 (m, IH), 2.62 (m, IH), 2.97 (s, 3H), 3.29 (s, 3H), 5.86 (m, IH), 6.94 (m, 2H), 7.13 (m, IH), 7.18 (m, IH), 7.41 (m, 6H), 7.62 (m5 IH), 7.81 (m, IH).
Example 46
2'-amino-6-bromo-2-(4-chlorophenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one
(Compound 53)
Figure imgf000257_0001
Figure imgf000257_0002
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 4-chloro- benzaldehyde (3.92 g, 28 mmol), and borax (10H2O, 10.67 g, 28 mmol) in H2O (60 mL) and EtOH (36 mL) was stirred at 110 0C 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%). 1H- NMR (CDCl3): 2.88 (m, IH), 3.04 (m, IH), 5.44 (m, IH)5 6.94 (m, IH), 7.39 (m, 4H), 7.57 (m, IH), 8.02 (m, IH).
Figure imgf000257_0003
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 (NlLO2CO3 (8.6 g, 90 mmol) in formamide (40 mL) was heated and stirred at 70 0C for 24 h and then at 110 0C 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 CH2Cl2. 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%). Step 3:
Lawsson's Reagent
Figure imgf000258_0002
Figure imgf000258_0001
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 1100C 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%). 1H-NMR (MeOD): 2.24 (m, IH), 2.45 (m, IH), 6.82 (m, IH), 6.91 (m, IH)5 7.20 (m, IH), 7.44 (m, 5H).
Figure imgf000258_0003
To a mixture of 6-bromo-2-(4-chlorophenyl)-2'-thioxospiro[chroman-4,4'- imidazolidin]-5'-one (450 mg, 1.07 mmol) and K2CO3 (588 mg, 4.27 mmol) in CH3CN (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)-l'-methyl-2'- (methylthio)spiro[chroman-4;4'-imidazol]-5'(l'H)-one (325 mg, 37%). 1H-NMR (CDCl3): 1.89 (m, IH), 2.41 (m, IH), 2.56 (t, 3H), 3.17 (m, 3H), 5.81 (m, IH), 6.79 (m, 2H), 7.23 (m, IH), 7.43 (m, 4H).
Figure imgf000259_0001
A solution of 6-bromo-2-(4-chlorophenyl)-l '-methyl-2'-(methylthio)spiro[chroman- 4,4'-imidazol]-5'(rH)-one (300 mg, 0.67 mmol) and NH4I (194 mg, 1.33 mmol) in NH3/EtOH (5 mL, 1.5 N) was heated at HO0C 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)-r- methylspiro[chroman-4:41-imidazol]-5'(l'H)-one (35 mg, 12%). 1H-NMR (MeOD): 2.19 (m, IH), 2.41 (m, IH), 3.11 (m, 3H), 5.15 (m, 0.5H), 5.38 (m, 0.5H), 6.78 (m, IH), 6.82 (m, 0.5H), 7.02 (m, 0.5H), 7.23 (m, IH), 7.31 (m, 3H), 7.44 (m, IH).
Example 47
2'-amino-6-(4-(methoxymethyl)phenyl)-r-methyl-2-phenylspiro[chτoman-4,4'-imi dazol]-
5'(l'H)-one (Compound 54)
Figure imgf000259_0002
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4.4'-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL); Cs2CO3 (2 N, 0.3 mL) and 4-
(methoxymethyl)phenylboronic acid (16.6 mg, 0.1 mmol). The mixture was heated at 120 °C 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 2'-amino- 6-(4-(methoxymethyl)phenyl)-r-methyl- 2-phenylsp-iro[chroman-4,4'-imidazol]-5'(rH)- one (3.8 mg, 15%). 1H-NMR (MeOD): 2.10 (t, IH), 2.24 (t, IH), 3.01 (s, 3H), 3.27 (s, 3H), 4.17 (m, 2H), 5.81 (d, IH), 6.90 (m5 2H), 7.12 (d, 2H), 7.27 (m, 3H), 7.49 (m, 5H). Example 48
3-((2R,4S)-2'-amino-r-methyl-5l-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4.4'- imidazole] -6-yl)-N- butylbenzamide (Compound 55a) and 3-((2S,4S)-2'-amino-l'- methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-N- butylbenzamide (Compound 55b)
Figure imgf000260_0001
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- (butylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3 -(2' -amino- 1 "'- methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro-[chroman-4,4'-imidazole]-6-yl)-N- butylbenzamide (12.4 mg, 50%). cis (2.50 mg, 10%). 1H-NMR (MeOD): 0.95 (m, 3H), 1.42 (m, 2H), 1.60 (m, 2H), 2.14 (d, IH), 2.31 (t, IH), 3.33 (s, 3H), 3.36 (d, 2H), 5.88 (d, IH), 7.04 (d, IH), 7.24 (s, IH), 7.37 (m; IH), 7.41 (t, 2H), 7.48 (d, 3H), 7.53 (d, IH), 7.66 (d, IH), 7.69 (d, IH), 7.94 (s, IH). trans (9.91 mg, 40%). 1H-NMR (MeOD): 0.96 (t,
3H), 1.43 (m, 2H), 1.61 (m, 2H), 2.03 (d, IH), 2.52 (t, IH), 3.33 (s, 3H), 3.39 (d, 2H), 5.30 (d, IH), 7.05 (d, IH), 7.25 (s, IH), 7.39 (m, IH), 7.42 (t, 2H), 7.47 (d, 3H), 7.53 (d, IH), 7.67 (d, IH), 7.70 (d, IH), 7.93 (s,lH).
Example 49
2'-amino-l '-methyl-2-phenyl-6-(4-(trifluoro methyl)phenyl)spiro[chroman-4,4'- imidazol]-
5'(17/)-one (Compound 56)
Figure imgf000261_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N5 0.3 mL) and 4- (trifluoromethyl)phenylboronic acid (20 mg, 0.104 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 HPLC twice to give pure 2'-amino-r-methyl-2-phenyl-6-(4-(trifluoro methyl)phenyl)spiro[chroman- 4,4'-imidazol]- 5'(l'H)-one (2.87 mg, 12%). 1H-NMR (MeOD): 2.46 (m, IH), 2.60 (m, IH), 3.32 (s, 3H), 5.25 & 5.85 (m, IH), 7.14 (m, IH), 7.37-7.54 (m, 6H), 7.66-7.78 (m, 5H).
Example 50
2'-amino-6-bromo-2-phenyl-r-propylspiro[chroman-4.4'-imidazol] -5'(l'H)-one
(Compound 57)
Figure imgf000261_0002
Figure imgf000261_0003
To a mixture of 6-bromo-2-phenyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5l-one (300 mg, 0.77 mmol) and K2CO3 (427 mg: 3.1 mmol) in CH3CN (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-r-propyl-2'-(propylthio)spiro[chroman-4,4'-imidazol]-5'(i 'H)- one (285 mg, 90%). 1H-NMR (CDCl3): 0.87 (m, 3H), 1.00 (m, 3H), 1.64 (m, 2H), 1.73 (m, 2H), 1.89 (m, IH), 2.48 (m, IH), 3.16 (m, 2H), 3.44 (m, 2H), 5.82 (m, IH), 6.81 (m, 2H), 7.22 (m, IH), 7.30 (m, 3H), 7.48 (m, 2H).
Step 2:
Figure imgf000262_0001
A solution of 6-bromo-2-phenyl- 1 '-propyl-2'-(propylthio)spiro[chroman-4,4'- imidazol]-5'(77f)-one (280 mg, 0.6 mmol) and NH4I (172 mg, 1.2 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 1100C 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-r-propylspiro[chroman-4,4'- imidazol] -5'(l'H)-one (45 mg, 18%). 1H-NMR (MeOD): 0.93 (m, 3H), 1.66 (m, 2H), 2.04 (m, IH), 2.25 (m, IH), 3.56 (m, 2H), 5.83 (m, IH), 6.87 (m, IH), 7.06 (m, IH), 7.31 (m, 2H), 7.40 (m, 4H).
Example 50a
(2i?,4S)-2'-amino-6-bromo-2-phenyl-r-propylspiro [chroman-4,4'-imidazol]-5'(rH)-one
(Compound 57a)
Figure imgf000263_0001
Step 1 :
Figure imgf000263_0002
To a mixture of 6-bromo-2-phenyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (131 mg, 0.34 mmol) and K2CO3 (186 mg, 1.35 mmol) in CH3CN (5 niL) 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 (2i?,4S)-6-bromo-2 -phenyl- l'-propyl-2'- (propylthio)spiro[chroman-4,4'-imidazol]-5'(rH)-one (75 mg, 47%). Step 2:
Figure imgf000263_0003
A solution of (2i?.45)-6-bromo-2-phenyl- 1 '-propyl-2'-(propylthio)spiro[chroman-4,4'- imidazol]-5'(l'//)-one (75 mg, 0.16 mmol): and NH4I (46 mg, 0.32 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110 0C 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 (2Λ,4ιS)-2'-amino-6-bromo-2 -phenyl- r-propylspiro-[chroman- 4,4'-imidazol]-5'(l'H)-one (15 mg, 23%). 1H-NMR (MeOD): 1.00 (m, 3H), 1.45 (m, 2H), 2.23 (m, IH), 2.48 (m, IH), 3.75 (m, 2H), 5.85 (m, IH), 6.90 (m, IH), 7.14 (m, IH), 7.40 (m, 6H).
Example 51 2'-amino-l '-methyl-2-phenyl-6-(pyridin-4- yl)spiro[chroman-4,4'-imidazol]-5'(17f)- one
(Compound 58)
Figure imgf000264_0001
Pd(PPhS)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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 0C 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-l'-methyl-2- phenyl-6-(pyridin-4- yl)sphO[chroman-4,4'-imidazol]-5'(l'H)-one (2.51 mg, 10%). 1H- NMR (MeOD): 2.50 (t, IH), 2.64 (dd, IH), 3.37 (s, 3H), 5.91 (d, IH), 7.26 (d, IH), 7.45 (m, 5H), 7.82 (d, IH), 7.94 (t, IH), 8.16 (s, 2H), 8.71 (s, 2H).
Example 52 2'-amino-6-bromo- 1 '-(2-cyclopropylethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(/ 'H)- one (Compound 59)
Figure imgf000265_0001
Figure imgf000265_0002
A mixture of 2-cyclopropylethanol (2g, 0.023 mol) and pyridine (0.51 g, 0.006 mol) was added dropwise with magnetic stirring over 2 hours to PBr3 (2.5 g, 0.009 mol) at 00C. Then ether was added and the mixture was washed with an aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give (2- bromoethyl) cyclopropane (1.3 g, 38%). 1H-NMR (CDCl3): 0.01 (m, 2H), 0.40 (m, 2H), 0.69 (m, IH), 1.51 (m, 2H), 4.08 (m, 2H). Step 2:
Figure imgf000265_0003
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 K2CO3 (356 mg, 2.58 mmol) in CH3CN (10 mL) was stirred for 4 hours at 600C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC to give 6-bromo-l'-(2-cyclopropylethyl)-2'-(2-cyclopropylethylthio)-2- phenylspiro[chroman-4,4'-imidazol]-5'(7 'H)-one (40 mg, 11%). Step 3:
Figure imgf000266_0001
A solution of 6-bromo- 1 '-(2-cyclopropylethyl)-2'-(2-cyclopropylethylthio)-2- phenylspiro[chroman-4,4'-imidazol]-5'(7 Η)-one (40 mg, 0.076 mmol), and NH4I (22 mg, 0.153 mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at 1100C 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-r-(2- cydopropylethyl)-2-phenylspiro[chroman-4,4'-imidazoi]-5'(i 'H)-one (8 mg, 24%). 1H- NMR (MeOD): 0.01 (m, 2H), 0.34 (m, 2H), 0.61 (m, IH), 1.48 (m, 2H), 2.10 (m, IH), 2.37 (m, IH), 3.67 (m, 2H), 5.12 (d, 0.3H), 5.74 (d, 0.7H), 6.70 (m, IH), 7.00 (m, IH), 7.31 (m, 6H).
Example 53
4-(2 ' -amino- 1 ' -methyl-5 ' -oxo-2-phenyl - 1 ' .5 ' -dihydrospiro [chroman-4,4 ' -imidazole] - 6- yl)- N-isobutylbenzamide (Compound 60)
Figure imgf000266_0002
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with T- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4- (isobutylcarbamoyl)- phenyl- boronic acid (23 mg. 0.1 mmol). The mixture was heated at 120 °C in a microwave reactor for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2'- amino-r-methyl-5'-oxo- 2-phenyl-l \5'-dihydrospiro[chroman-4.4"-imidazole]-6-yl)-ΛL isobutylbenzamide (1.28 mg, 5%). 1H-NMR (MeOD): 0.96 (d, 6H), 1.94 (m, IH), 2.15 (ds IH), 2.47 (t, IH)5 3.29 (s, 3H), 3.31 (ss IH), 3.32 (s, IH), 5.30 (d, IH)5 7.06 (t, 2H)5 7.33 (m, IH), 7.42 (t, 2H), 7.48 (d, 3H), 7.53 (d, IH), 7.66 (d, IH), 7.72 (d, IH), 7.91 (s, IH).
Example 54 2'-amino- 1 '-methyl-2-phenyl-6-(3 -(pyrrolidine- 1 -carbonyl)phenyl)spiro [chroman-4,41- imidazol]-5'(l'H)-one (Compound 61)
Figure imgf000267_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4l-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3 -(pyrrolidine- 1- carbonyl)phenylboronic acid (10 mg. 0.045 mmol). The mixture was heated at 120 0C 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 2'-amino-r-methyl-2-phenyl- 6-(3-(pyrrolidine-l-carbonyl)phenyl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (2.10 mg, 8%). 1H-NMR (MeOD): 1.82 (m, 2H)S 1.91 (m, 2H), 2.04 (m, IH), 2.21 (m, IH), 3.02 (s, 3H), 3.39 (t, 2H), 3.52 (t, 2H), 5.82 (d, IH), 6.95 (d, IH), 7.15 (m, IH), 7.27 (m, IH), 7.34 (m, 3H), 7.46 (m, 4H), 7.54 (m, 2H).
Example 55 N-(4-(2'-amino-r-methyl-5'-oxo-2- phenyl-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6- yl)benzyl)methanesulfonamide (Compound 62)
Figure imgf000267_0002
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(17/)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4- (methylsulfonamidomethyl) phenylboronic acid (24 mg, 0.104 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 jV-(4-(2'-amino-r-methyl-5'-oxo-2- phenyl-r,5'-dihydrospiro[chroman-454'- imidazole]-6-yl) benzyl)methanesulfonamide (4.26 mg, 17%). 1H-NMR (MeOD): 2.06 (m, IH), 2.22 (m, IH), 2.76 (s, 3H), 3.04 (s, 3H), 4.17 (s, 2H), 5.80 (m, IH), 6.92 (m, IH), 7.10 (m, IH), 7.24 (m, IH), 7.32 (m, 4H), 7.37 (m, 2H), 7.39 (m, 2H), 7.41 (m, IH).
Example 56
2'-amino-6-bromo-2-(2-fluorophenyl)-r-methylspiro-[chroman-4,4'-imidazol]-5'(l Η)-one
(Compound 63)
KCN, (NH4J2CO3 Lawsson's Reagent HCONH2
Figure imgf000268_0001
Figure imgf000268_0003
Figure imgf000268_0002
Figure imgf000268_0004
A mixture of l-(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 H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman- 4-one (15 g, 50%).
Figure imgf000269_0001
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 (NH4^CO3 (4.5 g, 46.87 mmol). Formamide (25 mL) was added to fill the steel bomb nearly completely. The mixture was heated at 70 0C for 48 h then at HO0C 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 Na2SO4, 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%). Step 3:
Lawsson's Reagent
Figure imgf000269_0002
Figure imgf000269_0003
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%). Step 4:
Figure imgf000269_0004
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 H2O (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)-r-methyl-2'-(methylthio)spiro[chroman-4,4'-imidazol]-5'(r//)- one (80 mg, 41%). Step 5:
Figure imgf000270_0001
A solution of 6-bromo-2-(2-fluorophenyl)-l '-methyl-2'-(methylthio)spiro-[chroman- 4,4'-imidazol]-5'(l'H)-one (80 mg, 0.183 mmol) and NH4I (53.21 mg, 0.367 mmol) in NH3/EtOH (2 mL, 1.5 N) was heated at HO0C 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)-r-methylspiro- [chroman-4,4'-imidazol]-5'(l 'H)-one (52 mg, 70%).
1H-NMR (MeOD): 2.15 (d, IH), 2.25 (d, IH), 3.20 (s, 3H), 6.15 (d, IH), 6.78 (d, IH), 6.99 (t, IH), 7.05 (s, IH), 7.15 (t IH), 7.25 (d, 2H), 7.50 (t, IH).
Example 57
2'-amino-r,6-dimethyl-2-phenylspiro[chroman-4,4'-imidizol]-5'(l 'H)-one (Compound
64)
Figure imgf000270_0002
SteD 1 :
Figure imgf000271_0001
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-methyl- phenyl ester (52.6 g, 76%). 1H-NMR (CDCl3): 2.25 (s, 3H), 2.36 (s, 3H), 6.96 (d, 2H), 7.18 (d, 2H).
Step 2:
Figure imgf000271_0002
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 60-800C 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%). 1H-NMR (CDCl3): 2.28 (s, 3H), 2.57 (s, 3H), 6.83 (d, IH), 7.25 (d, IH), 7.46 (s, IH), 12.01 (s, IH).
Figure imgf000271_0003
A mixture of l-(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 H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-methyl-2-phenyl-chroman-4-one (8.1 g, 34%). 1H-NMR (CDCl3): 2.32 (s, 3H), 2.86 (d, IH), 3.06 (t, IH), 5.44 (d, IH), 6.96 (d, IH), 7.38 (d, IH)5 7.44 (m, 5H), 7.71 (s, IH).
Figure imgf000272_0001
A steel bomb was charged with a mixture of 6-methyl-2-phenyl-chroman-4-one (1 g, 4.2 mmol), potassuim cyanide (0.82 g, 12.6 mmol), and (NKt)2CO3 (3.03 g, 31.5 mmol). Formamide (2OmL) was added to fill the steel bomb nearly completely. The mixture was heated at 7O0C 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 Na2SO4, 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%). Step 5:
Lawesson's Reagent
Figure imgf000272_0003
Figure imgf000272_0002
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%). 1H-NMR (CDCl3): 2.28 (s, 3H), 2.47 (d, IH), 2.51 (d, IH), 5.30 (s, IH), 6.92 (s, IH), 6.70 (d, 2H), 7.10 (m, IH), 7.41 (m, IH)5 8.18 (s, IH).
Figure imgf000273_0001
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 H2O (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 r,6-dimethyl-2'-(methylthio)-2- phenylspiro[chroman-4,4"-imidazol]-5'-(r//)-one (40 mg, 67%). Step 7:
Figure imgf000273_0002
A solution of 1 ',6-dimethyl-2'-(methylthio)-2-phenylspiro[chroman-4.4'-imidazol]-5'- (VH)- one (40 mg, 0.12 mmol), and NH4I (35 mg, 0.24 mmol) in NH3/EtOH (4 mL, 1.5N) was heated at HO0C 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'-ammo-l\6-dimethyl-2-phenylspiro[chroman- 4;4'-imidizol]-5'(l !H)-one (2.03 mg, 6%). 1H-NMR (MeOD): 2.28 (s, 3H)5 2.40 (d, IH), 2.55 (d, IH), 3.28 (s, 3H)5 5.74 (d, IH), 6.92 (d, IH), 7.13 (s, IH)5 7.35 (d, IH)5 7.40-7.50 (m. 6H).
Example 58
4-(2:-amino-l '-methyl- 5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4, 4:-imidazole]-6- yl)- ΛyV-dimethylbenzenesulfonamide (Compound 65)
Figure imgf000274_0001
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(JV,JV-dimethyl- sulfamoyl) phenylboronic acid (23.8 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120 °C 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 pure 4-(2' -amino- 1' -methyl- 5'-oxo-2-phenyl-l \5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)- N,N-dimethylbenzenesulfonamide (2.4 mg, 9%). 1H-NMR (CDCl3): 2.31 (t, IH), 2.57 (t, IH), 2.78 (s, 6H), 3.33 (d, 3H), 3.56 (s, 2H), 5.88 (d, IH), 7.20 (d, IH), 7.26 (s, IH), 7.48 (m, 5H), 7.57 (m, IH)5 7.62 (d, 2H), 7.80 (d, 2H).
Example 59 2-(2'-amino-r-methyl-5'-oxo-2- phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole] -6-yl)-
NjV-dimethylbenzamide (Compound 66)
Figure imgf000274_0002
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo- 1 '-methyl-2-phenylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2- (dimethylcarbamoyl) phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120 0C 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 2-(2'-amino-r-methyl-5'-oxo-2- phenyl-r.5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)- ΛUV-dimethylbenzamide (1.60 mg; 6%). 1H-NMR (MeOD): 2.45 (m, 3Η), 2.56 (m, IH), 2.64 (m, IH), 2.86 (m, 3H)5 3.36 (s, 3H), 5.81 (m, IH), 7.14 (m, IH), 7.21 (m, IH), 7.33 (m, IH), 7.44 (m, 9H)..
Example 60 2'-amino-6-bromo-l \2,2-trimethylspiro[chroman-.4,4'-imidazol]-5'(77f)-one (Compound
67) and 6-bromo- 1 ',2,2-trimethyl-2'-(methylamino)spiro[chronian-4,4'-imidazol]-5'(7 'H) -one
Figure imgf000275_0001
Step l :
Figure imgf000275_0002
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%). 1H-NMR (CDCl3): 2.28 (s, 3 H)5 6.98 (d, 2 H)8 7.48 (d, 2 H). Step 2
Figure imgf000276_0001
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 l-(5-bromo-2- hydroxyphenyl)-ethanone (101.0 g, 98%). 1H-NMR (CDCl3): 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).
Step 3:
Acetone
Figure imgf000276_0003
Figure imgf000276_0002
A solution of l-(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, 3x). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2.2-dimethyl- chroman-4-one (18.0 g, 71%). 1H-NMR (CDCl3): 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). Step 4:
Figure imgf000276_0004
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 (NH4^CO3 (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 1 10°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 Na2SO4, 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%). 1H-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), 1 1.08 (brs, 1 H). Step 5:
Figure imgf000277_0001
6-Bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.0 g, 12.3 mmol) and 1 M Et3O-BF4 (4.7 g, 24.7 mmol) were dissolved in dry CH2Cl2 (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-4,41- imidazol]-5'(5'H)-one (1.0 g, 25%). Step 6:
Figure imgf000277_0002
To a solution of 6-bromo-2'-ethoxy-2,2-dimethylspiro[chroman-4.4'-imidazol]-5'(5'//)- one (500 mg, 1.42 mmol) in EtOH (30 mL) was added NH3-H2O (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'(5'H)-one (120 mg, 30%). Step 7:
Figure imgf000278_0001
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 O0C under N2 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-r,2,2-trimethylspiro[chroman-4.4'-imidazol]- 5'(7 'H)-one (40 mg, 80%) and 6-bromo-r,2,2-trimethyl-2'-(methylamino)spiro[chroman- 4J4'-imidazol]-5'(; 'H) -one (5 mg, 10%).
1H-NMR (MeOD): 1.3 (s, 3 Η), 1.40 (s, 3 Η), 1.85 (d, 1 Η), 2.25 (d, 1 Η), 3.1 (s, 3 Η), 6.65 (d, 1 Η), 6.8 (s, 1 Η), 7.20 (s, 1 Η) (67).
1H-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).
Example 61
4-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)- iV.N-dimethylbenzamide (Compound 68)
Figure imgf000278_0002
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-l '-(cyclohexylmethyl)-2-phenylspiro[chroman-4.4'-imidazol]-5'(l 'H)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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 l,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-ΛζN- dimethylbenzamide (7.97 mg, 34%). 1H-NMR (MeOD): 2.07 (m, IH), 2.24 (m, IH)3 3.00 (m, 6H), 3.11 (m, 3H), 5.22 (d, 0.3H), 5.86 (d, 0.7H), 6.97 (m, IH), 7.18 (m, IH), 7.28 (m, IH), 7.34 (m, 2H), 7.39 (m, 4H), 7.46 (m, IH), 7.54 (m, 2H).
Example 62
2'-amino-6-bromo-r-ethyl-2-phenylspiro[chroman-4,4'- imidazol]-5'(lΗ)-one
(Compound 69)
Figure imgf000279_0001
Step l :
Figure imgf000279_0002
To a mixture of 6-bromo-2-phenyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (250 mg, 0.64 mmol) and K2CO3 (356 mg, 2.6 mmol) in CH3CN (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-l '-ethyl-2'-(ethylthio)-2-phenylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one (195 mg, 69%). Step 2:
Figure imgf000279_0003
A solution of 6-bromo-l l-ethyl-2'-(ethylthio)-2-phenylspiro[chroman-4,4'-imidazol]-
5'(l'H)-one (195 mg, 0.44 mmol), NH4I (128 mg, 0.88 mmol) in NH3/EtOH (5 mL, 1.5 N) was heated at 1100C 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 2l-amino-6-bromo-r-ethyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)- one (42 mg, 24%). 1H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, IH), 3.16 (m, IH), 3.54 (m, 2H), 5.75 (m, IH), 6.77 (m, IH), 6.95 (m, IH), 7.23 (m, 2H), 7.33 (m, 4H).
Example 63 tert-butyl 2-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5l-dihydrospiro[chroman-4,4'- imidazole]-6-yl)-lH-pyrrole-l-carboxylate (Compound 70)
Figure imgf000280_0001
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'- amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(l 'H)-one (30 mg, 0.099 mmol) in 1,4-dioxane (1.2 mL), Cs2CO3 (2 N, 0.3 mL) and l-(tert-butoxycarbonyl)- lH-pyrrol-2-ylboronic acid (30 mg, 0.142 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 tert-butyl 2-(2'-amino-l'- methyl-S'-oxo^-phenyl-r.S'-dihydrospirofchroman^^'-imidazoleJ-ό-y^-lH-pyrrole-l- carboxylate (0.8 mg, 2%). 1H-NMR (MeOD): 1.40 (s. 9H), 2.44 (m, IH), 2.61 (m, IH), 3.25 (s, 3H), 5.85 (d, IH), 6.14 (m, IH), 6.23 (m, IH), 7.05 (m, IH), 7.16 (m, IH), 7.32 (m, 2H), 7.49 (m, 5H).
Example 64
4-(2!-amino-r-methyl-5'-oxo-2-phenyl-r,5!-dihydro-spiro[chroman-4,4:-imidazole] -6- yl)- ΛyV-diethylbenzamide (Compound 71)
Figure imgf000281_0001
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'-amino-6-bromo-l '-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(lΗ)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4- (diethylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 1200C for 30 mins. 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-l ',5'-dihydro- spiro[chroman-4,4' -imidazole] -6-yl)- NJV- diethylbenzamide (6.95 mg, 28%). 1H-NMR (MeOD): 1.13 (s, 3H)5 1.24 (d, 3H), 2.13 (d,lH), 2.30 (s, IH), 3.17 (s, 3H), 3.32 (d, 4H), 5.91 (d, IH), 7.03 (d, IH), 7.22 (s, IH), 7.33 (m, IH), 7.40 (m, 4H), 7.49 (m, 2H), 7.51 (m, IH), 7.57 (m, 2H).
Example 65 Compound 72
Figure imgf000281_0002
-s I rGeaa8g=e'n"t B MeI NH4I
EtOWNH3
Figure imgf000281_0005
Figure imgf000281_0004
Figure imgf000281_0003
Figure imgf000281_0006
Experimental data:
Figure imgf000282_0001
Step 1. tetrahydro-pyran-3-ol
To the solution of 3,4-dihydro-2H-pyran (126 g, 1.5 mol) in dry THF (1 100 mL) was added a solution OfB2H6 in Me2S (10 M, 75 mL, 0.75 mol) under nitrogen atmosphere at 0 °C. The mixture was stirred at this temperature for 3h, and then 25 °C for another 2h. The mixture was warmed to 40°C ~ 45 °C, and aq. NaOH (3 N, 300 mL) and H2O2 (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 χ300 mL). The organic phase was washed with aq. Na2S2O3 (3 x 100 mL), dried over Na2SO4, and concentrated in vacuum to give the crude product, which was purified by distillation to give the product ( 43 g, 33%). 1H-NMR (CDCl3): 1.1.51-1.61 (m, 2H), 1.78-1.91 (m, 4H), 3.40 (m, IH), 3.54-3.65 (m, 2H), 3.69-3.76 (m, 2H).
Figure imgf000282_0002
Step 2. dihydro-pyran-3-one
To a solution of tetrahydro-pyran-3-ol (30 g, 0.29 mol) in dry CH2Cl2 (900 mL) was added 3A molecule sieves (3Og) and PCC (94.9g, 0.44mol). The mixture was stirred at room temperature overnight. When the reaction was completed, the mixture was filtered through celite, dried over Na2SO4, and concentrated in vacuum to give the crude product, which was distilled in vacuo to give dihydro-pyran-3-one (10.5 g. 36%). 1H- NMR (CDCl3): 2.06-2.13 (m, 2H), 2.53 (m, 2H), 3.85 (m, 2H), 4.02 (s, 2H).
Figure imgf000282_0003
72i
Step 3. compound 72i A solution of l-(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%). 1H-NMR (CDCl3): 1.49 (m, IH), 1.65 (m, IH), 1.86 (m, IH), 2.04 (m, IH), 2.63 (t, 2H), 3.48 (m, 2H), 3.79 (m, 2H), 6.88 (d, IH), 7.50 (dd, IH), 7.89 (m, IH).
Figure imgf000283_0001
Step 4. compound 72ii
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 (NtLt)2CO3 (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 Na2SO4 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%). 1H-NMR (CDCl3): 1.74-2.12 (m, 4H), 2.36 (m,
IH), 2.47 (m, IH), 3.51-3.55 (m, 4H), 6.85 (m, IH), 7.18 (m, IH)5 7.32 (m, IH), 8.18 (d,
IH), 8.93 (s, IH).
Lawesson's reagent
Figure imgf000283_0002
Figure imgf000283_0003
72ii 72iii Step 5. compound 72 Hi
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%). 1H-NMR (CDCl3): 1.52-1.74 (m, 2H), 1.95 (m, 2H), 2.15 (m, IH), 2.49 (m, IH), 3.56 (m, 2H), 3.84 (m, 2H), 7.12 (m, IH), 7.35 (m, IH), 7.14 (s, IH), 9.14 (s, IH).
Figure imgf000284_0001
72iii 72iv
Step 6. compound 72 iv
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 0C 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%).
Figure imgf000284_0002
72iv 72v
Step 7. compound 72 v
A solution of 72iv (93 mg, 0.227 mmol), NH4I (82 mg, 0.567 mmol) in NH3/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%).
Figure imgf000285_0001
72v 72
Step 8. Compound 72
Pd(PPh3)2Cl2 (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), Cs2CO3 (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%). 1H-NMR (MeOD): 1.68 (m, IH), 1.89 (m, 2H),
2.03 (m, IH), 2.12 (m, IH), 2.25 (t, IH), 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, IH), 7.86 (m, IH), 7.84 (m, IH).
Example 65 a Compound 72a and compound 72b
O 2.aq.NaOH, H2O2
Figure imgf000286_0001
σ0H HCONH2
72i
Figure imgf000286_0002
72ii 72iii 72iv
Figure imgf000286_0003
Experimental data:
Figure imgf000286_0004
Step 1 : tetrahydro-pyran-3-ol
To a solution of 3.4-dihydro-2//-pyran (126 g, 1.5 mol) in dry THF (HOOmL) was added a solution Of B2H6 in Me2S (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 N5 300 mL) and H2O2 (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. Na2S2O3 (3χ100 mL), dried over Na2SO4, and concentrated in vacuum to give the crude product, which was purified by distillation to give tetrahydro-pyran-3-ol ( 86 g, 33%). 1H-NMR (CDCl3): 1.51-1.61 (m, 2H), 1.78-1.91
(m, 4H), 3.40 (m, IH), 3.54-3.65 (m, 2H), 3.69-3.76 (m, 2H).
Figure imgf000287_0001
Step 2: dihydro-pyran-3-one
To a solution of tetrahydro-pyran-3-ol (30 g, 0.29 mol) in dry CH2Cl2 (900 mL) was added 3A 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 Na2SO4, and concentrated in vacuum to give the crude product, which was distilled in vacuo to give dihydro-pyran-3-one (10.5 g, 36%). 1H- NMR (CDCl3): 2.06-2.13 (m, 2H), 2.53 (m, 2H), 3.85 (m, 2H), 4.02 (s, 2H).
Figure imgf000287_0002
72i
Step 3: compound 72i
A solution of l-(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%). 1H-NMR (CDCl3): 1.49 (m, IH), 1.65 (m, IH), 1.86 (m, IH), 2.04 (m, IH)5 2.63 (t, 2H), 3.48 (m, 2H), 3.79 (m, 2H), 6.88 (d, IH), 7.50 (dd, IH), 7.89 (m, IH).
Figure imgf000287_0003
72i 72ii Step 4: compound 72ii
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 (NHj)2CO3 (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 Na2SO4 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%). 1H-NMR (CDCl3): 1.74-2.12 (m, 4H), 2.36 (m, IH)5 2.47 (m, IH), 3.51-3.55 (m, 4H), 6.85 (m, IH), 7.18 (m, IH), 7.32 (m, IH), 8.18 (d, IH), 8.93 (s, IH).
Figure imgf000288_0001
Step 5: compound 72iii
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%). 1H-NMR (CDCl3): 1.52-1.74 (m, 2H), 1.95 (m, 2H), 2.15 (m, IH), 2.49 (m, IH), 3.56 (m, 2H), 3.84 (m, 2H), 7.12 (m, IH), 7.35 (m, IH), 7.14 (s, IH), 9.14 (s, IH).
MeI
Figure imgf000288_0003
Figure imgf000288_0002
Step 6: compound 72 iv
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 0C 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%).
Figure imgf000289_0001
72iv 72v
Step 7: compound 72 v
A solution of 72iv (123 mg, 0.3 mmol), NH4I (109 mg, 0.75 mmol) in NH3/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 72 v (48 mg, 42%).
Figure imgf000289_0002
Step 8: Compound 72a
Pd(PPh3 )2C12 (20 mg) in a 10 mL of microwave tube under Ar2 was treated sequentially with the amine 72v (45 mg, 0.12 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N5 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: 1H-NMR (MeOD): 1.53-1.69 (m, IH), 1.88 (m, IH), 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, IH), 7.41 (m, IH),
7.54 (t, IH), 7.63 (m, 2H), 7.84 (m, IH), 7.92 (m, IH).
Compound 72a: 1H-NMR (MeOD): 1.48 (m, IH), 1.81 (m, IH), 1.92 (m, IH), 2.04 (m, IH), 2.38 (m, 2H), 3.30 (s, 3H), 3.58 (m, 2H), 3.85 (m, 2H), 7.09 (d, IH), 7.31 (m, IH), 7.58 (m, 3H), 7.79 (m, IH), 7.85 (m, IH).
Compound 72b: 1H-NMR (MeOD): 1.65 (m, IH), 1.92 (m, IH), 2.02 (m, IH), 2.10 (m, IH), 2.45 (s, 2H), 3.31 (s, 3H), 3.63 (m, 2H), 3.77 (m, 2H), 7.09 (m, IH), 7.40 (m, IH),
7.55 (t, IH), 7.64 (m, 2H), 7.83 (m, IH), 7.92 (m, IH).
Example 66 Compound 73
Figure imgf000290_0001
Figure imgf000290_0002
Figure imgf000290_0003
Experimental data:
Figure imgf000291_0001
Step 1. compound 73ii
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%).
Figure imgf000291_0002
73ii 73iii
Step 2. compound 73iii
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%). 1H NMR (CDCl3 / 400M): δ 7.25-7.19 (m, IH), 6.74-6.69 (m, 2H), 3.13 (s, 3H), 2.58-2.50 (m, 4H)5 2.31-2.19 (m, IH), 2.18-2.05(m, IH), 2.03-1.95 (m, IH), 1.90-1.60 (m, 3H) , 1.51-1.40 (m, IH) , 1.39-1.15 (m. 3H) , 0.95-0.80 (m, 3H).
Figure imgf000292_0001
73iii 73iv
Step 3. compound 73 iv
A solution of the compound 73iii (127 mg, 0.3 mmol), NH4I (87 mg, 0.6 mmol) in NH3/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 CH2Cl2 and filtered to separate off NH4I. The solution was concentrated in vacuo and purified by preparative TLC (CH2Cl2: CH3OH 11 :1) to afford the compound 73iv (85 mg, 72%).
Figure imgf000292_0002
73iv 73
Step 4. Compound 73
Pd(PPh3 )2C12 (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), Cs2CO3 (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 (CH2Cl2: CH3OH 13:1) and then by preparative HPLC to give the Compound 73 (32 mg, 43%). 1H NMR (MeOD / 400M): δ 7.91 (s, IH), 7.84 (d, IH, 9.2Hz), 7.66-7.40 (m, 3H), 7.39 (s, IH),
7.02-6.98 (m, IH), 3.30 (s, 3H), 2.64-2.59 (m, IH), 2.37-2.32 (m, IH), 2.30-2.09 (ms 2H), 2.08-1.92 (m, 2H), 1.91-1.66 (m, IH), 1.65-1.51 (m, IH), 1.50-1.21 (m, 3H), 0.98-0.88 (ms 3H). Example 67 Compound 75
Lawesson's reagent
Figure imgf000293_0001
Figure imgf000293_0002
Experimental data:
Figure imgf000293_0003
Step 1 6-bromo-4'-methylspiro(chroman-25l '-cyclohexan)-4-one
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g. 0.093 mol), 4- methylcyclohexanone (21.31 g, 0.187mol) 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 H2O and then added HCl until pH=l. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. filtered, and evaporated to give 6-bromo-4'-methylspiro(chroman-2,r-cyclohexan)-4-one (45 g, 100%).
Figure imgf000293_0004
Step 2 6-bromo-4'-methylspiro(chroman-4.4'- imidazolidine)-2'.5'-dione A glass pressure tube was charged with a mixture of 6-bromo-4'- methylspiro(chroman-2J '-cyclohexan)-4-one (2 g. 6.47 mmol), KCN (0.84 g, 12.94 rnrnol), and (NH4)2Cθ3 (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 Na2SO4 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%).
La wesson's reagent
Figure imgf000294_0001
Figure imgf000294_0002
Step 3 6-bromo-4'-methylspiro-2'- thioxospiro[chroman-4.4'-imidazolidin]-5'-one
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%).
Figure imgf000294_0003
Step 4 6-bromo-4'-methylspiro-l '-methyl-2'-(methylthio)spiro-[chroman-4.4'-imidazol]-5' (VH)-one 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 0C 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-21- (methylthio)spiro-[chroman-4,4'-imidazol]-5'(l'H)-one (22.5 mg, 53%).
Figure imgf000295_0001
Step5 2'-amino-6-bromo-4'-methylspiro-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)- one
A solution of 6-bromo-4'-methylspiro -l'-methyl-2'-(methylthio)spiro- [chroman- 4,4'- imidazol]-5'(lΗ)-one (90 mg, 0.212 mmol), NH4I (246 mg, 1.696 mmol) in
NH3/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-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (80 mg, 100%).
Figure imgf000295_0002
Step 6: Compound 75
Pd(PPh3 )2C12 (8 mg) in a 10 mL tube under Ar was treated sequentially with T- 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), Cs2CO3 (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 0C for 10 minutes. The reaction mixture was concentrated in vacuo give the residue, which was purified by preparative TLC and then by preparative ΗPLC to give Compound 75 (6.5 mg, 8%). 1H-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, IH), 7.40 (s, IH), 7.59 (m, 3H), 7.86 (d, 2H), 7.11 (s, IH).
Example 68 Compound 76
Figure imgf000296_0001
Step 1 :
In a 50 mL round bottom flask was added l-(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 Na2SO4. Solvent was removed in vacuo to give 6-bromospiro[chroman-2,r-cyclohexan]-4-one (2.25 g, 82%), which is used for the next step without purification.
Step 2:
A lO 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 (NfLO2CO3 (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 0C 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 H2O (10 mL X 3). The organic layer was dried over Na2SO4, 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+).
Step 3:
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 1 10 0C 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+).
Step 4:
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+).
Step 5:
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 NH4I (100 mg, 0.69 mmol) and NHa/MeOH (7 N5 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 x 3), and dried over Na2SO4. 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+).
Step 6:
To a solution of the above cyclohexyl-acyl-guanidine (50 mg, 0.13 mmol) in 1,4- dioxane (2 mL) was added Cs2CO3 (142 mg. 0.43 mmol), 3-cyanophenylboronic acid (29.1 mg, 0.20 mmol), and a catalytical amount of PdC^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. 1H NMR (400MHz, CD3COCD3): 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+).
Example 69 Compound 77
Lawesson's reagpnt
Figure imgf000298_0001
Figure imgf000298_0002
Experimental data:
Figure imgf000298_0003
Step 1: 6-bromo-2',3',5',6'-tetrahydrospiro [chroman-2,4'-pyran]-4-one
A mixture of l-(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 H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2',3',5',6'- tetrahydrospiro[chroman-2,4'-pyran]-4-one (15 g, 100%). 1HNMR (CDCl3): 1.74 (m, 2H), (m, 2H), 1.94 (t, 2H), 2.71 (s, 2H), 3.76 (m, 4H), 6.91 (d, IH), 7.54 (d, IH), 7.96 (s, IH).
Figure imgf000299_0001
Step 2: compound 77ii
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), (NH4^CO3 (22.7 g, 236.46 mmol) and formamide (60 mL) in a 10OmL 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 Na2SO4 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%). 1H-NMR (MeOD): 1.83 (m, 4H), 2.22 (d, IH), 2.46 (d, IH), 3.68 (m, 2H), 3.82 (m, IH), 3.93 (t, IH), 6.89 (d5 IH), 7.18 (s, IH), 7.38 (d, IH), 8.04 (s, IH).
Figure imgf000299_0002
77ii 77iii
Step 3: compound 77iii 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%).
Figure imgf000300_0001
77iii 77 iv
Step 4: compound 77iv
A mixture of compound 77iii (60 mg, 0.16 mmol), NaOH solution (0.6 N, 06 mL) and CH3I (0.2 mL) in methanol (2mL) 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%).
Figure imgf000300_0002
77iv 77v
Step 5: compound 77v
A solution of compound 77iv (28 mg. 0.07 mmol), NH4I (20 mg, 0.14 mmol) in NH3/EtOH (3 mL, 1.5 N) was heated at 120 0C 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%).
Figure imgf000300_0003
77v 77 Step 6: Compound 77
A mixture of compound 77v (24 mg, 0.06 mmol). 3-cyanophenylboronic acid (18.6 mg, 0.13 mmol), Pd(PPh3 )2C12 (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%). 1H-NMR (MeOD): 1.84 (m, 3H), 2.05 (s, IH), 2.34 (d, IH), 2.51 (d, IH), 3.29 (s, 3H), 3.73 (m, 3H), 3.93 (m, IH), 7.13 (d, IH), 7.42 (s, IH), 7.63 (m, 3H), 7.84 (m, IH), 7.92 (s, IH).
Example 70 Compound 78
Figure imgf000301_0001
Experimental data:
Figure imgf000301_0002
Step 1 : 6-bromospiro[chroman-2,r- cycloheptan]-4-one
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=l . The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6- bromospiro[chroman-2,l'- cycloheptan]-4-one (18.3 g, 100%). 1H-NMR (CDCl3): 1.34 (m, IH), 1.49 (m, IH), 1.62 (m, 10H)5 1.71 (m, IH), 2.02 (m, IH), 6.78 (m, IH), 7.47 (m, IH), 7.86 (m, IH).
Figure imgf000302_0001
78i
Step 2: compound 78i
In a steel bomb, a mixture of 6-bromospiro[chroman-2,l'- cycloheptan]-4-one (1.5 g, 4.87 mmol), KCN (0.633 g, 9.74 mmol) and (NH4^CO3 (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=l . The mixture was filtered, and the filtrate was extracted with CH2Cl2. The organic layer was concentrated to give compound 78i (370 mg, 20 %). 1H-NMR (DMSO): 1.79 (m, 4H), 1.96 (m, 6H), 2.13 (m, IH)3 2.22 (m, 2H), 2.36 (m, IH), 7.19 (m, IH), 7.50 (m, IH), 7.72 (m, IH).
Lawsson's Reagent
Figure imgf000302_0002
Figure imgf000302_0003
78i 78ii
Step 3 : compound 78ii
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 (10 mg, 13%).
Figure imgf000303_0001
78ii 78ΪΪΪ
Step 4: compound 78iii
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%).
Figure imgf000303_0002
78iii 78iv
Step 5 : compound 78iv
A solution of compound 78iii (20 mg, 0.047 mmol) and NH4I (14 mg, 0.094 mmol) in NH3/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%).
Figure imgf000303_0003
78iv 78
Step 5: Compound 78 Pd(PPh3)2Cl2 (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), Cs2CO3 (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%). 1H-NMR (MeOD): 1.41 (m, 2H), 1.60 (m, . 4H), 1.80 (m, 3H), 2.01 (m, 3H), 2.16 (m, IH), 2.22 (m, IH), 2.82-3.05 (m, 3H), 6.85 (m, IH), 6.91 (m, IH), 7.37 (m, IH), 7.48 (m, IH), 7.54 (m, IH), 7.68 (m, IH), 7.71 (m, IH).
Example 71 Compound 79
Lawsson's Reagent
Figure imgf000304_0002
Figure imgf000304_0001
Experimental data:
Figure imgf000304_0003
Step 1 : 6-bromospiro[chroman-2,l'- cyclopentan]-4-one
A mixture of l-(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=l. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6- bromospiro[chroman-2,l'- cyclopentan]-4-one (23 g, 100%). 1H-NMR (CDCl3): 1.64 (m, 4H), 1.72 (m, 2H), 2.03 (m, 2H), 2.78 (s, 2H), 6.78 (m, IH), 7.48 (m, IH), 7.91 (m, IH).
Figure imgf000305_0001
Step 2: compound 79i
In a steel bomb, a mixture of 6-bromospiro[chroman-2,r- cyclopentan]-4-one (1.5 g, 5.36 mmol), KCN (0.7 g, 10.72 mmol) and (NH4)2CO3 (3.86 g, 40.22 mmol) in formamide (30 mL) was heated to 80 0C for 3 days. The mixture was poured into ice/water. Concentrated HCl was added until pH=l . The mixture was filtered, and the filtrate was extracted with CH2Cl2. The organic layer was concentrated to give compound 79i (1.75 g, 93 %). 1H-NMR (CDCl3): 1.42 (m, IH), 1.61 (m, 5H), 1.76 (m, IH), 1.92 (m, 2H), 2.57 (m, IH), 6.57 (m, IH), 7.00 (s, IH), 7.13 (m, IH), 7.91 (m, IH).
Lawsson's Reagent
Figure imgf000305_0003
Figure imgf000305_0002
79i 79ii
Step 3 : compound 79ii
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 1 10 °C overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give compound 79ii (60 mg, 15%). 1H-NMR (CDCl3): 1.51 (m; IH), 1.69 (m, 3H); 1.79 (m, 2H), 1.98 (m, 2H), 2.17 (m, IH), 2.64 (m, IH), 6.68 (m, IH), 7.02 (m, IH), 7.25 (m, IH).
Figure imgf000306_0001
79ϋ 79iii
Step 4: compound 79iii
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%).
Figure imgf000306_0002
79iii 79iv
Step 5: compound 79iv
A solution of compound 79iii (20 mg. 0.051 mmol), NH4I (15 mg, 0.102 mmol) in NH3/EtOH (2 mL. 1.5 N) was heated at 1 10 °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%).
Figure imgf000306_0003
79iv 79
Step 6: Compound 79 Pd(PPh3)2Cl2 (5 mg, 0.005 mmol) in a 10 niL flask under Ar was treated sequentially with compound 79iv (10 mg, 0.027 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 1.69 (m, 4H), 1.86 (m, 3H)5 2.04 (m, IH), 2.22 (m, IH), 2.49 (m, IH), 3.07 (s, 3H), 6.82 (m, IH), 6.96 (m, IH), 7.11 (m, 2H), 7.39 (m, IH), 7.52 (m, IH), 7.70 (m, IH).
Example 72 Compound 84
Figure imgf000307_0001
To a solution of the cyclohexyl-acyl-guanidine (57 mg, 0.15 mmol) in 1,4-dioxane (1.5 mL) was added Cs2CO3 (161 mg, 0.45 mmol), pyridin-4-ylboronic acid (28 mg, 0.22 mmol), and PdCbdppf (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. 1H NMR (400MHz, CD3OD): 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+).
Example 73 Compound 81
Figure imgf000307_0002
Experimental data:
Lawsson's Reagent
Figure imgf000308_0001
Figure imgf000308_0002
Step 1.
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 8 IH (160 mg, 50%).
Figure imgf000308_0003
Step 2.
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 0C 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%).
Figure imgf000308_0004
Step A solution of the compound 81iii (80 mg, 0.168 mmol) and NH4I (195 mg, 1.34 mmol) in NH3/EtOH (2.5 mL, 8 N) was heated at 120 0C 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%).
Figure imgf000309_0001
81 iv
81v
Step 4.
Pd(PPh3 )2Cl2 (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), Cs2CO3 (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%). 1H-NMR (MeOD): 1.36 (t, IH), 1.52 (t, 2H), 1.70 (d, IH), 1.87 (m, IH), 2.00 (d, IH), 2.15 (dd, IH), 2.24 (t, IH), 2.34 (d, IH), 2.51 (m, 2H), 3.28 (s, 3H) , 7.11 (d, IH), 7.41 (t, IH), 7.56 (t, IH), 7.63 (m, 2H), 7.84 (d5 IH), 7.93 (s, IH).
Example 74 Compound 82
Figure imgf000310_0001
Lawsson's Reagent NH4I
Figure imgf000310_0002
Figure imgf000310_0003
Experimental data:
Figure imgf000310_0004
Step 1. 6-bromo-3'-methylspiro[chroman-2,r-cyclohexan]-4-one
A mixture of l-(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 H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6- bromo-3'-methylspiro[chroman-2,l'- cyclohexan]-4-one (18 g, 100%). 1HNMR (CDCl3): 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, IH), 2.48 (m, IH)5 2.60 (s, 2H), 2.72 (t, 3H), 6.81 (m, IH), 7.50 (m, IH), 7.9 l(m, IH).
Figure imgf000311_0001
Step 2.
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 (NtLO2CO3 (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 Na2SO4 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%). 1HNMR (MeOD): 0.81 (d, IH), 0.92 (m, 3H), 1.49 (m, 2H)5 1.71 (d, 2H), 2.03 (d, IH), 2.13 (s, 2H): 2.41 (dd, IH), 6.78 (dd, IH), 7.12 (d, IH), 7.30 (m, IH).
Figure imgf000311_0002
82i 82ii
Step 3.
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%).
Figure imgf000312_0001
82ii 82iii
Step 4.
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%).
Figure imgf000312_0002
Step 5
A solution of the compound 82iii (90 mg, 0.21 mmol) and NH4I (246 mg, 1.7 mmol) in NH3/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%).
Figure imgf000312_0003
82iv 82
Step 6 Pd(PPh3 )2C12 (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), Cs2CO3 (2 N5 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%). 1H-NMR (MeOD): 0.90 (dd, 3H), 0.95 (d, IH), 1.25 (m, 2H), 1.60 (m, 2H), 1.90 (m, 4H), 2.30 (dd, IH), 3.34 (s, 3H), 7.05 (dd, IH), 7.38 (s, IH), 7.61 (m, 3H) , 7.84 (d, IH) , 7.92 (s, IH).
Example 75 Compound 83
Figure imgf000313_0001
Lawsson's Reagent MeI NH4I
Figure imgf000313_0003
Figure imgf000313_0002
Figure imgf000313_0004
Experimental data:
Figure imgf000313_0005
Step 1. 6-bromo-3'.5'-dimethylspiro[chroman-2,r-cyclohexan]-4-one - _> l j -
A mixture of l-(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 H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6- bromo-3^5'-dimethylspiro[crπOman-2,l'-cyclohexan]-4-one (10 g, 100%). 1HNMR (CDCl3): 0.51 (m, IH), 0.71 (m, 4H), 0.72(m, 3H), 0.91 (m, 3H), 1.11 (d, IH), 1.19 (t, IH), 1.50 (s, IH), 1.64 (t, IH), 1.79 (m, 3H), 1.90 (m, 2H), 2.0 (m, 3H), 2.24 (t, IH), 2.53 (s, IH), 2.79 (s, IH), 6.75 (t, IH), 7.49 (t, IH), 7.89(d, IH).
Figure imgf000314_0001
83i
Step 2
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 (NH4)2CO3 (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 Na2SO4 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%).
Figure imgf000314_0002
Step 3
A suspension of the compound 83i (375 mg, 0.96 mmol) and Lawesson's Reagent (386 mg, 0.957mmol) in dry 1,4-dioxane (3.5 mL) was heated at 1 10 °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%).
Figure imgf000315_0001
83M 83iii
Step 4
To a solution of the compound 83ii (200 mg, 0.50 mmol) in MeOH (10 mL) was added a solution of NaOH (0.6 N5 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 83iϋ (15 mg, 10%).
Figure imgf000315_0002
Step 5
A solution of the compound 83iii (15 mg, 0.034 mmol) and NH4I (39.7 mg, 0.27 mmol) in NH3/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%).
Figure imgf000316_0001
Step 6
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with the compound 83iv (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 0.55 (dd, IH), 0.87 (m, 6H), 1.20 (m, 2H), 1.70 (m, 5H), 2.35 (m, IH), 2.51(m, IH), 6.99 (t, IH), 7.34 (s, IH), 7.54 (m, 3H) , 7.81 (d, IH) , 7.89 (s, IH).
Example 76
3-(3'-amino-21-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'H-spiro[chroman-4!5'-[L2,4] oxadiazole]-6-yl)benzonitrile (Compound 85)
Figure imgf000316_0002
MeNHOH HCI
NaOMe, MeOH
Figure imgf000316_0003
Experimental data:
Figure imgf000316_0004
Step 1 : 6-bromo-2-(tetrahydro-2//-pyran-3- yl)chroman-4-one
A mixture of l-(5-bromo-2-hydroxypheηyl)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 H2O (400 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-2-(tetrahydro-2H-pyran-3- yl)chroman-4-one (10 g, 20%).
Figure imgf000317_0001
Step 2: (£)-N-(6-bromo-2-(tetrahydro-2//-pyran-3-yl)chroman-4-ylidene)cyanamide
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 TiCl4 (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 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (£)-N-(6-bromo-2-(tetrahydro-2//-pyran-3-yl)chroman-4-ylidene)cyanamide (300 mg, 100%), which was used in next step without further purification.
MeNHOH. HCI
NaOMe, MeOH
Figure imgf000317_0002
Figure imgf000317_0003
Step 3: 6-bromo-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'//-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 MeOH5 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'//-spiro[chroman-4,5'-[L2,4]oxadiazol]-3'-amine (50 mg,
Figure imgf000318_0001
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(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6- bromo-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'//-spiro[chroman-4,5'-[1.2.4]oxadiazol]- 3'-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (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'//-spiro[chroman-4.5'- [l,2,4]oxadiazole]-6-yl)benzonitrile (5 mg, 10%). 1H-NMR (MeOD): 1.69 (m, 2.5H), 2.01 (m, 3H), 2.51 (m, IH), 2.72 (m, IH), 3.42 (d, 2H), 3.52 (m, 3H), 3.90 (m, 2H), 4.15 (m, 1.5H), 7.02 (d, IH), 7.59 (t, IH), 7.68 (m, 2H), 7.94 (m, 3H).
Example 77
3-(3'-amino-2'-methyl-2-(tetrahydro-2//-pyran-4-yl)-2'H-spiro[chroman-4,5'-[l,2,4]- oxadiazole]-6-yl)benzonitrile (Compound 88)
Figure imgf000319_0001
MeNHOH HCI
NaOMe, MeOH
Figure imgf000319_0003
Figure imgf000319_0002
Figure imgf000319_0004
Experimental data:
Figure imgf000319_0005
Step 1. methyl tetrahydro-2//-pyran-4-carboxylate
To a solution of tetrahydro-2/7-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfbnic 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 Na2SO4, filtered and concentrated to give methyl tetrahydro-2//-pyran-4- carboxylate (8.3 g, 75%) , which was used in next step without purification.
DlBAL-H
Figure imgf000319_0007
Figure imgf000319_0006
Step 2. tetrahγdro-2i/-pyran-4-carbaldehyde 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 NH4Cl. The mixture was filtrated and the filtrate was extracted with ethyl ether for 3 times. The combined organic layers were dried over Na2SO4. Filtration followed by concentration in vacuo gave tetrahydro-2H-pyran-4-carbaldehyde (450 mg, 50%), which was used in next step without purification.
Figure imgf000320_0001
Step 3. 6-bromo-2-(tetrahydro-2//-pyran-4-yl)chroman-4-one
To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (943.9mg, 4.39 mmol) in EtOH(5.6 mL) and H2O(9.4 mL) was added tetrahydro-2//-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 CH2Cl2 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-2i/-pyran-4-yl)chroman-4-one(270 mg, 20%). 1H-NMR (CDCl3, 400MHz): 1.54 (m, 2H), 1.78 (m, IH), 1.95 (m, IH), 2.75 (m, 2H); 3.44 (m, 3H), 4.09 (m, 2H), 4.15 (m, 1H); 6.89 (m; IH), 7.56 (m, IH), 8.01 (m, IH).
Figure imgf000320_0002
Step 4. (£)-jV-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide
To a solution of 6-bromo-2-(tetrahydro-2//-pyran-4-yl)chroman-4-one (310 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (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 6w-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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (£)-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.
Figure imgf000321_0001
Step 5 6-bromo-2'-methyl-2-(tetrahydro-2H-pyran-4-yl)-2'H-spiro[chroman-4,5'- [l,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 (£T)-iV-(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'-[l,2,4]oxadiazol]-3'-amine (50 mg. 40%).
Figure imgf000321_0002
Stepό 3-(3'-amino-2'-methyl-2-(tetrahydro-2H-pyran-4-yl)-2Η-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'-[l,2,4]oxadiazol]-3'-amine (50mg, 0.131 mmol). 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs2CO3 (2 M5 0.5 mL) and Pd(PPh3)2C,2 (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-(3l-amino-2'-methyl-2-(tetrahydro-2//-pyran-4-yl)-2lH- spiro[chroman-4,5'-[L2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1H-NMR
(CDCl3): 1.54 (m, 2H), 1.62 (m, IH), 1.88 (m, IH), 2.10 (m, IH), 2.48 (m, IH), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, IH), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).
Example 78 6-(3,5-difluorophenyl)-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'//-spiro[chroman- 4.5'-
[l,2,4]oxadiazol]-3'-amine (Compound 90)
Figure imgf000322_0001
In a 10 mL flask, 6-bromo-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'H- spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine (30 mg, 0.08mmol), Pd(PPh3)2Cl2 (15 mg), 3.5-difluorophenylboronic acid (25mg, 0.16 mg) were dissolved in 1,4-dioxane (4.0 mL), followed by addition Of Cs2CO3 (2 N. 1 mL). 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 6-(3,5- difluorophenyl)-2'-methyl-2- (tetrahydro-2//-pyran-3-yl)-2'//-spiro[chroman-4.5'- [L2,4]oxadiazol]-3'-amine (10 mg, 30%). 1H-NMR (MeOD): 1.62 (m, 2H), 1.96 (m, 3H), 2.70 (m, IH), 3.30 (s, 3H), 3.38 (m, 4H), 3.83 (m, 2H), 4.12 (m, 2H), 6.84 (m, IH), 6.96 (m, IH), 7.18 (m, 2H), 7.64 (m, IH), 7.86 (d, IH).
Example 79
6-(3-fluorophenyl)-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'H-spiro[chroman-4.5'- [l,2,4]oxadiazol]-3'-amine (Compound 93)
Figure imgf000323_0001
Pd(PPh3)2Cl2 (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'-[l,2,4]oxadiazol]- 3'-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3- fluorophenylboronic acid (29.3 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 product 6-(3-fluorophenyl)-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'H- spiro[chroman-4,5l-[l,2;4]oxadiazol]-3'-amine (5 mg, 10%). 1H-NMR (MeOD): 1.70 (m, 3H), 2.01 (m, 3H), 2.49 (m, 0.5H)5 2.71 (m, IH), 3.32 (d, 3H), 3.43 (m, IH), 3.53 (m, IH), 3.91 (dd, 2H), 4.19 (m, 2H), 7.03 (m. 2H), 7.32 (d, IH), 7.43 (m, 2H), 7.66 (t, IH), 7.89 (s, IH).
Example 80
3 -(3 ' -amino-2 " -methyl-2-(pyridine-3 -yl)-2 '//-spiro [chroman-4,5 " - [ 1 ,2,4] - oxadiazole] -6- yl)benzonitrile (Compound 95)
Figure imgf000323_0002
MeNHOH HCI
NaOMe, MeOH
Figure imgf000323_0003
Experimental data:
Figure imgf000324_0001
Step 1. 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile
A mixture of 6-bromo-2-(pyridine-3-yl)chroman-4-one (300 mg, 1 mmol), 3- cyanophenylboronic acid (294 mg, 2 mmol), Cs2CO3 (2 M, 5 mL) and Pd(PPh3)2Cl2 (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%). 1H-NMR (MeOD): 2.97-3.02 (d, IH), 3.25-3.33 (m, IH), 5.74-5.78 (d, IH), 7.23 (d, IH), 7.52 (m, IH), 7.60-7.64 (m, 2H), 7.70 (d, IH), 7.90-7.95 (m, 2H), 7.99 (s, IH), 8.07 (d, IH), 8.15 (s, IH), 8.57 (d, IH)5 8.75 (s, IH).
Figure imgf000324_0002
Step 2. (£)-N-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide
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 TiCl4 (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 Na2SO4, and filtered. The filtrate was concentrated to give (£)-Λ^-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman- 4-ylidene)cyanamide (70 mg, 93%). which was used in next step without further purification. MeNHOH. HCI
NaOMe, MeOH
Figure imgf000325_0002
Figure imgf000325_0001
Step 3. 3<3'-amino-2'-methyl-2-(pyridine-3-yl)-2'//-spiro[chroman-4,5'-[l,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)-jV-(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-(3r-amino-2'-methyl-2-(pyridine-3-yl)-2'//-spiro[chroman-4,5'- [l,2,4]oxadiazole]-6-yl)benzonitrile (2.5 mg, 3%). 1H-NMR (MeOD): 2.40-2.47 (t, IH), 2.92-3.16 (ΠL IH), 3.46 (s, 3H), 5.61-5.69 (m, IH), 7.21 (m, IH), 7.64-7.67 (m, IH), 7.75
Figure imgf000325_0003
Figure imgf000325_0004
Experimental data:
Figure imgf000325_0005
Step 1 : 3-(4-Bromophenoxy)propanoic acid 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 0C 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%). 1H-NMR (CDCl3): 2.72 (m, 2H), 4.90 (s, IH), 5.01 (d, IH), 5.50 (s, IH), 6.73 (m, IH), 7.21-7.43 (m, 6H), 7.61 (m, IH).
Figure imgf000326_0001
Step 2: 6-Bromochroman-4-one
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 CH2Cl2 (3χl5 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product (4 g, 88%).
Figure imgf000326_0002
Step 3: N-(6-Brornochrornan-4-ylidene)cyanamide
To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (289.3 mg, 1.28 mmol) in DCM (10 mL) was added TiCl4 (2.6 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, ΛW-methanediylidenebis(l,l,l- 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 CH2Cl2. The combined organic layer was dried and concentrated to give crude jV-(6-bromochroman-4-ylidene)cyanamide (300 mg, 94%). MeNHOH HCI NaOMe, MeOH
Figure imgf000327_0002
Figure imgf000327_0001
Step 4: 6-bromo-2'-methyl-27/-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine
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 _V-(6- bromochroman-4-ylidene)cyanainide (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-27/-spiro[chroman-4.5'-[l,2,4]oxadiazol]-3'-amine (315 mg, 88% o) .
Figure imgf000327_0003
Step 5: 3-(3'-Amino-2'-methyl-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazole]-6- yl)benzonitrile
Pd(PPh3)2Cl2 (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'-[ 152,4]oxadiazol]-3'-amine (59.4 mg, 0.2 mmol) in 1 ,4-dioxane (2.0 mL), Cs2CO3 (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'//-spiro[chroman-4,5' -[l,2.4]oxadiazole]-6-yl)benzonitrile (6.7 mg, 10%). 1H-NMR (MeOD): 2.31 (m, IH), 2.62 (m, IH), 3.39 (m, 3H), 4.32 (m, IH), 4.46 (m, IH)8 7.00 (d, IH), 7.58-7.71 (m, 3H), 7.95 (m, 3H).
Example 82 6-(3-isopropylphenyl)-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'//-spiro[chroman- 4,5' [l,2,4]oxadiazol]-3 '-amine (Compound 101)
Figure imgf000328_0001
Pd(PPh3)2Cl2 (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'-[l,2,4]oxadiazol]- 3'-amine (40 mg, 0.105 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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-p>τan-3-yl)-2'/f- spiro[chroman-4;5'-[l,2,4]oxadiazol]-3'-amine (7.5 mg, 18%). 1H NMR (MeOD): 1.31 (d, 6H), 1.68 (m, 2H), 1.92-2.07 (m, 3H), 2.43-2.72 (m, IH), 2.96 (m, IH), 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, IH), 7.21 (m, IH), 7.38 (m, 3H), 7.63 (m, IH), 7.79 (m, IH).
Example 83
5-(3'-amino-2'-methyl-2-phenyl-2'H-spiro(chroman-4,5'-(1.2,4)oxadiazole)-6yl)-2- fluorobenzonitrile (Compound 103)
TMSN=C=NTMS MeNHOH. HCI
TiCI4, DCM NaOMe, MeOH
Figure imgf000328_0004
Figure imgf000328_0003
Figure imgf000328_0002
Figure imgf000328_0005
Experimental data
Figure imgf000329_0001
Step 1 : (Z)-N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide
To a solution of 6-bromo-2phenylchroman-4-one (387 mg, 1.28 mmol) in anhydrous DCM (10 niL) was added TiCl4 (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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, 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.
Figure imgf000329_0002
Step 2: 6-bromo-2'methyl-2-phenyl-2'//-spiro(chroman-4,5'-(l,2.4)oxadiazol)-3 '-amine To a solution of methylhydroxylamine HCl salt (26 mg. 0.307 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25wt.% 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'-(l,2,4)oxadiazol)-3:-amine (100 mg, 87%), which was used in the next step without further purification.
Figure imgf000330_0001
Step 3: 5-(3'-amino-2'-methyl-2-phenyl-2'//-spiro(chroman-4,5'-(l,2,4)oxadiazole)-6yl)- 2- fluorobenzonitrile
To a solution of 6-bromo-2'methyl-2-phenyl-2'H-spiro(chroman-4,5'-(l,2,4) oxadiazol)-3' -amine (50 mg, 0.134 mmol), S-cyano-S-fluorinphenylboronic acid (38 mg, 0.228 mmol) and Cs2CO3 (109 mg, 0.338 mmol) in 1 ,4-dioxane (6.7 mL) and H2O (0.5 mL) was added PdCl2(PPh3 )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'-(l ,2,4)oxadiazole)-6yl)-2-fluorobenzonitrile (0.65 mg, 1.2%) as a TFA salt. 1H-NMR (MeOD): 2.26 (m, 0.3H), 2.57 (m, 0.7H), 2.72 (m, IH), 3.31 (m, 3H), 5.26 (m, IH), 7.00 (m, IH), 7.34 (m, 4H), 7.45 (m, 2H), 7.61 (s,lH), 7.94 (d, 3H).
Example 84
7-fluoro-6-(2-fluoropyridin-3-yl)-2'-methyl-2-phenyl-2'//-spiro[chroman-4,5'-[l,2,4] oxadiazol]-3'-amine (Compound 104)
Figure imgf000330_0002
MeNHOH.HCI NaOMe, MeOH
Figure imgf000330_0003
Experimental data:
Figure imgf000331_0001
Step 1. 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one
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), Na2CO3 (318 mg, 2.98 mmol), PPh3 (34 mg) and Pd(PPh3)2Cl2 (59 mg, 0.1 mmol) in toluene/EtOH (v/v=l/l, 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%).
Figure imgf000331_0002
Step 2. 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenyl-chroman-4-ylidene-cyanamide
To a solution of 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one (78 mg, 0.23 mmol) in CH2Cl2 (5 mL) under N2 was added TiCl4 (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 Na2SO4, and filtered. The filtrate was concentrated to give 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenyl- chroman-4- ylidene-cyanamide (100 mg, 100%).
Figure imgf000331_0003
- JJ I -
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'-[l,2,4]oxadiazol]-3'-amine (4.65 mg, 4%). 1H-NMR (MeOD): 2.21 (m, IH), 2.34 (m, IH), 3.03 (s, 3H), 5.46 (m, IH), 6.73 (m, IH), 7.32 (m, 4H), 7.49 (m, 3H), 7.91 (m, IH), 8.28 (m, IH).
Example 85
3-(3'-amino-2'-methyl-2- (pyridin-4-yl)-2'H-spiro[chroman-4,5'-[l ,2,4]oxadiazole]- 6- yl)benzonitrile (Compound 105)
Figure imgf000332_0001
Experimental data:
Figure imgf000332_0002
Step 1: (£)-l-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-l-one To a solution of l-(5-bromo-2-hydroxyphenyl)ethanone (50 g, 0.23 mol) in EtOH (285 mL) and H2O (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 (£)-l-(5-bromo-2- hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-l-one (30 g, 40%).
Figure imgf000333_0001
Step 2: 6-bromo-2-(pyridin- 4-yl)chroman-4-one
To a solution of (£)-l-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-l- one (20 g, 63.3 mmol) in EtOH (160 mL) and H2O (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 Na2SO4 and concentrated in vacuo to give 6-bromo-2-(pyridin- 4-yl)chroman- 4-one (10 g, 50%). 1H-NMR (CDCl3): 3.00 (t, 2H), 5.51 (dd, IH), 7.02 (d, IH)5 7.39 (d, 2H), 7.63 (t, IH), 8.04 (s, IH). 8.72 (d, 2H).
Figure imgf000333_0002
Step 3: (E)-N-(6-bromo-2-(pyridin-4- yl)chroman-4-ylidene)cyanamide
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 TiCl4 (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 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, 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.
MeNHOH HCl
NaOMe. MeOH
Figure imgf000334_0002
Figure imgf000334_0001
Step 4: 6-bromo-2'-methyl-2-(pyridin-4-yl)-2'H-spiro[chroman-4,5'-[l,2.4]oxadiazol]- 3'- amine
To a solution of methylhydroxylamine HCl salt (76.9 mg, 0.92 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25w% 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'-[l,2,4]oxadiazol]-3'-amine (80 mg, 30%).
Figure imgf000334_0003
Step 5: 3-(3'-amino-2'-methyl-2- (pyridin-4-yl)-2'//-spiro[chroman-4,5'- [l,2,4]oxadiazole]- 6-yl)benzonitrile Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6- bromo-2'-methyl-2-(pyridin-4-yl)-2'//-spiro[chroman-4,5'-[L2,4]oxadiazol]-3'-amine (20 mg, 0.053 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N8 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'//-spiro[chroman-4,5'-[L2,4]oxadiazole]-6- yl)benzonitrile (3 mg, 10%). 1H-NMR (MeOD): 2.24 (m, IH), 3.01 (m, IH)8 3.39 (t, 3H)S 5.54 (d, IH), 7.19 (m, IH)5 7.60 (m, IH), 7.62 (t, IH), 7.69 (m, IH), 7.89 (m, 3H), 8.02 (, 2H), 8.70 (s, 2H).
Example 86
3-(3'-amino-2'-methyl-2-(pyridin-2-yl)-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazole]- 6- yl)benzonitrile (Compound 106)
Figure imgf000335_0001
Experimental data:
Figure imgf000335_0002
Step 1. 3-(4-oxo-2-(pyridin-2-yl)chτoman-6-yl)benzonitrile
Pd(PPh3 )2C12 (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 rnrnol) in [l,4]dioxane (40 mL),
Cs2CO3 (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 (1 10 mg, 60%). 1H-NMR (CDCl3): 3.13 (m, 2H)3 5.61 (m, IH), 7.13 (m, IH), 7.27 (m, IH), 7.49 (m. IH), 7.58 (m, 2H), 7.68 (m, IH), 7.79 (m, 3H)5 8.09 (d, IH), 8.58 (ds IH).
Figure imgf000335_0003
Step 2. (Z)-N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide
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 TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, NJV-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 CH2Cl2. 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).
Figure imgf000336_0001
Step 3. 3-(3'-amino-2'-methyl-2-(pyridin-2-yl)-2'H-spiro[chroman-4,5'-[L2,4]oxadiazole]- 6-yl)benzonitrile
To a solution of N-methyl-hydroxylamine hydrochloride (14 mg, 0.14 mmol) in MeOH (4 mL) was added MeONa (0.03mL, 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'//- spiro[chroman-4,5'-[l, 2,4]oxadiazole]- 6-yl)benzonitrile (4.3 mg, 8%). 1H-NMR (MeOD): 2.1 1 (m, IH), 2.51 (m, IH), 3.02 (s, 2H), 3.28 (s, IH), 4.12 (m, IH), 5.32 (m, IH), 6.97 (m, IH), 7.32 (m, IH), 7.55 (m, 5H), 7.82 (m, 3H), 8.46 (m, IH).
Example 87
3-(3'-amino-2'-methyl-2-(4-(trifluoromethoxy)phenyl)-2'H-spiro[chroman-4,5'-[l,2,4] oxadiazole]-6-yl)benzonitrile (Compound 107)
Figure imgf000337_0001
MeNHOH HCI NC B(OH)2
NaOMe, MeOH
Figure imgf000337_0002
Figure imgf000337_0003
Experimental data:
Figure imgf000337_0004
Step 1 : (E)-l-(5-bromo-2-hydroxyphenyl)-3-(4- (trifluoromethoxy)phenyl)prop-2-en-l- one
To a solution of l-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.4 mmol) in EtOH (114 mL) and H2O (6 mL) was added 4-(trifluoromethoxy)benzaldehyde (17.75 g5
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 was collected by filtration to give (E)-I -(5-bromo-2-hydroxyphenyl)-3-(4- (trifluoromethoxy)phenyl)prop-2-en-l-one (30 g, 80%). 1H-NMR (CDCl3): 6.87 (d, IH),
7.21 (d, 2H), 7.49 (m, IH), 7.52 (m. IH), 7.59 (d, 2H), 7.84 (t, IH), 7.92 (s, IH).
Figure imgf000337_0005
Step 2: 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one To a solution of (£)-l-(5-bromo-2-hydroxyphenyl)-3-(4-
(trifluoromethoxy)phenyl)prop- 2-en-l-one (8 g, 20 mmol) in EtOH (144 mL) and H2O (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 Na2SO4 and then concentrated in vacuo to give 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (6 g, 80%). 1H- NMR (CDCl3): 2.91 (d, IH), 3.04 (m, IH), 5.49 (dd, IH), 6.94 (m, IH), 7.31 (d, 2H), 7.50 (d, 2H), 7.59 (m, IH), 8.03 (s, IH).
Figure imgf000338_0001
Step 3: (E)-N- (6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide
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 TiCl4 (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 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, 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.
MeNHOH HQ
NaOMe. MeOH
Figure imgf000338_0002
Figure imgf000338_0003
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 (25w% 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)-2Η- spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine (100 mg, 20%).
Figure imgf000339_0001
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(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6- bromo-2'-methyl-2-(4-(trifluoromethoxy)phenyl)-2'i/-spiro[chroman-4.5'- [l,2,4]oxadiazol]-3'-amine (50 mg, 0.1 1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (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'-[l,2,4]o- xadiazole]-6-yl)benzonitrile (1.39 mg, 5%). 1H-NMR (MeOD): 2.34 (t, IH), 2.89 (d, IH), 5.41 (t, IH), 7.13 (d, IH), 7.37 (t, 2H), 7.64 (m, 3H), 7.70 (d, IH), 7.78 (t, IH), 7.94 (t, IH), 8.04 (m, 2H).
Example 88
2'-methyl-6-phenoxy-2-phenyl-2'H-spiro[chroman-4,5l-[l,2,4]oxadiazol]-3'-amine
(Compound 108)
Figure imgf000340_0001
Figure imgf000340_0002
MeNHOH. HCI NaOMe, MeOH
Figure imgf000340_0004
Figure imgf000340_0003
Experimental data:
Figure imgf000340_0005
Step 1 : 4-phenoxyphenyl acetate
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%). 1H-NMR (CDCl3): 2.21 (s, 3H), 6.94 (m, 6H), 7.04 (m, IH), 7.28 (m, 2H).
Figure imgf000340_0006
Step 2: l-(2-hydroxy-5-phenoxyphenyl)ethanone A mixture of acetic acid 4-phenoxy-phenyl ester (114 g, 0.5 mol) and AlCl3 (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 Na2SO4. After concentration, the residue was purified by column (25.8 g, 23%). 1H-NMR (CDCl3): 2.57 (s, 3H), 6.96 (m, 3H)5 7.07 (m, IH), 7.21 (m, IH), 7.3 l(m, 2H), 7.40 (m, IH), 12.05 (s, IH).
Figure imgf000341_0001
Step 3: (£)-l-(3-phenoxyphenyl)-3-phenylprop-2-en-l-one
In a bottle l-(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 (I N, 200 mL) and filtered to give a solid. The solid was dried to give 3-(3-chloro-phenyl)-l-(2-hydroxy-5-phenoxy-phenyl)-propenone (5.87 g,
85%). 1H-NMR (CDCl3): 6.95 (m, 2H), 7.07 (m, 2H)5 7.23 (m, IH), 7.34 (m, 2H), 7.42
(m5 3H), 7.53 (m5 IH), 7.64 (m, 3H)5 7.95 (m, IH), 12.62 (s, IH).
Figure imgf000341_0002
Step 4: 6-phenoxy-2-phenylchroman-4-one
3-(3-Chloro-phenyl)-l-(2-hydroxy-5-phenoxy-phenyl)-propenone (5.85 g. 0.018 mol) was dissolved in H2O (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 H2O 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%). 1H-NMR (CDCl3): 2.87 (m, IH), 3.06 (m, IH)5 5.46 (m, IH)5 6.96 (m, 2H)5 7.08 (m. 2H), 7.25 (m, IH), 7.33 (m, 2H)5 7.39 (m, IH)5 7.42 (m, 2H)5 7.48 (m, 2H)5 7.51 (m, IH).
Figure imgf000342_0001
Step 5: (Z)-7V-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide
To a solution of 6-phenoxy-2-phenylchroman-4-one (316 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred forl 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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (2)-iV-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 90%), which was used in the next step without further purification.
MeNHOH. HCI NaOMe, MeOH
Figure imgf000342_0002
Figure imgf000342_0003
Step 6: 2'-methyl-6-phenoxy-2-phenyl-2'H-spiro[chroman-4,5'-[l ,2,4]oxadiazol]-3'-amine
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 (2)-Λ^-(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- 2lH-spiro[chroman4,5'-[l, 2, 4]oxadiazol]-31-amine (200 mg, 52%). 1H-NMR (CDCl3): 2.41- 2.66(m, IH), 2.65 (m, IH), 2.75 (m, IH)8 3.32 (m, 3H), 5.35 (m, IH), 6.95 (m, 2H), 7.06 (m, IH)5 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H). Example 89 Compound 109
MeNHOH. HCI NaOMe, MeOH
Figure imgf000343_0001
Figure imgf000343_0002
Experimental data:
Figure imgf000343_0003
Step 1. 6-bromo-3-fluoro-2',4'.5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one
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. CH2CL was added to the resulting residue and insoluble material filtered off. The filtrate was washed with H2O, dried and concentrate in vacuo. The crude product was purified by column chromatography to give 6-bromo-3-fluoro-21,4',5'.6'-tetrahydrospiro[chroman-2.3'-pyran]- 4-one (220 mg, 10%). 1H-NMR (CDCl3): 1.72-2.21 (m, 4H), 3.44 (m, IH), 3.63 (m, IH), 3.73 (m, IH), 3.92 (m, IH), 4.91 (m, IH), 6.94 (ms IH), 7.56 (m, IH), 7.90 (m, IH).
Figure imgf000343_0004
Step 2. (Z)-N-(6-bromo-3-fluoro-2'.4'.5',6'-tetrahydrospiro[chroman-2,3l-pyran]-4- ylidene)cyanamide 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 TiCl4 (1 M in DCM51.4 mL) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added iV,7V-methanediylidenebis(l,l,l-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 Na2SO4, filtered, and the filtrate was concentrated to give crude product, which was used in the next step without further purification.
Figure imgf000344_0001
109i
Step 3. Compound 109i
To a solution MeNHOH.HCI (25 mg. 0.3 mmol) in anhydrous MeOH was added NaOMe (14 mg, 25w% 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%).
Figure imgf000344_0002
109i 109
Step 4. Compound 109 Pd(PPh3 )2Cb (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), Cs2CO3 (2 N, 0.162 mL) and 3-cyanophenylboronic acid (32.6 mg, 0.22 mmol). The mixture was heated at 120 0C 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%). 1H-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, IH), 5.24 (m, IH), 7.13 (m, IH), 7.64 (m, IH), 7.71 (m, IH), 7.82 (m, IH), 7.97 (m, IH), 8.09 (m, 2H).
Example 90 Compound 110
Figure imgf000345_0001
110i
110
Step 1. Compound 110
Pd(PPh3 )2Cl2 (6 mg) under Ar was treated sequentially with the amine 11Oi (20 mg; 0.062 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 1.45-1.94 (m, 3H), 2.04 (m, 2H), 2.89 (m, IH), 3.37 (m, 3H), 3.61 (m, 2H)5 3.82 (m, 2H), 7.02 (m, IH), 7.34 (m, 2H), 7.51 (m, IH), 7.18 (m, 2H), 7.88 (m, IH).
Example 91 Compound 111
Figure imgf000346_0001
Experimental data:
Figure imgf000346_0002
Step 1. 4-bromophenyl propionate
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%). 1H NMR (MeOD, 400MHz): 1.12-1.24 (m, 3H), 2.57-2.63 (m, 2H), 7.02-7.06 (m, 2H), 7.51- 7.55 (m, 2H).
Figure imgf000346_0003
Step 2. l-(5-bromo-2-hydroxyphenyl)propan-l-one
4-Bromophenyl propionate (34 g. 0.15 mmol) and aluminum chloride (44 g, 0.3 mmol) were heated together at 100 0C 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 l-(5-bromo-2-hydroxyphenyl)propan-l- one. (20 g, 59%) 1H NMR (CDCl3, 400MHz): 1.24 (t, 3H), 2.98-3.04 (m, 2H), 6.88 (d, IH), 7.52 (t, IH), 7.76 (s, IH).
Step 3. 6-bromo-3-methyl-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one
A mixture of l-(5-bromo-2-hydroxyphenyl)propan-l-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 H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3-methyl- 2\4\5\6'-tetrahydrospiro [chroman- 2,3'- pyran]- 4-one (1.2 g, 16%). 1HNMR (CDCl3): 1.16-1.27 (m, 3H), 1.51-1.57 (m, IH), 1.66-1.73 (m, IH), 1.91-2.08 (m, 2H), 2.59-2.69 (m, IH), 3.46-3.56 (m, 2H), 3.88-3.98 (m, 2H), 6.97 (m, IH), 7.58 (m, IH), 7.95 (s, IH).
Figure imgf000347_0002
Step 4. (E)-N-(6-bτomo-3- methyl-2',4',5\6'-tetrahydrospiro [chroman-2.3'-pyran]-4- ylidene)cyanamide
A solution of 6-bromo-3-rnethyl-2\4',5',6'-tetrahydrospiro [chroman- 2,3'- pyran]- 4-one (200 mg, 0.65 mmol) and TiCl4 (864 mg, 4.55 mmol) in anhydrous DCM (8 mL) was heated at 50 0C under microwave for 5 mins. Then bis- trimethylsilylcarbodiimide (360 mg, 1.95 mmol) was added and the mixture was heated at 65 0C for another 1 hr. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (E)-N-(6-bτomo-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.
MeNHOH.HCI NaOMe, MeOH
Figure imgf000348_0002
Figure imgf000348_0001
11 Ii
Step 5. compound 11 Ii
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-bτomo-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 llli (100 mg, 25%). 1H-NMR (CDCl3): 1.02-1.11 (m, 3H), 1.89-2.17 (m, 2H), 1.17-2.24 (m, 2H)3 3.05 (s, 3H), 3.63-3.68 (m, IH), 3.95-4.33 (m, 2H), 4.25-4.40 (s, 2H), 6.79-6.87 (m, IH), 7.30-7.39 (m, IH), 7.47 (s, IH).
Figure imgf000348_0003
Step 6. Compound 111 A mixture of Compound llli (69 mg, 0.18 mmol), 3-cyanophenylboronic acid (53 mg, 0.36 mmol), Cs2CO3 (2 M, 1 mL) and Pd(PPh3)2Cl2 (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%). 1H-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, IH), 3.61-3.65 (m, 2H), 3.80-4.10 (m, 2H), 7.07-7.17 (m, IH), 7.59-7.79 (m, 3H), 7.90-8.01 (m, 3H).
Example 92 Compound 113a and 113b HOV PCC x> 't>
Figure imgf000349_0001
Figure imgf000349_0002
Experimental data:
Figure imgf000349_0003
Step 1 : dihydrofuran-3(2i/)-one
To a solution of tetrahydrofuran-3-ol (29.7 g, 0.337 mol) in dry DCM (1 L) was added 3A 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 Na2SO4 and concentrated in vacuo to give the crude product, which was distilled in vacuo to give product (7.07 g, 29%). 1H- NMR (MeOD): 2.45 (m, 2H)9 3.8 (m, 2H), 4.2 (m, 2H).
Figure imgf000349_0004
Step 2: 6-bromo-4'.5'-dihydro-2'H-spiro[chroman-2,3'-furan]-4-one
A solution of l-(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 pΗ 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%). 1H-NMR (CDCl3): 1.9 (m, IH), 2.3 (m, IH), 2.8 (m, 2H), 3.65 (m, IH), 3.9 (m, IH), 4.0 (m, 2H), 6.8 (m, IH), 7.5 (m, IH), 7.9 (m, IH).
Figure imgf000350_0001
Step 3: (JE)-N-(6-bromo-4',5'-dihydro-2'H-spiro[chroman-2,3'-furan]-4-ylidene)cyanamide
To a solution of 6-bromo-4',5'-dihydro-2'/f-spiro[chroman-2,3I-furan]-4-one (206 mg. 0.731 mmol) in anhydrous DCM(6 mL) was added TiCl4(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 Λr,Λ7'-methanediylidenebis(l,Ll-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 Na2SO4. filtered and concentrated to give crude product (225 mg, 100%), which was used in the next step without further purification.
Figure imgf000350_0002
113i
Step 4: compound 113i
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%). 1H-NMR (CDCl3): 2.0 (m, 2H), 2.25 (m, 2H), 3.0 (d, 3H), 3.65 (m, IH), 3.8 (m, IH), 3.9 (m, 2H), 6.65 (d, IH), 7.25 (d, 2H), 7.45 (d, IH).
Figure imgf000351_0001
Step 5: Compound 113
Pd(PPh3)2Cl2 (5 mg, 0.005mmol) in a 10 mL flask under Ar was treated sequentially with compound 113i (30 mg, 0.085 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 2.15 (m, 1H)S 2.35 (m, IH), 2.55 (m, IH), 2.8 (m, IH), 3.35 (m, 3H), 3.8 (mlH), 3.95 (m, 2H), 4.1 (m, IH), 7.0 (m,lH), 7.55 (m, IH), 7.7 (m, 2H), 7.9 (m, IH)5 8.0 (m, 2H) (113a). 1H- NMR (MeOD): 2.15 (m, 2H), 2.4 (m, IH), 2.8 (m, IH), 3.35 (m, 3H), 3.8 (m, IH), 3.95 (m, 2H), 4.05 (m, 1H),7.O (m, IH), 7.6 (m, IH), 7.7 (m, 2H), 7.9 (m, IH), 8.0 (m, 2H) (113b).
Example 93 Compound 114
Figure imgf000351_0002
TMSN=C=NTMS
Figure imgf000351_0003
Figure imgf000351_0004
Figure imgf000351_0005
114vii
114 Experimental data:
^r^ ^ Step 1. 2-(allyloxymethyl)oxirane
An oil slurry of NaH (68g of a 60% suspension) was rinsed with petroleum ether and added to THF (1600 mL). The prop-2-en-l-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 H2SO4, the solution was filtered, concentrated under reduced pressure and distilled under vacuo to give (Z)-2,3,4.5-tetrahydrooxepin-3-ol as colorless oil.
Figure imgf000352_0001
Step 2. (Z)-2,3,4,5-tetrahydrooxepin-3-ol
1.3 MsBuLi 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 (6χ30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure below 25 0C. 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%). 1H-NMR (CDCl3 / 400M): δ 6.32-6.30 (m, IH), 4.82-4.78 (m, IH), 4.04-3.94 (m, 2H), 3.93-3.88 (m, IH), 2.28-2.15 (m, IH), 2.14-2.05 (m, IH), 2.04-1.95 (m, IH), 1.89 (br, IH, OH), 1.76-1.68 (m, IH).
Figure imgf000352_0002
Step 3. oxepan-3-ol To a solution of (Z)-2,3,4,5-tetrahydrooxepin-3-ol (114H) (6.9 mmol, 786 mg) in MeOH (7.86 mL), was added Pd(OH)2 ( 78.6 mg ) at room temperature under protection ofH2. 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%). 1H-NMR (CDCl3 / 400M): δ 3.89-3.85 (m, IH), 3.81-3.73 (m, IH), 3.72-3.62 (m, 3H), 1.85-1.75 (m, 3H), 1.74-1.62 (m, 2H), 1.60-1.52 (m, IH).
Figure imgf000353_0001
Step 4. oxepan-3-one
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 CH2Cl2. 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%). 1H-NMR (CDCl3 / 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).
Pyrrolidine
Figure imgf000353_0002
Figure imgf000353_0003
114v
Step 5. compound 114v
A mixture of l-(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%). 1H-NMR (CDCl3 / 400M): δ 7.94 (d, IH, J= 2.8 Hz), 7.56-7.53 (m, IH), 6.90 (d, IH, J= 8.8 Hz), 4.00 (d, IH, J= 16 Hz), 3.91-3.82 (m, IH), 3.75-3.67 (m, IH), 3.64 (d, IH5 J= 14 Hz), 2.79-2.65 (m, 2H), 2.09- 2.00 (m, IH), 1.92-1.68 (m, 4H), 1.55-1.42 (m, IH).
Figure imgf000354_0001
114v 114vi
Step 6. compound 114vi
To a solution of compound 114v (223 mg, 0.72 mmol) in anhydrous DCM (5.6 mL) was added TiCl4 (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 x 20 mL).
The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give compound 114vi as light brown solid (168 mg), which was used for next step without further purification.
Figure imgf000354_0002
Step 7. compound 114vii
To a solution of methylhydroxylamine HCl salt (42 mg, 0.50 mmol) in anhydrous MeOH (5.9 mL) was added NaOMe (25w% 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 (CH2Cl2 : MeOH 12:1) to give the pure product 114vii (1 14 mg, 59%).
Figure imgf000355_0001
114vii
114
Step 8. Compound 114
Pd(PPh3 )2C12 (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), Cs2CO3 (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 (CH2Cl2 : MeOH 10:1) and preprative HPLC to give the target compound Compound 114. 1H-NMR (MeOD / 400M): δ 7.99-7.97 (m, IH), 7.95-7.87 (m, 2H), 7.72-7.68 (m, IH), 7.67-7.62 (m, IH), 7.61-7.55 (m, IH), 7.15-6.98 (m, IH), 3.92-3.85 (m, 2H), 3.82-3.65 (m, 2H), 3.41-3.35 (m, 3H), 3.05-2.88 (m, IH), 2.15-2.05 (m, IH), 2.04-2.01 (m, IH), 2.00-1.95 (m, IH), 1.92-1.71 (m, 3H), 1.68-1.48 (m, IH).
Example 94 Compound 115
Figure imgf000355_0002
MeNHOH.HCI
NaOMe, MeOH
Figure imgf000355_0003
Experimental data:
Figure imgf000356_0001
Step 1. 3-(4-oxo-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-6-yl)benzonitrile
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), Cs2CO3 (2 M, 4 mL) and Pd(PPh3)2Cl2 (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%). 1H-NMR (CDCl3): 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, IH), 7.52- 7.56 (t, IH), 7.61-7.64 (d, IH), 7.71-7.74 (d, IH), 7.78 (d, IH), 7.80 (s, IH), 8.07 (s, IH).
Figure imgf000356_0002
Step 2. (Z)-7V-(6-(3-cyanophenyl)-2',3',5\6'- tetrahydrospiro[chroman- 2,4'-pyran]-4- ylidene)cyanamide
A solution of 3-(4-oxo-2'.3'.5',6'-tetrahydrospiro[chroman-2,4'-pyran]-6- yl)benzonitrile (170 mg, 0.53 mmol) and TiCl4 (403 mg, 2.12 mmol) in anhydrous DCM
(5 mL) was heated at 50 0C under microwave for 5 mins. Then bis- trimethylsilylcarbodiimide (198 mg, 1.06 mmol) was added and the mixture was heated at 60 0C for another 30 mins. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (Z)-ΛL(6-(3-cyanophenyl)-2\3\5\6Metrahydrospiro[chroman-2,4'- pyran]-4-ylidene)cyanamide (147 mg, crude), which was used in the next step without further purification. MeNHOH.HCI
NaOMe, MeOH
Figure imgf000357_0001
Figure imgf000357_0002
Step 3. Compound 115
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)-JV-(6-(3 -cyanophenyl)-2 ' ,3 ' ,5 ' ,6 ' -tetrahydrospiro [chroman-2,4 ' -pyran] -A- 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%). 1H-NMR (CDCl3): 1.79-1.90 (m, 3H), 2.03-2.07 (d5 IH), 2.24 (d, IH), 2.33 (d, IH), 3.09 (s, 3H) 3.73-3.82 (m, 3H), 3.91-3.97 (m, IH), 6.97 (d, IH), 7.41-7.43 (d, IH), 7.47-7.51 (t, IH), 7.56-7.58 (m, 2H), 7.74-7.81 (m, 2H).
Example 95 Compound 116
Figure imgf000357_0003
Experimental data:
Figure imgf000357_0004
Step 1 : oxepan-4-one
To a solution of tetrahydro-pyran-4-one (15 g, 0.15 mol) in Et2O (90 mL) was added dropwise a solution Of CH2N2 (1 M in Et2O, 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. 1H-NMR (CDCl3): 1.79 (m, 2H), 2.61 (m, 4H), 3.81 (m, 4H).
Figure imgf000358_0001
116i Step 2: compound 116i
A mixture of oxepan-4-one (10 g, 87.7 mmol), l-(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=l. 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%). 1H-NMR (CDCl3): 1.52 (m, IH), 1.84 (m, 2H), 1.98 (m, IH), 2.13 (m, 2H), 2.70 (m, 2H), 3.65 (m, IH), 3.74 (m, 3H), 6.81 (d, IH), 7.49 (m, IH), 7.90 (m, IH).
Figure imgf000358_0002
116i 116ii
Step 3: compound 116H
To a solution of compound 116i (200 mg, 0.645 mmol) in anhydrous DCM (7 mL) was added TiCLt (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 Na2SO4, filtered, and concentrated to give compound 116ii, which was used in the next step without further purification.
Figure imgf000359_0001
116N 116iii
Step 4: compound llόiii
To a solution of methylhydroxylamine HCl salt (38 mg, 0.45 mmol) in anhydrous MeOH (6 mL) was added NaOMe (25w% 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 llόiii, which was purified by preparative TLC (60 mg, 34%).
Figure imgf000359_0002
116iii 116
Step 5: Compound 116
Pd(PPh3 )2C12 (8 mg) in a 10 mL of tube under Ar2 was treated sequentially with compound llόiii (30 mg, 0.0787 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 1.71 (m, IH), 2.05 (m, 4H), 2.20 (m, 3H), 3.01 (m, IH), 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, IH), 7.72 (m, IH), 7.97 (m ,3H), 8.30 (m. 0.3H). Example 96 Compound 117
TMSN=C=NTMS MeNHOH. HCI TiCI4, DCM NaOMe, MeOH
Figure imgf000360_0002
Figure imgf000360_0001
Figure imgf000360_0003
Figure imgf000360_0004
Experimental data:
Figure imgf000360_0005
Step 1 : (E)-jV-(6-bromo-2'.4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4- ylidene)cyanamide To a solution of 6-bromo-2',4l,5'.6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one
(379 mg, 1.28. mmol) in anhydrous DCM (10 mL) was added TiCl4 (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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, 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. MeNHOH. HCI NaOMe, MeOH
Figure imgf000361_0001
Figure imgf000361_0002
Step 2: compound 117i
To a solution of methylhydroxylamine HCl salt (62.7 mg, 0.75 mmol) in anhydrous MeOH (8 niL) was added NaOMe (25% in MeOH (Wt.%), 0.15 mL, 0.675 mmol), followed by (jE)-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%).
Figure imgf000361_0003
117i 117
Step 3: Compound 117
A mixture of compound 117i (50 mg, 0.157 mmol), 3-cyanophenylboronic acid (40 mg, 0.266 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (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%). 1H-NMR (MeOD): 1.61 (m, IH), 1.78 (m, 2H), 2.1 1 (m, 2H), 2.93 (m, IH), 3.37 (m, 3H), 3.64 (m; 2H), 3.75 (m, 2H), 7.09 (m, IH), 7.67 (m, IH), 7.75 (m; 2H), 7.97 (m, 3H).
Example 97
3-(3"-Imino-2"-methylspiro[spiro(chroman-2,l"-cyclohexane)-4,5'-[l,2.4]oxadiazolidine]-
6-yl)benzonitrile (Compound 118)
Figure imgf000362_0001
Suzuki
Figure imgf000362_0002
Step l :
To a solution of 6-bromospiro[chroman-2,r-cyclohexan]-4-one (379 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give N-(6-bromospiro[chroman-2,r-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)+.
Step 2:
To a solution of methylhydroxylamine HCl salt (107 mg, 1.28 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25w% in MeOH, 0.25 mL, 1.15 mmol), followed by N-(6-bromospiro[chroman-2,r-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,r- cyclohexane)-4,5"-[l,2,4]oxadiazolidin]-3"-imine. which is used for next step without further purification. MS ESI +ve m/z 366 (M+H)+.
Step 3: To a solution of 6-bromo-2"-methylspiro[spiro(chroman-2,r-cyclohexane)-4,5"- [l,2,4]oxadiazolidin]-3"-imine (77 mg, 0.2 mmol), 3-cyanophenylboronic acid (62 mg, 0.34 mmol), and Cs2CO3 (163 mg, 0.5 mmol) in 1,4-dioxane (10 mL) and H2O (0.5 mL) in a 25 mL round-bottom flask equipped with a condenser was added PdCl2(PPh3)2 (20 mg). After degassing by vaccum and purge with N2, 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,r-cyclohexane)-4,5"-[l,2,4]oxadiazolidine]-6- yl)benzonitrile (18 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H)+. 1H NMR (400MHz, CD3OD): 8.29-7.02 (m, 12H), 3.38 and 3.34 (s and s, 3H), 2.86 (m, IH), 2.12- 1.40 (m, HH).
Example 98 Compound 119
Figure imgf000363_0001
117i
119
Step 1. Compound 119
Pd(PPh3 )2C12 (10 mg) in a 10 mL tube under Ar was treated sequentially with compound 117i (50 mg, 0.136 mmol) in L4-dioxane (2 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 1.61 (m, IH), 1.92 (m, 2H), 2.13 (m, 2H), 2.69 (t, IH), 3.32 (d, 3H), 3.61 (m, 2H), 3.84 (m; 2H), 7.02 (m, 2H), 7.33 (d, IH), 7.42 (m, 2H), 7.62 (d, IH), 7.79 (d; IH).
Example 99 Compound 120 TMSN=C=NTMS TiCI4, DCM
Figure imgf000364_0002
Figure imgf000364_0001
Figure imgf000364_0003
Experimental data:
Figure imgf000364_0004
Step 1 : (E)-7V-(6-bromo-3'-ethylspiro[chroman-2,r-cyclopentane]-4-ylidene)cyanamide
To a solution of 6-bromo-3'-ethylspiro[chroman-2,r-cyclopentan]-4-one (226 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (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 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-ΛL(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.
Figure imgf000364_0005
12Oi Step 2: compound 12Oi
To a solution of methylhydroxylamine HCl salt (60 mg, 0.72 mmol) in anhydrous MeOH (8.5 mL) was added NaOMe (25w% in MeOH, 0.14 mL, 0.65 mmol), followed by (E)-N-(6-bromo-3'-ethylspiro[chroman-2,r-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 (CH2Cl2 : MeOH 12:1) to give the pure product 12Oi (174 mg, 63%). 1H NMR (CDCl3): 7.50 (s, IH), 7.27 (d, IH), 6.67 (d, IH), 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, IH) , 1.35-1.22 (m, 2H) , 0.92-0.79 (m, 3H).
Figure imgf000365_0001
120i 120
Step 3: Compound 120 Pd(PPh3^Cl2 (18.5 mg) in a 10 mL tube under Ar was treated sequentially with the compound 12Oi (50 mg, 0.13 mmol) in 1 ,4-dioxane (4.9 mL), Cs2CO3 (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%). 1H NMR (MeOD / 400M): δ 7.99 (s, IH), 7.95-7.92 (m, 2H), 7.71-7.64 (m, 2H), 7.62-7.60 (m, IH), 7.00-6.96 (m, IH), 3.39 (s, s, 3H), 2.78-2.67 (m, IH), 2.45-2.33 (m, IH), 2.31-2.19 (m, IH), 2.18-2.02 (m, 3H), 2.01-1.87 (m, 2H), 1,48-1.31 (m, 3H), 1.01-0.89 (m, 3H).
Example 100 Compound 121 TMSN=C=NTMS MeNHOH HCI
Figure imgf000366_0001
TiCI4, DCM NaOMe, MeOH
Figure imgf000366_0002
Figure imgf000366_0003
Experimental data:
Figure imgf000366_0004
Step 1. 3-isopropylcyclopentanone
To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr-SMe2 (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 0C, the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et2O. The organic layer was washed with aqueous NaHCO3 and brine. After dried over Na2SO4, the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).
Figure imgf000366_0005
Step 2. 6-bromo-3'-isopropylspiro[chroman-2.r-cyclopentan]-4-one A mixture of 3-isopropylcyclopentanone (0.5 g. 3.962 mmol), l-(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,r-cyclopentan]-4-one (500 mg, 79%). 1H-NMR (CDCl3): 0.78 (m, 3H), 0.82 (m, 3H), 1.34 (m, IH), 1.58 (m, 3H), 1.75 (m, IH), 1.91 (m, 2H), 2.08 (m, IHO, 2.73 (s, 2H)5 6.74 (m, IH), 7.44 (m, IH), 7.89 (d, IH).
Figure imgf000367_0001
Step 3. N-(6-bromo-3'-isopropylspiro[chroman-2, 1 '-cyclopentane]-4-ylidene)cyanamide To a solution of 6-bromo-3'-isopropylspiro[chroman-2,r-cyclopentan]-4-one (250 mg, 0.776 mmol) in DCM (10 mL) was added TiCl4 (1.55 niL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, iV,7V- methanediylidenebis(l,l,l-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 CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude ΛL(6-bromo-3'- isopropylspiro[chroman-2,r-cyclopentane]-4-ylidene)cyanamide (250 mg, 93%). 1H-
NMR (CDCl3): 0.82 (m, 6H), 1.36 (m, 2H), 1.69 (m, 3H), 1.96 (m, 3H), 3.10 (d, 2H), 6.75 (m, IH), 7.52 (m, IH), 8.04 (d, IH).
Figure imgf000367_0002
Step 4. compound 12 Ii
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.r-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%). 1H-NMR (CDCl3): 0.82 (m, 6H), 1.26 (m, 3H), 1.93 (m, 5H), 2.27 (m, 2H), 3.04 (m, 3H), 6.62 (m, IH), 7.22 (m, IH), 7.42 (m, IH).
Figure imgf000368_0001
Step 5. Compound 121
Pd(PPh3^Cl2 (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), Cs2CO3 (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%). 1H-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, IH), 2.71 (m, 0.8H), 3.01 (m, 0.3H) 3.38 (m, 3H), 7.02 (m, IH), 7.67 (m, 3H), 7.96 (m, 2.8H), 8.30 (m, 0.2H).
Example 101 Compound 122
Figure imgf000368_0002
MeNHOH HCI NaOMe
Figure imgf000368_0003
Experimental data:
Figure imgf000369_0001
Step 1. 6-cyclohexyl-2',4',5',6'-tetrahydrospiro[chronian-2,3'-pyran]-4-one
Pd(PPh3 )2C12 (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%). 1H-NMR (CDCl3): 1.31 (t, 4H), 1.48(m, IH), 1.62 (m, 5H), 1.76 (d, 4H), 1.89 (m, IH), 2.06 (d, IH), 2.49 (s, IH), 2.61 (m, 2H), 3.49 (m, 2H), 3.79 (m, 2H), 6.88 (d, IH), 7.29 (d, 2H) , 7.61 (s, IH).
Figure imgf000369_0002
Step 2. (£)-N-(6-cyclohexyl-2':4',5';6'-tetrahydrospiro[chroman-2,3'-pyran]-4- ylidene)cyan- amide
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 TiCl4 (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 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (£)-ΛL(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.. MeNHOH.HCI NaOMe
Figure imgf000370_0002
Figure imgf000370_0001
Step 3. Compound 122
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 (£)-7V-(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%). 1H-NMR (MeOD): 1.24 (m, 2H), 1.37 (m, 4H), 1.52 (m, IH), 1.72 (d, 1.5H), 1.79 (d, 5H), 1.88 (t, IH), 2.04 (m, IH), 2.42 (m, IH), 3.01 (d, 3H), 3.50 (m, 2H), 3.69 (d, 0.5H), 3.74 (m, IH), 3.90 (d, 0.5H), 6.71 (d, IH), 7.04 (d, IH) , 7.19 (d, IH).
Example 102 Compound 124
Figure imgf000370_0003
117i 124
Step 1 : Compound 124
Pd(PPlVj)2Cl2 (15 mg) in a 10 mL of flask under Ar2 was treated sequentially with the amine 117i (40 mg; 0.13 mmol) in 1,4-dioxane (2.3 mL), Cs2CO3 (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%). 1H-NMR (MeOD): 1.26 (m, 3H), 1.51 (m, IH), 1.75-2.06 (m, 3H), 2.66- 2.92 (m, IH), 3.22 (m. 3H), 3.32 (m, IH), 3.52 (m, 2H), 3.69 (m, 2H), 3.98 (m, 2H), 6.77 (m, IH), 6.91 (m, IH), 7.02 (m, 2H), 7.22 (m, IH), 7.38-7.54 (m, IH), 7.69-8.1 1 (m, IH). Example 103 Compound 125
Figure imgf000371_0001
Figure imgf000371_0002
Experimental data:
Figure imgf000371_0003
Figure imgf000371_0004
Pyrrolidine
Figure imgf000371_0005
Step 1 : 6-bromo-3'-methylspiro[chroman-2,r-cyclopentan]-4-one
A mixture of l-(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,l'-cyclopentan]-4-one, which was purified by chromatography (PE : EA 300 : 1-200 : 1 ) (2.3 g, 76%). 1H NMR (CDCl3): 7.94 (d, IH), 7.52-7.49 (m, IH), 6.83-6.79 (m, IH), 2.79 (m, 2H), 2.39-2.22 (m, 0.5H), 2.21-1.95 (m, 3H), 1.91-1.75 (m, IH), 1.67-1.57 (m, IH), 1.51-1.41 (m, 0.5H), 1.31-1.15 (m, IH), 1.08-0.98 (m, 3H).
Figure imgf000371_0006
Step 2: (E)-N-(6-bromo-3'-methylspiro[chroman-2, 1 '-cyclopentane]-4-ylidene)cyanamide
To a solution of ό-bromo-S'-methylspirotchroman^J'-cyclopentanj^-one (216 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (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 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-3'-methylspiro[chroman-2,r- cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Figure imgf000372_0001
Step 3: compound 125i
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 (£)-N-(6-bromo-3'-methylspiro[chroman-2,r-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 (CH2Cl2 : MeOH 12:1) to give the pure product 125i (197 mg; 76%).
Figure imgf000372_0002
Step 4: Compound 125
Pd(PPh3)2Cl2 (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), Cs2CO3 (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%). 1H-NMR (MeOD): 7.92 (s, IH), 7.89-7.87 (m, IH), 7.75 (s, IH)5 7.66-7.64 (m, IH), 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, IH), 1.09- 1.01 (m, 3H).
Example 104 Compound 126
Figure imgf000373_0001
117i
126
Step 1 : Compound 126
Pd(PPh3)2Cl2 (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). Cs2CO3 (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%). 1H-NMR (MeOD): 1.06 (m, 3H), 1.53-1.68 (m, IH), 1.74- 1.91 (m, 3H), 1.93-2.13 (m, 2H), 2.79-2.98 (m, IH), 3.56-3.68 (m, 2H), 3.72-3.89 (m, 2H), 3.97 (t, 2H), 6.88 (d, IH), 7.01-7.17 (m, 3H), 7.33 (t, IH), 7.63 (d, IH), 7.81 (m, IH).
Example 105 Compound 127a and 127b - j /3 -
Figure imgf000374_0001
Experimental data:
Figure imgf000374_0002
Step 1. 3-terf-butylhexanedioic acid
4-/erf-butylcyclohexanol (10 g, 64.1 mmol) was dissolved in trifluoroacetic acid and then NaNO2 (17.09 g, 256.4 mmol) was added to the solution at O °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% NaHCO3. 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- terf-butyl-6-hydroxyhexanoic acid (5.26 g, 41%).
Figure imgf000374_0003
Step 2. S-te/Y-butylcyclopentanone
A suspension of the 3-terr-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 oϊ3-tert- butylcyclopentanone (0.557g, 58%).
Figure imgf000375_0001
Step 3. 6-bromo-3'-terr-butylspiro[chroman-2,r-cyclopentan]-4-one
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3- /erf-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 H2O and then added HCl until pH = 1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3'-/ert-butylspiro[chroman-2,r-cyclopentan]-4- one (0.8 g, 89%). 1H NMR (CDCl3): 0.77 (s, 9H), 1.34 (m, IH), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, IH), 7.47 (d, IH), 7.89 (s, IH).
Figure imgf000375_0002
Step 4. (£)-iV-(6-bromo-3'-tert-butylspiro[chroman-2, 1 '-cyclopentane]-4- ylidene)cyanamide
To a solution of 6-bromo-3'-rert-butylspiro[chroman-2,r-cyclopentan]-4-one (200 mg, 0.60 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (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 fos-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 CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-bromo-3'-/er/- butylspiro[chroman-2,r -cyclopentane]-4-ylidene)cyanamide (200 mg, crude), which was used for the next step without further purification.
Figure imgf000376_0001
Step 5. Compound 127i
To a solution of MeNHOH.HCl (46.3 mg, 0.55 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25 wt% in MeOH, 0.1 1 mL, 0.50 mmol), followed by (E)-N-(6- bromo-3'-terr-butylspiro[chroman-2,r -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 CH2Cl2 and filtered. The filtrate was concentrated to give the residue, which was purified by preparative TLC to afford compound 127i (86 mg, 38%). 1H NMR (CDCl3): 1.48-1.61 (m, IH), 1.73-2.28 (m, 4H), 2.98 (d, 3H), 3.47-3.63 (m, 2H), 3.27 (m, 2H), 3.98 (m, IH), 6.81-6.93 (m, 4H), 7.02 (m, 2H), 7.24 (m, 2H).
Figure imgf000376_0002
127i 127a
127b
Step 6. Compound 127a and 127b
Pd(PPh3 )2C12 (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), Cs2CO3 (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%). 1H NMR (MeOD): 0.84-0.96 (m, 9H), 1.52-1.64 (m, IH), 1.77 (m, IH), 1.96 (m, 2H), 2.03-2.14 (ms 2H), 2.38 (t, IH), 2.76 (d, IH), 3.39 (s, 3H), 6.98 (m, IH), 7.58-7.73 (m, 3H), 7.99 (m, 3H) (127a). 1H NMR (MeOD): 0.88-0.97 (m, 9H), 1.36 (m, IH), 1.56-2.07 (m, 6H), 2.43 (m, IH), 2.73 (m, IH), 3.41 (s, 3H)5 7.01 (m, IH), 1.59-1.1 A (m, 3H)5 7.93-8.31 (m, 3H) (127b).
Example 106 Compound 128
Figure imgf000377_0001
Experimental data:
Step 1 : l-chloro-3-methoxypropane
3-Methoxypropan-l-ol (23.85 g, 0.294 mmol) was dissolved in pyridine (20.6 mL) and cooled to 5 °C. SOCl2 (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 K2CO3 and filtered. The filtrate was concentrated to give the residue, which was purified by fractional distillation to give l-chloro-3-methoxypropane (13 g, 41%). 1H-NMR (CDCl3): 1.99 (m, 2H)5 3.33 (s, 3H)5 3.49 (t, 2H), 3.62 (t, 2H).
Figure imgf000377_0002
Step 2 : 1 -bromo-3 -(3 -methoxypropoxy)benzene
A mixture of 3-bromophenol (5 g. 29 mmol). l-chloro-3-methoxypropane (4.33 g. 40 mmol) and K2CO3 (8 g, 57.8 mmol) in DMF (90 mL) was stirred at 100 0C 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 (IN), water (50 mL) and brine. The organic layer was dried and concentrated to give l-bromo-3-(3- methoxypropoxy)benzene (7 g, 99%). 1H-NMR (CDCl3): 2.02 (m, 2H), 3.33 (s, 3H), 3.54 (m, 2H), 4.02 (m, 2H), 6.82 (m, IH), 7.11 (m, 3H).
Figure imgf000378_0001
Step 3: 2-(3-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane l-Bromo-3-(3-methoxypropoxy)benzene (1 g, 4.61 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2, 2'-bi(l,3,2-dioxaborolane) (2.27 g, 5.07 mmol), K2CO3 (2.55 g,' 18.44 mmol) and Pd(PPh3)2Cl2 (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-l,3,2- dioxaborolane (65 mg, 6%).
Figure imgf000378_0002
128
Step 4: Compound 128
Pd(PPh3)2Cl2 (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), Cs2CO3 (2 M, 0.5 mL) and 2- (3-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (50 mg, 0.19 mmol). The mixture was heated under Ar at 120 0C 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%). 1H-NMR (MeOD): 1.52 (m, IH), 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, IH), 6.92 (m, IH), 7.02 (m, 2H), 7.24 (m, IH), 7.58 (m, IH), 7.76 (m, IH).
Example 107 Compound 129
Figure imgf000379_0001
Pd(PPh3J2Cl2
Figure imgf000379_0002
Figure imgf000379_0003
Experimental data:
Figure imgf000379_0004
Step 1 : l-bromo-3-(2-methoxyethoxy) benzene
A mixture of 3-bromophenol (5 g, 28.9 mmol), l-chloro-2-methoxyethane (3.77 g, 40 mmol) and K2CO3 (12.63 g, 0.178 mol) in DMF (90 mL) was stirred at 100 0C 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 l-bromo-3-(2- methoxyethoxy) benzene (5.28 g, 79%).
Figure imgf000379_0005
Step 2: 2-(3-(2-methoxyethoxy)phenyl)-4.4,5.5-tetramethyl-l .3,2-dioxaborolane l-Bromo-3-(2-methoxyethoxy)benzene (2 g, 12.6 mmol), K2CO3 (6.96 g, 50mmol) and Pd(PPh3)2Cl2 (0.687 g, 0.756mmol)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 Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give 2-(3-(2- methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (900 mg, 26%).
Figure imgf000380_0001
117i 129
Step 3 : Compound 129
Pd(PPh3 )2C12 (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), Cs2CO3 (2 N, 0.4 mL) and 2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-l,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%). 1H-NMR (MeOD): 1.60 (s, IH)5 1.91 (m, 2H), 2.12 (m, 2H), 2.85 (m, IH), 3.0 (m, 0.5H), 3.07 (m,3H), 3.35 (s,3H), 3.45 (s, 3H), 3.65 (m, 2H), 3.8 (m, 4H)5 4.2 (s, 2H), .6.95 (s, 1H),7.O5 (t, IH)5 7.2 (m, 2H), 7.35 (m5 IH)5 7.65 (d. IH)5 7.8-7.9 (m, IH)5 8.25 (s,0.2H)
Example 108 Compound 130
Figure imgf000381_0001
MeNHOH HCI NaOMe, MeOH
Figure imgf000381_0002
Experimental data:
Figure imgf000381_0003
Step 1 : 6-phenoxy-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one
To a solution of l-(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, 1 1.40 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%). 1H-NMR (CDCl3): 0.79 (m, IH), 1.52 (m, 2H), 1.67 (m, IH), 1.92 (m, IH), 2.08 (m, IH), 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, IH), 7.26 (t, 2H), 7.39 (m, IH).
Figure imgf000381_0004
Step 2: (£)-Λ?-(6-phenoxy-2',4',5'.6'-tetrahydrospiro[chroman-2,3'-pyran]-4-ylidene)cyan amide To a solution of 6-phenoxy-2',4l,5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one (500 mg, 1.27 mmol) and triethylamine (227 mg, 0.73 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (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 CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, 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.
Figure imgf000382_0001
Step 3: Compound 130 To a solution of MeNHOH.HCI (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 (£)-_V-(6- phenoxy-2',4',5l,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 CH2Cl2 and filtered. The filtrate was concentrated to give the residue, which was purified by preparative TLC to afford Compound 130 (29 mg, 25%). 1H NMR (CDCl3): 1.48-1.61 (m, IH), 1.73-2.28 (m, 4H), 2.98 (d, 3H), 3.47-3.63 (m, 2H), 3.27 (m, 2H), 3.98 (m, IH), 6.81-6.93 (m, 4H), 7.02 (m, 2H), 7.24 (m, 2H).
Example 109
3-(3'-amino-2'-methyl-2-phenyl-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazole]-6- yl)benzonitrile (Compound 96)
Figure imgf000383_0001
Step 1: Preparation of (£)-7V-(6-bromo-2-phenylchroman-4-ylidene)cyanamide
To a solution of 6-bromo-2-phenylchroman-4-one (1.016 g, 3.35 mmol) in anhydrous DCM under N2 atmosphere was added 1 M TiCl4 (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 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, 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)+.
Step 2: Preparation of 6-bromo-2'-methyl-2-phenyl-2'H-spiro[chroman-4,5'- [l,2,4]oxadiazol]-3'-amine
To a solution of methylhydroxylamine HCl salt (280 mg, 3.35 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25w% in MeOH, 0.67 mL5 3.02 mmol), followed by (£)-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'i/-spiro[chroman-4,5'- [l,2,4]oxadiazole]-6-yl)benzonitrile
To a solution of 6-bromo-2'-methyl-2-phenylspiro[chroman-4,5'-
[l,2,4]oxadiazolidin]-3'-imine TFA salt (45 mg, 0.092 mmol), 3-cyanophenylboronic acid (20 mg, 0.14 mmol) and Cs2CO3 (60 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (10 mg). After degassing by purging with N2, 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-(3l-amino-2'-methyl-2-phenyl-2'//-spiro[chroman- 4,5'-[l,2,4]oxadiazole]-6-yl)benzonitrile (10 mg) as a TFA salt. MS ESI +ve m/z 397 (M+H)+. 1H-NMR (400 MHz5 DMSO-d6): 8.14-8.12 (m, 2H), 8.03 (d, J = 8.4 Hz, IH), 7.84-7,79 (m, 2H), 7.66 (t, J = 8.0 Hz, IH), 7.54-7.40 (m, 5H), 7.09 (d, J = 8.8 Hz, IH), 5.29 (d, 11.6 Hz, IH), 3.34 (s, 3H), 2.75 (d, 14.0 Hz, IH), 2.37 (dd, J - 14.4, 13.2 Hz, IH).
Example 110
2'-methyl-2-phenyl-6-(pyridin-3-yl)-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine
(Compound 102)
acid U
Figure imgf000384_0001
Figure imgf000384_0002
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 Cs2CO3 (127 mg, 0.39 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3 )2 (10 mg). After degassing by purging with N2 the mixture was heated to 1000C 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'//-spiro[chroman-4,5'- [l,2,4]oxadiazol]-3'-amine (17 mg) as a TFA salt. MS ESI +ve m/z 393 (M+H)+. 1H- NMR (400 MHz, CD3OD): 9.19 (br s, IH), 8.87 (d, J = 7.6 Hz, IH), 8.78 (br s, IH), 8.23 (d, J = 2.4 Hz; IH), 8.11 (t, J = 6.4 Hz, IH), 7.91 (dd, J = 8.8, 2.4 Hz, IH), 7.54-7.38 (m, 5H), 7.21 (d, J = 8.8 Hz, IH), 5.37 (d, 12.8 Hz, IH), 3.43 (s, 3H), 2.88 (dd, J = 14.4, 2.0 Hz, IH), 2.42 (dd, J = 14.4, 12.8 Hz, IH).
Example 1 11
3-(2,2-bis(hydroxymethyl)-3'-imino-2'-methylspiro[chroman-4,5'-[l,2,4]oxadiazolidine]- 6-yl)benzonitrile (Compound 100) and 3-(3"-imino-2"-methylspiro[spiro(chroman-2,r- (4,4-dimethyl-3,5-dioxane))-4,5"- [1 ,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound
123 )
Figure imgf000385_0001
Step 1: Preparation of 6-bromo-2',2'-dimethylspiro[chroman-2,5'-[l,3]dioxan]-4-one
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, H2O 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'-[l,3]dioxan]-4- one as a brownish solid (2.06 g).
Step 2: Preparation of 3-(2',2'-dimethyl-4-oxospiro[chroman-2,5'-[13]dioxane]-6- yl)benzonitrile To a solution of 6-bromo-2',2'-dimethylspiro[chroman-2.5'-[l,3]dioxan]-4-one (498 mg, 1.5 mmol), 3-cyanophenylboronic acid (440 mg, 3.0 mmol) and Cs2CO3 (1.460 mg, 4.5 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3 )2 (75 mg). After degassed by purging with N2, 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'-[l,3]dioxane]-6-yl)benzonitrile as a yellowish solid (298 mg). MS ESI +ve m/z 350 (M+H)+.
Step 3: Preparation of (£)-iV-(6-(3-cyanophenyl)-2,2-bis(hydroxyinethyI)chronian-4- ylidene)cyanamide
To a solution of 3-(2',2'-dimethyl-4-oxospiro[chroman-2,5'-[l,3]dioxane]-6- yl)benzonitrile (155 mg, 0.44 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (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 Na2SO4, filtered, and concentrated to give yellowish gel like solid (E)-Λ;-(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'-[l,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 (25w% 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)+. 1H NMR (400 MHz, CD3OD): 7.98-7.90 (m, 3 H), 7.72-7.58 (m, 3H), 7.07 (d, J = 8.4 Hz, IH), 3.86-3.70 (m, 4H), 3.67 (s, 3H), 2.84 (d, J = 14.8 Hz, IH), 2.43 (d, J =14.8 Hz, IH).
Step 5: Preparation of 3-(3"-imino-2"-methylspiro[spiro(chroman-2,l'-(4,4- dimethyl-3,5-dioxane))-4,5M- [l,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 123)
To a solution of 3-(2,2-bis(hydroxymethyl)-3'-imino-2'-methylspiro[chroman-4,5'- [l,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)+. 1H NMR (400 MHz, CD3OD): 7.90 (d, J = 1.2 Hz, IH), 7.87 (m, IH), 7.66 (m, 2H), 7.61-7.56 (m, 2H), 7.03 (d, J = 8.4 Hz, IH), 4.12-3.85 (m, 4H), 3.09 (s, 3H), 2.42 (d, J = 14.4 Hz, IH), 2.01-1.43 (m, IH), 1.47 (s, 3H), 1.43 (s, 3H).
Example 112
3-(2'-amino-r,2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman- 4,4'- imidazole] -6-yl)benzonitrile (Compound 132)
Figure imgf000388_0001
Figure imgf000388_0002
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%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).
Step 2:
Figure imgf000388_0003
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 60-800C, 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%).
1H-NMR (CDCl3): 2.60 (s, 3H), 6.87 (d, IH), 7.53 (dd, IH), 7.81 (s, IH), 12.12 (s, IH).
Step 3:
Figure imgf000389_0001
A solution of l-(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 3x). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18 g, 71%). 1H-NMR (CDCl3): 1.45 (s, 6H), 2.71 (s, 2H), 6.82 (d, IH), 7.52 (dd, IH), 7.96 (d, IH). Step 4:
Figure imgf000389_0002
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 (NHO2CO3 (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 HCI yields a precipitate which is filtered, washed twice with water, and then resolved in ethyl acetate, dried over Na2SO4. 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%). 1H-NMR (DMSO): 1.24 (s, 3H), 1.40 (s, 3H), 2.16 (d, IH), 2.30 (d, IH), 6.80 (d, IH), 7.10 (m, IH), 7.39 (d, IH), 8.69 (s, IH), 11.08 (brs, IH).
Step 5:
Figure imgf000390_0001
6-Bromo-2,2-dimethylspiro[chroman-4J4'-imidazolidine]-2',5'-dione (4 g, 12.3 mmol) and 1 M Et3O-BF4 (4.7 g, 24.7 mmol) is dissolved in dry CH2Cl2 (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'(J'H)-one (1 g, 25%). Step 6:
Figure imgf000390_0002
6-Bromo-2'-ethoxy-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'(J 7/)-one (500 mg, 1.42 mmol) is dissolved in 30 mL of EtOH, and NH3-H2O (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'(5'H)-one (120 mg, 30%).
Figure imgf000390_0003
NaH (5.3 mg, 0.131 mmol) is added to a solution of 2'-amino-6-bromo-2.2-dimethyl- spiro[chroman-4,4'-imidazol]-5'(J'H)-one (45 mg, 0.131 mmol) in THF (3 mL) at 00C under N2. 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-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5\J 'H)-one (40 mg.
Ό .
1H-NMR (MeOD): 1.3 (s, 3H), 1.40 (s, 3H), 1.85 (d, IH), 2.25 (d, IH), 3.1 (s, 3H), 6.65 (d, IH), 6.8 (s, IH), 7.20 (s, IH).
Step 8:
Figure imgf000391_0001
Pd(PPh3)4 (15.13 mg, 0.013 mmol) is added to the solution of 2'-amino-6-bromo- l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(77/)-one (44.15 mg, 0.13 mmol) and 3- cyanophenylboronic acid (19.25 mg, 0.13 mmol) in dimethy-benzene (5 mL) and an aqueous solution OfNa2CO3 (2 M, 0.24 mL). The mixture is heated at 900C 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-l\2,2-trimethyl-5'-oxo-r,5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (10 mg, 15%). 1H-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, IH).
Example 113
2'-amino-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (Comp. 133)
KCN, (NH4J2CO3 Lawsson's Reagent
HCONH2
Figure imgf000391_0002
Figure imgf000391_0003
Figure imgf000391_0004
Step l :
Figure imgf000391_0005
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 H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O. and extracted with ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column to give 2- phenylchroman-4-one (20 g, 40%). Step 2:
Figure imgf000392_0001
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 (NH4^CO3 (25.7 g, 267.7 mmol). Formamide (100 mL) is added to fill the pressure tube nearly completely. The mixture is heated at 7O0C for 24 h then at 11O0C 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 Na2SO4. 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%). Step 3:
Lawesson's Reagent
Figure imgf000392_0002
Figure imgf000392_0003
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%). Step 4:
Figure imgf000392_0004
To a solution of 2-phenyl-2'-thioxospiro[chroman-4J4'-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 H2O (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'(17f)-one (50 mg, 30%). Step 5:
Figure imgf000393_0001
A solution of r-methyl-2'-(methylthio)-2-phenylspiro[chroman-4,4'-imidazol]-5l(rH)- one (50 mg, 0.148 mmol) and NH4I (42.9 mg, 0.296 mmol) in NH3/EtOH (4 mL, 1.5 N) is heated at 1100C 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-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)-one (5 mg, 10%). 1H-NMR (MeOD): 2.0 (d, IH), 2.35 (t, IH), 3.0 (s, 3H), 5.2 (d, 0.376H), 5.75 (d, IH), 6.78 (m, 2H), 6.99 (d, IH), 7.16 (t, IH), 7.2 (m, 3H), 7.4 (m, 2H).
Example 1 14 Compound 134
Figure imgf000394_0001
Step 1 :
To a 50 mL round bottom flask is added l-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by 4-rerr-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 6O0C 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 Na2SO4. Solvent is removed in vacuo to give 6-bromo-4'-r-butylspiro[chroman-2,l'-cyclohexan]-4-one (2.41 g, 74%), which is used for the next step without purification.
Step 2:
A 10 mL CEM microwave test tube is filled with a mixture of 6-bromo-4'-/- butylspiro[chroman-2,r-cyclohexan]-4-one (0.4 g, 1.1 mmol), KCN (0.15 g, 2.2 mmol). and (NHU)2CO3 (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 650C 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 H2O (10 mL X 3). The organic layer is dried over Na2SO4, 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+).
Step 3: 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 HO0C for 30 min and cooled to it. 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+).
Step 4:
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 6O0C 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 (MH-H+).
Step 5:
To a solution of the above dimethylated thiol-hydantoin (25.5 mg, 0.05 mmol) in
NH3MeOH (7 N, 1 mL) in a CEM microwave test tube, there is added NH4I (24 mg, 0.15 mmol). The resulting mixture is heated in a CEM microwave reactor at 11O0C 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 (MH-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 Cs2CO3, 3-cyanophenylboronic acid, and catalytical amount of l,l'-Bis(diphenylphosphino)ferrocene palladium dichloride. After degassing, the resulting mixture is heated in a CEM microwave reactor at 12O0C 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.
1H NMR (400MHz, CD3OD): 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+).
Example 115
3-(2'-Amino- 1 '-benzyl-5'-oxo-2 -phenyl- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile (Cmpds. 135a and 135b)
Figure imgf000396_0001
Step 1 :
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 11O0C for 40 min and cooled to it. 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+).
Step 2:
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'(lΗ)-one (63.3 mg, 39%). MS m/z 569 (M+H+).
To a solution of r-benzyl-2'-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1 :1, 2 mL) in a 10 mL CEM microwave test tube is added NH4I (50 mg, 0.34 mmol) and NH3/MeOH (7 N, 2 mL). The resulting mixture is heated in a CEM microwave reactor at 12O0C for 60 min. The cooled mixture is concentrated in vacuo and the residue is purified by a reversed HPLC to give T- amino-r-benzyl-6-bromo-2-phenylspiro[chroman-4,4'-imidazol]-5'(l Η)-one (17.3 mg. 34%) as a TFA salt. MS m/z 462 (M+H+).
Step 4.
To a solution of 2'-amino-r-benzyl-6-bromo-2-phenylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (17.3 mg, 0.04 mmol) in 1.4-dioxane (1.5 mL) there is added Cs2CO3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl2dppf. After degassing, the resulting mixture is heated in a CEM microwave reactor at 13O0C for 30 min. Solvent is removed in vacuo and the residue is purified by reversed phase HPLC to give 3-((2R,4R)-2'-amino-l'-benzyl-5'-oxo-2-phenyl-l',5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (6.0 mg, 33%) as a TFA salt (135a) and 3-((2S.4R)-2'-amino-r-benzyl-5'-oxo-2 -phenyl- r,5'-dihydrospiro[chroman- 4;4'-imidazole]-6-yl)benzonitrile (0.86 mg, 4.8 %) as a TFA salt. (135b).
1H NMR (400MHz; CD3OD): 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). 1U NMR (400MHz, CD3OD): 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).
Example 116 Compound 136
Figure imgf000398_0001
Step l :
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 15O0C 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+).
Step 2:
To a solution of the above crude product in MeCN/H2O (3:1, 1 mL) there is added K2CO3 (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+). Step 3:
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 6O0C 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+).
Step 4:
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 NH4I (excess) and NH3/MeOH (7 N, 1.5 mL). The resulting mixture is heated in a CEM microwave reactor at 12O0C 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+).
Step 5:
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 Cs2CO3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl2dppf. After degassing, the resulting mixture is heated in a CEM microwave reactor at 12O0C 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. 1U NMR (400MHz, CD3OD): 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+).
Example 1 17 4-(2'-amino-r-methyl-5'-oxo-2-phenyl-r.5'-dihydrospiro[chroman-4.4'-imidazole] -6-yl)- jV-(2-(dimethylamino)ethyl)benzamide (Compound 137)
Figure imgf000400_0001
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5' (l'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(2- (dimethylamino) ethylcarbamoyl)phenylboronic acid (25 mg, 0.104 mmol). The mixture was heated under 120 0C at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and ΗPLC to give 4-(2'-amino-r-methyl-5'-oxo-2-phenyl-r,5'-dihydrospiro[chroman -4,4'- imidazole]-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (4.68 mg, 18%). 1H-NMR (MeOD): 2.47 (m, IH), 2.63 (m, IH), 3.01 (s, 6H), 3.30 (s, 3H): 3.42 (m, 2H), 3.79 (m, 2H), 5.88 (m, IH), 7.17 (m, IH), 7.39 (m, IH), 7.46 (m, 2H), 7.52 (m, 2H), 7.58 (m, IH), 7.71 (m, IH), 7.76 (m, 2H), 7.96 (m, 2H).
Example 118 3-(2'-amino-5'-oxo-2 -phenyl- r-(2,2.2-trifluoroethyl)-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile (Compound 138)
(CF3CO)2O
F3C OH > F3C OTf pyπdine
Figure imgf000400_0002
Figure imgf000400_0003
Experimental Data:
Figure imgf000401_0001
Step 1 : trifluoro-methanesulfonic acid 2.2,2-trifluoro-ethyl ester
Combine 2,2,2-trifluoro-ethanol (6.2 mL), pyridine (6.8 mL) and CH2Cl2 (20 mL) cooled in an ice bath. Add Tf2O (25 g) over about 45 minutes. After 15 minutes, add water, separate the layers and extract with water. The organic layer was dried over Na2SO4 and concentrated through a short path distillation apparatus (8 g, 54%).
Figure imgf000401_0002
Step 2 : 6-bromo-2-phenyl- 1 '-(2,2,2-trifluoroethyl)-2'-(2,2?2-trifluoroethylthio)spiro [chroman -4,4'-imidazol]-5'(l'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 Cs2CO3 (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-l '- (2.2.2-trifluoroethyl)-2'- (2,2,2-trifluoroethylthio)spiro [chroman-4,4'-imidazol]-5'(l 'H)-one (60 mg, 36%).
Figure imgf000401_0003
Step 3: 2'-amino-6-bromo-2-phenyl-r-(2.2.2-trifluoroethyl)spiro [chroman-4.41- imidazol] -5 '( 1 Η)-one
A solution of 6-bromo-2-phenyl-r-(2,2,2-trifluoroethyl)-2'-(2,2,2- trifluoroethylthio)spiro[chroman-4.4'-imidazol]-5'(rH)-one (60 mg), NH4I (10 mg) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at 110 0C 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-r- (2,2,2-trifluoroethyl)spiro [chroman-4,4'-imidazol]-5'(l'H)-one (30 mg, 61%).
Figure imgf000402_0001
Step 4: 3-(2'-amino-5'-oxo-2-phenyl-r-(2,2,2-trifluoroethyl)-r.5'-dihydrospiro[chroman- 4,4'- imidazole] -6-yl)benzonitrile Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with
2'-amino-6-bromo-2-phenyl-r-(2.2.2-trifluoroethyl)spiro[chroman-4.4'-imidazol]-5'(rH)- one (20 mg, 0.044 mmol) in 1 ,4-dioxane (1 mL), Cs2CO3 (2 M, 0.3 mL) and 3- cyanophenylboronic acid (13 mg. 0.088 mmol). The mixture was heated at 120 0C 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- r-(2,2,2-trifluoroethyl)-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile (3.7 mg, 12%). 1H-NMR (MeOD): 2.27 (m, IH), 2.35 (m, IH), 3.87 (m, 2H), 5.83 (m, IH), 7.01 (d, IH), 7.26(m, IH), 7.32 (m, 5H), 7.59 (m, 3H), 7.76 (m, IH), 7.81 (m, IH).
Example 119
2'-amino-6-(4-(benzyloxy)phenyl)- 1 '-methyl-2- phenylspiro[chroman-4,4'-imidazol]
5'(lΗ)-one (Compound 139)
Figure imgf000402_0002
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2'-amino-6-bromo-r-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(rH)- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N5 0.3 mL) and 4- (benzyloxy)phenylboronic acid (24 mg. 0.104 mmol). The mixture was heated under 120
0C at Ar2 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'(l 'H) - one (1.75 mg, 7%). 1H-NMR (MeOD): 2.46 (m, IH), 2.59 (m, IH), 3.29 (s, 3H), 5.12 (s, 2H), 5.83 (m, IH), 7.04 (m, 2H), 7.09 (m, IH), 7.31 (m, IH), 7.38 (m, 4H), 7.45 (m, 4H), 7.50 (m, 4H), 7.56 (m, IH).
Example 120
2'-methyl-3l-(phenoxyamino)-2-phenyl-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-6-ol
(Compound 140 )
Figure imgf000403_0001
Figure imgf000403_0002
Experimental data:
Figure imgf000403_0003
Step 1 : (E)-Λf-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide
To a solution of 6-(benzylox)-2-phenylchroman-4-one (211.2 mg, 0.64 mmol) in anhydrous DCM (5 mL) was added TiCl4 (1 M solution in DCM5 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 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and then concentrated to give (JE)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (140 mg, 83%), which was used for next step without further purification.
Figure imgf000404_0001
Step 2: 3'-amino-2'-methyl-2-phenyl-2' H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-6-ol
To a solution of methylhydroxylamine HCl salt (28 mg, 0.326 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25wt.% 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'-[l,2,4]oxadiazol]-6-ol (20 mg, 20%). 1HNMR (CDCl3): 7.30-7.51 (m, 5H), 6.95 (s, IH), 6.69 (m, 2H), 5.15 (t, 3H), 2.98 (s, 3H), 2.28 (d, 2H), 1.17 (s, IH).
Figure imgf000404_0002
Step 3: 6-(benzyloxy)-2'-methyl-2-phenyl-2'H-spiro[chroman-4,5'- [l,2,4]oxadiazol]-3'- amine and 2'-Methyl-3'-(phenoxyamino)-2-phenyl-2Η-spiro[chroman-4.5'- [l,2,4]oxadiazol]-6-ol A mixture of 3'amino-2'-methyl-2-phenyl-2'H-spiro(chroman-4,5'- (l,2,4)oxadiazol)-6-ol (30 mg, 0.096 mmol), (bromomethyl)benzene (21.45 mg, 0.125 mmol) and K2CO3 (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-2Η- spiro[chroman-4,5'- [l,2,4]oxadiazol]-3'-amine (140) (0.95 mg, 3%). 1H-NMR (MeOD): 7.32-7.56 (m, 10H)5 6.91-7.23 (m, 3H), 5.12 (d, 2H), 5.23 (t, 2H), 3.31 (s, 3H) 2.73 (m, IH), 2.32 (m, IH);
2'-methyl-3'-(phenoxyamino)-2-phenyl-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-6-ol (1.05 mg, 3%). 1H-NMR (MeOD): 7.32 (s, 6H), 7.20 (s, 2H), 7.06 (s, 2H), 6.83 (d, IH), 6.74 (t, 2H), 4.91 (d, IH), 4.25 (d, IH), 3.36 (s, 3H), 2.37 (d, 2H), 1.86 (t,3H)
Example 121
6-bromo-2'-methyl-2-(pyridin-2-yl)-2'//-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine
(Compound 142)
Figure imgf000405_0001
Experimental data:
Figure imgf000405_0002
Step 1 : l-(5-bromo-2-hydroxy- phenyl)-3-pyridin-2-yl-propenone
In a bottle were combined l-(5-bromo-2-hydroxy-phenyl)-ethanone (12 g, 56 mmol), pyridine-2-carbaldehyde (5.4 mL, 56 mmol), EtOH (96%, 67 mL) and NaOH (19.75g, 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%).
Figure imgf000406_0001
Step 2: 6-bromo-2-pyridin-2-yl-chroman-4-one l-(5-Bromo-2-hydroxy- phenyl)-3-pyridin-2-yl-propenone (13 g, 43 mmol) was dissolved in H2O (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 H2O 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%). 1H-NMR (CDCl3): 3.14 (m, 2H), 5.57 (m, IH), 6.98 (m, IH), 7.29 (m, IH), 7.57 (m, IH), 7.76 (m, IH), 8.00 (m, IH), 8.61 (m, IH).
Figure imgf000406_0002
Step 3: 6-bromo-2- pyridin-2-yl-chroman-4-ylidene-cyanamide To a solution of 6-bromo-2-pyridin-2-yl-chroman-4-one (303 mg, 1 mmol) in
DCM (10 mL) was added TiCl4 (4 mL, 1 M in CH2Cl2) 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 CH2Cl2, 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%).
MeNHOH. HCI
NaOMe, MeOH
Figure imgf000406_0004
Figure imgf000406_0003
Step 4: 6-bromo-2'-methyl-2-(pyridin-2-yl)-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]- 3'- amine
To a solution ofN-methyl-hydroxylamine hydrochloride (31 mg, 0.31 mmol) in MeOH (4 mL) was added MeONa (0.06 rnL, 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'-[l,2,4]oxadiazol]-3'-amine (45 mg, 40%). 1H-NMR (MeOD): 2.13 (m, IH), 2.48 (m, IH), 3.08 (m, 3H), 5.32 (m, IH), 6.86 (m, IH), 7.36 (m, 2H), 7.51 (m, IH), 7.68 (m, IH), 7.90 (m, IH), 8.52 (m, IH.).
Example 122
6-bromo-2 ' -methyl-2-(pyridine-3-yl)-2 'H- spiro- [chroman-4,5 ' -[ 1 ,2,4]oxadiazol]-3 ' - amine (Compound 143)
MeNHOH. HCI
NaOMe, MeOH
Figure imgf000407_0002
Figure imgf000407_0001
Experimental data:
Figure imgf000407_0003
Step 1 : (E)-Λf-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide
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 TiCl4 (1 M solution in DCM5 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 Na2SO4, and filtered. The filtrate was concentrated to give (E)- Λf-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 64%), which was used for next step without further purification. MeNHOH HCI
NaOMe, MeOH
Figure imgf000408_0002
Figure imgf000408_0001
Step 2: 6-bromo-2'-methyl-2-(pyridine-3-yl)-2'//- spiro[chroman-4,5"- [l,2,4]oxadiazol]-
3 '-amine
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-455'-[l,2,4]oxadiazol]-3'-amine (190 mg, 24%). 1H- NMR (MeOD): 2.18-2.25 (m, IH), 2.39 (m, IH), 3.09 (s, 3H), 5.34-5.38 (m, IH), 6.81- 6.86 (t, IH)5 7.37-7.40 (m, IH), 7.45-7.55 (m, IH)5 7.62 (s, IH), 7.97-7.99 (m, IH), 8.52- 8.54 (m, IH), 8.66 (d, IH).
Example 123 8-chloro-2'-methyl-2'H5l lH-spiro[dibenzo[b5fJoxepine-10,5'-[l,2,4]oxadiazol]-3'-amine
(Compound 144)
Figure imgf000408_0003
MeNHOH HCI
NaOMe, MeOH
Figure imgf000408_0005
Figure imgf000408_0004
Experimental data:
Figure imgf000408_0006
Step 1 : methyl 2-(2-bromophenyl)acetate
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. Ethvl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4. filtered and concentrated to give methyl 2-(2-bromophenyl)acetate (2 g, 80%) , which was used for next step without purification.
Figure imgf000409_0001
Step 2: 2-(2-(4-chlorophenoxy)phenyl)acetic acid
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 0C. 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 NJV- 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 Na2SO4 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.
Figure imgf000409_0002
Step 3: 8-chlorodibenzo[b,fJoxepin-10(l l//)-one
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 CH2Cl2, 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%).
Figure imgf000410_0001
Step 4: (E)-N-(8-chlorodibenzo[b,f]oxepin-10(l lH)-ylidene)cyanainide
To a solution of 8-chlorodibenzo[b,f]oxepin-10(l lH)-one (732 mg, 3.84. mmol) in anhydrous DCM (30 niL) was added TiCl4 (1 M solution in DCM, 7.8 niL, 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 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(8-chlorodibenzo [b.fjoxepin- 10(1 IH)- ylidene)cyanamide (500 mg, 68%). which was used for next step without further purification.
MeNHOH. HCI
NaOMe, MeOH
Figure imgf000410_0002
Figure imgf000410_0003
Step5: 8-chloro-2'-methyl-2'Ha iH-spiro[dibenzo[b5fJoxepine-10;5'-[L2;4]oxadiazol]-3'- amine 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 (£)-N-(8-chlorodibenzo[b,f)oxepin-10(l lH)-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%). 1H-NMR (CDCl3): 3.20 (m; 2H), 3.48 (m, 2H), 1.95 (m; IH), 3.51 (m: IH), 7.12 (m, IH), 7.18 (m, 3H), 7.22 (m, 2H), 7.32 (m, IH)5 7.48 (m, IH). Example 124
6-bromo-7-fluoro-2'-methyl-2-phenyl-2'//-spiro[chroman-4,5'-[l,2,4] oxadiazol]-3'-amine
(Compound 146)
Figure imgf000411_0001
Figure imgf000411_0002
Experimental data:
Figure imgf000411_0003
Step 1 : 4-bromo-3 -fluorophenyl acetate
Figure imgf000411_0004
Step 2: l-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone
A mixture of 4-bromo-3 -fluorophenyl acetate (30 g, 0.13 mol) and AlCl3 (34.32 g,
0.26 mol) was stirred at 120-140 0C for 2 h. The reaction mixture was cooled to 60-80 0C 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 l-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (20 g. 67%). 1H-NMR (CDCl3): 2.61 (s; 3H)5 6.76 (d: IH), 7.92 (d, IH)5 12.41 (s5 IH).
Figure imgf000412_0001
Step 3: l-(5-bromo-4-fluoro-2- hydroxyphenyl)-3-phenylprop-2-en-l-one
In a bottle were combined l-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (8.63 & 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 l-(5- bromo-4-fluoro-2- hydroxyphenyl)-3-phenylprop-2-en-l-one (10.8 g, 91%).
Figure imgf000412_0002
Step 4: 6-bromo-7-fluoro-2-phenylchroman-4-one l-(5-Bromo-4-fluoro-2- hydroxyphenyl)-3-phenylprop-2-en-l-one (10.8 g, 33.75 mmol) was dissolved in H2O (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 H2O 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%). 1H-NMR (CDCl3): 2.85 (m, IH), 3.04 (m, IH), 5.43 (m, IH), 6.78 (m, IH)5 7.37 (m; 5H), 8.07 (m, IH).
Figure imgf000412_0003
Step 5: Λ7-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide
To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (400 mg, 1.25 mmol) in DCM (10 mL) was added TiCLi (2.5 mL. 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h. ΛyV-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 CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude iV-(6-bromo-7-fluoro-2-phenylchroman-4- ylidene)cyanamide (327 mg, 78%). 1H-NMR (CDCl3): 3.19 (m, IH), 3.49 (m, IH), 5.34 (m, IH)5 6.81 (d, IH), 7.41 (m, 5H), 8.27 (d, IH).
MeNHOH. HCI
NaOMe, MeOH
Figure imgf000413_0002
Figure imgf000413_0001
Step 6: 6-bromo-7-fluoro-2'-methyl-2-phenyl-2lH-spiro[chroman-4,5'-[L2,4] oxadiazol]- 3'- amine
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 _V-(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%). 1H-NMR (MeOD): 2.18 (m, 1Η), 2.33 (m, 1Η), 3.08 (d, 3Η), 5.28 (m, IH), 6.75 (m, IH), 7.38 (m, 5H), 7.61 (m, IH).
Example 125 Compound 148
Figure imgf000413_0003
Step 1 : Compound 148
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with the amine 117i (52 mg, 0.14 mmol) in [l,4]dioxane (2 mL), Cs2CO3 (2 N, 0.5 mL) and 3-butoxyphenylboronic acid (51 mg. 0.28 mmol). The mixture was heated under 120 0C at Ar2 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%). 1H-NMR (MeOD): 1.01 (m, 3H), 1.32 (m, IH), 1.53 (m, 2H), 1.79 (m, 2H), 1.87-2.05 (m, 4H); 2.95 (m, IH), 3.35 (m, 3H), 3.63 (m, 2H), 3.76- 3.87 (m, 2H), 4.04 (m, 2H), 6.87 (m, IH), 7.12 (m, 3H), 7.35 (m, IH) 7.50 (m, 0.5H)3 7.68 (m, 0.5H. ), 7.82 (m, IH).
Example 126
3-(3'-amino-2'-methyl-3-phenyl-3,4-dihydro-2H,2'H-spiro[benzo[b]oxepine-5,5'- [l,2,4]oxadiazole]-7-yl)benzonitrile (Compound 153)
Figure imgf000414_0001
Figure imgf000414_0002
Experimental data:
Figure imgf000414_0003
Step 1. 4-(4-Bromophenoxy)butanoic acid
4-Bromo-phenol (172 g, 1 mol), 4-bromo-butyric acid ethyl ester (212 g, l.lmol) and K2CO3 (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 Na2SO4 the solvent was removed, to the residue was added NaOH (3M, 1000 mol) and CH3OH (600 mL). the mixture was stirred at 70 0C for 30 minutes and concentrated .the residue was dissolved in H2O 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 Na2SO4. concentrated to give crude 4-(4-bromophenoxy)butanoic acid (239 g, 98%).
Figure imgf000415_0001
Step 2. 4-(4-bromophenoxy)butanoyl chloride
4-(4-Bromophenoxy)butanoic acid (39 g, 25.6 mmol) was dissolved in SOCl2(IOO ml) mixture was heated to refluxed overnight, the mixture was concentrated in vacuo to give 4-(4-bromophenoxy)butanoyl chloride (27.6 g. 67%).
Figure imgf000415_0002
Step 3. 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one A solution of 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 100 mmol) in DCM
(200 mL) was added dropwise to a solution OfAlCl3 (50 g, 0.38 mol) in DCM(IOO niL) at
0 °C within 40 minutes, the mixture was stirred at 0 0C 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 NaHCO3, dried over Na2SO4 and concentrated to give crude 7- bromo-3.4-dihydrobenz o[b]oxepin-5(2H)-one (25 g, 96%).
Figure imgf000415_0003
Step 4. (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dimethylsilane
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(IOO 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 NaHCO3, dried over Na2SO4. concentrated to give crude (7-bromo-2,3- dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dim ethylsilane (3,40 g, 81%).
Figure imgf000416_0001
Step 5. 7-bromobenzo[b]oxepin-5(2H)-one
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%). 1H-NMR (MeOD): 4.71 (m, 2H), 6.38 (m, IH)5 6.76 (m, IH), 6.99 (m, IH), 7.54 (m, IH), 8.06 (m, IH).
Figure imgf000416_0002
Step 6. 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one
To a solution of 7-bromobenzo[b]oxepin-5(2H)-one (1.33 g, 5.6 mmol), CuBr- SMe2(OO 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 0C for
1 hour. The mixture was quenched by HCl (10%, 5 mL), extracted with ethoxyethane, and then washed with NaHCO3, brine, dried over Na2SO4, concentrated and purified by column chromatography to give 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (300 mg,17%). 1H-NMR (CH2D2): 3.11 (m, 2H), 3.49 (m, IH), 4.28 (m, 2H), 6.93 (m, IH), 7.17 (m, IH), 7.23 (m, 4H), 7.45 (m, IH), 7.83 (m, IH)
Figure imgf000416_0003
Step 7. iV-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide
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 TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, AyV-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 CH2Cl2, 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%).
MθNHOH. HCI
Figure imgf000417_0002
NaOMe, MeOH
Figure imgf000417_0001
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 7V-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'- [l,2,4]oxadiazol] -3'-amine (140 mg, 72%).
Figure imgf000417_0003
Step 9. 3-(3'-amino-2'-methyl-3-phenyl-3,4-dihydro-2H,2'H-spiro[benzo[b]oxepine-5,5'- [l,2,4]oxadiazole]-7-yl)benzonitrile
Pd(PPh3)2Cl2 (3 mg, 0.003 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 7-bromo-2'-methyl-3-phenyl-3,4-dihydro-2H,2'H- spiro[benzo[b]oxepine-5,5'-[l,2,4]oxadiazol]-3'-amine (77.4 mg, 0.2 mmol) in [l,4]dioxane (2.0 mL). Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol) The mixture was heated under 120 0C at Ar2 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'-ammo-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%). 1H-NMR (MeOD): 2.67 (m, 2H), 3.48 (m, 3H), 3.65 (m, IH), 3.88 (m, 0.3H), 4.19 (m, 0.7H), 4.50 (d, IH), 7.23 (m, 6H), 7.66 (m, 3H), 7.81 (m, IH), 8.02 (m, 3H).
Example 127 Compound 154
Figure imgf000418_0001
Step 1 : Compound 154
Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 1 (40 mg, 0.1 mmol) in 1 ,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3- cyanophenylboronic acid (29 mg, 0.2 mmol). The mixture was heated under microwave at 1200C 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%). 1H-NMR (MeOD): 1.80 (m, IH), 2.01 (s, 3H), 2.23 (m, 2H), 2.74 (m, IH), 3.05 (m, IH), 3.39 (m, 3H), 3.61 (s, 2H), 3.92(m, IH), 4.34 (m, IH), 7.02 (m, IH), 7.64 (m, 2H), 7.92 (m, 2H). Example 128
3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3'-imino-2'-methylspiro[chroman-4,5'- [l,2,4]oxadiazolidine]-6-yl)benzonitrile (Compound 155)
Figure imgf000419_0001
Figure imgf000419_0002
Step 1: preparation of 6-bromo-2-(2,2-dimethyltetrahydro-2/T-pyran-4-yI)chroman- 4-one
A solution of 2,2-dimethyltetrahydro-2//-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, H2O 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)+.
Step 2: Preparation of 3-(2-(2,2-dimethyltetrahydro-2//-pyran-4-yl)-4-oxochroman- 6-yI)benzonitrile
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 Cs2CO3 (866 mg, 2.72 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) charged in a 10 mL CEM microwave test tube was added PdCb(PPh3)T (50 mg). then the system was degassed by sweeping N2 and capped. Then the mixture was heated to 1000C 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 gel 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 (£)-iV-(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 N2 atmosphere was added 1 M TiCl4 (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 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. and filtered, and concentrated to give yellowish gel like solid (E)-ΛL(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2//-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-2//-pyran-4-yl)-3'-imino-2'- methylspiro[chroman-4,5'-[l,2,4]oxadiazoIidine]-6-yI)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-yl)chroman-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'- [l,2.4]oxadiazolidine]-6-yl)benzonitrile TFA salt as a white solid. MS ESI +ve m/z 433 (M+H)+. 1H NMR (400 MHz, CD3OD): 8.00-7.92 (m, 3 H), 7.74-7.68 (m, 2H), 7.62 (t, J = 7.6 Hz, IH), 7.05 (d, J = 8.4 Hz; IH).. 4.07 (dd, J = 12.4, 5.6 Hz, IH), 3.78 (m, 2H), 3.38, 3.44, 3.43 (s, 3H, several isomers), 2.20 (m, IH), 2.01 (m, IH), 1.88 (m, IH), 1.66 (m, IH), 1.49-1.32 (m, 2H), 1.29 (s, 3H), 1.26 (m, 3H).
Example 129
3-(2-Amino-l-methyl-5-oxo-2'-phenyl-l,5-dihydrospiro[imidazole-4,4'-thiochroman]-6'- yl)benzonitrile (Cmpd. 156)
Figure imgf000421_0001
Step 1 :
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 (NH4)^CO3 (800 mg, 7.7 mmol) is added formamide (6.5 mL). The resulting mixture is heated in a CEM microwave reactor at 6O0C for 1.5 hrs, 650C for 1.5 hrs, then 7O0C for 2 hrs. The resulting mixture is diluted with EtOAc (20 mL) and washed with H2O (3 x 10 mL). The organic layer is dried over Na2SO4, 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)+.
Step 2: 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 1100C for 30 min. After cooled to rt, the solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6l-bromo-2'-phenyl-2-thioxospiro[imidazolidine- 4,4'-thiochroman]-5-one (200 mg, 81%). MS ESI +ve m/z 405 (M+H)+. Step 3:
To a solution of 6'-bromo-2l-phenyl-2-thioxospiro[imidazolidine-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 6O0C 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 H2O and brine successively, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which is purified by preparative HPLC to give 6'-bromo-l-methyl-2-
(methylthio)-2'-phenylspiro[imidazole-4,4'-thiochroman]-5(lif)-one (56 mg) MS ESI +ve m/z 433 (M+H)+.
Step 4: A suspension of 6'-bromo-l -methyl-2-(methylthio)-2'-phenylspiro[imidazole-4,4'- thiochroman]- 5(l/f)-one (56 mg, 0.13 mmol) and NH4I (100 mg, excess) in 7 M NH3MeOH (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-l-methyl-2'-phenylspiro[imidazole-4.4'- thiochroman]-5(l//)-one as TFA salt. MS ESI +ve m/z 402 (M+H)\
Step 5:
To a solution of 2-amino-6'-bromo-l-methyl-2'-phenylspiro[imidazole-4,4'- thiochroman]-5(lH)-one TFA salt (70 mg, 0.14 mmol), 3-cyanophenylboronic acid (51 mg, 0.34 mmol), and Cs2CO3 (250 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3 )2 (20 mg). Then the system is degassed by sweeping with N2. 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-l-methyl-5-oxo-2'-phenyl-l,5-dihydrospiro- [imidazole-4,4'-thiochroman]-6'-yl)benzonitrile (30 mg) as a TFA salt. MS ESI +ve m/z 425 (M+H)+.
1H NMR (400MHz, CD3OD): less polar isomer: 8.00-7.8? (m, 2H), 7.72-7.59 (m, 3H), 7.52-7.33 (m, 7 H)5 5.26 and 4.65 (dd and dd; IH), 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, 7 H), 5.30 (dd, IH), 3.34 and 3.08 (s and s, 3H), 2.82-2.63 (m, 2H).
Example 130
3-(2-Amino- 1 -methyl- 1 ',5-dioxo-2'-phenyl-l ,5-dihydrospiro[imidazole-4,4'-thiochroman]-
6'-yl)benzonitrile (Cmpd 157)
Figure imgf000423_0001
To a solution of 3-(2-amino-l-methyl-5-oxo-2'-phenyl-l,5-dihydrospiro[imidazole- 4.4'-thiochroman]-6'-yl)benzonitrile TFA salt (27 mg, 0.05 mmol) in MeOH (5 mL) and H2O (0.1 mL) is added NaIO4 (21.4 mg, 0.10 mmol). The resulting mixture is stirred overnight at rt, then purified by preparative HPLC to give 3-(2-amino-l-methyl-l',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)+. 1H NMR (400MHz, CD3OD): 8.10-7.41 (m, 12H). 5.20 (dd, IH), 3.61 (m, IH), 3.26, 3.25 and 3.1 1 (s, s and s, 3H), 2.70 (m, IH).
Example 131
3-(2 -Amino- 1 -methyl-1 ', 1 ',5-trioxo-2'-phenyl- 1 , 5-dihydrospiro[imidazole-4,4'- thiochroman]-6'-yl)benzonitrile (Cmpd. 158)
Figure imgf000423_0002
Step 1 :
A crude product of 3-(2-amino-l-methyl-5-oxo-2'-phenyl-l,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 Boc2O (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 Na2SO4. The solvent is removed in vacuo to give a crude product, which is purified by preparative HPLC to give 3-(N-Boc-2-amino-l-methyl-r,5-dioxo-2'-phenyl- l,5-dihydrospiro[iπu'dazole-4,4'-tWochroman]-6'-yl)benzonitrile. MS ESI +ve m/z 525 (M+H)+.
Step 2:
To a solution of 3-(N-Boc-2-amino-l-methyl-r,5-dioxo-2'-phenyl-l,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 00C, then it is allowed to warm to rt for 1.5 h. NaHCO3 (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 ', l',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)+. 1H NMR (400MHz, CD3OD): 8.12-7.42 (m, 12H), 5.20 (dd, IH), 3.59 (m, IH), 3.32 and 3.21 (s and s, 3H), 2.83 (m, IH). Example 132
Compound 163
Figure imgf000424_0001
HCI/1 4-dιoxane Cs2CO3
Figure imgf000424_0002
Figure imgf000424_0003
Experimental data:
Figure imgf000424_0004
Step 1. 6-bromospiro[chroman-2,r-cyclohexan]-4-one
To a solution of l-(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 H2O and HCl to make the mixture to PH=I, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6- bromospiro[chroman-2,l'- cyclohexan]-4-one. (90 g, 100%). 1H NMR (CDCl3): 1.49 (d, 4H), 1.64 (d, 4H), 1.83 (s, IH), 1.98 (d, 2H), 2.1 1 (t, IH), 2.31 (s, IH), 2.68 (s, IH), 6.87 (d, IH), 7.50 (d, IH), 7.92(s, IH).
Figure imgf000425_0001
Step 2. (£)-N-(6-bromospiro[chroman-2,l'-cyclohexane]-4-ylidene)-2-methylprop- ane-2- sulfinamide The compound of 2-methylpropane-2-sulfinamide (29.54 g, 244.2 mmol) was added the solution of 6-bromospiro[chroman-2,r-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 Na2SO4, filtered, and evaporated to give (£)-N-(6-bromospiro[chroman-2,r- cyclohexane]-4-ylidene) -2-methylpropane-2-sulfinamide (50 g, 40%). 1H NMR (CDCl3): 1.30 (s, 10H), 1.51 (m, 5H), 1.62 (m, 4H), 1.83 (d, 2H), 3.07(d, IH), 3.43 (d, IH), 5.29 (s, 2H), 6.79 (d, IH), 7.41 (dd, IH), 7.96 (d, IH).
Figure imgf000425_0002
Step 3. methyl 2-(6-bromo-4-(l , 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 0C. After stirring at -78 0C for 30 minutes, a solution of (£)-N-(6-bromospiro[chroman-2,r-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 0C for 3 h. The reaction was quenched with aqueous NH4Cl solution and allowed to warming to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give the product, which was purified by chromatography to afford methyl 2-(6-bromo-4-(l,l-dimethylethylsulfinamido)spiro[chroman-2,r- cyclohexane]- 4-yl)acetate (1.4 g, 33%). 1H NMR (CDCl3): 1.23 (s, 9H), 1.36-1.52 (m, 4H), 1.57 (m, IH), 1.66 (m, 3H), 1.86 (d, 2H), 2.24 (d, IH), 2.67 (d, IH), 2.93 (s, 3H), 3.71 (s, 3H), 5.34 (s, IH), 6.79 (d, IH), 7.26 (s, IH), 7.39 (s, IH).
Figure imgf000426_0001
Step 4. methyl 2-(4-amino-6-bromospiro[chroman-2,l'-cyclohexane]-4-yl)acetate To a solution of methyl 2-(6-bromo-4-(l,l-dimethylethylsulfmamido)spiro [chroman-2,r-cyclohexane]-4-yl)acetate (200 mg, 0.42 mmol) in MeOH (2 mL) was added 4 N HCl/l,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.r-cyclohexane]- 4-yl)acetate (140 mg, 90%). 1H NMR (CDCl3): 1.22-1.38 (m, IH), 1.39-1.52 (m, 6H), 1.72-1.88 (m, 3H)5 1.93-2.02 (d; 2H), 2.13-2.24 (L IH), 2.59 (d, IH), 2.86 (d: IH), 3.65 (s, 3H), 6.74 (d, IH), 7.24 (s, IH), 7.52 (s. IH).
Figure imgf000426_0002
163i
Step 5. Compouond 163i To a solution of methyl 2-(4-amino-6-bromospiro[chroman-2,r- 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 163U (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 Na2SO4, and concentrated to give the crude product, which was purified by preparative TLC to afford the compound 163i (80 mg, 165%). 1H NMR (CDCl3): 1.38 (s, 2H), 1.42 (s, 9H), 1.53 (m, 5H)5 1.76 (m, 3H), 1.91 (d, IH), 2.13 (d, IH), 2.68 (d, IH), 3.03 (d, IH), 3.31 (s, 3H), 6.73 (d, IH), 7.29 (d, IH), 7.43 (s, IH).
Figure imgf000427_0001
Step 6. Compound 163
Pd(PPh3 )2C12 (8 mg) in a 10 mL of flask under Ar2 was treated sequentially with the compound 1 (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3- cyanophenylboronic acid (44 mg, 0.24 mmol). The mixture was heated under 120 0C at
Ar2 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%). 1H NMR (MeOD): 1.32-1.71 (m, 7H), 1.78-1.91 (m, 2H), 1.98 (m, IH), 2.12 (d, IH), 2.44 (d, IH), 2.93 (d, IH), 3.38 (s, 3H), 3.68 (d, IH), 7.09 (d, IH), 7.62-7.72 (m, 3H), 7.89-8.03 (m, 3H).
Example 133 Compound 164 Experimental data:
PPh3 MeI
Figure imgf000427_0002
Figure imgf000427_0003
Step 1. 6-bromo-4-methylene-2-phenylchroman
A solution of n-BuLi (2.5 M5 3.80 mL) was added to a mixture of PPh3-MeI. (4.092 g, 10.13 mmol) in THF at -10 0C. 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%). 1H-NMR (CDCl3): 2.76 (m, 2H), 4.90 (d, IH), 5.01 (m, IH), 5.48 (d, IH), 6.76 (d, IH), 7.31 (m, 6H), 7.62 (d, IH).
Figure imgf000428_0001
Step 2. 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile
Pd(PPh3^Cl2 (40 mg) in a 100 mL of flask under Ar2 was treated sequentially with 6-bromo-4-methylene-2-phenylchroman (200 mg, 0.67 mmol) in [1.4]dioxane (20 mL), Cs2CO3 (2 N5 3.33 mL) and 3-cyanophenylboronic acid (167 mg, 1.13 mmol). The mixture was heated under 120 0C at Ar2 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%). 1H- NMR (CDCl3): 2.81 (m, 2H), 4.96 (d, IH), 5.10 (m5 IH), 5.61 (d, IH), 7.98 (d, IH), 7.29 (m, IH), 7.35 (m, 3H), 7.41 (m, 2H)5 7.46 (m, IH), 7.52 (m, IH), 7.72 (m, 2H)5 7.79 (d, IH).
Figure imgf000428_0002
Step 3. 3-(4-iodomethyl-4-isothiocyanato-2-phenyl-chroman-6-yl)-benzonitrile
To a solution of 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (50 mg, 0.156 mmol) in CHCl3 (5 mL) was added I2 (93 mg, 0.367 mmol), KSCN (76 mg, 0.78 mmol) and catalyst amount t-BtNBr. The mixture was stirred overnight and used directly.
Figure imgf000429_0001
Step 4. 3-(2'-(/ert-butylamino)-2-phenyl-5'H-spiro[chroman-4,4'-thiazole]-6- yl)benzonitrile t-BuNH2 (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 CHCl3 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%).
Figure imgf000429_0002
Step 4. 3-(2'-amino-2-phenyl-5'//-spiro[chroman-4,4'-thiazole]-6-yl) benzamide A mixture of 3-(2'-(terr-butylamino)-2-phenyl-51H-spiro[chroman-4,4'-thiazole]-6- yl) benzonitrile (30 mg, 0.066 mmol) in concentrated HCl (5 mL) was stirred at 100 0C 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'//-spiro[chroman-4,4'- thiazole]-6-yl) benzamide (20 mg, 73%).
Figure imgf000429_0003
Step 5. 3-(2'-amino-2-phenyl-5'H-spiro[chroman-4,4'-thiazole]-6-yl)benzonitrile
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 CH2Cl2 was added
TFAA (0.2 mL) at 0 0C. 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-57/-spiro[chroman-4, 4'-thiazole]-6-yl)benzonitrile (1.53 mg, 8%). 1H- NMR (MeOD): 2.27 (m, 2H), 3.36 (m, IH), 3.84 (m, IH), 5.24 (m, IH), 6.92 (m, IH), 7.31 (m, 4H), 7.48 (m, 4H), 7.81 (m, 3H).
Example 134
3-(2'-Amino-2-phenyl-5'.6'-dihydrospiro[chroman-4,4'-[l,3]thiazine]-6-yl)benzonitrile
(Cmpd. 165)
Figure imgf000430_0001
min
Figure imgf000430_0002
Figure imgf000430_0003
Step l : 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 00C and quenched with sat. aq. NH4CI and extracted with ethyl acetate (2 x 40 mL). The combined organic phases are washed with H2O, brine, and dried over Na2SO4, 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-H20)+.
Step 2:
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 400C 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)+.
Step 3:
The above mixture of 2-(6-bromo-2-phenylchroman-4-ylidene)ethyl carbamimidothioate HCl salt and thiourea is dissolved in TFA (4 mL) containing MeSO3H (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 NaHCO3. The separated aqueous phase is extracted with ethyl acetate once and the combined organic phases are washed with brine, and dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo-2-phenyl-5'.6'-dihydrospiro[chroman-4,4'-[l,3]thiazin]-2'-amine, which is used for next step without further purification. MS ESI +ve m/z 389 (M+H)+ .
1R NMR (400MHz, CD3OD): less polar isomer. 7.17 (s, IH), 7.50-6.65 (m 7H), 5.36 and 5.13 (d, IH), 3.53-1.28 (m, 6H); more polar isomer: 7.41-6.71 (m, 8 H), 4.66 and 4.39 (m, IH), 3.35-2.00 (m, 6H).
Step 4:
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 BoC2O (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 /-butyl 6-bromo-2-phenyl-5',6'-dihydrospiro[chroman-4,4'-[l .3]thiazine]-2'-ylcarbamate 415 mg (81% for 3 steps). MS ESI +ve m/z 489 (M+Hf. Step 5:
A solution of f-butyl 6-bromo-2-phenyl-5',6'-dihydrospiro[chroman-4,4'-[l,3]thiazine]- 2'-ylcarbamate (41 mg, 0.084 mmol), 3-cyanophenylboronic acid (23.5 mg, 0.16 mmol), Cs2CO3 (78 mg, 0.24 mmol), and a catalytic amount of Pd(dppf)Cl2 in 1.4-dioxane (4 mL) and H2O (0.4 mL)is heated at 1 10°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 Na2SO4, 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'- [l,3]thiazine]-6-yl)benzonitrile. MS ESI +ve m/z 412 (M+H)+
1U NMR (400MHz, CD3OD): less polar isomer. 8.03 (s, IH), 7.96 (m IH), 7.88 (s, IH), 7.70-7.60 (m; 3H), 7.53-7.52 (m, 2H), 7.46-7.38 (m, 3H), 7.16 (d, IH), 5.19 (d, IH), 3.54 (td, IH), 3.32 (m, IH), 2.81 (td, IH), 2.58 (d, IH), 2.36-2.27 (m, 2H); more polar isomer: 7.41-6.78 (m, 12 H), 4.69 (m, IH), 3.37-3.24, 3.04-2.88, 3.63, 3.42, 2.29-2.15, 1.28 (m, 6H).
Example 135
2-Phenyl-6-(pyridin-3-yl)-5'.6'-dihydrospiro[chroman-4,4'-[l,3]thiazin]-2'-amine (Cmpd. 166)
Figure imgf000432_0001
To a solution of t-butyl 6-bromo-2-phenyl-5',6'-dihydrospiro[chroman-4,4'- [l,3]thiazine]-2'-ylcarbamate (39 mg, 0.08 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.16 mmol), and Cs2CO3 (120 mg) in 1 ,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). The system is degassed by sweeping with N2. The tube is capped and heated to 1100C 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)÷. 1H NMR (400MHz, CD3OD): 8.59 (D, IH), 8.00-7.15 (m, 1 IH), 5.22 (d, IH), 3.56 (m, IH), 3.26 (m, IH), , 2.82 (td, IH), 2.60 (dd, IH), 2.38 (m, IH), 2.32 (m, IH).
Example 136
3-(2"-Amino-5",6"-dihydrospiro[spiro(chroman-2,r-(4-t-butylcyclohexan))-4,4"- [l,3]thiazine]-6-yl)benzonitrile (Cmpd. 167)
Figure imgf000433_0001
Step l :
To a solution of 6-bromo-4'-t-butylspiro[chroman-2,r-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. NH4Cl, and extracted with ethyl acetate (2 x 40 mL). The combined organic phases are washed with H2O and brine, then dried over Na2SO4, 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,r- cyclohexan]-4-ol as an oil (1. 907 g, 82%). MS ESI +ve m/z 361 (M+H-H20)+.
Step 2: The mixture of 6-bromo-2-phenyl-4-vinylchroman-4-ol (1.1 14 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 400C 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,l'-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)+.
Step 3:
The above crude product is dissolved in TFA (8 mL) containing MeSO3H (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 NaHCO3. The separated aqueous phase is extracted with ethyl acetate once, and the combined organic phases are washed with brine, and dried over Na2SO4, and filtered. The filtrate is concentrated to give crude product. Pure 6-bromo-5",6"-dihydrospiro[spiro(chroman-2,r-(4-t-butylcyclohexan))-4,4"- [l,3]thiazin]-2"-amine is obtained by preparative HPLC. MS ESI +ve m/z 437 (M+H)+
Step 4: To a solution of 6-bromo-5",6"-dmydrospiro[spiro(chroman-2,l"-(4-/- butylcyclohexane))-4,4'-[l,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 Cs2CO3 (146 mg, 0.45 mmol) and H2O (0.5 mL), followed by a catalytic amount of PdCl2dppf. The system is degassed by sweeping with N2. 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,l"-(4-/-butylcyclohexane))-4.4'-[l,3]thiazine]- 6-yl)benzonitrile respectively. MS ESI +ve m/z 460 (M+H)+. 1U NMR (400MHz, CD3OD): less polar isomer: 8.00 (s, IH), 7.93 (d, IH), 7.72 (s, IH), 7.68-7.58 (m, 3H), 7.06 (d, IH), 3.53 (td, IH), 3.28 (m, IH), 0.91 (s, 9H); more polar isomer: 8.00 (s, IH), 7.93 (d, IH), 7.71-7.59 (m, 4H), 7.02 (d, IH), 3.58 (td, IH), 3.34 (m, IH), 0.91 (s, 9H).
Example 137 3-(2"-Amino-5",6"-dihydrospiro[spiro(chroman-2,r-cyclohexane)-4,4"-[l,3]thiazine]-6- yl)benzonitrile (Cmpd 168)
Figure imgf000435_0001
Suzuki
Figure imgf000435_0003
Figure imgf000435_0002
Step l :
To a solution of 6-bromospiro[chrornan-2,r-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 (I 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 O0C and quenched with sat. aq. NH4Cl, and extracted with ethyl acetate (2 x 30 mL). The combined organic phases are washed with H2O5 brine, dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo-4-vinylspiro[chroman-2,r-cyclohexan]- 4-ol as an oil, which is used for the next step without further purification. MS ESI +ve m/z 305 (M+H-H20)+.
Step 2:
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'-/-butylspiro[chroman- 2,l'-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)+.
Step 3:
The above crude product is dissolved in TFA (5 mL) contain MeSO3H (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 NaHCO3. The separated aqueous phase is extracted with ethyl acetate once, and the combined organic phases are washed with brine, and dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo- 5",6"-dihydrospiro[spiro(chroman-2,r-cyclohexan)-4,4"-[l,3]thiazin]-2"-amine. Pure product is obtained by preparative HPLC. MS ESI +ve m/z 437 (M+H)+ .
Step 4: To a solution of 6-bromo-5",6"-dihydrospiro[spiro(chroman-2, 1 "-(4-/- butylcyclohexane))-4,4'-[13]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 Cs2CO3 (200 mg, 0.61 mmol) and H2O (0.5 mL), followed by a catalytic amount of PdCl2(PPh3 )2. The system is degassed by sweeping with N2. Then it is capped and heated for 30 min at 1100C 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)+. 1U NMR (400MHz, CD3OD): 8.00 (s, IH), 7.92 (d, IH), 7.71 (s, IH), 7.68-7.59 (m, 3H), 7.07 (d, IH), 3.53 (td, IH), 3.28 (m, IH), 2.56 (td, IH), 2.37-2.29 (m, 2H), 2.18 (d, IH), 1.90-1.82 (m, 3H), 1.67-1.61 (m, 4H), 1.55-1.37 (m, 3H).
Example 138
3-(2'-Imino-r-methyl-6'-oxo-2-phenyl-2',3',5',6'-tetrahydro-lΗ-spiro[chroman-4.4'- pyrimidine]-6-yl)benzonitrile (Cmpd. 169)
Figure imgf000436_0001
HQ, MeOH CSCI2, DCM MeNH2, THF Dioxane NaHCO3, H2O
Figure imgf000436_0002
Figure imgf000436_0003
Figure imgf000436_0004
Step l :
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 it, 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 Na2SO4, 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)+
Step 2:
To a solution of methyl acetate (383 mg, 0.41 mL, 5.17 mmol) in anhydrous THF (10 mL) at -780C under N2 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. NH4Cl. 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 Na2SO4, filtered and concentrated, and the residue is purified through chromatography on silica gel to afford methyl 2-(6-bromo-4- (1,1 -dimethyl ethylsulfinamido)-2-phenylchroman-4-yl)acetate 427 mg as an oil. MS ESI +ve m/z 480 (M+H)+
Step 3:
A solution of methyl 2-(6-bromo-4-(l.l-dimethylethylsulfinamido)-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)+.
Step 4: The above crude product is added to a solution OfNaHCO3 (714 mg, 8.5 mmol) in
H2O (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 Na2SO4, 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)+.
Step 5:
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 MeNH2 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-l'-methyl-2-phenyl- 2'-thioxo-2',3'-dihydro-rH-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)+.
Step 6:
To a solution of the above crude product in MeOH (9 mL) is added concentrated aqueous NH4OH (4.5 mL). followed by t-butyl hydroperoxide solution (ca. 5.5 M in nonane, 1 mL). The resulting suspension is stirred overnight. The resulting clear solution is concentrated in vacuo and the residue is purified through preparative HPLC to give 6- bromo-2'-imino- 1 '-methyl-2-phenyl-2',3'-dihydro- 1 Η-spiro[chroman-4,4'-pyrimidin]- 6'(5'H)-one TFA salt. MS ESI +ve m/z 400 (M+H)+.
Step 7:
To a solution of 6-bromo-2'-imino-r-methyl-2-phenyl-2'.3'-dihydro-lΗ- spiro[chroman-4.4'- pyrimidin]-6'(5'H)-one TFA salt (20 mg. 0.039 mmol) and 3- cyanophenylboronic acid (12 mg, 0.078 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs2CO3 (63 mg, 0.195 mmol) and H2O (0.5 mL), followed by Pd(PPh3)2Cl2 (8 mg). The resulting mixture is heated 30 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'-imino-l'-methyl-6'-oxo-2-phenyl-2',3t,5',6'- tetrahydro-l'H- spiro[chroman-4,4'-pyrimidine]-6-yl)benzonitrile. MS ESI +ve m/z 423 (M+H)+.
1H NMR (400MHz5 CD3OD): less polar isomer: 8.02 (s, IH), 7.97-7.88 (m, 2H), 7.71- 7.60 (m, 3H), 7.52-7.49 (m, 2H), 7.44-7.37 (m, 3H), 7.15 and 7.10 (d and d, IH), 5.34 and 5.17 (d and d, IH), 3.90 and 2.90 (d and d, IH), 3.57 (m, IH), 3.35 (s, 3H), 2.54 (t, IH), 2.34 (m, IH); more polar isomer. 8.02 (s, IH), 7.99-7.91 (m, 2H), 7.70-7.60 (m, 3H), 7.53-7.49 (m, 2H), 7.44-7.35 (m, 3H), 7.15 and 7.09 (d and d, IH), 5.36 and 5.23 (dd and d, IH), 3.84 and 2.73 (d and d, IH), 3.44 (m, IH), 3.00 and 2.94 (s and s, 3H).
Example 139
2'-Imino-r-methyl-2-phenyl-6-(pyridin-3-yl)-2',3'-dihydro-lΗ-spiro[chroman- 4,4'- pyrimidin]-6'(5'H)-one (Cmpd. 170)
Figure imgf000439_0001
To a solution of 6-bromo-2'-imino-r-methyl-2-phenyl-2',3'-dihydro-lΗ- spiro[chroman-4,4'- pyrimidin]-6'(5'H)-one TFA salt (12 mg, 0.023 mmol) and pyridin-3- ylboronic acid (9 mg, 0.070 mmol) in 1.4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs2CO3 (63 mg, 0.195 mmol) and H2O (0.5 mL), followed by Pd(PPh3)2Cl2 (8 mg). The resulting mixture is heated for 30 min at 130°C in CEM microwave reactor. The separated organic phase is concentrated and the purified through preparative HPLC to afford cis- and trans-2'-imino-r-methyl-2-phenyl-6-(pyridin-3-yl)- 2',3'-dihydro-l'H-spiro[chroman-4,4'-pyrimidin]-61(5'H)-one. MS ESI +ve m/z 423 (M+H)+.
1H NMR (400MHz, CD3OD): less polar isomer: 8.70 (m, 2H), 8.08 (s, IH)5 8.00 (s, IH), 7.78 (m, 2H)S 7.52-7.37 (m, 5H), 7.18 (m, IH), 5.37 and 5.20 (d and d, IH), 3.90 and 2.91 (d and d, IH), 3.35 (s, 3H), 2.60-2.29 (m, 2H); more polar isomer: 9.16 (s; IH), 8.82-8.73 (m, 2H), 8.15-8.04 (m, 2H), 7.80 (m, IH), 7.51-7.35 (m, 5H), 7.22 and 7.17 (d and d, IH), 5.39 and 5.27 (d and d, IH), 3.86 and 2.76 (d and d, IH)5 3.46 (s, IH), 2.99 and 2.94 (s and s, 3H), 2.57-2.31 (m, 2 H).
Example 140
Δ °'-Iimino- 1 '-methyl-2-phenyl-6-(pyridin-4-yl)-2',3'-dihydro-lΗ-spiro[chroman-4,4'- pyrimidin]-6'(5'H)-one (Cmpd. 171)
Figure imgf000440_0001
To a solution of 6-bromo-2'-imino-r-methyl-2-phenyl-2',3'-dihydro-lΗ- spiro[chroman-4,4'- pyrimidin]-6'(5'H)-one TFA salt (12 mg, 0.023 mmol) and pyridin-4- ylboronic acid (9 mg, 0.070 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs2CO3 (63 mg, 0.195 mmol) and H2O (0.5 mL), followed by Pd(PPh3)2Cl2 (8 mg). The resulting mixture is heated for 30 min at 130°C in CEM microwave reactor. The separated organic phase is concentrated and then purified through preparative HPLC to afford cis- and trans-2'-imino-l'-methyl-2-phenyl-6-(pyridin-4-yl)- 2\3'-dihydro-lΗ-spiro[chroman-4,4'-pyrimidin]-6'(5Η)-one. MS ESI +ve m/z 423 (M+H)+. 1H NMR (400MHz, CD3OD): less polar isomer. 8.80 (m, 2H), 8.35-8.24 (m, 3H), 7.51- 7.40 (m, 5H), 7.23 (m, IH), 5.43 and 5.24 (d and d, IH), 3.95 and 2.94 (d and d, IH), 3.56 (m, IH), 3.36 (s, 3H), 2.60-2.35 (m, 2H); morepolar isomer: 8.81 (d, 2H), 8.41-8.31 (m, 3H), 8.02 (m, IH), 7.54-7.51 (m, 2H), 7.46-7.37 (m, 3H), 7.27 and 7.22 (d and d, IH), 5.45 and 5.32 (d and d, IH), 3.92 and 2.79 (d and d, IH), 3.47 (s, IH), 3.00 and 2.96 (s and s, 3H), 2.56-2.34 (m, 2 H).
Example 141
3-(3"-imino-2"-methylspiro[spiro(chroman-2,l'-cyclohexane)-4.5"-[l,2,4]triazolidine]-6- yl)benzonitrile (Compound 175) MeNHNH2 H2SO4
NaOMe1 MeOH
Figure imgf000441_0002
Figure imgf000441_0001
Step 1: Preparation of 6-bromo-2"-methylspiro[spiro(chroman-2,l'-cyclohexane)- 4,5"-[l,2,4]triazolidine]-3M-imine
To a solution of methylhydrazine H2SO4 salt (144 mg, 1.0 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25w% in MeOH, 0.46 mL, 2.0 mmol), 1 h later, followed by (E)- N-(6-bromospiro[chroman-2,r-cyclohexane]-4-ylidene)cyanamide (319 mg, 1.0 mmol), After stirred 20 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. It was purified on preparative HPLC to 6-bromo-2"-methylspiro[spiro(chroman-2,l'- cyclohexane)-4.5"-[l ,2,4]triazolidine]-3"-imine TFA salt as a white solid. MS ESI +ve m/z 365 (M+H)+.
Example 142
Preparation of (2S,45'/27?,4/?)-6-(3,5-difluorophenyl)-2'-methyl-2-((5'/i?)-tetrahydro-2H- pyran-3-yl)-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine (326) and
(25,4i?/2i?,45)-6-(3,5-difluorophenyl)-2'-methyl-2-((5'//?)-tetrahydro-2//-pyran-3-yl)-2'H- spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine (322)
Figure imgf000442_0001
Step 1: Preparation of(S/R)-6-bromo-2-((S/R)-tetrahydro-2H-pyran-3-yl)chroman-4-one and (S/R)-6-bromo-2-((R/S)-tetrahydro~2H-pyran-3-yl)chroman-4-one To a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (6.069 g, 28.23 mmol) and tetrahydro-2H-pyran-3-carbaldehyde (3.218 g, 28.23 mmol) in MeOH (50 mL) was added pyrrolidine (1.5 mL). The resulting solution was heated to reflux and monitored with LC- MS. 50% conversion was achieved after 2h. After 12h. there was no improvement in conversion. The reaction mixture was cooled down to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel and eluted with EA in hexane (0-30%) to produce 1.981 g of 6-bromo-2- (tetrahydro-2//-pyran-3-yl)chroman-4-one. 1.321 g of 6-bromo-2-(tetrahydro-2//-pyran-3- yl)chroman-4-one was further purified by preparative HPLC to give (5//?)-6-bromo-2- ((S/Λ)-tetrahydro-2H-pyran-3-yl)chroman-4-one (A) (669 mg, polar isomer on preparative HPLC) and (5//?)-6-bromo-2-((Λ/S)-tetrahydro-2H-pyran-3 -yl)chroman-4-one (B)(512 mg, less polar isomer on preparative HPLC). MS ESI +ve m/z 311 (M+H)+. Step 2: Preparation of(S/R)-6-(3.5-difluorophenyl)-2-((S/R)-tetrahydro-2H-pyran-3- yl)chroman-4-one
To a 10 mL CEM microwave test tube was charged with CS2CO3 ( 600 mg. 1.84 mmol), PdCl2(PPh3)2 (42 mg: 0.06 mmol), (5//?)-6-bromo-2-((5/i?)-tetrahydro-2H-pyran-3- yl)chroman-4-one (285.5 mg. 0.92 mmol), 3.5-difluorophenylboronic acid (232 mg, 1.47 mmol), dioxane (5 mL) and H2O (0.5 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 10OC for 8 min. hi another tube charged with the same amount of reagents and starting material, repeated the same reaction at the same temperature and reaction time. The combined reaction mixtures were evaporated. The residue was dissolved in MeOH and filtered. The filtrate was evaporated and purified by flash chromatography on silica gel and eluted with EA in hexane (0-40%) to give (S/R)-6- bromo-2-((S//?)-tetrahydro-2H-pyran-3-yl)chroman-4-one (520 mg). 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J= 2.4 Hz, IH), 7.67 (dd, J= 8.8, 2.4, IH), 7.11-7.06 (m, 3H), 6.77 (m, IH), 4.34 (m, IH), 4.22 (m, IH), 3.91 (m, IH), 3.47-3.41 (m, 2H), 2.82-2.69 (m, 2H), 2.10 (m, IH), 1.88 (m, IH), 1.71-1.65 (m, 2H), 1.41 (m, IH); 19F NMR (375 Hz, CDCl3) δ: - 109.82; MS ESI +ve m/z 345 (M+H)+.
Step 3: preparation ofN-((S/R)-6-(3,5-difluorophenyl)-2-((S/R)-tetrahydro-2H-pyran-3- yl)chroman-4-ylidene)cyanamide
To a solution of (5/i?)-6-bromo-2-((5/J?)-tetrahydro-2i/-pyran-3-yl)chroman-4-one (509 mg, 1.52 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 4 mL, 4 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.623 g, 0.75 mL, 3.34 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (35 g), and stirred for 10 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give ΛL((5//?)-6-(3,5- difluorophenyl)-2-((iS/i?)-tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide as light brown solid (580 mg), which was used for next step without further purification. MS ESI +ve m/z 369 (M+H)+.
Step 4: Preparation of(2S,4S/2R,4R)-6-(3,5-difluorophenyl)-2'-methyl-2-((S/R)- tetrahydro-2H-pyran-3-yl)-2 'H-spiro[chroman-4, 5 '-[1, 2, 4]oxadiazol]-3 '-amine and (2S, 4R/2R, 4S)-6-(3, 5-difluorophenyl)-2 '-methyl-2-((S/R)-tetrahydro-2H-pyran-3-yl)-2 'H- spiro[chroman-4, 5 '-[I12, 4]oxadia∑ol]-3 '-amine To a solution of jV-methylhydroxylamine hydrochloride (129 mg, 1.54 mmol) in
MeOH (10 mL) was added 25wt% NaOMe in MeOH (0.32 mL, 1.39 mmol). The resulting mixture was stirred 5 min and transferred through a syringe to a suspension of ΛL((5//?)-6- (3,5-difluorophenyl)-2-((iS//?)-tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide (crude from previous step, 1.52 mmol) in MeOH (8 mL). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was taken in hexane and filtered, the cake was collected and purified by preparative PHLC to gave (25,45/2i?!4i?)-6-(3,5-difluorophenyl)-2'-methyl-2-((5'/i?)-tetrahydro-2H-pyran-3-yl)- 2'H-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine as TFA salt and (25'!4^/2i?,45)-6-(3,5- difluorophenyl)-2'-methyl-2-((5'//?)-tetrahydro-2H-pyran-3-yl)-2'H-spiro[chroman-4,5'- [l,2,4]oxadiazol]-3 '-amine as TFA salt.
Compound 326: 1H NMR (400 MHz, CD3OD) δ: 7.93 (d, J= 2.0 Hz, IH), 7.69 (td, J = 8.4, 2.4 Hz, IH), 7.26-7.22 (m, 2H), 7.01 (m, IH), 6.91 (m, IH), 4.22-4.14 (m, 2H), 3.88 (m, IH), 3.45 (m, 2H), 3.43 (s, 3H), 2.60 (dd, J= 10.0, 2.8 Hz, IH), 2.45 (dd, J= 14.0, 10.0 Hz, IH), 2.07-1.93 (m, 2H), 1.70-1.50 (m, 3H); 19F NMR (375 Hz, CD3OD) δ: - 111.95; MS ESI +ve m/z 416 (M+H)+.
Compound 322: 1U NMR (400 MHz, CD3OD) δ: 7.93 (d, J= 2.0 Hz, IH), 7.70 (dd, J = 8.8, 2.4 Hz, IH), 7.28-7.23 (m, 2H), 7.02 (d, J= 8.8 Hz, IH), 6.93 (m, IH), 4.22-4.17 (m, 2H), 3.89 (brd, J= 11.2 Hz, IH), 3.50-3.43 (m, 2H), 3.37 (s, 3H), 2.75 (dd, J= 14.0, 2.4 Hz, IH), 2.03-1.72 (m, 3H), 1.72-1.66 (m, 2H), 1.55 (m, IH); 19F NMR (375 Hz, CD3OD) δ: -1 1 1.95; MS ESI +ve m/z 416 (M+H)+.
Example 143. Preparation of Compound 210
Figure imgf000444_0001
KC N/( NH4J2CO3 MeI HCONH2 K2CO3
Figure imgf000444_0002
Figure imgf000444_0003
Experimental data
Figure imgf000445_0001
210a 210b
To a solution Of CH3OCH2PPh3Cl (171.4 g, 0.5 mol) in THF (1000 mL), was added NaH (20.4 g, 0.51 mol, 60%) at room temperature, and the solution was atirred at room temperature for 15 minutes. A solution of compound 210a (65.73 g, 0.45 mol) in THF was added at room temperature, after being stirred for 30 minutes, the reaction mixture was refluxed for 6 hours. Ethanol was added, the mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure, and purified by column chromatography to give the compound 210b (49.85 g, 64%). 1H-NMR (CDCl3 400 MHz): δl '.27-7.29 (m, IH), 7.23-7.25 (m, IH), 7.02 (m, IH), 6.98-7.00 (m, 2H), 6.54 (s, IH), 3.65 (s, 3H), 3.64 (s, IH), 2.63-2.67 (m, 2H), 2.42-2.45 (m, 2H), 1.67-1.73 (m, 2H).
Figure imgf000445_0002
210b 210c To a solution of compound 210b (30 g, 0.172 mol) in CH3OH (300 mL) was added aqueous HCl solution (1500 mL, 2 mol/L). The reaction mixture was refluxed overnight, evaporate in vacuo, extracted with diethyl ether, dried over Na2SO4, and evaporated to give the crude compound 210c (21 g, 76%). which was used for the next step without purifition. 1H-NMR (CDC13 400 MHz): 39.60 (m, IH), 7.14-7.19 (m, 2H), 7.08-7.13 (m, 2H), 3.52 (s, IH), 2.1 1-2.19 (m, IH), 1.85-1.87 (m, IH), 1.68-1.75 (m, 2H).
Figure imgf000445_0003
To a stirred solution of compound 210A (28.1 g, 0.131 mol) in a mixture of EtOH (128 mL) and water (211 mL) was added compound 210c (21 g, 0.131 mol) and borax (49.9 g, 0.131 mol). The mixture was refluxed for 2 days, filtrates, and dissolved in CH2Cl2. After filtration and evaporation, the crude product was purified by HPLC preparation to give the compound 21Od (1 1.5 g, 25%). 1H-NMR (CDCl3 300 MHz): (57.90-7.91 (m, IH), 7.46-7.51 (m, IH), 7.11 -7.19 (m, IH), 7.04-7.09 (m, 3H), 6.81-6.86 (m, IH), 4.58-4.79 (m, IH), 3.32-3.48 (m, IH), 2.66-2.79 (m, 3H), 2.47-2.62 (m, IH), 1.96-2.06 (m, IH), 1.75-1.95 (m, 2H), 1.68-1.74 (m, IH).
Figure imgf000446_0001
A steel slave was charged with a mixture of compound 21Od (6 g, 16.85 mmol), KCN (2.19 g, 33.7 mmol) and (NH4^CO3 (1 1.81 g, 123 mmol). Formamide (200 mL) was added. The mixture was heated at 70°C for 72 hours, cooled, and poured into ice. After acidification with concentrated HCl solution to pH=l, the mixture was filtered, and the solid was disoveled in CH2Cl2 (500 mL). The organic layer was washed with water (2x500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH = 50:1) to give the compound 21Oe (7 g, 97%) as orange solid. 1H-NMR (CDCl3 400 MHz): 57.40 (m, 2H), 7.13 (m, 4H), 6.83 (m, IH), 5.1 (d, J= 12.0 Hz, IH), 3.2 (m, IH), 2.70 (m, IH), 2.65 (m, 4H), 1.70 (ms 2H), 1.65 (m, IH).
Figure imgf000446_0002
To solution of compound 21Oe (0.4 g, 0.94 mmol) and Lawesson' reagent (0.38 g. 0.94 mmol) in dioxane (20 mL) was heated under 150°C for 25 minutes in a microwave reactor. The mixture was cooled, and concentrated in vacuo. The residue was purified by column chromatography (PE / EtOAc = 20: 1) to give the compound 21Of (0.15 g, 36%) as a light orange solid. 1H-NMR (CDCl3 400 MHz): «57.31 (d, J= 4.0 Hz5. IH), 7.12 (s, IH), 7.05 (m, 3H), 6.95 (d, J= 20.0 Hz, IH), 6.76 (m, IH), 4.95 (m, IH), 3.22 (m, IH), 2.65 (s, 2H), 2.05 (m, 2H), 1.90 (m, 2H), 1.70 (m, IH), 1.55 (s, IH).
Figure imgf000447_0001
To a solution of compound 21Of (IOO mg, 0.226 mmol) in CH3CN (2 mL) was added K2CO3 (125 mg, 0.904 mmol) and MeI (128 mg, 0.904 mmol). The mixture was stirred at room temperature for 3 hours. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 3: 1) to give the compound 21Og (74 mg, 70%) as a white solid. 1H-NMR (CDCl3 400 MHz): J7.25 (d, J= 8.0 Hz, IH), 7.15 (d, J= 8.0 Hz, IH), 7.04 (m, 3H), 6.72 (m, IH), 5.05 (m,. IH), 3.17 (m, IH), 2.97 (s, IH), 2.75 (m, 2H), 2.56 (s, 3H), 2.46 (d, J= 12.0 Hz, 2H), 2.22 (m, IH), 1.95 (m, 2H), 1.82 (m, IH), 1.65 (m, 2H).
Figure imgf000447_0002
A solution of compound 21Og (50 mg, 0.106 mmol) and NH4I (123 mg, 0.851 mmol) in a solution of NH3/EtOH (5 mL, 0.5 N) was heateded at 1200C in a CEM tube unedr microwave reactor for 3 hours. The mixture was concentrated in vacuo, and the residue was added CH2Cl2 (20 mL) and filtered. The filtrate was conentrated in vacuo, and the residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the compound 21Oh (36 mg, 77%) as yellow oil. 1H-NMR (CDCl3 400 MHz): <57.19 (d, J = 4.0 Hz; 2H), 7.02 (m, 4H), 6.78 (m, IH), 5.23 (m, IH), 3.09 (m, IH), 3.02 (s, 3H)5 2.67 (m, 3H), 2.20 (m, IH), 1.90 (m, 3H), 1.76 (m. 2H).
Figure imgf000448_0001
To a solution of compound 21Og (30 mg, 0.068 mmol), 3,5-dichlorophenylboronic acid (16 mg, 0.082 mmol), and Cs2CO3 (0.5 mL, 6 mmol, 2 M, aqueous) in dioxane (1.5 mL) was added Pd(PPh3)2Cl2 (5 mg). The mixture was heated at 120°C in a microwave reactor for 15 minutes under nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) and HPLC to give the compound 210 (4 mg, 12%) as a solid. 1HNMR (CD3OD 400 MHz): (57.49 (m, 3H), 7.45 (d, J= 12.0 Hz, IH), 7.38 (m, 2H)5 7.05 (m, 3H), 6.92 (d, J= 8.0 Hz, IH), 5.05 (m, IH), 3.22 (s, 3H), 2.70 (m, 2H), 2.56 (s, IH), 2.35 (d; J= 12.0 Hz, IH), 2.24 (m, IH), 1.96 (m, 2H), 1.68 (m, IH), 1.19 (s, IH): ESI MS: 506 [M+H]~.
Example 144
Preparation of (±)-(25",45)-6-(3.5-difluorophenyl)-2'-methyl-2-((R)-tetrahydro-2//-pyran-
3-yl)-2'H-spiro[chroman-4,5'-[L2,4]oxadiazol]-3'-amine (323) and (+)- (25,4Λ)-6-(3,5- difluorophenyl)-2'-methyl-2-((R)-tetrahydro-2H-pyran-3-yl)-2'H-spiro[chroman-4.5'-
[1.2;4]oxadiazol]-3'-amine (316)
Figure imgf000449_0001
Step 1: Preparation of(S/R)-6-(3.5-difluorophenyl)-2-((R/S)-tetrahydro-2H-pyran-3- yl)chroman-4-one To a 10 mL CEM microwave test tube was charged with Cs2CO3 ( 391 mg, 1.20 mmol), PdCl2(PPh3)2 (30 mg, 0.04 mmol), (S'//?)-6-bromo-2-((Λ/5)-tetrahydro-2//-pyran-3- yl)chroman-4-one (185.7 mg, 0.60 mmol), 3.5-difluorophenylboronic acid (142 mg, 0.90 mmol), dioxane (3 mL) and H2O (0.3 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 10OC for 8 min. Another tube charged with the same amount of reagents and starting material was repeated the same reaction at the same temperature and reaction time. Combined the reaction mixture and evaporated. The residue was dissolved in MeOH and filtered. The filtrate was evaporated and purified by flash chromatography on silica gel and eluted with EA in hexane (0-40%) to give (S/R)-6- (3,5-difluorophenyl)-2-((/?/S)-tetrahydro-2//-pyran-3-yl)chroman-4-one (281 mg). 1H NMR (400 MHz, CDCl3) δ: 8.07 (s, IH), 7.68 (dd, J= 8.4, 2.0, IH), 7.09-7.06 (m, 3H), 6.77 (m, IH), 4.38 (m, IH), 3.97-3.90 (m, 2H), 3.52-3.43 (m, 2H), 2.84-2.65 (m, 2H), 2.05 (m, 2H), 1.73-1.61 (m, 4H); 19F NMR (375 Hz, CDCl3) δ: -109.82: MS ESI +ve m/z 345 (M+H)+. Step 2: preparation ofN-((S/R)-6-(3,5-diβuorophenyl)-2-((R/S)-tetrahydro-2H-pyran-3- yl)chroman-4-ylidene)cyanamide
To a solution of (5//?)-6-(3,5-difluorophenyl)-2-((/?/S)-tetrahydro-2H-pyran-3- yl)chroman-4-one (273 mg, 0.82 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 2.1 mL, 2.1 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.336 g, 0.40 mL, 3.34 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (35 g), and stirred for 10 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-((S/R)-6-(3,5- difluorophenyl)-2-((i?/S)-tetrahydro-2/f-pyran-3-yl)chroman-4-ylidene)cyanamide as light brown solid (100% yield), which was used for next step without further purification. MS ESI +ve m/z 369 (M+H)+. Step 3: Preparation of(2S/2R)-6-(3,5-difluorophenyl)-2'-methyl-2-((R/S)-tetrahydro-2H- pyran-3-yl)-2 'H-spiro[chroman-4, 5 '-[1, 2, 4]oxadiazol]-3 '-amine
To a solution of iV-methylhydroxylamine hydrochloride (71 mg, 0.85 mmol) in MeOH (4 mL) was added 25wt% NaOMe in MeOH (0.17 mL, 0.75 mmol). The resulting mixture was stirred 5 min and then transferred through a syringe to a suspension of above crude product in MeOH (8 mL). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to gave compound 323 (25,4S'/2Λ,4i?)-6-(3,5-difluorophenyl)-2'-methyl-2-((i?/5)- tetrahydro-2//-pyran-3 -yl)-2'H-spiro [chroman-4.5 '- [ 1 ,2.4] oxadiazol] -3 '-amine and compound 316 (25',4Λ/2/?,45)-6-(3;5-difluorophenyl)-2'-methyl-2-((i?/5)-tetrahydro-2H- pyran-3-yl)-27/-spiro[chroman-4,5'-[l,2,4]oxadiazol]-3'-amine. Compound 323: 1H NMR (400 MHz, CD3OD) δ: 7.93 (d, J= 2.4 Hz, IH)5 7.67 (td,
J= 8.8, 2.4 Hz, IH), 7.26-7.22 (m, 2H), 7.01 (d, J = 8.8 Hz, IH), 6.90 (m, IH), 4.24 (m, IH), 3.958 (m, IH), 3.86 (m, IH), 3.53-3.46 (m, 2H), 3.44 (s, 3H), 2.57 (dd, J= 14.0, 2.4 Hz, IH), 2.41 (dd, J= 14.0, 10.8 Hz, IH), 2.04-2.02 (m, 2H), 1.74-1.63 (m, 3H); 19F NMR (375 Hz, CD3OD) δ: -1 11.92; MS ESI +ve m/z 416 (M+H)+. Compound 316: 1H NMR (400 MHz, CD3OD) δ: 7.93 (d, J= 2.4 Hz, IH), 7.70
(dd, J= 8.4, 2.0 Hz, IH), 7.26-7.24 (m, 2H), 7.01 (d, J= 8.4 Hz, IH), 6.91 (m, IH), 4.24 (m, IH), 3.97 (m, IH), 3.89 (m, IH), 3.57-3.43 (m, 2H), 3.37 (s, 3H), 2.65 (dd, J= 14.4, 2.4 Hz, IH), 2.08-1.95 (m, 3H), 1.73-1.64 (m, 3H); 19F NMR (375 Hz, CD3OD) δ: - 111.95; MS ESI +ve m/z 416 (M+H)+.
Example 145 Preparation of 3-(3'-amino-2'-methyl-2-((tetrahydrofuran-2-yl)methyl)-2'H-spiro[chroman- 4,5'-[l,2,4]oxadiazole]-6-yl)benzonitrile (compounds 360, 366 and 367)
CO2Et Suzuki
Figure imgf000451_0001
MeNHOH HCI
NaOMe, MeOH
Figure imgf000451_0002
Figure imgf000451_0003
Step 1 : Preparation of 2-(tetrahydrofuran-2-yl)ethanol
To a solution of ethyl 2-(tetrahydrofuran-2-yl)acetate (3.051 g, 19.29 mmol) in anhydrous THF (50 mL) chilled to 0°C was added 1 M LAH/THF solution (14.5 mL, 14.5 mmol) dropwise. The resulting mixture was stirred for another 30 min after the addition. Na2SO4 •10 H2O (18 g) was added slowly to quench the reaction at 00C. The reaction mixture was stirred for another 1 h at room temperature and filtered through a short pad of Celite and washed with THF. The filtrate was dried over anhydrous Na2SO4, and filtered, and concentrated to give 1.85 g of 2-(tetrahydrofuran-2-yl)ethanol, which was used for next step without further purification. Step 2: Preparation of 2-(tetrahydrofuran-2-yl)acetaldehyde To a solution of oxalyl chloride (3.666 g, 2.52 mL, 28.88 mmol) in anhydrous DCM (60 mL) at -78°C was added a solution of DMSO (3.761 g, 3.42 mL, 48.14 mmol) in anhydrous DCM (10 mL) through a pressure equalizing addition funnel in such a rate maintaining reaction temperature below -72°C. The reaction was stirred another 30 min after the addition. Then, a solution of 2-(tetrahydrofuran-2-yl)ethanol (2.792 g, 24.07 mmol) in DCM (30 mL) was added in such a rate maintaining the reaction temperature below -70°C. The reaction was stirred another 30 min after the addition, then TEA (12.167 g. 16.76 mL, 120.35 mmol) is added at -78°C. The reaction temperature was allowed to warm to room temperature slowly without removing dry ice-acetone bath and stirred overnight. The reaction mixture was washed with H2O (100 mL), 1 M HCl (2 x 150 mL), H2O (100 mL). brine (100 mL) successively, then, dried over anhydrous Na2SO4, and filtered, and concentrated to give 2.1 g of 2-(tetrahydrofuran-2-yl)acetaldehyde. It was used for next step without further purification. Step 3: Preparation of 6-bromo-2-((tetrahydrofuran-2-yl)methyl)chroman:4-one The solution of 2-Acetyl-4-bromophenol (1.754 g, 8.16 mmol), 2-(tetrahydrofuran-2- yl)acetaldehyde (2.1 g) and purrolidine (0.4 mL) in MeOH was heated to reflux for 2 h. The reaction mixture was cool down to room temperature and evaporated. The residue was dissolved in EA; washed with 1 M HCL 1 M NaOH (2 x 50 mL), brine (100 mL) successively, then, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0- 20%) to give 6-bromo-2-((tetrahydrofuran-2-yl)methyl)chroman-4-one (464 mg). ; MS ESI +ve m/z 311 (M+H)+. Step 4: Preparation of 3-(4-oxo-2-((tetrahydrofuran-2-yl)methyl)chroman-6- yl)benzonitrile
To a 10 mL CEM microwave test tube was charged with Cs2CO3 (971 mg, 2.98 mmol), PdCl2(PPh3)2 (52.2 mg, 0.075 mmol), (S/R)-6-bτomo-2-((R/S)-tetrahydxo-2H- pyran-3-yl)chroman-4-one (464 mg, 1.49 mmol), 3-cyanophenylboronic acid (329 mg, 2.24 mmol), dioxane (4 mL) and H2O (0.4 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 100°C for 10 min. Due to incompletion of the reaction, PdCl2(PPh3)? (10 mg) and 3-cyanophenylboronic acid (100 mg) was added and heated for another 10 min at 100°C. The reaction mixture was diluted with EA, washed with brine, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 3-(4-oxo-2-((tetrahydrofuran-2-yl)methyl)chroman-6-yl)benzonitrile (233 mg). MS ESI +ve m/z 334 (M+H)+.
Step 5: Preparation of Λf-(6-(3-cyanophenyl)-2-((tetrahydrofuran-2-yl)methyl)chroman-4- ylidene)cyanamide To a solution of 3-(4-oxo-2-((tetrahydrofuran-2-yl)methyl)chroman-6- yl)benzonitrile (233 mg, 0.70 mmol) in anhydrous DCM (18 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.287 g, 0.35 mL, 1.54 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (25 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(6-(3- cyanophenyl)-2-((tetrahydrofuran-2-yl)methyl)chroman-4-ylidene)cyanamide as light brown solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+. Step 6 : Preparation of 3 -(3 '-amino-2'-methyl-2-((tetrahydrofuran-2-yl)methyl)-2'H- spiro[chroman-4,5'-[l,2,4]oxadiazole]-6-yl)benzonitrile
To a solution of iV-methylhydroxylamine hydrochloride (58.5 mg, 0.70 mmol) in MeOH (4 mL) was added 25wt% NaOMe in MeOH (0.14 mL, 0.63 mmol). The resulting mixture was stirred 5 min and then transferred through a syringe to a suspension of above crude product MeOH (4 mL). The mixture was stirred at room temperature for 10 min. Solvent was removed under reduced pressure. The residue was purified by preparative PΗLC to gave 3 isomers of 3-(3'-amino-2'-methyl-2-((tetrahydrofuran-2-yl)methyl)-2'//- spiro[chroman-4,5'-[l,2,4]oxadiazole]-6-yl)benzonitrile as TFA salt. Compound 360: 1H NMR (400 MHz, CD3OD) δ: 7.99-7.96 (m, 2H), 7.92 (d, J= 8.0 Hz, IH), 7.71-7.68 (m, 2H), 7.61 (t, J= 8.0 Hz, IH), 7.03 (d, J= 8.0 Hz, IH), 4.51 (m, IH), 4.21 (m, IH), 3.87 (m, IH), 3.77 (m, IH), 3.43 (s, 3H), 2.66 (dd, J= 14.0, 2.4 Hz, IH), 2.36 (dd, J= 14.0, 2.8 Hz, IH), 2.15-1.81 (m, 5 H), 1.58 (m, IH); MS ESI +ve m/z 405 (M+H)+. Compound 367: 1H NMR (400 MHz, CD3OD) δ: 8.00-7.91 (m, 3H), 7.79-7.68 (m, 2H), 7.62 (t, J= 8.0 Hz, IH), 7.03 (t, J= 8.0 Hz, IH), 4.49 (m, IH), 4.23/4.1 1 (m, IH), 3.88 (m, IH), 3.76 (m, IH), 3.43/3.38 (s, 3H), 2.78-2.39 (m, 2H), 2.16-1.62 (m, 5 H), 1.61 (m, IH); MS ESI +ve m/z 405 (M+H)\
Compound 366: (most polar, major): 1K NMR (400 MHz, CD3OD) δ: 7.99-7.91 (m, 3H), 7.72-7.67 (m, 2H), 7.61 (t, J= 8.0 Hz, IH), 7.03 (d, J= 8.0 Hz, IH), 4.45 (m, IH), 4.23/4.15 (m, IH), 3.89 (m, IH), 3.77 (m, IH), 3.38 (s, 3H), 2.76 (d, J= 10.4 Hz, IH), 2.17-1.83 (m, 6 H), 1.528 (m, IH); MS ESI +ve m/z 405 (M+H)+.
Example 146 Preparation of 3-(2''H-3''-amino-2''-methyl-spiro(spiro(chroman-2,3'-[2,4.5.6-tetrahydro-6- methyl-pyran])-4,5"-[1.2.4]oxadiazole)-6-yl)benzonitrile (compound 387)
Figure imgf000454_0001
Step 1: Preparation ofN-((2S,6'R/2R,6'S)-6-(3-cyanophenyl)-6'-methyl-2',4',5',6'- tetrahydrospiro[chroman-2, 3 '-pyran]-4-ylidene)cyanamide To a solution of 3-((2S,6'R//2R,6'S)-6I-methyl-4-oxo-2',4l,5',6'- tetrahydrospiro[chroman-2,3'-pyran]-6-yl)benzonitrile (37.4 mg, 0.11 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.22 mL, 0.22 mmol) dropwise within 5 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.45 mg, 0.054 mL, 0.24 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (5 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. and filtered, and concentrated to give ΛH(2S,6'R/2R,6'S)-6-(3-cyanophenyl)-6'-methyl- 2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-ylidene)cyanamide as light brown solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+. Step 2: Preparation of 3 -(3 "-amino-2 "-methyl-4 " 5 "-dihydro-2 "H-spiro(spiro(chroman- 2, 3 '-[(2S, 6R/2R, 6SJ-2, 4, 5, 6-tetrahydror6-methyl-pyranJ)-4, 5 "-[1, 2, 4]oxadiazole)-6- yl)benzonitrile To a solution of iV-methylhydroxylamine hydrochloride (623 mg, 7.46 mmol) in
MeOH (10 mL) was added 25wt% NaOMe in MeOH (1.54 mL, 6.71 mmol). The resulting mixture was stirred 5 min and then diluted with MeOH to total volume 20 mL. 0.295 mL of this solution was added to a suspension of above crude product MeOH (3 mL). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to gave 3-(3"-amino-2"-methyl- 4",5"-dihydro-2"H-spiro(spiro(chroman-2,3'-[(251,6i?/2i?,65)-2,455,6-tetrahydro-6-methyl- pyran])-4,5"-[l,2;4]oxadiazole)-6-yl)benzonitrile as TFA salt. 1H NMR (400 MHz, CD3OD) δ: 1H NMR (400 MHz, CD3OD) δ: 7.88 (s: IH), 7.84 (d, J =8.0 Hz, IH), 7.79 (dd,. J= 7.6, 2.4 Hz, IH), 7.68-7.56 (m, 3H)S 7.10 (m,, IH), 4.20 (dd, J= 12.8, 2.0 Hz, 0.5H), 3.91 (dd, J= 12.4, 2.4 Hz, 0.5H), 3.59-3.41 (m, 2H), 3.53 (s, 1.5H), 3.34 (s, 1.5H), 2.80-1.48 (m, 6H), 1.23 (d, J = 6.4 Hz, 1.5H), 1.21 (d, J= 6.4 Hz, 1.5H); MS ESI +ve m/z 405 (M+H)+.
Example 147
Preparation of 3-(3"-amino-2"-methyl-4",5"-dihydro-2"H-spiro(spiro(chroman-2,3'- [(2R,6R/2S,6S)-2;4,5,6-tetrahydro-6-methyl-pyran])-(4R/4S)-4,5"-[l,2,4]oxadiazole)-6- yl)benzonitrile (compound 272) and 3-(3"-amino-2"-methyl-4",5"-dihydro-2"H- spiro(spiro(chroman-2,3'-[(2R,6R/2S,6S)-2,4,5,6-tetrahydro-6-methyl-pyran])-(4S/4S)-
4,5"-[l,2,4]oxadiazole)-6-yl)benzonitrile (compound 275)
Figure imgf000455_0001
Step 1: Preparation ofN-((2R,6'R/2S,6'S)-6-(3-cyanophenyl)-6'-methyl-2',4',5',6'- tetrahydrospirofchroman-2, 3 '-pyran]-4-ylidene)cyanamide
To a solution of 3-((2/?,6'i?//2S,6'5)-6'-methyl-4-oxo-2t,4',5',6'- tetrahydrospiro[chroman-2,3'-pyran]-6-yl)benzonitrile (37.4 mg, 0.11 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.22 mL, 0.22 mmol) dropwise within 5 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.45 mg. 0.054 mL, 0.24 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (5 g). and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. and filtered, and concentrated to give N-((2R,6'R/2S.6'S)-6-(3-cyanophenyl)-6'-methyl- 2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-ylidene)cyanamide as light brown solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+. Step 2: Preparation of3-(3"-amino-2"-methyl-4",5"-dihydro-2"H-spiro(spiro(chroman- 2, 3 '-[(2R, 6R/2S, 6SJ-2, 4, 5, 6-tetrahydro-6-methyl-pyran])-(4R/4S)-4, 5 "-[J, 2, 4]oxadiazole)- 6-yl)benzonitrile and 3 -(3 "-amino-2 "-methyl-4 ", 5 "-dihydro-2 "H-spiro(spiro(chroman- 2, 3 '-[(2R, 6R/2S, 6S)-2, 4, 5, 6-tetrahydro-6-methyl-pyran])-(4S/4S)-4, 5"-[J, 2, 4]oxadiazole)- 6-yl)benzonitrile
To a solution of N-methylhydroxylamine hydrochloride (623 mg, 7.46 mmol) in MeOH (10 mL) was added 25wt% NaOMe in MeOH (1.54 mL, 6.71 mmol). The resulting mixture was stirred 5 min and then diluted with MeOH to total volume 20 mL. 0.295 mL of this solution was added to a suspension of above crude product MeOH (3 mL). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to gave 3-(3"-amino-2"-methyl- 4",5"-dihydro-2"H-spiro(spiro(chroman-2,3'-[(2Λ,6i?/25',65)-2,4,5,6-tetrahydro-6-methyl- pyran])-(4i?/45)-4;5"-[l,2,4]oxadiazole)-6-yl)benzonitrile and 3-(3"-amino-2"-methyl- 4";5"-dihydro-2"H-spiro(spiro(chroman-2,3'-[(2Λ,6i?/25,65)-2,4;5J6-tetrahydro-6-methyl- pyran])-(45'/45)-4,5"-[L2;4]oxadiazole)-6-yl)benzonitrile as TFA salt. Compound 272: 1H NMR (400 MHz, CD3OD) δ: 8.01-7.91 (m, 3H), 7.74-7.68 (m, 2H), 7.62 (t, J= 8.0 Hz, IH), 7.02 (d, J= 8.4 Hz, IH), 3.81 (dd, J= 10.8, 2.8 Hz, IH), 3.62- 3.58 (m, 2H), 3.40 (s, 3H), 2.50 (ms IH), 2.10 (dd, J=UA, 1.6 Hz, IH), 1.76 (m, IH), 1.65 (m, IH), 1.46 (m, IH), 1.22 (d, J= 6.0 Hz, 3H); MS ESI +ve m/z 405 (M+H)+. Compound 275: 1H NMR (400 MHz, CD3OD) δ: 7.99 (d, J= 1.2 Hz, IH), 7.96-7.91 (m, 2H), 7.74-7.68 (m, 2H), 7.61 (m, IH), 7.01 (d, J= 8.8 Hz, IH), 4.20 (d, J= 1 1.2 Hz, IH), 3.59 (m, IH), 3.39 (s, 3H), 3.5 (m, IH), 2.06-2.00 (m, 3H), 1.83 (m, IH), 1.60-1.41 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H); MS ESI +ve m/z 405 (M+H)+.
Example 148
Preparation of 3-(spiro[spiro(chroman-2,4'-(l -acetylpiperidine))-4,5'-(3-amino-2-methyl- 2//-[L2,4]oxadiazole)]-6-yl)benzonitrile (Compound 409)
Figure imgf000457_0001
Step 1: Preparation of3-(r-acetyl-4-oxospiro[chroman-2!4'-piperidine]-6-yl)ben∑onitrile To a solution of 3'-acetyl-4'-hydroxybiphenyl-3-carbonitrile (0.802 g, 3.38 mmol) and 1 -acetylpiperidin-4-one (0.477 g, 3.38 mmol) in MeOH (50 mL) was added pyrrolidine (0.4 mL). The resulting solution was heated to reflux for 1.5 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with aqeous 1 M HCl, aqueous 1 M NaOH. and brine successively. Solvent was removed under reduced pressure after dried over anhydrous Na2SO4, to yield 0.768 g of 3-(r-acetyl-4-oxospiro[chroman-2.4'- piperidine]-6-yl)benzonitrile as a light brown solid. It was used for next step without further purification. MS ESI +ve m/z 361 (M+H)+.
Step 2: Preparation ofN-(l'-acetyl-6-(3-cyanophenyl)spiro[chroman-2,4'-piperidine]-4- ylidene)cyanamide To a solution of 3-(l '-acetyl-4-oxospiro[chroman-2,4'-piperidine]-6-yl)benzonitrile
(60 mg, 0.167 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.35 mL, 0.35 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.086 mL, 0.367 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (5 g), and stirred for 20 min. then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(l'-acetyl-6-(3- cyanophenyl)spiro[chroman-2,4'-piperidine]-4-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI +ve m/z 385 (M+H)τ. Step 3: Preparation of3-(spiro[spiro(chroman-2,4'-(l-acetylpiperidine))-4,5'-(3-amino-2- methyl-2H-[l, 2, 4] oxadiazole)] -6-yl)benzonitrile
To a suspension of above crude product was added a solution of N- methylhydroxylamine in MeOH (0.373 M, 0.45 mL, prepared from N- methylhydroxylamine HCl salt and 0.9 eq 25wt% ΝaOMe/MeOH in MeOH). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to yield the desired product. 1H ΝMR (400 MHz, CD3OD) δ: 8.00 (s, 2H), 7.94 (m, IH), 7.77-7.60 (m, 3H), 7.11 (dd, J= 8.8, 2.4 Hz, IH), 4.29 (m, IH), 3.86-3.40 (m, 2H), 3.38 (s, 3H), 2.98 (m, IH), 2.82 (d, J= 14.8, IH), 2.22 (d, J= 14.8, IH), 2.14 (s, 3H), 2.17-1.64 (m, 4H); MS ESI +ve m/z 432 (M+H)+.
Example 149 Preparation of compounds 302 and 311
Figure imgf000458_0001
Step 1: Preparation of compound (1)
To a 3 '-acetyl -4'-hydroxybiphenyl-3-carbonitrile (0.273 g, 1.15 mmol) and 2- methoxy-8,9-dihydro-5H-benzo[7]annulen-6(7H)-one (0.219 g, 1.15 mmol) in MeOH (5 mL) was added pyrrolidine (0.12 mL). The resulting solution was heated to reflux for 4 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to yield 310 mg of compound (1).. MS ESI +ve m/z 410 (M+H)÷. Step 2: preparation of compound (2)
To a solution of compound (1) (55 mg, 0.13 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.26 mL, 0.26 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.080 mL. 0.34 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (5 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 65 mg desired crude compound (2) as light brown solid which was used for next step without further purification. MS ESI +ve m/z 434 (M+H)+. Step 3: Preparation of compounds 302 and 311
To s suspension of the crude product obtained from previous step in MeOH (3 mL) was added a solution of jV-methylhydroxylamine in MeOH (0.373 M, 0.35 mL, prepared from N-methylhydroxylamine HCl salt and 0.9 eq 25 wt% NaOMe/MeOH in MeOH). The mixture was stirred at room temperature for 20 min, followed by adding another portion of iV-methylhydroxylamine in MeOH (0.373 M, 2 mL). Solvent was removed under reduced pressure after stirred another 20 min. The residue was purified by preparative PHLC to yield two isomers of the desired product as TFA salt. Compound 302: 1H NMR (400 MHz, CD3OD) δ: 8.00-7.85 (m, 3H), 7.73-7.59 (m, 3H), 7.07 (d, J= 8.4 Hz, IH), 7.01 (d, J= 8.8 Hz, IH), 7.74-7.69 (m, 2H), 3.78(m, 3H), 3.34(m, 3H), 2.99-1.55 (m, 10H); MS ESI +ve m/z 481 (M+H)+.
Compound 311 : 1H NMR (400 MHz,. CD3OD) δ: 8.02-7.94 (m, 3H), 7.73-7.60 (m, 3H)S 6.90 (d, J= 8.8 Hz, IH), 6.86 (d, J= 8.0 Hz, IH), 6.70 (d, J= 2.8 Hz, IH), 6.62 (dd, J = 8.4, 2.4 Hz, IH), 3.75(m, 3H), 3.37(m, 3H), 3.08-1.63 (m, 10H): MS ESI +ve m/z 481 (M+H)+.
Example 150 Preparation of 2"-methyl-6-(phenylethynyl)-2"//-spiro[spiro[chroman-2, 1 '-(3- oxacyclohexane)]-4,5'-[l,2,4]oxadiazol]-3"-amine (compound 454) CuI heat
Figure imgf000460_0002
Figure imgf000460_0001
MeNHOH HCl
NaOMe. MeOH
Figure imgf000460_0003
Step 1: Preparation of6-(phenylethynyl)-2',4',5', 6'-tetrahydrospiro[chroman-2,3'-pyran]- 4-one An oven dried 3-necked round bottom flask equipped with condenser was charged with 6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4-one (223 mg, 0.75 mmol), TEA (3 mL) and DEA (0.8 mL) under N2 atmosphere. To this solution was added CuI (5.7 mg, 0.03 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol) and PPh3 (16 mg, 0.06 mmol). The system was degas once again, then phenylacetylene (0.41 mL, 3.75 mmol) was added and the mixture was heated to 800C (oil bath) with stirring. The reaction was evaporated after 12 h and the residue was purified by flash chromatography (12 g silica gel, eluted with EA in hexane in a gradient of 0-25%, v/v) to afford 6-(phenylethynyl)-2',4',5',6'- tetrahydrospiro[chroman-2.3'-pyran]-4-one (216 mg, yield: 90%). MS ESI +ve m/z 319 (M+H)+. Step 2: Preparation ofN-(6-(phenylethynyl)-2 \4',5 ', 6'-tetrahydrospiro[chroman-2, 3 '- pyran]-4-ylidene)cyanam ide
To a solution of 6-(phenylethynyl)-2',4'.5'.6'-tetrahydrospiro[chroman-2.3'-pyran]- 4-one (86 mg, 0.27 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM. 0.54 mL, 0.54 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.16 mL, 0.427 mmol) dropwise. The resulting mixture was stirred 80 h. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 112 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 343 (M+H)+.
Step 3: Preparation of2"-methyl-6-(phenylethynyl)-2"H-spiro[spiro[chroman-2,r-(3- oxacyclohexane)] -4, 5 '-[1, 2, 4]oxadia∑ol]-3 "-amine
To s suspension of the crude product (34 mg, 0.10 mmol) obtained from previous step in MeOH (2 mL) was added a solution of iV-methylhydroxylamine in MeOH (prepared from N-methylhydroxylamine HCl salt (8.4 mg, 0.10 mmol) inanhydrous MeOH (4 mL) and 25wt% NaOMe/MeOH (21 μL, 0.09 mmol), stirred 5 min). The mixture was stirred at room temperature for 20 min. Due to low conversion, another portion of N- methylhydroxylamine (prepared in the same way, 3 fold scale) was added and stirred over night. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to yield 8.2 mg of the title compound as TFA salt. 1H NMR (400 MHz, CD3OD) δ: 7.81 (d, J= 6.8 Hz, IH), 7.55-7.47 (m, 4H), 7.40-7.33 (m, 4H), 6.98 (d, J = 8.8 Hz, IH), 3.88-3.73 (m, 2H), 3.65-3.55 (m, 2H), 3.37 (s, 3H), 2.84 (d, J= 14.8 Hz, IH), 2.12-1.55 (m, 5H); MS ESI +ve m/z 390 (M+H)+.
Example 151
Preparation of 2"-methyl-6-(cyclopropylethynyl)-2"//-spiro[spiro[chroman-2, 1 '-(3- oxacyclohexane)]-4,5'-[l,2.4]oxadiazol]-3"-amine (compound 407) cyclopropylacetylene PdCl2(PPh3),. CuI TMSNCNTMS TEA. Et2NH. N2. heat TiCl4. DCM
Figure imgf000461_0001
Figure imgf000461_0002
Figure imgf000461_0003
Figure imgf000461_0004
Step 1: Preparation of6-(cyclopropylethynyl)-2',4',5',6'-tetrahydrospiro[chroman-2,3'- pyranJ-4-one
An oven dried 3 -necked round bottom flask equipped with condenser was charged with 6-bromo-2'.4'.5'.6'-tetrahydrospiro[chroman-2.3'-pyran]-4-one (223 mg. 0.75 mmol). TEA (3 mL) and DEA (0.8 mL) under N2 atmosphere. To this solution was added CuI (5.7 mg, 0.03 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol) and PPh3 (16 mg, 0.06 mmol). The system was degas once again, then cyclopropyl acetylene (0.6 mL, excess) was added and the mixture was heated to 52°C (oil bath) with stirring. The reaction was evaporated after 12 h and the residue was purified by flash chromatography (12 g silica gel, eluted with EA in hexane in a gradient of 0-20%, v/v) to afford 6-(cyclopropylethynyl)-2',4',5',6'- tetrahydrospiro[chroman-2,3'-pyran]-4-one (202 mg, yield: 93%). MS ESI +ve m/z 283 (M+H)+.
Step 2: Preparation of(6-(cyclopropylethynyl)-2',4',5',6'-tetrahydrospiro[chroman-2,3'- pyran] -4-ylidene)cyanamide
To a solution of 6-(cyclopropylethynyl)-2',4',5',6'-tetrahydrospiro[chroman-2,3'- pyran]-4-one (76 mg, 0.27 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.54 mL, 0.54 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.16 mL. 0.427 mmol) dropwise. The resulting mixture was stirred 80 h. The reaction mixture was quenched with ice- water (15 g), and stirred for 30 min. then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 106 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 307 (M+H)x.
Step 3: 2"-methyl-6-(cyclopropylethynyl)-2"H-spiro[spiro[chroman-2J '-(3- oxacyclohexane)]-4, 5 '-[1, 2, 4]oxadiazol]-3 "-amine To s suspension of the crude product obtained from previous step in MeOH (5 mL) was added a solution of iV-methylhydroxylamme in MeOH (prepared from N- methylhydroxyl amine HCl salt (36 mg, 0.43 mmol) inanhydrous MeOH (4 mL) and 25wt% NaOMe/MeOH (88 μL, 0.39 mmol), stirred 5 min). The mixture was stirred at room temperature for 12 h. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to yield 16 mg of the title compound as TFA salt. 1H NMR (400 MHz, CD3OD) δ: 7.58 (s, IH), 7.34 (d, J = 8.4 Hz, IH), 6.87 (d, J= 8.4 Hz, IH), 3.84-3.70 (m, 2H), 3.63-3.54 (m, 2H), 3.35 (s, 3H), 2.79 (d, J= 14.8 Hz, IH), 2.09-1.78 (m, 4H), 1.64 (m, IH), 1.52 (m, IH), 1.42 (m, IH), 0.85 (m, 2H), 0.71 (m, 2H); MS ESI +ve m/z 354 (M+H)+.
Example 152
Preparation of 3-(3"-amino-2",7-dimethyl-2"H-spiro[spiro[chroman-2,l '-(3- oxacyclohexane)]-4,5'-[l ,2,4]oxadiazole]-6-yl)benzonitrile (compound 432)
Figure imgf000463_0001
MeNHOH HCl
NaOMe, MeOH
Figure imgf000463_0002
Figure imgf000463_0003
Step 1: Preparation of6-bromo-7-methyl-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]- 4-one
A solution of 2-Acetyl-4-bromophenol (920 mg, 4.02 mmol), dihydro-2H-pyran- 3(4H)-one (402 mg, 4.02 mmol) and pyrrolidine (0.5 mL) in MeOH (10 mL) was heated to reflux for 2 h. The reaction mixture was cooled down to room temperature and evaporated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 6-bromo-7-methyl-2',4',5',6'-tetrahydrospiro[chroman-2,3'- pyran]-4-one (593 mg). ; MS ESI +ve m/z 311 (M+H)+.
Step 2: Preparation of3-(7-methyl-4-oxo-2',4',5',6'-tetrahydrospiro[chroman-2.3'-pyran]- 6-yl)ben∑onitrile To a 10 mL CEM microwave test tube was charged with Cs2CO3 (147 mg. 0.45 mmol), PdCl2(PPh3)2 (8 mg, 0.01 1 mmol), 6-bromo-7-methyl-2';4l,5',61- tetrahydrospiro[chroman-2,3'-pyran]-4-one (70 mg, 0.225 mmol), 3-cyanophenylboronic acid (43 mg. 0.293 mmol), dioxane (4 mL) and H2O (0.2 mL). the system was swept with N2 and sealed, and heated in a CEM microwave reactor at 1000C for 10 min. The reaction mixture was filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 3-(7-methyl-4-oxo-2'.4'.5'.6'- tetrahydrospiro[chroman-2,3'-pyran]-6-yl)benzonitrile (72 mg). MS ESI +ve m/z 334 (M+H)+.
Step 3: Preparation of(6-(3-cyanophenyl)-7-methyl-2',4',5',6'-tetrahydrospiro[chroman- 2,3 '-pyran] -4-ylidene)cyanamide
To a solution of 3-(7-methyl-4-oxo-2',4I,5',6'-tetrahydrospiro[chroman-2,3'-pyran]- 6-yl)benzonitrile (72 mg, 0.22 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCU (in DCM, 0.44 mL, 0.44 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis- trimethylsilylcarbodiimide (0.114 mL, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (10 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 3 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 104 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+.
Step 4: Preparation of 3 -(3 "-amino- 2 ", 7-dimethyl-2"H-spiro[spiro[chroman-2,l '-(3- oxacyclohexane)]-4, 5 '-[1.2, 4]oxadiazole]-6-yl)benzonitrile
To s suspension of the crude product obtained from previous step in EtOH (3 mL) was added a solution of N-methylhydroxylamine in EtOH (0.6 mL, 0.22 mmol); prepared from jV-methylhydroxylamine HCl salt (184 mg, 2.20 mmol) inanhydrous EtOH (5 mL) and 21wt% NaOEt/EtOH (0.74 mL, 1.98 mmol), stirred 5 min and dilute with EtOH to total volume 6 mL). The mixture was stirred at room temperature for 20 min. Solvent was removed under reduced pressure. The residue was purified by preparative PHLC to yield 39 mg of desired compound as TFA salt. 1H NMR (400 MHz, CD3OD) δ: 7.74-7.58 (m, 4H), 7.45 (d, J= 6.4 Hz, IH), 6.92 (s, IH), 3.90-3.56 (m, 4H), 3.33 (s, 3H); 2.88 (m, 2H), 2.22 (s, 3H), 2.15-1.54 (m, 4H): MS ESI +ve m/z 405 (M+H)".
Example 153 Preparation of 3-(spiro[spiro[chroman-2,4l-(l-acetylpiperidine)]-4,4l-(2-amino-l -methyl-
5-oxo-lH-imidazole)]-6-yl)benzonitrile (compound 460)
Figure imgf000465_0001
Step 1: Preparation of6-bromo-spiro[spiro[chroman-2,4'-(l-acetylpiperidine)]-4,4'-(2- thioxoimidazolidin)]-5"-one
The solution of 6-bromospiro[spiro[chroman-2,4'-(l-(tert- butoxycarbonyl)piperidine)]-4,4'-imidazolidine]-2",5"-dione (127.7 mg, 0.274 mmol) and Lawesson's reagent (110.7 mg. 0.274 mmol) in 1,4-dioxane (5 mL) in a 10 mL CEM microwave test tube was heated in a CEM microwave reactor at 150 °C for 40 min. To this reaction mixture was added acitic acid anhydride (0.05 mL) and pyridine (0.07 mL), followed by one piece of DMAP, then the reaction mixture was stirred at room temperature for 20 min. MeOH (2 mL) was added to quench the reaction and stirred another 30 min. K2CO3 (150 mg) was added and stirred another 30. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH again and filtered. The filtrate was purified by preparative HPLC to yield 33 mg of the desired product. MS ESI +ve m/z 424 (M+H)+.
Step 2: Preparation of6-bromo-spiro[spiro[chroman-2,4'-(l-acetylpiperidine)]-4,4'-(l- methyl-2-(methylthio)-imida∑ol)]-5"(l "H)-one
To a solution of 6-bromo-spiro[spiro[chroman-2.4'-(l-acetylpiperidine)]-4,4'-(2- thioxoimidazolidin)]-5"-one (34 mg, 0.08 mmol) in MeOH (5 mL) charged in a 10 mL CEM microwave test tube was added a 0.6 N NaOH aqueous solution (0.5 mL). After stirring at room temperature for 10 min. MeI (0.07 mL) was added, and the reaction mixture was heated in a CEM microwave reactor at 60 0C for 10 min. The resulting mixture was diluted with EA, and washed with H2O, and brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to produce the crude product. It was used for next step without further purification. MS ESI +ve m/z 452 (M+H)+.
Step 3: Preparation of6-bromo-spiro[spiro[chroman-2,4'-(l-acetylpiperidine)]-4,4'-(l- methyl-2 -amino -imidazol)} '-5"(J "H)-one
A suspension of above crude product and NH4I (150 mg, excess) in dioxane (1 mL)and 7 M NH3ZMeOH (3 mL) charged in a 10 mL CEM microwave test tube was heated to 1 10°C for 1 h. Due to incompletion of the reaction, the reaction was heated at 120°C for another 30 min. The solvent was removed in vacuum and the residue was purified by preparative HPLC to give 8 mg of the desired product as a TFA salt. MS ESI +ve m/z 421 (M+H)+.
Step 4: Preparation of 3-(spiro[spiro[chroman-2, 4 '-(1 -acetylpiperidine)]-4, 4 '-(2-amino-l- methyl-5-oxo-l H-imidazole)] -6-yl)benzonitrile
To a solution of above product TFA salt (8 mg, 0.14 mmol), 3-cyanophenylboronic acid (51 mg, 0.07 mmol) and Cs2CO3 (30 mg, 0.09 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (2 mg), then the system was degassed by sweeping N2. The tube was capped and heated to 100°C for 10 min in a CEM microwave reactor. Solvent was removed in vacuum and the residue was purified by preparative HPLC to give 5 mg of the desired product as a TFA salt. 1H NMR (400 MHz, CD3OD): 7.95 (s, IH)5 7.94 (s, IH), 7.87 (m, IH), 7.75-7.46 (m, 3H),
7.15 (d, J= 8.4 Hz, IH), 4.32 (m, IH), 3.82-3.48 (m, 2H), 3.32 (s, 3H), 3.26-3.05 (m, IH), 2.53 (d, J= 14.8 Hz, IH), 2.37 (d, J= 14.8 Hz, IH), 2.14 and 2.11 (s and s, 3H), 2.10-2.00 (m, 2H), 1.87-1.62 (m, 2H): MS ESI +ve m/z 444 (M+H)+.
Example 154
Preparation of compounds 188, 282 and 335
Figure imgf000467_0001
NH4I, NH3 H2O
MeOH
Figure imgf000467_0002
Step I: Preparation of 6-bromo-2-(l ,2,3,4-tetrahydronaphthalen-l -yl)-2'- thioxospiro[chroman-4, 4 '-imidazolidinJ-5 '-one
A solution of 6-bromo-2-( 1,2,3, 4-tetrahydronaphthalen-l-yl)-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one(67.4 mg, 0.158 mmol) and Lawsson's reagent (63.8 mg, 0.158 mmol) in dioxane (3 mL) charged in a 10 mL CEM microwave test tube was heated to 140°C in a CEM microwave reactor for 30 min. Solvent was removed under reduced pressure, and purified by flash chromatography on silica gel to yield 46 mg of the desired product as white solid. MS ESI +ve m/z 443 (M+H)+.
Step 2: preparation of 6-bromo-l '-methyl-2'-(methylthio)-2-(l,2,3,4- tetrahydronaphthalen-l-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one
To a solution of 6-bromo-2-(l,2,3,4-tetrahydronaphthalen-l-yl)-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one (46 mg, 0.10 mmol) in MeOH (3 mL) charged in a 10 mL CEM microwave test tube was added a 0.6 N NaOH aqueous solution (0.35 mL). After stirring at room temperature for 10 min, MeI (0.5 mL, excess) was added, and the reaction mixture was heated in a CEM microwave reactor at 600C for 10 min. The reaction mixtures was diluted with ethyl acetate, and washed with H2O, brine successively, and dried over anhydrous Na2SO4. and filtered, and concentrated to produce the desired crude product, which was used for next step without further purification. MS ESI +ve m/z 471 (M+H)+.
Step 3: Preparation of ' 2'-amino-6-bromo-l '-methyl- 2 -(1 ,2,3,4-tetrahydronaphthalen-l '- yl)spiro[chroman-4,4'-imida∑ol]-5'(l 'H)-one A suspension of above product and NH4I (100 mg, excess) in 7 M NH3MeOH (4 mL) and 1,4-dioxane (1.5 mL) charged in a 10 mL CEM microwave test tube was heated to HO0C for 1 h. Another portion OfNH4I (100 mg, excess) was added and heated to 1100C for another 1 h due to incompletion. The solvent was removed in vacuum and the residue was purified by preparative HPLC to yield the desired product as TFA salt. MS ESI +ve m/z 440 (M+H)+.
Step 4: Preparation of3-(2'-amino-l '-methyl-5'-oxo-2-(l,2,3,4-tetrahydronaphthalen-l- yl)-l ', 5 '-dihydrospiro[chroman-4, 4 '-imidazole] -6-yl)benzonitrile To a solution of 2-amino-6'-bromo- 1 -methyl-2'-phenylspiro[imidazole-4,4'- thiochroman]-5(l//)-one TFA salt (20 mg, 0.036 mmol), 3-cyanophenylboronic acid (7 mg, 0.047 mmol) and Cs2CO3 (30 mg, 0.092 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube was added PdCl2(PPh3 )2 (3 mg, 0.004 mmol), then the system was degassed by sweeping N2. The tube was capped and heated to 1100C for 10 min in a CEM microwave reactor. Solvent was removed in vacuum and the residue was purified by preparative HPLC to yield 4 isomers of the desired product as a TFA salt.
Compound 188: 1H NMR (400 MHz, CD3OD) δ: 7.96 (m, IH), 7.88 (m, IH), 7.68-7.52 (m, 4H), 7.28 (m, IH), 7.11 (m, 4H), 5.38 (m, IH), 3.31 (s, 3H), 3.03 (m, 2H), 2.78 (m, 2H), 2.24-1.68 (m, 5H); MS ESI +ve m/z 463 (M+H)+.
Compound 282: 1H NMR (400 MHz, CD3OD) δ: 7.95 (d, J= 1.6 Hz, IH), 7.87 (dd, J = 7.6, 1.2 Hz, IH), 7.67-7.56 (m, 3H), 7.48 (d, J= 2.4 Hz, IH), 7.30 (m, IH), 7.13-7.11 (ms 4H), 5.34, 5.20 (two m, IH), 3.41 (m, IH), 3.31 (s, 3H), 2.78 (m, 2H), 2.24 (m, IH), 2.14- 1.84 (m, 4H), 1.76 (m, IH); MS ESI +ve m/z 463 (M+H)+. Compound 335: 1H NMR (400 MHz, CD3OD) δ: 7.92 (d, J= 1.6 Hz, IH), 7.85 (dd J = 6.0, 1.6 Hz, IH), 7.67-7.64 (m, 2H), 7.58 (m, IH), 7.38 (d, J= 2.4 Hz, IH), 7.34 (m, IH), 7.12-7.11 (m, 4H), 3.31 (s, 3H), 2.79 (m, 2H), 2.35 (m, IH), 2.11 (m, 2H), 1.93 (m, 4H), 1.78 (m, IH); MS ESI +ve m/z 463 (M+H)+.
Example 155
Preparation of 3-(spiro[spiro[chroman-2;r-(3-oxacyclohexane)]-4,5'-(3-amino-2-methyl- 2,6-dihydro-[1.2,4]oxadiazine)]-6-yl)benzonitrile (compound 455)
Figure imgf000469_0001
Step 1: Preparation of4-amino-6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]- 4-carboxylic acid
To a solution of 6-bromo-spiro[spiro[chroman-2,r-(3-oxacyclohexane)]-4.4'- imidazolidine]-2",5"-dione (1.004 g, 2.74 mmol) in THF (30 niL) was added BoC2O (1.791 g. 8.21 mmol), followed by DMAP (100 mg). The mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel to yield 410 mg of 6-bromo- spiro[spiro[chroman-2,r-(3-oxacyclohexane)]-4.4'-(l,3-di-Boc-imidazolidine)]-2".5"- dione. The product was dissolved in 2 M KOH (4.4 mL). The solution was charged in a 10 mL CEM microwave test tube and heated to 150°C for 2 h. The reaction mixture was acidified with 6 M HCl to pH 2 and evaporated to dryness. The residue was filtered through a funnel and washed with MeOH. The filtrate was concentrated to yield 232 mg of the desired product. Step 2: Preparation of methyl 6-bromo-4-(tert-butoxycarbonylamino)-2',4',5',6'- tetrahydrospiro[chroman-2, 3 '-pyranJ-4-carboxylate
To a solution of 4-amino-6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]- 4-carboxylic acid (232 mg, 0.68 mmol) in MeOH (10 mL) chilled to O0C was added SOCl2 (0.5 mL), the mixture was heated to reflux for 12 h. Every other 8-16 h, the reaction was cooled to 0°C again and SOCl2 (1 mL) was added carefully, and then the mixture was heated to reflux. The reaction was monitored by LC-MS, 90% conversion was achieved after repeat 6-8 times. In a separated reaction repeat the same reaction with starting material (300 mg, 0.88 mmol) till greater than 90% conversion. The two reactions was combined and evaporated. The residue was dissolved in EA, washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over anhydrous Na2SO4, and filtered, and concentrated to dryness. The residue was dissolved in CH3CN (20 mL) containing Boc2O (1.203 g, 5.51 mmol) and NaHCO3 (1.159g, 13.8 mmol). The mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with EA, washed with H2O, the separated aqueous phase was extracted with EA once. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel to yield 314 mg of the desired product. MS ESI +ve m/z 478 (M+Naf.
Step 3: Preparation oftert-butyl 6-bromo-4-(hydroxymethyl)-2',4',5',6'- tetrahydrospiro[chroman-2, 3 '-pyran] -4-ylcarbamate
To a solution of 6-bromo-4-(/err-butoxycarbonylamino)-2',4',5',6'- tetrahydrospiro[chroman-2,3'-pyran]-4-carboxylate (314 mg, 0.69 mmol) in anhydrous THF (10 mL) at -78°C under N2 atmosphere was added 1 M LAH (in THF, 1.4 mL: 1.4 mmol) dropwise. The mixture was stirred for 30 min at this temperature and then warmed to room temperature and stirred overnight. The reaction mixture was cooled to 00C and quenched with Na2SO4-H2O carefully, then stirred several hours. The reaction was filtered through a short pad of Celite and washed with THF. The filtrate was evaporated to give 165 mg of the desired product as colorless oil. MS ESI +ve m/z 428 (M+H)+. Step 4: Preparation oftert-butyl 6-bromo-spiro[spiro[chroman-2, 1 '-(3-oxacyclohexane)]- 4, 4 '-(2, 2-dioxo[l, 2, 3] oxathiazolidine)] -3 "-carboxylate
To a solution Of SOCl2 (0.07 mL, 114.7 mg, 0.964 mmol) in anhydrous in CH3CN (2 mL) at -400C under N2 atmosphere was added a solution of fe/Y-butyl 6-bromo-4- (hydroxymethyl)-2',4',5'.6'-tetrahydrospiro[chroman-2.3'-pyran]-4-ylcarbamate (165 mg, 0.386 mmol) in anhydrous in CH3CN (15 mL, low solubility) dropwise, followed by pyridine (0.156 mL, 153 mg, 1.93 mmol). The reaction was allowed to warm to room temperature within 1 h, and stirred another 2 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in EA, and filtered. The filtrate was concentrated to dryness, the residue was dissolved in CH3CN (6 mL) and H2O (3 mL) and chilled to O0C. To the solution was added RuO2 (8 mg, 0.06 mmol) and NaIO4 (124 mg, 0.579 mmol). The mixture was stirred 30 min at this temperature and warm to room temperature and stirred another 2 h. RuCl3 (8 mg, 0.039 mmol) and NaIO4 (624 mg, 2.92 mmol) was added. The mixture was stirred another 1 h and diluted with EA, washed with brine. The organic layer was dried over anhydrous Na2SO4, and filtered, and concentrated to dryness to yield 146 mg of the desired product. MS ESI +ve m/z 512 (M+Na)+.
Step 5: Preparation of 3"-aUyl-6-bromo-spiro[spiro[chroman-2, 1 '-(3-oxacyclohexane)]- 4, 4 '-(2, 2-dioxo[l, 2, 3] oxathiazolidine)]
A solution of tert-butyl 6-bromo-spiro[spiro[chroman-2,r-(3-oxacyclohexane)]- 4,4'-(2,2-dioxo[l,2,3]oxathiazolidine)]-3"-carboxylate (146 mg, 0.37 mmol) in DCM (4 mL) and TFA (ImL) was stirred 3 h at room temperature. Solvents were removed under reduced pressure and the residue was dissolved in DCM (8 mL) at room temperature. To this solution was added allyl iodide (0.4 mL, large excess), Bu4NCl (16 mg, 0.058 mmol) and 40% NaOH (3 mL). The resulting mixture was stirred at room temperature for 16 h. The separated organic phase was washed with H2O, brine successively, and dried over anhydrous Na2SO4. and filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (4 g) to yield 73 mg of the desired product. MS ESI +ve m/z 294 (M+H-allyl-NSO3)".
Step 6: Preparation oftert-butyl (4-(allylamino)-6-bromo-2',4',5',6'- tetrahydrospiro[chroman-2,3'-pyran]-4-yl)methoxy(methyl)carbamate To a solution of tert-butyl hydroxy(methyl)carbamate (112 mg, 0.76 mmol, prepared according the procedure described in Org. Lett 2007, 9, 4009) in anhydrous DMF (2 mL) at room temperature under N2 atmosphere was added NaH (60%, 30 mg, 0.76 mmol). The mixture was stirred for 15 min, then a solution of 3"-allyl-6-bromo- spiro[spiro[chroman-2,r-(3-oxacyclohexane)]-4,4'-(2,2-dioxo[l,2,3]oxathiazolidine)] (73 mg, 0.17 mmol) in anhydrous DMF (1 mL) was added. The resulting mixture was stirred 16 h (color changed from light yellow to green, then to light orange in the end). The reaction was quenched with saturated aquesous NH4Cl and extracted with EA, the separated organic phase was washed with H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to dryness. The residue was used for next step without further purification. MS ESI +ve m/z 497 (M+H)+.
Step 7: Preparation oftert-butyl (4-amino-6-bromo-2',4',5',6'-tetrahydrospiro[chroman- 2, 3 '-pyran]-4-yl)methoxy(methyl)carbamate A solution of Pd2(dba)3 (7.6 mg, 0.038 mmol) and 1,4- bis(diphenylphosphino)butane (3.6 mg, 0.038 mmol) in THF (3 mL) under N2 atmosphere was stirred for 15 min. Then the solution was added to a solution of tert-butyl (4- (allylamino)-6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-4- yl)methoxy(methyl)carbamate produced in previous step in THF (3 mL), followed by thiosalicylic acid (14 mg, 0.91 mmol). The mixture was stirred for 16 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to recover 28 mg of starting material as TFA salt and 10 mg of the desired product as TFA salt. MS ESI +ve m/z 457 (M+H)+.
Step 8: Preparation of6-bromo-spiro[spiro[chroman-2, 1 '-(3-oxacyclohexane)]-4,5'-(2- methyl-2, 6-dihydro-fl, 2, 4]oxadiazin)]-3 "-amine
The solution of tert-butyl (4-amino-6-bromo-2'.4',5',6'-tetrahydrospiro[chroman- 2,3'-pyran]-4-yl)methoxy(rnethyl)carbamate in 4 M HCl/dioxane (2 mL) was stirred 1 h. Due to incompletion of the reaction 4 M HCl/dioxane (3 mL) was added and stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL). washed with 1 M NaOH (10 mL). The separated aqueous phase was extracted with DCM twice. The combined organic phases were combined and dried over anhydrous Na2SO4. and filtered, and concentrated to dryness. The residue was dissolved in EtOH (3 mL). To this solution was added a solution of cyanogen bromide (0.5 M in THF, 0.052 mL, 0.026 mmol). The resulting mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with 1 M NaOH. The separated aqueous phase was extracted with DCM twice. The combined organic phases were combined and dried over anhydrous Na2SO4, and filtered, and concentrated to dryness to yield the desired product. It was used for next step without further purification. MS ESI +ve m/z 382 (M+H)+.
Step 9: Preparation ofS-fspirofspirofchroman^J '-β-oxacyclohexaneJJ^^'-β-amino^- methyl-2, 6-dihydro-[l, 2, 4]oxadiazine)]-6-yl)benzonitrile
To a solution of above crude product, 3-cyanophenylboronic acid (12 mg, 0.08 mmol) and Cs2CO3 (48 mg, 0.147 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube was added PdCl2(PPh3 )2 (6 mg, 0.008 mmol), then the system was degassed by sweeping N2. The tube was capped and heated to HO0C for 10 min in a CEM microwave reactor. Solvent was removed in vacuum and the residue was purified by preparative HPLC to yield 3.82 mg of the desired product as a TFA salt. 1H NMR (400 MHz, CD3OD) δ: 7.99 (s, IH), 7.91 (d, J= 7.6 Hz, IH), 7.74 (m, IH), 7.69-7.59 (m, 3H), 7.09 (dd, J= 8.4, 2.8 Hz, IH), 4.48-4.26 (m, 2H), 3.87-3.70 (m, 2H); 3.65-3.53 (m, 2H), 3.48 (s, 3H), 2.49, 2.43 (two d, J= 14.4 Hz, IH), 2.19, 2.14 (two d, J= 14.4 Hz, IH), 1.97 (m, 2H), 1.81 (m, IH), 1.57 (m, IH); MS ESI +ve m/z 405 (M+H)+.
Example 156
Preparation of Compound 313
Figure imgf000474_0001
Step 1. 6-bromo-4'-phenylspiro[chroman-2, 1 '-cyclohexanJ-4-one (RXN 1):
In a 50 mL round bottom flask was placed 5-bromo-2-hydroxyacetophenone (Ig, 4.65 mmol) and 4-phenylcyclo-hexanone (810 mg, 4.65 mmol). They were dissolved in MeOH (9.3 mL). To this solution was added pyrrolidine (764 μL, 9.30 mmol) dropwise. To the flask was attached a condenser and the reaction mixture was heated at reflux overnight (- 14 hours). The next morning the volatiles were remove under reduced pressure and the crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, Ethyl Acetate / Hexanes as the eluents). The corresponding fractions were combined and concentrated yielding 6-bromo-4'-phenylspiro[chroman-2,r-cyclohexan]-4- one (1.12 g, 3.03 mmol, 65 %). M+H = 370.9, 372.9
1H NMR = (CDCl3, 400 MHz) δ 7.98 (d, J = 2.4 Hz, IH), 7.57 (dd, J = 8.8, 2.8 Hz, IH), 7.34 - 7.31 (m, 2H), 7.26 - 7.20 (m, 3H), 6.96 (d, J = 8.8 Hz), 2.72 (s, 2H), 2.58 (m, IH), 2.25 (dd, J = 15.2, 2.4 Hz, 2H), 1.92 (m, 2H), 1.76 (m, 2H), 1.56 (dt, J = 14.0, 4.0 Hz) ppm.
Step 2. 3-(4-oxo-4'-phenylspiro[chroman-2J '-cyclohexane]-6-yl)benzonitrile (RXN 2): In a 50 mL round bottom flask was placed 6-bromo-4'-phenylspiro[chroman-2,l '- cyclohexan]-4-one (300 mg, 0.811 mmol), 3-cyanobenzeneboronic acid (155 mg. 1.06 mmol), PdCl2(PPh3)2 (57 mg, 0.08 mmol) and cesium carbonate (661 mg, 2.03 mmol). This solid mixture was dissolved in a Dioxane / water mixture (8 mL, 6 : 1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. A condenser was attached to the flask and the reaction was allowed to stir at 95° C for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (20 mL) and water (20 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (5 mL / each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12g SiO2 cartridge, ethyl acetate / hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4-oxo-4'-phenylspiro[chroman-2,l'- cyclohexane]-6-yl)benzonitrile (173 mg, 0.440 mmol, 58% yield) as a light yellow oil. M+H = 394.0
1H NMR = (CDCl3, 400 MHz) δ 8.09 (d, J = 2.0 Hz, IH), 7.86 (s, IH), 7.81 (d, J = 7.6 Hz, IH), 7.73 (dd, J = 8.8, 2.4 Hz, IH), 7.62 (d, J = 8.0 Hz, IH), 7.54 (t, J = 7.6 Hz, IH), 7.36 - 7.32 (m, 2H), 7.29 - 7.21 (m, 3H) 7.18 (d, J = 8.8 Hz, IH), 2.79 (s, 2H), 2.61 (m, IH), 2.31 (d, J = 12.8 Hz, 2H), 1.98 (m, 2H), 1.79 (d, J = 12.4 Hz, 2H), 1.60 (dt, J = 14.0, 3.6 Hz, 2H) ppm.
Step 3. Prepartion of compound 313 (RXN 3)
In a 20 mL vial was placed the cyanoketone (98 mg. 0.249 mmol), and it was azeotroped twice with toluene (2"τnL / each). Dichloromethane (6 mL) was added followed by TiCl4 (500 μL, 0.500 mmol, IM in DCM). The reaction mixture was allowed to stir at room temperature for 1 hour. At that time bis-trimethylsilylcarbodiimide (179 μL, 0.797 mmol) was added and the solution was allowed to stir overnight (14 hours) at room temperature. The reaction was quenched with ice cold water (5 mL). The two phases were separated and the aqueous phase was back-extracted twice with dichloromethane (2 mL / each). The combined organic phases were dried over MgSO4, filtered, concentrated under reduce pressure and azeotroped with toluene (2 mL). In a separate flame dried 4 mL vial was placed MeNH(OH)-HCl (23 mg, 0.275 mmol) and it was dissolved in MeOH (4 mL). To this solution was added NaOMe (50 μL, 25% in MeOH) and the solution was stirred for 5 minutes at room temperature. This solution was transferred, via syringe, to the cyanoimine prepared above and stirred at room temperature for 1 hour. After the hour, the reaction mixture was concentrated under reduce pressure and the crude material was purified on a HPLC (Gilson, 10 - 90% CH3CN / H2O with 0.1% TFA as the eluent). The corresponding fractions were combined and concentrated yielding the final product (12.7 mg, 0.027 mmol, 11% yield) as a white solid. M+H = 465.1
1H NMR = (CD3OD, 400 MHz) δ 8.00 (bs, IH), 7.98 (d, J = 2.4 Hz, IH), 7.95 - 7.93 (m, IH) 7.75 (dd, J = 8.8, 2.4 Hz, IH), 7.70 - 7.68 (m, IH), 7.62 (t, J = 8.0 Hz, IH), 7.31 - 7.25 (m, 4H), 7.18 - 7.16 (m, IH), 7.15 (d, J = 8.4 Hz, IH), 3.40 (s, 3H), 2.76 (d, J = 15.2 Hz, IH), 2.66 - 2.58 (m, IH), 2.41 -2.37 (m, IH), 2.25 - 1.99 (m, 4H), 1.88 - 1.59 (m 4H) ppm.
Example 157 Preparation of Compound 388
Figure imgf000476_0001
Step 1: Benzopyran formation (RXN 1)
In a 50 mL round bottom flask was placed 5-bromo-2-hydroxyacetophenone (Ig. 4.65 mmol) and 1,4-cyclohexanedione mono-ethylelene ketal (726 mg, 4.65 mmol). They were dissolved in MeOH (9.3 mL). To this solution was added pyrrolidine (764 μL, 9.30 mmol) dropwise. To the flask was attached a condenser and the reaction mixture was heated at reflux overnight (— 14 hours). The next morning a precipitate was observed in the reaction media. The reaction was allowed to cool down to room temperature and then placed on an ice bath. The solid was collected by filtration and it was rinsed with cold MeOH. The light yellow solid collected corresponded to the benzopyran (1.43 g, adduct. 4.06 mmoL 87% yield). M+H = 352.9, 354.9
1H NMR = (CDCl3, 400 MHz) δ 7.96 (d, J = 2.8 Hz, IH)5 7.55 (dd, J = 8.8, 2.8 Hz, IH), 6.88 (d, J = 8.8 Hz, IH), 3.96 (m, 4H), 2.70 (s, 2H), 2.09 (m, 2H), 1.95 (ddd, J = 13.2, 13.2, 3.6 Hz, 2H), 1.75 (ddd, J = 13.6, 13.6, 4.0 Hz, 2H), 1.60 (m, 2H) ppm.
Step 2: 6-bromospiro[chroman-2J '-cyclohexane]-4,4'-dione (RXN 2)
In a 20 mL vial was placed the previous spiro compound (400 mg, 1.136 mmol) and it was dissolve in THF (5 mL). To this solution was added 3M HCl (5 mL) at room temperature. The reaction was allowed to stir at room temperature until total consumption of the starting ketal (judge by TLC). After completion the reaction was slowly quenched with saturated aqueous NaHCO3 until pH 7 was reached. The solution was diluted with ethyl acetate (20 mL). The phases were separated and the aqueous phase was back- extracted with ethyl acetate twice (10 mL / each). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate / hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 6-bromospiro[chroman-2,r-cyclohexane]- 4,4'-dione (254 mg, 0.825 mmol, 73% yield). M+H = 308.8, 311.0 1H NMR = (CDCl3, 400 MHz) δ 8.01 (d, J = 2.8 Hz, IH), 7.62 (dd, J = 8.8, 2.8 Hz, IH), 6.96 (d, J - 8.8 Hz, IH), 2.80 (s, 2H), 2.71 (ddd, J = 14.8, 14.8, 6.0 Hz, 2H), 2.44 (m, 2H), 2.32 (m, 2H), 1.90 (ddd, J = 14.0, 14.0, 5.2 Hz, 2H) ppm.
Step 3: 6-bromo-4'-hydroxyspiro[chroman-2, 1 '-cyclohexanJ-4-one (RXN 3) In a 25 mL round bottom flask was placed 6-bromospiro[chroman-2, 1 '- cyclohexane]-4.4'-dione (240 mg, 0.779 mmol) and it was dissolved in THF (7.8 mL). To this solution was added NaBH4 (30 mg, 0.789 mmol) and the reaction was allowed to stir at room temperature for 5 minutes. At that time, TLC indicated total consumption of the diketone. The reaction was diluted with water (10 mL) and ethyl acetate (10 mL) and it was allowed to stir for 15 minutes. The phases were separated and the aqueous phase was back-extracted with ethyl acetate twice (5 mL / each). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate / hexanes as the eluents). A 3:1 mixture of separable isomers formed. The less-polar product (judge by TLC) was cleanly separated by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate / hexanes as the eluents) and use for further development. The corresponding fractions for less-polar product were combined and concentrated under reduce pressure yielding one of the isomers of 6-bromo-4'- hydroxyspiro[chroman-2,l'-cyclohexan]-4-one (58 mg, 0.187 mmol, 24% yield). M+H = 310.9, 312.9
1H NMR = (CDCl3, 400 MHz) δ 7.96 (d, J = 2.4 Hz, IH), 7.56 (dd, J = 8.8, 2.4 Hz, IH), 6.90 (d, J = 8.8 Hz, IH), 3.70 (m, IH), 2.67 (s, 2H), 2.14 (m, 2H), 1.83 - 1.67 (m, 4H), 1.46 (ddd, J = 14.0, 14.0, 4.4 Hz, 2H) ppm.
Step 4. 6-bromo-4'-methoxyspiro[chroman-2,r-cyclohexan]-4-one (RXN 4)
In a 20 mL vial was placed 6-bromo-4'-hydroxyspiro[chroman-2,r-cyclohexan]-4-one (46 mg, 0.148 mmol) and it was azeotroped with acetonitrile (3 mL). The solid was dissolved in acetonitrile (1 mL). To this heterogenous solution was added Ag2O (103 mg, 0.444 mmol) followed by freshly grounded Drierite (160 mg). Then MeI (185 μL, 2.97 mmol) was added, the vial was capped and the reaction was allowed to stir at room temperature. After 2 days stirring the alcohol was totally consumed. The reaction mixture was filtered through a plug of Celite and the cake was rinsed with ethyl acetate three times (2 mL / each). The filtrate was concentrated yielding crude 6-bromo-4'-methoxyspiro[chroman- 2,l'-cyclohexan]-4-one (48 mg, 0.148 mmol, 100% yield) which by 1H NMR looked >90% pure. M+H = 324.9, 326.9 1H NMR = (CDCl3, 400 MHz) δ 7.95 (d, J = 2.4 Hz, IH), 7.54 (dd, J = 8.8, 2.4 Hz, IH), 6.88 (d, J = 8.8 Hz, IH), 3.36 (s, 3H), 3.21 (m, IH), 2.67 (s, 2H), 2.14 (m, 2H), 1.85 (m, 2H), 1.67 (m, 2H), 1.44 (ddd, J = 13.6, 13.6, 4.0 Hz) ppm.
Step 5: 3-(4'-methoxy-4-oxospiro[chroman-2,r-cyclohexane]-6-yl)ben∑onitrile (RXN 5) In a μwave vial was placed 6-bromo-4'-methoxyspiro[chroman-2,r-cyclohexan]-4-one (48 mg, 0.148 mmol), 3-cyanobenzeneboronic acid (28 mg, 0.191 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and cesium carbonate (121 mg, 0.371 mmol). This solid mixture was dissolved in a Dioxane / water mixture (2.0 mL, 6 : 1 ratio, respectively). The solution was purged with a N2 stream for 20 seconds. The vessel was placed in the μwave and heated to 100° C for 5 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (10 mL) and water (10 niL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (5 mL). The combined organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12g SiO2 cartridge, ethyl acetate / hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4'-methoxy-4-oxospiro[chroman-2,l'-cyclohexane]-6-yl)benzonitrile (32 mg, 0.092 mmol, 62% yield). M+H = 348.1
1U NMR = (CDCl3, 400 MHz) δ 8.05 (d, J = 2.4 Hz, IH), 7.83 (dd, J = 1.6, 1.6 Hz, IH), 7.78 (ddd, J = 8.0, 1.6, 1.6 Hz5 IH), 7.69 (dd, J = 8.4, 2.4 Hz, IH), 7.60 (ddd, J = 7.6, 1.6, 1.6 Hz, IH), 7.52 (t, J = 7.6 Hz, IH), 7.09 (d, J = 8.4 Hz, IH), 3.37 (s, 3H), 3.24 (m, IH), 2.73 (s, 2H), 2.19 (m, 2H), 1.88 (m, 2H), 1.72 (m, 2H), 1.48 (ddd, J = 14.0, 14.0, 4.0 Hz, 2H) ppm.
Step 6: Prepartion of compound 389 (RXN 6)
In a 20 mL vial was placed 3-(4'-methoxy-4-oxospiro[chroman-2,r-cyclohexane]- 6-yl)benzonitrile (32 mg, 0.092 mmol), and it was azeotroped with toluene (2 mL). Dichloromethane (3 mL) was added followed by TiCl4 (184 μL, 0.184 mmol, IM in DCM). The reaction mixture was allowed to stir at room temperature for 1 hour. At that time bis-trimethylsilylcarbodiimide (66 μL, 0.294 mmol) was added and the solution was allowed to stir overnight (14 hours) at room temperature. The reaction was quenched with ice cold water (5 mL). The two phases were separated and the aqueous phase was back- extracted twice with dichloromethane (2 mL / each). The combined organic phases were dried over MgSO4, filtered, concentrated under reduce pressure and azeotroped with toluene (2 mL). In a separate flame dried 4 mL vial was placed MeNH(OH)-HCl (9 mg, 0.108 mmol) and it was dissolved in MeOH (2 mL). To this solution was added NaOMe (19 μL, 25% in MeOH) and the solution was stirred for 5 minutes at room temperature. This solution was transferred, via syringe, to the cyanoimine prepared above and stirred at room temperature for 1 hour. After that time, the reaction mixture was concentrated under reduce pressure and the crude material was purified on a HPLC (Gilson, 10 - 90% CH3CN / H2O with 0.1% TFA as the eluent). The corresponding fractions were combined and concentrated yielding the final product (7.1 mg. 0.017 mmol, 18% yield) as a colorless oil. M+H = 419.1
1H NMR = (CD3OD, 400 MHz) δ 7.99 (bs, IH), 7.96 (d, J = 2.4 Hz, IH), 7.94 - 7.91 (m, IH), 7.74 - 7.71 (dd, J = 8.8, 2.4 Hz, IH), 7.71 - 7.67 (m, IH), 7.66 - 7.59 (m, IH), 7.05 (d, J = 8.8 Hz, IH), 3.38 (s, 3H), 3.37 (s, 3H), 3.34 (bs, IH), 2.76 (d, J = 14.8 Hz, IH), 2.17 (d, J = 14.8 Hz, IH), 2.22 - 213 (m, IH), 2.01 - 1.78 (m, 4H), 1.73 - 1.47 (m, 3H) ppm.
Example 158 Preparation of Compounds 379, 403 and 408
Pd/C
Figure imgf000480_0001
Figure imgf000480_0002
MeNHOH HCI NaOMe, MeOH
Figure imgf000480_0003
Figure imgf000480_0004
Experimental data:
Figure imgf000480_0005
1
Preparation of compound 1 A solution OfAgNO3 (155 g, 913 mmol) in water (200 mL) was added to a stirred solution of 3,4-dihydro-2H-pyran-2-carbaldehyde (31 g, 277 mmol) in ethanol (900 mL), followed by addition of a solution of KOH (102 g, 1.83 mol) in water (900 mL) in 1 hour. The mixture was filtered and evaporated. The residue was extracted with ether. The aqueous layer was adjusted to pH=3 with 6 N HCl and extracted with ether. The organic layer was evaporated and the residue was treated with 1 N NaOH (332 mL, 332 mmol). The mixture was co-evaporated with methanol to dryness to give compound 1 (39 g, 94%). 1H-NMR (400 MHz D2O): 56.24 (d, IH), 4.16 (dd, IH), 1.93 (d, 2H), 1.65-1.85 (m, 2H).
Figure imgf000481_0001
Preparation of compound 2
To a suspension of sodium 3,4-dihydro-2H-pyran-2-carboxylate (13.6 g, 90.9 mmol) in THF (150 mL) was added triethylamine (919 mg, 9.1 mmol), DMF (336 mg, 4.6 mmol), followed by addition of isobutyl chloroformate (13.6 g, 100 mmol) at -10°C. After being stirred at room temperature for 2 hours, the mixture was added a solution of diazomethane in ether (1 N, 500 mL, 500 mmol) at -78°C. The reaction mixture was stirred at room temperature overnight. The diazomethane was bumped off by N2 for 2 h hours and filtered. The filtrate was concentrated, and the residue was purified by silica gel column by using dichloromethane as eluant to give the compound 2 (11.8 g, 86%).
Figure imgf000481_0002
Preparation of compound 3
To a suspension of rhodium acetate dimer (120 mg) in dichloromethane (60 mL) was added a solution of 2-diazo-l-(3,4-dihydro-2//-pyran-2-yl)-ethanone (6 g, 39.5 mmol) in dichloromethane (60 mL). When the addition was completed, the reaction was stirred for another 1 hour. The mixture was washed with 5% aqueous NaHCO3 and concentrated. The residue was purified by flash chromatograph to give the compound 3 (2 g, 41%).
Figure imgf000482_0001
Preparation of compound 4
To a solution of 6-oxa-tricyclo[3.2.1.02'7]octan-8-one (0.5 g, 4 mmol) in ethyl acetate (10 mL) was added Pd/C (100 mg). The mixture was stirred at room temperature under H2 (50 psi) for 6 hours. The mixture was filtered, the filtrate was concentrated to give the compound 4 (440 mg, 87%).
Figure imgf000482_0002
Preparation of Isomer A and Isomer B A solution of 2-oxa-bicyclo[2.2.2]octan-6-one (252 mg, 2 mmol), l-(5-bromo-2- hydroxy -phenyl)-ethanone (215 mg, 1 mmol) and pyrrolidine (142 mg, 2 mmol) in toluene (5 mL) was refluxed overnight. The mixture was treated with 1 N HCl, and the aqueous layer was adjusted to pH=10 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried, and concentrated. The residue was purified by preparative TLC to give the Isomer A (160 mg, 50%) and Isomer B (90 mg, 28%).
Isomer A: 1H-NMR (400 MHz CDCl3): <57.89 (d, IH), 7.46 (m, IH), 6.78 (d, IH), 3.79 (d, IH), 3.66 (t, IH), 3.61 (m, IH), 2.90 (m, 2H), 2.00 (m, 3H), 1.81 (m, 2H),1.64 (m, 2H). Isomer B: 1H-NMR (400 MHz CDCl3): «57.86 (d, IH), 7.48 (dd, IH), 6.91 (d, IH), 3.88 (m, IH), 3.80 (m, 2H), 2.69 (d, 2H), 2.01 (m, 2H), 1.60-1.85 (m, 4H), 1.46 (m, IH).
Figure imgf000483_0001
Preparation of compound 5
A mixture of Pd(PPh3)2Cl2 (35 mg, 0.05 mmol), Isomer A (160 mg, 0.5 mmol), Cs2CO3 (2 N, 0.5 mL, 1 mmol) and 3-cyanophenylboronic acid (147 mg, 1 mmol) in 1,4- dioxane (1 mL) was stirred at 1000C in microwave for 30 minutes. The reaction mixture was treated with ethyl acetate and water. The organic layer was concentrated in vacuo to give the crude product, which was purified by preparative TLC to give the compound 5 (50 mg, 29%).
Figure imgf000483_0002
Preparation of compound 6
To a solution of compound 5 (50 mg, 0.145 mmol) in anhydrous DCM (2 mL) was added TiCl4 (0.72 mL, 0.72 mmol. 1 M in DCM) at room temperature. It was stirred at 50°C in microwave for 10 minutes. To this mixture was added ΛyV-methanediylidenebis (1.1.1-trimethylsilanamine) (135 mg, 0.72 mmol). The resulting mixture was stirred at 60°C in microwave for another 15 minutes. The reaction mixture was poured into ice- water, extracted with DCM. The combined organic phases were dried and concentrated to give the crude compound 6 (60 mg, crude), which was used in the next step without further purification.
Figure imgf000483_0003
403, 408 Preparation of Compound 408 and Compound 403
To a solution of MeNHOH.HCl (60.56 mg, 0.73 mmol) in anhydrous MeOH (3 mL) was added NaOMe (35 mg, 0.65 mmol, 25 w% in MeOH), followed by compound 6 (60 mg, 0.145 mmol, crude). After being stirred for 1 h, the solvent was removed in vacuum. The residue was dissolved in DCM, and the mixture was filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC followed by preparative HPLC to give compound 408 (4.47 mg, 7%) and compound 403 (2 mg, 3%). compound 408: 1H-NMR (400 MHz CD3OD): <S7.95 (m, 3H), 7.72 (m, 2H), 7.63 (m, IH), 7.00-7.20 (m, IH), 4.03 (s, IH), 3.91 (m, IH), 3.88 (m, IH), 3.37 (m, 3H), 3.17 (m, IH), 2.21 (d, IH), 2.17 (m, IH), 1.90 (m, 4H), 1.78 (m, 2H); ESI MS: m/z 417 [M+H]+. compound 403: 1H-NMR (400 MHz CD3OD): «57.99 (m, 2H), 7.95 (m, IH), 7.73 (m, 2H), 7.64 (m, IH), 7.00-7.20 (m, IH), 3.92-4.05 (m, IH), 3.62-3.74 (m, 2H), 3.31 (t, 3H), 3.13 (m, IH), 2.35 (m, IH), 2.19 (d, IH), 1.85-2.15 (m, 4H), 1.78 (m, 2H); ESI MS m/z 417 [M+H]+.
Figure imgf000484_0001
isomer B
Preparation of compound 7
By using the same strategy as compound 5, compound 7 was made (60 mg, 62%) from Isomer B.
Figure imgf000484_0002
Preparation of compound 8 By using the same synthetic strategy as compound 6, compound 8 was obtained
(80 mg, crude).
Figure imgf000485_0001
379
Preparation of compound 379
By using the synthetic strategy for compound 408, compound 379 (9.44 mg, 13%) was obtained. 1H-NMR (400 MHz, CD3OD): <S7.98 (m, IH)3 7.91 (m, 2H), 7.73 (m, IH), 7.65 (m, IH), 7.60 (m, IH), 7.07 (t, IH), 3.93 (m, 2H), 3.85 (m, IH), 3.34 (m, 3H), 2.97 (m, IH), 2.24 (d, IH), 2.10-2.18 (m, 2H), 1.72-1.87 (m, 4H), 1.60 (m, IH); ESI MS: m/z 417 [M+H]+.
Example 159. Preparation of Compound 350
Figure imgf000485_0002
Preparation of compound 1
Figure imgf000485_0003
A mixture of 3-bromo-5-chlorobenzonitrile (1 g. 4.74 rnmol), 4,4,4',4',5,5,5',5'- octamethyl-2J2l-bi(L3,2-dioxaborolane) (1.3 g, 5.12 mmol), KOAc (1.366 g, 13.8 mmol) and Pd(dppf)Cl2 (236 mg) in 1,4-dioxane (30 mL) under Ar2 was stirred in microwave at 100°C for 1.2 hours. The reaction mixture was concentrated in vacuo to give the residue, which was purified by chromatography to give compound 1 (70 mg, 7%).
Figure imgf000486_0001
Preparation of compound 350
A mixture of 6-bromo-2'-methyl-2-(tetrahydro-2//-pyran-4-yl)-2'//-spiro[chroman -4,5'-[l,2,4]oxadiazol]-3'-amine (50 mg, 0.13 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)benzonitrile (51.285 mg, 0.195 mmol), Cs2CO3 (2 M, 0.35 mL) and Pd(PPh3 )2C12 (9.25 mg) in 1,4-dioxane (1.25 mL) under Ar2 was stirred in microwave 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 compound 350 (1.34 mg, 2%). 1H-NMR (400 MHz CD3OD): £7.91 (m, IH), 7.89 (m, 2H), 7.65 (m, 2H), 6.94 (m, IH), 3.88-4.01 (m, 3H), 3.38 (m, 2H), 3.27 (m, 3H), 2.36-2.60 (m, IH), 1.72-1.94 (m, 3H), 1.54 (m, 3H); ESI MS: m/z 439 [M+H]+.
Example 160. Preparation of Compounds 394, 416 and 443
Figure imgf000486_0002
MeNHOH HCI NaOMe, MeOH
Figure imgf000486_0003
Figure imgf000486_0004
Preparation of compound 1
o
Figure imgf000486_0005
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (1.9 g, 8.88 mmol), octahydronaphthalen-l(2H)-one (900 mg, 5.92 mol) and pyrrolidine (546 mg, 7.69 mol) in toluene (30 mL) was refluxed overnight. The reaction mixture was removed in vacuum. The residue was diluted with H2O, and added HCl (PH=I). The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give the compound 1 (474 mg, 15%). 1H TSfMR (400 MHz CDCl3): #7.96 (m, IH), 7.53 (m, IH), 6.88 (m, IH), 2.61-3.22 (m, 2H), 2.22 (m, IH), 1.56-1.97 (m, 7H), 0.95-1.43 (m, 8H).
Preparation of compound 2
Figure imgf000487_0001
Pd(PPh3 )?Cb (30 mg) in a 50 mL of flask under Ar2 was treated sequentially with the 6- bromo-3',4';4aI ;5',6',7',8',8a'-octahydro-2'H-spiro[chroman-2,l'-naphthalen]-4-one (300 mg, 0.86 mmol) in 1,4-dioxane (6 mL), Cs2CO3 (2 N, 1.3 mL) and 3-cyanophenylboronic acid (235 mg, 1.29 mmol). The mixture was heated under 1000C under Ar2 in a microwave for 6 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 2 (286 mg, 90%). 1H NMR (400 MHz CDCl3): 58.01 (m, IH), 7.76 (m, 2H), 7.63 (m, IH), 7.54 (m, IH),
7.46 (m, IH), 7.01 (m, IH), 2.52-3.21 (m, 2H), 2.23 (m, IH), 1.89 (m, 2H), 1.69 (m, 4H),
1.53 (m, 2H), 1.38 (m, 4H), 1.26 (m, 2H), 1.13 (m, IH), 0.98 (m, 2H).
Figure imgf000487_0002
Preparation of compound 3 A solution of S-C^oxo-S'^'^a'^^ό'J'^'^a'-octahydro-I'H-spirotchroman^,!'- naphthalene]-6-yl)benzonitrile (110 mg, 0.296 mmol) and TiCl4 (225 mg, 1.184 mmol) in anhydrous dichloromethane (5 mL) was heated at 50°C under microwave for 5 minutes. The bis-trimethylsilylcarbodiimide (110 mg. 0.592 mmol) was added and the mixture was heated at 600C for 20 min. The reaction mixture was poured into water, and extracted with dichloromethane. The combined organic phases were dried over anhydrous Na2SO4. filtered, and concentrated to give the compound 3 (145 mg, crude), which was used in the nxet step directly.
Figure imgf000488_0001
Preparation of compounds 443, 416 and 394
To a solution of methylhydroxylamine HCl salt (31 mg, 0.367 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25% in MeOH(Wt.%), 0.1 mL), followed by (E)-N- (6-(3- cyanophenyl)-3',4',4al ;5',6',7',8',8a'-octahydro-2'//-spiro[chroman-2,l'-naphthalne] - 4- ylidene) cyanamide (145 mg, 0.367 mmol). After being stirred for 10 min.. the solvent was removed in vacuo. The residue was redissolved in DCM (10 mL). The mixture was filtered and concentrated to give compound 443 1H-NMR (400 MHz CD3OD): (58.02 (m, IH), 7.95 (m, IH), 7.70-7.74 (m, IH), 7.62-7.69 (m, 2H), 6.99-7.15 (m, IH), 3.36-3.43 (m, 3H), 2.95-3.25 (m, IH), 2.35-2.49 (m,lH), 1.97-2.04 (m, 3H), 1.74-1.81 (m, 3H); 1.74 (m, 2H), 1.58 (m, 2H), 1.48-1.57 (m, 3H), 1.05-1.47(m, 3H); ESI MS: m/z 443 [M+H]+. compound 416: 58.02 (m, IH), 7.96 (m, 2H), 7.70-7.74 (m, 1H); 7.62-7.68 (m, 2H), 7.03- 7.18 (m, IH), 3.32-3.39 (m, 3H), 2.75-2.94 (m, IH), 2.20-2.50 (m, IH), 1.97-2.15 (m, 3H), 1.75-1.93 (m, 3H), 1.68 (m, 2H), 1.59 (m, 2H), 1.44-1.50 (m, 3H), 1.29-1.33 (m, 3H): ESI MS: m/z 443 [M+H]+. compound 394: «58.01 (m, IH), 7.94 (m, 2H), 7.63-7.74 (m, 3H), 7.01-7.17 (m, IH), 3.35- 3.42 (m, 3H), 2.75-3.03 (m, IH), 2.42-2.58 (m, IH), 1.96-2.24 (m, 2H), 1.73-1.95 (m, 6H), 1.48-1.68 (m, 3H), 1.15-1.37 (m, 5H); ESI MS: m/z 443 [M+H]÷. Example 161. Preparation of Compound 334
Figure imgf000489_0001
Experimental data:
Figure imgf000489_0002
334a
Preparation of compound 334a
In a 500 mL dry three-neck flask under N2, 2,2.6,6-tetramethylpiperidine (14.6 mL, 86.4 mmol) was dissolved in dry THF (140 mL) and cooled to -100C before H-BuLi (2.5 M in hexane, 35 mL, 86.4 mmol) was added over 2 min. The mixture was stirred for 10 minutes before cooling to -78°C. At -78°C, B(O1Pr)3 (23.3 mL, 100.7 mmol) was added over 2 minutes, and stirred for 5 minutes at -78°C before 2,6-difluorobenzonitrile (10 g, 71.9 mmol) dissolved in dry THF (75 mL) was added dropwise over 5 minutes. The reaction was left in the cooling bath overnight, slowly reaching room temperature. At room temperature, the reaction was quenched with glacial acetic acid (5.8 mL), followed by addition of 2,2-dimethyl-1.3-propandiol (11.2 g, 107.9 mmol). The mixture was stirred for 1 hour at room temperature, then transferred to a separating funnel by using ethyl acetate and the organic layer was washed with aqueous KH2PO4 (10w/v%, 3x100 mL). The combined water phase was extracted with ethyl acetate. The combined organic layer was dried, and evaporated to give the crude product, which was purified by column chromatography to give compound 334a (8.9 g, 49%). 1H-NMR (400 MHz CDCl3): ^7.94-7.99 (m, IH), 6.98-7.03 (t, IH)5 3.79 (ss 3H), 1.04 (s, 6H).
Figure imgf000490_0001
Preparation of compound 334
A mixture of 6-bromo-2'-methyl-2-(tetrahydro-2H-pyran-3-yl)-2'H-spiro[chroman- 4,5'- [l,2,4]oxadiazol]-3'-amine (50 mg, 0.13 mmol), 3-(5,5-dimethyl-l,3,2-dioxaborinan- 2-yl)- 2,6-difluorobenzonitrile (65 mg, 0.26 mmol), Cs2CO3 (2 M, 0.7 mL) and Pd(PPh3)2Cl2 (30 mg) in 1 ,4-dioxane (3 mL) under Ar2 was heated at 120°C 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 334 (2.67 mg, 5%). 1H-NMR (400 MHz CD3OD): <57.84-7.90 (m, 2H), 7.59-7.61 (t, IH), 7.32-7.37 (t, IH), 7.08 (t, IH), 3.93-4.24 (m, 2H), 3.50-3.90 (m, 2H), 3.37-3.43 (m, IH), 3.36 (s, 3H), 2.76-2.80 (m, IH), 2.48-2.69 (m, IH), 1.98-2.13 (m, 3H), 1.69-1.75 (m, 2H); ESI MS: m/z 441 [M+H]+.
Example 162. Preparation of Compound 320
Figure imgf000490_0002
Experimental data:
Figure imgf000491_0001
320a
Preparation of compound 320a
A mixture of l-(5-bromo-2-hydroxy-phenyl)-ethanone (600 mg, 2.8 mmol), 3- cyanophenylboronic acid (700 mg, 4.76 mmol), Cs2CO3 (2.8 mL, 2 M) and Pd(PPh3)2Cl2 (50 mg) in 1,4-dioxane (24 mL) was degassed, and stirred in microwave at 100°C for 5 minutes. The organic layer was concentrated in vacuo to give the residue, which was purified preparative TLC to give the compound 320a (560 mg, 84%).
Figure imgf000491_0002
320b
Preparation of compound 320b
A mixture of 3'-acetyl-4'-hydroxy-biphenyl-3-carbonitrile (215 mg, 0.91 mmol), 7,8-dihydroquinolin-5(6H)-one (200 mg, 1.36 mmol) and pyrrolidine (97 mg, 1.36 mmol) in MeOH (5 mL) was refluxed overnight. The solvent was removed in vacuo to give the residue, which was purified by preparative TLC to give the compound 320b (55 mg, 16%). 1H-NMR (400 MHz CDCl3): £8.81 (m, IH), 8.58 (m, IH), 8.09 (s, IH), 7.76 (m, 4H), 7.56 (m, 2H), 7.04 (d, IH), 3.32 (m, 2H), 3.28 (m, IH), 2.94 (m, IH), 2.21 (m, 3H), 1.96 (m, IH).
Figure imgf000491_0003
320c
Preparation of compound 320c To a solution of 3-(4-oxo-7'.8'-dihydro-6'H-spiro[chroman-2,5'-quinoline]-6-yl) benzonitrile (100 mg, 0.273 mmol) in CH2Cl2 (2 mL) under N2 was added TiCl4 (1 M solution in DCM, 1.1 mL, 1.1 mmol). It was stirred in microwave at 50°C for 5 minutes. Bis-trimethylsilylcarbodiimide (112 mg, 0.6 mmol) was added. The resulting mixture was stirred in microwave at 6O0C for 10 minutes. The reaction mixture was poured into ice- water, and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the compound 320c (100 mg, crude).
Figure imgf000492_0001
Preparation of compound 320:
To a solution of methylhydroxylamine HCl salt (25 mg, 0.256 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25%wt. in MeOH, 5 drops), and N-(6-(3- cyanophenyl)-7',8'-dihydro-6'//-spiro[chroman-2,5'-quinoline]-4-ylidene) cyanamide (100 mg. 0.256 mmol). After being stirred 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 HPLC to give compound 320 (4.99 mg, 2%). 1H-NMR (400 MHz CD3OD): <58.55-8.92 (m, 2H), 7.92- 8.47 (m, 3H), 7.42-7.91 (m, 4H), 7.15 (m, IH), 3.56 (m; IH), 3.38 (m, 3H), 2.95-3.24 (m, 3H), 2.56 (m, IH), 2.02-2.42 (m, 3H); ESI MS m/z 438 [M+H]+.
Example 163. Preparation of Compounds 305 and 345 EtOOC
B00CγN NaBH4 1 EtOOC xx TBSCI
Figure imgf000493_0001
Figure imgf000493_0002
TMSN=C=NTMS MeNHOH HCI
Figure imgf000493_0004
Figure imgf000493_0003
compound 305 1.22 mg compound 345 0.51 mg
Experimental data:
Figure imgf000493_0005
305a
Preparation of compound 305a
To a solution of ethyl 4-oxocyclohexanecarboxylate (118 g, 0.69 mol) in MeOH (1 L) was added NaBH4 (44 g. 1.17 mol), and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the compound 305a (105 g, 89%). 1H NMR (400 MHz CDCl3): «54.10 (m, 2H), 3.52 (m, IH), 2.32 (m, IH), 1.89 (ms 4H), 1.48 (m, 4H), 1.21 (t, 3H).
TBSCI
Figure imgf000493_0007
imidazole
Figure imgf000493_0006
305b Preparation of compound 305b
To a solution of ethyl 4-hydroxycyclohexanecarboxylate (105 g, 0.61 mol) in DMF (700 mL) was added imidazole (83 g, 12.2 mol) and TBSCl (101 g, 0.67 mol). The resulting mixture was stirred overnight. Ether was added, and the aqueous layer was washed with 1 N HCl, and extracted ether. The combined organic layer was washed 1 N HCl and brine, dried over NaSO4, and concentrated to give the compound 305b (215 g, 100%).
EtOOC EtOOC
Figure imgf000494_0001
^-^OTESS
305c
Preparation of compound 305c
A three necked flask was charged with THF (300 mL) and diisopropylamine (68.9 g, 0.68 mol). The mixture was cooled to -70°C, «-BuLi (2.5 M, 286 mL, 0.714 mol) was added via syringe, and the mixture was stirred 30 minutes. Ethyl 4-(tert- butyldimethylsilyloxy)cyclohexanecarboxylate (195 g, 0.68 mol) was added dissolved in THF (20 mL) at -70°C. After 1 hour stirring, ethyl carbonochloridate (76.8 g, 0.7 mol) was added dropwise. and the reaction was stirred for 2 hours. The mixture was warmed to 0°C, and quenched with water, and extracted with EtOAc. The organic layer was washed with brine. 1 N HCl, water, dried, and concentrated to give the residue, which was purified by chromatography to afford the compound 305c (146 g, 60%). 1H NMR (400 MHz
CDCl3): <54.14 (m, 4H), 2.25 (m, 2H), 1.83 (m, 2H), 1.68 (m, 2H), 1.47 (m, 2H), 1.21 (m, 6H), 0.85 (s, 10H), 0.00 (s, 6H).
Et
Figure imgf000494_0002
305d
Preparation of compound 305d
LiAlH4 (8 g, 0.21 mol) was suspended in 400 mL of dry THF in a ice-cooled bath, the solution of diethyl 4-(?er/-butyldimethylsilyloxy)cyclohexane-l,l-dicarboxylate (50 g. 0.14 mol) dissolved in 150 mL of THF was added dropwise. After being stirred for 1 hour, 8 mL OfH2O and 8 mL of 10% NaOH solution were added at 0°C. The mixture was stirred at room temperature and filtered. The filtrate was concentrated, and the residue was re-crystallized from petrol ether to afford the compound 305d (25 g, 68%). 1H NMR (400MHz CDCl3): <B.62 (m, 3H), 3.48 (s, 2H), 2.62 (s, 2H), 1.68 (m, 4H), 1.42 (m, 2H), 1.16 (m, 2H), 0.85 (s, 9H), 0.00 (s, 6H).
Figure imgf000495_0001
305e
Preparation of compound 305e To a solution of (4-(tert-butyldimethylsilyloxy)cyclohexane- 1 , 1 -diyl)dimethanol
(10 g, 37 mmol) and pyridine (5.85 g, 74 mmol) in CHCl3 (120 mL) in an ice-water bath was added TsCl (21 g, 111 mmol) in one portion. After being stirred for 20 minutes, the ice-water bath was removed, and the mixture was stirred at room temperature overnight. The solution was diluted with CH2Cl2, washed with 1 N HCl, water and brine, dried, and concentrated. The residue was purified by chromatography to afford the compound 305e (18.5 g, 86%). 1R NMR (400 MHz CDCl3): <S7.70 (d, 4H), 7.33 (d, 4H), 3.82 (s, 2H), 3.79 (s, 2H), 3.58 (s, IH), 2.47 (d, 6H), 1.53 (m, 2H), 1.27 (m, 6H), 0.85 (s, 9H), 0.00 (s, 6H).
Figure imgf000495_0002
305f
Preparation of compound 305f
To a solution of (4,4-bis(tosylmethyl)cyclohexyloxy)(/ert-butyl)dimethylsilane (18.5 g, 31.8 mmol) in CH3CN (200 mL) was added 40% HF (45 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into the saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried and concentrated to give the compound 305f (14 g, 100%). 1H NMR (400 MHz CDCl3): (57.66 (d: 4H),7.23 (d, 4H), 3.81 (s, 2H), 3.68 (s, 2H), 3.59 (s, IH), 2.41 (s, 6H), 1.92 (s, IH), 1.56 (m, 4H), 1.22 (m, 4H).
Figure imgf000496_0001
305g
Preparation of compound 305g
To a solution of 4,4-bis(tosylmethyl)cyclohexanol (15 g, 34.5 mmol) in dry THF (500 ml) was added powdered NaOH (25 g, 625 mmol). The reaction mixture was stirred under reflux for 48 hours, cooled to room temperature, diluted with water, and extracted with EA. The organic layer was dried and concentrated to give the crude product, which was purified by chromatography to afford the compound 305g (6 g, 70%). 1H-NMR (400 MHz CDCl3): δl .11 (d, 2H), 7.36 (d, 2H), 3.78 (m, IH), 3.66 (s, 2H), 3.65 (s, 2H), 2.46 (s, 3H), 1.98 (m, 2H), 1.62 (m, IH), 1.60 (m, 2H), 1.57 (m, IH), 1.47 (m, 2H).
Figure imgf000496_0002
305h
Preparation of compound 305h
DMSO (30 mL) was heated to 150°C for 10 min., and cooled to room temperature under N2. Toluene-4-sulfonic acid 2-oxa-bicyclo[2.2.2]oct-4-ylmethyl ester (1 g, 3.38 mmol) and NaHCO3 (2.83 g, 33.8 mmol) were added. The mixture was heated to 1500C for 4 hours. After being cooled to room temperature, the mixture was treated with water and ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated to give the crude product, which was purified by preparative TLC to give the compound 305h (200 mg, 42%). 1H-NMR (400 MHz CDCl3): (59.41 (s, IH), 3.89 (m, 2H), 3.85 (m, IH), 2.10 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.62 (m, 4H).
Figure imgf000496_0003
Preparation of compound 305i A solution of 2-oxa-bicyclo[2.2.2]octane-4-carbaldehyde (200 mg, 1.43 mmol), 1- (5-bromo-2-hydroxy -phenyl)-ethanone (307 mg. 1.43 mmol) and Na2B4O7JOH2O (545 mg, 1.43 mmol) in a mixture of ethanol (6 mL) and water (10 mL) was reflux for overnight. The mixture was concentrated. The residue was added water and ethyl acetate. The organic layer was dried, and concentrated to give the crude product, which was purified by preparative TLC to give the compound 305i (320 mg, 67%).
Figure imgf000497_0001
Preparation of compound 305j
A mixture of Pd(PPh3)2Cl2 (66 mg, 0.095 mmol), 6-bromo-2-(2-oxa-bicyclo[2.2.2] oct-4-yl)-chroman-4-one (320 mg, 0.95 mmol), Cs2CO3 (2 N, 4.75 mL, 9.5 mmol) and 3- cyanophenylboronic acid (281 mg, 1.9 mmol) in 1 ,4-dioxane (3 mL) was stirred at 100°C in microwave for 20 minutes. The reaction mixture was treated with ethyl acetate and water. The organic layer was concentrated in vacuo to give the crude product, which was purified by preparative TLC to give the compound 10 (70 mg, 20%).
Figure imgf000497_0002
305k
Preparation of compound 305k
To a solution of 3-[2-(2-oxa-bicyclo[2.2.2]oct-4-yl)-4-oxo-chroman-6-yl]- benzonitrile (70 mg, 0.19 mmol) in anhydrous DCM (5 mL) was added TiCl4 (0.98 mL, 0.98 mmol, 1 M in DCM) at room temperature. The mixture was stirred at 50°C in microwave for 10 minutes. To this mixture was added ΛϋV-methanediylidenebis (1,1.1- trimethylsilanamine) (182 mg, 0.98 mmol). The resulting mixture was stirred at 60°C in microwave for another 15 minutes. The reaction mixture was poured into ice-water, and extracted with DCM. The combined organic phases were dried and concentrated to give the crude compound 305k (70 mg, 94%), which was used in the next step without further purification. MeNHOH.HCI
Figure imgf000498_0002
Figure imgf000498_0001
compound 305 + compound 345
Preparation of compound 305 and compound 345
To a solution MeNHOH.HCl (76.32 mg, 0.91 mmol) in anhydrous MeOH (2 niL) was added NaOMe (44.4 mg, 0.82 mmol, 25w% in MeOH) and 6-(3-cyano-phenyl)-2-(2- oxa-bicyclo[2.2.2]oct-4-yl)-chroman-4-ylidene-cyanamide (70 mg, 0.18 mmol, crude). After being stirred for 2 hours, the solvent was removed in vacuum, and the residue was dissolved in DCM. The mixture was filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC and preparative HPLC to give compound 305 (1.22 mg, 2%) 1H-NMR (400 MHz CD3OD): 31.98 (s, IH), 7.92 (d, 2H), 7.70 (t, 2H), 7.61 (t, IH), 7.03 (d, IH), 4.03 (d, IH), 3.96 (d, IH), 3.81 (m, 2H), 3.35 (s, 3H); 2.60 (d, IH), 2.07 (m, 2H), 1.90 (m, 3H), 1.75 (m, 4H); ESI MS: m/z 431 [M+H]+ and compound 345 (0.51 mg, 1%). 1H-NMR (400 MHz CD3OD): <S7.86 (s, IH), 7.80 (d, IH), 7.74 (s, IH), 7.57 (t, 2H), 7.51 (t, 3H), 6.90 (d, IH), 3.93 (m, IH), 3.85 (s, IH), 3.71 (m, 2H), 3.38 (s, 3H), 3.03 (m, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 1.65 (m, 4H); ESI MS: m/z 431 [M+H]+.
Example 164. Preparation of Compound 319
Figure imgf000499_0001
Experimental data:
Figure imgf000499_0002
Preparation of compound 319a
2.6-Dimethyl-4/f-pyran-4-one (12 g, 96.8 mmol) was dissolved in ethanol (60 mL). and 10% Pd/C (1.2 g) was added. The mixture was hydronated under H2 (30 Psi) at room temperature for 24 hours, passed through celite, and concentrated under reduced pressure at 30°C to give the compound 319a (12 g, crude).
Figure imgf000499_0003
319b
Preparation of compound 319b
To a solution of witting reagent (46.3 g, 135 mmol) in THF (375 mL) at 0°C was added dropwise a solution of 2.5 M M-BuLi (in hexane, 25.3 mL). The reaction mixture was warmed to room temperature, stirred for 1 hour, recooled to 00C, and added a solution of 2.6-dimethyldihydro-2H-pyran-4(3H)-one (12 g, 93.8 mmol) in TΗF (60 mL) dropwise. The reaction mixture was stirred at 00C for 3 hours. The reaction mixture was concentrated under reduced pressure at about 25-30°C. The crude product was purified by silica gel column to give the compound 319b (2.3 g, 16%). 1H-NMR (400 MHz CDCl3,): £5.79-5.80 (t, IH)5 3.53 (s, 3H), 2.59-2.68 (m, IH), 1.88-1.95 (m, IH)5 1.70-1.82 (m, IH), 1.50-1.59 (m, IH), 1.20 (d, 3H, J= 6.4 Hz), 1.18 (d, 3H, J= 6.0 Hz).
Figure imgf000500_0001
319c
Preparation of compound 319c
A solution of 4-(methoxymethylene)-2,6-dimethyltetrahydro-2i/-pyran (2.1 g, 13.7 mmol) in a mixture of HCl (2 M, 64 mL) and H2O (21 mL) was refluxed for 2 hours. The mixture was extracted by CH2Cl2, after drying and concentration, the crude compound 319c (1.9 g) was obtained.
Figure imgf000500_0002
319d
Preparation of compound 319d The mixture of l-(5-bromo-2-hydroxyphenyl)ethanone (2.9 g, 13.5 mmol), 2,6- dimethyltetrahydro-2//-pyran-4-carbaldehyde (1.9 g, 13.5 mmol) and borax (5.1 g. 13.5 mmol) in a mixture of ethanol (17 mL) and water (29 mL) was refluxed overnight. The reaction mixture was cooled by ice-water bath and dissolved in EtOAc. The organic layer was separated and concentrated to give the residue, which was purified by silica gel column to give the pure compound 319d (2.9 g, 64%).
Figure imgf000500_0003
319e
Preparation of compound 319e Pd(PPh3)2Cl2 (20.7 mg, 0.03 mmol) in a tube under Ar2 was treated sequentially with 6-bromo-2-(2,6-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one (200 mg, 0.59 mmol), 3-cyanophenylboronic acid (173.5 mg, 1.18 mmol) in [1, 4]-dioxane (23.6 mL) and Cs2CO3 (2 M, 3.54 mL). The mixture was heated at 10O0C under Ar2 for 5 minutes in a microwave reactor. The reaction mixture was extracted with EtOAc, concentrated, and purified by preparative TLC to give compound 319e (140 mg, 66%). 1H-NMR (400 MHz CDCl3): <58.O9 (s, IH), 7.81-7.85 (m, IH), 7.75-7.80 (m, IH), 7.66-7.72 (m, IH), 7.56-7.62 (m, IH), 7.48-7.55 (m, IH), 7.05-7.10 (m, IH), 4.20-4.30 (m, IH), 3.71-3.76 (m, IH), 3.42-3.58 (m, 2H), 2.71-2.78 (m, IH), 2.01-2.11 (m, IH), 1.89-1.95 (m, IH), 1.61-1.69 (m, IH), 1.20-1.28 (m, 6H), 1.05-1.19 (m, 2H).
Figure imgf000501_0001
319f
Preparation of compound 319f
A solution of 3-(2-(2,6-dimethyltetrahydro-2//-pyran-4-yl)-4-oxochroman-6-yl) benzonitrile (70 mg, 0.19 mmol) and TiCl4 (258 mg, 1.36 mmol) in CH2Cl2 (7 mL) was heated at 50°C for 5 minutes in a microwave. Then AϋV'-methanediylidenebis (1,1,1- trimethylsilanamine) (0.17 mL, 0.78 mmol) was added and heated at 600C for 10 minutes in a microwave. CH2Cl2 was added, and the solution was extracted with dichloromethane. The CH2Cl2 was removed under reduced pressure to give the crude compound 319f (80 mg).
Figure imgf000501_0002
Preparation of compound 319
To a solution of N-methylhydroxylamine hydrochloride (18.9 mg, 0.23 mmol) in anhydrous MeOH (2.65 mL) was added NaOMe (25% w% in MeOH, 44.2 uL) and (E)-N- (6-(3-cyanophenyl)-2-(2,6-dimethyltetrahydro-2H-pyran-4-yl)chroman-4- ylidene)cyanamide (80 mg, 0.23 mmol). After being stirred for 1 hour, the solvent was removed in vacuo. The residue was redissolved in CH2Cl2 (10 mL), and filtered, and the solvent was removed in vacuo to give the crude pruduct, which was purified by preparative TLC to give compound 319 (6.53 mg, 7.3%). 1H-NMR (400 MHz CD3OD): (57.80-7.91 (m, 3H), 7.56-7.65 (m, 2H), 7.48-7.55 (m, IH), 6.91-6.98 (m, IH), 3.91-4.05 (m, IH), 3.40-3.51 (m, 2H), 3.28-3.34 (m, 3H), 2.55-2.65 (m, IH), 1.86-2.05 (m, 2H), 1.80-1.85 (m5 IH), 1.60-1.65 (m, IH), 1.13 (d, 6H, J= 6.0 Hz), 0.95-1.10 (m, 2H); ESI MS: m/z 433 [M+H]+.
Example 165. Preparation of Compound 327
Figure imgf000502_0001
TMSN=C=NTMS MeNHOH HCI NaOMe
Figure imgf000502_0003
Figure imgf000502_0002
Experimental data:
Figure imgf000502_0004
327a
Preparation of compound 327a
2;6-Dimethylhepta-2;5-dien-4-one (90 g) was dissolved in 1 N HCl (700 mL), and the mixture was stirred for seven days at 400C. The mixture was extracted with ether, and the organic phase was concentrated. The residue was purified by distillation to afford the compound 327a (26 g, 20%). 1H-NMR (400 MHz CDCl3): <S2.38 (s, 4H), 1.29 (s, 12H).
Figure imgf000503_0001
Preparation of compound 327b
To a solution of (methoxymethyl)-triphenylphosphonium chloride (40 g, 1 15 mmol) in anhydrous THF (50 mL) was added w-BuLi (41 ml, 103 mmol) dropwise at - 78°C. The mixture was warmed to room temperature and stirred for 1 hour at room temperature. 2,2,6,6-Tetramethyldihydro-2/f-pyran-4(3H)-one (10 g, 64 mmol) was added, and the mixture was stirred for another 2 h. The reaction was quenched by sat. NH4Cl solution, and extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the compound 327b (5.3 g, 45%). 1H-NMR (400 MHz CDCl3): (55.85 (s, IH), 3.50 (s, 3H), 2.10 (s, 2H), 1.82 (s, 2H), 1.12 (s, 12H).
Figure imgf000503_0002
327c
Preparation of compound 327c
To a solution of 4-(methoxymethylene)-2.2,6,6-tetramethyltetrahydro-2H-pyran (5.3 g) was added 2 N HCl (30 mL). The mixture was refluxed for 3 h, TLC showed that the reaction was completed. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to get the product. 1H-NMR (400 MHz CDCl3): <59.62 (s, IH), 2.73 (m, IH), 2.01 (m, IH), 1.86 (m, IH), 1.78 (m, 2H), 1.69 (m, 2H), 1.31 (m, 2H),1.22 (m, 12H).
Figure imgf000504_0001
327d
Preparation of compound 327d
A mixture of l-(5-bromo-2-hydroxyphenyl)-ethanone (8.2 g, 37.9 mmol), 2,2,6,6- tetramethyltetrahydro-2H-pyran-4-carbaldehyde (3.2 g, 18.9 mmol) and borax (7.2 g) was dissolved in ethanol : water = 3 : 5 (80 mL), and the mixture was refluxed overnight. The solvent was removed in vacuum, water and EtOAc were added. The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel column to afford the compound 327d (3.5 g, 51%). 1H-NMR (400 MHz CDCl3): <57.93
(m, IH), 7.50 (m, IH), 6.83 (m, IH), 4.11 (m, IH), 2.62 (d, 2H), 2.19 (m, IH), 1.78 (d, IH), 1.52 (m, IH), 1.20 (m, 14H),1.12 (m, IH).
Figure imgf000504_0002
327e
Preparation of compound 327e
A mixture of 6-bromo-2-(2,2,6,6-tetramethyltetrahydro-2i/-pyran-4-yl)chroman-4- one (150 mg), 3-cyanophenylboronic acid (90 mg), Cs2CO3 (2 M, 1 mL) and Pd(PPh3)2Cl2 (30 mg) in 1,4-dioxane (5 mL) under N2 was stirred in microwave at 100°C for 5 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give the compound 327e (80 mg, 51%).
Figure imgf000504_0003
327f
Preparation of compound 327f To a solution of 3-(4-oxo-2-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl) chroman-6-yl)benzonitrile (80 mg, 0.207 mmol) in dichloromethane (5 mL) was added titanium (FV) chloride (0.2 mL, 1 M solution in dichloromethane) dropwise, and the mixture was stirred in microwave for 5 minutes at 5O0C. This mixture was added compound N, N-methanediylidenebis(l,l,l-trimethylsilanamine) (77 mg, 0.415 mmol) dropwise. The resulting mixture was stirred in microwave for 10 minutes at 600C. The reaction mixture was poured into ice- water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and concentrated to give the product.
MeNHOH.HCI
NaOMe
Figure imgf000505_0001
Figure imgf000505_0002
Preparation of compound 327
To a solution of 7V-methylhydroxylamine hydrochloride (16 mg, 0.194 mmol) in anhydrous methanol (1 mL) was added sodium methanolate (25% in methanol, 94 mg, 0.174 mmol), and ((E)-N-(6'-(3-cyanophenyl)-5,7,8,9-tetrahydrospiro[benzo[7]-annulene- 6,2'-chroman]-4'-ylidene)-cyanamide (80 mg, 0.194 mmol). After being stirred for 10 minutes, the solvent was removed in vacuum. The residue was redissolved in dichloromethanae. The mixture was filtrated, concentrated, and purified by preparative TLC and HPLC to give compound 327 (3.94 mg, 4 %). 1H-NMR (400 MHz CD3OD): <58.O1 (m, 3H), 7.75 (m, 2H), 7.66 (m, IH), 7.09 (m, IH), 4.13 (m, IH), 3.42 (m, 3H), 2.56 (m, IH), 2.37 (m, IH), 2.07 (m, IH), 1.94 (m, IH), 1.70 (m, IH), 1.40 (m, IH), 1.23 (m, 12H); ESI MS: m/z 461 [M+H]+.
Example 166. Preparation of Compound 402 TMSN=C=NTMS MeNHQH.HD TiCI4, DCM NaOMe, MeOH
Figure imgf000506_0001
Figure imgf000506_0002
Figure imgf000506_0003
Figure imgf000506_0004
Experimental data:
Figure imgf000506_0005
402a
Preparation of compound 402a
To a solution of 6-bromo-3'.4'-dihydro-2'H-spiro[chroman-2,r-naphthalen]-4-one (50 mg, 0.15 mmol) in DCM (10 mL) was added TiCl4 (111 mg, 0.58 mmol) dropwise. After the mixture was stirred at 50°C under Ar2 in microwave for 5 minutes, N,N- methanediylidenebis(l,l,l-trimethylsilanamine) (108 mg, 0.58 mmol) was added dropwise. The mixture was stirred at 60°C under Ar2 in microwave for 10 minutes, and poured into ice-water (50 mL). The aqueous layer was extracted with CH2Cl2. The organic layer was dried and concentrated to give the crude compound 402a (50 mg, crude).
MeNHOH.HCl NaOMe, MeOH
Figure imgf000506_0007
Figure imgf000506_0006
402b
Preparation of compound 402b
To a solution of N-methyl-hydroxylamine hydrochloride (11.3 mg, 0.14 mmol) in MeOH (3 mL) was added MeONa (0.029 mL, 25% in MeOH) and (£)-N-(6-bromo-3',4'- dihydro-2'//-spiro[chroman-2.1 '-naphtha! ene]-4-ylidene) cyana mide (50 mg, 0.14 mmol). After being stirred for 10 minutes, the solvent was removed in vacuo, and the residue was purified by preparative TLC to give the compound 402b (20 mg, 35%).
Figure imgf000507_0001
Preparation of compound 402
Pd(PPh3^Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with compound 402b (20 mg, 0.058 mmol) in [l,4]dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3,5-difluorophenylboronic acid (15.8 mg, 0.1 mmol). The mixture was heated under 100°C under Ar2 in microwave for 5 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give compound 402 (1.44 mg, 7%). 1H-NMR (400 MHz CD3OD): δl.9% (s, IH), 7.72 (d, IH), 7.54 (m, IH), 7.28 (m, 4H), 7.17 (m, IH), 7.01 (d, IH), 6.90 (m, IH), 3.38 (s, 3H), 3.02 (m, IH), 2.87 (m, 2H), 2.53 (m, IH), 2.45 (m, IH), 2.03 (m, IH), 1.86 (m, 2H); ESI MS: m/z 448 [M+H]+.
Example 167. Preparation of Compound 324
Figure imgf000508_0001
Experimental data:
Figure imgf000508_0002
324a
Preparation of compound 324a l-(5-Bromo-2-hydroxyphenyl)-ethanone (7 g, 34 mmol) and 3,4- dihydronaphthalen -2(l/f)-one (5 g, 34 mmol) were dissolved in toluene (150 mL), and pymolidine (4.9 g, 69 mmol) was added. The reaction mixture was refluxed overnight, concentrated, washed with water, and extracted with EtOAc. The organic phase was dried and concentrated to give the crude product, which was purified by a silica gel column to afford the compound 324a (500 mg, 5%). 1H-NMR (400 MHz CDCl3): <57.92 (s, IH), 7.46 (d, IH), 7.10 (m, 3H), 6.97 (d, IH), 6.75 (d, IH), 3.12 (d, IH), 2.92 (d, 2H), 2.81 (d, IH), 2.72 (d, 2H), 2.20 (m, IH), 1.85 (m, IH).
Figure imgf000508_0003
324b
Preparation of compound 324b Pd(PPh3)2Cl2 (10 mg) under Ar2 was treated sequentially with the 6-bromo-3',4'- dihydro-r//-spiro[chroman-2.2'-naphthalen]-r-one (150 mg. 0.44 mmol) in [l,4]dioxane (4 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (119 mg, 0.66 mmol). The mixture was heated at 120°C in microwave for 20 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give the compound 324b (60 mg, 38%). 1H-NMR (400 MHz CDCl3): (58.15 (s, IH)5 7.45-7.80 (m, 6H)5 6.95-7.19 (m, 4H), 3.19 (d, 2H), 2.92 (m, 3H)5 2.75 (m, 2H)5 2.28 (m, IH)5 1.89 (m5 IH).
Figure imgf000509_0001
324c
Preparation of compound 324c To a solution of 3-(4-oxo-3',4'-dihydro- 1 '//-spiro[chroman-252'-naphthalene]-6-yl) benzonitrile (80 mg, 0.22 mmol) in dried CH2Cl2 (5 mL) was added TiCl4 (1 M solution in DCM5 0.88 mmol) dropwise within 15 minutes, and the mixture was stirred for 1 h. bis- Trimehtlysilylcarbodiimide (164 mg. 0.88 mmol) was added dropwise, and the resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 324c (70 mg, crude), which was used for the next step without further purification.
Figure imgf000509_0002
Preparation of compound 324
To a solution of MeNHOH.HCI (15 mg, 0.18 mmol) in anhydrous MeOH (3 mL) was added NaOMe (25 wt% in MeOH, 35 mg, 0.0.16 mmol), followed by (E)-N-(6-(3- cyanophenyl)-3'.4'-dihydro-r//-spiro[chroman-2.2'-naphthalene]-4-ylidene)cyanamide (70 mg, 0.18 mmol). After being stirred for 5 minutes, the solvent was removed in vacuum. The residue was re-dissolved in CH2Cl2 and filtered. The filtrate was concentrated to give the residue, which was purified by preparative TLC and preparative HPLC to afford compound 324 (10.15 mg, 13%). 1H NMR (400 MHz CD3OD): <57.89 (m, 3H), 7.58 (m, 3H), 7.04 (m, 4H), 6.88 (m, IH), 3.29 (d, 3H), 3.13 (m, 3H), 2.73 (m, 2H), 2.22 (m, 2H), 1.96 (m, IH); ESI MS: m/z 437 [M+H]+.
Example- 168. Preparation of Compound 315
Figure imgf000510_0001
TMSN=C=NTMS MeNHOH HCl TiCI4, DCM NaOMe, MeOH
Figure imgf000510_0003
Figure imgf000510_0002
Experimental data:
Figure imgf000510_0004
315a
Preparation of compound 315a
A mixture of compound l-(5-bromo-2-hydroxyphenyl)-ethanone (2 g, 9.3 mmol), lH-inden-2(3H)-one (2.46 g, 18.6 mmol) and pyrrolidine (0.99 g, 1.2 rnL) in toluene (20 mL) was refluxed overnight, concentrated, washed with 1 M HCl, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to afford 2.3 g of the crude product. 500 mg the crude product was purified by preparative TLC to afford the compound 315a (100 mg). IH-NMR (400 MHz CD3OD): <S7.90 (s, IH), 7.57 (d, IH), 7.16 (m, 4H), 6.83 (d, IH), 3.31 (s, IH), 3.29 (m, 2H), 3.17 (d, 2H), 3.03 (s, 2H).
Figure imgf000511_0001
Preparation of compound 315b
A mixture of 6-bromo-r,3'-dihydrospiro[chroman-2,2'-inden]-4-one (100 mg, 0.30 mmol), 3-cyanophenylboronic acid (83 mg, 0.46 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (5 mg) in 1 ,4-dioxane (3 mL) under N2 was stirred in microwave at 100°C for 20 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give compound 315b (40 mg, 37%). IH-NMR (400 MHz CDCl3): (58.04 (s, IH), 7.77 (s, IH), 7.74 (d, IH), 7.42-7.63 (m, 4H), 7.19 (m, 3H), 6.81 (d, IH), 3.37 (d, 2H), 3.12 (d, 2H), 2.97 (s, 2H).
Figure imgf000511_0002
315c
Preparation of compound 315c
To a solution of 3-(4-oxo-r,3'-dihydrospiro[chroman-2,2'-indene]-6-yl)ben zonitrile (40 mg, 0.11 mmol) in dichloromethane (2 mL) was added titanium (IV) chloride (1 M solution in dichloromethane, 43 mg, 0.23 mmol) dropwise, and the mixture was stirred in microwave for 20 minutess at 50°C. To this mixture was added N,N- methanediylidenebis (1,1,1-trimethylsilanamine) (64 mg, 0.34 mmol) dropwise. The resulting mixture was stirred in microwave for 10 minutes at 60°C. The reaction mixture was poured into ice-water, extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and concentrated to give the compound 315c, which was used directly for the next step.
Figure imgf000511_0003
Preparation of compound 315
To a solution of JV-methylhydroxylamine hydrochloride (14 mg. 0.16 mmol) in anhydrous methanol (2 ml) was added sodium methanolate (25% in methanol, 0.026 mL, 0.12 mmol), and (E)-jV-(6-(3-cyanophenyl)-r,3'-dihydrospiro[chroman-2,2'-in dene]-4- ylidene) cyanamide (50 mg, 0.13 mmol). After being stirred 10 min., the solvent was removed in vacuum, and the residue was redissolved in dichloromethanae (10 mL), after filtration and concerntration, the residue was purified by preparative TLC to give compound 315. 1H-NMR (400 MHz CDCl3): δl.lβ (s, IH), 7.72 (s, IH), 7.60 (s, IH), 7.42 (s, 4H), 7.38 (m, 3H), 7.18 (m, 4H), 6.76 (d, IH), 3.15-3.36 (m, 6H), 3.12 (s, 3H); ESI MS: m/z 423 [M+H]+.
Example 169. Preparation of Compound 273
Figure imgf000512_0001
Experimental data:
Lawesson's reagent 1 ,4-dιoxane
Figure imgf000512_0003
Figure imgf000512_0002
273a
Preparation of compound 273a
A suspension of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4.4'- imidazolidine]-2',5'-dione (320 mg. 0.84 mmol) and Lawesson's Reagent (340.2 mg, 0.84 mmol) in dry 1,4-dioxane (4 mL) was heated at 1200C for 30 minutes in microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give the compound 273a (300 mg; 90%).
Figure imgf000513_0001
Preparation of compound 273b
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2'-thioxospiro[chroman- 4,4'-imidazolidin]-5'-one (120 mg, 0.3 mmol) in MeOH (16 mL) was added NaOH (0.6 N, 1.2 mL) and MeI (0.3 mL). The reaction mixture was heated at 60°C for 8 minutes in microwave. The mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give the compound 273b (80 mg, 60%).
Figure imgf000513_0002
273c
Preparation of compound 273c
A solution of 6-bromo-r-methyl-2'-(methylthio)-2- (tetrahydro-2H-pyran-3-yl)- spirofchroman-^'-imidazolJ-S'Q'Hyone (75 mg, 0.177 mmol), NH4I (200 mg) in NH3/EtOH (2 mL, 8 N) was heated at 120°C in a tube in a microwave reactor for 2 hours. After cooling, the mixture was concentrated in vacuum to afford the compound 273c (70 mg, 100%).
Figure imgf000513_0003
Preparation of compound 273 Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with a solution of 2'-amino-6-bromo-r-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one (35 mg, 0.089 mmol) in 1,4-dioxane (2 mL), Cs2CO3 solution (2 N, 0.4 mL), and 3-cyanophenylboronic acid (25 mg, 0.18 mmol). This mixture was heated in microwave at 120°C for 30 min., and concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give compound 273 (4.9 mg, 10%). 1H-NMR (400 MHz CD3OD): <57.58 (m, IH), 7.41 (m, 2H), 7.29 (m, 2H), 7.01 (m, 2H), 4.68 (dd, 0.7H), 4.21 (m, 0.6H), 3.88 (dd, 1.6H), 3.49 (m, 2H), 3.31 (m, 3H), 3.10 (m, 2H), 2.41 (m, IH), 2.24 (m, IH), 1.97 (m, 2H), 1.68 (m, 2H); ESI MS: m/z 410 [M+H]+.
Exmample 170. Preparation of Compound 267
Experimental data:
Figure imgf000514_0001
Preparation of compound 267
By using the same synthetic strategy for compound 273 described in Exmaple 169; compound 267 (2.74 mg, 5%) was obtained. 1H-NMR (400 MHz CD3OD): 57.94 (d, IH), 7.86 (m, IH), 7.61 (m, IH), 7.50 (m, IH), 7.21 (m, 2H), 7.05 (m, H), 6.89 (m, IH), 4.70&4.40 (m, IH), 3.88 (dd, 2H), 3.49 (m, 2H), 3.24 (s, 3H), 3.08 (t, 2H), 2.48 (m, IH), 2.18 (t, IH), 1.97 (m, 2H), 1.68 (m, 2H); ESI MS: m/z 428 [M+H]+.
Example 171. Preparation of Compounds 230 and 453
Figure imgf000514_0002
By using the same strategy for compound 273 described in Example 169, cmpound 230 (2.00 mg, 10%) and compound 453 (1.81 mg, 9%) were obtained. compound 230: 1H-NMR (400 MHz CD3OD): <S7.89 (m, 2H), 7.53-7.68 (m, 3H)5 7.38- 7.50 (m, IH), 7.06 (d, IH), 4.51 (m, IH), 3.77 (m, 2H), 3.25-3.22 (m, 3H), 2.44 (m, IH), 2.18 (m, 2H), 1.90 (m, IH), 1.63 (m, IH), 1.33 (m, 2H), 1.24-1.28 (m, 6H); ESI MS: m/z 445 [M+H]+ compound 453: 1H-NMR (400 MHz CD3OD): <57.86-7.94 (m, 2H), 7.48-7.67 (m, 6H), 7.08 (d, IH)3 4.58 (m, IH), 3.76 (m, 2H), 3.06 (m, 3H), 2.46 (m, IH), 2.13 (m, 2H), 1.89 (m, IH), 1.61 (m, IH), 1.45 (m, 2H), 1.27-1.39 (m, 6H); ESI MS: m/z 889 [2M+H]+.
Example 172. Preparation of Compound 451
Figure imgf000515_0001
MeNHOH.HCI
Figure imgf000515_0003
Figure imgf000515_0002
Experimental data:
Figure imgf000515_0004
NaHCO3
Figure imgf000515_0005
451a Preparation of compound 451a
To a vigorously stirred mixture Of Bu4NI (33.2 g, 90 mmol) in a mixture of 5% aqueous NaHCO3 solution (1200 mL) and CH2Cl? (280 mL) was added dropwise at room temperature a solution of l,2-bis(bromomethyl)benzene (39.3 g. 15 mmol) and diethyl 3- oxopentanedioate (39.4 g, 1.3 mmol) in CH2Cl2 (280 mL). After 21 h, the reaction mixture was quenched with aqueous NH4Cl solution, and the organic layer was separated, dried, and evaporated in vacuo, purified by silica gel column to give compound 451a (40 g, crude).
Figure imgf000516_0001
451b
Preparation of compound 451b
A mixture of 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]arinulene-6,8-dicarboxylate (27.8 g, 91.0 mmol), NaOH (8 %, 480 mL ) in ethanol (730 mL) was refluxed for 2.5 h, the mixture was concentrated to removed to remove most ethanol. and then extracted with CH2Cl2. The combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to give the compound 451b (10 g, 69%).
Figure imgf000516_0002
451c
Preparation of compound 451c l-(5-Bromo-2-hydroxyphenyl)-ethanone (2.14 g, 10 mmol), pyrroidine (1.065 g,15 mmol) and 3-(4-oxo-3',4'-dihydro-2'//-spiro[chroman-2,r-naphthalene]-6- yl)benzonitrile (2.4 g, 15 mmol) was dissolved in CH3OH (20 mL), the mixture was refluxed for 24 hour. The mixture was poured into ice-water (20 mL), extracted with EA for (3χl5 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel column to give the compound 451c (1.21 g, 34%). 1H-NMR (400 MHz CDCl3): δl.93 (s, IH), 7.51 (d, "IH), 7.15 (m, IH), 7.05 (m, 4H); 6.89 (d, IH), 3.20 (m, 2H), 2.63 (m, 2H), 2.43 (m, 2H); 2.26 (m, 2H), 1.55 (m, 2H).
Figure imgf000516_0003
451 d
Preparation of compound 451d Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 6'-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-chroman]-4'- one (150 mg, 0.42 mmol) in [l,4]dioxane (2.0 mL), Cs2CO3 solution (2 N, 1 mL), and 3- cyanophenylboronic acid (124 mg, 0.84 mmol). The mixture was heated at 100°C under Ar2 in microwave for 5 minutes. The reaction mixture was concentrated, and purified by preparative TLC to give the compound 45 Id (40 mg, 25%).
Figure imgf000517_0001
4S1e
Preparation of compound 451e To a solution of 3-(4'-oxo-5,6.8,9-tetrahydrospiro[benzo[7]annulene-7,2'-chroman]
-6'-yl)benzonitrile (40 mg, 0.1 mmol) in DCM (6 mL) was added TiCl4 (37.6 mg, 0.2 mmol) dropwise, and the mixture was stirred at 50°C under Ar2 in microwave for 5 minutes. N,Λ^-Methanediylidenebis(l,l,l-trimethylsilanamine) (37 mg, 0.2 mmol) was added dropwise, the mixture was stirred at 60°C under Ar2 in microwave for 10 minutes and poured into ice-water (50 mL). The aqueous layer was extracted with CH2Cl2, the organic layer was dried and concentrated to give the crude compound 451e (30 mg, 71%).
MeNHOH HCI
Figure imgf000517_0003
Figure imgf000517_0002
Preparation of compound 451 To a solution of N-methyl-hydroxylamine hydrochloride (6.2 mg, 0.07 mmol) in
MeOH (2 mL) was added MeONa (0.014 mL, 25% in MeOH), and (E)-iV-(6-(3- cyanophenyl)-3'.4'-dihydro-2'//-spiro[chroman-2,r-naphthalene]-4-ylidene)cyanamide (30 mg, 0.07 mmol). After being stirred for 20 minutes, the solvent was removed in vacuo, and the residue was purified by preparative TLC to give compound 451 (6.5 mg, 13%). 1H-NMR (400 MHz CDCl3): <57.88 (m, 3H), 7.53-7.69 (m, 3H), 7.00 (m, 5H), 3.28 (s, 3H)5 2.80-3.07 (m, 2H), 2.24-2.63 (m, 4H), 2.02 (m, 2H), 1.53-1.84 (m, 2H); ESI MS: m/z 451 [M+H]+.
Example 173. Preparation of Compound 217
Figure imgf000518_0001
Experimental data:
Figure imgf000518_0002
217a Preparation of compound 217a
A solution of «-BuLi (88 mL, 2.5 M) was added to a mixture of PPh3CH3 +Me- (IOO g. 246 mmol) in THF (600 mL) at -10°C. After the mixture was stirred for 1 h at the this temperature, 3,4-dihydronaphthalen-l(2/f)-one(20 g, 137 mmol) was added. The mixture was warmed to room temperature and stirred for 3 hours, concentrated, and purified by column chromatography to afford the compound 217a (9.6 g. 49 %). 1H-NMR (400 MHz CDCl3): £7.64 (d, IH), 7.17 (m, 2H), 7.15 (m, IH)5 5.48 (s, IH)5 4.95 (s, IH)5 2.83 (t, 2H), 2.53 (t, 2H), 1.91 (m, 2H).
Figure imgf000518_0003
217b
Preparation of compound 217b Crystalline HTIB (18.9 g, 48.1 mmol) was added to a stirred solution of 1- methylene- 1,2,3,4-tetrahydronaphthalene (6.6 g, 45.8 mmol) in 95 % methanol (200 mL). The mixture was stirred for 20 minutes at room temperature, and the solvent was removed in vacuo. The mixture was partitioned between dichloromethane and water, and the organic phase was concentrated in vacuo, the residue was purified by a silica gel column to afford the compound 217b (3.9 g, 53 %). 1H-NMR (400 MHz CDCl3): «57.19 (m, 4H), 3.72 (s, 2H), 2.94 (t, 2H), 2.53 (t, 2H), 1.99 (m, 2H).
Figure imgf000519_0001
217c
Preparation of compound 217c
A mixture of 8,9-dihydro-5H-benzo[7]annulen-6(7H)-one (2 g, 12.5 mmol), l-(5- bromo-2-hydroxyphenyl)ethanone (5.4 g, 25.0 mmol) and pyrrolidine (1.3 g, 1.5 ml) in toluene (50 mL) was refluxed overnight. The resulting mixture was concentrated, and the residue was washed with 1 M HCl, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated to afford 2.3 g crude product. The crude product was purified by flash column chromatography on silica gel to afford the compound 217c (1 g, 22 %). 1H-NMR (400 MHz CDCl3): *57.91 (s, IH), 7.76 (d, IH), 7.08 (m, 3H), 6.75 (d, IH), 6.68 (d, IH), 3.21 (d, IH), 3.00 (d, IH), 2.75 (m, 2H), 2.52 (m, 2H), 2.10 (t, 2H), 1.87 (m, IH), 1.52 (m, IH).
Figure imgf000519_0002
Preparation of compound 217d
A mixture of 6'-bromo-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2'-chroman]-4'- one (100 mg, 0.28 mmol), 3-cyanophenylboronic acid (102 mg, 0.56 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3 )2C12 (5 mg) in 1.4-dioxane (3 mL) under N2 was stirred in microwave at 100°C for 20 minutes. The reaction mixture was concentrated in vacuo, the residue was purified by preparative HPLC to afford the compound 217d (80 mg, 75%). 1H-NMR (400 MHz CDCl3): (58.04 (s, IH), 7.77 (s, IH), 7.74 (d, IH), 7.55 (m, 4H), 7.19 (m, 3H), 6.81 (d, IH), 3.37 (d, 2H), 3.12 (d, 2H), 2.97 (s, 2H), 2.54 (m, IH).
Figure imgf000520_0001
217e
Preparation of compound 217e
To a solution of 6'-(3-bromophenyl)-5,7,8,9-tetrahydrospiro[benzo[7]ann ulene- 6,2'-chroman]-4'-one (80 mg, 0.21 mmol) in dichloromethane (2 mL) was added titanium(IV) chloride (1 M solution in dichloromethane, 161 mg, 0.85 mmol) dropwise, and the mixture was stirred in microwave for 20 minutes at 5O0C. The mixture was added iVJ^'-methanediylidenebis(l,l,l-trimethylsilanamine) (118 mg, 0.85 mmol) dropwise, and stirred in microwave for 10 minutes at 6O0C. The reaction mixture was poured into ice- water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the product 217e.
MeNHOH.HCI
Figure imgf000520_0003
Figure imgf000520_0002
Preparation of compound 217
To a solution of N-methylhydroxylamine hydrochloride (18 mg, 0.21 mmol) in anhydrous methanol (2 mL) was added sodium methanolate (25% in methanol, 0.041 mL, 0.19 mmol), and ((E)-N-(6'-(3-cyanophenyl)-5,7,8,9-tetrahydrospiro[benzo[7] annulene- 6,2'-chroman] -4'-ylidene)-cyanamide (85 mg, 0.21 mmol). After being stirred for 10 minutes, the solvent was removed in vacuum, and the residue was redissolved in dichloromethanae (10 mL). After filtration, the solvent was removed, the residue was purified by preparative TLC and preparative HPLC to give compound 217 (2.80 mg, 2.9 %). 1H-NMR (400 MHz CD3OD): <57.78 (m, IH), 7.53 (m, 4H), 7.07 (m, 4H), 6.62-6.70 (m, IH), 3.35 (m, IH), 3.02 (m, IH)5 2.97 (d, 3H), 2.74 (ms 3H), 2.42 (m, IH), 1.95 (m, 3H), 1.52 (m, IH): ESI MS: m/z 451 [M+H]+. Example 174. Preparation of Compound 434
Figure imgf000521_0001
Preparation of compound 434
Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with the solution of 3-(3'-amino-6-bromo-2'-methyl-2'H-spiro[chroman-4,5'-[l,2,4]oxadiazole]- 2-yl)-5-methylhex-4-en-l-ol (35 mg, 0.085 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.3 mL), and 2,5-difiuorophenylboronic acid (26.8 mg, 0.17 mmol). The mixture was heated in microwave at 1200C for 20 minutes. The reaction mixture was concentrated in vacuo, the residue was purified by preparative TLC and preparative HPLC to give compound 434 (5 mg, 10%). 1H-NMR (400 MHz CDCl3): <S8.70 (bs, 2H), 7.49-7.61 (m, 2H), 6.84-7.05 (m, 4H), 4.88-5.12 (m, IH), 4.02-4.23 (m, IH), 3.55-3.72 (d, 2H), 3.24 (d, 3H), 2.74 (s, IH), 2.34-2.51 (m, IH), 2.05 (m, IH), 1.84 (m, IH), 1.68 (m, 6H), 1.42 (s, IH), 1.21 (d, IH); ESI MS: m/z 444 [M+H]+.
Example 175 Preparation of Compounds 341 and 384
Figure imgf000521_0002
By using the same strategy as compound 434 described in Example 174. compound 341 (8.13 mg, 36%) & compound 384 (0.99 mg, 12%) were obtained. compound 341: 1H-NMR (400 MHz CD3OD): S7.82 (d, IH), 7.60 (m, IH), 7.23 (m, 2H), 7.12 (m, 2H), 4.09 (m, IH), 3.78 (m, 2H), 3.38 (m, 3H), 2.68 (d, IH), 2.22 (m, IH), 1.85- 1.95 (m, 2H), 1.68 (m, IH), 1.32-1.50 (m, 2H), 1.28 (d, 6H); ESI MS: m/z 444 [M+H]+. compound 384: 1H-NMR (400 MHz CD3OD): (57.82 (d, IH), 7.60 (m, IH), 7.23 (m, 2H), 7.12 (m, 2H), 4.09 (m, IH), 3.78 (m, 2H), 3.38 (m, 3H), 2.68 (m, IH), 2.22 (m, IH), 1.85- 1.95 (m, 2H), 1.68 (m, IH), 1.32-1.50 (m, 2H), 1.28 (d, 6H); ESI MS: m/z 444 [M+H]+. Example 176. Preparation of Compound 456
Figure imgf000522_0001
By using the same strategy as compound 434 described in Example 174, compound 456 was obtained (5.31 mg, 14 %). 1H-NMR (400 MHz CDCl3): J7.19-7.71 (m, 3H), 6.80-7.15 (m, 3H), 4.91-5.07 (m, IH), 3.98-4.33 (m, IH), 3.65-3.75 (m, IH), 3.50-3.60 (m, IH), 3.20-3.30 (s, 3H), 2.70-2.80 (t, IH), 2.20-2.60 (m, 6H), 1.70-1.80 (d, 3H), 1.55-1.65 (d, 3H); ESI MS: m/z 444 [M+H]+.
Example 177. Preparation of Compounds 362 and 365
Figure imgf000522_0002
By using the same strategy as compound 434 described in Example 174, compound 365 (2.40 mg, 8%) and compound 362 (0.79 mg, 3%) were obtained. compound 365: 1H-NMR (400 MHz CD3OD): S7.S3 (s, IH), 7.63 (d, IH), 7.49 (m, IH), 7.38 (m, IH), 7.27 (m5 IH), 6.99 (d, IH), 4.04 (m, IH), 3.74 (m, 2H), 3.34 (m, 3H), 2.65 (d; IH), 2.16 (m, IH), 1.98 (m, IH), 1.84 (m, IH), 1.62 (m, IH), 1.41 (m, 2H), 1.22 (d, 6H); ESI MS: m/z 444 [M+H]+. compound 362 :Η-NMR (400 MHz CD3OD): <57.86 (s, IH), 7.64 (d, IH), 7.52 (m, IH), 7.32 (m, 2H), 7.03 (d, IH), 4.06 (m, IH), 3.78 (m, 2H), 3.43 (m, 3H), 2.68 (d, IH), 2.18 (m, IH), 1.94 (m, 2H), 1.63 (m, IH), 1.47 (m, IH), 1.37 (m, IH), 1.23 (m, 6H); ESI MS:
Figure imgf000522_0003
Example 178. Preparation of Compound 404
Figure imgf000523_0001
Preparation of compound 404
By using the same strategy as compound 434 described in Example 174, compound 404 (1.92 mg, 5%) was obtained. 1H-NMR (400 MHz CD3OD): <S7.88 (s, IH), 7.62 (m, IH), 7.48 (m, IH), 7.32 (m, IH), 7.13 (m, IH), 6.99 (m, IH), 5.06 (m, IH), 4.29 & 4.07 (m, IH), 3.63 (m, IH), 3.51 (m, IH), 3.37 (m, 3H), 2.88 (m, IH), 2.57 (m, IH), 2.15 (m, IH), 1.88 (m,lH), 1.72 (m, 6H); ESI MS: m/z 460 [M+H]+.
Example 179. Preparation of Compounds 295 and 299
Figure imgf000523_0002
By using the same synthetic strategy for compound 434 described in Example
174, compound 295 (3.07 mg, 9%) and compound 299 (1.18 mg, 3%) were obtained.
compound 295: IH-NMR (400 MHz CD3OD): (57.92 (s, IH), 7.68 (d, IH), 7.48 (m, IH), 7.36 (d, IH), 7.14 (d, IH), 7.02 (m, IH), 4.05 (m, IH), 3.74 (m, 2H), 3.39 (m, 3H), 2.64
(d, IH), 2.16 (m, IH), 1.96 (m, IH), 1.84 (m, IH), 1.62 (m, IH), 1.42 (m, 2H), 1.23 (m,
6H); ESI MS: m/z 460 [M+H]+. compound 299: IH-NMR (400 MHz CD3OD): 37. S9 (s, IH), 7.67 (m, IH), 7.44 (m, IH),
7.31 (m, IH), 7.14 (m, IH), 6.99 (m ,1H), 4.04 (m, IH), 3.72 (m, 2H), 3.46 (m, 3H), 2.18 (m ,1H), 1.98 (m, IH), 1.84 (m, IH), 1.62 (m, IH), 1.41 (m, 2H), 1.22 (m ,6H); ESI MS: m/z 460 [M+H]+.
Example 180. Preparation of Compound 377
Figure imgf000524_0001
By using the same synthetic strategy as compound 434 described in Example 174, compound 377 (2.56 mg, 5%) was obtained. 1H-NMR (400 MHz CD3OD): SlM (s, IH), 7.82 (m, IH), 7.71 (m, 2H), 7.50 (m, IH), 7.12 (m, IH), 5.16 (m, IH), 5.01 (m, IH), 4.32 (m, 0.5H), 4.12 (m, 0.5H), 3.66 (m, IH), 3.52 (m, IH), 3.48 (s, 3H), 2.79 (m, IH), 2.61 (m, IH), 1.86-2.20 (m, 2H), 1.76 (m, 6H), 1.45 (m, IH); ESI MS: m/z 451 [M+H]+.
Example 181. Preparation of Compound 260
Figure imgf000524_0002
By using the same strategy as compound 434 described in Example 174, compound 260 was obtained (2.31 mg, 10%). 1H-NMR (400 MHz CD3OD): <58.03 (m, IH), 7.88 (m, IH), 7.74 (m, 2H), 7.52 (m, IH), 7.03 (m, IH), 4.09 (m, 1H); 3.78 (m, 2H), 3.44 (m, 3H), 2.51-2.67 (m, IH), 1.82-2.32 (m, 3H), 1.38-1.72 (m, 3H), 1.28 (m, 6H); ESI MS: m/z 451 [M+H]+.
Example 182. Preparation of Compound 344
Figure imgf000524_0003
By using the same strategy as compound 434 described in Example 174, compound 344 (2.7 mg, 12%) was obtained. 1H-NMR (400 MHz CD3OD): <57.86 (m. IH), 7.62 (m, IH), 7.12 (m, 3H), 4.12 (m, IH), 3.82 (m, 2H), 3.41 (m, 3H), 2.61 (m, IH)5 •2.23 (m, IH), 1.98 (m, 2H), 1.64 (m, IH), 1.42 (m, 2H), 1.29 (m, 6H); ESI MS: m/z 462 [M+H]+.
Example 183. Preparation of Compounds 420, 392 and 441
Figure imgf000525_0001
By using the same synthetic strategy as compound 434 described in Example 174, compound 420 (3.19 mg, 8%), compound 392 (0.49 mg, 1%), and compound 441 (1.18 mg, 3%) were obtained. compuond 420: 1H NMR (400 MHz CD3OD): <S7.82 (s, IH), 7.62 (d, IH), 7.03-7.18 (m, 3H), 5.15 (m, IH), 4.11-4.31 (m, IH), 3.63 (m, IH), 3.54 (m, IH), 3.32 (s, 3H), 2.91 (m, IH), 2.61 (m, IH), 1.87-2.18 (m, 2H), 1.76 (d, 6H), 1.51 (m, IH); ESI MS: m/z 462 [M+H]+. compound 392: 1H NMR (400 MHz CD3OD): £7.82 (d, IH), 7.57 (t, IH), 6.98-7.21 (m; 3H), 4.93-5.14 (m, IH), 4.10-4.35 (m, IH), 3.63 (m, IH), 3.54 (m, IH), 3.37 (d, 3H), 2.89 (m, IH), 2.62 (m, IH), 2.33 (m, 0.5H), 1.88-2.19 (m, 2H), 1.76 (d, 6H), 1.51 (m, IH). compound 441: 1H NMR (400 MHz CD3OD): (57.82 (d; IH), 7.56 (m, IH), 6.98-7.19 (m: 3H), 5.12 (m, IH), 4.38 (m, IH), 3.64 (m, IH), 3.56 (m, IH), 3.45 (s, 0.5H), 3.37 (d, 3H), 3.13 (m; 0.5H), 2.88 (m, IH), 2.49 (m, IH), 2.32 (m, IH), 2.08 (m, IH), 1.92 (m, IH), 1.72 (t, 6H), 1.48 (m, IH); ESI MS: m/z 462 [M+H]+.
Example 184. Preparation of Compound 436a and 436b
Figure imgf000525_0002
436a, b By using the same synthetic strategy as compound 434 described in Example 174, compound 436a (6.61 mg, 16%) and compound 436b (1.30 mg, 3%) were obtained. compound 436a: 1H-NMR (400 MHz CD3OD): <57.86 (d, IH), 7.66 (dd, IH), 7.41 (m, 2H), 7.32 (d, IH), 7.01 (m, 2H), 4.97-5.13 (m, IH), 4.01-4.35 (m, IH), 3.63 (m, IH), 3.52 (m, IH), 3.34 (d, 3H), 2.87 (m, IH), 2.45-2.66 (m, IH), 2.12 (m, IH), 2.05 (t, IH), 1.90 (m, IH), 1.76 (d, 3H), 1.71 (d, 3H), 1.40-1.65 (m, IH); ESI MS: 426 [M+H]+. compound 436b: 1H-NMR (400 MHz CD3OD): (57.86 (m, IH), 7.67 (m, IH), 7.41 (m, 2H), 7.34 (t, IH), 7.01 (m, 2H), 4.95-5.15 (m, IH), 4.01-4.35 (m, IH), 3.65 (m, IH), 3.52 (m, IH), 3.34-3.45 (d, 3H), 2.90 (m, IH), 2.50-2.70 (m, IH), 2.30 (t, IH), 2.15 (m, IH), 1.92 (m, IH), 1.78 (d, 3H), 1.72 (d, 3H), 1.48 (m, IH); ESI MS: 426 [M+H]+.
Example 185. Preparation of Compound 339
Figure imgf000526_0001
By using the same synthetic strategy as compound 434 described in Example 174, compound 339 (4.73 mg, 22%) was obtained. 1H-NMR (400 MHz CD3OD): δl .92 (m, 1H),7.69 (m, IH), 7.25 (m, 2H), 6.92 (m, IH), 6.67 (m, IH), 4.29 (m, IH), 3.67 (m, 3H), 3.40 (m, 3H), 2.84 (m, IH), 2.46 (m, 2H), 2.04 (m, IH), 1.88 (m, 3H), 1.69 (m, 3H), 1.42- 1.24 (m, 2H); ESI MS: m/z 444 [M+H]+.
Example 186. Preparation of Compounds 421, 444 and 419
Figure imgf000526_0002
By using the same synthetic strategy as compound 434 described in Example 174, compound 421 (2.38 mg, 7%), compound 444 (1.05 mg, 3%), and compound 419 ( 0.51 mg, 1.5%) were obtained: ESI MS: m/z 444 [M+H]+. compound 421: 1H-NMR (400 MHz CD3OD): £7.93 (m, IH), 7.72 (m, IH), 7.25 (m, 2H), 7.05 (m, IH), 6.90 (m, IH), 5.0-5.2(m. 2H), 4.1-4.4 (m, IH), 3.62 (m, IH), 3.62 (m, IH), 3.51 (m, IH), 3.43 (m, 3H), 2.9 (m, IH), 2.51-2.74 (m, IH), 2.0-2.2 (m, 2H), 1.75- 1.80 (m, 6H), 1.45-1.50 (m, IH); ESI MS: m/z 444 [M+H]+. compound 444: 1H-NMR (400 MHz CD3OD): <57.85 (m, lH),7.55-7.65 (m, IH), 7.19 (m, 2H), 6.97 (m, IH), 6.82 (m, IH), 4.0-4.25(m, IH), 3.62 (m, IH), 3.61 (m, IH), 3.51 (m, 2H), 3.35 (m, IH), 3.23 (m, 3H), 2.84 (m, IH), 2.25-2.50 (m, IH), 2.23 (m, IH), 1.65-1.70 (m, 6H), 1.30-1.45 (m, 2H); ESI MS: m/z 444 [M+H]+. compound 419: 1H-NMR (400 MHz CD3OD): <57.93 (m, IH), 7.67(m, IH), 7.25 (m, 2H), 6.80-7.01 (m, 2H), 4.44 (m, IH), 3.56-3.65 (m, 3H), 3.45 (m, 3H), 2.90 (m, IH), 2.3- 2.50 (m, 2H), 2.22 (m, IH), 1.65-1.70 (m, 6H), 1.45 (m, 2H); ESI MS: m/z 444 [M+H]+.
Example 187. Preparation of Compound 248
Figure imgf000527_0001
Experimental data:
Figure imgf000527_0002
248a
Preparation of compound 248a
The isophthalic acid (19.8 g, 300 mmol) was taken up in concentrated H2SO4 (136 mL) and heated at 600C. To this solution was added NBS (64.4 g, 360 mmol) in three portions every 20 minutes. When the reaction was completed based on TLC analysis, the mixture was poured into crushed ice (300 g) to get the solid. After filteration, the mixture was washed with water and hexane, and dried to give compound 248a (51 g, 70%). H- NMR (400 MHz DMSO-d6): (58.35-8.40 (s, IH), 8.20-8.30 (s, 2H).
Figure imgf000528_0001
248b
Preparation of compound 248b
A solution of 5-bromo-isophthalic acid (48 g, 197 mmol) in tulene was added SOCl2 (48 mL) and DMF (4 mL) at room temperature over 10 minute. The reaction mixture was refluxed for 3.5 hr and cooled to 0°C. The reaction mixture was added dropwise to NH4OH (400 mL) for 1 hr. The mixture was filtered to give the compound 248b (42 g, 87.5%). 1H-NMR (400 MHz DMSO-d6): <58.30-8.40 (s, IH), 8.10-8.20 (m, 4H), 7.50-7.60 (s, 2H).
Figure imgf000528_0002
Preparation of compound 248c
To a solution of dry DMF in dry CH3CN at -5°C to 0°C under a nitrogen atmosphere was added (ClCO)2 over 10 minutes. After being stirred for 15 minutes, 5- bromo-isophthalamide (42 g, 174 mmol) was added in one portion, and the mixture was stirred at 00C for 1.5 hrs. Pyridine was added dropwise over 5 mintutes. and the mixture was stirred at O0C for 2 hrs. 1 M HCl (80 mL) was added, and the mixture was extracted with ether (200 mL) for 2 times. The organic layer was concentrated in vacuo to give the compound 248c (28 g, 78.2%). 1H-NMR (400 MHz CDCl3): (58.00-8.10 (ss 2H)S 7.70- 7.80 (s, IH).
Figure imgf000529_0001
248d
Preparation of compound 248d
A solution of 4,4,4';4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (5.96 g, 24 mmol), 5-bromo-isophthalonitrile (4.52 g, 22 mmol), KOAc (6.28 g, 64 mmol) and
PdCl2(dppf)2 in DMSO (30 mL). The mixture was degassed, heated at 8O0C for 4 hr.
Water (20 mL) was added, and the mixture was extrated with ether (40 mL) for 3 times. The organic layer was added IN HCl (20 mL). dried over Na2SO4 and concentrated in vacuo to give the compound 248d (0.6 g, 10%). 1H-NMR (400 MHz DMSO-d6): <S8.60- 8.70 (s, 2H), 8.45-8.50 (s, IH), 8.30-8.40 (s, 2H).
Figure imgf000529_0002
Preparation of compound 248
By using the same strategy as compound 434 as described in Example 174. compound 248(2.22 mg, 6%) was obtained. 1H-NMR (400 MHz CD3OD): (58.32-8.34 (m, 2H), 8.10-8.20 (m, 2H)5 7.70-7.80 (m, IH), 7.00-7.10 (m, IH), 3.77 (ms IH), 3.43-3.45 (m, 2H), 3.31-3.32 (m, 3H), 2.68-2.71 (m ,1H), 1.41-1.23 (m, 5H), 1.20-1.35 (m, 7H); ESI MS: m/z 458 [M+H]".
Example 188. Preparation of Compound 297
Figure imgf000529_0003
By using the same strategy as compound 434 as described in Example 174, compound 297 (7.44 mg, 32%) was obtained. 1H-NMR (400 MHz CD3OD): <57.85 (m, 3H),7.71 (m, IH), 7.66 (m, 2H), 7.00 (m, IH)5 4.0 (m, IH), 3.77 (m, 2H), 3.30 (m, 3H), 2.69 (m, IH), 2.20 (m, IH), 1.88-2.10 (m, 2H), 1.63 (m, IH), 1.47 (m, 2H), 1.26 (m, 6H); ESI MS: m/z 476 [M+H]+.
Example 189. Preparation of Compounds 442, 450 and 423
Figure imgf000530_0001
By using the same strategy as compound 434 as described in Example 174, compound 442 (4.31 mg, 10%), compound 450 (1.23 mg, 3%), and compound 423 (0.65 mg, 2%) were obtained. compound 442: 1H NMR (400 MHz CD3OD): <57.88 (m, 3H), 7.70 (d, IH), 7.59 (d, 2H), 7.04 (d, IH), 5.13 (d, IH), 5.02 (d, IH), 4.19-4.33 (m, IH), 3.61 (d, 2H), 3.37 (s, 3H), 2.86 (m, IH), 2.61 (m, IH), 1.82-2.18 (m; 2H), 1.75 (d, 6H), 1.51 (m, IH); ESI MS: m/z 476 [M+H]+. compound 450: 1H NMR (400 MHz CD3OD): <57.82 (m, 3H), 7.58 (m, 3H), 6.96 (m, IH), 5.03 (m, 0.6H), 4.21 (m, 0.5H), 4.01 (m, IH), 3.52 (m, 2H), 3.31 (d, 3H), 2.81 (m, IH), 2.48 (m, IH), 2.23 (m, IH), 1.82-2.10 (m, 2H), 1.67 (d, 6H), 1.38 (m, IH); ESI MS: m/z 476 [M+H]+. compound 423: 1H NMR (400 MHz CD3OD): J7.79 (m, 3H), 7.63 (m, 3H), 6.95 (t, IH), 5.06 (m, IH), 4.22 (m, IH), 3.45-3.52 (m, 2H), 3.30 (d, 3H), 2.72 (m, 2H), 2.48 (m, IH), 2.23 (m, 0.5H), 1.97 (m; 0.5H), 1.83 (m, IH), 1.66 (t, 6H), 1.23 (m, IH): ESI MS: m/z 476 [M+H]+.
Example 190. Preparation of Compound 412
Figure imgf000530_0002
By using the same strategy as compound 434 as described in Example 174, compound 412 (5.16 mg, 12%) was obtained. 1H-NMR (400 MHz CD3OD): <57.85-7.95 (m, IH)5 7.66-7.72 (m, IH), 7.61-7.65 (m, IH), 7.52-7.60 (m, IH), 7.40-7.48 (m, IH), 7.31-7.38 (m, IH), 7.04-7.05 (m, IH), 4.98-5.20 (m, 2H), 4.09-4.39 (m, IH), 3.62-3.75 (m, IH), 3.56-3.61 (m, IH), 3.38 (s, 3H), 2.90-2.94 (m, IH), 2.57-2.70 (m, IH), 2.07-2.21 (m, IH), 1.90-2.06 (m, IH), 1.81-1.83 (m, 3H), 1.75-1.77 (m, 3H), 1.48-1.70 (m, IH); ESI MS: m/z 442 [M+H]+.
Example 191. Preparation of Compound 264
Figure imgf000531_0001
Compound 1
By using the same strategy as compound 434 as described in Example 174, compound 264 (2.20 mg, 10%) was obtained. 1H-NMR (400 MHz CD3OD): 57.85 (m, IH), 7.64 (m, IH), 7.59 (m, IH), 7.50 (m, IH), 7.39 (t, IH), 7.32 (m, IH), 7.01 (d, IH), 4.03 (m, IH), 3.76 (d, 2H), 3.32-3.42 (m, 3H), 2.67 (d, IH), 2.18 (m, IH), 1.98 (m, IH), 1.86 (m, IH), 1.63 (m, IH), 1.25-1.50 (m, 2H), 1.23 (d, 6H); ESI MS: m/z 442 [M+H]+.
Example 192. Preparation of Compound 294
Figure imgf000531_0002
Pd(PPh3 )4 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with a solution of 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-methyl-2'//- spiro[cruOman-4,541,2:4]oxadiazol]-3'-amine (50 mg, 0.12 mmol) in TΗF (5 mL), K2CO3 (2 N, 0.1 mL) and 3-bromophenylboronic acid (24.6 mg, 0.12 mmol). The mixture was refluxed overnight, and concentrated in vacuo, the residue was purified by preparative TLC and preparative HPLC to give compound 294 (1.62 mg, 3%). 1H-NMR (400 MHz CD3OD): (57.84 (m, IH), 7.75 (s, IH), 7.66 (m, IH), 7.56 (t, IH), 7.48 (m, IH), 7.34 (t, IH), 7.02 (m, IH), 4.01-4.12 (m, IH), 3.73 (m, 2H), 3.38 (d, 3H), 2.67 (d, IH), 2.10-2.26 (m, IH), 1.98 (t, IH), 1.72-1.90 (m, IH)5 1.61-1.69 (m, IH), 1.36-1.49 (m, 2H), 1.22-1.31 (m, 6H); ESI MS: m/z 488 [M+3H]+.
Example 193. Preparation of Compound 391
Figure imgf000532_0001
Figure imgf000532_0002
Experimental data:
Figure imgf000532_0003
Preparation of compound 1
Under nitrogen, 2,2,6,6-tetramethylpiperidine (7.1 g, 49.6 mmol) was dissolved in dry THF (100 mL) and cooled to -100C before H-BuLi (2.5 M in hexane, 19.8, 49.6 mmol) was added in 2 minutes. The mixture was stirred for 10 minutes, cooled down to -78°C, added B(OZ-Pr)3 (10.8 g. 57.4 mmol) in 2 minutes, stirred for 5 minutes, added the solution of 4-fluorobenzonitrile (5 g, 41 mmol) in dry THF (140 mL) dropwise in 5 minutes. The reaction mixture was left in the cooling bath overnight, slowly warmed to room temperature, quenched with glacial acetic acid (3.3 mL), added of 2.2-dimethyl-l,3- propandiol (6.4 g. 61.5 mmol), stirred for lhr at room temperature, added ethyl acetate, and washed with aqueous KH2PO4 solution (10w/v%, 3 x 10OmL). The water phase was extracted with ethyl acetate, and the combined organic layer was dried and evaporated to give the crude product, which was recrystallize to give the compound 1 (1 g, 10%). H- NMR (CDCl3): <58.OO (m, IH), 7.62 (m, IH), 7.03 (m, IH), 3.75 (d, 4H), 1.01 (s, 6H).
Figure imgf000533_0001
By using the procedure for compound 434 as described in Example 174, compound 391 (5.38 mg, 2.6%) was obtained. 1H-NMR (400 MHz CD3OD): (57.91 (m, IH), 7.71-7.88 (m, 2H), 7.63 (m, IH), 7.38-7.43 (m,lH), 7.04 (d, IH), 4.48-5.12 (m, IH), 4.08-4.35 (m, IH), 3.44-3.69 (m, 2H), 3.34 (m, 3H), 2.89 (m, IH), 2.49-2.65 (m, IH), 1.84-2.19 (m, 2H), 1.68-1.73 (m, 6H), 1.51 (m, IH), 1.26 (m, IH): ESI MS: m/z 451 [M+H]+ .
Example 194. Preparation of Compound 261
Figure imgf000533_0002
By using the same procedure for compound compound 434 as described in Example 174, compound 261 (1.52 mg, 4 %) was obtained. 1H-NMR (400 MHz CD3OD): (57.68 (d, IH), 7.56 (m, 2H), 7.47 (m, IH), 7.18 (m, IH), 6.91 (d, IH), 4.03 (m, IH), 3.71 (m, IH), 3.66 (m, IH), 3.31 (m, IH), 3.27 (s, 3H), 2.34-2.56 (m, IH), 1.92-2.23 (m, 2H), 1.65-1.87 (m, IH), 1.56 (m, IH), 1.48 (m, IH), 1.33 (m, IH), 1.23 (m, 3H), 1.18 (m, 3H); ESI MS: m/z 451 [M+H]+.
Example 195. Preparation of Compound 425
Figure imgf000533_0003
C "» Λ
Experimental data:
Figure imgf000534_0001
Preparation of compound 1
A stirred solution of 3-bromo-4-methylbenzonitrile (3.5 g, 17.86 mmol) in dry THF was added «-BuLi (10.71 m L) slution dropwise at -78°C, and the mixture was stirred for 15 minutes, followed by the addition of triisopropyl borate (6.71g, 35.71 mmol) in one portion. The reaction flask was kept in a cooling bath for 30 min., and room temperature for 3 hours. The solvent was removed, and the residue was dissolved in ether. The solution was washed with IN HCl solution and water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by recrystallyzation from the mixture of CH2Cl2 and hexane to give 5-cyano-2-methylphenylboronic acid (800 mg, 20%). 1H- NMR (CDCl3 400 MHz): (57.50-7.78 (m, 2H), 7.30 (d, IH), 2.42 (d, 3H).
Figure imgf000534_0002
By using the same procedure for compound 434 as described in Example 174. compound 425 (5 mg, 10%) was obtained. 1H-NMR (400 MHz CD3OD): (57.48 (t, 2H), 7.38 (m, 2H), 7.16 m, IH), 6.88 (d, IH), 5.06 (d, IH), 4.89 (d, IH), 4.03-4.28 (m, IH), 3.54-3.72 (m, 2H), 3.18-3.32 (m, 3H), 2.72 (m, IH), 2.15-2.32 (m, 8H),1.61-1.73 (m, 6H); ESI MS: m/z 447 [M+H]+.
Example 196. Preparation of Compound 292
Figure imgf000535_0001
By using the same procedure as compound 434 as described in Example 174, compound 292 (5 mg, 10%) was obtained. 1H-NMR (400 MHz CD3OD): «57.54-7.62 (m, IH)5 7.52 (d, IH), 7.45 (d, IH), 7.32-7.38 (m, IH), 7.00 (t, IH), 4.05 (d, IH), 3.76 (m, 2H), 3.36 (s, 3H), 2.63 (d, IH), 2.41-2.58 (m, 0.4H), 2.31 (s, 3H)5 2.11-2.27 (m, IH), 2.04 (t, IH)5 1.82-1.92 (m, IH), 1.61-1.69 (m, IH)5 1.40-1.52 (m, IH), 1.34 (t, IH), 1.22-1.31 (m, 6H); ESI MS: m/z 447 [M+H]+.
Example 197. Preparation of Compound 354
Figure imgf000535_0002
354a 354b 354c
Figure imgf000535_0003
Experimental data:
Figure imgf000535_0004
Preparation of compound 354a
A solution of 3-nitro-4-(trifluoromethyl)benzoic acid (10 g. 43 mmol) in EtOH (100 mL) was added Pd/C (1 g, 10%). The reaction was carried under H2 at room temperature overnight. The solution was filtered, and the filtrate was concentrated to give the compound 354a (10.2 g, crude). 1H NMR (400 MHz DMSO-d6): £7.42 (s, 2H)5 7.08 (s5 IH)5 5.82 (s5 2H).
Figure imgf000536_0001
354b
Preparation of compound 354b
3-Amino-4-(trifluoromethyl)benzoic acid (10.2 g, 0.05 mol) was dissolved in a solution of 47% HBr (40 mL) in H2O (80 mL). A solution OfNaNO2 (4.12g, 0.06 mol) in H2O (40 mL) was added dropwise at 0°C. After being stirred for 30 minutes, the mixture was added the solution of CuBr (12.16 g, 0.085 mol) in a mixture of HBr (40 mL) and H2O (60 mL) at 0°C. and heated at 75°C for 2 h, treated with 20 % NaOH until PH>10. The resulting copper salts were removed by filtration. The mixture was acidified to PH=I with HCl solution, extracted with DCM, dried over Na2SO4, filtered, and concentrated to give the crude compound 354b (9.4 g, 70%). 1H NMR (400 MHz DMSO-d6): «58.27 (m, IH), 8.09 (m, IH), 7.98 (d, IH).
Figure imgf000536_0002
354c
Preparation of compound 354c A solution of 3-bromo-4-(trifluoromethyl)benzoic acid (9.4 g, 35 mmol) in SOCl2
(60 mL) was refluxed for 2 hours. After removal of the extra SOCl2, NH3-H2O (40 mL) was added dropwise at -500C, and the mixture was stirred at room temperature overnight. The mixture was concentrated, added H2O, extracted with DCM. The organic layer was dried and concentrated to give the compound 354c (10.2 g, crude).
Figure imgf000536_0003
354d
Preparation of compound 354d
To a solution of 3-bromo-4-(trifluoromethyl)benzamide (5 g. 18.7 mmol) in DCM (50 mL) was added TFAA (1 1.75 g, 56 mmol) and DIEA (12 g, 94 mmol) at 0°C, and the mixture was stirred at°C for 2 hour. The solution was washed by 1 N HCl. water and brine, dried, and concentrated, the residue was purified by chromatography to afford the compound 354d (2.3 g, 49%). 1H NMR (400 MHz CDCl3): (57.94 (s, IH), 7.73 (t, IH), 7.66 (t, IH).
Figure imgf000537_0001
354e
Preparation of compound 354e
To a solution of 3-bromo-4-(trifluoromethyl)benzonitrile (288 mg, 0.91 mmol) in 1,4-dioxane (8 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (254 mg, 1 mmol), KOAc (268 mmol, 2.74 mmol) and Pd(dppf)Cl2 under N2. The reaction mixture was heated at 100°C in microwave for 1 hour, and filtered. The filtration was concentrated, and the residue was purified by preparative TLC to afford the compound 354e (83 mg, 31%). 1H NMR (400 MHz CDCl3): <57.97 (s, IH), 7.72 (m, 2H), 1.30 (s, 12H).
Figure imgf000537_0002
Preparation of compound 354
By using the same procedure for compound 434 as described in Example 174, compound 354 (5.12 mg, 21%) was obtained. 1H NMR (400 MHz CD3OD): <J7.98 (m, 2H)5 7.77 (s, IH), 7.63 (m, 1 H), 7.42 (m, IH), 7.02 (m, IH), 4.12 (m, IH), 3.79 (m, 2H), 3.48 (s, 3H), 2.71 (d, IH), 2.51 (m, IH), 2.24 (m, IH), 2.07 (t, IH), 1.95 (m, IH), 1.68 (m, IH), 1.49 (m, 2H), 1.38 (d, 6H); ESI MS: m/z 501 [M+H]+.
Example 198. Preparation of Compound 430
Figure imgf000538_0001
Preparation of compound 430
By using the same strategy for compound 434 as described in Example 174, compound 430 (6.1 mg, 12%) was obtained. 1H-NMR (400 MHz CD3OD): <57.68 (m, 3H), 7.46 (m, IH), 7.32 (m, IH), 6.92 (m, IH)5 5.02 (m, IH), 4.38 (m, IH), 4.21 (m, 0.5H), 3.98 (m, 0.5H), 3.52 (m, IH), 3.41 (m, IH), 3.24 (m, 3H), 2.78 (m, IH), 2.48 (m, IH), 1.75-2.09 (m, 2H), 1.65 (m, 6H), 1.45 (m, IH); ESI MS: m/z 451 [M+H]+.
Example 199. Preparation of Compounds 312 and 306
Figure imgf000538_0002
By using the same synthetic strategy for compound 434 as described in Example 174. compound 312 and compound 306 (5.50 mg, 25%) were obtained. compound 312: 1H-NMR (400 MHz CD3OD): (57.82-7.84 (d, 2H), 7.77-7.80 (d, IH), 7.70-7.73 (t, IH), 7.56-7.60 (d, IH), 7.40-7.42 (t IH), 7.02-7.06 (t, IH), 4.05-4.08 (t, IH), 3.72-3.77 (m, 2H), 3.28-3.39 (m, 3H), 2.65-2.69 (m, IH), 2.17-2.18 (m, IH), 2.01-2.02 (m, IH), 1.83-1.86 (m, IH), 1.62-1.65 (m, IH), 1.44-1.48 (m, IH), 1.33-1.36 (m, IH), 1.24-1.30 (m, 6H); ESI MS: m/z 451 [M+H]+. compound 306: 1H-NMR (400 MHz CD3OD): <57.82-7.84 (d, 2H), 7.77-7.80 (d, IH), 7.70-7.73 (t, IH), 7.56-7.60 (d, IH), 7.40-7.42 (t, IH), 7.02-7.06 (t, IH), 4.05-4.08 (t, IH), 3.73-3.78 (m, 2H), 3.33-3.46 (m, 3H), 2.65-2.69 (m, IH), 2.17-2.18 (m, IH), 2.01-2.02 (m, IH), 1.83-1.86 (m, IH), 1.62-1.65 (m, IH), 1.44-1.48 (m, IH), 1.33-1.36 (m, IH), 1.24-1.30 (m, 6H): ESI MS: m/z 451 [M+H]+.
Example 200. Preparation of Compound 257
Figure imgf000539_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 257 (0.5 mg, 3%) was obtained. 1H-NMR (400 MHz CD3OD): £8.31 (s, IH), 8.22 (s, IH), 8.05 (s, IH), 7.73-7.81 (d, IH), 7.08-7.11 (d, IH), 4.08-4.12 (m, 2H), 3.74-3.82 (m, 2H), 3.44-3.49 (m, 3H), 2.66-2.74 (m, IH), 2.13-2.31 (m, 2H), 1.96-2.08 (t, IH), 1.80-1.92 (m, IH), 1.62-1.69 (m, IH), 1.38-1.51 (m, IH), 1.22-1.30 (m, 6H); ESI MS: m/z 501 [M+H]+.
Example 201. Preparation of Compound 300
Figure imgf000539_0002
Experimental data:
Figure imgf000539_0003
300a
Preparation of compound 300a
A glass tube was charged with a mixture of 6-bromo-2-(2,2-dimethyltetrahydro- 2H-pyran-4-yl)chroman-4-one (3 g, 8.88 mmol): KCN (1.14 g, 17.76 mmol); and (NHO2CO3 (5.96 g, 62.12 mmol). After formamide (20 mL) was added to fill the tube completely, the mixture was heated at 70°C for 2 days and at 110°C for 1 day, cooled, and poured into ice. After acidification with concentrated HCl solution, the precipitate was filtered, washed with water, solved in ethyl acetate, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the compound 300a (2.6 g, 70%). 1H-NMR (400 MHz CDCl3): <58.61 (br, IH, CONH), 7.20-7.29 (m, 2H), 6.71-6.74 (m, IH), 6.03- 6.05 (m, IH), 4.47-4.52 (m, IH), 3.66-3.77 (m, IH), 3.58-3.64 (m, IH), 2.15-2.18 (m, IH), 1.89-1.98 (m, IH), 1.64-1.76 (m, 2H), 1.30-1.50 (m, 2H), 1.14-1.21 (m, 6H).
Lawesson's reagent
Figure imgf000540_0001
Figure imgf000540_0002
300b
Preparation of compound 300b
A suspension of 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4- yl)spiro[chroman- 4,4'-imidazolidine]-2',5'-dione (2.6 g, 6.37 mmol) and Lawesson's Reagent (2.574 g, 6.36 mmol) in dry 1,4-dioxane (36 mL) was heated at 120°C for 30 minutes in microwave. The mixture was concentrated in vacuo and the residue was purified by column chromatography to give the compound 300b (1.4 g, 50%).
Figure imgf000540_0003
300c
Preparation of compound 300c
To a solution of 6-bromo-2-(2.2-dimethyltetrahydro-2//-pyran-4-yl)-2'- thioxospiro- [chroman-4.4'-imidazolidin]-5'-one (1.4 g, 3.3 mmol) in MeOH (70 mL) was added NaOH (0.6 N, 12 mL) and MeI (12 mL). The reaction mixture was refluxed for 60 min., and concentrated in vacuo, the residue was purified by column chromatography to give the compound 300c (200 mg, 13 %).
Figure imgf000541_0001
Preparation of compound 30Od
A solution of 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)- 1 '-methyl -21- (methyltnio)spiro[chroman-4,4'-imidazol]-5'(l'H)-one (200 mg, 0.44 mmol), NH4I (200 mg) in NH3/EtOH (15 mL, 1 N) was heated at 120°C in a tube in a microwave reactor for 2.5 h. After cooling, the mixture was concentrated in vacuum to afford the compound 30Od (100 mg, 50%).
Figure imgf000541_0002
Preparation of compound 300
By using the same synthetic strategy for compound 434 as described in Example 174, compound 300 (1.96 mg, 10%) was obtained. 1H-NMR (400 MHz CDCl3): (57.49 (d, IH), 7.35 (d, IH), 7.17 (m, 2H), 7.06 (m, 2H), 4.58 (m, IH), 3.79 (d, 2H), 3.28 (s, 1.3H), 3.08 (d, 1.5H), 2.47 (m, IH), 2.16 (m, 2H), 1.92 (t, IH), 1.63 (m, IH), 1.42 (m, 2H), 1.26 (m, 6H); ESI MS: m/z 444 [M+H]+.
Example 202. Preparation of Compounds 431 and 254
Figure imgf000541_0003
By using the same synthetic strategy for compound 434 as described in Example 174, compounds 431 and 254 were obtained. compound 431: (2.19 mg, 10%), 1H-NMR (400 MHz CD3OD): «57.52 (d, IH), 7.48 (t, IH), 7.52 (d, IH), 7.48 (L IH), 7.40 (s, IH), 7.32 (t, IH), 7.28 (t, IH), 7.00 (L IH), 4.55- 4.57 (m, IH), 3.76 (d, 2H), 3.07 (d, 3H), 2.43 (d, IH), 2.06-2.17 (m, 2H), 1.85-1.91 (m, IH), 1.57-1.66 (m, IH), 1.32-1.45 (m, 2H), 1.22-1.31 (m, 6H); ESI MS: m/z 456 [M+H]+. compound 254 (7.53 mg, 35%), 1H-NMR (400 MHz MeOD): 7.56 (d, IH), 7.48 (t, IH), 7.40 (s, IH), 7.32 (t, IH), 7.28 (t, IH), 7.00 (t, IH), 4.53-4.56 (m, IH), 3.76 (d, 2H), 3.24 (s, 3H), 2.43 (d, IH), 2.10-2.16 (m, 2H), 1.88-1.91 (m, IH), 1.58-1.60 (m, IH), 1.38-1.44 (m, 2H), 1.22-1.31 (m, 6H); ESI MS: m/z 456 [M+H]+.
Example 203. Preparation of Compounds 417 and 190
Figure imgf000542_0001
By using the same synthetic strategy for compound 434 as described in Example 174, two compounds were obtained. compound 417 (1.59 mg, 15%), 1H-NMR (400 MHz CD3OD): δl.59 (d, IH), 7.43 (d, 2H), 7.32 (d, IH)5 7.12 (d, IH), 7.03 (d, IH), 4.56-4.67 (m, IH), 3.76 (d, 2H), 3.09 (d, 3H), 2.43 (d, IH), 2.08-2.15 (m, 2H), 1.87-1.91 (m, IH), 1.59-1.62 (m, IH), 1.32-1.43 (m, 2H), 1.21-1.26 (m, 6H); ESI MS: m/z 472 [M+H]+. compound 190 (3.97 mg, 20%), 1H-NMR (400 MHz CD3OD): <57.59 (d, IH), 7.43 (d, 2H), 7.32 (d, IH), 7.12 (d, IH), 7.03 (d, IH), 4.54-4.57 (m, IH), 3.76 (d, 2H), 3.22 (s, 3H), 2.43 (d, IH), 2.06-2.17 (m, 2H), 1.84-1.93 (m, IH), 1.61-1.69 (m, IH), 1.36-1.49 (m, 2H), 1.22-1.31 (m, 6H); ESI MS: m/z 472 [M+H]+.
Example 204. Preparation of Compound 194
Figure imgf000542_0002
By using the same synthetic strategy for compound 434 as described in Example 174, compound 194 (4.61 mg, 21%) was obtained. 1H-NMR (400 MHz CD3OD): <57.71- 7.74 (m, IH), 7.54-7.64 (m, 2H), 7.38-7.46 (m, 2H), 6.97-7.00 (m, IH), 4.35-4.51 (m, 0.6H), 3.66 (m, 0.4H), 3.16 (m, 2H), 2.93 (m, IH), 2.32 (m, IH), 2.06 -2.20 (m, 2H), 1.70- 1.90 (m, 2H), 1.31-1.60 (m, 2H), 1.15-1.18 (m, 2H); ESI MS: m/z 463 [M+H]+.
Example 205. Preparation of Compound 229
Figure imgf000543_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 229 (3.11 mg, 15%) was obtained. 1H-NMR (400 MHz CD3OD): <S7.51 (d, IH), 7.40 (s, IH), 7.03-7.11 (m, 3H), 4.56-4.59 (m, IH), 3.75 (d, 2H), 3.24 (s, 3H), 2.43 (d, IH), 2.08-2.27 (m, 2H), 1.84-1.93 (m, IH), 1.52-1.62 (m, IH), 1.32-1.45 (m, 2H), 1.22-1.27 (m, 6H); ESI MS: m/z 474 [M+H]+.
Example 206. Preparation of Compounds 452 and 241
Figure imgf000543_0002
By using the same synthetic strategy for compound 434 as described in Example
174, compound 452 and compound 241 (3.57 mg, 18%) were obtained. compound 452: 1H-NMR (400 MHz CD3OD): δlM (d, IH), 7.25-7.40 (m, 4H), 7.01- 7.04 (m, 3H), 4.55-4.56 (m, IH), 3.74 (d, 2H), 3.06(d, 3H), 2.43 (d, IH), 2.11 (m, 2H), 1.84-1.93 (m, IH), 1.61-1.64 (m, IH)5 1.34-1.42 (m, 2H), 1.22-1.31 (m, 6H); ESI MS: m/z 438 [M+H]+. compound 241: 1H-NMR (400 MHz CD3OD): <S7.54 (d, IH), 7.29-7.40 (m, 4H), 7.00- 7.04 (m, 2H), 4.52-4.60 (m, IH), 3.79 (d, 2H), 3.26(s, 3H), 2.43 (d, IH), 2.09-2.20 (m, 2H), 1.86-1.93 (m, IH), 1.60-1.65 (m, IH), 1.36-1.49 (m, 2H), 1.22-1.31 (m, 6H): ESI
Figure imgf000543_0003
Example 207. Preparation of Compounds 372 and 231
Figure imgf000544_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 372 (0.86 mg, 4%) and compound 231 (1.25 mg, 5%) were obtained. compound 372: 1H NMR (400 MHz CD3OD): δl '.46-7.77 (m, 2H), 6.89-7.21 (m, 4H), 4.56 (m, IH), 3.78 (m, 2H), 3.06 (d, 3H), 2.44 (m, IH), 2.14 (m, 2H), 1.91 (m, IH), 1.60- 1.70 (m, IH), 1.43 (m, 2H), 1.28 (m, 6H); ESI MS: m/z 456 [M+H]+. compound 231: 1H NMR (400 MHz CD3OD): 37.53 (m, IH), 7.38 (m, IH), 7.18 (m, 2H), 6.96 (m, IH), 6.75 (m, IH), 4.47 (m, 0.7H), 3.84 (m, 0.3H), 3.66 (m, 2H), 3.23 (s, 3H), 2.01-2.42 (m, 3H), 1.89 (m, IH), 1.53 (m, IH), 1.30-1.36 (m, 2H), 1.17 (m, 6H); ESI MS: m/z 456 [M+H]+.
Example 208. Preparation of Compound 185
Figure imgf000544_0002
By using the same synthetic strategy for compound 434 as described in Example 174, compound 185 (2.26 mg, 4%) was obtained. 1H-NMR (400 MHz CD3OD): <58.28 (m, 2H), 8.10 (m, IH), 7.68 (m, IH), 7.60 (m, IH), 7.12 (ms IH), 4.61 (m, IH), 3.78 (m, 2H), 3.34 (s, IH), 3.26 (s, 2H), 2.48 (m, IH), 2.12-2.19 (m, 2H), 1.91 (m, IH), 1.63 (m, IH)5 1.46 (m, 2H), 1.25 (m, 6H); ESI MS: m/z 470 [M+H]÷.
Example 209. Preparation of Compound 200
Figure imgf000544_0003
By using the same synthetic strategy for compound 434 as described in Example 174, compound 200 (4.49 mg, 19%) was obtained. 1H-NMR (400 MHz CD3OD): <57.77- 7.82 (m, 2H), 7.51-7.63 (m, 3H), 7.35-7.46 (m, IH), 7.06-7.09 (m, IH), 4.56-4.60 (m, 0.8H), 3.96 (m, 0.2H), 3.75-3.78 (m, 2H), 3.32 (s, IH), 3.24 (s, 2H), 2.42-2.48 (m,lH), 2.12-2.19 (m, 2H), 1.90-1.93 (m, IH), 1.61-1.65 (m, IH), 1.37-1.46 (m, 2H), 1.25-1:30 (m, 6H); ESI MS: m/z 488 [M+H]+.
Example 210. Preparation of Compound 197
Figure imgf000545_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 197 (1.61 mg, 7%) was obtained. 1H NMR (400 MHz CD3OD): δl.54 (m, 2H), 7.46 (m, IH), 7.38 (m, 2H), 7.30 (m, IH), 7.02 (m, IH), 4.56 (m, IH), 3.76 (m, 2H), 3.24 (s, 3H), 2.46 (m, IH), 2.12 (m, 2H), 1.90 (m, IH), 1.62 (m, IH), 1.44 (m, IH), 1.38 (m, IH), 1.27 (s, 3H), 1.23 (s, 3H); ESI MS: m/z 454 [M+H]+.
Example 211. Preparation of Compound 246
Figure imgf000545_0002
Pd(PPh3)4 (3 mg) under Ar2 was treated sequentially with the compound 246a (20 mg, 0.05 mmol), K2CO3 (2 N, 40 uL) in THF (1 mL), and 3-bromophenylboronic acid (11 mg, 0.1 mmol). The mixture was refluxed overnight, concentrated in vacuo, the residue was purified by preparative TLC and preparative HPLC to give compound 246 (2.0 mg, 7%). 1H-NMR (400 MHz CD3OD): <57.66 (d, IH), 7.51 (m, IH), 7.47 (m, IH), 7.38-7.41 (t, IH), 7.35-7.39 (d, IH), 7.24-7.28 (t, IH), 6.97-7.00 (t, IH), 4.53-4.56 (m, IH), 3.70- 3.72 (m, 2H), 3.25 (s, 3H), 2.36-2.40 (m, IH), 2.05-2.12 (m, 2H), 1.84-1.85 (m, IH), 1.54- 1.58 (m, IH), 1.31-1.38 (m, 2H), 1.19-1.28 (m, 6H); ESI MS: m/z 500 [M+3H]+.
Example 212. Preparation of Compound 218
Figure imgf000546_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 218 (1.08 mg, 3%) was obtained. 1H NMR (400MHz CD3OD): <57.86- 7.88 (d, IH), 1.12-1.16 (d, IH), 7.51-7.53 (m, IH), 7.35-7.40 (m, 2H), 7.06-7.08 (d, IH), 3.76-3.79 (m, 2H), 3.23 (s, 2H), 2.40-2.48 (m, IH), 2.12-2.16 (m, 2H), 1.87-1.96 (m, IH), 1.60-1.65 (m, IH), 1.30-1.38 (m, 2H), 1.22-1.28 (m, 6H); ESI MS: m/z463 [M+H]+.
Example 213. Preparation of Compounds 222 and 437
Cs2CO3
Figure imgf000546_0002
Figure imgf000546_0003
By using the same synthetic strategy for compound 434 as described in Example 174. compound 222 (2.45 mg, 7%) and compound 437 (1.08 mg, 6%) were obtained. compound 222: 1H-NMR (400 MHz CD3OD): <57.51-7.53 (d, IH), 7.37-7.43 (m, 2H), 7.20-7.22 (m, IH), 7.10 (d, IH), 6.95-7.00 (m, IH), 4.51-4.54 (m, IH), 3.70-3.72 (m, 2H), 2.92-3.02 (s, 3H), 2.37-2.47 (m, IH), 2.21 (m, 3H), 2.04-2.10 (m; 2H), 1.80-1.87 (m, IH), 1.55-1.58 (m, IH), 1.38-1.43(m, 2H), 1.18 (m, 6H); ESI MS: m/z 459 [M+Hf. compound 437: 1H-NMR (400 MHz CD3OD): δl.51-7.52 (d, IH), 7.34-7.40 (m, 2H), 7.18-7.22 (m, IH), 7.07 (s, IH), 6.94-7.00 (m, IH), 4.50 (m, 0.7H), 3.85 (m, 0.3H), 3.64- 3.70 (m, 2H), 3.12 (s, 3H), 2.39 (m, 0.8H), 2.23 (m, 0.4H), 2.16-2.20 (m, 3H), 2.03-2.07 (m, 2H), 1.79-1.85 (m, IH), 1.52-1.57 (m, IH), 1.25-1.35 (m, 2H); 1.17 (m, 6H); ESI MS: m/z 459 [M+Hf. Example 214. Preparation of Compound 284
Figure imgf000547_0001
By using the same synthetic strategy for compound 434 as described in Example 174, compound 284 (3.89 mg, 16%) was obtained. 1H NMR (400 MHz CD3OD): <57.88- 7.95 (m, 2H)5 7.68-7.71 (m, IH), 7.27-7.30 (m, IH)5 7.00-7.08 (m, 2H), 4.55-4.60 (m, IH)5 3.70-3.79 (m, 2H), 3.19 (s, 3H), 2.42-2.47 (m, IH), 2.10-2.29 (m, 2H), 1.82-1.91 (m, IH)5 1.60-1.65 (m, IH)5 1.37-1.43 (m, 2H)5 1.27-1.30 (m, 6H); ESI MS: m/z 513 [M+H]+.
Example 215. Preparation of Compound 212
Figure imgf000547_0002
By using the same synthetic strategy for compound 434 as described in Example 1745 compound 212 (2.02 mg, 9%) was obtained. 1H NMR (400 MHz CD3OD): J7.70- 7.80 (m, 2H), 7.50-7.52 (m, IH), 7.31-7.44 (m, 2H), 7.09-7.11 (m, IH)5 4.59-4.62 (m5 IH)5 3.78-3.80 (m, 2H), 3.26 (s, 3H)5 2.46-2.50 (m, IH), 2.14-2.21 (m, 2H), 1.92-1.95 (m, IH), 1.62-1.64 (m, IH)5 1.35-1.48 (m, 2H), 1.26-1.32 (m, 6H); ESI MS: m/z 463 [M+H]+.
Example 216. Preparation of Compound 213
Figure imgf000547_0003
By using the same synthetic strategy for compound 434 as described in Example
174, compound 213 (2.0 mg5 8%) was obtained. 1H-NMR (400 MHz CD3OD): (58.23- 8.26 (d, IH), 8.12-8.14 (d, IH), 8.01-8.06 (t, IH), 7.63-7.68 (d, IH), 7.58-7.60 (t, IH), 7.08-7.13 (t, IH), 4.52-4.56(m, IH), 3.74-3.77 (m, IH), 3.25 (s, 3H), 2.42-2.48 (m, IH), 2.11-2.18 (m, 2H), 1.85-1.92 (m, IH), 1.59-1.62 (m, IH), 1.38-1.45 (m, 2H), 1.23-1.35 (m, 6H); ESI MS: m/z 513 [M+H]+.
Example 217. Preparation of Compound 332
Figure imgf000548_0001
Experimental data:
Figure imgf000548_0002
Preparation of compound 332a
A steel autoclave was charged with a mixture of 6-bromo-2',4',5',6'-tetrahydrosp- iro[chroman-2,3'-pyran]-4-one (8.6 g, 28.86 mmol), KCN (3.75 g, 57.72 mmol) and (NILO2CO3 (19.4 g, 202.02 mmol) in formamide (80 mL). The mixture was stirred at 70°C for 2 days and at 110°C for 1 day. The reaction mixture was then cooled to room temperature and poured into ice (80 g). The solution was acidified with concentrated HCl solution to pH=l , and filtered. The filter cake was washed with water (15 mLχ2), and dissolved in ethyl acetate (200 mL). After drying over Na2SO4 and concentrated in vacuo. the pure compound 332a (8 g, 80%) was obtained. 1H-NMR (CDCl3 400MHz): <57.30- 7.26 (m, IH), 7.16 (d, IH), 6.83-6.69 (m, IH), 3.79 (m, IH), 3.61 (m, IH), 3.49 (m, 2H), 2.42 (m, IH), 2.06 (d, IH), 1.88-1.73 (m, 2H), 1.67-1.51 (m; 2H). Lawesson's reagent 1 ,4-dioxane
Figure imgf000549_0002
Figure imgf000549_0001
Preparation of compound 332b
A suspension of the compound 332a (9 g, 24.57 mmol) and Lawesson's Reagent (9.9 g, 24.57 mmol) in dry 1,4-dioxane (135 mL) was heated at 1200C in microwave for 30 min. The mixture was concentrated in vacuo, and the residue was purified by column chromatography to give the compound 332b (8 g, 85%).
Figure imgf000549_0003
Preparation of compound 332c To a solution of compound 332b (2.4 g, 6.3 mmol) in MeOH (300 mL) was added aq. NaOH solution (0.6 N, 21 mL) and MeI (15 mL). The reaction mixture was heated for 60 min. under reflux. The mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give compound 332c (1.6 g, 50%). 1H-NMR (CDCl3 400MHz): δl.22 (d, IH)5 6.79 (dd, IH), 6.62 (dd, IH), 3.78-3.69 (m, 2H), 3.61- 3.45 (m, 2H), 3.10 (s, 3H), 2.49 (d, 3H), 2.18 (m, IH), 1.82 (m, IH), 1.69-1.48 (ms 4H).
Figure imgf000549_0004
Preparation of compound 332d
A solution of the compound 332c (1.54 g. 37.56 mmol). NH4I (1.4 g) in a solution of NH3/EtOH (140 mL, 8 N) was heated at 120°C in microwave for 2.5 hrs. After being cooled, the mixture was concentrated in vacuum to give the compound 332d (1.5 g, crude), which was used for the next step directly.
Figure imgf000550_0001
Preparation of compound 332
Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with the compound 332d (20 mg, 0.05 mmol) in 1,4-dioxane (2 mL), aq. Cs2CO3 solution (2 N, 0.3 mL) and 2,5-difluorophenylboronic acid (16.67 mg, 0.1 mmol). The mixture was heated at 1200C under microwave for 20 min. The reaction mixture was concentrated in vacuo, the residue was purified by preparative TLC and preparative HPLC to give the pure compound 332 (4.11 mg, 10%) as a TFA salt. 1H-NMR (CD3OD 400MHz): ^7.46-7.50 (m, IH), 7.25-7.30 (m, IH), 7.12-7.20 (m, 2H), 7.01-7.11 (m, 2H), 3.75-3.96 (m, 2H), 3.55-3.68 (m, 2H), 3.26 (s, 3H), 2.30-2.48 (m, 2H), 1.79-2.10 (m, 3H), 1.51-1.61 (m, IH); ESI MS: m/z 414.0 [M+H]+.
Example 218. Preparation of Compound 351
Figure imgf000550_0002
Experimental data:
Figure imgf000550_0003
Preparation of 3,4-difluorophenylboronic acid
To a stirred solution of 4-bromo- 1 ,2-difluorobenzene (3.5 g, 17.86 mmol) in dry THF was cooled to -78°C, was added a w-BuLi (10.71 mL) slution dropwise. After completion of the addition, the mixture was stirred for 15 min., and triisopropyl borate (6.71 g, 35.71 mmol) was added in one portion. The reaction flask was kept in a cooling bath for 30 min., and warmed to room temperature for 3 hours. The solvent was removed, the residue was dissolved in ether, washed with IN HCl and water, dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by recrystallyzation with CH2Cl2 and hexane to give the pure 3.4-difluorophenylboronic acid (800 mg, 20%).
Figure imgf000551_0001
Preparation of compound 351
By using the same synthetic strategy for compound 332 described in Example 217, compound 351 (5 mg, 12%) was obtained. 1H-NMR (CD3OD 400 MHz): 57.51- 7.54 (m, IH), 7.39-7.45 (m, IH), 7.19-7.28 (m, 3H), 7.00-7.03 (m, IH), 3.70-3.87 (m, 2H), 3.50-3.59 (m, 2H), 3.24 (s, 3H), 2.26-2.39 (m, 2H), 1.74-2.04 (m, 3H), 1.50-1.54 (m, IH); ESI MS: m/z 414.0 [M+H]+.
Example 219. Preparation of Compound 286
Figure imgf000551_0002
By using the same synthetic strategy for compound 332 described in Example 217, compound 286 (2.58 mg, 6%) was obtained. 1H-NMR (CD3OD 400 MHz): 57.61- 7.63 (m, IH), 7.38-7.41 (m, 2H), 7.28 (m, IH), 7.10-7.16 (m, 2H), 3.76-3.97 (m, 2H), 3.57-3.69 (m, 2H), 3.31 (s, 3H), 3.04-3.10 (m, 2H), 2.31-2.52 (m, 2H), 1.79-2.16 (m, 3H), 1.55-1.71 (m, IH); ESI MS: m/z 430.0 [M+H]+.
Example 220. Preparation of Compounds 215 and 270
Figure imgf000552_0001
By using the same synthetic strategy for compound 332 described in Example 217, compound 215 (6.22 mg, 18%) and compound 270 (1.07 mg, 3%) were obtained. compound 215: 1H-NMR (CD3OD 400M): <57.62-7.64 (m, IH), 7.42-7.44 (m, 2H), 7.29- 7.32 (m, IH), 7.10-7.16 (m, 2H), 3.83-3.94 (m, 2H), 3.61-3.66 (m, 2H), 3.31 (s, 3H), 2.33- 2.46 (m, 2H), 1.78-2.10 (m, 3H), 1.53-1.64 (m, IH). ESI MS: m/z 430.0 [M+H]+. compound 270: 1H-NMR (CD3OD 400M): <57.61-7.64 (m, IH), 7.40-7.43 (m, 2H), 7.28- 7.31 (m, IH), 7.09-7.18 (m, 2H), 3.75-3.80 (m, 2H), 3.61-3.64 (m, 2H), 3.31 (s, 3H), 2.45 (s, 2H), 1.90-2.15 (m, 3H), 1.60-1.68 (m, IH); ESI MS: m/z 430.0 [M+H]+.
Example 221. Preparation of Compounds 250 and 356
Figure imgf000552_0002
By using the same synthetic strategy for compound 332 described in Example 217, compound 250 (2.48 mg, 1 1%) and compound 356 (1.75 mg, 8%) were obtained. compound 250: 1H-NMR (CD3OD 400MHz): £7.76 (s, IH), 7.61-7.66 (m, 2H), 7.42-7.44 (m, 2H), 7.06-7.08 (m, IH), 3.76-3.88 (m, 2H), 3.51-3.57 (m, 2H), 3.24 (s, 3H), 2.27-2.40 (m, 2H), 1.72-2.05 (m, 3H), 1.48-1.58 (m, IH): ESI MS: m/z 420.9 [M+H]+. compound 356: 1H-NMR (CD3OD 400MHz): 7.83 (m, IH)5 7.69-7.73 (m. 2H), 7.49-7.52 (m, 2H), 7.12-7.15 (m, IH), 3.77-3.80 (m, 2H), 3.63-3.66 (m, 2H), 3.33 (s, 3H), 2.47 (s, 2H), 1.94-2.14 (m, 3H), 1.69 (m, IH); ESI MS: m/z 420.9 [M+H]+.
Example 222. Preparation of Compound 346
Figure imgf000553_0001
By using the same synthetic strategy for compound compound 332 described in Example 217, compound 346 (8.2 mg, 19%) was obtained. 1H NMR (CDCl3 400 MHz): <57.53-7.55 (m, IH), 7.32 (m, IH), 6.98-7.18 (m, 3H), 3.77-3.95 (m, 2H), 3.55-3.72 (m, 2H), 3.28 (s, 3H), 3.02-3.12 (m, IH), 2.41-2.54 (m, IH), 1.80-2.18 (m, 3H), 1.55-1.71 (m, IH); ESI MS: m/z 432.0 [M+H]+.
Example 223. Preparation of Compounds 280 and 359
Figure imgf000553_0002
By using the same synthetic strategy for compound 332 described in Example 217, compound 280 (1.76 mg, 9%) and compound 359 (0.61 mg, 3%) were obtained. compound 280: 1H-NMR (CD3OD 400MHz): «57.51-7.53 (m, IH)5 7.31 (m, IH), 7.07- 7.14 (m, 2H), 7.00-7.04 (m, IH), 3.90-3.93 (m, IH), 3.80-3.86 (m, lH),3.56-3.64 (m, 2H), 3.26 (s, 3H), 2.32-2.46 (m, 2H), 1.97-2.09 (m, IH), 1.88-1.96 (m, IH), 1.77-1.80 (m, IH), 1.55-1.62 (m, IH); ESI MS: m/z 432.0 [M+H]+. compound 359: 1H-NMR (CD3OD 400MHz): «57.45-7.51 (m, IH), 7.29 (m, IH), 7.07- 7.14 (m, 2H), 7.00-7.04 (m, IH), 3.75-3.78 (m, 2H), 3.57-3.62 (m, 2H), 3.26 (s, 3H), 2.45 (m, 2H), 2.09-2.13 (m, IH), 1.90-1.97 (m, IH), 1.73-1.88 (m, IH), 1.62-1.71 (m, IH); ESI MS: m/z 432.1 [M+H]+.
Example 224. Preparation of Compound 347
Figure imgf000553_0003
By using the same synthetic strategy for compound 332 described in Example 217, compound 347 (5.16 mg, 25%) was obtained. 1H-NMR (CD3OD 400MHz): <57.61-7.77 (m, IH)5 7.29-7.47 (m, 4H), 7.02-7.11 (m, 2H), 3.77-3.95 (m, 2H)5 3.58-3.64 (m, 2H)5 3.26 (s, 3H)5 2.28-2.46 (m, 2H), 1.79-2.17 (m, 3H)5 1.56-1.71 (m, IH); ESI MS: m/z 395.1 [M+H]+.
Example 225. Preparation of Compound 314
Figure imgf000554_0001
By using the same synthetic strategy for compound 332 described in Example 217, compound 314 (4.2 mg, 10%) was obtained. 1H-NMR (CDCl3 400MHz): J7.62-7.67 (m, - IH), 7.39-7.44 (m, IH)5 7.18-7.27 (m, 2H), 7.7.09-7.14 (m, IH), 6.89-6.94 (m, IH)5 3.79- 4.00 (m, 2H), 3.59-3.79 (m, 2H)5 3.32 (s, 3H), 2.29-2.52 (m, 2H)5 1.80-2.18 (m, 3H)5 1.56- 1.74 (m, IH); ESI MS: m/z 414.0 [M+H]+.
Example 226. Preparation of Compounds 255 and 309
Figure imgf000554_0002
By using the same synthetic strategy for compound 332 described in Example 217, compound 255 (1.08 mg, 3%) and compound 309 (1.08 mg, 3%) were obtained. compound 255: 1H NMR (CD3OD 400MHz): «58.17-8.18 (d, 2H)5 8.01 (s, IH)5 7.62-7.65 (m, IH)5 7.43-7.45 (m, IH)5 7.04-7.07 (m, IH), 3.67-3.85 (m, 2H)5 3.47-3.55 (m, 2H)5 3.21 (s, 3H), 2.25-2.38 (m, 2H)3 1.72-1.97 (m, 3H), 1.49-1.52 (m, IH); ESI MS: m/z 428.1
[M+H]+. compound 309: 1H NMR (CD3OD 400MHz): 58.17-8.18 (d, 2H), 8.01 (s, IH), 7.62-7.64
(m, IH), 7.42-7.43 (m, IH), 7.04-7.06 (m, IH), 3.67-3.72 (m, 2H)5 3.52-3.55 (m, 2H), 3.21
(s, 3H), 2.37 (s, 2H), 1.78-2.06 (m, 3H), 1.55-1.62 (m, IH); ESI MS: m/z 427.9 [M+H]+.
Example 227. Preparation of Compounds 259 amd 325
Figure imgf000555_0001
By using the same synthetic strategy for compound 332 described in Example 217, compound 259 (2.60 mg, 12%) and compound 325 (0.73 mg, 4%) were obtained. compound 259: 1H-NMR (CD3OD 400MHz): 57.78-7.80 (m, 2H), 7.60-7.65 (m, 3H), 7.40 (s, IH), 7.12-7.14 (m, IH), 3.83-3.95 (m, 2H), 3.60-3.64 (m, 2H), 3.26 (s, 3H), 2.33- 2.47 (m, 2H), 1.81-2.09 (m, 3H), 1.58-1.63 (m, IH); ESI MS: m/z 446.0 [M+H]+. compound 325: 1H-NMR (CD3OD 400MHz): 57.78-7.80 (m, 2H), 7.60-7.65 (m, 3H), 7.38-7.39 (m, IH), 7.11-7.13 (m, IH), 3.74-3.85 (m, 2H), 3.56-3.67 (m, 2H), 3.26 (s, 3H), 2.47 (s, 2H), 1.87-2.15 (m, 3H), 1.59-1.68 (m, IH); ESI MS: m/z 446.0 [M+H]+.
Example 228. Preparation of Compound 290
Figure imgf000555_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 290 (2.42 mg, 11%) was obtained, 1H NMR (CD3OD 400MHz): 57.61 (m, 2H), 7.45 (m, IH), 7.33 (m, 3H), 7.10 (m, .1H), 3.84 (m, 2H), 3.63 (m, 2H), 2.65-3.10 (m: 3H), 2.48 (m, 2H), 2.10 (m, 2H), 1.93 (m, IH), 1.64 (m, IH); ESI MS: 412 [M+H]+.
Example 229. Preparation of Compounds 224 and 289
Figure imgf000556_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 224 (2.78 mg, 13%) and compound 289 (2.10 mg, 9%) were obtained. compound 224: 1H NMR (CD3OD 400MHz): «57.53-7.59 (m, 2H), 7.44-7.45 (m, IH), 7.29-7.38 (m, 3H), 7.07-7.09 (d, IH), 3.81-3.92 (m, 2H), 3.58-3.62 (m, 2H), 3.26 (s, 3H), 2.31-2.44 (m, 2H), 1.77-2.06 (m, 3H), 1.52-1.62 (m, IH); ESI MS: m/z 412.0 [M+H]+. compound 289: 1H NMR (CD3OD 400MHz): «57.57-7.67 (m, 2H), 7.46-7.51 (m, IH), 7.35-7.44 (m, 3H), 7.10-7.12 (m, IH), 3.75-3.85 (m, 2H), 3.61-3.69 (m, 2H), 3.26 (s, 3H), 2.48 (m, 2H), 1.90-2.18 (m, 3H), 1.64-1.72 (m, IH); ESI MS: m/z 412.0 [M+H]+.
Example 230. Preparation of Compounds 318 and 336
Figure imgf000556_0002
The solution of compound 318a (20 mg), 3-bromophenylboronic acid (11 mg), and K2CO3 (2 N, 0.06 mL) in THF (5 mL) was added Pd(PPh3)4 (3 mg) under N2. The mixture was refluxed overnight, the solvent was removed in vacuum, and the crude product was purified by preparative TLC and HPLC to give compound 318 (2.72 mg, 11%) and compound 336 (0.78 mg, 3%). compound 318: 1H-NMR (CD3OD 400MHz): δl.lQ-1.69 (m, IH), 7.58-7.60 (m, IH), 7.45-7.52 (m, 2H), 7.32-7.34 (m, 2H), 7.09-7.11 (m, IH), 3.89-3.97 (m, IH), 3.79-3.88 (m, IH), 3.58-3.64 (m, 2H), 3.41 (s, 3H), 2.31-2.46 (m, 2H), 1.78-2.08 (m, 3H), 1.56-1.62 (m, IH): ESI MS: m/z 457.8 [M+Hf. compound 336: 1H-NMR (CD3OD 400MHz): <57.6O (m, IH), 7.48-7.52 (m, IH), 7.36- 7.42 (ms 2H), 7.20-7.24 (m, 2H)5 6.98-7.00 (m, IH), 3.72-3.63 (m, 2H), 3.48-3.56 (m, 2H), 3.41 (s, 3H), 2.36 (s, 2H), 1.83-2.06 (m, 3H), 1.52-1.62 (m, IH): ESI MS: m/z 457.8 [M+H]+. Example 231. Preparation of Compound 288
Figure imgf000557_0001
Figure imgf000557_0002
Experimental data:
Figure imgf000557_0003
Preparation of 3-(5,5-Dimethyl-l,3»2-dioxaborinan-2-yl)-4-fluorobenzonitrile
The solution of 2,2,6,6-tetramethylpiperidine (7.1 g, 49.6 mmol) in dry THF (100 mL) at -100C in a 500 mL dry three-neck flask was added «-BuLi (2.5 M in hexane, 19.8, 49.6 mmol) over 2 min. under N2, and the mixture was stirred for 10 min. At -78°C, B(O1Pr)3 (10.8 g. 57.4 mmol) was added over 2 min.. and the mixture was stirred for 5 min., followed by addition of a solution of 4-fluorobenzonitrile (5 g. 41 mmol) in dry THF (140 mL) over 5 mins. The reaction mixture was left in the cooling bath overnight, and warmed to room temperature. At room temperature, the reaction mixture was quenched with glacial acetic acid (3.3 mL), and 2,2-dimethyl- 1,3- propandiol (6.4 g, 61.5 mmol) was added. The mixture was stirred for 1 h at room temperature, and was added ethyl acetate. The organic layer was washed with aqueous KH2PO4 (10w/v%. 3χ100 mL). The water phase was extracted with ethyl acetate, and the combined organic layer was dried and evaporated to give 3-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-4-fluoroben zonitrile (1 g, 10%). 1H-NMR (CDCl3 400MHz): (58.00 (m, IH), 7.62 (m, IH), 7.03 (m, IH), 3.75 (d, 4H), 1.01 (s, 6H).
Figure imgf000558_0001
Preparation of compound 288
By using the same synthetic strategy as compound 332 described in Example 217, compound 288 (2.15 mg, 10%) was obtained. 1H-NMR (CD3OD 400MHz): <57.86-7.84 (m, IH), 7.74-7.77 (m, IH), 7.55-7.57 (m, IH), 7.35-7.40 (m, 2H), 7.1 1-7.14 (m, IH), 3.78-3.98 (m, 2H), 3.56-3.68 (m, 2H), 3.29 (s, 3H), 2.34-2.49 (m, 2H), 1.78-2.18 (m, 3H), 1.58-1.75 (m, IH); ESI MS: m/z 421.2 [M+H]+.
Example 232. Preparation of Compound 368
Figure imgf000558_0002
Experimental data:
Figure imgf000558_0003
Preparation of 5-cyano-2-methylphenylboronic acid To a stirred solution of 3-bromo-4-methylbenzonitrile (3.5 g, 17.86 mmol) in dry
THF at -78°C was added n-BuLi (2N, 10.71 mL) dropwise. The mixture was stirred for 15 min., and added triisopropyl borate (6.71 g, 35.71 mmol). The reaction flask was kept in the. cooling bath for 30 min., and at room temperature for 3 hours. The solvent was removed, and the residue was dissolved in ether. The organic phase was washed with IN HCl solution and water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized from a mixture Of CH2Cl2 and hexane to give 5- cyano-2-methylphenylboronic acid (800 mg; 20%). 1H-NMR (CDCl3 400MHz): <57.50- 7.78 (m, 2H), 7.30 (d, IH), 2.42 (s, 3H).
Figure imgf000559_0001
Preparation of compound 368
By using the same synthetic strategy as compound 332 described in Example 217, compound 368 (15 mg, 15%) was obtained. 1H-NMR (CD3OD 400MHz): <57.56-7.58 (d, IH), 7.41-7.48 (m, 2H), 7.27-7.31 (m, IH), 7.06-7.11 (m, 2H), 3.77-3.98 (m, 2H), 3.56- 3.68 (m, 2H), 3.24 (s, 3H), 2.99-3.02 (m, 2H), 2.30-2.51 (m, IH), 2.26 (m, 3H), 1.80-2.15 (m, 3H), 1.52-1.68 (m, IH); ESI MS: m/z 417.1 [M+H]+.
Example 233. Preparation of Compounds 277 and 413
Figure imgf000559_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 277 (2.71 mg, 13%) and compound 413 (1.25 mg, 6%) were obtained. compound 277: 1H-NMR (CD3OD 400MHz): «57.81-7.84 (m, IH), 7.67-7.72 (m, 2H), 7.55-7.57 (m, IH), 7.32-7.37 (m, 2H), 4.16-4.19 (m, IH), 4.06-4.13 (m, IH), 3.84-3.88 (m, 2H), 3.49 (s, 3H), 2.72-2.57 (m, 2H), 2.51 (s, 3H), 2.06-2.37 (m, 3H), 1.80-1.91 (m, IH); ESI MS: m/z 417.1 [M+H]+. compound 413: 1H-NMR (CD3OD 400MHz): <57.81-7.83 (m, IH), 7.66-7.71 (m, 2H), 7.54-7.56 (m, IH), 7.31-7.35 (m, 2H), 4.02-4.05 (m, 2H), 3.86-3.89 (m, 2H), 3.49 (s, 3H), 2.70 (s, 2H), 2.50 (s, 3H), 2.11-2.39 (m, 3H), 1.86-1.96 (m, IH); ESI MS: m/z 417.1
Example 234. Preparation of Compounds 380 and 449
Figure imgf000560_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 380 (1.12 mg, 4%), and compound 449 (1.73 mg, 7%) were obtained. compound 380: 1H NMR (CD3OD 400MHz): £7.90-7.96 (m, 2H), 7.72 (s, IH), 7.32-7.34 (d, IH), 7.14 (s, IH), 7.08-7.10 (d, IH), 3.84-3.98 (m, 2H), 3.58-3.65 (m, 2H), 3.24 (s, 3H), 2.33-2.50 (m, 2H), 1.81-2.12 (m, 3H), 1.59-1.63 (m, IH); ESI MS: m/z 471.0 [M+H]+. compound 449: 1H NMR CD3OD 400MHz): <57.89-7.95 (m, 2H), 7.70 (s, IH), 7.30-7.33 (d, IH), 7.12 (s, IH), 7.05-7.07 (d, IH), 3.76-3.79 (m, 2H), 3.61-3.64 (m, 2H), 3.22 (s, 3H), 2.41-2.50 (m, 2H), 1.90-2.14 (m, 3H), 1.63-1.65 (m, IH); ESI MS: m/z 471.0 [M+H]+.
Example 235. Preparation of Compound 291
Figure imgf000560_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 291 (1.63 mg, 7%) was obtained. 1H-NMR (CD3OD 400M): δl.10-1.11 (m, 2H), 7.53-7.55 (m, IH), 7.35-7.43 (m, 2H), 7.12-7.15 (m, IH), 3.83-3.96 (rn. 2H), 3.58- 3.65 (m, 2H), 3.28 (s, 3H), 2.35-2.49 (m, 2H), 1.85-2.08 (m, 3H), 1.55-1.68 (m, IH); ESI MS: m/z 421.0 [M+H]+.
Example 236. Preparation of Compounds 216 and 304
Figure imgf000561_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 216 (0.8 mg, 4%) and compound 304 (0.8 mg, 4%) were obtained. compound 216: 1H-NMR (CD3OD 400MHz): «58.14 (s, IH), 8.05 (s, IH), 7.95 (s, IH), 7.61-7.64 (dd, IH), 7.44-7.45 (d, IH), 7.06-7.08 (dd, IH), 3.74-3.86 (m, 2H), 3.48-3.56 (m, 2H), 3.21 (s, 3H), 2.25-2.38 (m, 2H), 1.72-1.98 (m, 3H), 1.49-1.52 (m, IH); ESI MS: m/z 471.1 [M+H]+. compound 304: 1H-NMR (CD3OD 400MHz): <S8.18 (s, IH), 8.08 (s, IH), 7.98 (s, IH), 7.65-7.67 (dd, IH)5 7.47-7.48 (d, IH), 7.09-7.11 (d, IH), 3.71-3.80 (m, 2H), 3.54-3.60 (m, 2H), 3.24 (s, 3H), 2.41 (s, 2H), 1.80-2.11 (m, 3H), 1.59-1.62 (m, IH); ESI MS: m/z 471.1 [M+H]+.
Example 237. Preparation of Compound 414
Figure imgf000561_0002
The mixture of compound 1 (30 mg, 0.08 mmol), 5-methylthiophen-3-ylboronic acid (17 mg, 0.12 mmol), Pd(PPh3)4 (1 mg, 0.001) and Na2CO3 (2 M, 0.30 mL), in the mixture of EtOH (0.2 mL) and tolune (1 mL) was heated at 120°C under Ar2 overnight. The reaction mixture was extracted with EtOAc, concentrated, and purified by preparative TLC and HPLC to give compound 414 (4.50 mg, 14%), 1H-NMR (CD3OD 400MHz): ,57.41-7.44 (m, IH), 7.09-7.11 (m, IH), 6.96-6.97 (m, IH), 6.89-6.92 (m, IH), 6.61 (m, IH), 3.61-3.83 (m, 2H), 3.46-3.58 (m, 2H)5 3.25 (s, 3H), 2.26-2.42 (m. 5H), 1.67-2.03 (m, 3H)5 1.44-1.62 (m, IH): ESI MS: m/z 398.0 [M+H]+.
Example 238. Preparation of Compound 301
Figure imgf000562_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 301 (3.45 mg, 16%) was obtained. 1H-NMR (CD3OD 400MHz): (57.60 (m, IH), 7.26-7.34 (m. 4H), 7.13-7.15 (m, IH), 7.06-7.09 (m, IH), 3.75-3.95 (m, 2H), 3.62- 3.67 (m, 2H), 3.30 (s, 3H), 2.34-2.49 (m, 5H), 1.81-2.12 (m, 3H), 1.56-1.72 (m, IH); ESI MS: m/z 392.1 [M+H]+.
Example 239. Preparation of Compounds 296 and 405
Figure imgf000562_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 296 (4.32 mg, 20%) and compound 405 (1.40 mg, 6%) were obtained. compound 296: 1H-NMR (CD3OD 400MHz): «57.55-7.61 (m, IH), 7.36-7.40 (m, IH), 7.23-7.35 (m, 3H), 7.18-7.22 (m, IH), 7.05-7.10 (m, IH), 3.80-3.95 (m, 2H), 3.55-3.65 (m, 2H), 3.38 (s, 3H)5 2.50 (s, 3H), 2.31-2.48 (m, 2H), 1.77-2.07 (m, 3H), 1.55-1.65 (m, IH); EI MS: /z 424.1 [M+H]+. compound 405: 1H-NMR (CD3OD 400M): <57.55-7.61 (m, IH), 7.31-7.40 (m, 2H), 7.23-
7.30 (m, 2H), 7.18-7.22 (m, IH)5 7.05-7.10 (m, IH), 3.75-3.85 (m, 2H), 3.62-3.65 (m, 2H),
3.31 (s, 3H), 2.50 (s, 3H)5 2.46 (s, 2H), 1.88-2.16 (m, 3H), 1.61-1.71 (m, IH): ESI MS: m/z 424.1 [M+H]+.
Example 240. Preparation of Compounds 262 and 357
Figure imgf000562_0003
By using the same synthetic strategy as compound 332 as described in Example 217, compound 262 (8.46 mg, 40%), 1H-NMR (CD3OD 400M): S7.5S (dd, IH), 7.42- 7.51 (m, 2H), 7.37 (s, IH), 7.31 (s, IH), 7.18 (d, IH), 7.06 (d, IH), 3.89-3.92 (m, IH), 3.80-3.84 (m, IH), 3.50-3.60 (m, 2H), 3.26 (s, 3H), 2.42 (d, IH), 2.34 (d, IH), 1.97-2.05 (m, IH), 1.89-1.98 (m, IH), 1.79-1.84 (m, IH), 1.52-1.62 (m, IH); ESI MS: m/z 462.1 [M+H]+, and compound 357 (2.47 mg, 10%), 1H-NMR (CD3OD 400M): £7.58 (dd, IH), 7.42-7.51 (m, 2H), 7.37 (s, IH), 7.31 (s, IH), 7.18 (d, IH), 7.06 (d, IH), 3.74-3.80 (m, 2H), 3.52-3.63 (m, 2H), 3.26 (s, 3H), 2.63 (s, IH), 2.42 (s, 2H), 1.85-2.13 (m, 3H), 1.52- 1.62 (m, IH); ESI MS: m/z 462.1 [M+H]+ were obtained.
Example 241. Preparation of Compounds 243 and 337
Figure imgf000563_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 243 (3.23 mg, 14%) and compound 337 (1.95 mg, 8%) were obtained. compound 243: 1H-NMR (CD3OD 400MHz): (57.70-7.71 (m, 2H), 7.48-7.56 (m, 3H), 7.31 (s, IH), 7.02-7.04 (d, IH), 3.72-3.85 (m, 2H), 3.47-3.56 (m, 2H), 3.27 (s, 3H), 2.24- 2.37 (m, 2H), 1.72-2.03 (m, 3H), 1.48-1.52 (m, IH); ESI MS: m/z 446.1 [M+H]+.
compound 337: 1H-NMR (CD3OD 400MHz): <57.68-7.72 (m, 2H), 7.48-7.56 (m, 3H), 7.30 (s, IH), 7.01-7.03 (d, IH), 3.67-3.76 (m, 2H), 3.49-3.59 (m, 2H), 3.20 (s, 3H), 2.37 (s, 2H), 1.79-2.08 (m, 3H), 1.52-1.64 (m, IH); ESI MS: m/z 446.1 [M+H]+.
Example 242. Preparation of Compounds 41 1 and 448
Figure imgf000563_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 411 (2.61 mg, 14%) and compound 448 (1.24 mg, 6%) were obtained. compound 411: 1H-NMR (CD3OD 400MHz): 37.61 (m, IH), 7.43 (d, IH), 7.28 (d, IH),
6.97 (d, IH), 6.63 (m, IH)5 6.40 (m, IH), 3.74-3.86 (m, 2H)5 3.49-3.56 (m, 2H), 3.26 (s,
3H), 2.25-3.39 (m, 2H), 1.71-2.05 (m, 3H), 1.50-1.54 (m, IH); ESI MS: m/z 368.0
[M+H]+. compound 448: 1H-NMR (CD3OD 400MHz): £7.61 (m, IH), 7.43 (d, IH), 7.28 (d, IH),
6.97 (d, IH), 6.61 (m, IH), 6.40 (m, IH), 3.72 (m, 2H), 3.56 (m, 2H), 3.26 (s, 3H), 2.38 (s,
2H), 1.79-2.06 (m, 3H), 1.61 (m, IH); ESI MS: m/z 368.0 [M+H]+.
Example 243. Preparation of Compounds 428 and 458
Figure imgf000564_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 428 (5.50 mg, 25%) and compound 458 (1.49 mg, 15%) were obtained. compound 428: 1H-NMR (CD3OD 400MHz): £7.52-7.55 (m, IH), 7.19 (d, IH), 7.03- 7.05 (m, 3H), 6.95-6.97 (d, IH), 3.91 (d, IH), 3.78-3.91 (m, 7H), 3.55-3.67 (m, 2H), 3.26 (s, 3H), 2.33-2.46 (m, IH), 1.97-2.05 (m, IH), 1.89-1.98 (m, IH), 1.78-1.84 (m, IH), 1.52- 1.62 (m, IH); ESI MS: m/z 438.2 [M+H]+. compound 458: 1H-NMR (CD3OD 400MHz): £7.52 (d, IH), 7.18 (s, IH), 7.01 (m, 3H), 6.92 (d, IH), 3.83 (d, 6H), 3.69-3.79 (m, 2H), 3.52-3.64 (m, 2H), 3.26 (s, 3H), 2.41(s, 2H), 2.03-2.12 (m, IH), 1.98-2.03 (m, IH), 1.84-1.93 (m, IH), 1.52-1.62 (m, IH); ESI MS: m/z 438.2 [M+H]+.
Example 244. Preparation of Compounds 276 and 340
Figure imgf000564_0002
By using the same synthetic strategy as compound 332 described in Example 217, compounds 276 and 340 were obtained. compound 276 (3.55 mg, 17%), 1H-NMR (CD3OD 400MHz): <57.57-7.58 (m, IH), 7.27- 7.28 (d, IH), 7.13 (s, 2H), 7.07-7.10 (d, IH), 6.99 (s, IH), 3.83-3.98 (m, 2H), 3.59-3.68 (m, 2H), 3.33 (s, 3H), 2.32-2.52 (m, 8H), 1.82-2.13 (m, 3H), 1.58-1.67 (m, IH); ESI MS: m/z 406.0 [M+H]+. compound 340 (0.93 mg, 4%), 1H-NMR (CD3OD 400MHz): <57.55-7.58 (m, IH), 7.23- 7.24 (d, IH), 7.11 (s, 2H), 7.05-7.07 (d, IH), 6.97 (s, IH), 3. 75-3.85 (m, 2H), 3.58-3.67 (m, 2H), 3.31 (s, 3H), 2.46 (s, 2H), 2.34 (m, 6H), 1.88-2.16 (m, 3H), 1.66-1.72 (m, IH); ESI MS: m/z 406.1 [M+H]+.
Example 245. Preparation of Compound 364
Figure imgf000565_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 364 (5.67 mg, 27%) was obtained. 1H-NMR (CD3OD 400M): <57.25-7.30 (m, IH), 7.10-7.14 (m, IH), 7.01-7.09 (m, 2H), 6.98-7.00 (m, IH), 6.90-6.96 (m, IH), 3.75- 3.98 (m, 2H), 3.58-3.68 (m, 2H), 3.26 (s, 3H), 2.31-2.48 (m, 2H), 2.29 (s, 3H), 2.12 (s, 3H), 2.01-2.10 (m, IH), 1.90-2.00 (m, IH), 1.78-1.88 (m, IH), 1.55-1.68 (m, IH); ESI MS: m/z 406.1 [M+H]+.
Example 246. Preparation of Compounds 307 and 321
Figure imgf000565_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 307 (7.91 mg, 35%) and compound 321 (2.23 mg, 10%) were obtained. compound 307: 1H-NMR (CD3OD 400MHz): <57.39-7.42 (d, IH), 7.1 1 (s, IH), 6.92 (d, IH), 6.89 (d, 1H); 6.81 (d, 1H); 6.72 (s, IH), 3.78-3.90 (m, 2H), 3.72 (s, 3 H), 3.66 (s, 3H), 3.52-3.61 (m, 2H), 3.26 (s, 3H), 2.42 (d, IH), 2.31 (d, IH), 1.97-2.05 (m, IH), 1.89-1.98 (m, IH), 1.78-1.84 (m, IH), 1.52-1.62 (m, IH); ESI MS: m/z 438.1 [M+H] \ compound 321: 1H-NMR (CD3OD 400MHz): <57.39-7.42 (d, IH), 7.10 (s, IH), 6.92 (d, IH), 6.89 (d, IH), 6.79 (d, IH)5 6.72 (s, IH), 3.74 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H), 3.52- 3.61 (m, 2H), 3.24 (s, 3H), 2.41 (d, 2H), 1.97-2.09 (m, IH), 1.89-1.98 (m, IH), 1.78-1.84 (m, IH), 1.52-1.62 (m, IH); ESI MS: m/z 438.1 [M+H]+.
Example 247. Preparation of Compounds 233 and 310
Figure imgf000566_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 233 (6.55 mg, 23%) and compound 310 (2.18 mg, 8%) were obtained. compound 233: 1U NMR (CD3OD 400MHz): «57.67-7.69 (d, IH), 7.59-7.61 (d, IH),
7.49-7.51 (m, IH), 7.37 (s, IH), 7.26-7.31 (t, IH), 7.10-7.12 (d, IH), 3.92-3.96 (m, 2H),
3.58-3.69 (m, 2H), 3.33 (s, 3H), 3.34-2.48 (m, 2H), 1.82-2.08 (m, 3H), 1.56-1.67 (m, IH):
ESI MS: m/z 430.0 [M+H]+. compound 310: 1H NMR (CD3OD 400MHz): «57.68-7.71 (d, IH), 7.60-7.62 (d, IH), 7.49-7.51 (m, IH), 7.37 (s, IH), 7.28-7.32 (t, IH), 7.10-7.13 (d, IH), 3.79-3.82 (m, 2H),
3.64-3.68 (m, 2H), 3.34 (s, 3H), 2.48 (s, 2H), 1.92-1.98 (m, 3H), 1.65-1.75 (m, IH). ESI
MS m/z 430.0 [M+H]+.
Example 248. Preparation of Compounds 287 and 385
Figure imgf000566_0002
1
By using the same synthetic strategy as compound 332 described in Example 217, compound 287 (3.25 mg; 15%) and compound 385 (2.49 mg, 12%) were obtained. compound 287: 1H-NMR (CD3OD 400MHz): <57.12-7.21 (m, 2H), 6.96-6.98 (m, 2H), 6.83-6.88 (m, IH), 6.75-6.78 (m, IH), 3.73-3.85 (m, 2H), 3.47-3.54 (m, 2H), 3.16 (s, 3H), 2.23-2.36 (m, 2H), 2.05 (s, 3H), 1.62-2.03 (m, 3H), 1.52 (m, IH); ESI MS: m/z 410.1
[M+H]+. compound 385: 1H-NMR (CD3OD 400MHz): 57.18-7.21 (m, 2H), 6.94-6.97 (m, 2H),
6.83-6.88 (m, IH), 6.75-6.78 (m, IH), 3.69-3.74 (m, 2H), 3.51-3.56 (m, 2H), 3.16 (s, 3H),
2.36 (s, 2H), 2.05 (s, 3H), 1.62-2.03 (m, 3H), 1.52 (m, IH); ESI MS: m/z 410.1 [M+H]+.
Example 249. Preparation of Compounds 202 and 281
Figure imgf000567_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 202 (2.95 mg, 13%) and compound 281 (2.06 mg, 9%) were obtained. compound 202: 1H-NMR (CD3OD 400MHz): 57.62 (d, 2H), 7.53 (s, 2H), 7.53 (s, IH), 7.42 (s, IH), 7.12 (d, IH), 3.82-3.94 (m, 2H), 3.56-3.63 (m, 2H), 3.27 (s, 3H), 2.32-2.45 (m, 2H), 1.79-2.08 (m, 3H), 1.53-1.65 (m, IH); ESI MS: m/z 446.0 [M+H]+. compound 281: 1H-NMR (CD3OD 400MHz): 57.62 (d, 2H), 7.53 (s, 2H), 7.52 (d, 2H), 7.12 (d, IH), 3.78-3.87 (m, 2H), 3.56-3.63 (m, 2H), 3.38 (s, 3H), 2.49 (s, 2H), 1.88-2.18 (m, 3H); 1.52 (m, IH); ESI MS: m/z 446.0 [M+H]+.
Example 250. Preparation of Compound 397
Figure imgf000567_0002
The solution of compound 397a (30 mg, 0.08 mmol). thiophen-3-ylboronic acid
(15.2 mg, 0.12 mmol), Pd(PPh3)4 (1 mg, 0.001) and Na2CO3 (2 M, 0.30 mL) in a mixture of EtOH (0.2 mL) and tolune (1 mL) was heated at 120°C under Ar2 overnight. The reaction mixture was extracted with EtOAc, concentrated, and purified by preparative TLC and preparative HPLC to give compound 397 (7.37 mg, 24%). 1H-NMR (CD3OD 400MHz): 57.58-7.63 (m, IH), 7.52 (m, IH), 7.41 (m, IH), 7.35 (m, IH), 7.29 (m, IH), 6.98-7.01 (m, IH)5 3.72-3.94 (m, 2H), 3.56-3.62 (m, 2H), 3.25 (s, 3H), 2.26-2.42 (m, 2H), 1.78-2.08 (m, 3H), 1.53-1.63 (m, IH); ESI MS: m/z 384.1 [M+H]+.
Example 251. Preparation of Compounds 358 and 427
Figure imgf000568_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 358 (6.53 mg, 30%) and compound 427 (3.67 mg, 16%) were obtained. compound 358: 1H-NMR (CD3OD 400MHz): <58.O6 (s, IH), 7.92-7.95 (m, IH), 7.76-7.78 (m, IH), 7.62-7.64 (m, IH), 7.51-7.55 (m, IH), 7.35 (m, IH), 7.09-7.11 (m, IH), 3.94 (m, IH), 3.83 (m, IH), 3.55-3.62 (m, 2H), 3.28 (s, 3H), 2.62 (s, 3H), 2.32-2.47 (m, 2H), 1.80- 2.08 (m, 3H), 1.59 (m, IH); ESI MS: m/z 420.0 [M+H]+. compound 427: 1H-NMR (CD3OD 400MHz): <58.O7 (m, IH), 7.93-7.95 (m, IH), 7.76-
7.78 (m, IH), 7.62-7.65 (m, IH), 7.52-7.56 (t, IH), 7.34 (s, IH), 7.08-7.11 (d, IH), 3.75-
3.79 (m, 2H), 3.60-3.64 (m, 2H), 3.28 (s, 3H), 2.62 (s, 3H), 2.45 (m, 2H), 1.89-2.13 (m, 3H), 1.65 (m, IH); ESI MS: m/z 420.0 [M+Hf .
Example 252. Preparation of Compounds 386 and 429
Figure imgf000568_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 386 (3.77 mg. 16%) and compound 429 (1.98 mg, 8%) were obtained. compound 386: 1H-NMR (CD3OD 400MHz): S8Λ4 (s, IH), 7.98 (m, IH), 7.80 (m, IH), 7.62 (m, IH), 7.53 (t, IH), 7.38 (d, IH), 7.13 (m, IH), 4.42 (m, 2H)8 3.92 (m, 2H), 3.63 (m, 2H), 3.33 (s, 3H), 2.35-2.49 (m, 2H), 1.82-2.13 (m, 3H), 1.62 (m, IH), 1.42 (m, 3H); ESI MS: m/z 449.9 [M+H]+. compound 429: 1H-NMR (CD3OD 400MHz): <58.14 (s, IH), 7.98 (m, IH), 7.78 (m, IH), 7.64 (m, IH)5 7.55 (m, IH), 7.36 (s, IH), 7.13 (m, IH), 4.38-4.43 (m, 2H), 3.78-3.82 (m, 2H), 3.62-3.67 (m, 2H), 3.31 (s, 3H), 2.48 (s, 2H), 1.91-2.18 (m, 3H), 1.68 (m, IH), 1.40- 1.43 (m, 3H); ESI MS: m/z 449.9 [M+H]+.
Example 253. Preparation of Compounds 342 and 378
Figure imgf000569_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 342 (5.08 mg, 21%) and compound 378 (1.84 mg, 8%) were obtained. compound 342: 1H-NMR (CD3OD 400MHz): <S7.44-7.47(m, IH), 7.21-7.25 (m, 3H), 6.98-7.05 (m, 2H), 3.96-4.01 (m, 2H), 3.83-3.94 (m, 2H), 3.60-3.63 (m, 2H), 3.26 (s, 3H), 2.32-2.46 (m, 2H), 179-2.10 (m, 3H), 1.55-1.64 (m, IH), 1.27-1.31 (t, 3H); ESI MS: m/z 456.0 [M+H]+. compound 378: 1H-NMR (CD3OD 400MHz): «57.35-7.38 (m, IH), 7.11-7.16 (m, 3H), 6.89-6.96 (m, 2H), 3.87-3.93 (m, 2H), 3.68-3.71 (m, 2H), 3.52-3.56 (m, 2H), 3.20 (m, 3H), 2.38 (s, 2H), 1.80-2.06 (m, 3H), 1.53-1.62 (m, IH), 1.17-1.23 (t, 3H); ESI MS: m/z 456.0 [M+H]+.
Example 254. Preparation of Compounds 389 and 440
Figure imgf000569_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 389 (3.55 mg, 17%) and compound 440 (0.93 mg, 4%) were obtained. compound 389: 1H-NMR (CD3OD 400MHz): δl.2S (m, IH), 7.03-7.12 (m, 3H), 6.92- 6.95 (m, 2H), 3.95 (m, IH), 3.86 (m, IH), 3.60-3.64 (m, 2H)5 3.25 (s, 3H)5 2.32-2.47 (m, 2H), 2.29 (s, 3H), 2.05-2.10 (m, 4H), 1.82-2.03 (m, 2H), 1.57-1.64 (m, IH); ESI MS: m/z 406.0 [M+H]+. compound 440: 1H-NMR (CD3OD 400MHz): <57.26 (m, IH), 7.03-7.14 (m, 3H), 6.93- 6.96 (m, 2H), 3.79-3.82 (m, 2H), 3.64-3.67 (m, 2H), 3.26 (s, 3H), 2.47 (s, 2H), 2.30 (s, 3H), 1.90-2.18 (m, 6H), 1.67 (m, IH); ESI MS: m/z 406.1 [M+H]+.
Example 255. Preparation of Compounds 214 and 256
Figure imgf000570_0001
By using the same synthetic strategy as compound 332 described in Example 217, compound 214 (5.35 mg, 18%) and compoudn 256 (1.17 mg, 4%) were obtained. compound 214: 1H NMR (CD3OD 400MHz): <57.53 (d, IH), 7.25 (s, IH), 7.02-7.07 (m, 2H), 6.92 (s, IH), 6.86 (s, IH), 3.88 (d, IH), 3.82 (m, 4H), 3.51-3.59 (m, 2H), 3.24 (s, 3H), 2.27-2.40 (m, 2H), 1.75-2.01 (m, 3H), 1.57 (m, IH); ESI MS: m/z 442.0 [M+H]+. compound 256: 1R NMR (CD3OD 400MHz): 37.55 (d, IH), 7.29 (s, IH), 7.05-7.10 (m, 2H), 6.96 (s, IH), 6.89 (s, IH), 3.81 (s, 3H), 3.74-3.78 (m, 2H), 3.59-3.62 (m, 2H), 3.28 (s, 3H), 2.43 (s; 2H), 1.88-2.13 (m, 3H), 1.65 (m, IH); ESI MS: m/z 442.0 [M+H]+.
Example 256. Preparation of Compounds 376, 395 and 435
Figure imgf000570_0002
By using the same synthetic strategy as compound 332 described in Example 217, compound 376 (2.60 mg, 12%), compound 395 (1.03 mg, 5%) and compound 435 (1.58 mg, 7%) were obtained. compound 376: 1H-NMR (CD3OD 400MHz): «57.50 (m, IH), 7.36 (m, IH), 7.28 (m, IH), 7.22 (s; IH), 7.06-7.13 (m, 2H), 4.58 (s, 2H), 3.80-3.96 (m, 2H), 3.55-3.65 (m, 2H), 3.26 (s, 3H), 2.31-2.46 (m, 2H), 1.78-2.06 (m, 3H), 1.58 (m, IH); ESI MS: m/z 426.0
[M+H]+. compound 395: 1H-NMR (CD3OD 400MHz): £7.49 (m, IH), 7.35 (m, IH), 7.29 (m,
IH), 7.22 (m, IH), 7.05-7.12 (m, 2H), 4.59 (s, 2H), 3.75-3.96 (m, 2H), 3.53-3.62 (m, 2H),
3.26 (s, 3H), 2.31-2.46 (m, 2H), 1.77-2.14 (m, 3H), 1.55-1.72 (m, IH); ESI MS: m/z 426.0
[M+H]+. compound 435: 1H-NMR (CD3OD 400MHz): <57.50 (m, IH), 7.35 (m, IH), 7.28 (m,
IH), 7.21 (s, IH), 7.05-7.13 (m, 2H), 4.58 (s, 2H), 3.69-3.78 (m, 2H), 3.60-3.63 (m, 2H),
3.22 (s, 3H), 2.45 (s, 2H), 1.83-2.09 (m, 3H), 1.62-1.72 (m, IH); ESI MS: m/z 426.0
[M+H]+.
Example 257. Preparation of Compound 253
Figure imgf000571_0001
The solution of compound 253a (30 mg), and 5-bromo-2-fluoro-3- methylphenylboronic acid (18 mg), and K2CO3 (2 N, 0.1 mL) in THF (1 mL) was added Pd(PPh3)4 (4.5 mg) under N2, and the mixture was refluxed overnight. The solvent was removed in vacuum, and the crude material was purified by preparative TLC and HPLC to give compound 253 (0.85 mg, 2%). 1H-NMR (CD3OD 400MHz): <S7.48 (m, IH), 7.34- 7.39 (m, 2H), 7.26 (m, IH), 7.09 (m, IH), 3.76-3.97 (m, 2H), 3.57-3.68 (m, 2H), 3.29 (m, 3H), 2.33-2.48 (m, 2H), 2.29 (s, 3H), 1.80-2.18 (m, 3H), 1.56-1.72 (m, IH); ESI MS: m/z 488.0 [M+H]+.
Example 258. Preparation of Compound 207
Figure imgf000571_0002
Pd(PPh3)2Cl2 (2 mg) was added to the mixture of 6-bromo-2-(2;2- dimethyltetrahydro-2//-pyran-4-yl)-2'-methyl-2'H-spiro[chroman-4.5'-[l,254]oxadiazol]- 3'-amine (20 mg, 0.05 mmol), Cs2CO3 (32 mg, 0.10 mmol) and 3-cyanophenylboronic acid (18 mg, 0.10 mmol) in dioxane (3 mL) under Ar2. The mixture was heated at 12O0C in microwave for 15 minutes, and concentrated in vacuo. The residue was purified by preparative TLC and HPLC to give compound 207 (6.49 mg, 31%). 1H-NMR (CD3OD): (57.90-8.05 (m, 3H), 7.60-7.80 (m, 3H), 7.02-7.10 (m, IH), 4.05-4.15 (m, IH), 3.78-3.85 (m, 2H), 3.37-3.45 (m, 3H), 2.68-2.75 (d, IH), 2.10-2.30 (m, IH), 1.85-2.05 (m, 2H), 1.60-1.68 (m, IH), 1.32-1.50 (m, 2H), 1.27-1.30 (d, 6H); ESI MS: m/z=433 [M+H]+.
Example 259. Preparation of Compounds 203 and 263
Figure imgf000572_0001
203c
Experimental data:
Figure imgf000572_0002
203a
Preparation of compound 203a
A solution of 1, 3-dibromo-5-chlorobenzene (10 g, 37.34 mmol), pyridine (6.03 mL). and copper (I) cyanide (3.34 g, 37.34 mmol) in DMF (57.74 mL) was refluxed under nitrogen for 2 days. The reaction was difficult to be monitored by TLC, when the impurities were observed, the reaction was cooled to room temperature. The reaction mixture was quenched with 40 mL of ether, the precipitate was filtered and washed with ether (20 mL><2). The organic layer was washed with a mixture of water and concentrated ammonium hydroxide (2:1, 40 mL), saturated ammonium chloride solution (40 mL><2), and saturated sodium bicarbonate solution (40 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give the compound 203a (2 g, 25%).
Figure imgf000573_0001
203a 203b
Preparation of compound 3
A mixture of [l,10-bis(diphenylphosphino)-feπOcenyl]dichloropalladium(II) (0.256 g, 0.279 mmol), potassium acetate (1.365 g, 13.95 mmol), bis(pinacolato)diboron (1.3 g, 5.12 mmol) and 3-bromo-5-fluorobenzonitrile (1 g, 4.65 mmol) in anhydrous DMSO (15 mL) was refluxed under N2 atmosphere overnight. The mixture was extracted with ethyl acetate, dried and concentrated, the residue was purified by preparative TLC to afford the compound 203b (0.08 g, 7%). 1H-NMR (CDCl3): «57.90 (t, 2H), 7.65 (t, IH), 1.18 (d, 12H, J= 5.2 Hz).
Figure imgf000573_0002
203c
Preparation of compounds 203 and 263
A mixture of compound 203c (20 mg, 0.0526 mmol), 3-chloro-5-(4,4,5,5- tetramethyl-1.3,2-dioxaborolan -2-yl) benzonitrile (20.8 mg. 0.079 mmol), Cs2CO3 solution (2 M, 0.3 mL), and Pd(PPh3 )2C12 (5 mg) in 1.4-dioxane (1 mL) under Ar2 was stirred in microwave at 12O0C for 18 minutes. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC to give compound 203 (1.26 mg, 5%). and compound 263 (1.45 mg. 7%). compound 203: 1H-NMR (400 Hz CD3OD): <S7.85-7.95 (m, 2H), 7.50-7.70 (m, 2H),
7.40-7.50 (m, IH), 7.05-7.12 (m, IH), 3.80-3.95 (m, 2H), 3.55-3.65 (m, 2H), 3.25-3.35
(m, 3H), 2.3-2.5 (m, 2H), 1.82-2.00 (m, 3H), 1.50-1.55 (m, IH); ESI MS: m/z=437
[M+H]+. compound 263: 1H-NMR (400 Hz CD3OD): «57.91 (m, 2H), 7.72 (m, 2H), 7.47 (m, IH),
7.12 (m, IH), 3.71 (m, 2H), 3.61 (m, 2H), 3.30 (m, 3H), 2.43 (m, 2H), 1.82-2.20 (m, 3H),
1.65 (m, IH); ESI MS: m/z=437 [M+H]+.
Example 260. Preparation of Compounds 410 and 446
Figure imgf000574_0001
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with the solution of compound 1 (20 mg, 0.05 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.3 mL), and 6-cyanopyridin-2-ylboronic acid (14.8 mg, 0.1 mmol). The mixture was heated in microwave at 12O0C for 20 min. The reaction mixture was concentrated in vacuo, the residue was purified by preparative TLC and HPLC to give compound 410 and compound 446 (0.84+0.98mg, 8%). compound 410: 1H NMR (CD3OD): J7.94 (t, 2H), 7.64 (m, IH), 7.31 (m, IH), 7.04 (d,
IH), 6.86 (t, IH), 3.82 (t, IH), 3.57 (t, 2H), 3.47 (s, IH), 3.38 (s, 3H), 2.19 (t, 2H), 1.82 (t,
2H), 1.51-1.71 (m, 2H); ESI MS: m/z= 404 [M+H]+. compound 446: 1H NMR (CD3OD): <58.12 (d, IH), 8.04 (m, 2H), 7.79 (t 2H), 7.17 (t,
IH), 3.82 (d, IH), 3.66 (t, 2H), 3.47 (s, IH), 2.17 (s, IH), 2.04 (t, IH), 1.94 (t, IH), 1.68
(s, IH); ESI MS: m/z=404 [M+H]+.
Example 261. Preparation of Compounds 424 and 459
Figure imgf000575_0001
424a
Pd(PPh3 )2C12 (10 mg) under Ar2 was added to the mixture of compound 424a (20 mg, 0.05 mmol), Cs2CO3 (32 mg, 0.10 mmol) and 2-(cyclopenta-2,4-dienyl)-6-(4,4,5,5- tetramethyl-1,3- dioxolan-2-yl) pyridine (21 mg, 0.08 mmol) in [l,4]dioxane (1 mL). The mixture was heated at 12O0C in microwave for 20 minutes, and concentrated in vacuo, the residue was purified by preparative TLC and HPLC to give compound 424 (1.66 mg, 7%) and compound 459 (1.22 mg, 6%). compound 424: 1H NMR (400 MHz CD3OD): <58.O5-8.15 (m, IH), 7.80-7.95 (m, 2H), 7.60-7.70 (m, 3H), 7.40-7.50 (m, IH), 7.10-7.20 (m, IH), 6.30-6.40 (t, 2H), 3.85-3.95 (m, 2H), 3.55-3.70 (m, 2H), 3.30-3.40 (s, 3H), 2.35-2.53 (m, 2H), 1.80-2.12 (m, 3H), 1.55- 1.65 (m, IH); ESI MS: m/z=443 [M+H]+. compound 425: 1H NMR (400 MHz CD3OD): (58.10-8.15 (m, IH), 7.80-7.95 (m5 2H), 7.60-7.70 (m, 3H), 7.40-7.50 (m, IH), 7.10-7.15 (m, IH), 6.30-6.40 (t, 2H), 3.75-3.85 (m, 2H), 3.60-3.70 (m, 2H), 3.30-3.40 (s, 3H), 2.40-2.60 (m, 2H), 1.90-2.28 (m, 3H), 1.65- 1.75 (m, IH); ESI MS: m/z=444 [M+H]+.
Example 262. Preparation of Compound 439
Figure imgf000575_0002
By using the same synthetic strategy as compound 424 described in Example 261, compound 439 (1.46 mg, 7%) was obtained. 1H NMR (400 MHz CD3OD): <59.45-9.55 (s, IH), 8.20-8.30 (m, 2H), 8.05-8.15 (t, IH), 7.95-8.05 (d, IH), 7.75-7.85 (d, IH), 7.70- 7.75 (d, IH), 7.55-7.65 (s, IH), 7.14-7.20 (t, IH), 3.90-4.00 (s, IH), 3.76-3.82 (m, IH), 3.52-3.67 (m, 2H), 3.30-3.40 (s, 3H), 2.30-2.50 (m, 2H), 1.81-2.03 (m, 2H), 1.51-1.70 (m, 2H); ESI MS: m/z=445 [M+H]+. Example 263. Preparation of Compounds 433 and 457
Figure imgf000576_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 433 (2.26 mg, 10%) and compound 457 (1.69 mg, 8%) were obtained. compound 433: 1H NMR (400 MHz CD3OD): (58.05-8.10 (s, IH), 7.80-7.90 (d, IH), 7.65-7.75 (m, 2H), 7.30-7.45 (m, 2H), 7.09-7.12 (d, IH), 3.75-3.95 (m, 2H), 3.50-3.70 (m, 2H), 3.20-3.40 (s, 3H), 2.40-2.4540(m, IH), 2.30-2.40(m, IH), 1.62-2.03 (m, 3H), 1.50- 1.55 (m, IH); ESI MS: m/z=418 [M+H]+. compound 457: 1H NMR (400 MHz CD3OD): (57.90-8.00 (s, IH), 7.65-7.75 (d, IH), 7.55-7.65 (m, 2H), 7.20-7.30 (m, 2H), 7.00-7.05 (d, IH), 3.65-3.75 (m, 2H), 3.50-3.60 (m, 2H), 3.20-3.0 (m, 3H), 2.30-2.40(s, 2H), 1.75-2.10 (m, 3H), 1.50-1.60 (m, IH); ESI MS: m/z=418 [M+H]+.
Example 264. Preparation of Compounds 426 and 447
Figure imgf000576_0002
By using the same synthetic strategy as compound 410 described in Example 260, compound 426 (2.86 mg, 13%) and compound 427 (1.44 mg, 7%) were obtained.
compound 426: 1H NMR (400 MHz CD3OD): <58.95-8.05 (m, IH), 7.75-7.90 (m, 3H), 7.30-7.40 (m, IH), 7.10-7.20 (d; IH), 3.80-4.00 (m, 2H), 3.55-3.65 (m, 2H): 3.30-3.40 (s, 3H), 2.30-2.50(m, 2H), 1.80-2.10 (m, 3H), 1.55-1.65 (m; IH); ESI MS: m/z=413 [M+H]+. compound 427: 1R NMR (400 MHz CD3OD): <57.85-7.95 (m, IH), 7.65-7.75 (m, 3H); 7.20-7.30 (m, IH), 7.00-7.10 (d, IH), 3.65-3.75 (m, 2H), 3.50-3.60 (m, 2H), 3.20-3.30 (s, 3H), 2.30-2.50 (m, 2H), 1.80-2.10 (m, 3H), 1.50-1.60 (m, IH): ESI MS: m/z=413 [M+H]\
Example 265. Preparation of Compound 406
Figure imgf000577_0001
By using the same synthetic strategy as compound 410 described in Example 260. compound 406 (2.37 mg, 11%) was obtained. 1H NMR (400 MHz CD3OD): (58.35-8.45 (m, 2H)5 7.95-8.20 (m, 2H), 7.70-7.80 (m, IH), 7.45-7.55 (m, IH), 7.30-7.45 (m, IH), 7.00-7.10 (m, IH), 4.05-4.15 (m, IH), 3.70-3.80 (m, 2H), 3.30-3.50 (m, 3H), 2.55-2.65 (m, IH), 2.10-2.30 (m, IH), 1.80-2.05 (m, 2H), 1.60-1.70 (m, IH), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 6H); ESI MS: m/z=434 [M+H]+.
Exmaple 266. Preparation of Compound 445
Figure imgf000577_0002
By using the same synthetic strategy as compound 424 described in Example 261, compound 445 (2.15 mg, 9%) was obtained. 1H NMR (400 MHz CD3OD): <58.35-8.45 (m, IH), 8.15-8.20 (m, IH), 7.85-7.95 (m, IH), 7.50-7.65 (m, 3H), 7.40-7.50 (m, IH), 7.00-7.10 (m, IH), 6.25-6.35 (m, 2H), 4.05-4.15 (m, IH), 3.75-3.85 (m, 2H), 3.35-3.50 (m, 3H)8 2.65-2.75 (m, IH), 2.15-2.30 (ms IH), 2.00-2.10 (m, IH), 1.85-1.95 (m, IH), 1.65-1.75 (m, IH), 1.35-1.55 (m, 2H), 1.25-1.35 (m, 6H); ESI MS: m/z=474 [M+H]+.
Example 267. Preparation of Compound 400
Figure imgf000577_0003
By using the same synthetic strategy as compound 424 described in Example 261, compound 400 (2.23 mg, 10%) was obtained. 1H NMR (400 MHz CD3OD): <59.50-9.60 (s, IH), 8.35-8.45 (m, IH), 8.25-8.35 (m, 2H), 8.10-8.20 (m, IH), 8.00-8.10 (m, IH), 7.85- 7.95 (m, IH), 7.70-7.80 (m, IH), 7.55-7.65 (m, IH), 7.00-7.10 (m, IH), 4.05-4.15 (m, IH), 3.60-3.70 (m, 2H), 3.35-3.50 (m, 3H), 2.65-2.75 (m, IH), 2.15-2.30 (m, IH), 2.00-2.10 (m, IH), 1.85-1.95 (m, IH), 1.60-1.70 (m, IH), 1.35-1.50 (m, 2H), 1.25-1.35 (m, 6H); ESI MS: m/z-475 [M+H]+.
Example 268. Preparation of Compounds 361 and 369
Figure imgf000578_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 361 (2.13 mg, 10%) and compound 369 (0.60 mg, 3%) were obtained. compound 361: 1H NMR (400 MHz CD3OD): <58.OO-8.1O (s, IH), 7.90-8.00 (m, IH), 7.80-7.90 (m, IH), 7.70-7.80 (m, 2H), 7.65-7.70 (s, IH), 7.35-7.45 (m, IH), 7.00-7.10 (m, IH), 4.05-4.15 (m, IH), 3.75-3.85 (m, 2H), 3.35-3.50 (m, 3H), 2.65-2.75 (m, IH), 2.15- 2.30 (m, IH), 2.00-2.10 (m, IH), 1.85-1.95 (m, IH), 1.60-1.70 (m, IH), 1.30-1.55 (m, 2H), 1.20-1.30 (m, 6H); ESI MS: m/z-448 [M+H]+. compound 369: 1K NMR (400 MHz CD3OD): <57.90-8.00 (s, IH), 7.80-7.90 (m, IH), 7.70-7.80 (m, IH), 7.60-7.70 (m, IH), 7.55-7.60 (s, IH), 7.35-7.45 (m, IH), 6.90-7.00 (m, 2H)5 3.90-4.00 (m, IH), 3.65-3.75 (m, 2H), 3.35-3.50 (m, 3H), 2.65-2.75 (m, IH), 2.00- 2.20 (m, IH), 1.85-1.95 (m, IH), 1.75-1.85 (m, IH), 1.60-1.70 (m, IH), 1.30-1.55 (m, 2H), 1.20-1.30 (m, 6H); ESI MS: m/z=448 [M+Hf.
Example 269. Preparation of Compound 393
Figure imgf000579_0001
By using the same synthetic strategy as compound 424 described in Example 261, compound 393 (1.31 mg, 6%) was obtained. 1H NMR (400 MHz CD3OD): <58.20-8.30 (s, IH), 7.90-8.00 (m, IH), 7.70-7.80 (m, 2H), 7.20-7.30 (m, IH), 6.95-7.00 (m, IH), 3.95- 4.05 (m, IH), 3.60-3.70 (m, 2H), 3.25-3.40 (m, 3H), 2.65-2.75 (m, IH), 2.00-2.20 (m, IH), 1.85-1.95 (m, IH), 1.70-1.85 (m, IH), 1.50-1.60 (m, IH), 1.35-1.45 (m, 2H), 1.10-1.20 (m, 6H); ESI MS: m/z=443 [M+H]+.
Example 270. Preparation of Compound 196
Figure imgf000579_0002
By using the same synthetic strategy as compound 410 described in Example 260, compound 196 (7.58 mg, 32%) was obtained. 1H-NMR (400 Hz CD3OD): 7.50-7.60 (m, 3H), 7.40-7.50 (s, IH), 7.30-7.40 (s, IH), 7.00-7.10 (m, IH), 4.50-4.60 (m, IH), 3.70-3.80 (m, 2H); 3.20-3.30 (s, 3H), 2.35-2.50 (m IH), 2.05-2.15 (m, 2H), 1.85-1.95 (m, IH), 1.55- 1.65 (m, IH), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 6H); ESI MS: m/z=488 [M+H]+.
Example 271. Preparation of Compound 182
Figure imgf000579_0003
By using the same synthetic strategy as compound 410 described in Example 260, compound 182 (2.11 mg, 12%) was obtained. 1H-NMR (400 Hz CD3OD): 57.80-8.00 (m, 2H), 7.50-7.60 (m, IH), 7.30-7.50 (m, 2H), 7.00-7.10 (m, IH), 4.50-4.60 (m, 0.7H), 3.90-4.00 (m, 0.3H), 3.70-3.80 (m, 2H), 3.30-3.35 (s, IH), 3.20-3.30 (s, 2H), 2.35-2.50 (m IH), 2.05-2.30 (m, 2H), 1.85-1.95 (m, IH), 1.55-1.65 (m, IH), 1.30-1.50 (m, 2H), 1.15- 1.30 (m, 6H); ESI MS: m/z=463 [M+H]+.
Example 272. Preparation of Compounds 268 and 187
Figure imgf000580_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 268 and compound 187 (3.52 mg, 16%) were obtained. compound 268: 1H-NMR (400 Hz CD3OD): δl.55-1.65 (m, IH), 7.45-7.55 (m, 2H)5 7.30-7.40 (m, IH), 7.20-7.30 (m, IH), 6.90-7.10 (m, IH), 4.50-4.60 (m, IH), 3.00-3.20 (m, 3H), 2.35-2.50 (m IH), 2.05-2.30 (m, 2H), 1.85-1.95 (m, IH), 1.55-1.65 (m, IH), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 6H); ESI MS: m/z=460 [M+H]+. compound 187: 1H-NMR (400 Hz CD3OD): J7.60-7.70 (m, IH), 7.45-7.55 (m, 2H), 7.30-7.40 (s, IH), 7.20-7.30 (m, IH), 6.90-7.10 (m, IH), 4.50-4.60 (m, IH), 3.70-3.80 (m, 2H), 3.20-3.30 (s, 3H), 2.40-2.50 (m IH), 2.05-2.20 (m, 2H), 1.85-1.95 (m, IH), 1.55-1.65 (m, IH), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 6H); ESI MS: m/z=460 [M+H]+.
Example 273. Preparation of Compounds 271 and 328
Figure imgf000580_0002
By using the same synthetic strategy as compound 410 described in Example 260, compuond 271 (1.69 mg, 8%) and compound 328 (1.54 mg, 7%) were obtained. compound 271: 1H NMR (400 Hz CD3OD): δl.55-1.65 (m, IH), 7.30-7.40 (s, IH), 7.05- 7.15 (m, IH), 6.80-6.90 (m, 2H): 6.60-6.70 (m, IH), 3.75-4.00 (m, 5H), 3.55-3.65 (m, 2H), 3.30-3.40 (s, 3H), 2.30-2.50 (m, 2H), 1.80-2.10 (m, 3H), 1.50-1.70 (m, IH): ESI MS: m/z=426 [M+H]+. compound 328: 1H NMR (400 Hz CD3OD): <57.50-7.60 (m, IH), 7.30-7.40 (s, IH), 6.95- 7.05 (m, IH), 6.75-6.85 (m, 2H), 6.55-6.65 (m, IH), 3.25-3.30 (s, 3H), 3.15-3.25 (m, 2H), 3.50-3.60 (m, 2H), 3.30-3.40 (s, 3H), 2.35-2.45 (s, 2H), 1.80-2.10 (m, 3H), 1.55-1.65 (m, IH); ESI MS: m/z=426 [M+H]+.
Example 274. Preparation of Compound 223
Figure imgf000581_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 223 (4.50 mg, 20%) was obtained. 1H NMR (400 Hz CD3OD): <57.60-7.70 (m, IH), 7.45-7.50 (s, IH), 7.30-7.40 (m, 2H), 7.20-7.25 (m, IH), 7.05-7.15 (m, IH), 3.70- 4.00 (m, 5H), 3.55-3.65 (m, 2H), 3.30-3.40 (s, 3H), 2.30-2.50 (m, 2H), 1.80-2.10 (m, 3H), 1.50-1.70 (m, IH); ESI MS: m/z=433 [M+H]+.
Example 275. Preparation of Compounds 283 and 333
Figure imgf000581_0002
By using the same synthetic strategy as compound 410 described in Example 260, compound 283 (1.97 mg, 7%) and compound 333 (1.78 mg, 6%) were obtained. compound 283: 1H NMR (400 Hz CD3OD): J7.50-7.60 (m, IH), 7.10-7.20 (m, IH), 6.95- 7.05 (m, IH), 6.50-6.60 (s, 2H), 6.35-6.45 (s, IH), 3.70-4.00 (m, 8H), 3.50-3.65 (m, 2H), 3.30-3.40 (ss 3H), 2.35-2.50 (m, 2H), 1.70-2.10 (m, 3H), 1.50-1.70 (m, IH): ESI MS:
Figure imgf000581_0003
compound 333: 1H NMR (400 Hz CD3OD): J7.50-7.60 (m, IH), 7.20-7.30 (s, IH), 7.00- 7.10 (m, IH), 6.60-6.70 (s, 2H)S 6.40-6.50 (s, IH), 3.75-3.85 (ms 6H), 3.60-3.70 (m, 2H), 3.30-3.40 (s, 3H), 2.40-2.50 (s, 2H), 1.90-2.20 (m, 3H), 1.60-1.80 (m, IH); ESI MS: m/z=438 [M+H]+.
Example 276. Preparation of Compound 193
Figure imgf000582_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 193 (2.76 mg, 12%) was obtained. 1H NMR (400 Hz CD3OD): «57.50-7.60 (m, IH), 7.20-7.40 (m, IH), 7.05-7.15 (m, IH), 6.95-7.05 (m, 2H), 6.85-6.90 (s, IH), 4.50- 4.60 (m, IH), 3.80-3.85 (s, 3H), 3.70-3.80 (m, 2H), 3.20-3.30 (s, 3H), 2.00-2.50 (m, 3H), 1.85-1.95 (m, IH), 1.55-1.65 (m, IH), 1.30-1.50 (m, 2H), 1.20-1.30 (m, 6H); ESI MS:
Figure imgf000582_0002
Example 277. Preparation of Compound 183
Figure imgf000582_0003
By using the same synthetic strategy as compound 424 described in Example 261, compound 183 (2.38 mg, 10%) was obtained. 1H NMR (400 Hz CD3OD): <57.85-7.95 (m, 2H), 7.60-7.75 (m, 2H), 7.40-7.55 (m, IH), 7.05-7.15 (m, IH), 4.50-4.60 (m, IH), 3.80-3.85 (s, 3H), 3.70-3.80 (m, 2H), 3.35-3.45 (m, 3H)8 2.05-2.50 (m, 3H), 1.85-1.95 (m, IH), 1.55-1.65 (m, IH),. 1.40-1.50 (m, 2H), 1.30-1.40 (m, 6H): ESI MS: m/z=479 [M+H]+.
Example 278. Preparation of Compound 184
Figure imgf000583_0001
By using the same synthetic strategy as compound 410 described in Example 260, compound 184 (2.0 mg, 15%) was obtained. 1U NMR (400 Hz CD3OD): <57.40-7.65 (m, 5H), 7.15-7.25 (m, IH), 7.00-7.10 (m, IH), 4.50-4.60 (m, IH), 3.70-3.80 (m, 2H), 3.20- 3.25 (s, 3H), 2.40-2.50 (m, 2H), 2.00-2.20 (m, 2H)5 1.80-1.90 (m, IH), 1.55-1.65 (m, IH), 1.30-1.50 (m, 2H), 1.20-1.30 (m, 6H); ESI MS: m/z=504 [M+H]+.
Example 279. Preparation of Compound 195
Figure imgf000583_0002
By using the same synthetic strategy as compound 410 described in Example 260, compound 195 (2.0 mg, 8%) was obtained. 1U NMR (400 Hz CD3OD): δl.55-1.10 (m, 3H), 7.50-7.55 (s, IH), 7.30-7.40 (m, IH), 7.00-7.10 (m, IH), 4.50-4.60 (m, IH), 3.70- 3.80 (m, 2H)5 3.20-3.25 (s, 3H)5 2.40-2.50 (m, IH), 2.00-2.20 (m, 2H), 1.85-1.95 (m, IH), 1.55-1.65 (ms IH)5 1.30-1.50 (m, 2H), 1.20-1.30 (m, 6H): ESI MS: m/z=506 [M+H]+.
Example 280. Preparation of Compound 418
Figure imgf000583_0003
Pd(PPhS)2Cl2 (10 mg) in a 10 mL tube was treated sequentially with the solution of compound 418a (20 mg, 0.05 mmol) in 1,4-dioxane (2 mL), Cs2CO3 solution (2 N5 0.3 mL), and 2-(lH-imidazol-l-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydrothiazole (27.7 mg, 0.1 mmol) under Ar2. The mixture was heated in microwave at 12O0C for 20 min., concentrated in vacuo, and the residue was purified by preparative TLC and HPLC to give compound 418 (1.45 mg, 12%). 1H-NMR (400 MHz CD3OD): »58.51 (d, IH), 7.86 (t, IH), 7.73 (s, IH), 7.62 (s, IH), 7.52 (d, IH), 7.17 (d, IH), 7.00 (s, IH)5 3.62-3.86 (m, 2H), 3.52 (d, 2H), 3.24 (s, 3H), 2.28-2.41 (m, 2H), 2.02 (s, IH), 1.92 (s, IH), 1.83 (d, IH), 1.54 (s, IH); ESI MS: m/z 451.2 [M+Na]+.
Example 281. Preparation of Compound 370
Figure imgf000584_0001
370a
Pd(PPh3 )2C12 (10 mg) in a 10 rnL of tube under Ar2 was treated sequentially with the compound 370a (20 mg, 0.05 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.3 mL) and 2-(lH-imidazol-l-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydrothiazole (27.7 mg, 0.1 mmol). The mixture was heated under microwave at 12O0C for 20 min. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC and HPLC to give compound 370 (1.58 mg, 14%). 1H-NMR (400 MHz CD3OD): <58.52 (s, IH), 8.21 (s, IH), 7.94 (d, IH), 7.82 (s, IH), 7.68 (s, IH), 7.21 (s, IH), 6.96 (t, IH), 4.03 (d, IH), 3.73 (t, 2H), 3.41 (d, 3H), 2.64 (d, IH), 2.19 (s, IH), 1.98 (t, IH), 1.84 (t, IH), 1.63 (t, IH), 1.32-1.51 (m, 2H), 1.26 (d, 6H); ESI MS: m/z 481.3 [M+H]+.
Example 282. Preparation of Compounds 245 and 247 H
LAH PCC
Figure imgf000585_0003
Figure imgf000585_0002
Figure imgf000585_0001
245a 245b 245c 245d 245e
Figure imgf000585_0004
TMSN=C=NTMS MeNHOH HCI
Figure imgf000585_0005
Figure imgf000585_0006
Experimental data:
TMSCN
Figure imgf000585_0007
Figure imgf000585_0008
245a 245b
Preparation of compound 245b
A mixture of compound 245a (20 g, 137 mmol) and zinc(II) iodide (0.874 g, 2.74 mmol) in CH2Cl2 (300 mL) was slowly added trimethylsilanecarbonitrile (40.9 mL, 205.5 mmol) at O0C. This mixture was stirred at room temperature overnight, washed with 300 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4), and concentrated in vacuo to give the compound 245b (32 g, 97%), which was used for the next step without purification. H
Figure imgf000585_0009
245b 245c Preparation of compound 245c
A mixture of compound 245b (16.1 g, 65.5 mmol) and SnCl2. 2H2O (56 g, 248.3 mmol) in a mixture of acetic acid (60 mL) and concentrated HCl solution (60 mL) was refluxed overnight. The mixture was extracted with CH2Cl2 (150 mLx3). The combined organic phase was washed with 2N sodium hydroxide solution (100 mL x 3). The combined basic washes were extracted with ether (100 mLx2), and subsequently acidified to pH = 2 with 5N HCl solution. The acidic aqueous mixture was extracted with EA (150 mLx3), and the combined organic layer was dried and concentrated in vacuo to give the compound 245c (10 g, 85%), which was used for the next step without purification. 1H- NMR (400 MHz CDCl3): <510.7 (br s, IH), 7.05 -7.20 (m, 4H), 3.76 (m, IH)5 2.78 (m, 2H), 2.08 (m, 2H), 1.85-2.01 (m, 2H).
Figure imgf000586_0001
245c 245d
Preparation of compound 245d
To a stirred solution of LAH (3.5 g, 92 mmol) in THF (50 mL) was cooled to O0C, and was added compound 245c (8 g, 45.5 mmol). The mixture was stirred overnight, quenched by water (3.5 mL) and aqueous NaOH (10 %, 3.5 mL) at O0C, and filtered. The cake was washed with EtOAc for 3 times, and the filtrate was dried and concentrated in vacuo to give the compound 245d (7.2 g, 98%). 1H-NMR (400 MHz CDCl3): δl.05 -7.20 (m, 4H), 3.76 (m5 2H), 2.98 (m, IH), 2.78 (m, 2H), 1.65-1.94 (m, 5H).
Figure imgf000586_0002
245d 245e Preparation of compound 245e
To a solution of compound 245d (3 g, 18.5 mmol) in dry CH2Cl2 (60 mL) was added 3 A molecule series (1.9 g) and PCC (6 g. 27.8 mmol). The mixture was stirred at room temperature for 2 h, and TLC showed that the reaction was completed. The mixture was filtered through celite, dried over Na2SO4. and concentrated in vacuo to give the compound 245e (1.4 g, 46%).
245f 245g
Preparation of compound 245g
To a stirred solution of compound 245f (1.8g, 8.7 mmol) in a mixture of EtOH (11.4 mL) and H2O (18.3 mL) was added compound 245e (1.4 g, 8.7 mmol) and borax (3.31 g, 8.7 mmol). The mixture was refluxed for 2 days. The mixture was filtrated, and the filtrate was removed in vacuo. The residue was dissolved in CH2Cl2, and filtrated. The solvents were evaporated, the crude product was purified by column chromatography to give the compound 245g (600 mg, crude).
Figure imgf000587_0002
Preparation of compound 245i
To a solution of compound 245g (300 mg, 0.84 mmol), compound 245h (247 mg. 1.68 mmol), Cs2CO3 solution (2 M, 1.OmL) in 1,4-dioxane (4.2 mL) was added Pd(PPh3)2Cl2 (15 mg) under N2. The mixture was stirred at 1000C for 6 mimutes, and cooled to room temperature. After extraction, the organic layer was dried and concentrated. The residue was purified by TLC to give the compound 245i (100 mg, 31%). 1H-NMR (400 MHz CDCl3): <S8.00 (m,lH), 7.74 (m, 3H), 7.63 (m, IH), 7.52 (m, IH), 7.48 (m, IH), 7.06 (m, 4H), 4.61-4.32 (m, IH), 3.21-3.47 (m, IH), 2.74 (m, 3H), 2.58 (m, IH), 2.08 (m, IH), 1.84 (m, 2H), 1.75 (m, IH).
Figure imgf000587_0003
Preparation of compound 245j
To a solution of compound 245i (75 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added TiCl4 (1 M in DCM, 74 mg, 0.40 mmol). The mixture was stirred in microwave at 5O0C for 10 minutes. Bis-trimethylsilylcarbodiimide (74 mg, 0.40 mmol) was added, and the resulting mixture was stirred in microwave at 6O0C for 10 minutes. The reaction mixture was poured into the ice-water, extracted with DCM, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the compound 245j (70 mg, 87.5%
)•
MeNHOH.HCI
Figure imgf000588_0002
Figure imgf000588_0001
Preparation of compounds 245 and 247
To a solution of methylhydroxylamine HCl salt (16 mg, 0.17 mmol) in anhydrous MeOH (5 mL) was added NaOMe (10% in MeOH, 24 mg, 0.16 mmol) and compound 245j (70 mg, 0.17 mmol). After being stirred for 20 minutes, the solvent was removed in vacuo, and the residue was dissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed, the residue was purified by preparative HPLC to give the compound 245 (6.48 mg, 8%) and compound 247 (1.5 mg, 2%). compound 245: 1H-NMR (400 MHz CD3OD): <57.98 (m, IH), 7.92 (m, 2H), 7.72 (m, 2H), 7.59 (m, IH), 7.30 (m, IH), 7.15 (m, 3H), 7.00 (m, IH), 461-4.74 (m, IH), 3.47 (m, IH), 3.33 (m, 3H), 2.78(m, 2H), 2.45-2.61 (m, IH), 1.85-2.10 (m, 4H), 1.75 (m, IH); ESI MS: m/z 451 [M+H]+. compound 247: 1H-NMR (400 MHz CD3OD): δl.92-1..97 (m, 3H), 7.59-7.72 (m, 3H), 7.34 (m, IH), 7.14 (m, 3H), 7.00 (m, IH), 461-4.74 (m, IH), 3.36 (m, 4H), 2.78 (m, 2H), 2.45-2.61 (m, 2H), 1.85-2.10 (m, 3H), 1.75 (m, IH): ESI MS: m/z 451 [M+H]+.
Example 283. Preparation of Compounds 279 and 331
Figure imgf000589_0001
MeNHOH.HCI
Figure imgf000589_0003
Figure imgf000589_0002
Experimental data:
TMSCN
Figure imgf000589_0004
Figure imgf000589_0005
Preparation of compound 279b
To the mixture of compound 279a (15 g, 67.5 mmol) and zinc (II) iodide(0.6 g, 1.25 mmol) in CH2Cl2 (300 mL) was cooled to O0C, and slowly added trimethylsilanecarbonitrile (15 g, 101.8 mmol). The mixture was stirred at room temperature overnight, washed with 300 mL of saturated aqueous sodium bicarbonate solution, and the organic layer was dried (MgSO4), and concentrated in vacuo to give the compound 279b (25 g, 98%), which was used for the next step without purification. 1H- NMR (400 MHz CDCl3): <57.45 (m, IH), 7.1 1 (m, IH), 6.85 (m, IH), 6.71 (m, IH), 4.18 (m, 2H), 2.22 (m, 2H), 0.05 (m, 9H). H
Figure imgf000589_0006
Preparation of compound 279c A mixture of compound 279b (16.2 g, 65.5 mmol) and SnCb (56 g, 248.3 mmol) in a mixture of acetic acid (60 mL) and concentrated HCl (60 mL) was heated to reflux for 3 days. The mixture was extracted with CH2Cl2 (150 mLx3), washed with 2N sodium hydroxide (100 mL x3). The combined basic washes were extracted with ether (100 mLx2), and subsequently acidified to pH = 2 with 5N HCl solution. The acidic aqueous mixture was extracted with EA (150 mLx3), and the combined organic layer was dried and concentrated in vacuo to give the compound 279c (1O g, 85%), which was used for the next step without purification. 1H-NMR (400 MHz CDCl3): <58.O5-9.O5 (m, IH), 7.20 (m, IH), 7.05 (m, IH), 6.85 (m, 2H), 4.21 (m, 2H), 3.51-3.74 (m, IH), 2.01-2.31 (m, 2H).
Figure imgf000590_0001
Preparation of compound 279d
To a stirred solution of LAH (5.34 g. 140.5 mmol) in THF (100 mL) under N2 was added compound 279c (10 g, 56.18 mmol) at O0C. The mixture was stirred overnight. Aqueous NaOH (1 N, 12 mL) was added at 0°, and the mixture was filtered. The cake was washed with EtOAc for three times, and the filtrate was dried and concentrated to give the compound 279d (7.8 g, 86%).
Figure imgf000590_0002
Preparation of compound 279e
To a solution of compound 279d (3 g, 18.5 mmol) in dry CH2Cl2 (60 mL) was added 3A molecule series (1.9 g) and PCC (6 g. 27.8 mmol). The mixture was stirred at room temperature for 2 h, and TLC showed that the reaction was completed. The mixture was filtered through celite, dried over Na2SO4. and concentrated in vacuum to give the compound 279e (1.6 g, 53%). 1H-NMR (400 MHz CDCl3): <59.62 (m; IH), 7.82 (m, IH), 7.45 (m, IH), 7.05-7.21 (m, 2H), 4.50 (m; 2H): 4.1 1 (m, IH), 2.75 (m; 2H).
Figure imgf000591_0001
Preparation of compound 279g
To a stirred solution of compound 279f (2.12 g, 10 mmol) in a mixture of EtOH (13 mL) and H2O (21.3 mL) was added compound 279e (1.6 g, 10 mmol) and borax (3.81 g, 10 mmol). The mixture was refluxed overnight. The mixture was filtrated, and the filtrate was removed in vacuo. The residue was dissolved in CH2Cl2. After filtration, the solvents were evaporated, the crude product was purified by column chromatography to give the compound 279g (600 mg, crude).
Figure imgf000591_0002
Preparation of compound 279i
To a solution of compound 279g (100 mg, 280 mmol), compound 279h (61.74 mg, 420 mmol), Cs2CO3 solution (2 M, 1.5mL) in L4-dioxane (4 mL) was added Pd(PPh3)2Cl2 (25 mg) under N2. The mixture was stirred at 1000C for 20 min., cooled to room temperature, dried, and concentrated. The residue was purified by pre-TLC to give the compound 279i (30 mg, crude).
Figure imgf000591_0003
Preparation of compound 279j To a solution of compound 279i (30 mg, 0.079 mmol) in CH2Cl2 (1 mL) was added TiCl4 (1 M in DCM5 0.157 mL, 0.157 mmol). This mixture was stirred in microwave at 5O0C for 10 minutes, and bis-trimethylsilylcarbodiimide (0.039 mL, 0.174 mmol) was added. The resulting mixture was stirred in microwave at 6O0C for 10 minutes, poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the compound 279j (30 mg, crude).
MeNHOH.HCI
Figure imgf000592_0001
Figure imgf000592_0002
Preparation of compounds 279 and 331
To a solution of methylhydroxylamine HCl salt (6.2 mg, 0.074 mmol) in anhydrous MeOH (2 mL) was added NaOMe (10% in MeOH (Wt.%), 3.6 mg, 0.067 mmol), followed by compound 279j (30 mg, 0.074 mmol). After being stirred at room temperature for 20 minutes, the solvent was removed in vacuo. The residue was dissolved in DCM (5 mL), and the mixture was filtered. The solvent was removed, and the residue was purified by preparative HPLC to give the compound 279 (2.03 mg, 6%), and compound 331 (1.12 mg, 4%). compound 279: 1H-NMR (400 MHz CD3OD): (57.91 (m, 3H), 7.55-7.62 (m, 3H), 7.22 (m; IH), 7.01 (m, 2H), 6.71 (m, 2H), 4.51 (m, IH), 4.22 (m, 2H), 3.33 (m, 3H), 2.88(m, IH), 2.55-2.61 (m, IH), 2.33(m, IH), 2.05 (m, 2H): ESI MS: m/z 453 [M+H]+. compound 331: 1H-NMR (400 MHz CD3OD): <57.88 (m, 3H), 7.51-7.63 (m, 3H), 7.19 (m, IH), 7.01-7.32 (m, 2H), 6.70-6.82 (m, 2H), 4.57 (m, IH), 4.13-4.25 (m, 2H), 3.42 (m, 3H), 2.88-3.05(m, IH), 2.33-2.61(m, 3H), 2.05 (m, 2H); ESI MS: m/z 453 [M+H]+.
Example 284. Preparation of Compound 396
Figure imgf000593_0001
Experimental data
Figure imgf000593_0002
To a stirred solution of compound 396a (0.64 g, 5 mmol) in MeOH (40 mL) was added compound 396A (0.72 g, 3.3 mmol) and pyrrolidine (0.41 mL). The mixture was refluxed overnight. TLC showed that the reaction was completed, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (60 mL), dried over Na2SO4 and concentrated. The residue was purified by pre- TLC (petroleum ether: EA = 5:1) to give the compound 396b (359 mg, yield 22%) as a yellow solid. 1H-NMR (CDCl3 400 MHz): «57.91 (s, IH), 7.49-7.52 (d, IH), 6.80-6.83 (d, IH), 3.96-4.04 (t, IH), 3.62-3.67 (dd, IH), 2.51-2.69 (dd, 2H), 1.87-1.97 (t, 2H), 1.58-1.68 (m, IH), 1.33-1.37 (d, IH), 1.27 (s, 3H), 1.12 (s, 3H).
Figure imgf000593_0003
To a solution of compound 396b (124 mg. 0.38 mmol), 3-cyanophenylboronic acid (112 mg, 0.76 mmol), Cs2CO3 (2 M, 2.25 mL) in 1,4-dioxane (4 mL) under N2 was added Pd(PPh3)2Cl2 (37 mg). The mixture was stirred in microwave at 1000C for 30 mimutes, cooled to room temperature, TLC showed that the reaction was completed. After work up and purification by pre-TLC (petroleum etheπEA = 5:1), compound 396c (118 mg, 89%) was obtained as a white solid. 1H-NMR (CDCl3 400 MHz): (58.01 (s, IH), 7.72-7.78 (t, 2H), 7.63-7.67 (d, IH), 7.55-7.57 (d, IH), 7.45-7.50 (t, IH), 7.02-7.05 (d, IH), 4.01-4.10 (t, IH), 3.65-3.72 (m, IH), 2.57-2.76 (q, 2H), 1.92-2.03 (t, IH), 1.37-1.49 (m, IH), 1.32 (s, 3H), 1.14 (s, 3H).
Figure imgf000594_0001
To a solution of compound 396c (60 mg, 0.173 mmol) in CH2Cl2 (4mL) was added TiCl4 (1 M in CH2Cl2, 0.22 mL, 0.224 mmol). This mixture was stirred at room temperature for 1 h, bis-trimethylsilylcarbodiimide (0.085 mL, 0.38 mmol) was added, and the resulting mixture was stirred at room temperature overnight. TLC showed that the reaction was completed, the reaction mixture was poured into ice- water (12 mL), and extracted with CH2Cl2 (20mL><2). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the compound 396d (66 mg, crude, 100%) as a white solid, which was used directly for the next step without purification.
Figure imgf000594_0002
To a solution of MeNHOH.HCI (7.2 mg; 0.086 mmol) in anhydrous MeOH (3 mL) was added MeONa (10% in MeOH, 40 mg, 0.077 mmol) and compound 396d (32 mg, 0.086 mmol). After being stirred for 30 min at room temperature, TLC showed that the reaction was completed. The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (10 mL). The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC and pre-HPLC to give compound 396 (3.94 mg, yield 11%) as a white solid. 1H-NMR (CD3OD 400 MHz): 57.87-7.91 (t, 2H), 7.67-7.68 (s, 2H), 7.56-7.63 (m, 2H), 6.95-6.98 (d, IH), 4.17-4.25 (m, 0.6H), 3.95- 4.01 (t, 0.4H), 3.68-3.74 (m, 0.6H), 3.58-3.65 (m, 0.4H), 3.10 (s, 3H), 1.75-2.38 (m, 4H), 1.54-1.74 (m, 2H), 1.52 (s, 1.4H), 1.34 (s, 1.6H), 1.23 (s, 1.4H), 1.65 (s, 1.6H): ESI MS: 419 [M+H]+.
Example 285. Preparation of Compound 206
KCN/(NH4)2CO3 Lawesson's reagent HCONH2
Figure imgf000595_0003
Figure imgf000595_0002
206a 206b
Figure imgf000595_0004
Figure imgf000595_0001
206d 206e
Experimental data:
Figure imgf000595_0005
206a 206b
Preparation of compound 206b
A mixture of compound 206a (0.5 g. 1.48 mmol). KCN (193 g, 3 mmol), and (NH4)^CO3 (1.1 g, 1 1 mmol) in a mixture of formamide (34 mL) and DMF (3 mL) was heated at 11O0C in a microwave reactor for 2 h. The reaction mixture was cooled and poured into ice water. The mixture was acidified with concentrate HCl solution. The resulting precipitate was filtered, washed twice with water, and dissolved in ethyl acetate. The organic solution was dried over Na2SO4. and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column to give the compound 206b (480 mg, 60%). 1H-NMR (400 Hz CDCl3): J7.30 (m, IH)5 7.29 (m, IH), 7.23 (m, IH), 7.23 (m, IH), 6.77 (m, IH), 4.46 (m, IH), 3.96 (m, IH), 3.75 (m, 2H), 2.11 (m, 5H), 1.93 (m, IH), 1.67 (m, 7H).
Lawesson's reagent
Figure imgf000596_0002
Figure imgf000596_0001
206b 206c
Preparation of compound 206c
A suspension of compound 206b (360 mg, 0.89 mmol) and Lawesson's Reagent (358 mg, 0.89 mmol) in dry 1,4-dioxane (5 mL) was heated at 12O0C in microwave for 0.5 h. The mixture was concentrated in vacuo, and the residue was purified by TLC to give the compound 206c (1 14 mg. 40%).
Figure imgf000596_0003
206c 206d
Preparation of compound 206d
To a solution of compound 206c (100 mg, 0.24 mmol) in MeOH (25 mL) was added NaOH solution (0.5 mL, 0.3 mol, 0.6 N aq.) and MeI (240 mg, 1.7 mmol). The reaction mixture was heated at 6O0C in microwave reactor for 15 min., and concentrated in vacuo. The residue was purified by preparative TLC to give the compound 206d (47 mg,
44%).
Figure imgf000596_0004
206d 206e Preparation of compound 206e
A solution of compound 206d (47 mg, 0.1 mmol), NH4I (38 mg, 0.26 mmol) in NH3/EtOH (4 mL, 1.5 N) in a tube was heated at 12O0C in a microwave reactor for 2 h. After being cooled down, the mixture was concentrated in vacuum, the residue was purified by preparative TLC to afford the compound 206e (20 mg. 47%).
Figure imgf000597_0001
206e
Preparation of compound 206 Pd(PPh3)2Cl2 (8 mg; 0.011 mmo), Cs2CO3 (2 N, 0.3 mL) and 3- cyanophenylboronic acid (10 mg, 0.068 mmol) were added to a solution of compound 5 (20 mg, 0.048 mmol) in 1,4-dioxane (1 mL) in a 10 mL tube. The mixture was heated at
12O0C in a microwave reactor for 20 min., concentrated in vacuo, the residue was purified by preparative TLC and HPLC to give compound 206 (5.26 mg, 25%). 1H-NMR (400 Hz CD3OD): <57.8O-8.OO (m, 2H), 7.50-7.65 (m, 3H), 7.30-7.50 (m, IH), 7.00-7.10 (m, IH), 4.40-4.50 (m, IH), 3.95-4.05 (m, IH), 3.70-3.80 (m, 2H), 3.30-3.35 (m, IH), 3.20- 3.25 (s, 2H), 2.30-2.45 (m, IH)5 2.00-2.20 (m, 3H), 1.65-1.85 (m, 6H); ESI MS: m/z=443 [M+H]+.
Example 286. Preparation of Compound 422
Figure imgf000598_0001
MeNHOH HCI
Figure imgf000598_0002
Experimental data:
Figure imgf000598_0003
Preparation of compound 422b
The solution of LAH (640 mg, 16.8 mmol) in 20 niL of dry THF at O0C was added the solution of compound 422a (2 g. 1 1.2 mmol) in THF (10 mL) dropwise. and the reaction mixture was stirred at room temperature for 2 hour. The reaction was quenched with 7 mL of H2O and 7 mL of 10% NaOH solution. The solution was filtered, and the filtrate was concentrated to give the compound 422b (1.8 g, 100%). 1H NMR (400 MHz CDCl3): «57.12 (m, 2H)5 6.87 (m, 2H), 4.34 (m, IH), 4.08 (m, IH)5 3.75 (m, 2H)5 2.91 (m, IH)5 2.53 (m, 13H), 2.29 (m, IH).
Figure imgf000598_0004
Preparation of compound 422c
To a solution of compound 422b (970 mg. 5.99 mmol) in DCM (25 mL) was added 3A molecular sieves (500 mg) and PCC (1.94 g. 8.98 mmol). The reaction mixture was stirred at room temperature for 2 h, filtered, washed with DCM, dried, and concentrated to give compound 422c (681 mg, 71%). 1H NMR (400 MHz CDCl3): (57.04- 7.22 (m, 2H), 6.73-6.88 (m, 2H), 2.91-3.13 (m, 3H)5 1.31-4.42 (m, 2H).
Figure imgf000599_0001
Preparation of compound 422d
To a solution of compound 422c (681 mg, 4.23 mmol) in a mixture of H2O (6 mL) and EtOH (3.6 mL) was added l-(5-bromo-2-hydroxyphenyl)ethanone (1.09 mg, 5.08 mmol) and borax (2.42 mg, 6.35 mmol). The reaction mixture was refluxed overnight, cooled, and filtered. EtOH was removed, and the aqueous was extracted with DCM (30 mL><3). The organic layer was dried, concentrated, and purified by preparative TLC to afford the compound 422d (170 mg, 11%). 1H NMR (400 MHz CDCl3): (57.92 (s, IH), 7.51 (m, IH), 7.06 (m, 2H), 6.72-6.88 (m, 3H), 4.45 (m, IH), 4.22-4.38 (m, IH), 4.08 (m, IH), 2.95 (m, IH), 2.52-2.89 (m, 3H), 2.46 (m, IH).
Figure imgf000599_0002
Preparation of compound 422e
Pd(PPh3 )2C12 (10 mg) in a 10 mL of flask under N2 was treated sequentially with the solution of compound 422d (90 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 solution (2 N, 0.25 mL), and 3-cyanophenylboronic acid (37 mg, 0.5 mmol). The mixture was heated at 1000C under N2 in microwave for 10 minutes. The organic layer was concentrated in vacuo, and the residue was purified by preparative TLC to give the compound 422e (75 mg, 78%). 1H NMR (400 MHz CDCl3): (58.03 (s, IH), 7.77 (m, 2H), 7.66 (m, IH), 7.54 (m, IH), 7.48 (ms IH), 6.99-7.11 (m, 3H), 6.72-6.88 (m, 2H), 4.49 (m, IH), 4.1 1-4.30 (m, 2H), 2.62-3.03 (m, 4H), 2.48 (m, IH).
Figure imgf000600_0001
Preparation of compound 422f
To a solution of compound 422e (85 mg, 0.22 mmol) in dried CH2Cl2 (5 mL) was added TiCl4 (I M solution in DCM, 0.44 mL) at room temperature dropwise within 15 minutes. The mixture was stirred for 1 h, and added ό/s-trimehtlysilylcarbodiimide (125 mg, 0.66 mmol) dropwise. The resulting mixture was stirred overnight, poured into ice- water, and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the compound 422f (100 mg, crude), which was used for the next step without further purification.
MeNHOH.HCI
Figure imgf000600_0003
Figure imgf000600_0002
422f
Preparation of compound 422 To a solution of MeNHOHΗCl (21 mg, 0.25 mmol) in anhydrous MeOH (3 mL) was added NaOMe (10% in MeOH, 122 mg, 0.225 mmol) and compound 422f (100 mg, 0.25 mmol) at room temperature. After being stirred for 10 minutes, the solvent was removed in vacuum. The residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated, the residue was purified by preparative TLC and HPLC to afford the compound 422 (5.5 mg, 5%). 1H NMR (400 MHz CD3OD): δl.9% (m, 3H), 7.66 (m, 3H), 7.09 (m, 3H), 6.81 (d, 2H), 4.46 (m, 2H), 4.17 (m, IH), 3.43 (m, 3H), 2.70-3.09 (m, 3H), 2.49 (m, IH), 2.11 (m, IH): ESI MS: m/z 452 [M+H]+.
Example 287. Preparation of Compound 219
Figure imgf000601_0001
219a
Preparation of compound 219
A mixture of compound 219a (30 mg, 0.079 mmol), 3,5-dichlorophenylboronic acid (22 mg, 0.12 mmol), Cs2CO3 solution (2 M, 0.3 mL), and Pd(PPh3)2Cl2 (5 mg) in 1,4- dioxane (1 mL) under N2 was stirred at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give the compound 219 (1.85 mg, 5%). 1H-NMR (400MHz CD3OD): (57.91 (m, IH), 7.67 (m, IH), 7.58 (m, 2H), 7.45 (m, IH), 7.12 (m, IH), 4.18 (m, 0.3H), 3.82 (m, 0.7H), 3.58 (m, 2H), 3.37 (m, 3H), 3.16 (m, 0.6H), 2.48 (m, 0.4H), 1.95-2.20 (m, 2H), 1.41-1.96 (m, 3H), 1.21 (m, 3H); ESI MS: m/z 448 [M+H]+.
Example 288. Preparation of Compound 371
MeNHOH HCI
Figure imgf000601_0003
Figure imgf000601_0002
371a 371b 371c
Figure imgf000601_0004
Experimental data:
Figure imgf000601_0005
371a 371b
Preparation of compound 371b
To a solution of compound 371a (100 mg, 0.32 mmol) in CH2Cl2 (15mL) was added TiCl4 (1 M in DCM, 0.65 mL, 0.65 mmol). This mixture was stirred for 1 h at room temperature. Bis-trimethylsilylcarbodiimide (0.157 mL, 0.704 mmol) was added, and the resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with DCM, dried over anhydrous Na2SO4, filtered, and concentrated to give the compound 371b (30 mg, 28%).
MeNHOH.HCI
Figure imgf000602_0002
Figure imgf000602_0001
371b 371c
Preparation of compound 371c
To a solution of methylhydroxylamine HCl salt (7.56 mg, 0.090 mmol) in anhydrous MeOH (2 mL) was added NaOMe (10% in MeOH, 0.045 mL) at room temperature, followed by addition of compound 371b (30mg, 0.09 mmol). After being stirred for 25 minutes, the solvent was removed in vacuo, and the residue was redissolved in DCM (50 mL). The mixture was filtered, and the solvent was removed. The residue was purified by TLC to give the compound 371c (20 mg, 59%). 1H-NMR (400 MHz CDCl3): δlΛ5 (m, IH), 7.21 (m, IH), 6.60 (m, IH), 4.08 (m, IH), 3.80 (m, IH), 3.32-3.52 (m, 2H), 3.00 (m, 3H), 2.65 (m, IH), 2.3 (m, 3H), 2.11-2.2 (m, 2H), 1.22 (m, 3H).
Figure imgf000602_0003
371c
Preparation of compound 371
A mixture of compound 371c (20mg, 0.052 mmol). 3,5-dichlorophenylboronic acid (14.7 mg, 0.078 mmol), Cs2CO3 solution (2 M, 0.300 mL), and Pd(PPh3)2Cl2 (5 mg) in 1,4-dioxane (1 mL) under Ar2 was stirred in microwave at 12O0C for 18 minutes. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative TLC and HPLC to give compound 371 (1.50 mg, 7%). 1H-NMR (400 MHz CD3OD): (58.00 (ms IH), 7.70 (m, IH), 7.55(m, 2H). 7.45 (m, IH), 7.00 (m, IH)5 3.88-4.20(m, IH), 3.50 (m, 2H), 3.33(m, 3H), 2.55-2.72 (m, 2H), 1.80-2.22 (m, 2H), 1.50-1.88 (m, 2H), 1.3 (m, 3H); ESI MS: m/z 448 [M+H]+.
Example 289. Preparation of Compound 274
Figure imgf000603_0001
274a
A mixture of compound 274a (25mg, 0.116 mmol), 3-chloro-5- methoxyphenylboronic acid (43.15 mg, 0.232 mmol), Cs2CO3 solution (2 M, 0.375 mL), and Pd(PPh3 )2C12 (6.25 mg) in 1,4-dioxane (1 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give the compound 274 (1.17 mg, 6%). 1H- NMR (400 MHz CD3OD): £7.66-7.91 (m, 3H), 7.55 (m, IH), 7.35 (m, IH), 7.00 (m, IH), 3.88-4.20 (m, IH), 3.50 (m, 2H), 3.33(m, 3H), 2.55-2.72 (m, 2H), 1.80-2.22 (m, 2H), 1.50- 1.88 (m, 2H), 1.30 (m, 3H); ESI MS: m/z 444 [M+H]+.
Example 290. Preparation of Compound 232
Figure imgf000603_0002
232a
A mixture of compound 232a (25mg, 0.066 mmol). 3-chloro-5- fluorophenylboronic acid (23 mg, 0.132 mmol), Cs2CO3 solution (2 M. 0.325 mL), and Pd(PPh3)2Cl2 (6.25 mg) in 1,4-dioxane (1.2 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 232 (2.65 mg, 9%). 1H-NMR (400 MHz CD3OD): «57.00 (m, IH), 6.75 (m, IH), 6.55(m, IH), 6.45 (m, IH), 6.00-6.20 (m, 2H), 2.88-3.20 (m, IH), 2.60 (m, 2H), 2.50 (m, 3H), 1.55-2.21 (m, IH), 1.00-1.18 (m, 2H), 0.55-1.04 (m, 3H), 0.3 (m, 3H): ESI MS: m/z 432 [M+H] \ Example 291. Preparation of Compound 298
Figure imgf000604_0001
298a
A mixture of compound 298a (35mg, 0.092 mmol), 3-chloro-5- fluorophenylboronic acid (32 mg, 0.184 mmol), Cs2CO3 solution (2 M, 0.525 mL), and Pd(PPh3 )2C12 (9 mg) in 1,4-dioxane (1.8 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 298 (2.73 mg, 7%). 1H-NMR (400 MHz CD3OD): <S7.00 (m, IH), 6.75 (m, IH), 6.55(m, IH), 6.45 (m, IH), 6.00-6.20 (m, 2H), 2.88-3.20 (m, IH), 2.60 (ra, 2H), 2.50 (m, 3H), 1.55-2.21 (m, IH), 1.00-1.18 (m, 2H), 0.55-1.04 (m, 3H), 0.3 (m, 3H); ESI MS: m/z 432 [M+H]+.
Example 292. Preparation of Compound 236
Figure imgf000604_0002
236a
A mixture of compound 236a (30 mg, 0.079 mmol), 3-chlorophenylboronic acid (18 mg, 0.12 mmol), Cs2CO3 solution (2 M, 0.3 mL), and Pd(PPh3)2Cl2 (5 mg) in 1,4- dioxane (1 mL) under N2 was stirred at 1000C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give the compound 236 (2.16 mg, 10%). 1H-NMR (400 MHz CD3OD): <57.85 (m, IH), 7.67 (m, IH), 7.62 (m, IH), 7.52 (m, IH), 7.41 (m, IH), 7.32 (m, IH), 6.98 (m, IH), 4.19 (m, 0.3H), 3.86 (m, 0.7H), 3.58 (m; 2H), 3.36 (m, 3H), 3.16 (m, 0.6H); 2.48 (m, 0.4H), 2.12 (m, 2H), 1.72 (m, IH), 1.41-1.74 (m, 2H), 1.18 (m, 3H): ESI MS: m/z 414 [M+H]+.
Example 293. Preparation of Compound 303
Figure imgf000605_0001
303a
A mixture of compound 303a (30 mg, 0.079 mmol), 3-chlorophenylboronic acid (25 mg, 0.159 mmol), Cs2CO3 (2 M, 0.45 niL) and Pd(PPh3)2Cl2 (7.5 mg) in 1,4-dioxane (1.5 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 303 (2.78 mg, 8%). 1H-NMR (400 MHz CD3OD): <57.91 (m, IH), 7.33-7.67(m, 5H), 7.10 (m, IH), 4.02 (m, IH), 3.52(m, 2H), 3.33 (m, 3H), 266- 2.71(m, IH), 2.35 (m, IH), 1.80-2.22 (m, 2H), 1.50-1.77 (m, 2H), 1.3 (m, 3H); ESI MS: m/z 414 [M+H]+.
Example 294. Preparation of Compound 249
Figure imgf000605_0002
249a
A mixture of compound 249a (20mg, 0.052 mmol), 3-chloro-4- fluorophenylboronic acid (18.27 mg, 0.105 mmol), Cs2CO3 (2 M, 0.300 mL) and Pd(PPh3)2Cl2 (5 mg) in 1,4-dioxane (1 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 249 (2.88 mg, 13%). 1H-NMR (400 MHz CD3OD): <57.66-7.91 (m, 3H), 7.55 (m, IH), 7.35 (m, IH), 7.00 (m, IH), 3.88- 4.20(m, IH), 3.50 (m, 2H), 3.33(m, 3H), 2.55-2.72 (m, 2H), 1.80-2.22 (m, 2H), 1.50-1.88 (m, 2H), 1.3 (m, 3H): ESI MS: m/z 432 [M+H]+.
Example 295. Preparation of Compound 330
Figure imgf000606_0001
330a
A mixture of compound 330a (30 mg, 0.079 mmol), 3-chloro-4- fluorophenylboronic acid (27 mg, 0.157 mmol), Cs2CO3 solution (2 M, 0.450 mL, and Pd(PPh3)2Cl2 (7.5 mg) in 1,4-dioxane (1.5 mL) under Ar2 was stirred in microwave at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 330 (2.02 mg, 7%). 1H-NMR (400 MHz CD3OD): 57.66-7.91 (m, 3H), 7.55(m, IH), 7.35 (m, IH), 7.00 (m, IH), 3.88- 4.20(m, IH), 3.50 (m, 2H)3 3.33(m, 3H), 2.55-2.72 (m, 2H), 1.80-2.22 (m, 2H), 1.50-1.88 (m, 2H)5 1.3 (m, 3H); ESI MS: m/z 432 [M+H]+.
Example 296. Preparation of Compound 208
Figure imgf000606_0002
A mixture of compound 296a (20 mg, 0.047 mmol), 3-chloro-5-(4 ,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile (24.6 mg, 0.094 mmol), Cs2CO3 solution (2 M, 0.300 mL), and Pd(PPh3)2Cl2 (5 mg) in 1,4-dioxane (1 mL) under Ar2 was stirred in microwave at 12O0C for 20 minutes. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative TLC and HPLC to give compound 208 (1.15 mg, 5%). 1H-NMR (400 MHz CD3OD): (58.00 (m, 3H), 7.71 (m, 2H), 7.35 (m, IH), 7.00 (m, 4H), 4.66 (m, IH), 3.45 (m, IH), 3.38 (m, 3H), 2.75 (m, 2H), 2.40-2.61 (m, 2H), 2.01 (m, 3H), 1.75 (m, IH); ESI MS: m/z 485 [M+H]+.
Example 297. Preparation of Compound 198
Figure imgf000607_0001
198a
To a solution of compound 198a (20 mg, 0.047 mmol), 3-fluoro-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (17 mg, 0.071 mmol), and Cs2CO3 solution (2M, 0.3 mL) in [l,4]-dioxane (0.7 mL) was added Pd(PPh3)2Cl2 (0.5 mg). The mixture was heated at 12O0C in microwave for 15 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give compound 198 (3.13 mg, 14%). 1H-NMR (400 MHz CD3OD): <58.O1 (s, IH), 7.85 (m, IH), 7.75 (m, 2H), 7.50 (m, IH), 7.32 (s, IH), 7.17 (m, 3H), 7.02 (m, IH), 4.64 (m, IH), 3.40 (m, IH), 3.30 (m, 3H), 2.81 (s, 2H), 2.61 (m, IH), 2.43 (m, IH), 2.06 (m, 3H), 1.75 (s, IH); ESI MS: m/z 469 [M+H]+.
Example 298. Preparation of Compound 240
Figure imgf000607_0002
298a
Pd(PPh3 )2C12 (10 mg) under Ar2 was treated sequentially with the solution of compound 298a (20 mg, 0.047 mmol) in [l,4]dioxane (1 mL), Cs2CO3 solution (2 M, 0.3 mL). and 3-chloro-5-fluorophenylboronic acid (12 mg, 0.07 mmol). The mixture was heated at 12O0C in microwave for 15 minutes, and concentrated in vacuo. The residue was purified by preparative TLC and HPLC to give compound 298 (7.7 mg, 34%). 1H-NMR (400 MHz CD3OD): (56.95-7.91 (m, 10H), 4.65 (m, IH),. 3.45 (m, IH), 3.35 (m, 3H), 2.82 (m. 2H), 2.45 and 2.65 (d, IH), 2.00 (m, 4H), 1.75 (m, IH); ESI MS: m/z 478 [M+H]+.
Example 299. Preparation of Compound 239
Figure imgf000608_0001
299a
A mixture of compound 299a (20 mg, 0.047 mmol), 3-chlorophenylboronic acid (14 mg, 0.07 mmol), Cs2CO3 solution (2 M, 0.3 mL), and Pd(PPh3)2Cl2 (5 mg) in 1,4- dioxane (1 mL) under N2 was stirred at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative TLC and HPLC to give compound 299. 1H-NMR (400 MHz CD3OD): S7.S6 (m, IH), 7.62 (m, 2H), 7.47 (m, 2H), 7.30 (m, 2H), 7.12 (m, 3H), 6.96 (m, IH), 4.76 (m, 0.5H), 4.64 (m, 0.5H), 3.42 (m, IH), 3.34 (m, 3H), 2.82 (m, 2H), 2.52 (m, IH), 2.02 (m, 4H), 1.74 (m, IH); ESI MS: m/z 460 [M+H]+.
Example 300. Preparation of Compounds 235 and 252
Figure imgf000608_0002
235a
A mixture of compound 235a (20 mg, 0.047 mmol), 3-chloro-4- fluorophenylboronic acid (12 mg, 0.07 mmol), Cs2CO3 solution (2 M, 0.3 mL). and Pd(PPh3)2Cl2 (5 mg) in 1,4-dioxane (1 mL) under N2 was stirred at 12O0C for 15 minutes. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative TLC and HPLC to give compound 235 (2.7 mg. 12%) and compound 252 (1.12 mg, 5%). compound 235: 1H-NMR (400 MHz CD3OD): δl.%1 (m5 IH)5 7.72 (m, 2H)m, 7.53 (m, IH), 7.32 (m, 2H), 7.16 (m, 3H), 7.02 (m, IH), 4.62-4.82 (m, IH), 3.48 (m, IH), 3.35 (s, 3H), 2.83 (m, 2H), 2.42-2.68 (m, IH), 1.85-2.18 (m, 4H), 1.78 (m, IH); ESI MS: m/z 478 [M+H]+. compound 252: 1H-NMR (400 MHz CD3OD): (57.78 (m, IH), 7.38-7.66 (m, 3H)5 7.22 (m, 2H), 7.06 (m, 3H), 6.92 (m, IH), 4.48-4.67 (m, IH)5 3.47 (m, IH)5 3.37 (m, 3H)5 2.71 (m, 2H)5 2.24-2.51 (m, IH), 1.80-2.08 (m, 4H)5 1.48 (m, IH); ESI MS: m/z 478 [M+H]+.
Example 301. Preparation of Compounds 201 and 221
Figure imgf000609_0001
201a
Pd(PPh3 )2C12 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with the compound 201a (21 mg, 0.05 mmol) in 1,4-dioxane (2 mL), Cs2CO3 solution (2 N, 0.3 mL), and 3-cyano-4-fluorophenylboronic acid (22 mg. 0.13 mmol). The mixture was heated in microwave at 12O0C for 20 minutes, concentrated in vacuo, and purified by preparative TLC and HPLC to give compound 201 (1.90 mg, 3.4%) and compound 221 (1.25 mg, 2.9%). compound 201: 1H-NMR (400 MHz CD3OD): <57.91-8.04 (m, 3H), 7.65-7.71 (m, IH), 7.33-7.48 (m, 2H)5 7.11-7.20 (m, 3H), 6.95-7.06 (m, IH), 4.52-4.62 (m, IH)5 3.48-3.52 (m, IH)5 3.33-3.40 (m, 3H)5 2.79-2.90 (m, 2H), 2.40-2.65 (m, IH), 1.85-2.16 (m, 4H)5 1.70-1.82 (m, IH): ESI MS: m/z 470 [M+H]+. compound 221: 1H-NMR (400 MHz CD3OD): <57.91-8.02 (m, 3H)5 7.66-7.69 (m, IH), 7.33-7.44 (m, 2H), 7.11-7.15(m, 3H), 6.98-7.07(m, IH), 4.58-4.65(m, IH), 3.45-3.52 (m, IH)5 3.33-3.43 (m, 3H), 2.75-2.83 (m, 2H), 2.41-2.62 (m, IH), 1.92-2.16 (m, 4H)5 1.71- 1.80 (m, IH); ESI MS: m/z 470 [M+H]+.
Example 302. Preparation of Compound 180
Figure imgf000609_0002
A mixture of compound 1 (20mg, 0.048 mmol), 3,5-dicyanophenylbronic acid (16 mg, 0.094 mmol), Cs2CO3 solution (2 M, 0.300 mL), and Pd(PPh3)2Cl2 (8 mg) in 1,4- dioxane (1 mL) was stirred in microwave at 12O0C for 18 minutes under Ar2. The reaction mixture was concentrated in vacuum, the residue was purified by preparative TLC and HPLC to give compound 180 (2.78 mg, 13%). 1H-NMR (400 MHz CD3OD): £8.29 (s, 2H), 8.06 (d, 2H), 7.74 (m, IH), 7.30 (m, IH), 7.15 (m, 3H), 7.00 (m, IH), 4.63 (m, IH), 3.40 (m, IH), 3.30 (m, 3H), 2.80(m, 2H), 2.62 (m, IH), 2.40 (m, IH), 2.08 (m, 3H), 1.75 (m, IH); ESI MS: m/z 476 [M+H]+.
Example 303. Preparation of Compound 278
Figure imgf000610_0001
278a 278b 278d
Figure imgf000610_0002
278e 278f
Experimental data:
Figure imgf000610_0003
278a 278b
Preparation of compound 278b
To a solution of compound 278a (2 g, 12.5 mmol) in dry CH2Cl2 (40 mL) was added 3 A molecule series (1.3 g) and PCC (4.05 g, 18.75 mmol). The mixture was stirred at room temperature for 2 h. When the reaction was completed, the mixture was filtered through celite, dried over Na2SO4, and concentrated in vacuum to give the compound 278b (1.4 g, 68%).
Figure imgf000611_0001
278b 278d
Preparation of compound 278d
To a stirred solution of compound 278c (1.8 g, 8.7 mmol) in a mixture of EtOH (11.4 mL) and H2O (18.3 mL) was added compound 2 (1.4 g, 8.7 mmol) and borax (3.31 g, 8.7 mmol). The mixture was refluxed for 2 days, filtrated, and concentrated in vacuo. The crude product was purified by column chromatography and pre-HPLC to give the compound 278d (600 mg, 20%).
Figure imgf000611_0002
278d 278e
Preparation of compound 278e
To a solution of compound 278d (356 mg, 1 mmol) in CH2Cl2 (25 mL) was added TiCl4 (1 M in DCM. 2 mg, 2 mmol). This mixture was stirred at room temeparature for 60 minutes. Bis-trimethylsilylcarbodiimide (372 mg. 2 mmol) was added, and 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 Na2SO4. and filtered. The filtrate was concentrated to give the compound 278e (300 mg, 79% ).
MeNHOH.HCI
Figure imgf000611_0004
Figure imgf000611_0003
278e 278f Preparation of compound 278f To a solution of methylhydroxylamine HCl salt (66 mg, 0.79 mmol) in anhydrous MeOH (10 mL) was added NaOMe (10% in MeOH3 38.4 mg, 0.71 mmol) and compound 278e (300 mg, 0.79 mmol) at room temperature. After being stirred for 20 minutes, the solvent was removed in vacuo. The residue was dissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed. The residue was purified by pre-TLC to give compound 278f ( 280 mg, 83%). 1H-NMR (400 MHz CDCl3): #7.53 (m,lH), 7.27 (m, 2H), 7.08 (m, 3H), 6.65 (m, IH), 4.53 (m, IH), 3.31 (m, IH), 3.15 (m, IH), 3.05 (m, 3H), 2.74 (m, 3H), 2.18 (m, IH), 1.94 (m, 2H), 1.75 (m, IH).
Figure imgf000612_0001
278f
Preparation of compound 278
To a solution of compound278f (20 mg, 0.05 mmol), 3-chloro-5- methoxyphenylboronic acid (18.6 mg, 0.1 mmol), Cs2CO3 solution (2 M, 0.5mL) in 1,4- dioxane (1 mL) under N2 was added Pd(PPh3 )2C12 (5 mg). The mixture was stirred at 1000C for 6 mimutes. After being cooled to room temperature, the organic layer was dried, and concentrated to give the residue, which was purified by preparative HPLC to give compound 278 (2.20 mg, 10%). 1H-NMR (400 MHz CD3OD): £7.86 (m, IH), 7.69 (m, IH), 7.48 (m, IH), 7.30 (m, 2H), 7.11 (m, 3H), 7.01 (m, IH), 6.95 (m, IH), 461-4.74 (m, IH), 3.81-4.08 (m, 3H), 3.47 (m, IH), 3.33 (m, 3H), 2.78(m, 2H), 2.45-2.61 (m, 1.4H), 1.85-2.10 (m, 3.6H), 1.75 (m, IH); ESI MS: m/z 490 [M+H]+.
Example 304. Preparation of Compound 269
Figure imgf000612_0002
269a Pd(PPh3)2Cl2 (5 mg) in a 10 mL of flask under N2 was treated sequentially with the compound 269a (20 mg, 0.047 mmol) in 1,4-dioxane (1 mL), Cs2CO3 solution (2 N, 0.1 mL), and 3-fluoro-5-(trifluoromethyl)phenylboronic acid (19.5 mg, 0.094 mmol). The mixture was heated under 1200C at N2 under microwave for 20 minutes, and the reaction mixture was concentrated in vacuo, the residue was purified by preparative TLC and HPLC to give compound 269 (5.1 mg, 21%). 1U NMR (400 MHz CD3OD): <S7.98 (s, IH), 7.69 (m, 3H), 7.39 (d, 2H), 7.08 (m, 4H), 4.67 (m, IH), 3.47 (m, IH), 3.36 (m, 3H), 2.81 (m, 2H), 2.52 (m, IH), 2.10 (m, 4H), 1.73 (m, IH). 1.38 (m, IH); ESI MS: m/z 512 [M+H]+.
Example 305. Preparation of Compound 226
Figure imgf000613_0001
226a 226b 226c 226d 226e
Figure imgf000613_0002
MeNHOH HCI
Figure imgf000613_0004
Figure imgf000613_0003
226h
Experimental data:
Figure imgf000613_0005
226a 226b
Preparation of compound 226b
To a solution of compound 226a (20 g, 151 mmol) and 1.9 g of Zinc iodide in 400 mL of dichloromethane was added 15 g (151 mmol) of cyanotrimethylsilane O0C. After being stirred overnight, the mixture was warmed to room temperature, washed with 300 mL of saturated aqueous sodium bicarbonate solution, dried, filtrated, and concentrated in vacuum to give the compound 226b (26.84 g, 77%). 1H NMR (400 MHz CDCl3): «57.35- 7.40 (m, IH), 7.02-7.21 (m, 3H), 2.79-2.90 (m, 2H), 2.48-2.55 (m, IH), 2.23-2.28 (m, IH)5 0.01-0.19 (m, 9H).
Figure imgf000614_0001
226b 226c
Preparation of compound 226c
A solution of compound 226b (26.84 g, 116 mmol) and SnCl2-2H2O (104.86 g, 464 mmol) in 100 mL of a mixture of acetic acid and concentrated hydrochloric acid (10:1) was reflux ed for 1 day. After being cooled to room temperature, the mixture was extracted with 150 mL of dichloromethane, and the organic layers were washed with 130 mL of 2 N sodium hydroxide solution. The basic washes were extracted with 100 mL of ether, and acidified to PH=2 with 5 N hydrochloric acid solution. The acidic aqueous mixture was extracted with 150 mL of EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to give the compound 226c. 1H-NMR (400 MHz CDCl3): «57.35-7.40 (m, IH), 7.21-7.31 (m, 3H), 4.07-4.19 (m, IH), 3.11-3.21 (m, IH), 2.89-2.98 (m, IH), 2.32-2.54 (m, 2H).
Figure imgf000614_0002
226c 226d
Preparation of compound 226d
The solution OfLiAlH4 (2.1 g, 54 mmol) in 50 mL of dry THF was added a solution of compound 226c in THF (40 mL). The reaction mixture was stirred at room temperature for 2 h, quenched with 2.1 mL of H2O and 2.1 mL of 10% NaOH, filtered, and concentrated to give the compound 226d. 1H-NMR (400 MHz CDCl3): «57.05-7.30 (m, 4H), 3.62-3.87 (m, 2H), 3.27-3.49 (m, IH), 2.71-3.01 (m, 2H), 2.11-2.38 (m, 1H): 1.83-1.94 (m, IH).
Figure imgf000615_0001
226d 226e
Preparation of compound 226e
To a solution of compound 226d (2 g, 13.5 mmol) in DCM (50 mL) was added PCC (4.36 g, 20 mmol) and 3A molecule serves (2.0 g), and the mixture was stirred at room temperature for 1 h. After work up and purification, compound 226e (1.9 g, 96%) was obtained. 1H-NMR (400 MHz CDCl3): J2.21-2.54 (m, 2H), 2.81-3.18 (m, 2H), 3.91- 4.01 (m, IH), 7.18-7.30 (m, 4H), 9.66-9.67 (m, IH).
Figure imgf000615_0002
226e 226f
Preparation of compound 226f
To a solution of l-(5-bromo-2-hydroxyphenyl)-ethanone (2.79 g, 12.99 mmol) in a mixture of EtOH (18 mL) and H2O (28.8 mL) was added compound 226e (1.9 g, 12.99 mmol) and borax (4.96 g, 12.99 mmol). The mixture was refluxed overnight, filtered, and concerntrated. The residue was dissolved in EtOAc, and the organic layer was washed with brine, dried, and concentrated. The residue was purified by chromatography to afford the compound 226f (1.0 g, 22.4%). 1H NMR (400 MHz CDCl3): <57.89-7.91(m, IH), 7.34-7.56 (m, 2H), 7.12-7.27 (m, 3H), 6.80-6.89 (m, IH), 4.52-4.56 (m, IH), 3.52-3.67 (m, IH), 2.87-3.09 (m, 2H), 2.51-2.81 (m, 2H), 2.22-2.26 (m, IH), 1.97-2.21 (m, IH).
Figure imgf000615_0003
Preparation of compound 226g To a solution of compound 226f (320 mg, 0.93 mmol) in 1,4-dixoane (5 mL) was added 3-cyanophenylboronic acid (273 mg, 1.86 mmol), Pd(PPh3 ^Cl2 (20 mg) and Cs2CO3 solution (2 M, 1.4 mL). The reaction mixture was stirred in microwave at 1000C for 10 minutes. The organic layer was concentrated, and the residue was purified by HPLC to give the compound 226g (127 mg, 38%). 1H-NMR (400 MHz CDCl3): <52.21- 2.41 (m, IH), 2.52-2.76 (m, 2H), 2.81-3.01 (m, 2H), 3.57-3.69 (m, IH), 4.52-4.67 (m, IH), 7.02-7.26 (m, 6H), 7.42-7.79 (m, 4H), 7.99-8.01(m, IH).
Figure imgf000616_0001
226g 226h Preparation of compound 226h
To a solution of compound 226g (127 mg, 0.35 mmol) in DCM (18 mL) was added TiCl4 (194.3 mg, 1.04 mmol) at room temperature. After being stirred for 1 h, bis- trimehtlysilylcarbodiimide (131 mg, 0.70 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with ice water and extracted with DCM. The organic layer was washed with water and brine, dried, and concentrated to give the compound 226h (79 mg, 58%).
MeNHOH HCI
Figure imgf000616_0003
Figure imgf000616_0002
226h
Preparation of compound 226 To a solution of MeNHOH.HCl (16.9 mg, 0.2 mmol) in anhydrous MeOH (3 mL) was added NaOMe (10% in MeOH, 98 mg, 0.18 mmol) at room temperature and 226h (79 mg, 0.2 mmol). After being stirred for 5 minutes, the mixture was concemtrated in vacuum, and the residue was redissolved in CH2Cl2 and filtered. The filtrate was concentrated, and the residue, was purified by preparative TLC and HPLC to give compound 226 (18 mg: 20%). 1H-NMR (400 MHz CD3OD): <57.85-7.90 (m, 3H)5 7.50- 7.66(m, 3H), 7.16-7.25 (m, 2H), 6.90-7.11 (m, 3H), 4.39-4.71 (m, IH), 3.57-3.59 (m, 2H)S 3.32-3.55 (s, 3H), 2.61-2.98 (m, 2H), 2.45-2.58 (m, IH), 2.00-2.25 (m, IH), 1.57-1.97 (m, IH); ESI MS: m/z 437 [M+H]+.
Example 306. Preparation of Compound 204
Figure imgf000617_0001
204h
Experimental data:
Figure imgf000617_0002
204a 204b
Preparation of compound 204b
NaH (5.12 g, 128 mmol) was added to a solution of compound 204a (25 g, 107 mmol) in THF (200 mL) at room temperature in small portions. Allyl bromide (11.1 mL, 128 mmol) was added via syringe, and the mixture was stirred overnight at room temperature, quenched by the addition OfH2O (100 mL) slowly, and diluted with 300 mL Of Et2O. The organic layer was washed with H2O and brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield the compound 204b (31 gDcrude, 100%) as faint yellow oil. 1H-NMR (400 MHz CDCl3): «57.45 (m: IH), 7.11 (m, IH), 6.85 (m, IH), 7.81-7.83 (d; IH), 7.45-7.47 (t, IH), 7.33-7.37 (t, IH), 6.96-7.00 (t, IH), 5.95-6.05 (m, IH), 5.33-5.39 (d, IH), 5.22-5.26 (d, IH), 4.50 (s, 2H), 4.11-4.13 (d, 2H).
Figure imgf000618_0001
204b 204c Preparation of compound 204c
The solution of compound 204b (55 g, 201 mmol) in a mixture 250 mL of CH3CN and 145 mL OfEt3N was degassed, and added Pd (OAc)2 (2.23 g, 10 mmol) and PPh3 (5.28 g, 20.1 mmol). The mixture was heated at 8O0C until TLC indicated completion of the reaction. The mixture was cooled to room temperature, diluted with Et2O (500 mL), washed with 1 N HCl. NaHCO3, and brine, dried (sodium sulfate), filtered, and concentrated in vacuo to yield the compound 204c (15 g, 51%) as oil. 1H-NMR (400 MHz CDCl3): δl.59-1.63 (d, IH), 7.15-7.19 (t, 2H), 6.95-6.98 (d, IH), 5.54 (s, IH), 4.94 (s, IH), 4.74 (s. 2H), 4.38 (s, 2H).
Figure imgf000618_0002
Preparation of compound 204d To a solution of compound 204c (13 g. 89 mmol) in THF (400 mL) was added a solution Of B2H6 THF (1.0 M. 45 mL, 45 mmol) under N2 at O0C. The mixture was.stirred at room temperature for 3 hours, added aqueous NaOH solution (3 N. 22 mL. 67-mmol) and H2O2 (30%. 15.2 mL, 134 mmol) at room temperature, stirred for 2 hours, quenched by addition of brine. The reaction mixture was extracted with EtOAc, and the organic layer was washed with aq. Na2S2O3. dried, and concentrated to give the crude compound 204d (10 g. 69%). 1H-NMR (400 MHz CDCl3): δl.59-1.63 (d. IH). 7.17-7.24 (a 3H), 6.99-7.01 (t. IH), 4.73-4.89 (q, 2H), 4.25-4.28 (d. IH), 3.61-3.95 (m, 3H), 2.83-2.S4 (m. IH).
Figure imgf000619_0001
204d 204e
Preparation of compound 204e
To a solution of compound 204d (5 g, 30 mmol) in dry CH2Cl2 (150 niL) was added 3 A molecule series (6 g) and PCC (9.7 g, 45 mmol). The mixture was stirred at room temperature for 1 h, when the reaction was completed, the mixture was filtered through celite, dried over Na2SO4, and concentrated in vacuum to give the compound 204e (5 g, crude, 100%).
Figure imgf000619_0002
Preparation of compound 204f
To a stirred solution of compound 204e (6.5g, 30 mmol) in a mixture of EtOH (50 mL) and H2O(80 mL) was added isochroman-4-carbaldehyde (5.0 g, 30 mmol) and borax
_ , (11.4 g, 30 mmol). The mixture was refluxed overnight, filtrated, and concerntrated in vacuo. The residue was dissolved in CH2Cl2, after filtration, the solvents were evaporated, and the crude product was purified by column chromatography to give the compound 204f
' (200 mg: 2%). 1H-NMR (400 MHz CDCl3): <57.89 (s, IH), 7.48-7.51 (d, IH), 7.13-7.21 v (m, 3H), 6.95-6.97 (d, IH), 6.88-6.90 (d, IH), 4.69-4.81 (q, 3H), 4.38-4.41 (dd} IH), 3.73-
. 3.77 (dd, IH), 3.02-3.04 (d, IH), 2.72-2.77 (dd, IH), 2.54-2.61 (t, IH).
Figure imgf000619_0003
1 Preparation of compound 204g
To a solution of compound 204f (123 mg. 0.84 mmol) in a mixture of Cs2CO3 solution (2 M, 2.25 mL) and 1,4-dioxane (5 mL) was added Pd(PPh3)2Cl2 (37.5 mg) under N2. The mixture was stirred in microwave at 10O0C for 20 mimutes. After being cooled to room temperature, the mixture was concentrated, and the residue was purified by TLC to give the compound 204g (31 mg, 19%). 1H-NMR (400 MHz CDCl3): «52.40-2.45 (d, 0.7H), 2.58-2.83 (m, 0.3H), 3.07-3.19 (m, 1.6H), 3.72-3.86 (m, 1.4H), 4.53-4.57 (d, IH), 4.71-4.79 (m, 3H), 6.98-7.00 (d, IH), 7.07-7.09 (d, IH), 7.18-7.19 (m, 3H), 7.45-7.49 (t, IH), 7.54-7.56 (d, IH), 7.64-7.66 (d, IH), 7.72-7.78 (t, 2H), 8.01 (s, IH).
Figure imgf000620_0001
Preparation of compound 204h To a solution of compound 204g in CH2Cl2 (2 mL) was added TiCl4 (1 M in DCM,
0.22 mL, 0.22 mmol), and the mixture was stirred in microwave at 5O0C for 10 minutes. The bis-trimethylsilylcarbodiimide (0.053 mL, 0.237 mmol) was added, and the resulting mixture was stirred in microwave at 6O0C for 10 minutes. The reaction mixture was poured into ice-water, extracted with DCM. dried over anhydrous Na2SO4, filtered, and concentrated to give the compound 204h (42 mg, crude, 96%).
MeNHOH HCI
Figure imgf000620_0002
Figure imgf000620_0003
Preparation of compound 204 To a solution of methylhydroxylamine HCl salt (9.1 mg. 0. 108 mmol) in anhydrous MeOH (3 mL) was added NaOMe (10% in MeOH, 52 mg, 0.097 mmol) and compound 204h (42 mg. 0.108 mmol). After being stirred for 20 minutes, the solvent was removed in vacuo, and the residue was dissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed, and the residue was purified by preparative HPLC to give the compound compound 204 (18 mg, 41%). 1H-NMR (400 MHz CD3OD): (57.90-7.98 (m, 3H), 7.60-7.75 (m, 3H), 7.35 (m, IH), 7.25-7.27 (m, 2H), 7.08-7.10 (m, 2H), 4.73-4.83 (m, 4H), 4.42-4.53 (m, IH), 3.82-3.94 (m, IH), 3.21-3.40 (m, 3H), 2.52- 2.78 (m, IH), 2.29-2.31 (m, IH); ESI MS: m/z 453 [M+H]+.
Example 307. Preparation of Compound 349
Figure imgf000621_0001
Experimental data
Figure imgf000621_0002
349a 349b
To a solution of methyltriphenylphosphonium iodide (250 g, 0.615 mol) in anhydrous THF (1500 mL) was cooled to -1000C. rc-BuLi (220 mL, 0.55 mol, 2.5 M in hexane) was added dropwise at this temperature under nitrogen atmosphere, and the mixture was stirred at -1000C for 1 hour. Compound 349a (50 g, 0.343 mol) was added dropwise at -1000C, and the mixture was warmed to room temperature, and stirred at this temperature for 3 hours. The reaction was quenched with water, and extracted with
EtOAc (3χ500 mL). The organic layer was dried over Na2SO4. filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 100: 1) to give the compound 349b (36.5 g, 74%) as a colorless liquid. 1H MNR (CDCl3, 400 MHz): <57.55 (d, 1 H), 7.05 (m, 3 H), 5.37 (s, 1 H), 4.85 (s, 1 H), 2.48 (t, 2 H), 2.44 (t, 2 H).1.78 (t, 2 H),
Figure imgf000622_0001
349b 349c
To a solution of 1 -methylene- 1,2, 3, 4-tetrahydronaphthalene (10 g, 61.0 mol) in a mixture of acetone (100 mL) and water (25 mL) was added NH4OAc (0.47 g, 0.61 mmol) and NBS (15.1 g, 67.1 mmol). The mixture was stirred at room temperature for 30 minutes, concentrated in vacuo, and extracted with EtOAc (3><100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by column chromatography (petroleum ether/EtOAc=5:l) to give the compound 349c (10 g, 68%) as a colorless liquid. 1H-MNR (CDCl3, 400 MHz): (57.45 (d, 1 H), 7.15 (m, 2 H), 7.07 (m, 1 H), 3.65 (m, 2 H), 2.81 (m, 2H), 2.36 (m, 1 H), 1.84 (m, 2 H), 1.64 (m, I H)
Figure imgf000622_0002
349c 349d
To a solution of diethylzinc (25 mL, 23.1 mmol) in dry CH2CL2 (50 mL) was added diiodomethane (6.19 g, 23.1 mmol) at 0°C under nitrogen. The mixture was stirred at 0°C for 20 minutes, and followed by the addition of the solution of compound 349c (10 g, 38.5 mmol) in dried CH2CL2 (33 mL). The mixture was stirred at room temperature for 4 hours, and concentrated NH4Cl aqueous solution (30 mL) was added. The organic layer was washed with water, and dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by column chromatography (petroleum ether/EtOAc=30 : 1 ~ 5 : 1) to give compound 349d (4.4 g, 71%) as a colorless liquid. 1H-NNR (CDCl3, 400 MHz): (57.17 (m, 4 H), 3.72 (s, 2 H), 2.95 (t, 2 H), 2.00 (m, 2 H), 2.58 (t, 2 H).
Figure imgf000622_0003
349d 349e
To a solution of 8,9-dihydro-5H-benzo[7]annulen-6(7H)-one (0.898 g, 5.61 mmol) in dried MeOH (5 mL) was added l-(5-bromo-2-hydroxyphenyl)ethanone (1 g. 4.67 mmol) and pyrrolidine (0.6 mL). The mixture was stirred at room temperature for 1 hour, and refluxed overnight. The mixture was concentrated in vacuo, the residue was purified by column chromatography (petroleum ether / EtOAc = 30: 1 ~ 5: 1) to give the compound 349e (341 mg, 20%) as an orange solid. 1H MNR (CDCl3, 400 MHz): (58.01 (d, 1 H), 7.51 (m, 1 H), 7.17 (m, 3 H), 6.81 (m, 1 H), 6.72 (m, 1 H), 3.32 (m, 1 H), 3.10 (m, 1 H), 2.65 (m, 2 H), 2.63 (m, 2 H), 2.12 (m, 2 H), 1.95 (m, 1 H), 1.55 (m, 1 H).
Figure imgf000623_0001
349e
349f
To a solution of compound 349e (2 g, 5.62 mmol) in dry CH2Cl2 (140 mL) was added TiCl4 (16.8 mL, 16.8 mmol, 1 M in CH2Cl2) at 15°C under N2 atmosphere. The mixture was stirred at 15°C for 1 hour, and added ΛyV-methanediylidenebis (1, 1,1- trimethylsilanamine) (2.77 mL. 12.36 mmol). The mixture was stirred at 15°C overnight, poured into ice, and extracted with CH2Cl2 (3><100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, to give the crude compound 349f (1.9 g, 90%) as a yellow solid, which was used for the next step directly without purification.
Figure imgf000623_0002
349f
To a solution of N-methylhydroxylamine hydrochloride (415 mg, 5 mmol) in dry MeOH (124 mL) was added MeONa (2.7 mL, 5 mmol, 10% in MeOH) solution and compound 349f (1.9 g, 5 mmol) in portions. The mixture was stirred at 20°C till the solid was dissolved completely. Water (300 mL) was added, and the mixture was extracted with CH2Cl2 (3x300 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo, the residue was purified by column chromatography (CH2Cb / MeOH = 50 : 1) to give the compound compound 349 (1.03 g, 48%) as a yellow solid. 1H-NMR (CDCl3 400 MHz): (57.42 (d, J= 3.2 Hz, IH), 7.04 (m, 4H), 6.53 (m, IH), 3.35 (m, IH), 2.95 (m, 4H), 2.76 (m, 2H), 2.36 (m, IH), 2.13 (m, IH), 1.95 (m, 2H), 1.87 (m, 2H); MS: m/z 428 [M+H]+.
Example 308. Preparation of Compound 191
Figure imgf000624_0001
191a
An dried flask was charged with compound 191a (20 mg, 0.046 mmol) in 1,4- dioxane (1 mL), Cs2CO3 solution (2 N, 0.5 mL), and S-chloro-S-cyanophenyl- boronic acid (12.7 mg, 0.07 mmol) sequentially. Pd(PPh3)2Cl2 (5 mg) was added under nitrogen atmosphere, and the mixture was heated at 120°C in microwave for 10 minutes. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC and HPLC to give compound 191 (2 mg, 8%) as a white solid. 1H NMR (CD3OD 400MHz): <57.73-8.35 (m, 5H), 6.89-7.35 (m, 5H), 3.30-3.56 (m, 3H), 2.85-2.96 (m, 4H), 2.81 (s, IH), 2.40-2.49 (m, IH), 1.93-2.21 (m, 3H), 1.49-1.70 (m, IH); ESI MS: m/z 485 [M+H]+.
Example 309. Preparation of Compound 186
Figure imgf000624_0002
186a
By using the same synthetic procedure as compound 191 described in Example 308, compound 186 (2.41 mg, 11%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): (57.95 (m, IH), 7.81 (m, IH), 7.68 (m, 2H), 7.48 (m, IH), 7.09 (m, 3H), 6.86 (m, 2H), 3.45 (ms IH), 3.32 (m, 3H), 3.12 (m, IH), 2.47-2.93 (m, 3H), 2.36 (m, IH), 2.12 (m, IH), 1.87 (m, 2H),1.35-1.64 (m, IH); ESI MS: m/z 469 [M+H]+. Example 310. Preparation of Compound 227
Figure imgf000625_0001
310a
By using the same synthetic procedure as compound 191 described in Example 308, compound 227 (1.90 mg, 8%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): (58.80-8.30 (m, IH), 7.68 (m, IH), 7.48 (m, IH), 7.33 (m, IH) 7.14 (m, 4H), 7.03 (m, IH), 6.86 (m, IH), 3.51 (m, IH), 3.48 (m, 3H), 3.15 (m, IH), 2.72-3.02 (m, 3H), 2.33- 2.52 (m, IH) 2.08-2.25 (m, IH), 1.41-1.74 (m, IH); ESI MS: m/z 478 [M+H]+.
Example 311. Preparation of Compound 189
Figure imgf000625_0002
189a
By using the same synthetic procedure as compound 191 described in Example 308, compound 189 (2.3 mg, 11%) was obtained as a white solid. 1H NMR (CD3OD 400 MHz): <57.76 (m, IH), 7.53 (m, 2H), 7.41 (m, IH), 7.28 (m, 2H), 7.02 (m, 3H), 6.71-6.95 (m, 2H), 3.41 (m, IH), 3.28 (s, 3H), 3.02 (m, IH), 2.51-2.85 (m, 3H), 2.33 (m, IH), 2.08 (m, IH), 1.85 (m, 2H), 1.31-1.63 (m, IH); ESI MS: m/z 460 [M+H]+.
Example 312. Preparation of Compound 192
Figure imgf000625_0003
312a
By using the same synthetic procedure as compound 191 described in Example 308, compound 192 (2.64 mg, 12%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): (57.70-8.20 (m, IH) , 7.66 (m, IH), 7.58 (m, IH) , 7.48 (m, IH), 7.22 (m, IH) 7.09 (m, 3H), 6.86 (m, 2H), 3.46 (m, IH), 3.37 (m, 3H), 3.08 (m, IH)5 2.71-2.93 (m, 3H), 2.41 (m, IH), 2.12 (m, IH), 1.80-2.03 (m, 2H), 1.38-1.70 (m, IH); ESI MS: m/z 478 [M+H]+.
Example 313. Preparation of Compound 199
Figure imgf000626_0001
By using the same synthetic procedure as compound 191 described in Example 308, compound 199 (2.45 mg, 12%) was obtained as a white solid. 1H-NMR (400 MHz,
CD3OD): (57.95 (m, 3H), 7.61 (s, IH), 7.36 (m, IH), 7.2 (s, 3H), 6.95 (m, IH), 6.85 (m,
IH), 3.44 (d, IH), 3.30 (m, 3H), 3.08 (m, IH), 2.65 (m, 3H), 2.41 (m, IH), 2.13 (s, IH),
1.91 (s, 2H), 1.55 (m, IH); ESI MS: m/z 469 [M+H]+.
Example 314. Preparation of Compound 178
Figure imgf000626_0002
By using the same synthetic procedure as compound 191 described in Example 308, compound 178 (1.84 mg, 10%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): (58.35 (m, 2H) , 8.11 (m, 2H), 7.75 (d, IH) 7.20 (m, 2H), 7.0 (s, IH), 6.95 (m, IH), 6.85 (m, IH), 3.44 (d, IH), 3.30 (m, 3H), 3.08 (m, IH), 2.65 (m, 3H), , 2.41 (m, IH), 2.13 (s, IH) , 1.91 (s, 2H), 1.55 (m, IH); ESI MS: m/z 476 [M+H]÷.
Example 315. Preparation of Compound 234
Figure imgf000627_0001
By using the same synthetic procedure as compound 191 described in Example 308, compound 234 (2.71 mg, 12%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): J7.78-8.31 (m, IH), 7.64 (m, IH), 7.18 (m, 4H), 6.88 (m, 4H), 3.88 (m, 3H), 3.52 (m, IH), 3.37 (m, 3H), 3.15 (m, IH), 2.91 (m, 3H), 2.44 (m, IH), 2.22 (m, IH), 2.01 (m, 2H), 1.48-1.76 (m, IH); ESI MS: m/z 460 [M+H]+.
Example 316. Preparation of Compound 242
Figure imgf000627_0002
By using the same synthetic procedure as compound 191 described in Example 308, compound 242 (2.63 mg, 11%) was obtained, 1H-NMR (400 MHz CD3OD): (57.86- 8.27 (m, IH), 7.62 (m, 3H), 7.38 (m, IH), 6.76-7.18 (m, 5H), 3.42 (m, IH), 3.27 (m, 3H), 3.02 (m, IH), 2.77 (m, 3H), 2.35 (m, IH), 2.12 (m, IH), 1.86 (m, 2H), 1.31-1.62 (m, IH); ESI MS: m/z 490 [M+H]+.
Example 317. Preparation of Compound 181
Figure imgf000627_0003
By using the same synthetic procedure as compound 191 described in Example 308, compound 181 (5 mg, 10%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): J8.64 (m, IH), 8.40 (m, IH), 7.98 (m, IH), 7.62 (m, IH), 7.48 (m, 2H), 6.83- 7.08 (m, 4H)5 6.7-6.83 (mJH), 3.32 (m, 2H), 3.06 (m, IH), 2.92 (s, 3H), 2.82 (m, 2 H), 2.7 (m, 1H),1.57-2.1 (m, 3H), 1.53 (m, IH): MS: m/z 427 [M+Hf. Example 318. Preparation of Compound 352
Figure imgf000628_0001
By using the same synthetic procedure as compound 191 described in Example 308, compound 352 (5 mg, 11%) was obtained as a white solid. 1H-NMR (400 MHz CD3OD): δl.9 (m, IH), 7.82 (m, IH), 7.71 (m, IH), 7.61 (m, IH), 7.3 (m, 2H), 7.28 (m, 4H), 7.0 (m, IH), 6.48 (m, IH), 3.56 (m, 2H), 3.39 (s, 3H), 3.27 (m,lH), 2.95 (m, 3H), 2.5-2.8 (m, IH), 2.39 (m, IH), 2.01 (m, 2H); MS: m/z 465 [M+H]+.
Example 319. Preparation of Compound 381
Figure imgf000628_0002
381a 381b 381c 381 d
Figure imgf000628_0003
3819 381 h
Experimental data
Figure imgf000628_0004
381a 381b The solution of methyltriphenylphosphonium iodide (250 g, 0.615 mol) in anhydrous THF (1500 mL) was added rc-BuLi (220 mL, 0.55 mol, 2.5 M in hexane) dropwise at -10°C under nitrogen. The mixture was stirred at -10°C for 1 hour, compound 381a (50 g, 0.343 mol) was added, and the mixture was warmed to room temperature, and stirred for 3 hours. The reaction was quenched with water, and extracted with EtOAc
(3x500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by column chromatography (petroleum ether / EtOAc = 100:1) to give the compound 381b (36.5 g, 74%) as a colorless liquid. 1H-MNR (CDCl3, 400 MHz): <S7.55 (d, 1 H), 7.05 (m, 3 H), 5.37 (s, 1 H), 4.85 (s, 1 H), 2.48 (t, 2 H), 2.44 (t, 2 H).1.78 (t, 2 H).
Figure imgf000629_0001
381b 381c
To a solution of 1 -methylene- 1,2, 3, 4-tetrahydronaphthalene (10 g, 61.0 mol) in a mixture of acetone (100 mL) and water (25 mL) was added NH4OAc (0.47 g, 0.61 mmol) and NBS (15.1 g, 67.1 mmol). The mixture was stirred at room temperature for 30 minutes, concentrated in vacuo, and extracted with EtOAc (3x100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=5:l) to give the compound 381c (10 g, 68%) as a colorless liquid. 1H-MNR (CDCl3, 400 MHz): <57.45 (d,
1 H), 7.15 (m, 2 H), 7.07 (m, 1 H), 3.65 (m, 2 H), 2.81 (m, 2H), 2.36 (m, 1 H), 1.84 (m, 2
H), 1.64 (m, 1 H).
Figure imgf000629_0002
To a solution of diethylzinc (25 mL, 23.1 mmol) in dried CH2CL2 (50 mL) was added diiodomethane (6.19 g, 23.1 mmol) at 00C under nitrogen. The mixture wsa stirred at 0°C for 20 minutes, and the solution of compound 381c (10 g, 38.5 mmol) in dry CH2CL2 (33 mL) was added. The ice bath was removed, after the mixture was stirred at room temperature for 4 hours, the concentrated NH4Cl solution (30 mL) was added. The organic layer was washed with water, and dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by column chromatography (petroleum ether/EtOAc=30 : 1 ~ 5 : 1) to give compound 381d (4.4 g, 71%) as a colorless liquid. 1H-MNR (CDCl3, 400 MHz): 57.17 (m, 4 H), 3.72 (s, 2 H), 2.95 (t, 2 H), 2.00 (m, 2 H), 2.58 (t, 2 H).
Figure imgf000630_0001
381 d 381e
To a solution of 8,9-dihydro-5H-benzo[7]annulen-6(7H)-one (0.898 g, 5.61 mmol) in dry MeOH (5 mL) was added l-(5-bromo-2-hydroxyphenyl)ethanone (1 g, 4.67 mmol) and pyrrolidine (0.6 mL). The mixture was stirred at room temperature for 1 hour, and refluxed overnight, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 30: 1 ~ 5: 1) to give the compound 381e (341 mg; 20%) as an orange solid. 1H-MNR (CDCl3, 400 MHz): 58.01 (d, 1 H), 7.51 (m, 1 H), 7.17 (m, 3 H), 6.81 (m, 1 H), 6.72 (m, 1 H), 3.32 (m, 1 H), 3.10 (m, 1 H), 2.65 (m, 2 H), 2.63 (m, 2 H), 2.12 (m, 2 H), 1.95 (m, 1 H), 1.55 (m, 1 H).
Figure imgf000630_0002
A steel slave was charged with a mixture of compound 381e (3 g, 8.1 mmol), KCN (1.053 g, 16.2 mmol), and (MLt)2CO3 (8.532 g. 60.75 mmol). Formamide (30 mL) was added to fill the tube completely. The mixture was heated at 70°C for 72 hours, at 1100C for 3 hours, cooled, and poured into ice water. After acidification with concentrated HCl solution (pH =1). the mixture was extracted with EtOAc (50 mL><3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2 / MeOH = 50:1) to give the compound 381f (1.5 g: 43%) as an orange solid. 1H-MNR (CDCl3, 400 MHz): Sl.17 (m, IH), 6.96 (m, 5H), 6.65 (m, IH), 3.32 (m, IH), 3.25-3.05 (m, 2H), 2.83 (m, IH), 2.73 (m, 2H), 2.22 (m, IH), 2.12 (m, IH), 1.75 (m, 2H).
Figure imgf000631_0001
To a solution of compound 38If (I g, 2.348 mmol) and Lawesson' reagent (948.6 mg, 2.348 mmol) in 1, 4-dioxane (22.5 mL) was heated under 120°C for 35 minutes in a microwave reactor. The mixture was cooled, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 20: 1) to give the compound 381g (0.5 g, 48%) as an orange solid. 1H-NMR (CDCl3, 400 MHz): (57.35 (m, 1 H), 7.21 (m, 5 H), 6.75 (m, 1 H), 3.91 (m, 3 H), 3.41(m, 1 H), 2.38 (m, 1 H), 2.15 (m, 1 H), 2.02 (m, 3 H), 1.45 (m, 2 H).
Figure imgf000631_0002
381 g 381 h
To a solution of compound 381g (500 mg, 1.311 mmol) in MeOH (30 mL) was added NaOH solution (4.35 mL, 2.601 mmol, 0.6 N, aqueous). The mixture was stirred at room temperature for 5 minutes, added MeI (0.71 mL, 1.31 mmol), and stirred for another 5 minutes. The mixture was stirred in a microwave reactor at 60°C for 10 minutes, concentrated in vacuo, added water (30 mL), and extracted with EtOAc (30 mL><3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc = 3:1) to give the compound 381h (60 mg, 11%) as a yellow oil. 1H-MNR (CDCl3, 400 MHz): <S7.35 (m, 1 H)5 7.15 (m, 2H), 7.05 (m, 2 H), 6.65-6.82 (m, 2 H), 3.62 (m, IH), 3.15 (s, 3 H), 2.83 (m, 3H), 2.62 (s, 3 H), 2.1 1 (m, 3 H), 1.94 (m, 2H), 1.66 (m, IH), 1.51 (m, IH).
Figure imgf000632_0001
381 h
The solution of compound 381h (20 mg, 0.043 mmol) and NH4I (62.64 mg, 0.432 mmol) in a solution of NH3/EtOH (1.72 mL, 5 N) was heated at 120°C in a CEM tube in microwave reactor for 3 hours. The mixture was concentrated in vacuo, the residue was added CH2Cl2, filtered, and conentrated in vacuo. The residue was purified by preparative HPLC to give the compound compound 381 (4.37 mg, 23%) as a white solid. 1H-MNR (CD3OD, 400 MHz): <57.41 (m, 2 H), 7.15 (m, 3 H)5 6.85 (m, 1 H), 6.75 (d, 1 H), 3.35-3.55 (m, IH), 3.27 (s, 3 H), 3.05 (m, IH), 2.96 (m, 2H), 2.35 (m, 3 H), 1.95 (m, 2 H), 1.65 (m, I H); ESI MS: 440 [M+H]+.
Example 320. Preparation of Compound 179
Figure imgf000632_0002
The solution of compound 179a (20 mg, 0.045 mol), 3-cyanophenyl- boronic acid
(10 mg, 0.068 mmol), Cs2CO3 solution (0.3 mL, 2M, aqueous), Pd(PPh3)2Cl2 (0.5 mg) in 1,4-dioxane (1 mL) under nitrogen was heated at 1200C in microwave for 15 minutes. The dark reaction mixture was filtered, and concentrated in vacuo, the residue was purified by preparative TLC (CH2Cl2:MeOH=10:l) and HPLC to give the compound compound 179 (1.3 mg, 6%) as a yellow solid. 1H-NMR (CD3OD, 400 MHz): 57.88 (s, IH), 7.78 (d, J= 3.0 Hz IH), 7.60 (d, J= 4.0 Hz IH), 7.53 (m, 2H), 7.37 (s, IH), 7.05 (m, 2H), 6.97 (m, IH), 6.83 (m, 2H), 3.33 (m, IH), 3.17 (s, 3H), 2.99 (m, IH), 2.25 (m, 2H), 2.46 (m, IH), 2.38 (s, 2H), 1.98 (m, IH), 1.86 (m, IH) 1.55 (m, IH); ESI MS: 463 [M+H]+.
Example 321. Preparation of Compound 238 CuI
Figure imgf000633_0001
Figure imgf000633_0002
238a
A dry flask was charged with compound 238a (107 mg, 0.25 mmol), TEA (1 mL) and DEA (0.3 mL) under N2 atmosphere. To this solution was added CuI (2.0 mg, 0.01 mmol), and PdCl2(PPh3 )2 (7 mg, 0.01 mmol). The system was degassed, and cyclopropyl acetylene (0.25 mL, excess) was added, and the mixture was heated to 52°C with stirring. The reaction was evaporated, and the residue was purified by preparative TLC (CH2Cl2: MeOH=10:l) and HPLC to afford compound 238 (17 mg, 16.4%). 1H-NMR (400MHz CDCl3): <57.55 (m, IH), 7.34 (d, J= 17.6 Hz, IH), 7.16 (m, 4H), 6.73 (m, IH), 3.49 (d, J= 13.6 Hz, IH), 3.30 (d, J= 11.6 Hz, IH), 3.05 (m, IH), 2.85 (m, 4H), 2.42 (m, IH), 2.15 (m, IH), 1.96 (m, 2H), 1.45 (m, 2H), 0.90 (m, 4H); ESI MS: m/z 414 [M+H]+.
Example 322. Preparation of Compound 265
CuI
Figure imgf000633_0003
Figure imgf000633_0004
263a
A deoxygenated solution of compound 263a (50 mg, 0.12 mmol) in triethylamine (2 mL) was treated with triphenylphosphine (1.2 mg, 4.7 umol), palladium acetate (0.5 mg, 2.3 umol) and copper (I) iodide (0.4 g, 2.3 umol). After 10 minutes, 3, 3-dimethyl-l- butyne (0.2 mL) was added via syringe. The reaction was refluxed for 12 hours, and cooled to room temperature. The solution was filtered, and partitioned between diethyl ether (10 mL) and water (10 mL). The organic layer was dried (MgSO4), evaporated, and the resulting crude product was purified by preparative TLC (CH2Cl2ZMeOH=I 0:1) and HPLC to yield compound 263 (1.5 mg, 3%) as a white solid. 1H-NMR (400MHz CD3OD): ^7.38-7.91 (m, 2H), 7.24 (m, IH), 7.15 (m, 3H), 6.56-6.81 (m, IH), 3.41 (m, IH), 3.15 (s, 3H), 3.02 (m, IH), 2.91 (m, IH), 2.62-2.84 (m, 5H), 2.35 (m, IH), 2.17 (m, IH), 1.86 (m, 2H), 1.36 (m, IH), 1.18 (m, IH), 1.14 (t J= 7.2 Hz, 6H): ESI MS: 416 [M+Hf. Example 323. Preparation of Compound 308
Figure imgf000634_0001
By using the same synthetic procedure as compound 238 described in Example 321, compound 308 (5.3 mg, 9%) was obtained as a white solid. 1H-NMR (400MHz CD3OD): (57.48-7.92 (m, IH), 7.21-7.35 (m, IH), 7.08 (m, 3H), 6.81-6.95 (m, IH), 6.56- 6.70 (m, IH), 3.21 (d, 3H), 2.73 (m, 3H), 2.32 (m, IH), 2.06 (m, IH), 1.87 (m, 2H), 2.35 (m, IH), 1.31-1.63 (m, IH), 1.20 (d, J=7.2 Hz, 9H); ESI MS: 430 [M+H]+.
Example 324. Preparation of Compound 317
Figure imgf000634_0002
By using the same synthetic procedure as compound 238 described in Example 321, compound 317 (7.4 mg, 14%) was obtained as a white solid. 1H-NMR (CD3OD, 400MHz): <57.48-7.92 (m, IH), 7.21-7.35 (m, IH), 7.08 (m, 3H), 6.81-6.95 (m, IH), 6.72 (m, 2H), 3.21 (d, 3H), 2.93 (m, IH), 2.76 (m, 4H), 2.32 (m, IH), 2.06 (m, IH), 1.93 (m, 4H), 1.66 (m, 6H), 1.31 (m, IH); ESI MS: 442 [M+H]+.
Example 325. Preparation of Compound 373
Figure imgf000635_0001
Experimental data
Figure imgf000635_0002
A solution of «-BuLi (88 mL, 2.5M) was added to a solution Of PPh3CH3 +F (IOO g, 246 mmol) in THF (600 mL) at -10°C. The mixture was cooled to -10°C, and stirred for 1 h. Compound 373a (20 g, 137 mmol) was added, and the mixture was warmed to ambient temperature, and stirred for 3 hours. The resulting mixture was quenched by addition of saturated NH4Cl solution (200 mL), extracted with EtOAc (3><150 mL), washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether: EA=100:l) to give the compound 373b (13.1 g, 66%) as colorless liquid. 1H-NMR (CDCl3 400MHz): £7.25 (m, IH), 7.12 (m, IH), 6.72 (m, IH), 3.8 (s, 3H), 5.45 (s, IH), 4.95 (s, IH), 2.48 (m, 2H), 2.25 (m, 2H), 1.89 (m, 2H).
Figure imgf000635_0003
To a suspension of compound 373b (1 g, 5.7 mmol) and NH4OAc (44.3 mg. 0.57 mmol) in acetone (11 mL), was added NBS (1.4 g, 6.27 mmol) and water (3 mL). The mixture was stirred at ambient temperature, concentrated in vacuo, and purified by column chromatography (petroleum ether: EA=50:l) to give the compound 373c (0.5 g, 45%) as yellow liquid. 1H-NMR (CDCl3 400MHz): 57.23 (m, 2H), 6.69 (m, IH), 3.74 (s, 3H), 2.31 (m, 2H), 2.66 (m, IH), 2.65 (m, IH), 2.55 (m, IH), 1.80-1.91 (m, IH).
Figure imgf000636_0001
To a solution Of Et2Zn (0.44 mL, 0.44 mmol, 1 M) in dichloromethane (3 niL) was added diiodo methane (118 mg, 0.44 mmol) at 0°C under nitrogen atmosphere. After being stirred for 20 minutes, compound 373c (200 mg, 0.737 mmol) was added, and the mixture was warmed to room temperature. After being stirred for 2 h, the reaction mixture was quenched by addition of saturated NH4Cl solution (10 mL), extracted with CH2Cl2 (3x10 mL), washed with brine, dried over Na2SO4, concentrated, and purified on column chromatography (petroleum ether: EA=50:l) to give the compound 373d (86 mg, 61%). 1H-NMR (CDCl3 400MHz): <S7.13(m, IH), 6.73-6.85 (m, 2H), 3.82 (s, 3H), 3.72 (m, 2H), 3.00 (m, 2H), 2.52 (m, 2H), 1.95 (m, 2H).
Figure imgf000636_0002
The mixture of compound 373d (3.8 g, 20.0 mmol), l-(5-Bromo-2-hydroxy- phenyl)-ethanone (3.56 g, 16.7 mmol) and pyrrolidine (5 mL) in MeOH (20 mL) was stirred at ambient temperature for 1 h and at refluxing overnight. The solvent was removed in vacuo, and the crude product was purified by silica column chromatography (petroleum ether: EA=10:l) to give the compound 373e as a yellow solid (3 g, 50%). 1H- NMR (CDCl3 400MHz): c57.98 (s, IH), 7.53 (d, IH)5 7.03 (t, IH), 6.75 (t, 2H), 6.48 (d, J = 7.6 Hz, IH), 3.82 (s, 3H), 3.02-3.42 (m, 3H), 2.47-2.71 (m, 3H), 2.13 (m, 2H), 1.88 (m, IH), 1.48 (m, IH),
Figure imgf000637_0001
To a solution of compound 373e (200 mg, 0.51 mmol) in CH2Cl2 (15 mL) was added TiCl4 solution (1 M in CH2Cl2, 1.02 mL, 1.02 mmol). The mixture was stirred in microwave at 50°C for 10 minutes. After being cooled to room temperature, N, N— methanediylidenebis (1,1,1-trimethyl silanamine) (189.4 mg, 1.02 mmol) was added. The mixture was stirred at 60°C for 10 minutes, poured into ice- water, extracted with CH2Cl2 (2χ50 mL). The combined organic layer was washed with brine (100 mL). dried, and concentrated to give the compound 373f (168 mg, 100%) as a yellow solid, which was used for the next step directly without purification. 1H-NMR (CDCl3 400MHz): «58.14 (s, IH), 7.58 (d, J = 2.4 Hz, IH), 7.03 (t5 IH), 6.78 (m, 2H), 6.40 (d, J = 12 Hz, IH), 3.82 (s, 3H), 3.23 (m, 2H), 3.02 (m, 2H), 2.50-2.70 (m, 2H), 2.13 (m, 2H), 1.95 (m, IH), 1.28 (m, IH).
Figure imgf000637_0002
To a solution of methylhydroxylamine HCl salt (32.8 mg, 0.4 mmol) in anhydrous
MeOH (12 mL) was added NaOMe (10% in MeOH, 20 drops) and compound 373f (168 mg, 0.4 mmol). After being stirred for 10 minutes, the solvent was removed in vacuum, and the residue was dissolved in CH2Cl2 (25 mL). The mixture was filtered, concentrated, and purified by preparative HPLC to give compound 373 as a yellow solid (27 mg, 14%). 1H-NMR (CDCl3 400MHz): <57.58 (d, J= 2.4 Hz, IH), 7.03 (m, 2H), 6.78 (m, 3H), 3.82 (s; 3H), 3.45 (m, IH), 3.32 (m, IH), 1.85 (m, 2H)5 2.91-3.12 (m, 4H), 2.45-2.55 (m, 2H), 2.35 (m, IH), 2.27 (m, IH), 2.13 (m, IH), 2.05 (m, IH); ESI MS: 458 [M+H]+
Example 326. Preparation of Compound 225
Figure imgf000638_0001
A mixture of compound 225a (27 mg, 0.06 mmol), 3-cyanophenylboronic acid (14 mg, 0.09 mmol), Cs2CO3 solution (2 M, 0.3 mL), and Pd(PPh3)2Cl2 (1 mg) in 1,4-dioxane (1 mL) was stirred at 100°C under N2 for 45 minutes. The reaction mixture was concentrated in vacum and purified by preparative TLC (CH2Cl2: MeOH=I 0:1) and HPLC to give compound 225 as a white solid (0.3 mg, 25%). 1H-NMR (CD3OD, 400MHz): (58.04 (m, 3H), 7.03 (m, 3H), 7.71 (m, 2H), 6.52(m, 1H),3.8 (m, 3H), 3.40 (m, 2H), 3.28 (m, 1H),3.13 (m, 2H), 2.85 (m, IH), 2.4-2.60 (m, lH),2.23(m, IH), 1.95 (m, 2H),1.51 (m, 3H).
Example 327. Preparation of Compound 399
Figure imgf000638_0002
Experimental data
Figure imgf000639_0001
399a 399b
To a solution Of P+Ph3CH2OMeCl" (50 g, 145 mmol) in THF (200 mL) was added f-BuOK (16.2 g, 145 mmol) in THF (200 mL) under N2 at -20°C, and the reaction mixture was stirred for 80 min. The solution of compound 399a (12.65 g, 96.6 mmol) in THF (100 mL) at -200C was added, and the reaction mixture was stirred at -20°C for 90 min. and at room temperature overnight. The reaction mixture was quenched by water (150 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried by Na2SO4 concentrated, and purified by column chromatography (petroleum ether:EA=20:l) to afford the compound 399b as yellow liquid (3 g, 19.6%). 1H-NMR (CDCl3, 400MHz): 57.87-7.91 (m, IH)5 7.40-7.58 (m, IH), 7.23-7.27 (m, IH), 6.99-7.18 (m, IH), 6.15-6.17 (d, IH), 5.66-5.70 (d, IH), 3.84 (s, 3H).
Figure imgf000639_0002
399b 399c
To a solution of compound 399b (2.44 g, 15.32 mmol) in acetone (20 mL) was added HCl (IN, 10 mL) under N2. The mixture was refluxed for 80 min., and concentrated in vacuo. The aqueous layer was extracted with EtOAc (3χ25 mL), and the combined organic layers were washed with brine (2x30 mL). The organic layer was dried over Na2SO4 and concentrated to give the compound 399c as yellow liquid, which was used for the next step directly without further purification (2 g, 88%). 1H-NMR (CDCl3, 400MHz): <59.8O (s, IH), 7.62-7.63 (d, IH), 7.27-7.60 (m, 3H), 3.80 (d; 2H).
Figure imgf000639_0003
399c 399d
To a solution of chroman-4-one (1.23 g. 8.28 mmol) in THF (20 mL) was added n- BuLi (3.3 mL, 8.28 mmol) at -78°C under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 1 hour, after addition of the solution of compound 399c (1.2 g, 8.28 mmol) in THF (10 rtiL), the mixture was stirred for another 1.5 hourss at - 78°C, quenched by satureate NH4Cl solution (5 mL), and extracted with EtOAc (3><20 mL). The combine organic layers were washed by brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (petroleum ether:EA=20:l) to afford the compound 399d as a white solid (2 g, 83%). 1H-NMR (CDCl3, 400MHz): (57.81-7.84 (m, IH), 7.32-7.54 (m, 5H), 6.90-6.99 (m, 2H), 4.38-4.60 (m, 3H), 2.78-2.89 (m, 3H).
Figure imgf000640_0001
399d 399e To a solution of compound 399d (50 mg, 0.17 mmol) in toluene (3 mL) was added p-TsOH (3.2 mg, 0.017 mmol) under nitrogen atmosphere. The mixture was heated at 120°C for 1 hour, and the solvent was evaporated. The residue was purified by preparative TLC (petroleum ether: EtOAc = 5:1) to afford the compound 399e as a white solid (10 mg, 21.3%). 1H-NMR (CDCl3, 400MHz): δl .95-1..97 (m, IH), 7.42-7.95 (m, 5H), 7.05-7.10 (m, 2H), 6.65 (d, IH), 6.41-6.44 (m, 2H), 4.65-4.69 (m, IH), 4.51-4.55 (m, IH), 3.63-3.66 (m, IH).
Figure imgf000640_0002
To a stirred solution of compound 399e (220 mg. 0.81 mmol) in MeOH (20 mL) was added 10% palladium on carbon, and the resulting suspension was stirred under H2 balloon at room temperature for 3 hours. The catalyst was filtrated through a pad of celite, and the filtrate was evaporated. The crude product was purified by preparative TLC (petroleum ether: EtOAc = 5:1) to give the compound 399f (50 mg, 23%) as a white solid. 1H-NMR (CDCl3, 400MHz): <57.80-7.83 (m, IH), 7.31-7.44 (m, 5H), 6.87-7.19 (m, 2H), 4.43-4.47 (m, IH), 4.19-4.24 (m, IH), 2.57-2.60 (m, 3H), 2.1 1-2.18 (m, IH), 1.59-1.77 (m, IH).
Figure imgf000641_0001
To a solution of compound 399f (100 mg, 0.36 mmol) in dry CH2Cl2 (5 mL) was added TiCl4 (1 M solution in CH2Cl2, 0.72 mmol) dropwise within 15 minutes. The mixture was stirred for another 1 h, bw-trimehtlysilylcarbodiimide (202 mg, 1.08 mmol) was added dropwise, and the mixture was stirred for 18 h. The reaction mixture was poured into ice-water (10 g), and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the compound 399g (60 mg, crude), which was used for the next step directly without further purification.
Figure imgf000641_0002
To a solution of MeNHOH.HCl (16 mg, 0.20 mmol) in anhydrous MeOH (3 mL) was added NaOMe (25% in MeOH, 0.20 mmol) and compound 399g (60 mg, 0.20 mmol). After being stirred for 5 minutes, the solvent was removed in vacuum. The residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated, and the residue was purified by preparative TLC and HPLC to give compound 399 as a white solid. 1H-NMR (CD3OD, 400MHz): <57.34-7.53 (m, 5H), 7.26-7.30 (m, IH), 6.95-6.97 (m, IH), 6.78-6.93 (m, IH), 4.07-4.33 (m, 2H), 2.88 (s, 3H), 2.83-2.88 (m, IH), 2.67-2.71 (m, IH), 2.32-2.36 (m, IH), 1.53-1.67 (m, 2H); ESI MS: 349[M+H]+.
Example 328. Preparation of Compound 415
Figure imgf000642_0001
415d 415e
MeNHOH HCI MeONa, MeOH
Figure imgf000642_0002
Experimental data
Grignard reagent was prepared from Mg (0.56 g, 23mmol) and compound 415a (4 g, 25.6 mmol) in THF (10 mL) in the presence of I2 and a catalytic amount of CuBr (0.16 g, 1.1 mmol). The solution of compound 415a (2 g, 20.8 mmol) in THF (5 mL) was added dropwise at 0°C. After being stirred at room temperature (18°C) for 3 hours, the aqueous HCl solution (1 N) was added, and the mixture was extracted with EA. After drying with anhydrous MgSO4, the solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: EA=20:l) to give the compound 415b (2 g, yield 55%). 1H-NMR (CDCl3 400 MHz): δl.2>6 (m, 2H), 7.27 (m, 3 H), 3.04 (m, IH), 2.65-2.39 (m. 2 H), 2.18 (m, IH), 1.85 (m, 1 H), 1.31 (m, IH), 0.96 (m, 3 H).
Figure imgf000642_0003
pyrrolidine, MeOH
Figure imgf000642_0004
415b 415c A mixture of compound 415b (2 g, 1 1.5 mmol), compound 415B (1.2 g, 5.6 mmol), and pyrrolidine (1 mL) in anhydrous MeOH (140 mL) was refluxed overnight. The solvent was removed, the crude product was purified by silica column (petroleum ether: EA=80:l) to give the compound 415c (1.16 g, yield 27%). 1H-NMR (CDCl3, 300 MHz): (57.89-7.85 (m, 1 H), 7.52-7.48 (m, 1 H), 7.26-7.11 (m, 5H), 6.9-6.73 (m, 1 H), 2.97-2.91 (m, 1 H), 2.63-2.5 (m, 2H), 2.22-2.08 (m, 2 H), 1.87.-1.69 (m, 2 H), 1.51-1.43 (m, 2 H), 0.85-0.72 (m, 1 H).
Figure imgf000643_0001
415c 415d
To a solution of compound 415c (200 mg, 0.535 mmol), compound 415C (102 mg, 0.7 mmol), Cs2CO3 (2 mL) in dioxane (10 mL) was added Pd(PPh3)2Cl2 (50 mg, 0.05 mmol), and the mixture was refluxed overnight. Water was added to quench the reaction, and the mixture was extracted with EA. The organic layer was washed by brine, dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was purified by preparative TLC (petroleum ether: EA=5:1) to give the compound 415d (145 mg, yield 69%). 1H-NMR (CDCl3 400 MHz): <57.99-7.98 (m, 1 H), 7:9-7.85 (m, 1 H), 7.67-7.65 (m, 1 H), 7.61-7.44 (m, 6H), 7.25 (m, IH), 7.0 (m, 1 H), 2.74 (m, 2H), 2.2-2 (m, 2 H), 1.98 (m, IH), 1.53-1.44 (m, 4 H), 1.28 (m, IH).
Figure imgf000643_0002
415e
To a solution of compound 415d (50 mg. 0.127 mmol) in CH2Cl2 (3mL) was added TiCl4 (0.635 mL, 0.635 mmol). After being stirred in microwave at 50°C for 1 hour, compound 415D (0.064 mL, 0.28 mmol) was added, and the resulting mixture was stirred in microwave at 700C for 30 minutes. The reaction mixture was poured into ice- water (10 mL). extracted with CH2Cl2 (15 mL><2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the compound 415e (93 mg, yield 95%) as yellow oil, which was used directly for the next step without purification.
Figure imgf000644_0001
To a solution of methylhydroxylamine HCl salt (10.08 mg, 0.12 mmol) in anhydrous MeOH (2.5 mL) was added NaOMe (10% in MeOH, 0.061 mL) and compound 415e (50 mg, 0.12 mmol). After being stirred for 20 minutes, the solvent was removed in vacuo, and the residue was dissolved in CH2Cl2 (20 mL). The mixture was filtered, and the solvent was removed, the residue was purified by pre-TLC and HPLC to give the compound 415 (3.20 mg, yield 7%) as a white solid. 1H-NMR (CD3OD 400 MHz): (58.09 (s, IH), 7.95-8.03 (m, 3H), 7.72-7.77 (m, 2H), 7.66-7.64 (m, 2H), 7.20-7.32 (m, 2H), 7.15- 7.21 (m, 2H), 3.42 (s, 3H), 3.23 (m, IH), 2.68-2.97 (s, 2H), 2.19-2.23 (m, 2H), 1.95-2.04 (m, 2H), 1.71-1.74 (m, 2H), 1.56-1.73 (m, 2H); ESI MS: m/z 465 [M+H]+.
Example 329. Preparation of Compound 329
Figure imgf000644_0002
329d 329e
MeNHOH HCI MeONa, MeOH
Figure imgf000644_0003
Figure imgf000644_0004
Experimental data
Figure imgf000645_0001
To a solution of compound 329a (10 g, 46.74 mmol) and compound 329A (11.2 g, 56.08 mmol) in anhydrous toluene (100 mL) was added pyrrolidine (0.7 g, 9.348) under N2 atmosphere. The resulting mixture was stirred for Ih at room temperature, and refluxed overnight. The solvent was evaporated, and the residue was purified by chromatograph on sillica gel (eluted with petroleum ether: EtOAc=8:l) to afford the compound 329b (9.0 g, yield 50%). 1H-NMR (CDCl3 300MHz): 57.89 (s, IH), 7.49 (d, IH), 6.78 (s, IH), 3.60-3.91 (m, 2H), 3.01 (m, 2H), 2.64 (m, 2H), 1.79-2.08 (m, 2H), 1.10- 1.47 (m, HH).
Figure imgf000645_0002
To a mixture of compound 329b (17 g, 47.04 mmol), compound 329B (8.2 g, 55.95 mmol) and Cs2CO3 aqueous solution (2 M, 150 mL) in dioxane (200 mL) was added Pd(dppf)2Cl2 (4.2 g, 4.704 mmol) under N2 atmosphere. The mixture was refluxed overnight, water was added to quench the reaction, and the mixture was extracted with EtOAc (100 mL><3). The organic layer was washed by sat.NaCl solution, dried over Na2SO4 and evaporated. The residue was purified by chromatograph sillica gel (diluted with EtOAc: petroleum ether=l :30 to 1 :3) to afford the compound 329c (15 g. yield 76%)
Figure imgf000645_0003
To a solution of compound 329c (7.5 g, 0.01744 mol) in CH2Cl2 (100 mL) was added TFA (20 mL) at 00C. The reactio mixture was warmed to room temperature, and stirred overnight. The solvent was evaporated at room temperature to afford the compound 329d (5.0 g, yield 88%), which was used for the next step directly without purification.
Figure imgf000646_0001
329d 329e
To a solution of compound 329d (2 g, 6.289 mmol), and 2-chloropyrimidine (0.9 g, 8.176 mmol) in DMF (30 mL) was added K2CO3 (1.7 g, 12.58 mmol). The mixture was stirred at 50°C overnight. Water (30 mL) was added to quench the reaction, and the
mixture was extracted with EtOAc (2><50 mL). The organic layers were washed with brine (20 mL><3), dried over Na2SO4, and evaporated in vacuum. The residue was purified by chromatograph on sillica gel (eluting with petroleum ether: EA=8:1) to afford the compound 329e (0.8 g, yield 40%). 1H-NMR (CDCl3 300MHz): S8.5 (d, 2H), 8.02 (s, IH), 7.74 (m, 2H), 7.40-7.62 (m, 3H), 6.70 (d, IH), 6.39 (t, IH), 4.41 (d, IH), 4.07-4.21 (m, IH), 3.50-3.67 (m, 2H), 2.62-2.89 (m, 2H), 2.04-2.17 (m, IH), 1.75-1.95 (m, 2H), 1.58 (m, IH).
Figure imgf000646_0002
329e 329f
To a solution of compound 329e (200 mg, 0.50 mmol) in CH2Cl2 (2 mL) was added TiCl4 (1 M 4.04 mL, 4.0404 mmol). The mixture was stirred for 15min. at 50°C in microweave. TMSN=C=NTMS (280 mg, 2.02 mmol) was added, and the mixture was stirred for 30 min. at 600C in mixro weave. The reaction mixture was poured into ice- water, and extraced with EtOAc (5 mL). The organic layer was dried over Na2SO4 and evaporated to afford the compound 329f (40 mg, yield 19%), which was used for the next step directly without purification.
MeNHOH. HCl MeONa, MeOH
Figure imgf000647_0001
Figure imgf000647_0002
329f
A solution of compound 329f (40 mg, 0.095 mmol) in dry MeOH (3 mL) was added MeNHOH.HCl (8 mg, 0.095 mmol) and NaOCH3 (25% in MeOH, 0.02 mL). The resulting mixture was stirred for 10 min. at room temperature, and concentrated. The residue was dissolved in CH2Cl2 and the solid was filtered off. The filtrate was evaporated, and purified by prep-TLC and pr-HPLC to afford compound 329 (7.3 mg, yield 21%). 1H-NMR (CD3OD 400MHz): (58.36 (m, IH), 8.25 (m, IH), 8.11 (m, IH), 8.01 (m, 2H), 7.94 (m, IH), 7.71 (m, IH), 7.63 (m, 2H), 7.28-7.42 (m, IH), 6.47-6.65 (m, 2H), 4.21-4.64 (m, 2H), 3.47-3.60 (m, IH), 3.40 (s, 3H), 3.10-3.37 (m, 2H), 3.88-3.91 (m, IH), 1.97-2.27 (m, 5H); ESI MS: m/z 468 [M+H]+.
Example 330. Preparation of Compound 355
Cu(OAc)2, pyridine
Figure imgf000647_0003
Figure imgf000647_0004
MeNHOH.HCl
MeONa, MeOH
Figure imgf000647_0005
Experimental data
Figure imgf000648_0001
To a solution of compound 355a (7.5 g, 17.44 mmol) in CH2Cl2 (100 mL) was added TFA (20 mL) at 0°C. The reaction mixture was warmed to room temperature, and stirred overnight. The solvent was evaporated to afford the compound 355b (5.0 g, yield 88%), which was used for the next step directly without purification.
Figure imgf000648_0002
355b 355c
To a solution of compound 355b (1 g, 3.145 mmol), pyridine (14 mL) in CH2Cl2 (30 mL) was added phenylboronic acid (0.96 g, 6.289 mmol), and Cu(OAc)2 (1.16 g, 6.29 mmol). The reaction mixture was stirred at 50°C overnight. Water (30 mL) was added to quench the reaction, and the mixture was extracted by EtOAc (50 mL). The organic layers were washed with brine (20 mL><3), dried over Na2SO4, and evaporated in vacuum. The residue was purified by chromatograph sillica gel (petroleum ether: EA=8:1) to afford the compound 355c (0.5 g, yield 40%). 1H-NMR (CDCl3 400MHz): 58.12 (s, IH)5 7.89 (s, IH), 7.84 (d, IH), 7.72 (m, IH), 7.64 (m, IH), 7.57 (m, IH), 7.24 (m, 2H), 7.07 (d, IH), 6.87 (m, 3H), 3.02 (m, IH), 3.23-3.34 (m, 2H), 3.10-3.20 (m, IH), 2.02-2.12 (m, 3H), 1.71-1.91 (m, 3H).
Figure imgf000648_0003
355c 355d
To a solution of compound 355c (100 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added TiCl4 (1 M 0.76 mL, 0.76 mmol). The mixture was stirred for 15 min. at 50°C in microweave. TMSN=C=NTMS (106 mg, 0.76 mmol) was added, and the mixture was stirred for 30 min. at 60°C in mixroweave. The reaction mixture was poured into ice- water, and extraced with EtOAc (5 mL). The organic layer was dried over Na2SO4 and evaporated to afford the compound 355d (20 mg, yield 19%), which was used for the next step directly without purification.
MeNHOH. HCl MeONa, MeOH
Figure imgf000649_0002
Figure imgf000649_0001
355d
A solution of compound 355d (20 mg, 0.04785 mmol) in dry MeOH was added MeNHOH.HCl (14 mg, 0.04785 mmol), and the solution OfNaOCH3 (25% (wt%) in MeOH, 0.02 mL). The mixture was stirred for 10 min. at room temperature, and concentrated. The residue was dissovled in CH2Cl2 and the solid was filtered off. The filtrate was evaporated, and purified by TLC and pr-HPLC to afford the compound 355 (7.5 mg, yield: 34%). 1H-NMR (CD3OD 400MHz): <58.04 (s, 2H), 7.89 (m, IH), 7.75 (m, 2H), 7.64 (m, IH), 7.44 (m, IH), 7.12-7.26 (m, 2H), 6.78-7.03 (m, 3H), 3.44-3.59 (m, IH), 3.40 (S5 3H), 3.03-3.30 (m, 5H)5 1.78-2.23 (m, 6H); ESI MS: m/z 466 [M+H]+.
Example 331. Preparation of Compound 390
Figure imgf000650_0001
Experimental data
Figure imgf000650_0002
390a 390b
The mixture of compound 390a (27.8 g, 139 m mol). compound 390A and pyrrolidine (9.43 g, 132 mmol) in MeOH (150 mL) was stirred at ambient temperature for Ih. and refluxed overnight. The solvent was removed in vacuo, the residue was purified by column chromatography on silica gel with petroleum ether: EtOAc=20:l to give the compound 390b (20 g, 72%) as a yellow solid. 1H-NMR (CDCl3 400 MHz) : <57.82 (s, IH), 7.47(d, IH), 6.82 (d, IH), 3.61 (m, 4H), 2.61 (s, 2H), 2.32 (m, 4H) 1.5 (s, 9H).
Figure imgf000650_0003
390b 390c Pd(PPh3)2Cl2 (83 mg,0.126 mmol) in a 150 mL flask under N2 atomsphere was treated sequentially with compound 390b (5 g, 12.6 mmol) Cs2CO3 (2 N, 23.7 mL), and the solution of 3-cyanophenylboronic acid (2.74 g, 18.7 mmol) in 1,4-dioxane (50 mL), The mixture was refluxed for 1 hour, poured into water, extracted with EtOAc (100mLχ2), washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=10:l) to give the compound 390c (3 g, 57%) as a yellow solid. 1H-NMR (CDCl3 300MHz): <S8.0 (m, IH) 7.73 (m, 2H) 7.63 (m, IH), 7.56 (m,lH), 7.47 (m, IH), 7.0 (d, IH), 3.82 (m, 2H), 3.21 (s, 2H), 2.70 (s, 2H), 2.01 (m, 2H), 1.63 (m, 2H), 1.39 (s, 9H).
Figure imgf000651_0001
To a solution of compound 390c (2 g, 4.7 mmol) in anhydrous CH2Cl2 (8 mL) was added TFA 2 mL), the mixture was stirred for 2 hours. TLC (petroleum ether:EtOAc=5:l) showed that the reaction was completed, the mixture was neutralized with sat. NaHCO3 solution (50 mL) until no CO2 was evolved. The organic layer was washed with brine (100 mL), and concentrated to give the compound 39Od as a yellow solid (1.39 g, 92%), which was used for the next step directly without purification.
Figure imgf000651_0002
A mixture of compound 39Od (1 g; 3 mmol), 390B (0.946 g, 7.7 mmol), and Cu(OAc)2 (1.13 g, 6 mmol) in a mixture of CH2Cl2 (20 mL) and pyridine (10 mL) was refluxed overnight. The reaction mixture was poured into water, extracted with CH2Cl2 (50mLχ2), washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (petroleum ether: EtOAc= 10:1) to give the compound 39Oe (440 mg, 35%) as a yellow solid. 1H-NMR (CDCl3 400 MHz): <58.O (s, IH), 7.74 (m, 2H), 7.72 (m, IH), 7.65 (m, IH), 7.49 (m, IH), 7.23 (m, 2H), 7.19 (m, IH), 6.99 (m, 2H), 6.79 (m, IH)5 3.42 (m, 2H), 3.20 (m, 2H), 2.75 (s, 2H), 2.14 (m, 2H), 1.83 (m, 2H).
Figure imgf000652_0001
To a solution of compound 39Oe (100 mg, 0.25mmol) in anhydrous CH2Cl2 (2mL) was added TiCl4 (0.5 mL) under N2 atmosphere, and the mixture was stirred in microwave at 50°C for 15 min. TMSN=C=TMS (93 mg, 0.5 mmol) was added, and the mixture was stirred in microwave at 600C for 15 min. The mixture was poured into ice-water (5 mL), extracted with CH2Cl2 (20χ2), washed with brine (50 mL), dried over Na2SO4 and concentrated to give the compound 39Of (74 mg) as a yellow solid, which was used for the next step directly without purification.
Figure imgf000652_0002
To a solution of MeNHOH.HCl (14.8 mg, 0.17 mmol) in MeOH (4 mL) was added MeONa (95 mg, 0.17 mmol, 10% in MeOH) and compound 39Of (74 mg, 0.17 mmol), After being stirred for 10 minutes, the reaction was completed based on LCMS, and the solvent was removed in vacuo. The residue was purified by prep-TLC and HPLC to afford compound 390 (12 mg, 15%) as a white solid. 1H-NMR (CD3OD 400 MHz): «58.05 (m, 2H)5 7.95 (m, IH), 7.82 (m, IH), 7.76 (m, IH), 7.69 (m, IH), 731-7.49 (m, 4H), 7.29 (m, 2H), 3.75 (m, 2H), 3.54 (m, 2H), 3.47 (s, 3H), 2.90 (d, IH), 2.46 (m, IH), 2.12- 2.42 (m, 4H): ESI MS: m/z 466 [M+H]+. Example 332. Preparation of Compound 353
Figure imgf000653_0001
Experimental data
Figure imgf000653_0002
353a 353b
The mixture of compound 353a (27.8 g. 139 m mol). compound 353 A. and pyrrolidine (9.43 g, 132 mmol) in MeOH (150 mL) was stirred at ambient temperature for Ih, and reflux ed overnight. The solvent was removed in vacuo, the residue was purified by column chromatography on silica gel with petroleum ether: EtOAc=20:l to give the compound 353b (20 g, 72%) as a yellow solid. 1H-NMR (CDCl3 400 MHz): <57.82 (s, IH), 7.47(d, IH), 6.82 (d, 1H); 3.61 (m, 4H), 2.61 (s, 2H)S 2.32 (ms 4H) 1.5 (s, 9H).
Figure imgf000654_0001
To a solution of compound 353b (10 g, 25.2 mmol) in anhydrous CH2Cl2 (40 mL) was added TFA 10 mL), and the mixture was stirred for 2 hours. TLC (petroleum ether:EtOAc=5:l) showed that the reaction was completed, and the mixture was neutralized with sat. NaHCO3 solution (50 mL) until no CO2 was evolved. The organic layer was washed with brine (100 mL), and concentrated to give the compound 353c as a yellow solid (6 g, 80%), which was used for the next step directly without purification.
Figure imgf000654_0002
To a solution of compound 353c (2 g, 6.7 mmol) in anhydrous DMF (20 mL) was added K2CO3 (1.87 g, 13.4 mmol) and 353B (928 mg, 8.1mmol). The reaction mixture was stirred overnight, quenched by sat. NH4Cl solution, extracted with EtOAc (100 ml_χ2), washed with brine, dried over Na2SO4, and concentrated to give the compound
353d as a yellow solid (1.1 g, 43%), which was used directly for the next step without purification. 1H-NMR (CDCl3 300 MHz): <58.57 (m,lH), 8.30 (m,lH),7.91 (m; IH), 7.52 (m, 1H);6.87 (d, IH) 6.44 (m, IH), 4.44 (m, 2H)5 3.39 (m, 2H), 2.77 (s, 2H); 2.04 (d, 2H), 1.64 (m, 2H).
Figure imgf000654_0003
Pd(PPh3)2Cl2 (19.3 mg, 0.029 mmol) in a 100 mL flask under N2 was treated sequentially with compound 353d (1.1 g, 2.9 mmol), Cs2CO3 (2 N, 5.3 mL), and the solution of 3-cyanophenylboronic acid (652 mg, 4.3 mmol) in 1,4-dioxane (26 mL). The mixture was refluxed for at 120°C for Ih, poured into water, extracted with EtOAc (100
ml_x2), washed with brine (100 mL), dried over Na2SO4, and concentrated, and the residue was purified by prep-TLC to give the compound 353e (100 mg, 10%) as a yellow solid. 1H-NMR (CDCl3 400 MHz): (58.38 (m, 2H), 8.10 (s, IH), 7.86 (m, IH), 7.83 (m, IH), 7.75 (m, IH), 7.64 (m, IH), 7.57 (m, IH), 7.15 (d, IH), 6.51 (m, IH), 4.51 (d, 2H), 3.51 (m, 2H), 2.80 (m, 2H), 2.14 (s, 2H), 1.73 (m, 2H).
Figure imgf000655_0001
To a solution of compound 353e (100 mg, 0.25 mmol) in anhydrous CH2Cl2 (2 mL) was added TiCl4 (3.78 mL, 1 M in CH2Cl2) under N2 atmosphere, and the mixture was stirred in microwave at 50°C for 15 min. TMSN=C=TMS (93 mg, 0.5 mmol) was added, and the mixture was stirred in microwave at 600C for 15 min., poured into ice- water (5 mL). The aqueous layer was extracted with CH2Cl2 (20 mL><2), the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the crude compound 353f (74 mg, crude) as a yellow solid, which was used directly for the next step without purification.
Figure imgf000655_0002
To a solution of MeNHOH.HCl (14.8 mg, 0.17 mmol) in MeOH (4 mL) was added MeONa (95 mg, 0.17 mmol, 10% in MeOH) and compound 353f (74 mg, 0.17 mmol). After being stirred for 10 minutes, the reaction was completed based on by LCMS, the solvent was removed in vacuo, the residue was purified by prep-TLC and prep-HPLC purification to afford compound 353 (10 mg, 12%) as a white solid. 1H-NMR (CDCl3 400 MHz): (58.25 (m, 2H), 7.68-7.92 (m, 4H), 7.61 (m, 1H),7 .53 (m, IH), 7.05 (d, IH), 6.51 (m, IH), 4.2-4.4 (m, 2H), 3.52 (m, IH), 3.30 (s, 3H), 2.72 (d, 2H), 2.14 (m, 2H), 1.8 (m, 2H), 1.7 (m, IH); ESI MS: m/z 468 [M+H]+.
Example 333. Preparation of Compound 383
Figure imgf000656_0002
Figure imgf000656_0001
pyrrolidine, MeOH
383a 383b 383c
Figure imgf000656_0003
Experimental data
Figure imgf000656_0004
To a solution of compound 383a (2 g, 12.65 mmol). phenol (1.07 g, 1 1.38 mmol), and PPh3 (3.3 g, 12.65 mmol) in THF (15 mL) at 00C was added diethyl azodicarboxylate (2.2 g. 12.65 mmol). The reaction mixture was stirred at room temperature for 48 h. evaporated, and purified by column chromatography on silica gel (petroleum ether/EA=50/l) to compound 383b (1.16 g, 40%) as a solid. 1H-NMR (CDCl3 400MHz): «57.33 (m, 2H), 6.93(m, 3H), 4.45 (s, IH), 4.00 (m, 3H), 1.95 (m, 5H), 1.66 (m, 2H), 1.33 (s, IH).
Figure imgf000657_0001
To a solution of compound 383b (1.158 g, 4.9 mmol) in H2O (30 mL) was added a catalytic amount ofp-TsOH (93.2 mg), and the mixture was refluxed for 1 h. The solution was extracted with EtOAc (30 mL><3), washed with brine (30 mL), dried over Na2SO4, and concentrated to give the compound 383c (I g, 89%) as yellow liquid, which was used for the next step without purification. 1H-NMR (CDCl3 400 MHz): <57.33 (m, 2H), 6.93 (m, 3H), 4.65 (m, IH), 2.65 (m, 2H), 2.13-2.35 (m, 4H), 2.02 (m, IH), 1.85 (m, IH).
Figure imgf000657_0002
383d
The mixture of compound 383c (400 mg, 2.1 mmol), compound 383A (398 mg, 1.7 mmol) and pyrrolidine (1 mL) in MeOH (5 mL) was refluxed overnight. The solvent was removed in vacuo, the residue was purified by TLC (petroleum ether: EA=3:1) to give the compound 383d as a yellow solid (96 mg, 11%). 1H-NMR (CDCl3 400MHz): <58.15 (m, IH), 7.5-7.45 (m, 5H), 7.33 (m, IH), 7.21 (m, IH), 6.9 (m, 4H), 4.32 (m, IH), 2.80 (s, 2H), 2.28 (m, 2H), 1.98 (m, 4H), 1.62 (m, 2H).
Figure imgf000657_0003
383e To a solution of compound 383d (96 mg, 0.25 mmol) in CH2Cl2 (5 mL) was added TiCl4 (1 M in CH2Cl2, 0.5 mL, 0.5 mmol), and the mixture was stirred in microwave at 50°C for 10 minutes. After being cooled to room temperature, N, iV-methanediylidenebis (1,1,1 - trimethylsilanamine) (92.85 mg, 0.5 mmol) was added. The mixture was stirred in microwave at 6O0C for 10 minutes, and poured into ice-water. The mixture was extracted with CH2Cl2 (2χ50 mL), washed with brine (100 mL), dried, and concentrated to give the compound 383e as a yellow solid (61 mg, 60%), which was used for the next step without purification.
MeNHOH HCI MeONa, MeOH
Figure imgf000658_0001
Figure imgf000658_0002
383e
To a solution of methylhydroxylamine HCl salt (7 mg, 0.09 mmol) in anhydrous MeOH (4 mL) was added NaOMe (10% in MeOH, 5 drops) and compound 383e (35 mg, 0.09 mmol). After being stirred for 10 minutes, the solvent was removed in vacuum. The residue was dissolved in CH2Cl2 (25 mL). The mixture was filtered, and the solvent was removed, the residue was purified by preparative HPLC to give compound 383 as a yellow solid (2.0 mg, 5%). 1H-NMR (CD3OD 400MHz): <57.88 (m, 3H), 7.5-7.7 (m, 3H), 7.18 (m, 2H), 7.03 (m, IH), 6.82 (m, 3H), 4.30 (m, IH), 3.53 (m, IH), 3.28 (s, 3H), 2.63 (d, IH), 2.55 (s, 2H), 2.10 (m, IH), 1.95 (m, 2H), 1.78 (m, 2H), 1.56 (m, IH): ESI MS: m/z 481 [M+H]+.
Example 334. Preparation of Compound 375
Figure imgf000659_0001
Figure imgf000659_0002
Experimental data
Figure imgf000659_0003
375a
To a solution of compound 375a (30 g, 192.2 mtnol) in anhydrous MeOH (650 mL) at 0°C was added NaBH4 (13.2 g, 345.96 mmoL). The reaction mixture was stirred at room temperature for 1 hour, water was added to quench the reaction. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (30 mL><3), washed with brine (30 mL). dried over Na2SO4 and concentrated to afford the compound 375b (30 g, 100%) as colorless liquid, which was used for the next step without purification. 1H-NMR (CDCl3 400MHz): 53.73 (m, 4H), 3.62 (s, IH), 2.75 (s, IH), 1.6- 1.8 (m, 3H), 1.43 (m, 4H).
Figure imgf000659_0004
375b 375c To a suspension of sodium hydride (1 g, 25.2 mmol) in DMF (20 mL) was added compound 375b (2 g, 12.6 mmol) at 0°C. The reaction mixture was stirred at O0C for 1.5 hours, followed by the addition of benzyl bromide (2.37 g, 15.2 mmol). The reaction mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (30 mL><2), washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified on column chromatography on silica gel (petroleum ether/EA=20:l) to give the compound 375c (2.7 g, 87%) as colorless liquid. 1H-NMR (CDCl3 300MHz): (57.18-7.26 (m, 5H), 4.42 (s, 2H), 3.83 (m, 4H), 3.48 (s, IH), 1.62-1.9 (m, 6H), 1.43 (m, 2H).
Figure imgf000660_0001
To a solution of compound 375c (2.7 g, 10.9 mmol) in H2O (50 mL) was added a catalytic amount of/?-TsOH (207 mg), and the mixture was refluxed for Ih. The solution was extracted with EtOAc (40mLχ 3), and the organic phase was washed with brine (40 mL). The combine organic layers were dried over Na2SO4, the solvent was removed in vacuo to give the compound 375d (1.6 g, 75%) as yellow liquid, which was used for the next step without purification. 1H-NMR (CDCl3 400MHz): <S7.25-7.4 (m, 5H), 4.65 (s, IH), 3.85 (m, IH), 2.62 (m, 2H), 2.22 (m, 2H), 1.95 (m, 2H).
Figure imgf000660_0002
The mixture of compound 375d (5.17 g. 25.3 mmol), compound 375A (4.33 g,
20.3 mmol), and the solution of pyrrolidine (7 mL) in MeOH (30 mL) was refluxed overnight. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (petroleum ether: EA=30:l) to give the compound 375e as a yellow solid (3.5g, 35%). 1H-NMR (CDCl3 300MHz): £7.88 (m, IH), 7.48 (m, IH), 7.33 (m, 5H), 6.75 (d, IH)5 4.43 (s, 2H), 3.62 (s, IH), 2.63 (s, 2H), 1.62-1.88 (m, 8H).
Figure imgf000661_0001
A mixture of compound 375e (500 mg, 1.24 mmol), 3-cyanophenylboronic acid (292.5 mg, 1.87 mmol), Cs2CO3 solution (2 M, 7.5mL), and Pd(PPh3)2Cl2 (62.5 mg) in 1,4-dioxane (20 mL) was stirred at 100°C under N2 for 45 minutes. The reaction mixture was concentrated in vacum. The residue was purified by silica column chromatography (petroleum ether: EA= 10:1) to give the compound 375f as a yellow solid (324 mg, 60%). 1H-NMR (CDCl3 400MHz): £8.0 (m, IH), 7.6-7.7 (m, 2H), 7.6 (m, IH), 7.52 (m, IH), 7.48 (m, IH), 7.23 (m, 4H), 7.2 (m, IH), 6.70 (m, IH), 4.43 (s, 2H), 3.63 (s, IH), 2.6 (m, 2H), 1.6-1.9 (m, 8H).
Figure imgf000661_0002
375g
To a solution of compound 375f (100 mg, 0.24 mmol) in CH2Cl2 (3 mL) was added TiCl4 (1 M in CH2Cl2, 0.48 mL, 0.48 mmol), and the mixture was stirred in microwave at 50°C for 10 minutes. After being cooled to room temperature, N, N- methanediylidenebis (1.1,1- trimethylsilanamine) (89.13 mg, 0.48 mmol) was added, the mixture was stirred at 60°C for 10 minutes, poured into ice-water, and extracted with CH2CL2 (2χlO mL). The combined organic layer was washed with brine (10 mL), dried, and concentrated to give the compound 375g as a yellow solid (94 mg, 89%).
Figure imgf000662_0001
To a solution of methylhydroxylamine HCl salt (9.25 mg, 0.111 mmol) in anhydrous MeOH (5 mL) was added NaOMe (10% in MeOH, 10 drops) and compound 375g (50 mg, 0.11 1 mmol). After being stirred for 10 minutes, the solvent was removed, and the residue was dissolved in CH2Cl2 (25 mL). After filteration, the solvent was removed, and the residue was purified by preparative HPLC to give the compound 375 as a yellow solid (2.0 mg, 5%). 1H-NMR (CD3OD 400MHz): <57.75-7.95 (m, 3H), 7.6-7.7 (m, 3H), 7.13-7.42 (m, 5H), 6.92-7.1 (m, IH), 4.45 (s, 2H), 3.63 (m, IH), 3.45 (m, 3H), 2.55-2.78 (m, 2H), 2.00 (m, IH)3 1.95(m, 2H), 1.7-2.0 (m, 5H), 1.56 (m, 2H); ESI MS: m/z 495 [M+H]+.
Example 335. Biological Activities Biological Assay Procedures
BACE Assay
Inhibitory activity of compounds was assessed by a fluorescence quench assay of BACE activity using commercially available substrate HiLyte Fluor™488-Glu-Val-Asn- Leu-Asp-Ala-Glu-Phe-Lys-(QXL™ 52O)-OH (AnaSpec, San Jose, CA) and truncated human beta-secretase (residues 1-458, His6-tagged at the C-terminus) expressed in insect cells D. melanogaster S2 using a baculovirus expression system (Mallender et ah,
Characterization of recombinant, soluble beta-secretase from an insect cell expression system., MoI Pharmacol 59:619-26, 2001). The assay was performed at room temperature in 96-well white opaque Optiplates aque Optiplates (PerkinElmer, Waltham, MA) in a total volume of 200 μl of the incubation mixture containing 50 mM sodium acetate buffer, pH 4.5, 0.4 μM FRET substrate, 2.4 nM enzyme, 5% DMSO, and 0.05% Brij-35. The tested compounds were serially diluted in DMSO and pre-incubated with the substrate. The reaction was started by addition of enzyme, and the progress of the reaction was followed by measuring fluorescence with an excitation wavelength of 480 nm and an emission wavelength of 520 nm. Ten measurements were taken every 5-10 min, and the intensity of fluorescence was regressed against time in order to derive velocities of reaction in all 96 wells. These velocities were used for calculating percent inhibition using an uninhibited control containing 5% DMSO and a fully inhibited control incubations performed in the absence of enzyme. IC50 values were calculated by fitting percent inhibition vs. inhibitor concentration into a four-parametric logistic model using XLFit software (IDBS, Guildford, UK).
RESULTS The in vitro enzyme activity studies were carried out for compounds of the invention and the data is shown below:
Compounds 1-130 and 178-458 have an IC50 for BACE (fluorescence assay) ranging from InM to less than 50 μM.
Figure imgf000663_0001
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
Figure imgf000667_0001
Figure imgf000668_0001
# represents IC50 from less than 50 μM to 10 μM; * represents IC50 from less than 10 μM to 5 μM: ** represents IC50 from less than 5 μM to 1 μM; *** represents IC50 from less than 1 μM to 500 nM; **** represents IC50 from less than 500 nM to 100 nM: ***** represents IC50 from less than 100 nM to 1 nM.
BACE cell assay
H4 neuroglioma cell line that stably expresses Amyloid Precursor Protein (APP) containing the KM-NL Swedish mutation (H4-APPsw) was generated. For the assay, cells are treated overnight in the presence of inhibitor and the culture media are subjected to ELISA analysis of soluble Amyloid Beta 1 -40 (Aβ 1 -40).
Materials
H4 neuroglioma cell line: ATCC, Cat #HTB-148
Dulbecco's Minimal Essential Medium (DMEM): Invitrogen, Cat #11995
Fetal bovine serum (FBS): Hyclone, Cat #SH30070.03) Penicillin/streptomycin: Invitrogen, Cat# 15140- 122
Zeocin: Invitrogen, Cat #R25001
0.5% Trypsin/EDTA: Invitrogen, Cat #25300
96-well plate for compound serial dilution in DMSO
96-well deep well plate 96-well Black Polymer BTM P-D-L plate: Nunc, Cat #152037
96-well White polystyrene λA area optiplate: Corning, Cat #3642
DMSO: Sigma, Cat #494429
Aβ 1-40 ELISA kit: Covance, Cat #sig38940
CellTiter GIo Viability Assay: Promega, Cat #G7571 Aβ 1 -40 AlphaLISA kit: PerkinElmer, Cat #AL202F
Microscope
Wallac Victor2 Multilabel HTS counter
PerkinElmer Fusion- Alpha FP-HT Multiplate reader SpectraMax 384 plus plate reader
Generation and maintenance of H4-APPsw cell line
H4 neuroglioma cell line was cultured in DMEM with 10% FBS and 1% penicillin/streptomycin (Culture Medium) at 370C, 5% CO2. The culture plate (150 mm) with 50% confluence of H4 cells was transfected with 15 ug plasmid pcDNA3.1/Neo(+) containing a 2310-bp insert of APPsw at Hind3/Xbal sites. 24 hrs after transfection, the cells were replaced into three new plates (150 mm) in fresh Culture Medium with 250 ug/ml Zeocin. The stably transfected cell colonies were isolated in about 2-3 weeks. The levels of APPsw expression were analyzed by immunoblotting and the production of Aβ 1-40 was detected by ELISA of culture supernatants. The selected clones are maintained in Culture Medium with 250μg/ml Zeocin and routinely split in 3-4 days to maintain 20- 80% confluence.
Assay Protocol
Final Assay Conditions (96-well plate)
H4-APPsw cells 6xl03cells/well
DMEM 200μL
DMSO 0.2% Day 1
Split cells. Split H4-APPsw cells in Culture Medium and culture overnight such that cells will be -80% confluent next morning.
Day 2
Create Compound Dilution Plate. After determining the desired final concentration of compound to be tested, create a 500X dilution plate. Add DMSO, but not inhibitor, to each well of Column 1. Use Column 2 for Control Compound (BACE inhibitor FV, EMD
Bioscience, Cat #565788) serial dilution starting at 5mM (final concentration of 2.5μM).
Add compounds of interest at 500X desired final concentration to wells A3- A 10. Add
DMSO, but not inhibitor, to each well of Columns 11 and 12. Dilute contents of Row A 1 :3 in Row B, then continue through Rows C-H.
Create Media Plate. To create a 2X solution of compound in media, add 996μL Culture
Medium to each well of a 96-well 2ml deep well plate (Media Plate) in biosafety hood.
Add 4μL 5mM control compound to Media Plate wells Al-Dl for determination of full inhibition. Add 4μL from Compound Dilution Plate to corresponding wells of Medium Plate (do not add additional DMSO to wells Al-Dl).
Add media to Cell Plate. With a multichannel pipettor, mix each well of Media Plate several times to insure homogeneity. Add lOOμL of mixture to Black polymer bottom P- D-L plates. Next, place Medium Plate and Cell Plate in the incubator.
Add cells to Cell Plate. Trypsinize and count H4-APPsw cells. Dilute cells 6x105 cells/ml in Culture Medium and remove Cell Plate from incubator. Vortex cells to homogeneity, then using a multichannel repeating pipettor, add lOOμL cell suspension to Cell Plate, adding cells from Row H to Row A. Place Cell Plate in incubator.
Change media in Cell Plate. After 5h, check Cell Plate by microscope to insure cells are attached. In culture hood, remove media from Cell Plate using multichannel repeating pipettor. Add lOOμl Culture Medium to each well. Remove Media Plate from incubator and mix with pipettor as previous. Add lOOμl from each well of Media Plate to corresponding well in Cell Plate. Place Cell Plate in incubator overnight. Day 3
Perform ELISA to determine levels of secreted Aβ 1-40. After 16h incubation, spin Cell Plate for 8 min at 1200 rpm. The primary reading of Aβ 1-40 levels is done using PerkinElmer AlphaLISA technology. Follow the manufacturer's protocol for performing AlphaLISA in a white V. area Optiwell plate using Row 12 for peptide standard (1 :2 dilutions, starting at 15ng/ml). Data are acquired using PerkinElmer Fusion- Alpha FP- HT, Alpha protocol (Count Time 0.6s, Count Time Ratio 30%:70%). To validate IC50 determinations, a second Aβ 1-40 ELISA was performed using a kit from Covance that uses different antibodies to Aβ 1 -40 and a different detection method (absorbance at 49OnM) than the PerkinElmer kit.
Perform viability assay to determine compound toxicity. Remove remaining media from Cell Plate and add 1 OOμL CellTiter GIo reagent to cells. Incubate 9 min at room temperature and read luminescence counts on Wallac Victor Multilabel HTS counter.
Data Reduction
Export data from Fusion using Columnar Report format into a separate file for each plate. Upload data into Activity Base using RIA-DOSE-RESPONSE protocol (Version 1). Data from at least eight doses were fitted to a four parameter logistical model using XLfit software to determine potency.
Results The in vitro cell activity studies were carried out for compounds of the invention and the data is shown below:
Figure imgf000671_0001
Figure imgf000672_0001
Figure imgf000673_0001
Figure imgf000674_0001
# represents IC50 from less than 50 μM to 10 μM; * represents IC50 from less than 10 μM to 5 μM; ** represents IC50 from less than 5 μM to 1 μM; *** represents IC50 from less than 1 μM to 500 nM; **** represents IC50 from less than 500 nM to 100 nM; ***** represents IC50 from less than 100 nM to 1 nM.

Claims

CLAIMSWhat is claimed is:
1. A compound represented by the following Structrual Formula:
Figure imgf000675_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri is -H, (C,-C6)alkyl, aryl(Ci-C6)alkyl, or heteroaryl(Ci-C6)alkyl; each R2 is independently selected from a) -H, -F, -Cl, -Br, and -CN, and b) (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyL aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5,
-NR11SC=O)1R55 -CC=O)OR5, -CC=O)NR12R13, -NR11CC=O)R5, -CC=S)NR12R13, -CC=O)R5, (C,-C6)alkyl, (C3-C8)cycloalkyl, CC2-C6)alkenyl, halo(CrC6)alkyl, (Ci- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(C]-C6)alkyl, (Ci-C3)alkoxy, halo(C]-C3)alkoxy ,(Ci- C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl; each R3 and R4 are idependently -H, -halogen, -CN, -NO2, -OR5, -NR6R7, -S(O)1R5, -C(=O)OR5, -C(=O)NR12R13, -C(O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cg)cycloalkyl, aryl, or heteroaryl, wherein each (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cg)cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F5 -Cl5 -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRnS(O)1R5, -C(O)OR5, -C(O)NRi2R13, -NRnC(O)R5, -C(=S)NRi2R,3, -C(O)R5, (C,- C6)alkyl, (C2-C6)alkenyl, halo(Ci-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci -C6)alkyl, cyano(C i -C6)alkyl, (C i -C3)alkylcarbonylamino(C i -C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy: (CrC6)alkoxy(Ci-C3)alkyL an aryl group, and a heteroaryl group; X is -O-, -S-, -SO-, -SO2-, -CH2O- or -OCH2-; each Y is independently -C(R8R9)-;
W is -N(Ri4)-, -S-, -O-;
Z is -C(=O>, -C(=S)-S -CC=NR15)-, -O-, -CC=O)C(R16R17)-,
Figure imgf000676_0001
-CC=NR15)C(R16R17)-, -N(R18)-, -CCR16R17V or -0-(CR16R17)-;
R5 is -H, (Cι-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, CC2-C6)alkynyl, (C1-C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C7) 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 i -C6)alkyl, halo(C , -C6)alkyl, and (C i-
C3)alkoxy(C!-C6)alkyl; each R6 and R7 are independently selected from -H, (C]-C6)alkyl, hydroxy(C]-C6)alkyl, halo(CrC6)alkyl, (C3-C8) cycloalkyl, and (C3- C8)cycloalkyl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C1-
C6)alkyl, halo(CrC6)alkyl and (Ci-C3)alkoxy(C]-C6)alkyl; each R8 and R9 are independently selected from -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C14) cycloalkyl, (C3-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, -OR5, -NR6R7, -S(O)1R5, -NRπS(=O)iR5, -C(=O)OR5; -C(=O)NR12R13, -NR11C(O)R5, -C(=S)NR12R13, -C(K))R5, (Q-C^alkyl, (C2- C6)alkenyl, halo(Ci-C6)alkyl, (C)-C3)alkylsulfonylaminoalkyl, hydroxy(Ci- C6)alkyL cyano(C!-C6)alkyl, (C]-C3)alkylcarbonylamino(C1-C6)alkyl, (C1- C3)alkoxy, halo(CrC3)alkoxy, (Ci-C6)alkoxy(C1-C3)alkyl, aryl, heteroaryl, (C3-
C8)cycloalkyl and (C3-C7)cycloheteroalkyl; or
R8 and R9, together with the carbon to which they are attached, form ring A, which is a 3-14 membered monocyclic. 9-14 membered bicyclic 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,
-OR5, -NR6R7, -S(O)jR55 -NR11S(K))JR5, -C(K))OR5, -C(K))NR12R13, -NR1 1C(K))R5, -C(=S)NR12R13, -C(O)R5, (CrC6)alkyl, (C2-C6)alkenyl, ImIo(C1- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci- C6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (CrC3)alkoxy, halo(Ci- C3)alkoxy, (Ci-C6)alkoxy(C]-C3)alkyl, aryl and heteroaryl;
R11 is -H, (Ci-C6)alkyl or halo(C,-C6)alkyl; each Rj2 and R13 are independently -H, (Ci-C6)alkyl, (CrC3)alkoxy(Ci-
C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(CrC6)alkyl, amino(Ci-C6)alkyl, (C r C3)alkylamino(Ci-C6)alkyl, or di(C]-C3)alkylamino(Ci-C6)alkyl; or R)2 and Rj3, 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, -CN5 -OR5, -NR6R7, -S(O)jR5,
-NR11SC=O)1R5, -C(=O)OR5, -CC=O)NR12R13, -NR11CC=O)R5, -CC=S)NR12R13, -CC=O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, halo(C,-C6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxyCCi-C6)alkyl, cyano(C1-C6)alkyl, (C]- C3)alkylcarbonylamino(C)-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy and (Ci- C6)alkoxy(C]-C3)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 nitrogens is substituted with -H. (Ci-C3)alkyl or halo(Ci-C3)alkyl, and when the additional heteroatom is sulfur, the sulfurs is optionally mono or di -oxygenated: R14 is -H, (C i -C6)alkyl, halo(C i -C6)alkyl, (C3-C8)cycloalkyl; cycloheteroalkyl(C i -C3)alkyl, (C3-C8)cycloalkyl(C i -C3)alkyl, aryl(C i -C6)alkyl, heteroaryl(Ci-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN. (C1- C6)alkyl, halo(CrC6)alkyl and (Ci-C3)alkoxy; Ri5 is -H or (Ci-C6)alkyl;
R)6 and Rj7 are each independently -H or (Ci-C3)alkyl;
Ri8 is -H or (Ci-C3)alkyl: i is 0, 1 or 2; p is 1 or 2; m is 1 or 2; and n is 1 or 2.
2. The compound of Claim 1, wherein the compound is represented by the following Structural Formula:
Figure imgf000678_0001
or a pharmaceutically acceptable salt thereof.
The compound of Claim 2, wherein ring A is a 5-7 membered monocyclic ring or a 9-14 membered bicyclic ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR,,S(=O)iR5, -C(=O)OR5, -C(K))NR12R13, -NR11C(O)R5, -C(=S)NR12RI3, -CC=O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, halo(Ci-C6)alkyl, (Ci- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy and (Ci- C6)alkoxy(Ci-C3)alkyl, wherein ring A contains O to 3 heteroatoms, which are selected from O, N, S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with -H, (Ci-C6)alkyl halo(Ci-C6)alkyl or (CrCjJalkylcarbonyl. and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated.
The compound of Claim 3, wherein the compound is represented by any one of the following structural formulas:
Figure imgf000678_0002
Figure imgf000678_0003
(IVa) (Va)
Figure imgf000679_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 4, wherein X is -O-.
6. The compound of Claim 5. wherein R2 is -H, -Br, -F, (Ci-C6)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy. each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -CL -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRπS(=O)iR5, -C(O)OR5, -C(O)NRi2Ri3, -NR11C(O)R5, -C(=S)NR12R13, -C(O)R5, (Q-QOalkyl, (C3-C8)cycloalkyL (C2- C6)alkenyl, halo(Ci-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci- C6)alkyl, cyano(Ci-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyL (C1- C3)alkoxy, halo(Ci-C3)alkoxy ,(C1-C6)alkoxy(Ci-C3)alkyl and a heteroaryl group.
The compound of Claim 6, wherein the compound is represented by any one of the following structural formulas:
Figure imgf000680_0001
(XIVb),
Figure imgf000681_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri0 is selected from a group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR, ,S(=O)iR5, -C(=O)OR5, -C(O)NR12R13, -NR11C(O)R5, -C(=S)NR12Ri3, -C(O)R5: (Ci-C3)alkyl, halo(Ci-C3)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(C!-C6)alkyl, (C]- C3)alkylcarbonylamino(Ci-C6)alkyl, and (Ci-C6)alkoxy(Cj-C3)alkyl; and s is O, 1. 2, or 3.
The compound of Claim 7. wherein 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-l H-indene. tetrahydronaphthalene, decahydronaphthalene, 5.6,7,8-tetrahydroquinoline. 5,6.
7.
8-tetrahydroisoquinoline. 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci- C6)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, 5-6 membered heteroaryl. phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy or halo(CrC3)alkoxyl.
9. The compound of Claim 8, wherein R]4 is methyl.
10. The compound of Claim 9, wherein Rj is -H; and R3 and R4 are -H.
11. The compound of Claim 6, wherein R2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl, thiozolyl or cyclohexyl, each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -Cl5 -Br, -CN, -OR5, -SR5, -NR6R7, -S(O)1R5, -NRπC(=0)R5, -CC=S)NR12R13, -C(K))R5, (d-C^alkyl, (C3-C8)cycloalkyl, (C2- C6)alkenyl, halo(Ci-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-
C6)alkyl, cyano(CrC6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (C1- C3)alkoxy, halo(Ci-C3)alkoxy ,(Ci-C6)alkoxy(C1-C3)alkyl and a heteroaryl group.
12 The compound of Claim 11, wherein 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-lH-indene, tetrahydronaphthalene, decahydronaphthalene, 5.6.7.8-tetrahydroquinoline, 5.6,7.8-tetrahydroisoquinoline, 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(C]-C6)alkyl, hydroxy(d- C6)alkyl, (Ci-C3)alkoxy, halo(Cj-C3)alkoxy 5-6 membered heteroaryl, phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(CrC3)alkoxyl.
13. The compound of Claim 12. wherein Ri4 is methyl.
14. The compound of Claim 13. wherein R| is -H: and R3 and R4 are -H.
15. The compound of Claim 1, wherein Rg and R9 are each independently -H, (Ci-
C6)alkyl, hydroxy(CrC6)alkyl, halo(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br5 -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C,- C6)alkyl, (C]-C3)alkoxy, halo(Ci-C3)alkoxy and (C3-C8)cycloheteroalkyl.
16. The compound of Claim 15, wherein the compound is represented by any one of the following Structural Formulas:
Figure imgf000683_0001
or a pharmaceutically acceptable salt thereof.
17. The compound of Claim 16, wherein X is -O-.
18. The compound of Claim 17, wherein R2 is -H, -Br, -F, (C]-C6)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consiting of F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR1 , S(O)1R5, -C(K))OR5, -C(=O)NR12R13, -NR1 1C(O)R5, -C(=S)NRi2R13, -C(O)R5, (d-C^alkyl, (C3-C8)cycloalkyl, (C2-
C6)alkenyl, halo(Cj-C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci- C6)alkyl, cyano(Ci-C6)alkyl, (CrC3)alkylcarbonylamino(Ci-C6)alkyl, (C i- C3)alkoxy, halo(Ci-C3)alkoxy ,(Ci-C6)alkoxy(Ci-C3)alkyl, aryl and heteroaryl.
19. The compound of Claim 18. R2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl, cyclohexyl, thiazolyl, phenoxy, or benzyloxy, each optionally substituted with 1 to
3 substituents independently selected from the group consiting of -F, -Cl, -Br, -CN, -OR5, -SR5, -NR6R7, -S(O)1R5, -NR11S(O)1R5, -C(O)OR5, -C(O)NR12R13, -NRnC(O)R5, -C(=S)NRi2R13, -C(O)R5, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C2- C6)alkenyl, halo(Ci-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(Cr C6)alkyl, cyano(C ] -C6)alkyl, (C i -C3)alkylcarbonylamino(C i -C6)alkyl, (C i -
C3)alkoxy,
Figure imgf000684_0001
aryl and heteroaryl.
20. The compound Claim 16, wherein the compound is represented by any one of the following Structural Formulas:
Figure imgf000684_0002
(IXb)
Figure imgf000685_0001
(Xb)
Figure imgf000685_0002
(XIIb)
Figure imgf000685_0003
Figure imgf000686_0001
(IXc)
Figure imgf000686_0002
Figure imgf000687_0001
(IXd)
Figure imgf000687_0002
(IXe)
Figure imgf000688_0001
(Xe) , or
Figure imgf000688_0002
or a pharmaceutically acceptable salt thereof, wherein:
Rio is selected from a group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NR11SC=O)JR55 -CC=O)OR5, -CC=O)NR12R13, -NRnCC=O)R5,
Figure imgf000688_0003
-CC=O)R5; (CrC3)alkyl, halo(C,-C3)alkyl, CC1- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(Ci-C6)alkyl, (Cp C3)alkylcarbonylaminoCC]-C6)alkyl, and (Ci-C6)alkoxy(C]-C3)alkyl; and s is O. 1. 2, or 3.
21. The compound of Claim 20, wherein R8 and R9 are both -H, CCi -C3)alkyl or hydroxy(C]-C3)alkyl.
22. The compound of Claim 20, wherein R8 and R9 are both -H, methyl or hydroxymethyl.
23. The compound of Claim 20, wherein one Of R8 and R9 is -H, the other is phenyl optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, haloCCrC6)alkyl, hydroxyCCi- C6)alkyl, CCi-C3)alkoxy, halo(CrC3)alkoxy, (Ci-C3)alkylcarbonyl and (Ci- C3)alkoxycarbonyl .
24. The compound of Claim 23, wherein the phenyl is unsubstituted.
25. The compound of Claim 23, wherein Rj is -H; R3 and R4 are -H, and Rj4 is methyl.
26. The compound of Claim 20, wherein one OfR8 and R9 is -H, 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-lH-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8- tetraliydroquinoline, 5,6,7.8-tetrahydroisoquinoline, 2-oxabicyclo[2.2.2]octane. each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, ImIo(C1 -C6)alkyl, hydroxy(d- C6)alkyl, (C1-C3)alkoxy, halo(C!-C3)alkoxy 5-6 membered heteroaryl, phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C1-C6)alkyl, ImIo(C1 -C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy or halo(Ci-C3)alkoxyl.
27. The compound of Claim 26, wherein R] is -H; R3 and R4 are -H, and Rj4 is methyl.
28. A compound represented by the following Structrual Formula:
Figure imgf000689_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri is Ri is -H, (d-C6)alkyl, aryl(CrC6)alkyl, or heteroaryl(CrC6)alkyl; R2 is a) -H, -F, -Cl, -Br, or -CN or b) (CrC6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents selected from the group consisting of -F, -Cl, -Br5 -CN, -OR5, -NR6R7, -S(O)1R5, -NR, 1S(O)1R5, -C(O)OR5, -C(O)NR12Rn, -NRnC(O)R5, -C(=S)NR12Ri3, -C(O)R5, (C,-C6)alkyl, (C2- C6)alkenyl, halo(CrC6)alkyL (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci- C6)alkyl, cyano(CrC6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (C1- C3)alkoxy, halo(d-C3)alkoxy and (C1-C6)alkoxy(d-C3)alkyl;
R3 and R4 are each independently -H5 -F, -Br, -Cl or (Ci-C6)alkyl.;
X is -O-, -S-, -SO-, -SO2-, -CH2O- or -OCH2-; Y is -C(R8R9)-;
W is -N(R14)-, -S-, -O-;
Z is -C(=0)-, -C(=S)-, -CC=NR15)-, -0-, -C(=O)C(R16R17)-, -CC=S)C(R16R17)-, -CC=NR15)C(R16R17)-, -N(R18)-, or -(CR16R17)m-;
R5 is -H, (C]-C6)alkyl, halo(CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C]-C3)alkoxy(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl,
(C3-C7) 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, (CrC6)alkyl, halo(Ci-C6)alkyl, and (C1- C3)alkoxy(Ci -C6)alkyl; R6 and R7 are each independently -H, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, (C3-C8) cycloalkyl, (C3-C8)cycloalkyl(CrC6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CL -Br, -CN, (d-C6)alkyl, halo(d-C6)alkyl and (C1- C3)alkoxy(C i -C6)alkyl; R8 and R9 are each independently -H, (C]-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CC3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-QOalkyl, halo(d-C6)alkyl, hydroxy(Ci-C6)alkyl, (d-C3)alkoxy and halo(Cr C3)alkoxy; or
R8 and R9, 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, -OR5, -NR6R7, -SCO)jR5, -NR11SC=O)1R5, -CC=O)OR5, -CC=O)NR12R13, -NR11CC=O)R5, -CC=S)NR12Rj3, -CC=O)R5, (d-C6)alkyl, (C2-C6)alkenyl, halo(d-C6)alkyl, (C1-
C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(d-C6)alkyl, (C1- C3)alkylcarbonylamino(C1-C6)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy and (C1- C6)alkoxy(C]-C3)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, (CrC6)alkyl, halo(CrC6)alkyl or (C1- C3)alkylcarbonyl, and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated;
Rn is -H, (Q-QOalkyl or halo(CrC6)alkyl;
R12 and R13 are each independently -H, (Ci-C6)alkyl, (C1-C3)alkoxy(C1- C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(d-C6)alkyl, aminoCCrC^alkyl, (Cr C3)alkylamino(Ci-C6)alkyl, or di(C1-C3)alkylamino(C1-C6)alkyl; or Rj2 and R13, 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, -OR5, -NR6R7, -S(O)1R5, -NR1, S(=O)iR5, -C(O)OR5, -C(=O)NR12R13, -NR11C(O)R5, -C(=S)NR12R13, -C(O)R5, (CrC6)alkyl, (C2-C6)alkenyl, halo(CrC6)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(C1-C6)alkyl, (C1-
C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy and (Ci- C6)alkoxy(Ci-C3)alkyl, wherein ring A contains O to 3 heteroatoms, which are independently selected from O, N and S, wherein when the heteroatom is nitrogen, the nitrogens is substituted with -H, (Cj-C3)alkyl or halo(C1-C3)alkyl. and when the heteroatom is sulfur, the sulfurs is optionally mono or di-oxygenated;
R14 is -H, (d-C^alkyl, halo(CrC6)alkyl, (C3-C8)cycloalkyl, cycloheteroalkyl(C1-C3)alkyl, (C3-C8)cycloalkyl(C1-C3)alkyL aryl(C1-C6)alkyl, heteroaryl(Cj-C6)alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Cr C6)alkyl, halo(d-C6)alkyl and (Ci-C3)alkoxy;
R15 is -H or (Ci-C6)alkyl:
Ri6 and R17 are each independently -H or (C1-C3)alkyl;
R18 is -H or (Ci-C3)alkyl; i is O, 1 or 2; p is 1 or 2: m is 1 or 2; and n is 1 or 2.
29. The compound of Claim 28, wherein the compound is represented by the following Structural Formula:
Figure imgf000692_0001
or a pharmaceutically acceptable salt thereof.
30. The compound of Claim 29, wherein ring A is a 5-7 membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br5 -CN, -OR5, -NR6R7, -S(O)iR5, -NRπS(=O)iR5, -C(=O)OR5, -CC=O)NR12R13, -NRnCC=O)R5, -CC=S)NR12R13, -C(=0)R5, (C1- C6)alkyl, (C2-C6)alkenyl, hak>CCi-C6)alkyl, CCi-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci-C3)alkylcarbonylamino(C1-C6)alkyl,
(Ci-C3)alkoxy, halo(C]-C3)alkoxy and (C]-C6)alkoxyCCi-C3)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]-C6)alkyl halo(Ci- C6)alkyl or (Ci-C3)alkylcarbonyl. and when the heteroatom is sulfur, the sulfur is optionally mono- or di-oxygenated.
31. The compound of Claim 30. wherein the compound is represented by:
Figure imgf000692_0002
Figure imgf000693_0001
or a phaπnaceutically acceptable salt thereof.
32. The compound of Claim 315 wherein X is -O-.
The compound of Claim 32, wherein R2 is -H, -Br, -F, (Ci-C6)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy. each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)iR5, -NR1 iS(O)iR5, -C(O)OR5, -Q=O)NR12R13, -NRnC(O)R5, -C(=S)NR12R13, -C(O)R5, (d-C6)alkyl, (C2-C6)alkenyl, ImIo(C1- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl, cyano(Cr C6)alkyl, (Ci-C3)alkylcarbonylamino(CrC6)alkyl, (C1-C3)alkoxy, halo(Cr C3)alkoxy and (C)-C6)alkoxy(C1-C3)alkyl.
34. The compound of Claim 33, wherein the compound is represented by a structural formula:
Figure imgf000693_0002
Figure imgf000694_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rio is selected from a group consisting of -F. -Cl. -Br, -CN, -OR5, -NRsR7, -S(O)iR5, -NRnSC=O)1R5, -C(=O)OR5, -CC=O)NR12Rn5 -NR11CC=O)R5,
Figure imgf000694_0002
-C(K))R5; (C,-C3)alkyL halo(CrC3)alkyl, (C1- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(C]-C6)alkyl, (C1- C3)alkylcarbonylamino(Ci-C6)alkyl, and (C1-C6)alkoxy(C1-C3)alkyl; and s is 0, 1, 2, or 3.
35. The compound of Claim 34. wherein 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 (Ci-C6JaIkVl. halo(Ci-C6)alkyl and (C]-C3)alkylcarbonyl.
36. The compound of Claim 35, wherein Rj4 is methyl.
37. The compound of Claim 36, wherein R] is -H; and R3 and R4 are -H.
38. The compound of Claim 33, wherein R2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl or cyclohexyl, each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRnS(=O)iR5, -C(O)OR5, -C(O)NRi2Ri3, -NR11C(O)R5, -C(=S)NR12R13, -C(O)R5, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C,-C6)alkyl, (Ci- C3)alkylsulfonylaminoalkyl, hydroxy(C]-C6)alkyl, cyano(Ci-C6)alkyl, (C1-
C3)alkylcarbonylamino(C]-C6)alkyl, (Cj-C3)alkoxy, halo(Ci-C3)alkoxy and (C1- C6)alkoxy(C1-C3)alkyl.
39 The compound of Claim 38, wherein 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]-C6)alkyl, halo(Ci-C6)alkyl and (C1-C3)alkylcarbon}d.
40. The compound of Claim 39, wherein R]4 is methyl.
41. The compound of Claim 40, wherein R] is -H: and R3 and R4 are -H.
42. The compound of Claim 28, wherein R8 and R9 are each independently -H, (Ci- C6)alkyl. hydroxy(d-C6)alkyl, halo(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C8) cycloalkyl, (C3-C7)cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (CrC6)alkyl, halo(CrC6)alkyl, hydroxy(Ci- C6)alkyl, (d-C3)alkoxy and halo(C]-C3)alkoxy.
43. The compound of Claim 42, wherein the compound is represented by the following Structural Formula:
Figure imgf000696_0001
(IXa) (Xa) (XIa)
Figure imgf000696_0002
or a pharmaceutically acceptable salt thereof.
44. The compound of Claim 43, wherein X is -O-.
45. The compound of Claim 44, wherein R2 is -H, -Br, -F, (Ci-C6)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)1R5, -NRnS(=O)iR5, -C(=O)OR5, -C(O)NR12R13, -NRnQ=O)R5, -C(=S)NR12Ri3, -C(O)R5, (C,-C6)alkyl, (C2-C6)alkenyl, halo(d- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Cr C6)alkyl, (Ci-C3)alkylcarbonylamino(Ci-C6)alkyl, (d-C3)alkoxy, halo(Ci- C3)alkoxy and (Ci-C6)alkoxy(CrC3)alkyl.
46. The compound of Claim 45, R2 is pyridinyl, thiophenyl, pyrrolyl, pyrimidinyl, cyclohexyl, phenoxy, or benzyloxy, each optionally substituted with 1 to 3 substituents independently selected from the group consiting of -F, -Cl, -Br, -CN, -OR5, -NR6R7, -S(O)jR5, -NRHS(=O)iR5, -C(=O)OR5, -C(=O)NR12R]3, -NR11CC=O)R5, -CC=S)NR12R13, -C(=O)R5, (d-C6)alkyl, (C2-C6)alkenyl, halo(d- C6)alkyl, (Ci-C3)alkylsulfonylaminoalkyl, hydroxyCCi-C6)alkyl, cyano(Ci- C6)alkyl, (Cj-C3)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C3)alkoxy, halo(C,- C3)alkoxy and (CrC6)alkoxy(Ci-C3)alkyl.
47. The compound Claim 43, wherein the compound is represented by the following Structural Formulas:
Figure imgf000697_0001
(IXb)
Figure imgf000697_0002
(Xb)
Figure imgf000697_0003
(XIb)
Figure imgf000698_0001
(XIIb)
Figure imgf000698_0002
(XIIIb)
Figure imgf000698_0003
(IXc)
Figure imgf000698_0004
(Xc)
Figure imgf000699_0001
(IXd)
Figure imgf000699_0002
(Xd)
Figure imgf000699_0003
(IXe)
Figure imgf000699_0004
(Xe) or a pharmaceutically acceptable salt thereof, wherein:
Ri0 is selected from a group consisting of -F, -Cl, -Br, -CN, -OR5, -NR6R?= -S(O)JR55 -NR11SC=O)JR5, -C(=O)OR5, -C(=O)NR12R13j -NRnC(O)R5,
Figure imgf000700_0001
-C(=O)R5; (CrC3)alkyl, halo(CrC3)alkyl, (C,- C3)alkylsulfonylaminoalkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci- C3)alkylcarbonylamino(C]-C6)alkyl, and (Ci-C6)alkoxy(C]-C3)alkyl; and s is O, 1, 2, or 3.
48. The compound of Claim 47. wherein R8 and R9 are both -H, (Ci-C3)alkyl or hydroxy(CrC3)alkyl.
49. The compound of Claim 47, wherein R8 and R9 are both -H, methyl or hydroxymethyl.
50. The compound of Claim 47, wherein one OfR8 and R9 is -H, the other is phenyl optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C,- C6)alkyl, (CrC3)alkoxy and halo(Ci-C3)alkoxy.
51. The compound of Claim 50, wherein the phenyl is unsubstituted.
52. The compound of Claim 50, wherein Ri is -H; R3 and R4 are -H, and Ri4 is methyl.
53. The compound of Claim 47, wherein one of R8 and R9 is -H, the other is cyclopentyl, cyclohexyl, tetrahydrofuran, tetrahydropyran, pyridinyl or thiophenyl, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C3)alkoxy and halo(Ci-C3)alkoxy.
54. The compound of Claim 53. wherein Rj is -H; R3 and R4 are -H. and Rj4 is methyl.
55. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of any one of Claims 1-54 or a pharmaceutically acceptable salt thereof.
56. A method of inhibiting BACE activity in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of Claims 1-54 or a pharmaceutically acceptable salt thereof.
57. A method of treating a BACE mediated disorder in a subject comprising administering to the subject an effective amount of a compound of any one of Claims 1-54 or a pharmaceutically acceptable salt thereof.
58. The method of Claim 57, wherein the disorder is 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.
59. The method of Claim 57, wherein the disorder is Alzheimer's disease.
60. The method of Claim 57, wherein the disorder is glaucoma.
61. 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 of any one of Claims 1 -54 or a pharmaceutically acceptable salt thereof.
62. The method of Claim 61 , wherein the disorder is Alzheimer' s disease.
63. The method of Claim 61 , wherein the disorder is glaucoma.
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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105179A3 (en) * 2009-03-13 2010-11-11 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011072064A1 (en) * 2009-12-08 2011-06-16 Array Biopharma Inc. S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors
WO2011115928A1 (en) * 2010-03-15 2011-09-22 Amgen Inc. Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as beta - secretase modulators and their medical use
WO2011123674A1 (en) * 2010-03-31 2011-10-06 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2011130741A1 (en) * 2010-04-16 2011-10-20 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2012071279A1 (en) 2010-11-23 2012-05-31 Amgen Inc. Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
WO2012087237A1 (en) * 2010-12-22 2012-06-28 Astrazeneca Ab Compounds and their use as bace inhibitors
WO2012093148A1 (en) 2011-01-06 2012-07-12 Eisai R&D Management Co., Ltd Fused aminodihydrothiazine derivatives
WO2012109165A1 (en) 2011-02-07 2012-08-16 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use
WO2012112462A1 (en) 2011-02-15 2012-08-23 Amgen Inc. Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
WO2012163790A1 (en) 2011-05-27 2012-12-06 F. Hoffmann-La Roche Ag Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors
WO2013054108A1 (en) * 2011-10-10 2013-04-18 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2013134085A1 (en) 2012-03-05 2013-09-12 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
WO2013190299A1 (en) * 2012-06-20 2013-12-27 Astrazeneca Ab Cyclohexane-1,2'-indene-1',2"-imidazol compounds and their use as bace inhibitors
WO2014035860A1 (en) 2012-08-27 2014-03-06 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
WO2014127816A1 (en) 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydropteridinones ii
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8940734B2 (en) 2011-01-21 2015-01-27 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US8975415B2 (en) 2012-05-30 2015-03-10 Comentis, Inc. Chromane compounds
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9079832B2 (en) 2012-11-21 2015-07-14 Boehringer Ingelheim International Gmbh Process for making N-sulfinyl α-amino amides
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9175013B2 (en) 2011-01-21 2015-11-03 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9296759B2 (en) 2011-09-21 2016-03-29 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
JP2016515109A (en) * 2013-03-12 2016-05-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel process for producing 3-oxotetrahydrofuran
US9376409B2 (en) 2012-05-09 2016-06-28 Boehringer Ingelheim International Gmbh Methods for making oxetan-3-ylmethanamines
US9434693B2 (en) 2012-08-16 2016-09-06 Janssen Pharmaceutica Nv Substituted pyrazoles as N-type calcium channel blockers
US9580396B2 (en) 2012-12-21 2017-02-28 Merck Sharp & Dohme Corp. C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
US9725469B2 (en) 2012-11-15 2017-08-08 Amgen, Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US9974775B2 (en) 2013-08-16 2018-05-22 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
WO2018230555A1 (en) * 2017-06-14 2018-12-20 日本曹達株式会社 Oxadiazoline compound and pest control agent
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
CN109776415A (en) * 2019-03-07 2019-05-21 福建南方济民医药研发中心有限公司 A kind of preparation method of Roxadustat intermediate
CN109942531A (en) * 2019-04-24 2019-06-28 上海卡洛化学有限公司 A kind of preparation method of 4- amino tetrahydro -2- pyrans -4- carboxylic acid
US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt
WO2020179859A1 (en) 2019-03-06 2020-09-10 第一三共株式会社 Pyrrolopyrazole derivative
CN115322208A (en) * 2021-05-10 2022-11-11 中国药科大学 Novel 2-aminothiazole derivatives, and preparation method and medical application thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112014023384A8 (en) * 2012-03-20 2018-01-16 R Artis Dean spirocyclic bace inhibitors of dihydro-thiazine and dihydro-oxazine, and compositions and uses thereof.
CN112094234B (en) * 2020-09-21 2023-07-07 山东理工大学 Synthesis method of 6-phenyl-2, 3,4, 7-tetrahydro-1H-3-azepine derivative
CN112142709B (en) * 2020-09-21 2022-11-15 山东理工大学 Synthetic method of 6-aryl-2,3,4,5-tetrahydrooxaheptin-3-alcohol derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030412A2 (en) 2006-09-07 2008-03-13 Merck & Co., Inc. Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2113818A1 (en) * 1991-08-28 1993-03-18 Robert C. Gadwood Spirocyclic benzopyran imidazolines
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
JP5020638B2 (en) 2003-12-15 2012-09-05 シェーリング コーポレイション Heterocyclic aspartyl protease inhibitors
US7592348B2 (en) 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7700603B2 (en) 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
NZ552031A (en) 2004-06-16 2009-06-26 Wyeth Corp Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase
JP2008503460A (en) 2004-06-16 2008-02-07 ワイス Diphenylimidazopyrimidine and imidazolamine as inhibitors of β-secretase
US7759353B2 (en) 2005-06-14 2010-07-20 Schering Corporation Substituted spiro iminopyrimidinones as aspartyl protease inhibitors, compositions, and methods of treatment
ATE482214T1 (en) 2005-06-14 2010-10-15 Schering Corp ASPARTYL PROTEASE INHIBITORS
TW200738683A (en) 2005-06-30 2007-10-16 Wyeth Corp Amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
WO2007005404A1 (en) 2005-06-30 2007-01-11 Wyeth AMINO-5-(6-MEMBERED)HETEROARYLIMIDAZOLONE COMPOUNDS AND THE USE THEREOF FOR ß-SECRETASE MODULATION
TW200730523A (en) 2005-07-29 2007-08-16 Wyeth Corp Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation
BRPI0616757A2 (en) 2005-09-26 2011-06-28 Wyeth Corp compound of formula i; process for treating a disease or disorder associated with excessive bace activity; process for modulating bace activity; process for treating alzheimer's disease; and pharmaceutical composition
ES2537898T3 (en) 2005-10-25 2015-06-15 Shionogi & Co., Ltd. Aminothiazolidine and aminotetrahydrotiazepine derivatives as BACE 1 inhibitors
DE102005057688A1 (en) 2005-12-01 2007-06-14 Endress + Hauser Flowtec Ag Device for determining and / or monitoring the mass flow rate of a gaseous medium
CA2634037A1 (en) 2005-12-19 2007-07-12 Wyeth 2-amino-5-piperidinylimidazolone compounds and use thereof for .beta.-secretase modulation
EP1974278A4 (en) 2005-12-20 2012-01-04 Fieldbus Foundation System and method for implementing safety instrumented systems
WO2007100536A1 (en) 2006-02-24 2007-09-07 Wyeth DIHYDROSPIRO[DIBENZO[A,D][7]ANNULENE-5,4'-IMIDAZOL] COMPOUNDS FOR THE INHIBITION OF β-SECRETASE
US8168641B2 (en) 2006-06-12 2012-05-01 Schering Corporation Aspartyl protease inhibitors
WO2008076044A1 (en) 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino-5, 5-diaryl-imidazol-4-ones
TW200831091A (en) 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
TW200831484A (en) 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
PE20090160A1 (en) 2007-03-20 2009-02-11 Wyeth Corp AMINO-5- [4- (DIFLUOROMETOXI) SUBSTITUTE PHENYL] -5-PHENYLIMIDAZOLONE COMPOUNDS AS ß-SECRETASE INHIBITORS
AR065814A1 (en) 2007-03-23 2009-07-01 Wyeth Corp DERIVATIVES OF 5-PHENYLIMIDAZOLONE, INHIBITORS OF BETA-SECRETASA, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USES TO PREVENT AND / OR TREAT ASSOCIATED DISORDERS AT LEVELS BETA-AMYLOOES ELEVATED.
JP5383484B2 (en) 2007-04-24 2014-01-08 塩野義製薬株式会社 Aminodihydrothiazine derivatives substituted with cyclic groups
JP5383483B2 (en) 2007-04-24 2014-01-08 塩野義製薬株式会社 Pharmaceutical composition for the treatment of Alzheimer's disease
TW200902503A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
CN101952260B (en) 2008-02-18 2013-02-13 弗·哈夫曼-拉罗切有限公司 4, 5-dihydro-oxazol-2-yl amine derivatives
TWI431004B (en) 2008-05-02 2014-03-21 Lilly Co Eli Bace inhibitors
US8501733B2 (en) 2008-07-28 2013-08-06 Eisai R&D Management Co., Ltd. Spiroaminodihydrothiazine derivatives
WO2010013302A1 (en) 2008-07-28 2010-02-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Spiroaminodihydrothiazine derivative
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
SG173466A1 (en) 2009-03-13 2011-09-29 Vitae Pharmaceuticals Inc Inhibitors of beta-secretase
EP2539322B1 (en) 2010-02-24 2014-01-01 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030412A2 (en) 2006-09-07 2008-03-13 Merck & Co., Inc. Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease

Cited By (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9212153B2 (en) 2009-03-13 2015-12-15 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
JP2012520324A (en) * 2009-03-13 2012-09-06 ヴァイティー ファーマシューティカルズ，インコーポレイテッド β-secretase inhibitor
AP2866A (en) * 2009-03-13 2014-03-31 Vitae Pharmaceuticals Inc Inhibitors of beta-secretase
EA020875B1 (en) * 2009-03-13 2015-02-27 Вайтаи Фармасьютиклз, Инк. Inhibitors of beta-secretase
US8633212B2 (en) 2009-03-13 2014-01-21 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US10336717B2 (en) 2009-03-13 2019-07-02 Vitae Pharmaceuticals, Llc Inhibitors of beta-secretase
KR101908255B1 (en) * 2009-03-13 2018-10-15 비타이 파마슈티컬즈, 인코포레이티드 Inhibitors of beta-secretase
EP2801570A1 (en) * 2009-03-13 2014-11-12 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2010105179A3 (en) * 2009-03-13 2010-11-11 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9428475B2 (en) 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
WO2011072064A1 (en) * 2009-12-08 2011-06-16 Array Biopharma Inc. S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors
US9045500B2 (en) 2010-02-24 2015-06-02 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
AU2011227501B9 (en) * 2010-03-15 2013-08-22 Amgen Inc. Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as Beta - secretase modulators and their medical use
AU2011227501B2 (en) * 2010-03-15 2013-08-15 Amgen Inc. Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as Beta - secretase modulators and their medical use
US8497264B2 (en) 2010-03-15 2013-07-30 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2011115928A1 (en) * 2010-03-15 2011-09-22 Amgen Inc. Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as beta - secretase modulators and their medical use
JP2013522304A (en) * 2010-03-15 2013-06-13 アムジエン・インコーポレーテツド Amino-dihydrooxazine and amino-dihydrothiazine spiro compounds as β-secretase modulators and their medical use
WO2011123674A1 (en) * 2010-03-31 2011-10-06 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2011130741A1 (en) * 2010-04-16 2011-10-20 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2012071279A1 (en) 2010-11-23 2012-05-31 Amgen Inc. Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
US8957083B2 (en) 2010-11-23 2015-02-17 Amgen Inc. Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
EA025746B1 (en) * 2010-12-22 2017-01-30 Астразенека Аб Compounds and their use as beta site app cleaving enzyme (bace) inhibitors
CN106008355A (en) * 2010-12-22 2016-10-12 阿斯利康(瑞典)有限公司 Compounds and their use as BACE inhibitors
JP2017008072A (en) * 2010-12-22 2017-01-12 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ Compounds and their use as BACE inhibitors
WO2012087237A1 (en) * 2010-12-22 2012-06-28 Astrazeneca Ab Compounds and their use as bace inhibitors
US9918985B2 (en) 2010-12-22 2018-03-20 Astrazeneca Ab Compounds and their use as BACE inhibitors
CN106008355B (en) * 2010-12-22 2019-05-03 阿斯利康(瑞典)有限公司 Compound and its purposes as BACE inhibitor
US8415483B2 (en) 2010-12-22 2013-04-09 Astrazeneca Ab Compounds and their use as BACE inhibitors
JP2014504300A (en) * 2010-12-22 2014-02-20 アストラゼネカ・アクチエボラーグ Compounds and their use as BACE inhibitors
US10231967B2 (en) 2010-12-22 2019-03-19 Astrazeneca Ab Compounds and their use as BACE inhibitors
US9248129B2 (en) 2010-12-22 2016-02-02 Astrazeneca Ab Compounds and their use as BACE inhibitors
US8865911B2 (en) 2010-12-22 2014-10-21 Astrazeneca Ab Compounds and their use as BACE inhibitors
WO2012093148A1 (en) 2011-01-06 2012-07-12 Eisai R&D Management Co., Ltd Fused aminodihydrothiazine derivatives
US8822455B2 (en) 2011-01-06 2014-09-02 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US8940734B2 (en) 2011-01-21 2015-01-27 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US9175013B2 (en) 2011-01-21 2015-11-03 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US9346827B2 (en) 2011-02-07 2016-05-24 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
WO2012109165A1 (en) 2011-02-07 2012-08-16 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use
US8962859B2 (en) 2011-02-15 2015-02-24 Amgen Inc. Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
WO2012112462A1 (en) 2011-02-15 2012-08-23 Amgen Inc. Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9079919B2 (en) 2011-05-27 2015-07-14 Hoffmann-La Roche Inc. Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as BACE1 and/or BACE2 inhibitors
WO2012163790A1 (en) 2011-05-27 2012-12-06 F. Hoffmann-La Roche Ag Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9296759B2 (en) 2011-09-21 2016-03-29 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US9777019B2 (en) 2011-09-21 2017-10-03 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2013054108A1 (en) * 2011-10-10 2013-04-18 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US9650336B2 (en) 2011-10-10 2017-05-16 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US9526727B2 (en) 2012-03-05 2016-12-27 Vitae Pharmaceutical, Inc. Inhibitors of beta-secretase
WO2013134085A1 (en) 2012-03-05 2013-09-12 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9949975B2 (en) 2012-03-05 2018-04-24 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9376409B2 (en) 2012-05-09 2016-06-28 Boehringer Ingelheim International Gmbh Methods for making oxetan-3-ylmethanamines
US9242973B2 (en) 2012-05-30 2016-01-26 Comentis, Inc. Chromane compounds
US8975415B2 (en) 2012-05-30 2015-03-10 Comentis, Inc. Chromane compounds
US9000183B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors
CN104395294A (en) * 2012-06-20 2015-03-04 阿斯利康(瑞典)有限公司 Cyclohexane-1,2'-indene-1',2"-imidazol compounds and their use as bace inhibitors
WO2013190299A1 (en) * 2012-06-20 2013-12-27 Astrazeneca Ab Cyclohexane-1,2'-indene-1',2"-imidazol compounds and their use as bace inhibitors
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt
US9434693B2 (en) 2012-08-16 2016-09-06 Janssen Pharmaceutica Nv Substituted pyrazoles as N-type calcium channel blockers
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
WO2014035860A1 (en) 2012-08-27 2014-03-06 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9725469B2 (en) 2012-11-15 2017-08-08 Amgen, Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US9079832B2 (en) 2012-11-21 2015-07-14 Boehringer Ingelheim International Gmbh Process for making N-sulfinyl α-amino amides
US9580396B2 (en) 2012-12-21 2017-02-28 Merck Sharp & Dohme Corp. C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use
WO2014127816A1 (en) 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydropteridinones ii
JP2016515109A (en) * 2013-03-12 2016-05-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel process for producing 3-oxotetrahydrofuran
US9974775B2 (en) 2013-08-16 2018-05-22 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
US10653673B2 (en) 2013-08-16 2020-05-19 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
WO2018230555A1 (en) * 2017-06-14 2018-12-20 日本曹達株式会社 Oxadiazoline compound and pest control agent
AU2018282859B2 (en) * 2017-06-14 2020-06-18 Nippon Soda Co., Ltd. Oxadiazoline compound and formulation for controlling harmful organisms
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
WO2020179859A1 (en) 2019-03-06 2020-09-10 第一三共株式会社 Pyrrolopyrazole derivative
CN109776415A (en) * 2019-03-07 2019-05-21 福建南方济民医药研发中心有限公司 A kind of preparation method of Roxadustat intermediate
CN109776415B (en) * 2019-03-07 2020-11-17 福建南方制药股份有限公司 Preparation method of Roxadustat intermediate
CN109942531A (en) * 2019-04-24 2019-06-28 上海卡洛化学有限公司 A kind of preparation method of 4- amino tetrahydro -2- pyrans -4- carboxylic acid
CN115322208A (en) * 2021-05-10 2022-11-11 中国药科大学 Novel 2-aminothiazole derivatives, and preparation method and medical application thereof
CN115322208B (en) * 2021-05-10 2023-04-11 中国药科大学 2-aminothiazole derivative and preparation method and medical application thereof

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